vitamin-k-semiquinone-radical and Venous-Thromboembolism

The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial.. The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs).. We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used.. Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I. Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Fibrinolytic Agents; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Thrombosis; Venous Thromboembolism; Vitamin K

Thromboembolic events in myeloproliferative neoplasms (MPNs) are one of the most important causes of mortality and morbidity, in which vitamin K antagonists (VKAs) have been used mostly. Recently, direct oral anticoagulants (DOACs) are used in venous thromboembolism (VTE) and cancer-associated thrombosis (CAT). With the adoption of data from CAT and VTE, the usage of DOACs in MPNs is increasing.. In this paper, we performed a systematic review to the current literature regarding the usage of DOACs in MPNs. Eleven studies involving 944 patients were included. The reasons for initiating DOACs were secondary prophylaxis for thrombosis (arterial or venous) and atrial fibrillation (AF) in 562 and 382 patients, respectively. A total of 84 (8.9%) recurrent thrombotic (arterial or venous) events recorded. Forty-six (8.1%) events occurred in the thrombosis group (arterial or venous) and 38 (9.9%) events occurred in patients with AF.. Ease of management and patient comfort should be regarded as benefits of DOACs compared to VKAs. However, it would be appropriate to bring an individualized approach until we obtain high-quality data with prospectively designed studies involving more patients and longer follow-up time concerning the use of DOACs in patients with MPNs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Myeloproliferative Disorders; Neoplasms; Thrombosis; Venous Thromboembolism; Vitamin K

Thromboembolism (TE) is a common and serious complication of nephrotic syndrome (NS). NS is associated with hypercoagulability, which may be induced by changes in coagulation, anticoagulant, and fibrinolytic factors. Moreover, accumulating evidence supports the hypothesis that the complex interactions between genetic and acquired risk factors in TE should be considered and that genetic susceptibility should not be ignored. Extracellular vesicles (EVs) also play unique roles. Further research on EVs may provide new insights into the discovery and treatment of TE associated with NS. The occurrence of NS accompanied by TE may be associated with various risk factors. Preventive anticoagulant therapy can not only reduce the risk of TE in patients but also aggravate the risk of bleeding. Heparin and vitamin K antagonists (VKAs), traditional anticoagulant drugs, have been extensively applied in the prevention and treatment of thromboembolic diseases, and emerging direct oral anticoagulants (DOACs) also provide an alternative choice. Owing to the particularity of NS, the safe application of DOACs still needs to be addressed. This review aimed to comprehensively describe the pathophysiology of TE in NS, as well as analyze the associated risk factors, the opportunity for preventive anticoagulation, and current anticoagulant information.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin; Humans; Nephrotic Syndrome; Thromboembolism; Venous Thromboembolism; Vitamin K

Life-long anticoagulation is the recommended management for chronic thromboembolic pulmonary hypertension (CTEPH). Evidence regarding the use of direct oral anticoagulants (DOAC) for CTEPH is yet to be established. We performed a systematic review and meta-analysis to clarify the outcomes of CTEPH in patients who used DOAC or vitamin K antagonists (VKA).. We reviewed literature in PubMed and EMBASE through March 2023. We included studies involving patients with CTEPH where DOAC and VKA were compared. We collected data including intervention history for CTEPH, bleeding events, recurrence of VTE (venous thromboembolism), and mortality. We performed a meta-analysis using the Mantel-Haenszel method with a fixed-effects model.. We included one randomized clinical trial and six observational studies, with a total of 2969 patients. Six studies investigated major bleeding outcomes, and seven investigated all bleeding outcomes. There were no differences in major bleeding (RR 0.59, 95 % CI [0.34-1.02], I. DOAC compared to VKA was associated with a significantly lower mortality and higher risk of recurrent PE. Since most of the included studies are observational, we must consider the existence of multiple biases and confounding factors.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

This paper aims to provide a narrative review of the risks, diagnosis, and management of recurrent venous thromboembolism (VTE) in cancer patients. There is an established association between cancer and VTE, with cancer being a major risk factor for VTE. A history of VTE, short duration of oral anticoagulation, and a proximal DVT are all associated with increased risk for recurrent VTE. Studies have shown that certain cancers (e.g., metastatic genitourinary, lung, and colorectal cancers) are associated with recurrent VTE. Published literature shows that cancer is prothrombotic, and various mechanisms have been postulated as pathways for increased thrombogenesis and hence recurrent VTE in cancer. The symptoms, signs, laboratory information, and imaging results for the diagnosis of recurrent VTE are similar to those of an initial VTE. Management of recurrent VTE involves using low molecular weight heparin (LMWH) or a direct oral anticoagulant (DOAC). Vitamin K antagonists (VKA) or inferior vena cava (IVC) filters are less commonly used.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Thrombosis; Venous Thromboembolism; Vitamin K

Thromboprophylaxis is the cornerstone strategy for thrombotic antiphospholipid syndrome (APS). Data comparing direct oral anticoagulants (DOACs) to Vitamin K antagonists (VKAs) in the secondary prevention of thrombosis in APS patients remain contentious. We aim to review and analyse literature on the efficacy and safety of DOACs compared with VKAs in treating patients with APS. A literature search was performed from inception to 31 December 2021. Subgroups were analysed based on the risk stratification of APS profiles and different DOAC types. A total of nine studies with 1131 patients were included in the meta-analysis. High-risk APS patients (triple positive APS) who used DOACs displayed an increased risk of recurrent thrombosis [risk ratio = 3.65, 95% confidence interval (95% CI): 1.49-8.93; I2  = 29%, P  = 0.005] compared with those taking VKAs. Similar risk of recurrent thrombosis or major bleeding was noted in low-risk APS patients (single or double antibody-positive) upon administering DOACs or VKAs. The utilization of Rivaroxaban was associated with a high risk of recurrent thromboses (RR = 2.63; 95% CI: 1.56-4.42; I2  = 0, P  = 0.0003), particularly recurrent arterial thromboses (RR = 4.52; 95% CI: 1.99-10.29; I2  = 0, P  = 0.18) in overall APS patients. Comparisons of the rate of recurrent thrombosis events and major bleeding events when using dabigatran or apixaban versus VKAs yielded no statistical differences. In the absence of contraindications, this meta-analysis suggests that VKAs remain the first-choice treatment for high-risk APS patients, with DOACs a more appropriate option for low-risk APS patients. Different DOACs may exhibit different levels of efficacy and safety for thromboprophylaxis in APS patients and require further exploration.

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Dabigatran; Fibrinolytic Agents; Hemorrhage; Humans; Rivaroxaban; Thrombosis; Venous Thromboembolism; Vitamin K

High level evidence for direct oral anticoagulants (DOACs) in patients with cerebral venous thrombosis is lacking. We performed a systematic review and meta-analysis to assess the efficacy and safety of DOACs versus vitamin K antagonists in patients with cerebral venous thrombosis.. This systematic review was registered in PROSPERO (CRD42021228800). We searched MEDLINE (via Ovid), EMBASE, CINAHL, and the Web of Science Core Collection between January 1, 2007 and Feb 22, 2022. Search terms included a combination of keywords and controlled vocabulary terms for cerebral venous thrombosis, vitamin K antagonists/warfarin, and DOACs. We included both randomized and nonrandomized studies that compared vitamin K antagonists and DOACs in 5 or more patients with cerebral venous thrombosis. Where studies were sufficiently similar, we performed meta-analyses for efficacy (recurrent venous thromboembolism and complete recanalization) and safety (major hemorrhage) outcomes, using relative risks (RRs).. This systematic review and meta-analysis suggest that in patients with cerebral venous thrombosis, DOACs, and warfarin may have comparable efficacy and safety. Given the limitations of the studies included (low number of randomized controlled trials, modest total sample size, rare outcome events), our findings should be interpreted with caution pending confirmation by ongoing randomized controlled trials and large, prospective, observational studies.

Topics: Administration, Oral; Anticoagulants; Fibrinolytic Agents; Hemorrhage; Humans; Intracranial Thrombosis; Prospective Studies; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Venous thromboembolism (VTE) is the third most common cardiovascular disorder, affecting up to 5% of the population. VTE commonly manifests as lower-extremity deep venous thrombosis (DVT) or pulmonary embolism. Half of these events are associated with a transient risk factor and may be preventable with prophylaxis. Direct oral anticoagulants are effective and safe and carry a lower risk for bleeding than vitamin K antagonists. Many patients with VTE will have a chronic disease requiring long-term anticoagulation. Postthrombotic syndrome affects 25% to 40% of patients with DVT and significantly impacts function and quality of life.

Topics: Anticoagulants; Humans; Quality of Life; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Direct oral anticoagulants (DOACs) are being increasingly used in patients with chronic thromboembolic hypertension (CTEPH), however, the data on their safety and efficacy are scarce and contradictory. We systematically searched MEDLINE and Google Scholar databases from January 2010 to January 2021 for studies of DOACs in CTEPH. Three observational studies, 2 abstracts and one case series met our inclusion criteria. While these studies reported similar or even less rates of major bleeding in patients receiving DOACs compared with vitamin K antagonists, there were concerns about the possibility of increased risk of venous thromboembolism recurrence with DOAC therapy. Further studies are warranted to better define the role of DOACs in CTEPH.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Hypertension, Pulmonary; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants recently became the first-line choice for anticoagulation in venous thromboembolic disease. Many studies have shown its non-inferiority regarding the risk of thromboembolic recurrence compared to anti-vitamin K without increasing the risk of bleeding in the general population. However, specific populations such as patients with cancer, patients with kidney failure, patients with constitutional thrombophilia, elderly patients, or patients with extreme weight are at risk of intolerance to the use of direct oral anticoagulants. Precautions in use may be necessary as discussed in recently published guidelines about antiphospholipid syndrome. This review aims to list the main clinical trials investigating direct oral anticoagulants in venous thromboembolic disease in the general population and populations at risk, as well as to provide an update on current international and French guidelines.

Topics: Administration, Oral; Aged; Anticoagulants; Humans; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Obesity is associated with increased risks of atrial fibrillation (AF) and venous thromboembolism (VTE) for which anticoagulation is commonly used. However, data on the efficacy and safety of oral anticoagulants in patients with morbid obesity are limited.. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) for AF or VTE in patients with morbid obesity.. Patients with morbid obesity on DOACs had similar risks of stroke/systemic embolism, lower rates of recurrent VTE, and major bleeding events compared to those on VKAs. However, the certainty of evidence was low given that studies were mostly observational with high risk of confounding.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Obesity, Morbid; Stroke; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Factor Xa Inhibitors; Humans; Male; Middle Aged; Myeloproliferative Disorders; Venous Thromboembolism; Vitamin K

Cancer-associated thrombosis (CAT) is a common complication in patients with malignancy. Although direct oral anticoagulants (DOACs) have emerged as a treatment option for CAT, there have not been head-to-head comparisons of these agents. We searched MEDLINE and EMBASE from inception to April 2020 for studies comparing the effect of different long-term anticoagulation strategies for venous thromboembolism (VTE) in patients with cancer. We performed a network meta-analysis comparing the antithrombotic strategies in the selected studies using random-effects model. We identified a total of 20 studies [9 randomized control trials (RCTs) and 11 subgroup analyses from other unique RCTs] with total of 6699 patients for inclusion in our analysis. There was no significant difference in recurrent VTE, all-cause death, major bleeding and clinically relevant non-major bleeding among DOACs. When DOACs were combined, recurrent VTE was significantly decreased in DOACs compared to low-molecular weight heparin (LMWH) and Vitamin K antagonist (VKA) [RR (95% CI) 0.75 (0.59-0.94); RR (95% CI) 0.51 (0.39-0.66), respectively] without significant increase in major bleeding or clinically relevant non-major bleeding. In patients with CAT, there was no significant difference in recurrent thrombotic event among different DOACs. Bleeding risk was comparable among all anticoagulation strategies. When DOACs were combined, DOACs were associated with a significant decrease in recurrent VTE with comparable bleeding risk to LMWH and VKA.

Topics: Anticoagulants; Blood Coagulation; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain Ischemia; COVID-19; Drug Monitoring; Drug Substitution; Factor Xa Inhibitors; Humans; Inpatients; Prognosis; SARS-CoV-2; Thrombophilia; Venous Thromboembolism; Vitamin K

Recent clinical guidelines suggest direct oral anticoagulants (DOACs) as treatment for cancer-associated thrombosis (CAT), but the strength of such recommendations was not clear. Newly released trials add uncertainties to the benefit and risk assessment between DOACs and conventional therapy (low-molecular-weight heparin [LMWH] or vitamin K antagonists [VKAs]).. To evaluate the efficacy and safety of DOACs in patients with CAT, as compared with LMWH and VKAs.. PubMed, EMBASE, Cochrane Library, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) that reported outcomes of DOACs for treating CAT were included. Relative risk (RR), risk difference, and 95% CIs were pooled using the Mantel-Haenszel method.. A total of 8 RCTs were included. DOACs significantly reduced VTE recurrence (RR = 0.59; 95% CI = 0.48-0.73) compared with conventional therapy. Results were similar in the LMWH and VKA subgroups. DOACs had a higher, though nonsignificant, risk of major bleeding compared with LMWH (RR = 1.33; 95% CI = 0.94-1.89) but lower risk of major bleeding compared with VKAs (RR = 0.60; 95% CI = 0.39-0.93). Findings were consistent across patients with active cancer and history of cancer.. DOACs have better efficacy to prevent recurrent VTE compared with conventional therapy. Regarding the safety profile, DOACs may carry higher risk of bleeding compared with LMWH but lower risk of bleeding compared with VKAs. Further studies are needed to inform the optimal anticoagulation approach for different types of cancers.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Assessment; Secondary Prevention; Treatment Outcome; Venous Thromboembolism; Vitamin K

 To undertake a systematic review and meta-analysis to assess the satisfaction of patients receiving nonvitamin K anticoagulants (NOACs), compared with vitamin K antagonists (VKAs)..  We searched CENTRAL, MEDLINE, Embase, and Clinicaltrials.gov for randomized controlled trials (RCTs) and observational studies. Two reviewers screened, extracted, and appraised data independently. We pooled data using a random-effects model. Outcome included treatment satisfaction, which was assessed by scores of Duke Anticoagulation Satisfaction Scale (DASS), Anticlot Treatment Scale (ACTS), Perception of Anticoagulant Treatment Questionnaire 2 (PACT-Q2), or Treatment Satisfaction Questionnaire for Medication version II (TSQM-VII) and their domains reported with 95% confidence intervals (95% CIs). We followed MOOSE and PRISMA guidelines..  In patients with nonvalvular atrial fibrillation or venous thromboembolism, NOAC treatment is associated with greater satisfaction compared with VKAs. The switch from VKAs to NOACs was associated with improved patients' satisfaction. These effects were largely due to a lower degree of treatment burden with NOAC treatment.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Patient Satisfaction; Thrombosis; Treatment Adherence and Compliance; Venous Thromboembolism; Vitamin K

Chronic thromboembolic pulmonary hypertension (CTEPH) represents the later stage consequence of at least one or more unresolved episodes of acute pulmonary embolism; thus, indefinite anticoagulation is strongly recommended by current practice guidelines. Historically, vitamin K antagonists have been widely used in these patients. However, recent data indicate a shift toward direct oral anticoagulants (DOACs), despite lack of data on the safety and efficacy in this patient population. Herein, we briefly discuss the current rationale for oral anticoagulation use in CTEPH, addressing important issues and controversies involved with the use of DOACs, opening a strategy for further clinical research in the field of oral anticoagulation.

Topics: Administration, Oral; Anticoagulants; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Venous Thromboembolism; Vitamin K

The holy grail of anticoagulation in patients with intracardiac devices, such as mechanical heart valves (MHVs) and left ventricular assist devices (LVADs), comprises safe prevention of thrombosis without interrupting normal hemostasis. Device-induced thrombosis and anticoagulant-related bleeding problems are dreaded complications that may cause a significantly reduced quality of life and increased morbidity and mortality. Vitamin K antagonists are the current standard for oral anticoagulation therapy in patients with MHVs and LVADs. Even within the therapeutic range, hemorrhage is the primary complication of these drugs, which emphasizes the need for safer anticoagulants for the prevention of device-induced thrombosis. Device-induced thrombosis is a complex multifactorial phenomenon that likely requires anticoagulant therapy targeting multiple pathways. Here, we review the preclinical and clinical data describing the efficacy of a variety of anticoagulants as thromboprophylaxis after implantation of intracardiac devices.

Topics: Anticoagulants; Heart Valves; Humans; Quality of Life; Venous Thromboembolism; Vitamin K

 In this study-level meta-analysis, we evaluated the clinical outcome with nonvitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients with cancer..  Anticoagulation in AF patients with cancer is challenging given the coexistence of elevated thrombotic and bleeding risk. The efficacy and safety of NOACs in this setting remain unclear..  We included three randomized trials in our primary analysis (.  In AF patients with malignancy, NOACs appear at least as effective as VKAs in preventing thrombotic events and reduce intracranial bleeding. NOACs may represent a valid and more practical alternative to VKAs in this setting of high-risk patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Data Interpretation, Statistical; Embolism; Hemorrhage; Humans; Intracranial Hemorrhages; Neoplasms; Observational Studies as Topic; Odds Ratio; Patient Safety; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Thromboembolism; Venous Thromboembolism; Vitamin K

Traditionally, venous thromboembolism (VTE) resulting from major transient risk factors (e.g., surgery or trauma) or a major persistent risk factor such as cancer, has been defined as being provoked, whereas unprovoked VTE encompasses events without an identifiable cause. These categorizations influence anticoagulant treatment duration; unlike VTE provoked by major transient risk factors, extended anticoagulation beyond 3 months is advised for patients with cancer or unprovoked VTE due to risk persistence after treatment cessation. However, some patients with VTE provoked by minor transient or minor persistent risk factors may also be candidates for extended anticoagulation therapy due to the continuing risk of recurrence. In patients who require extended therapy, vitamin K antagonists (VKAs) are effective but are associated with an increased risk of bleeding and various treatment burdens (e.g., anticoagulation monitoring and dose adjustment). Evaluations of extended VTE treatment with the less-burdensome direct oral anticoagulants such as apixaban, dabigatran, edoxaban, and rivaroxaban show that they are at least as safe and effective as VKAs in a broad range of patients. In addition, apixaban and rivaroxaban offer more than one dosing option, allowing tailoring of treatment to the patient's specific risk factor profile. Analysis of more granular definitions for risk factor groupings has also yielded vital information on the most appropriate strategies for the treatment of patients with specific risk factors, highlighting that extended anticoagulation treatment may benefit those with minor transient and persistent environmental and nonenvironmental risk factors who commonly receive shorter-duration therapy.

Topics: Aged; Anticoagulants; Humans; Patient Selection; Precision Medicine; Pyrazoles; Pyridones; Renal Insufficiency; Risk Factors; Rivaroxaban; Venous Thromboembolism; Vitamin K; Withholding Treatment

The optimal duration of oral anticoagulant therapy for patients with venous thromboembolism (VTE) remains highly uncertain in clinical practice. It is essential to accurately assess the effect of anticoagulant therapy in reducing recurrent VTE against the risk of inducing major bleeding.. Randomized controlled trials were identified by searching PubMed, Web of Science, Embase, and the Cochrane library, reporting rates of recurrent VTE and major bleeding in patients taking Vitamin K Antagonists (VKA) with VTE and comparing different durations.. Eleven RCTs with 3109 participants utilizing varied durations were included in the meta-analysis. Longer VKA therapy was associated with significantly lower rates of VTE recurrence compared with shorter duration of VKA therapy (OR 0.75, 95%CI 0.57-0.99), with significant difference noted in major bleeding risk (OR 2.31, 95%CI 1.17-4.56). During anticoagulation duration, patients treated by 6-month VKA had higher risk of major bleeding compared with 3-month VKA regimen (OR 33.45, 95%CI 2.00-559.67).. Regimen longer than 6 months did not show statistical elevation of major bleeding risk. VKA treatment strongly reduces the risk of recurrent VTE during anticoagulation therapy. The absolute risk of recurrent VTE declines over time while the risk for major bleeding after 6 months' treatment did not demonstrate a continuous significant increase with extended duration of VKA therapy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Drug Administration Schedule; Hemorrhage; Humans; Middle Aged; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

Anticoagulation in patients with pulmonary embolism.. To identify how non-vitamin K antagonist oral anticoagulants are associated with multiple outcomes in patients with pulmonary embolism.. We performed a systematic search of systematic reviews via multiple electronic databases from inception to August 19th, 2019, without language restriction. Two authors independently extracted data and assessed the methodological quality of the included systematic reviews using the ROBIS tool.. We found twelve systematic reviews. Eleven SRs collected their data from randomized clinical trials and one from observational studies. All the included studies were published between 2014 and 2019 in English. The methodological quality of the 12 systematic reviews was low to high. None of the systematic reviews, which are included in our overview of systematic reviews, has evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach.. This is the first effort to summarize evidence about non-vitamin K antagonist oral anticoagulants in an overview of systematic reviews focusing exclusively on patients with pulmonary embolism. The evidence suggests that the non-vitamin K antagonist oral anticoagulants seem to be more effective and safer than a dualdrug approach with LMWH- VKA.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Pulmonary Embolism; Systematic Reviews as Topic; Venous Thromboembolism; Vitamin K

Four direct-acting oral anticoagulants (DOACs) are currently approved by the Food and Drug Administration for the treatment of venous thromboembolism (VTE). Limited efficacy and safety data are available for their use in older adults (aged ≥75 years).. Medline, Cochrane Central Register of Controlled Trials, Embase, EBSCO, Web of Science, and CINAHL databases were searched for trials comparing DOACs with vitamin K antagonists (VKAs) for the treatment of VTE in older adults from inception through January 1, 2020. Meta-analysis was performed to assess the combined endpoint of recurrent VTE and related deaths and bleeding events (composite of major and clinically relevant nonmajor bleeding). The Mantel-Haenszel relative risk (RR) random effects model was used to pool results across studies.. Six randomized controlled trials at low risk of bias met criteria for inclusion with a total of 3,665 patients aged 75 years and older with follow-up of 24 weeks or longer. Data for bleeding events were not available for dabigatran. Overall, DOACs had an improved efficacy over VKAs (RR = .56; 95% confidence interval [CI] = .38-.82). There was no statistically significant difference in the safety outcomes (RR = .77; 95% CI = .56-1.05). No significant heterogeneity was observed for efficacy outcome, and only moderate heterogeneity was observed for safety outcome.. In older adults with VTE, DOACs appear to improve rates of recurrent VTE and VTE-related deaths compared with VKAs with similar bleeding outcomes.

Topics: Administration, Oral; Aged; Anticoagulants; Antifibrinolytic Agents; Antithrombins; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism; Vitamin K

"Acute venous thromboembolism is a common disease seen by nearly all hospitalists. The advent of low molecular weight heparin (LMWH) several decades ago ushered in the era of early hospital discharge and home treatment. More recently, the direct oral anticoagulants (DOACs) have further simplified outpatient treatment and some offer treatment without parenteral therapy. Use of DOACs for cancer-associated venous thromboembolism is emerging and is a welcome evolution of care to spare oncologic patients the burden of daily LMWH injections."

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Risk Assessment; Surgical Procedures, Operative; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Cancer-associated venous thromboembolism (VTE) is associated with high VTE recurrence and bleeding. We included all randomized clinical trials that evaluated the efficacy and safety of various anticoagulants in cancer-associated VTE. Trial-level data were extracted from 13 trials. Aggregate odds ratios (ORs) were calculated using direct and network meta-analysis. The primary outcome was VTE (pulmonary embolism and/or deep vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. We identified 13 trials with 4869 patient-years of follow-up (6595 total patients; mean age 62.4 ± 12.2; 50.4 % female; 17.7 % hematological malignancies). The most common cancer type was colorectal and 48 % had metastatic cancer at baseline. Compared to vitamin-K-antagonists (VKAs), non-vitamin-K-antagonist-oral-anticoagulants (NOACs) were associated with significantly reduced VTE recurrence (OR, 0.58; 95 % CI, 0.40-0.83) and reduced major bleeding risks (OR, 0.56; 95 % CI, 0.35-0.91). However, no differences were observed in the subgroup analysis of patients with active cancer. Although NOACs were associated with reduced VTE recurrence compared with low-molecular-weight-heparin (LMWHs) (OR, 0.46; 95 % CI, 0.25- 0.85), there was a significant increased major bleeding in high-quality trials. LMWHs were associated with significantly reduced VTE recurrence compared with VKAs (OR, 0.52; 95 % CI, 0.39-0.71) and similar bleeding risks. Conclusions: Among patients with cancer-associated VTE, NOACs were associated with significantly reduced VTE recurrence and bleeding compared with VKAs, however, with similar outcomes in the active cancer population. NOACs were associated with reduced VTE recurrence but higher bleeding risks compared with LMWHs. LMWHs were associated with significantly reduced VTE recurrence and similar bleeding compared with VKAs.

Topics: Administration, Oral; Aged; Anticoagulants; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Network Meta-Analysis; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

Topics: Anticoagulants; Child; Heparin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Thrombophilia; Venous Thromboembolism; Vitamin K

The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Dabigatran; Glycosaminoglycans; Hemorrhage; Humans; Middle Aged; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

Topics: Anticoagulants; Central Venous Catheters; Factor Xa Inhibitors; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Vena Cava Filters; Venous Thromboembolism; Vitamin K

Cancer is associated with an increased risk of venous thromboembolism of four to sixfold. Cancer-related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of venous thromboembolism. Low molecular weight heparin for at least 3-6 months is the current standard of care for the treatment of cancer associated venous thromboembolism. Anticoagulation should be continued as long as the cancer is active. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In the randomized controlled trials comparing direct oral anticoagulants with vitamin K antagonists, the direct oral anticoagulants all provide non-inferior in prevention of thromboembolic events in patients with atrial fibrillation, for the prevention and treatment of venous thromboembolism and in acute coronary syndrome. In people with cancer, these drugs have emerged as attractive alternatives for the treatment of venous thromboembolism with the potential to overcome the limitations of low molecular weight heparin. Randomized controlled studies comparing direct oral anticoagulants to low molecular weight heparin in cancer patients are still limited and direct oral anticoagulants are not recommended for the treatment of cancer associated venous thromboembolism yet. However, new emerging data are supporting the use of direct oral anticoagulants in cancer-associated thrombosis. Here, we review recent data on the evidence related to the efficacy and safety of direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer.

Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Thrombosis; Venous Thromboembolism; Vitamin K

Non-vitamin K antagonist oral anticoagulants (NOACs) include dabigatran, which inhibits thrombin, and apixaban, betrixaban, edoxaban and rivaroxaban, which inhibit factor Xa. In large clinical trials comparing the NOACs with the vitamin K antagonist (VKA) warfarin, dabigatran, apixaban, rivaroxaban and edoxaban were at least as effective for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism, but were associated with less intracranial bleeding. In addition, the NOACs are more convenient to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. Consequently, the NOACs are now replacing VKAs for these indications, and their use is increasing. Although, as a class, the NOACs have a favourable benefit-risk profile compared with VKAs, choosing among them is complicated because they have not been compared in head-to-head trials. Therefore, selection depends on the results of the individual trials, renal function, the potential for drug-drug interactions and preference for once- or twice-daily dosing. In addition, several 'special situations' were not adequately studied in the dedicated clinical trials. For these situations, knowledge of the unique pharmacological features of the various NOACs and judicious cross-trial comparison can help inform prescription choices. The purpose of this position article is therefore to help clinicians choose the right anticoagulant for the right patient at the right dose by reviewing a variety of special situations not widely studied in clinical trials.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Arginine; Atrial Fibrillation; Benzamides; Biomarkers; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Drug Administration Schedule; Factor Xa; Heart Diseases; Humans; Piperazines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Risk; Rivaroxaban; Stroke; Thiazoles; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Vitamin K antagonists (VKA) are the most widely used anticoagulants, and bridging is commonly administered during periprocedural VKA interruption. Given the unclear benefits and risks of periprocedural bridging in patients with previous venous thromboembolism, we aimed to assess recurrent venous thromboembolism and bleeding outcomes with and without bridging in this population.. We performed a systematic review searching the PubMed and Embase databases from inception to December 7, 2017 for randomized and nonrandomized studies that included adults with previous venous thromboembolism requiring VKA interruption to undergo an elective procedure, and that reported venous thromboembolism or bleeding outcomes. Quality of evidence was graded by consensus.. We included 28 cohort studies (20 being single-arm cohorts) with, overall, 6915 procedures for analysis. In 27 studies reporting perioperative venous thromboembolism outcomes, the pooled incidence of recurrent venous thromboembolism with bridging was 0.7% (95% confidence interval [CI], 0.4%-1.2%) and 0.5% (95% CI, 0.3%-0.8%) without bridging. Eighteen studies reported major or nonmajor bleeding outcomes. The pooled incidence of any bleeding was 3.9% (95% CI, 2.0%-7.4%) with bridging and 0.4% (95% CI, 0.1%-1.7%) without bridging. In bridged patients at high thromboembolic risk, the pooled incidence for venous thromboembolism was 0.8% (95% CI, 0.3%-2.5%) and 7.5% (95% CI, 3.1%-17.4%) for any bleeding. Quality of available evidence was very low, primarily due to a high risk of bias of included studies.. Periprocedural bridging increases the risk of bleeding compared with VKA interruption without bridging, without a significant difference in periprocedural venous thromboembolism rates.

Topics: Anticoagulants; Hemorrhage; Humans; Venous Thromboembolism; Vitamin K

The number of hip fractures in anticoagulated patients is predicted to increase, due to people living longer. However, evidence regarding urgent perioperative management of elderly patients with hip fracture who take oral anticoagulants (vitamin K antagonists or direct oral anticoagulants) is scarce. In this article, the authors present a narrative review of the evidence to date supporting the urgent management of hip fracture in anticoagulated elderly patients. They discuss the complexity of managing the high risk of procedure-related bleeding and, at the same time, the high risk of thromboembolism. The role of a bridging procedure and the best strategy of anticoagulation reversal are also reviewed. Further studies are required to improve the evidence in urgent surgery, especially in frail elderly patients.

Topics: Administration, Oral; Aged; Anticoagulants; Hemorrhage; Hip Fractures; Humans; Risk Assessment; Risk Factors; Venous Thromboembolism; Vitamin K

For procedures associated with minimal bleeding risk, there are data and experience to support the practice of continuing vitamin K antagonists rather than interrupting therapy, to prevent exposing patients to the undue risk of developing thromboembolism during anticoagulation cessation. Despite the increasing use of non-vitamin K oral anticoagulants (NOACs), there is little evidence to guide the management of these drugs around minimal bleeding risk procedures. This review examines and discusses the major society guidelines and recommendations addressing the management of NOACs around minimal bleeding risk procedures. Additionally, it summarizes the existing evidence, and highlights the gaps in knowledge where evidence is not yet available. Finally, recommendations are made to assist the proceduralist deal with this area of limited evidence.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Practice Guidelines as Topic; Risk Factors; Venous Thromboembolism; Vitamin K

Cancer-associated venous thromboembolism (CAT) is a common complication associated with high morbidity and mortality. In accordance with major clinical trials comparing low-molecular-weight heparin (LMWH) with a vitamin K antagonist (VKA), LMWH is currently the standard treatment for CAT, owing to its efficacy for thrombosis recurrence and improved safety profile compared to VKA. Over the past few years, direct oral anticoagulants (DOACs) have emerged as potential alternative therapies to LMWH due to their convenient route of administration and predictable pharmacokinetics, but evidence for their use in CAT is inconclusive, as only a small fraction of the study populations in these trials had CAT. Recently, two large head-to-head trials comparing DOACs to LMWH in CAT patients reported comparable efficacies of DOACs with increased bleeding risk. Occasionally, CAT treatment can be challenging due to the heterogeneity of underlying malignancies and comorbidities. Renal insufficiency and gastrointestinal defects are the main obstacles in anticoagulant selection. Careful choice of treatment candidates and proper anticoagulant strategies are critical for the treatment of CAT; hence, more studies are required to address these challenges.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Renal Insufficiency; Risk Factors; Venous Thromboembolism; Vitamin K

The direct oral anticoagulants (DOACs) have emerged as an effective and safe alternative to vitamin K antagonists (VKAs) for stroke and venous thromboembolism (VTE) prevention. However, patients with chronic kidney disease (CKD) experience an increase in the risk of both thromboembolism and bleeding, and the risk-benefit profile of DOACs, particularly in advanced CKD remains a source of ongoing debate. This review summarizes the recent evidence on the effects of DOACs in CKD across a range of clinical indications including newly emerging indications.. Data on early-to-moderate stage CKD derived from pivotal randomized controlled trials in broader atrial fibrillation and VTE populations support the favorable risk-benefit ratio of DOACs compared with VKAs in patients in these groups. However, safety data from observational studies comparing DOACs with VKAs in patients with atrial fibrillation and CKD (moderate to advanced) have been conflicting. Recent trials have evaluated the efficacy of low-dose DOACs on major cardiovascular outcomes, showing promising risk-benefit ratios in high-risk populations with concurrent CKD.. Current data on patients with CKD derived from trials in the broader population suggest that DOACs are an effective alternative to VKAs in patients with early-to-moderate stage CKD. However, studies on patients with advanced CKD are lacking. Further randomized controlled trials, particularly those evaluating the risk of any clinically relevant bleeding as part of a more accurate assessment of the risk-benefit profile of DOACs in people with CKD, are needed.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Stroke; Venous Thromboembolism; Vitamin K

Low-molecular-weight heparin (LMWH) is usually recommended for the treatment of cancer-associated thrombosis (CAT) but this treatment requires burdensome daily injections. We did a systematic review to compare the efficacy and safety of direct oral anticoagulants (DOAC), vitamin K antagonists (VKA) and LMWH in patients with CAT.. We searched Pubmed, Embase and CENTRAL for randomised controlled trials comparing DOAC, VKA and LMWH in patients with CAT. Pairwise and network meta-analyses were computed for venous thromboembolism (VTE) recurrence and bleeding complications.. We identified 14 studies, including 4,661 patients. In pairwise comparison, DOAC were superior to LMWH to prevent VTE recurrence (HR 0.63; 95% CI 0.42-0.96) and LMWH was superior to VKA (HR 0.53; 95% CI 0.40-0.70). The rate of major bleeding was higher with DOAC compared to LMWH (HR 1.78; 95% CI 1.11-2.87). In the network meta-analysis, DOAC had a lower, but non-significant, rate of VTE recurrence compared to LMWH (HR 0.74; 95% CI 0.54-1.01). Both DOAC (HR 0.42; 95% CI 0.29-0.61) and LMWH (HR 0.57; 95% CI 0.44-0.75) were associated with lower rates of recurrence compared to VKA. No significant difference in major bleeding rate was observed in the network meta-analysis. Inconsistency was observed between pairwise and network meta-analysis comparisons for major bleeding.. DOAC are effective to prevent VTE recurrence in patients with CAT but are associated with an increased risk of bleeding compared to LMWH. The choice of anticoagulant should be personalised, taking into account the patient's bleeding risk, including cancer site, and patient's values and preferences.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Network Meta-Analysis; Recurrence; Risk Factors; Safety; Secondary Prevention; Venous Thromboembolism; Vitamin K

The aim of this study was to systematically review published network meta-analyses (NMAs) that compare venous thromboembolism (VTE) treatments. A systematic literature search (in MEDLINE, Embase, and Cochrane Database of Systematic Reviews through September 2017) was conducted to identify NMAs that compared the safety and efficacy of direct oral anticoagulants (DOACs) for the treatment of VTE in the acute and extended treatment settings. The NMAs included randomized controlled trials comparing multiple DOACs, low-molecular weight heparin, unfractionated heparin, and vitamin K antagonists (VKAs). The quality of the NMA results were evaluated using the Grading of Recommendations and Evaluation (GRADE) assessment. The SLR identified 294 records and nine NMAs (68 trials). Among the NMAs, three evaluated the acute treatment setting, five the extended, and one in both treatment settings. The NMAs showed a significant reduction in major bleeding and clinically relevant bleeding (CRB) with apixaban compared to other DOACs. Major bleeding with apixaban was reduced compared to dabigatran, edoxaban, and fondaparinux-VKA combination in all comparisons in the acute setting (range of effect estimates: 0.30-0.43). CRB was reduced with apixaban compared to dabigatran, edoxaban, and rivaroxaban in the acute and extended settings (range of effect estimates: 0.23-0.72). No significant differences were seen in efficacy outcomes between the DOACs. This SLR of NMAs systematically collected all indirect evidence of the impact of apixaban compared to other anticoagulants in patients with VTE. In the absence of head-to-head trials, well-conducted NMAs provide the best evidence.

Topics: Anticoagulants; Hemorrhage; Heparin; Humans; Randomized Controlled Trials as Topic; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; England; Fibrinolytic Agents; Humans; Incidence; Venous Thromboembolism; Vitamin K

Extended treatment is preconized in a significant proportion of patients with unprovoked venous thromboembolism (VTE). However, limited direct/indirect comparisons are available to appropriately weight the benefit/risk ratio of the diverse treatments available. We aimed to compare the rate of symptomatic recurrent VTE and major bleeding (MB), the net clinical benefit (VTE+MB) and death on vitamin-K antagonist (VKA), direct oral anticoagulants (DOAC) and antiplatelet drugs for extended anticoagulation.. A systematic literature search through September 2018 identified randomized trials studying these pharmacologic therapies for extended anticoagulation following VTE. Treatment effects were calculated using network meta-analysis with frequentist fixed-effects model.. 18 trials (18,221 patients) were included in the analysis. All treatments reduced the risk of recurrence compared to placebo/observation. Nonetheless, VKA (RR 0.22; 95%CI 0.13-0.39) and DOAC (RRs ranging from 0.25-0.32; 95%CI ranging from 0.13-0.52) were more effective than aspirin, whereas low-dose VKA was less effective than standard-dose VKA (RR 2.47; 95%CI 1.34-4.55). The efficacy of DOAC was globally comparable to standard-adjusted dose VKA. Low- (RR 3.13; 95%CI 1.37-7.16) and standard-dose (RR 3.23; 95%CI 1.16-8.99) VKA also increased the risk of MB, which was not the case for any DOAC. Low-dose VKA and low-dose DOAC had similar effects on MB compared to standard-doses. Although there was a trend for reduced MB and enhanced net clinical benefit for DOAC compared to VKA, this was not statistically significant. The specific anticoagulant therapies had no significant effects on deaths.. Standard-dose VKA and low/standard-dose DOAC share similar effects on VTE recurrence and MB, whereas aspirin and low-dose VKA were associated with lower benefit/risk ratio.

Topics: Administration, Oral; Anticoagulants; Aspirin; Blood Coagulation; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Network Meta-Analysis; Platelet Aggregation Inhibitors; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Drug Monitoring; Hemorrhage; Humans; Venous Thromboembolism; Vitamin K

The aim was to review the relative efficacy and safety of anticoagulation for managing venous thromboembolism (VTE) in patients with cancer.. A systematic review and meta-analysis was carried out. On 17 May 2018 the MEDLINE and Scopus databases were searched for randomised controlled trials (RCTs). Eligible RCTs had to be performed in patients with cancer exclusively or to report results on a subset of patients with cancer. The main study outcomes (efficacy/recurrent VTE and safety/bleeding events) were expressed as risk ratios (RR) with a 95% confidence interval (CI). The quality of evidence was assessed following the GRADE method.. Twenty-three RCTs with 6980 patients were identified. Low molecular weight heparins (LMWHs) were more effective than vitamin K antagonists (VKAs) in preventing recurrent VTE (RR 0.58, 95% CI 0.45-0.75) and deep vein thrombosis (RR 0.44, 95% CI 0.29-0.69) but not pulmonary embolism (PE), bleeding, or overall mortality. Direct oral anticoagulants (DOACs) were more effective than VKAs in preventing recurrent VTE (RR 0.65, 95% CI 0.45-0.95) but not DVT, PE, overall mortality, or bleeding. However, anti-Xa DOACs were more effective (RR for VTE 0.64, 95% CI 0.42-0.97) and caused less bleeding than VKAs, although major bleeding was reduced only with DOACs not requiring initial parenteral anticoagulation (RR 0.45, 95% CI 0.21-0.97). In a direct comparison, DOACs were more effective than LMWHs in preventing VTE recurrence (RR 0.64, 95% CI 0.45-0.90) but caused more major bleeding (RR 1.75, 95% CI 1.10-2.77), with no difference in fatal bleeding and overall mortality. Quality of evidence, where sufficient, was mostly moderate or high.. Compared with VKAs, LMWHs and DOACs are more effective in treating VTE, but the former caused less bleeding. DOACs are more effective than LMWHs in preventing VTE recurrence but may carry a higher risk of major bleeding, pending additional information by ongoing trials.

Topics: Anticoagulants; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Pulmonary Embolism; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K

The efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) during extended anticoagulation for a VTE remains largely unknown, especially in terms of potential survival benefit. The goal of this study was to assess the effects of VKAs and DOACs on overall mortality and VTE-related mortality, as well as VTE recurrence and safety.. PubMed, EMBASE, and the Cochrane Library were searched from January 1990 through September 2018 for randomized controlled trials evaluating the effect of extended anticoagulants as secondary prevention for VTE compared with placebo. The primary outcome was the specific effects of standard-intensity VKAs and DOACs on overall mortality.. Sixteen studies (12,458 patients) were included. DOACs were associated with a reduction in overall (risk ratio [RR], 0.48; 95% CI, 0.27-0.86; P = .01) and VTE-related (RR, 0.36; 95% CI, 0.15-0.89; P = .03) mortality, whereas VKAs were not (P > .50). Although VKAs and DOACs similarly prevented recurrent VTE, only VKAs were associated with an increased risk of major bleeding (RR, 2.67; 95% CI, 1.28-5.60; P < .01), resulting in an improved net clinical benefit for DOACs (RR, 0.25 [95% CI, 0.16-0.39; P < .01] vs 0.46 [95% CI, 0.30-0.72; P < .01]; P. DOACs for extended anticoagulation were associated with a significant reduction in overall mortality compared with observation alone.. PROSPERO; No.: CRD42018088739; URL: https://www.crd.york.ac.uk/prospero/.

Topics: Anticoagulants; Factor Xa Inhibitors; Humans; Risk Assessment; Secondary Prevention; Survival Analysis; Treatment Outcome; Venous Thromboembolism; Vitamin K

This review summarizes the available evidence concerning direct oral anticoagulant (DOAC) use to treat venous thromboembolism (VTE) in patients with cancer as well as pertinent safety data on the use of DOACs in patients with both cancer and atrial fibrillation.. The introduction of DOACs into clinical practice changed the way thrombotic complications are managed and prevented in diverse patient populations, including VTE and atrial fibrillation. Low-molecular-weight heparins have been the standard of care for treating VTE in cancer patients due to superiority over vitamin K antagonists in preventing recurrent VTE. Therefore, widespread DOAC use for VTE in patients with active cancer has not been adopted.. Recent randomized clinical trials (SELECT-D, Hokusai VTE Cancer) have provided evidence that DOACs may have a role in treating VTE in cancer patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Standard of Care; Treatment Outcome; Venous Thromboembolism; Vitamin K

Identifying patients who are likely to achieve and maintain a therapeutic international normalized ratio when prescribed a vitamin K antagonist for stroke prevention in atrial fibrillation (AF) and venous thromboembolism (VTE) is challenging. The SAMe-TT

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Clinical Decision-Making; Humans; Venous Thromboembolism; Vitamin K

Patients with end-stage renal disease (ESRD) were excluded from pivotal clinical trials with oral anticoagulants. While such patients are at an increased risk of venous and arterial thromboembolism, their risk of bleeding is also elevated. It is thus of little surprise that stroke prevention with vitamin K antagonists (VKAs) in ESRD patients with atrial fibrillation is controversial, with observational evidence ranging from beneficial to harmful. This uncertainty extends to the less studied use of VKAs for venous thromboembolism in ESRD. The direct oral anticoagulants (DOACs) apixaban and rivaroxaban have now permissive labeling in the United States for atrial fibrillation in patients with ESRD; this expanded labeling has not yet occurred either in Europe or for venous thromboembolism. This review summarizes the current evidence for the pharmacology of DOACs in ESRD as well as their utilization and safety in patients with ESRD and atrial fibrillation.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Rivaroxaban; United States; Venous Thromboembolism; Vitamin K

The association between venous thromboembolism (VTE) and cancer has been recognized for more than 100 years. Numerous studies have been performed to investigate strategies to decrease VTE incidence and to establish whether treating VTE impacts cancer progression and overall survival. Accordingly, it is important to understand the role of the hemostatic system in tumorigenesis and progression, as there is abundant evidence associating it with cell survival and proliferation, tumor angiogenesis, invasion, and dissemination, and metastasis formation. In attempts to further the scientific evidence, several studies examine survival benefits in cancer patients treated with anticoagulant therapy, specifically treatment with vitamin K antagonists, unfractionated heparin, and low-molecular-weight heparin. Several studies and meta-analyses have been conducted with a special focus on brain tumors. However, no definitive conclusions have been obtained, and more well-designed clinical trials are needed.

Topics: Anticoagulants; Clinical Trials as Topic; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Vitamin K antagonist (VKA) therapy is safer and more effective when patients have a high time within the therapeutic range and low international normalised ratio variability. The SAMe-TT2R2 score aims to identify those at risk for poor VKA control.. To evaluate the predictive value and clinical usefulness of the SAMe-TT2R2 score to identify those at risk for poor VKA control.. We performed a systematic review in MEDLINE and Embase for original research papers assessing the SAMe-TT2R2's relation to poor TTR. We performed a meta-analysis where scores ≥ 2 and ≥ 3 predicting TTR < 70%. When studies evaluated other cutoffs for TTR or SAMe-TT2R2, they were harmonised by multiple simulations with patient characteristics from the individual studies, if the data were available.. 16 studies were identified and used in the meta-analysis: 4 and 2 times directly, 8 and 8 times harmonised for scores ≥ 2 and ≥ 3, respectively (not all studies provided information about both cutoffs). The sensitivities and specificities were too heterogeneous to pool. The positive likelihood ratios were 1.25 (1.14-1.38) for a score ≥ 2, and 1.24 (1.09-1.40) for a score ≥ 3; the negative ones were 0.87 (0.82-0.93) and 0.96 (0.91-1.02), respectively. This shows that the post-test probabilities hardly differ from the prior probability (prevalence).. The SAMe-TT2R2 score does predict low TTR, but the effect is small. Its effect on individual patients is too limited to be clinically useful.

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Humans; International Normalized Ratio; Likelihood Functions; Risk; Venous Thromboembolism; Vitamin K

The standard for treatment and secondary prevention of venous thromboembolism (VTE) has been vitamin K antagonist (VKA), which might be associated with a higher risk of bleeding particularly in Asian patients. Direct oral anticoagulants (DOAC) have been shown to be safer alternatives for VTE. It remains unclear whether this is the case in Asian ethnicity.. We performed a meta-analysis of randomized controlled trials to evaluate the efficacy and safety of DOACs in Asian and non-Asian patients with acute VTE. We searched MEDLINE, CENTRAL, and ClinicalTrials.gov. The efficacy endpoint was recurrent VTE or VTE-related death. The safety endpoint was major bleedings or clinically relevant non-major bleedings. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated.. We identified 6 studies that comprised 3542 Asian and 23,481 non-Asian patients. The efficacy of DOACs was comparable with VKA in both Asian and non-Asian patients (OR, 0.90; 95% CI, 0.55-1.49; P = 0.69 for Asian patients; OR, 0.92; 95% CI, 0.78-1.08; P = 0.32 for non-Asian patients; P interaction = 0.94). DOACs significantly reduced the safety endpoint compared with VKA in Asian patients (OR, 0.64; 95% CI, 0.51-0.80; P < 0.001), while DOACs were associated with non-significant reduction in non-Asian patients (OR, 0.73; 95% CI, 0.53-1.01; P = 0.06), indicating that the reduction seemed numerically more prominent in Asian patients, although there was no statistically significant interaction (P interaction = 0.49).. The efficacy of DOACs was comparable with VKA irrespective of ethnicity, and DOACs could be safer alternatives in Asian patients.

Topics: Administration, Oral; Anticoagulants; Asian People; Humans; Venous Thromboembolism; Vitamin K

Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.. To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.. We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.. Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.. We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).. Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months. For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Catheter ablation for atrial fibrillation (AF) is associated with a transitory increase in the risk of both thromboembolic and bleeding events. Evidence on the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients undergoing AF ablation mostly comes from small observational studies, underpowered to detect differences in clinical outcomes between NOACs and vitamin K antagonists (VKAs) treated patients. This updated meta-analysis aimed to determine the safety and efficacy of periprocedural anticoagulation with NOACs compared with VKAs in AF patients undergoing catheter ablation.. We searched MEDLINE, Cochrane library, and web sources for randomized and observational studies comparing periprocedural treatment with NOACs and VKAs in patients undergoing AF ablation. The primary safety endpoint was major bleeding events, and the primary efficacy endpoint was thromboembolic events (a composite of systemic thromboembolism, transient ischemic attack, and stroke).. Use of NOACs compared to VKAs significantly reduced the risk of bleeding in patients with AF ablation. Similarly, the risk of bleeding was lower with uninterrupted NOACs than with uninterrupted VKAs, and with interrupted NOACs than with interrupted VKAs. The rate of thromboembolic complications was extremely low in both study groups without any differences.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Blood Loss, Surgical; Catheter Ablation; Drug Administration Schedule; Humans; Patient Safety; Postoperative Hemorrhage; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Blood Coagulation; Humans; Thrombolytic Therapy; Venous Thromboembolism; Vitamin K

Much new evidence on oral anticoagulation has come to light in recent years. Non-vitamin-K-dependent oral anti- coagulants (NOAC) have been developed and have been introduced into clinical practice. In this review, we present the current state of the evidence on anticoagulation for various indications with vitamin K antagonists (VKA) and with NOAC.. This review is based on pertinent articles retrieved by a selective search in PubMed (search terms: anticoagulation, atrial fibrillation, prosthetic valve, thrombosis, pulmonary embolism) and on specialty society recommendations and relevant guidelines from the years 2000-2018.. The main indications for oral anticoagulation are atrial fibrillation, venous thromboembolism, and status post heart valve replacement. In patients with atrial fibrillation and without valvular heart disease, anticoagulation is recommended for men with a CHA2DS2-VASc score ≥ 1 and for women with a score ≥ 2. NOAC for this indication are associated with a marginally lower rate of stroke than VKA (3.5% vs. 3.8%, number needed to treat [NNT] = 333) as well as a lower rate of major hemorrhage (5.1% vs. 6.2%, NNT = 91). NOAC are contraindicated for patients with mechanical heart valves. Anticoagulation with VKA can be predictably antagonized. Among the various types of NOAC, the anticoagulant effect of dabigatran can be safely antagonized with an antidote; no specific antidote is yet available for apixaban, rivaroxaban, or edoxaban.. The evidence base for anticoagulation over a time frame of several years is inadequate at present, and direct comparative data for the different types of NOAC are not yet available.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Heart Valve Prosthesis; Humans; Risk Assessment; Venous Thromboembolism; Vitamin K

The non-vitamin K antagonist oral anticoagulants (NOACs) exert their anticoagulant effect closely related to their plasma concentrations. Since their distribution volume is related to body weight (and its correlates, i.e., surface area and body mass index, BMI), extremes in body weight may affect their efficacy or safety. Four NOACs are currently available for long-term use, with few exceptions, in atrial fibrillation and venous thromboembolism: the direct thrombin inhibitor dabigatran etexilate, and the factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience in patients with low (<50 kg) or extremely high (>150 kg) body weight is still quite limited, as such patients were rare in registration trials and sometimes directly excluded. In general, increased bleeding and higher mortality rates are observed in patients weighing <50 kg compared with patients weighing 50-100 kg. This may however also be explained by the presence of underlying conditions such as cancer. At the opposite end of the spectrum of body weight, lower antithrombotic efficacy may occur, perhaps due to the dilutional effect of a higher distribution volume. In this article, we review the pertinent literature and analyze the effects of low or high body weight on anticoagulant activity and clinical outcomes of the NOACs, their dose recommendations, and areas of uncertainty.

Topics: Administration, Oral; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Humans; Venous Thromboembolism; Vitamin K

Randomised controlled trials have provided important information on the efficacy and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) for treatment of venous thromboembolism (VTE), leading to registration and increasing use in clinical practice. Many questions remain to be answered, and observational studies are often more suitable for answering "real-world" questions than randomised controlled trials. Patient satisfaction, quality of life, and adherence and persistence in clinical practice with the drug regimen can only be assessed with an open-label design. Evaluation of risk for long-term sequelae of the disease requires much longer follow-up than is possible in registration trials. Treatment patterns and utilisation of health care resources can be assessed from observations in the clinical practice setting. We will review published as well as currently active observational studies with NOACs in VTE, with or without a comparator anticoagulant. These studies are based on cohorts of different sizes, registries, or administrative health care databases. We will also discuss some limitations in analysis and interpretation of observational studies.

Topics: Administration, Oral; Anticoagulants; Cohort Studies; Databases, Pharmaceutical; Humans; Observational Studies as Topic; Patient Satisfaction; Product Surveillance, Postmarketing; Quality of Life; Registries; Venous Thromboembolism; Vitamin K

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Topics: Administration, Oral; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Gastrointestinal Hemorrhage; Humans; Medication Adherence; Venous Thromboembolism; Vitamin K; Warfarin; Women's Health

Thrombosis is a leading cause of death and disability worldwide, and anticoagulants are the mainstay of its prevention and treatment. Starting with unfractionated heparin (UFH) and vitamin K antagonists (VKAs) such as warfarin, the choices of anticoagulants have exploded in the past 20 years. With over 90 % subcutaneous bioavailability, no need for coagulation monitoring and dose adjustment, and a lower risk of heparin-induced thrombocytopenia, low-molecular-weight heparin and fondaparinux have replaced UFH for prevention and initial treatment of venous thromboembolism and for secondary prevention in cancer patients. In patients undergoing percutaneous interventions, bivalirudin is often used instead of UFH. Oral anticoagulation therapy has advanced with the introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban and edoxaban. With efficacy at least equal to that of VKAs but with greater safety and convenience, the NOACs are now replacing VKAs for many indications. This paper a) highlights these advances, b) outlines how specific reversal agents for the NOACs will enhance their safety, c) reviews some of the ongoing trials with the NOACs, and d) describes the inhibitors of factor XII and XI that are under investigation as anticoagulants.

Topics: Anticoagulants; Antidotes; Coronary Artery Disease; Drug Discovery; Factor XI; Factor XII; Heart Failure; Heparin; Humans; Peripheral Arterial Disease; Stroke; Thrombosis; Venous Thromboembolism; Vitamin K; Warfarin

The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).. The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models.. A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40-1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding.. Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Observational Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Venous Thromboembolism; Vitamin K

Approximately 3% of Tuberculosis (TB) patients have a venous thromboembolic events (VTE). The use of Vitamin K antagonists (VKAs), as anticoagulant, in patients receiving anti TB antimicrobials is often complicated by drug interactions, especially with rifampicin. These patients require frequent monitoring of the International Normalized Ratio (INR), and it is reported that warfarin can not achieve a therapeutic INR. In such cases, abruptly stopping the rifampicin once the course of anti TB antimicrobials is not completed is potentially hazardous. The most recent alternative to prevent thrombotic episodes by using oral agents is represented by novel oral anticoagulants (NOAs) an important breakthrough since they do not require strict laboratory monitoring, frequent dosing adjustments, or dietary restrictions; moreover, they and they are linked with far fewer drug-drug interactions.. We have performed a Systematic Review to retrieve information about studies that have assessed the effect of NOAs administered in combination with anti TB antimicrobials in order to investigate if NOAs could be used in TB patients with VTE that do not achieve a therapeutic INR with VKAs.. The MEDLINE and Google Scholar databases were screened from the inception to 5th of February 2017, using two search strategies: the first one was antimicrobials AND novel oral anticoagulants; the second was antibiotics AND novel oral anticoagulants.. 1011 titles were identified on PubMed and Google Scholar published from the inception to February 5, 2017, of these 17 studies were included in the qualitative synthesis Conclusion: No published data were found that properly assessed the effect of NOAs administered in combination with anti TB antimicrobials. Further studies are needed to establish the safety of NOAs in this clinical scenario. In the meanwhile, a viable alternative to VKAs, in order to prevent complications of VTE related to TB, may be represented by Low Molecular Weight Heparin (LMWH), notwithstanding the limitation of the parental route of administration.

Topics: Administration, Oral; Anticoagulants; Antitubercular Agents; Blood Coagulation; Drug Interactions; Heparin, Low-Molecular-Weight; Humans; Treatment Outcome; Tuberculosis; Venous Thromboembolism; Vitamin K

People with venous thromboembolism (VTE) generally are treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH), followed by three months of vitamin K antagonists (VKAs). Treatment with VKAs requires regular laboratory measurements and carries risk of bleeding; some patients have contraindications to such treatment. Treatment with LMWH has been proposed to minimise the risk of bleeding complications. This is the second update of a review first published in 2001.. The purpose of this review was to evaluate the efficacy and safety of long term treatment (three months) with LMWH versus long term treatment (three months) with VKAs for symptomatic VTE.. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), The Cochrane Vascular Information Specialistalso searched clinical trials registries for ongoing studies.. Randomised controlled trials comparing LMWH versus VKA for long treatment (three months) of symptomatic VTE. Two review authors independently evaluated trials for inclusion and methodological quality.. Review authors independently extracted data and assessed risk of bias. We resolved disagreements by discussion and performed meta-analysis using fixed-effect models with Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs). Outcomes of interest were recurrent VTE, major bleeding, and mortality. We used GRADE to assess the overall quality of evidence supporting these outcomes.. Sixteen trials, with a combined total of 3299 participants fulfilled our inclusion criteria. According to GRADE, the quality of evidence was moderate for recurrent VTE, low for major bleeding, and moderate for mortality. We downgraded the quality of the evidence for imprecision (recurrent VTE, mortality) and for risk of bias and inconsistency (major bleeding).We found no clear differences in recurrent VTE between LMWH and VKA (Peto OR 0.83, 95% confidence interval (CI) 0.60 to 1.15; P = 0.27; 3299 participants; 16 studies; moderate-quality evidence). We found less bleeding with LMWH than with VKA (Peto OR 0.51, 95% CI 0.32 to 0.80; P = 0.004; 3299 participants; 16 studies; low-quality evidence). However, when comparing only high-quality studies for bleeding, we observed no clear differences between LMWH and VKA (Peto OR 0.62, 95% CI 0.36 to 1.07; P = 0.08; 1872 participants; seven studies). We found no clear differences between LMWH and VKA in terms of mortality (Peto OR 1.08, 95% CI 0.75 to 1.56; P = 0.68; 3299 participants; 16 studies; moderate-quality evidence).. Moderate-quality evidence shows no clear differences between LMWH and VKA in preventing symptomatic VTE and death after an episode of symptomatic DVT. Low-quality evidence suggests fewer cases of major bleeding with LMWH than with VKA. However, comparison of only high-quality studies for bleeding shows no clear differences between LMWH and VKA. LMWH may represent an alternative for some patients, for example, those residing in geographically inaccessible areas, those who are unable or reluctant to visit the thrombosis service regularly, and those with contraindications to VKA.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Odds Ratio; Randomized Controlled Trials as Topic; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Factor Xa (fXa)-inhibitors are as effective and safer than vitamin-K-antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35 % and 48 % of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95 % CI 0.36-0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22 % of the fXa inhibitor and 25 % of the VKA associated bleeds (OR 0.83, 95 % CI 0.47-1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Transfusion; Chi-Square Distribution; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Logistic Models; Male; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

To update on new data for low-molecular weight heparins (LMWHs) and the direct oral anticoagulants (DOACs) for the treatment and prevention of cancer-associated thrombosis (CAT), to discuss progress with the risk-adaptive management scores (RAMS) and update on increased dose primary thromboprophylaxis (IDPTP).. In a pooled meta-analysis of 1132 cancer patients who received DOACs vs. vitamin K analogues (VKAs), recurrence of venous thromboembolism (VTE) was reduced from 6.0% on VKA schedules to 3.9% on DOACs. In a randomized trial of warfarin vs. once daily sc. tinzaparin (175 IU/kg), cumulative 6-month VTE incidence reduced from 10.5 to 7.2% [hazard ratio, 0.65 (95% confidence interval, 0.41-1.03); P = 0.07]. Despite early suggestions that DOACs may have a role in CAT, 3-6 months of LMWH remain the standard for initial treatment of CAT. A prospective comparison of RAMS found the Vienna CATS or the PROTECHT scores superior to the Khorana score but concluded that RAMS did not perform well enough to be used in the clinic. An efficacy scale of LMWHs in pancreatic cancer facilitates IDPTP. Practical implementation of IDPTP was needed to control the 40% VTE incidence of the HALO-109-202 study in metastatic pancreatic cancer.. DOACs have some encouraging data, but LMWHs remain the standard for CAT treatment. RAMS generated to predict VTE occurrence or recurrence are still of unproven significance and IDPTP for advanced pancreatic cancer has tools and guidance for implementation.

Topics: Anticoagulants; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Risk Assessment; Venous Thromboembolism; Vitamin K

The worldwide increase in the aging population and the associated increase in the prevalence of atrial fibrillation and venous thromboembolism as well as the widespread use of direct oral anticoagulants (DOAC) have resulted in an increase of the need for the management of bleeding complications and emergency operations in frail, elderly patients, in clinical practice. When severe bleeding occurs, general assessment should include evaluation of the bleeding site, onset and severity of bleeding, renal function, and concurrent medications with focus on anti-platelet drugs and nonsteroidal anti-inflammatory drugs (NSAID). The last intake of the DOAC and its residual concentration are also relevant. The site of bleeding should be immediately localized, anticoagulation should be interrupted, and local measures to stop bleeding should be taken. In life-threatening bleeding or emergency operations immediate reversal of the antithrombotic effect may be indicated. If relevant residual DOAC-concentrations are expected and surgery cannot be postponed, prothrombin complex concentrate (PCC) and/or a specific antidote should be given. While idarucizumab, the specific antidote for dabigatran, has been recently approved for clinical use, the recombinant factor X protein andexanet alfa, an antidote for the reversal of inhibitors of coagulation factor Xa, and ciraparantag, a universal antidote, are not available. Future cohort studies are necessary to assess the efficacy and safety of specific and unspecific reversal agents in "real-life" conditions. This was the rationale for introducing the RADOA-registry (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists), a prospective non-interventional registry, which will evaluate the effects of specific and unspecific reversal agents in patients with life-threatening bleeding or emergency operations either treated with DOACs or vitamin K antagonists.. Durch eine weltweit alternde Bevölkerung nehmen Vorhofflimmern und venöse Thromboembolien und dadurch auch der Einsatz direkter oraler Antikoagulantien (DOAK) deutlich zu. Das Management von Blutungskomplikationen und Notfalloperationen bei diesen fragilen, alten Patienten stellt eine Herausforderung im klinischen Alltag dar. Bei Auftreten schwerer Blutungen sollten der Ort der Blutung, der Beginn und Schweregrad, sowie die Nierenfunktion und Begleitmedikationen wie Thrombozytenaggregationshemmer oder nichtsteroidale Antirheumatika (NSAR) Berücksichtigung finden. Der Zeitpunkt der letzten Tabletteneinnahme sowie die Restkonzentration des DOAK bei Aufnahme sind ebenfalls relevant. Die Antikoagulation sollte sofort unterbrochen und lokale Maßnahmen ergriffen werden, um die Blutung zu stillen. Bei lebensbedrohlicher Blutung oder rasch notwendiger Notfalloperation sollte der anti-koagulierende Effekt sofort aufgehoben werden. Die Gabe von PPSB kann erwogen werden, wenn spezifische Antidots nicht zur Verfügung stehen. Wenn relevante DOAK-Rest-konzentrationen vermutet werden und die Operation nicht aufgeschoben werden kann, dann sollten PPSB und/oder ein spezifisches Antidot präoperativ appliziert werden. Während Idarucizumab, das spezifische Antidot für Dabigatran, inzwischen zur Behandlung zugelassen ist, sind der rekombinante Faktor X Andexanet Alfa, der als Antidot gegen Faktor X-Inhibitoren wirkt und Ciraparantag, ein universelles Antidot, noch nicht für die klinische Anwendung verfügbar. Zukünftige Studien und Register sollten Effektivität und Sicherheit spezifischer und unspezifischer Gegenmittel im klinischen Alltag untersuchen. Diese Überlegungen haben zur Etablierung des RADOA-Registers (RADOA: Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists) geführt, ein prospektives, multizentrisches, nicht-interventionelles Register, das die Ef-fektivität spezifischer und unspezifischer Gegenmittel bei Patienten mit lebensbedrohlichen Blutungen oder Notfalloperation unter Behandlung mit DOAK oder Vitamin-K-Antagonisten erfassen und auswerten wird.

Topics: Administration, Oral; Aged; Anticoagulants; Antidotes; Atrial Fibrillation; Emergency Medical Services; Frail Elderly; Hemorrhage; Humans; Population Dynamics; Prothrombin; Registries; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) are increasingly prescribed substances in patients with indication for effective anticoagulation. Patients with chronic kidney disease (CKD) have a high burden of cardiovascular risk and are more likely to develop atrial fibrillation (AF) than patients without CKD. Patients with mild to moderate CKD benefit from DOACs, especially when having intolerance to vitamin K-antagonists (VKA). DOACs may in some cases be considered in patients with rare renal disease and hypercoagulabilic state. DOACs are to a large extent eliminated by renal excretion. Since prospective randomised data in CKD patients are sparse, the decision for anticoagulative therapy is challenging especially in patients with severe renal impairment. The direct factor Xa-inhibitors are approved for use even in patients with an estimated glomerular filtration rate (eGFR) between 15 and 30 ml/min. Careful monitoring of renal function on a regular basis is essential before initiation and after start of DOAC, especially for patients at risk for acute renal failure (elderly, diabetics, patients with preexisting kidney disease). None of the DOACs is approved in CKD patients with end-stage-renal-disease (ESRD) with or without dialysis. DOACs are not recommended for kidney transplant patients under immunosuppression with calcineurin inhibitors. In these patients conventional therapy with VKA is the only option, which has to be monitored closely since it has potential adverse effects.. Die direkten oralen Antikoagulantien (DOAK) werden zunehmend häufiger bei Patienten mit einer Indikation für eine effektive Antikoagulation verordnet. Im Vergleich zu Patienten ohne chronische Nierenerkrankung (CKD) haben Patienten mit CKD ein höheres kardiovaskuläres Risiko und eine höhere Wahrscheinlichkeit, Vorhofflimmern zu entwickeln. Die Behandlung mit DOAK ist bei Patienten mit milder bis mäßiger CKD von Vorteil, insbesonde-re wenn eine Unverträglichkeit gegen Vitamin-K-Antagonisten (VKA) besteht. DOAK können in Einzelfällen auch bei Patienten mit seltenen Nierenerkrankungen und Hyperkoagulabilität eingesetzt werden. Die DOAK werden zu einem großen Teil renal eliminiert. Da prospektive, randomisierte Daten zu CKD-Patienten rar sind, ist die Entscheidung für eine Antikoagulation schwierig, insbesondere bei Patienten mit deutlich eingeschränkter Nierenfunktion. Die direkten Faktor-Xa-Hemmer sind auch bei Patienten mit einer geschätzten glomerulären Filtrationsrate (GFR) von 15 bis 30 ml/min zugelassen. Es ist jedoch notwendig, die Nierenfunktion vor und nach Beginn der DOAK sorgfältig und regelmäßig zu evaluieren, besonders bei Patienten mit einem höheren Risiko für ein akutes Nierenversagen (Ältere, Diabetiker, Patienten mit bekannter Nierenerkrankung). Kein DOAK ist bei CKD-Patienten mit terminaler Nierenerkrankung, ob mit oder ohne Dialysetherapie, zugelassen. DOAK sind nicht empfohlen bei nierentransplantierten Patienten, die unter Immunsuppression mit Calcineurin-Hemmern stehen. Bei diesen Patienten ist die konven-tionelle Therapie mit VKA die einzige Möglichkeit und muss aufgrund potenziell uner-wünschter Nebenwirkungen engmaschig kontrolliert werden.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Contraindications; Factor Xa Inhibitors; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Risk Factors; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a frequent complication in cancer patients and represents an important cause of morbidity and mortality. The treatment of VTE complications in cancer patients remains a difficult clinical task. Low-molecular-weight heparins (LMWH) are the cornerstone of VTE treatment in cancer patients, including the treatment of catheter-related thrombosis. LMWH dose adjustment is effective in treating recurrent thrombosis and in patients with bleeding or thrombocytopenia. The duration of treatment is dependent on several factors that need to be individually evaluated. The novel anticoagulants should be investigated more carefully before being routinely implemented in the treatment of cancer-associated VTE. Incidentally detected isolated sub-segmental pulmonary embolism is unlikely to require systematic full-dose anticoagulation. Whether the long-term use of LMWHs has the potential to prolong survival in subgroups of cancer patients requires further investigations.

Topics: Administration, Oral; Anticoagulants; Drug Administration Schedule; Drug Dosage Calculations; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Vascular Access Devices; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Intracranial hemorrhage (ICH) in cancer patients can result from tumor bleeding and from antitumor and anticoagulation therapy. The effect of anticoagulation on the incidence of ICH in cancer patients has not been quantified. Our objective was to determine the risk of intracranial hemorrhage associated with anticoagulation therapy for cancer-associated venous thromboembolism (VTE). Systematic review and meta-analysis of studies assessing the safety of anticoagulation therapy in patients with cancer-associated VTE. The primary endpoint of interest was the incidence of ICH and secondary outcomes included all major bleeding, and the time to ICH and major bleeding. After identifying 595 studies, five studies and 2089 patients were included in the analyses. We found that the relative risk (RR) for ICH was 0.494, 95 % CI (0.105-2.331) when low molecular weight heparin (LMWH) with vitamin K antagonist (VKA) anticoagulants were compared. No statistically significant differences in risk were measured. The risk of major bleeding using any type of anticoagulation therapy in patients with cancer-associated VTE was RR 0.853, 95 % CI (0.549, 1.327). After meta-analytic review of data published through August 2015, we conclude that therapeutic anticoagulation with LMWH given ≤6 months does not increase the risk of ICH in cancer patients compared to VKA. The risk of ICH in cancer patients is also similar to that of non-cancer patients. Available data were insufficient to determine if the ICH risk increase changes when the duration of anticoagulation is >6 months.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Intracranial Hemorrhages; Neoplasms; Risk; Venous Thromboembolism; Vitamin K

Few data are available about safety of vitamin K antagonists (VKAs) in patients with clinical/demographic characteristics predisposing to an increased risk of bleeding. We performed a meta-analysis to evaluate the safety of VKAs in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) in the following subgroups of "high-risk" patients: elderly patients, patients with low body weight and patients with impaired renal function.. Major electronic databases were systematically searched to identify randomized controlled trials (RCTs) addressing this issue. Pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for each outcome using a random effects model.. Eleven RCTs for a total of 41,015 patients treated with VKAs (25,901 with AF and 15,114 with VTE) were included. We found a significant association between age>75years and bleeding in patients receiving VKAs (RR: 1.62, 95%CI: 1.28-2.05; P<0.0001). Moreover, the prevalence of bleeding events under VKAs was significantly higher in patients with low body weight (RR: 1.20, 95%CI: 1.03-1.40; P=0.02) and in those with impaired renal function (RR: 1.59, 95%CI: 1.30-1.94; P<0.00001). Results were confirmed when separately analyzing data on AF and VTE. Regression models showed that treatment duration did not impact on the differences found in the safety profile of VKAs in different settings analyzed.. Results of our meta-analysis suggest an increased risk of bleeding complications in "high-risk" patients. Although all results are significant, other studies focused on this issue are warranted to further validate these results.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Risk Factors; Venous Thromboembolism; Vitamin K; Warfarin

Evidence from the use of traditional therapy (low-molecular-weight heparin/vitamin K antagonists) for venous thromboembolism (VTE) treatment and prevention suggests that extending treatment beyond the acute phase reduces recurrence. More recently, several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12months offers additional benefits to patients with VTE. This review examines the evidence for NOAC use in longer-duration anticoagulation treatment, and discusses guidelines from major societies. Clinical data from the phase III extension studies for apixaban, dabigatran and rivaroxaban are presented, and the clinical and economic costs and benefits are examined. Evidence from other therapy areas utilising extended treatment regimens highlights the possible impact of factors relevant to extended anticoagulation therapy. Phase IV studies of NOACs are presented. US and European guidelines advise long-term therapy in certain instances, taking into account evidence on NOAC use in VTE accumulated recently. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3months. The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk. Phase IV data are also emerging, with the recent XALIA study showing that a broad range of patients with VTE can benefit from continued rivaroxaban treatment; ongoing research will yield data on long-term use of the other NOACs in routine clinical practice.

Topics: Administration, Oral; Anticoagulants; Humans; Practice Guidelines as Topic; Recurrence; Secondary Prevention; Venous Thromboembolism; Vitamin K

Prior meta-analysis studies showed that direct oral anticoagulants (DOAs) are as effective and safe as warfarin for the prevention of recurrences in patients with venous thrombo-embolism(VTE) and cancer. However, randomized studies also showed that low-molecular-weight-heparin (LMWH) performs better than warfarin in subjects with cancer. We therefore aimed to assess whether, even after pooling data with warfarin and LMWH, the use of DOAs remains safe and effective.. We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. Data on recurrent VTE and major and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs.. Nine studies were included in the meta-analysis, seven in comparison with VKI, 2 with LMWH, accounting for a total of 1952 patients. VTE recurred in 5.4% and in 5.9% of patients with cancer treated with DOAs and conventional treatment, respectively (OR 0.79; 95% CI, 0.53-1.17; I. DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer in comparison with VKI. Higher bleeding rates were found when DOAs are compared with LMWH.

Topics: Administration, Oral; Anticoagulants; Dose-Response Relationship, Drug; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Patients with cancer are at increased risk of venous thromboembolism, and emergency physicians can play a significant role in addressing one of the leading causes of morbidity and mortality in this patient population. However, there are no comprehensive guidelines addressing the approach to cancer-associated venous thromboembolism in the emergency department. Here, we review the guidelines put forth by various national and international cancer societies and highlight how emergency physicians can help institute appropriate treatment and prevent the recurrence of venous thromboembolism in cancer patients. We also address areas of controversy and highlight topics that require further research.

Topics: Anticoagulants; Contraindications; Emergency Service, Hospital; Guidelines as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Recurrence; Risk Factors; Secondary Prevention; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Humans; Recurrence; Venous Thromboembolism; Vitamin K

Over the past several years, non-vitamin K oral anticoagulants (NOACs) have been introduced into clinical practice for the treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Clinical trials have shown these agents to have similar or less risk of major bleeding as compared to warfarin therapy. Moreover, when patients do experience a major bleeding event administration of advanced factor products is rare, and post-bleed outcomes are similar in those receiving a NOAC compared to those receiving warfarin. However, there are situations where urgent reversal of NOAC anticoagulation would be desirable. The following review focuses on the outcomes and management strategies for patients experiencing a major bleed with warfarin or NOAC agents and describes the rationale for the development of therapies capable of targeted NOAC-reversal.

Topics: Administration, Oral; Animals; Anticoagulants; Antidotes; Hemorrhage; Humans; Stroke; Venous Thromboembolism; Vitamin K

Trousseau's syndrome (cancer-associated thrombosis) is the second leading cause of death in cancer patients, after death from cancer itself. The risk of a venous thromboembolism is 4- to 7-fold higher in patients with cancer than in those without cancer. The causes of this impaired coagulation are associated with general patient-related risk factors, and other factors that are specific to the particular cancer or treatment. It is important to assess the risk of thrombotic events in cancer patients and administer effective prophylaxis and treatment. Effective prophylaxis and treatment of venous thromboembolism reduces morbidity and mortality, and improves patients' quality of life. Low molecular weight heparin is the first-line treatment for venous thromboembolism, as an effective and safe means for prophylaxis and treatment, according to guidelines released by international scientific societies. Oral anticoagulation therapy with warfarin is preferable to no therapy. However, warfarin has low efficacy and is associated with high rates of recurrence. If low molecular weight heparin is unavailable, some guidelines recommend the use of vitamin K antagonists that have a target international normalized ratio in the range of 2-3, as acceptable alternatives. Novel oral anticoagulants that directly inhibit factor Xa or thrombin are promising for the prophylaxis of high-risk cancer patients and in the long-term treatment of venous thromboembolism. However, to date, there is insufficient evidence to support the use of these new anticoagulants.

Topics: Administration, Oral; Anticoagulants; Asian; Black or African American; Disease Management; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Polysaccharides; Prevalence; Quality of Life; Recurrence; Risk Factors; Taiwan; Thrombosis; United States; Venous Thromboembolism; Vitamin K; Warfarin; White People

Cancer and venous thromboembolism (VTE) are closely related, with a high risk of VTE associated with cancer and a strong impact of VTE on cancer prognosis. The management and treatment of cancer-associated VTE are particularly challenging and, in many cases, are not guided by a high level of evidence.. In this review, we present the best therapeutic approach to acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and to some controversial issues, such as home treatment, optimal duration of anticoagulation, management of VTE recurrence during anticoagulant treatment, and of unsuspected PE. Then, the available evidence on other cancer-related VTE manifestations is presented, such as catheter-related thrombosis and splanchnic vein thrombosis.. While solid evidence exists on the advantage of low molecular weight heparin (LMWH) over vitamin K antagonists (VKAs) during the first 3 to 6 months after acute DVT and/or PE, several issues have not been sufficiently investigated yet. These include the role of LMWH beyond the first 3 to 6 months, whether it is still more effective than VKA and if its intensity could be safely reduced, the strategies to identifying accurate predictors of VTE recurrence and the role of direct oral anticoagulants.

Topics: Acute Disease; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Arterial and venous thromboembolism are leading causes of morbidity and mortality around the world. For almost 70 years, heparins (unfractionated heparin and low molecular weight heparins) and vitamin K antagonists have been the leading therapeutic medical options for the treatment and prevention of thromboembolic disorders. Nevertheless, the many limitations of these traditional anticoagulants have fuelled the search for novel agents over the past 15 years, and a new class of oral anticoagulants that specifically target activated factor X and thrombin has been developed and is now commercially available. In this narrative review, the evolution of anticoagulant therapy is summarised, with a focus on newer oral anticoagulants.

Topics: Administration, Oral; Factor Xa Inhibitors; Heparin; History, 20th Century; History, 21st Century; Humans; Venous Thromboembolism; Vitamin K

The optimal duration of thromboprophylaxis after total hip or knee replacement, or hip fracture repair remains controversial. It is common practice to administer prophylaxis using low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) until discharge from hospital, usually seven to 14 days after surgery. International guidelines recommend extending thromboprophylaxis for up to 35 days following major orthopaedic surgery but the recommendation is weak due to moderate quality evidence. In addition, recent oral anticoagulants that exert effect by direct inhibition of thrombin or activated factor X lack the need for monitoring and have few known drug interactions. Interest in this topic remains high.. To assess the effects of extended-duration anticoagulant thromboprophylaxis for the prevention of venous thromboembolism (VTE) in people undergoing elective hip or knee replacement surgery, or hip fracture repair.. The Cochrane Vascular Information Specialist searched the Specialised Register (last searched May 2015) and CENTRAL (2015, Issue 4). Clinical trials databases were searched for ongoing or unpublished studies.. Randomised controlled trials assessing extended-duration thromboprophylaxis (five to seven weeks) using accepted prophylactic doses of LMWH, UFH, vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) compared with short-duration thromboprophylaxis (seven to 14 days) followed by placebo, no treatment or similar extended-duration thromboprophylaxis with LMWH, UFH, VKA or DOACs in participants undergoing hip or knee replacement or hip fracture repair.. We independently selected trials and extracted data. Disagreements were resolved by discussion. We performed fixed-effect model meta-analyses with odds ratios (ORs) and 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity.. We included 16 studies (24,930 participants); six compared heparin with placebo, one compared VKA with placebo, two compared DOAC with placebo, one compared VKA with heparin, five compared DOAC with heparin and one compared anticoagulants chosen at investigators' discretion with placebo. Three trials included participants undergoing knee replacement. No studies assessed hip fracture repair.Trials were generally of good methodological quality. The main reason for unclear risk of bias was insufficient reporting. The quality of evidence according to GRADE was generally moderate, as some comparisons included a single study, low number of events or heterogeneity between studies leading to wide CIs.We showed no difference between extended-duration heparin and placebo in symptomatic VTE (OR 0.59, 95% CI 0.35 to 1.01; 2329 participants; 5 studies; high quality evidence), symptomatic deep vein thrombosis (DVT) (OR 0.73, 95% CI 0.39 to 1.38; 2019 participants; 4 studies; moderate quality evidence), symptomatic pulmonary embolism (PE) (OR 0.61, 95% CI 0.16 to 2.33; 1595 participants; 3 studies; low quality evidence) and major bleeding (OR 0.59, 95% CI 0.14 to 2.46; 2500 participants; 5 studies; moderate quality evidence). Minor bleeding was increased in the heparin group (OR 2.01, 95% CI 1.43 to 2.81; 2500 participants; 5 studies; high quality evidence). Clinically relevant non-major bleeding was not reported.We showed no difference between extended-duration VKA and placebo (one study, 360 participants) for symptomatic VTE (OR 0.10, 95% CI 0.01 to 1.94; moderate quality evidence), symptomatic DVT (OR 0.13, 95% CI 0.01 to 2.62; moderate quality evidence), symptomatic PE (OR 0.32, 95% CI 0.01 to 7.84; moderate quality evidence) and major bleeding (OR 2.89, 95% CI 0.12 to 71.31; low quality evidence). Clinically relevant non-major bleeding and minor bleeding were not reported.Extended-duration DOAC showed reduced symptomatic VTE (OR 0.20, 95% CI 0.06 to 0.68; 2419 participants; 1 study; moderate quality evidence) and symptomatic DVT (OR 0.18, 95% CI 0.04 to 0.81; 2459 participants; 2 studies; high quality evidence) compared to placebo. No differences were found for symptomatic PE (OR 0.25, 95% CI 0.03 to 2.25; 1733 participants; 1 study; low quality evidence), major bleeding (OR 1.00, 95% CI 0.06 to 16.02; 2457 participants; 1 study; low quality evidence), clinically relevant non-major bleeding (OR 1.22, 95% CI 0.76 to 1.95; 2457 participants; 1 study; moderate quality. Moderate quality evidence suggests extended-duration anticoagulants to prevent VTE should be considered for people undergoing hip replacement surgery, although the benefit should be weighed against the increased risk of minor bleeding. Further studies are needed to better understand the association between VTE and extended-duration oral anticoagulants in relation to knee replacement and hip fracture repair, as well as outcomes such as distal and proximal DVT, reoperation, wound infection and healing.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Hemorrhage; Heparin; Hip Fractures; Humans; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) and cancer are strongly associated, and present a major challenge in cancer patient treatment. Cancer patients have a higher risk of developing VTE, although the risk differs widely between tumour types. VTE prophylaxis is routinely given to cancer patients, in the form of vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). Several studies have reported that cancer patients receiving anticoagulants show prolonged survival and this effect was more pronounced in patients with a good prognosis, although the mechanism is poorly understood. Tissue Factor (TF) is the initiator of extrinsic coagulation, but its non-haemostatic signalling via protease-activated receptors (PARs) is a potent driver of tumour angiogenesis. Furthermore, coagulation activation is strongly implicated in tumour cell migration and metastasis. This review discusses the effects of anticoagulants on cancer progression in patients, tumour cell behaviour, angiogenesis, and metastasis in in vitro and in vivo models. Inhibition of TF signalling shows great promise in curbing angiogenesis and in vivo tumour growth, but whether this translates to patients is not yet known. Furthermore, non-haemostatic properties of coagulation factors in cancer progression are discussed, which provide exciting opportunities on limiting oncologic processes without affecting blood coagulation.

Topics: Animals; Anticoagulants; Blood Coagulation; Coumarins; Heparin, Low-Molecular-Weight; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Thromboplastin; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is one of the leading causes of death in cancer patients, which are known to have a 5- to 7-fold increased risk for VTE. The anticoagulant treatment of VTE in cancer patients is less effective with a three-fold increased risk of VTE recurrence compared to non-cancer patients, and it is less safe with more than double rates of major bleeding. Compared to vitamin-K antagonists (VKA), long-term secondary prevention with low molecular weight heparin (LMWH) has been shown to reduce the risk of recurrent VTE in cancer-associated thrombosis (CAT), and therefore, current international guidelines recommend the use of LMWH over VKA. With increasing age, cancer prevalence and VTE incidence increase while renal function decreases. Anti-cancer treatment may impair renal function additionally. Therefore, renal insufficiency is a frequent challenge in CAT patients, which is associated with a higher risk of both bleeding and recurrent VTE. Both VKA and LMWH may be associated with less efficacy and higher bleeding risk in renal insufficiency. Unfortunately, there is a lack of prospective data on renal insufficiency and CAT. A recent sub-analysis from a large randomized controlled trial shows that the bleeding risk in patients with severe renal insufficiency in CAT is not elevated with the use of LMWH compared to VKA while efficacy is maintained. In addition, LMWH treatment has several practical advantages over VKA, particularly in patients with CAT while they are receiving anti-cancer treatment.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Renal Insufficiency; Venous Thromboembolism; Vitamin K; Warfarin

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings.

Topics: Anticoagulants; Humans; International Normalized Ratio; Venous Thromboembolism; Vitamin K

Anticoagulants are beneficial for prevention and treatment of venous thromboembolism and stroke prevention in atrial fibrillation. The development of target-specific oral anticoagulants is changing the landscape of anticoagulation therapy and created growing interest on this subject. Understanding the pharmacology of different anticoagulants is the first step to adequately treat patients with best available therapy while avoiding serious bleeding complications. This article reviews the pharmacology of the main anticoagulant classes (vitamin K antagonists, direct oral anticoagulants, and heparins) and their clinical indications based on evidence-based data currently available in the literature.

Topics: Age Factors; Anticoagulants; Antithrombins; Arthroplasty, Replacement; Atrial Fibrillation; Comorbidity; Critical Illness; Drug Interactions; Drug Monitoring; Hemorrhage; Heparin; Humans; Neoplasms; Perioperative Care; Pulmonary Embolism; Stroke; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is associated with a risk of recurrence that depends on factors specific to index event and patient. A first unprovoked VTE increases the risk of a recurrent event, particularly during the first year after anticoagulation cessation. Determining a strategy for the long-term prevention of recurrent VTE poses challenges that stem from a lack of agreement on recommended therapy duration and varying treatment burden for the patient. Oral anticoagulants, including vitamin K antagonists and non-vitamin K antagonist oral anticoagulants (NOACs), are the main treatment options for the long-term prevention of recurrent VTE. However, the risk of VTE recurrence must be balanced against the risk of bleeding in each patient. Phase III clinical trials have evaluated rivaroxaban, apixaban and dabigatran for extended treatment and prevention of VTE versus placebo, and versus warfarin in the case of dabigatran. Compared with placebo treatment, each NOAC showed superior efficacy together with an acceptable safety profile during extended treatment periods of 6-18months. Patients receiving long-term NOAC therapy will still require regular risk factor assessment, but these agents may permit longer treatment duration with an improved benefit-risk profile.

Topics: Anticoagulants; Chemoprevention; Humans; Recurrence; Secondary Prevention; Venous Thromboembolism; Vitamin K

In the past 2 decades, the direct oral anticoagulants (DOACs) have emerged as alternatives to the standard therapy (unfractionated or low-molecular-weight heparin followed by vitamin K antagonists [VKA]), for the acute and extended treatment of venous thromboembolism. The DOACs have a more favorable pharmacologic profile and a predictable anticoagulant response and, therefore, have the potential to overcome some of the limitations associated with the use of VKA. Several ongoing registries are evaluating the use of the DOACs in routine clinical practice and will provide additional information in less selected patient populations.

Topics: Administration, Oral; Anticoagulants; Humans; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) have been approved for the treatment of venous thromboembolism and atrial fibrillation based on randomized controlled trials (RCTs) of direct comparisons with vitamin K antagonists. Despite having more than 100,000 patients enrolled, safety and efficacy are debated in selected populations. Although DOACs are reviewed as a class of anticoagulant, pharmacokinetic differences exist such that different medications may be beneficial in distinct clinical settings. Synthesizing available evidence based on phase III RCTs, post hoc subgroup analyses, and pooled metaanalyses, this review provides an overview of DOACs and scrutinizes individual differences in their applications for the special populations.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Humans; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in the western world. The approval of non-vitamin K oral anticoagulants (NOACs) as antithrombotic alternatives to vitamin K antagonists (VKAs) has offered more treatment options to physicians for the prevention of VTE recurrence, fatal pulmonary embolism (PE) and long-term complications. Four NOACs (dabigatran, rivaroxaban, apixaban and edoxaban) that have been approved for the treatment of acute VTE following large phase III trials, where NOACs demonstrated similar efficacy and superior safety profile compared to VKAs.. The purpose of this review article is to summarise current knowledge of oral anticoagulation for the treatment of acute VTE and to compare NOACs with VKAs, highlighting the factors that might influence the decisions of physicians. Data for this article were obtained through a search of PubMed for trials comparing NOACs with VKAs in acute VTE setting and articles or analyses that interpreted results from these trials.. The NOACs have changed clinical practice regarding oral anticoagulation for acute VTE. Despite their advantages, 'grey zones' still remain and more studies are needed to provide evidence and confirm the superiority (or at least non-inferiority) of NOACs over VKAs. Real world data might give additional insights.

Topics: Administration, Oral; Anticoagulants; Antifibrinolytic Agents; Fibrinolytic Agents; Humans; Pulmonary Embolism; Venous Thromboembolism; Vitamin K

Anticoagulant agents have been approved by international regulatory agencies to prevent and treat venous thromboembolism (VTE). However, chronic kidney disease (CKD) is: (1) highly frequent in VTE patients; (2) strongly linked to VTE; and (3) a risk factor for cardiovascular morbidity/mortality and fatal pulmonary embolism. Therefore, an increasing number of patients are presented with CKD and VTE and more and more physicians must face the questions of the management of these patients and that of the handling of anticoagulant agents in CKD patients because of the pharmacokinetic modifications of these drugs in this population. These modifications may lead to overdosage and dose-related side effects, such as bleeding. It is therefore necessary to screen VTE patients for CKD and to modify the doses of anticoagulants, if necessary.

Topics: Anticoagulants; Cardiovascular Diseases; Drug Overdose; Heparin; Heparin, Low-Molecular-Weight; Humans; Kidney; Pulmonary Embolism; Renal Insufficiency, Chronic; Risk Factors; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is not uncommon among patients with cancer and is one of the major causes of mortality and morbidity. Treatment with low-molecular-weight heparin (LMWH) is effective, yet accompanied by the need for daily administration of injections for a prolonged time and (even rarely) thrombocytopenia. The discovery of novel oral anticoagulants (NOACs) was based on an effort to improve the pharmacodynamic and pharmacokinetic properties of previous generation anticoagulants while maintaining efficacy without the need for daily subcutaneous administration and frequent laboratory monitoring. The MEDLINE database was searched using PubMed in order to find relevant studies on the use of NOACs in patients with active malignancy and VTE. Furthermore, critical reading of references in recently published studies and reviews was performed. NOACs appear to be at least equivalent to coumarin anticoagulants in terms of efficacy and safety and their administration is easier, but data specifically concerning patients with active malignancy or comparing them to LMWH in this specific clinical setting are not yet available. Furthermore, patients with active cancer present several unique characteristics and drawing conclusions from studies involving other patient groups may not be appropriate. Specific studies in cancer patients are still pending that will help decide if NOACs will be the drugs of choice in this group of patients in need of efficient and simple to administer treatments.

Topics: Administration, Oral; Anticoagulants; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Diagnosis of venous thromboembolism (VTE) requires prompt treatment with anticoagulants in therapeutic doses. Since these drugs are associated with the occurrence of haemorrhage, identification of patients at increased risk of major bleeding is of utmost clinical importance for defining the optimal treatment regimen and duration of anticoagulation. Current suggested prediction scores for bleeding risk in VTE patients have been derived from observational studies of moderate quality, or from patients with various indications for therapeutic anticoagulation other than VTE. To date, none of the scores have been adequately validated in cohorts that underwent dedicated monitoring and independent adjudication of bleeding complications. In addition, while the scarce available evidence has focused on patients treated with heparins and/or vitamin K antagonists, risk stratification scores for bleeding complications in VTE patients treated with non-vitamin K dependent anticoagulants have not yet been developed. This clinically oriented review covers the incidence and risk factors of anticoagulation-related bleeding in VTE patients treated with different anticoagulant drugs as well as the available bleeding-prediction scores. Further, we attempt to provide guidance for bleeding-prevention in clinical practice and speculate on developments in the near future that may fundamentally change our current thinking on VTE management.

Topics: Anticoagulants; Blood Coagulation; Cardiology; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Factors; Severity of Illness Index; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOAs) have been shown to be as effective and at least as safe as conventional anticoagulation for the prevention of recurrences in patients with VTE. Whether this is the case in patients with cancer-associated VTE remains undefined.. We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. MEDLINE, EMBASE, and CENTRAL were searched up to December 2013 with no language restriction. The primary outcome of the analysis was recurrent VTE. Data on major bleeding (MB) and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs.. Overall, 10 studies comparing DOAs with conventional anticoagulation for treatment of VTE including patients with cancer were included in the review. Six studies were included in the meta-analysis (two with dabigatran, two with rivaroxaban, one with edoxaban, and one with apixaban), accounting for a total of 1,132 patients. VTE recurred in 23 of 595 (3.9%) and in 32 of 537 (6.0%) patients with cancer treated with DOAs and conventional treatment, respectively (OR, 0.63; 95% CI, 0.37-1.10; I2, 0%). MB occurred in 3.2% and 4.2% of patients receiving DOAs and conventional treatment, respectively (OR, 0.77; 95% CI, 0.41-1.44; I2, 0%).. DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer. Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

Topics: Anticoagulants; Antithrombins; Factor Xa Inhibitors; Heparin; Humans; Neoplasms; Recurrence; Venous Thromboembolism; Vitamin K

The prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non-VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit-risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and "real-life" data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Humans; Male; Orthopedic Procedures; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Rivaroxaban; Thiazoles; Thromboembolism; Treatment Outcome; Venous Thromboembolism; Vitamin K

New oral anticoagulants (NOACs) may represent an alternative to standard therapy with vitamin K antagonists (VKA). However, up to the present, it is unknown whether these drugs are safer than VKA. The aim of this study was to perform a meta-analysis of the interventional trials with NOACs vs VKA in patients with acute venous thromboembolism (VTE) to obtain the balance between clinical efficacy and complications. A meta-analysis of double blind randomized controlled trials (RCTs) was performed. We included RCTs that compared, in acute VTE, the beneficial and harmful effects of NOACs (ximelagatran, apixaban, dabigatran, edoxaban and rivaroxaban) vs VKA (warfarin). Seven studies including 29,482 patients were selected. Compared with warfarin, recurrent VTE and death from any cause were not significantly reduced by NOACs. Myocardial infarction was significantly increased with NOACs compared with warfarin (RR 2.55; 95% CI 1.1-5.6; p = 0.02). NOACs significantly reduced the major bleedings (RR 0.63; 95% CI 0.47-0.83; p = 0.001). This meta-analysis suggests that treatment with NOACs in patients with acute VTE is not inferior to conventional therapy with warfarin for recurrent VTE and death from any cause, but there might be an increased incidence of myocardial infarction.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Double-Blind Method; Humans; Myocardial Infarction; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Apixaban is one of the new oral anticoagulants, which is prescribed as an alternative to vitamin K antagonists (VKAs). Concerns regarding its bleeding profile persist and require further evaluation. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to compare the risks of bleeding and all-cause mortality between apixaban and VKAs. The MEDLINE, EMBASE, and Cochrane Library of Clinical Trials databases were systematically searched for RCTs comparing the risks of bleeding and all-cause mortality of apixaban (2.5 or 5 mg twice daily) with those of VKAs. We included RCTs conducted in adults and published in English or French. Data were pooled across RCTs using random-effects meta-analytical models. Our systematic search identified 5 RCTs meeting our inclusion criteria (n = 24,435). They included patients with atrial fibrillation (n = 18,358), total knee replacement surgery (n = 458), and venous thromboembolism (n = 5,619). Data pooled across RCTs revealed that apixaban was associated with reduced risks of any bleeding (relative risk [RR] 0.73, 95% confidence interval [CI] 0.59 to 0.90) and a composite of major or clinically relevant nonmajor bleeding (RR 0.60, 95% CI 0.40 to 0.88). Apixaban was also associated with a lower risk of intracranial bleeding (RR 0.42, 95% CI 0.31 to 0.58) whereas analyses of major and minor bleeding were inconclusive. Moreover, apixaban was associated with decreased all-cause mortality (RR 0.89, 95% CI 0.81 to 0.99) although this finding was driven by the results of the ARISTOTLE trial. In conclusion, our meta-analysis found that apixaban is associated with a lower risk of bleeding than VKAs, providing some reassurance regarding its safety.

Topics: Anticoagulants; Factor Xa Inhibitors; Global Health; Hemorrhage; Humans; Incidence; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Venous Thromboembolism; Vitamin K

Novel oral anticoagulants (NOACs) including apixaban, dabigatran and rivaroxaban have been approved by international regulatory agencies to prevent venous thromboembolism as well as treat atrial fibrillation and venous thromboembolism in individuals with chronic kidney disease (CKD). However, alterations in their metabolism in the setting of CKD may impact their efficacy and lead to an increased risk of bleeding. This review summarizes the current literature on the efficacy and safety of these agents in individuals with moderate CKD.. In clinical trials, the use of the NOACs in patients with moderate CKD has demonstrated efficacy and safety similar to those seen with vitamin K antagonists. However, no universal reversal agent for the anticoagulant effect of the NOACs exists in the setting of bleeding. Limited data have demonstrated that hemodialysis has been effectively used to aid in reversing the effects of dabigatran, and the use of prothrombin complex concentrate has also been used for serious and major adverse bleeding events with some success.. As the use of the NOACs in patients with CKD increases, it will be important to monitor their safety, and clinicians who prescribe them should carefully monitor kidney function and recognize the potential for adverse effects.

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Fibrinolytic Agents; Humans; Renal Insufficiency, Chronic; Venous Thromboembolism; Vitamin K

To evaluate the effect of body weight (BW) on safety and efficacy of direct oral anticoagulants (DOACs).. We performed a meta-analysis of randomized controlled trials (RCTs) comparing DOACs with vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Efficacy (prevention of recurrent VTE or VTE-related death) and safety (occurrence of major or clinically relevant non-major bleeding) outcomes were stratified according to patients' BW (low, normal, and high).. Six RCTs with a total of 27,023 patients were included. DOACs showed a similar efficacy to VKA in patients with high BW, normal BW, and low BW (RR 0.98, 95% CI 0.72, 1.35; RR 0.91, 95% CI 0.75, 1.09; and RR 0.84, 95% CI 0.57, 1.24, respectively). Safety was comparable among DOACs and VKA in patients with high BW and low BW (RR 0.93, 95% CI 0.65, 1.32; and RR 0.80, 95% CI 0.54, 1.20), whereas DOACs were marginally safer than VKA in normal-BW subjects (RR 0.82, 95% CI 0.67, 1.00). However, the difference among DOACs and VKA in the rate of bleeding episodes appeared similar in the three BW groups.. Results of our meta-analysis suggested that DOACs might be a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies with larger study populations are warranted to confirm our findings.

Topics: 4-Hydroxycoumarins; Acute Disease; Administration, Oral; Anticoagulants; Body Weight; Female; Humans; Indenes; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Venous Thromboembolism; Vitamin K

Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non-vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug-drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Drug Interactions; Humans; Intestinal Absorption; Neoplasms; Venous Thromboembolism; Vitamin K

The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.

Topics: Anticoagulants; Coronary Disease; Embolism; Humans; Incidence; Myocardial Infarction; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Humans; Venous Thromboembolism; Vitamin K

Patients with cancer are at increased risk of (recurrent) venous thromboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging.. In this review, we will focus on the safety of anticoagulant treatment of VTE in cancer patients. We will discuss the absolute and relative bleeding risks associated with the various types of anticoagulants, specifically focusing on low-molecular-weight heparins (LMWH), vitamin K antagonist (VKA) and the new oral anticoagulants (NOACs).. Monotherapy with LMWH is recommended for treatment of acute VTE in cancer patients. The bleeding risk associated with LMWH is comparable to VKAs, but LMWH are more effective in preventing recurrent VTE. More evidence on the efficacy and safety of NOACs in cancer patients is needed.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a disease state that carries significant morbidity and mortality, and is a known cause of preventable death in hospitalized and orthopedic surgical patients. There are many identifiable risk factors for VTE, yet up to half of VTE incident cases have no identifiable risk factor and carry a high likelihood of recurrence, which may warrant extended therapy. For many years, parenteral unfractionated heparin, low-molecular weight heparin, fondaparinux, and oral vitamin K antagonists (VKAs) have been the standard of care in VTE management. However, limitations in current drug therapy options have led to suboptimal treatment, so there has been a need for rapid-onset, fixed-dosing novel oral anticoagulants in both VTE treatment and prophylaxis. Oral VKAs have historically been challenging to use in clinical practice, with their narrow therapeutic range, unpredictable dose responsiveness, and many drug-drug and drug-food interactions. As such, there has also been a need for novel anticoagulant therapies with fewer limitations, which has recently been met. Dabigatran etexilate is a fixed-dose oral direct thrombin inhibitor available for use in acute and extended treatment of VTE, as well as prophylaxis in high-risk orthopedic surgical patients. In this review, the risks and overall benefits of dabigatran in VTE management are addressed, with special emphasis on clinical trial data and their application to general clinical practice and special patient populations. Current and emerging therapies in the management of VTE and monitoring of dabigatran anticoagulant-effect reversal are also discussed.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Comorbidity; Dabigatran; Hemorrhage; Humans; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a common and potentially preventable cause of morbidity and mortality. Unfractionated heparin, low-molecular-weight heparin, and warfarin have been the cornerstone of VTE prevention and treatment but are being replaced by recently approved non-vitamin K antagonist oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, and edoxaban. The NOACs are at least as effective and as safe as heparins and warfarin for VTE prevention and treatment and are more convenient because they have a low propensity for food and drug interactions and are given in fixed doses without routine coagulation monitoring. The remaining limitations of currently available NOACs include their dependence on renal and hepatic function for clearance, and the lack of an approved antidote. Betrixaban is a new NOAC with distinct pharmacological characteristics: minimal renal clearance, minimal hepatic metabolism, and long half-life. It has undergone successful Phase II studies in orthopedic thromboprophylaxis, and in stroke prevention in atrial fibrillation. Currently, it is being evaluated in a Phase III trial of extended thromboprophylaxis in medical patients (APEX study). In this article, we describe the development of betrixaban, review its pharmacological profile, discuss the results of clinical trials, and examine its potential for VTE prevention and treatment.

Topics: Administration, Oral; Animals; Benzamides; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; Factor Xa Inhibitors; Heparin; Humans; Pyridines; Venous Thromboembolism; Vitamin K; Warfarin

Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE.. A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model.. LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies.. The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable.. Austrian Science Fund (FWF-SFB-54).

Topics: Anticoagulants; Causality; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Neoplasms; Risk Assessment; Treatment Outcome; Venous Thromboembolism; Vitamin K

Limited information exists on gender-related differences in the safety and efficacy of non-vitamin K antagonist oral anticoagulants (NOACs).. To assess the safety and efficacy of direct oral anticoagulants (DOACs)/NOACs in men and women pooling data from randomized controlled trials on the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and on the acute and extended treatment of venous thromboembolism (VTE).. MEDLINE and EMBASE databases were searched up to June 2014. The efficacy outcome was defined as the prevention of stroke and systemic embolism (AF studies), or as the prevention of recurrent VTE or VTE-related death (VTE studies). The safety outcome was defined as the occurrence of major and/or clinically relevant non-major bleeding. Differences in the efficacy and safety outcomes were expressed as risk ratio (RR) with pertinent 95% confidence intervals (95% CI).. A total of 13 studies (> 100,000 patients) were included. DOACs appeared to have a similar efficacy and safety compared with vitamin K antagonists in female and male patients treated for nonvalvular AF and acute VTE. In the extended treatment of VTE NOACs had a RR of bleeding of 4.97 (95% CI 1.06, 23.41) in males and 1.33 (95% CI 0.63, 2.83) in females compared with placebo (subgroup difference chi-square test: 2.25, p = 0.13).. No gender-related difference in the efficacy and safety of NOACs in patients with AF or acute VTE was found. A trend toward an increased risk of bleeding in male patients as compared with female patients was detected in the extended treatment of VTE.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Female; Humans; Male; Randomized Controlled Trials as Topic; Sex Characteristics; Venous Thromboembolism; Vitamin K

The major practical advantage of the direct oral anticoagulants (DOACs), comprising the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, over vitamin K antagonists is their fixed dosing without the need for laboratory monitoring. With the recent, rapid introduction of the DOACs for the treatment of acute venous thromboembolism (VTE), clinicians are now faced with various questions regarding the efficacy and safety of these compounds overall and in specific high-risk populations. The collective evidence from 6 large clinical trials involving 27,000 patients has demonstrated that DOACs are as effective as vitamin K antagonists (VKA) in preventing recurrent VTE while being associated with a significantly lower risk of major bleeding. These findings are consistent in subgroups of patients with pulmonary embolism, the elderly, and those patients with a high body weight or moderate renal insufficiency, making these agents suitable for a broad spectrum of patients with VTE. DOACs are also an attractive treatment option in patients with VTE and concomitant cancer, thrombotic antiphospholipid syndrome, or heparin-induced thrombocytopenia, but the currently available clinical data is insufficient to make evidence-based recommendations on the use of DOACs in these settings. Several studies evaluating the efficacy and safety of DOACs in these high-risk populations are underway.

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Pulmonary Embolism; Recurrence; Renal Insufficiency; Risk; Thrombin; Thrombocytopenia; Thrombosis; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

In recent years, four nonvitamin K antagonist oral anticoagulants (NOACs) were approved to prevent stroke in patients with nonvalvular atrial fibrillation (AF) and to treat venous thromboembolism (VTE). Edoxaban, a direct factor Xa inhibitor, is the latest NOAC to be approved for use by the U.S. Food and Drug Administration. The other NOACs include two direct factor Xa inhibitors, apixaban and rivaroxaban, and one direct thrombin inhibitor, dabigatran. The purpose of this article is to introduce these agents to providers, discuss dosing, and offer insights into practical considerations for each NOAC.. PubMed was searched to identify randomized controlled trials and cost-effectiveness analyses evaluating NOACs. In addition, package inserts for the four NOACs provided pharmacologic data.. All four NOACs are equivalent to or better than warfarin for the treatment of VTE and stroke prevention in AF, and may reduce the risk of bleeding complications, particularly intracranial bleeding.. NOACs may benefit some patients by avoiding the numerous food or drug interactions and frequent laboratory monitoring associated with warfarin. Adherence to proper dosing is critical for NOAC efficacy and safety.

Topics: Administration, Oral; Anticoagulants; Humans; Randomized Controlled Trials as Topic; Stroke; United States; United States Food and Drug Administration; Venous Thromboembolism; Vitamin K

Venous thrombosis is a common medical disorder affecting nearly one million Americans each year. This review will focus primarily on the formation of venous thrombosis as well as current and future treatment options. While the full pathophysiology of venous thrombosis is not known, recent evidence points to a role for von Willebrand Factor, platelets, and neutrophils in thrombus formation. Many laboratory and imaging tests may be used for the diagnosis of venous thrombosis (VTE), but risk factor identification and clinical examination should not be overlooked as they are vital in assuring accurate treatment and patient identification. Historically heparin followed by a vitamin K antagonist has been the standard of care for treatment of VTE, but increasing data involving factor Xa inhibitors and direct thrombin inhibitors may mean a shift in first-line therapy in the very near future. Invasive therapies such as catheter-directed thrombolysis have also shown promise in the treatment of venous thrombosis and will likely see increased use in the future.

Topics: Anticoagulants; Antithrombins; Clinical Trials as Topic; Factor Xa Inhibitors; Heparin; Humans; Venous Thromboembolism; Vitamin K

New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE.. We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models.. Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI] 0.74-1.05), 1.02 (95% CI 0.39-5.96), and 0.97 (95% CI 0.83-1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban.. NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

The use of new oral anticoagulants (NOACs) in patients with impaired renal function has raised major concerns, in particular the possibility of an increased risk of bleeding due to accumulation. The aims of this work were to assess the safety of NOACs in patients with renal failure and describe the relationship between clinical events and drug renal excretion magnitude.. All phase III trials comparing NOACs with vitamin K antagonists (VKAs) in patients with estimated glomerular filtration (eGFR) rate < 50 mL min(-1) were eligible. The main safety and efficacy outcomes were major bleeding and thrombosis. A meta-regression was performed to estimate the correlation between the treatment effect estimate and the percentage of renal excretion.. Nine studies (12 272 patients) were included. A significantly greater relative reduction in major bleeding was seen for NOACs with renal excretion <50% (RR, 0.61; CI, 0.51-0.74) than for those with high renal excretion (RR, 0.96; CI, 0.85-1.07) (interaction test, P < 0.0001). A linear relationship between the relative risk of major bleeding and the magnitude of renal excretion was found by meta-regression (R(2)  = 0.66, P = 0.03). For thrombosis, a greater treatment effect of NOA vs. INR-adjusted VKA was observed in patients with eGFR < 50 mL min(-1) (RR 0.78, CI 0.67-0.92), but no correlation between treatment effect and renal excretion was found.. New oral anticoagulants were at least as effective as VKAs, with reduced risks of major bleeding and thrombosis in patients with eGFR < 50 mL min(-1) . The renal excretion of these new drugs seemed to modify the safety profile, contrary to the efficacy.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Glomerular Filtration Rate; Hemorrhage; Humans; Renal Insufficiency; Thrombosis; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Novel oral anticoagulants (NOACs) (rivaroxaban, dabigatran, apixaban) have been approved by international regulatory agencies to treat atrial fibrillation and venous thromboembolism in patients with kidney dysfunction. However, altered metabolism of these drugs in the setting of impaired kidney function may subject patients with CKD to alterations in their efficacy and a higher risk of bleeding. This article examined the efficacy and safety of the NOACs versus vitamin K antagonists (VKAs) for atrial fibrillation and venous thromboembolism in patients with CKD. A systematic review and meta-analyses of randomized controlled trials were conducted to estimate relative risk (RR) with 95% confidence interval (95% CIs) using a random-effects model. MEDLINE, Embase, and the Cochrane Library were searched to identify articles published up to March 2013. We selected published randomized controlled trials of NOACs compared with VKAs of at least 4 weeks' duration that enrolled patients with CKD (defined as creatinine clearance of 30-50 ml/min) and reported data on comparative efficacy and bleeding events. Eight randomized controlled trials were eligible. There was no significant difference in the primary efficacy outcomes of stroke and systemic thromboembolism (four trials, 9693 participants; RR, 0.64 [95% CI, 0.39 to 1.04]) and recurrent thromboembolism or thromboembolism-related death (four trials, 891 participants; RR, 0.97 [95% CI, 0.43 to 2.15]) with NOACs versus VKAs. The risk of major bleeding or the combined endpoint of major bleeding or clinically relevant nonmajor bleeding (primary safety outcome) (eight trials, 10,616 participants; RR 0.89 [95% CI, 0.68 to 1.16]) was similar between the groups. The use of NOACs in select patients with CKD demonstrates efficacy and safety similar to those with VKAs. Proactive postmarketing surveillance and further studies are pivotal to further define the rational use of these agents.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving.

Topics: Acute Disease; Administration, Oral; Antithrombins; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Long-Term Care; Morpholines; Perioperative Care; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

Long term treatment of venous thromboembolism is essential to complete therapy of the index episode and to reduce recurrences. Vitamin K antagonists are the mainstay for the long term treatment of venous thromboembolism for the majority of the patients as they allow oral administration. Low-molecular weight heparins are recommended for the long term treatment of cancer patients. The duration of long term anticoagulation depends on the features of the index venous thromboembolism and on the presence of associated risk factors. Patients at high risk for recurrence - mainly those who suffered unprovoked venous thromboembolism and those with cancer - should be evaluated for extended anticoagulation. The risk for major bleeding complications and the inconvenience for monitoring, dose adjustment and drug-food interactions are the main constraints for indefinite anticoagulant treatment. New anticoagulants with more favourable efficacy- safety profile and reduced need for monitoring could improve the feasibility of extended anticoagulation.

Topics: Anticoagulants; Antithrombins; Clinical Trials as Topic; Drug Administration Schedule; Heparin, Low-Molecular-Weight; Humans; Time Factors; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs), direct inhibitors of thrombin or factor Xa (FXa), are increasingly used in clinical practice for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (NVAF) and for therapy of venous thromboembolism (VTE). Like any anticoagulant treatment, their use is associated with the risk of bleeding events. The first aim of this article is to review the data on bleeding complications from the phase III clinical studies on chronic use of DOACs and from the few available phase IV registers in use of these drugs. In all randomized studies the DOACs showed a statistical non-inferiority for safety versus comparators (in most cases warfarin), although the rates of major bleeding were significantly lower for some DOACs and treatment doses than for warfarin. Data from available phase IV registers confirm that the use of DOACs in clinical practice is not associated with higher bleeding rates versus warfarin. Secondly, we will try to propose a possible treatment of bleeding complications associated with DOACs. Given the absence of specific antidotes, strategies for proper treatment of bleeding events are crucial; however, due to the lack of data, only proposals rather than recommendations are possible.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Hemorrhage; Heparin; Humans; Risk Factors; Severity of Illness Index; Venous Thromboembolism; Vitamin K; Warfarin

Hospitalized medical and surgical patients encompass a group of patients in whom venous thromboembolism (VTE) poses a major concern on morbidity and mortality. Recently, direct oral anticoagulants for the prevention of VTE have been developed to overcome the drawbacks of the food/drug interactions and the need for frequent laboratory monitoring and dose adjustments associated with the use of vitamin K antagonists and the inconvenience of the subcutaneous administration of low-molecular-weight heparins and fondaparinux. The novel oral anticoagulants that have been tested in major clinical trials for VTE prevention in medical and surgical patients are the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, which will be the focus of this review. While the new drugs proved to be highly effective and safe in the prevention of VTE following major orthopedic surgery, they failed to show a favorable benefit-to-risk profile in hospitalized medical patients receiving extended anticoagulation beyond the hospital stay.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Half-Life; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Vitamin K

Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients.. We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed.. Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient=-0.46, p=0.01) and major bleeding (beta-coefficient=-0.30, p=0.02). Patients with an INR<2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR>3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p=0.04) and treated in the community (-7%, p<0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p=0.003) greater time.. Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.

Topics: Anticoagulants; Drug Monitoring; Hemorrhage; Humans; International Normalized Ratio; Treatment Outcome; Venous Thromboembolism; Vitamin K

To aid trialists, systematic reviewers and others, we evaluated the degree of standardisation of control measure reporting that has occurred in atrial fibrillation (AF) and venous thromboembolism (VTE) studies since 2000; and attempted to determine whether the prior recommendation of reporting ≥2 measures per study has been employed.. Systematic review.. We searched bibliographic databases (2000 to June 2013) to identify AF and VTE studies evaluating dose-adjusted vitamin K antagonists (VKAs) and reporting ≥1 control measure. The types of measures reported, proportion of studies reporting ≥2 measures and mean (±SD) number of measures per study were determined for all studies and compared between subgroups.. Through the use of a standardised data extraction tool, we independently extracted all data, with disagreements resolved by a separate investigator.. 148 studies were included, 57% of which reported ≥2 control measures (mean/study=2.13±1.36). The proportion of time spent in the target international normalised ratio range (TTR) was most commonly reported (79%), and was frequently accompanied by time above/below range (52%). AF studies more frequently reported ≥2 control measures compared with VTE studies (63% vs 37%; p=0.004), and reported a greater number of measures per study (mean=2.36 vs 1.53; p<0.001). Observational studies were more likely to provide ≥2 measures compared with randomised trials (76% vs 33%; p<0.001) and report a greater number of measures (mean=2.58 vs 1.63; p<0.001). More recent studies (2004-2013) reported ≥2 measures more often than older (2000-2003) studies (59% vs 35%; p=0.05) and reported more measures per study (mean=2.23 vs 1.48; p=0.02).. While TTR was often utilised, studies reported ≥2 measures of VKA control only about half of the time and lacked consistency in the types of measures reported. A trend towards studies reporting greater numbers of VKA control measures over time was observed over our review time horizon, particularly, with AF and observational studies.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Studies as Topic; Drug Monitoring; Humans; International Normalized Ratio; Venous Thromboembolism; Vitamin K

In the last 4 years, 6 phase 3 trials including a total of 27,023 patients with venous thromboembolism (VTE) compared a direct oral anticoagulant (DOAC) with vitamin K antagonists (VKAs). To aid the clinician in assessing the amount of information, we address frequently raised clinical questions in a review of combined trial results. We included the phase 3 trials that compared dabigatran etexilate, rivaroxaban, apixaban, or edoxaban with VKA therapy in patients with acute symptomatic VTE. Recurrent VTE occurred in 2.0% of DOAC recipients compared with 2.2% in VKA recipients (relative risk [RR] 0.90, 95% confidence interval [CI] 0.77-1.06). Treatment with a DOAC significantly reduced the risk of major bleeding (RR 0.61, 95% CI 0.45-0.83). In parallel, intracranial bleeding, fatal bleeding, and clinically relevant nonmajor bleeding occurred significantly less in DOAC recipients. The efficacy and safety of DOACs were consistent in patients with pulmonary embolism, deep venous thrombosis, a body weight ≥100 kg, moderate renal insufficiency, an age ≥75 years, and cancer. In conclusion, DOACs and VKAs have similar efficacy in the treatment of acute symptomatic VTE, a finding that is consistent in key clinical subgroups. Treatment with a DOAC significantly reduces the risks of major bleeding.

Topics: Acute Disease; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Thiophenes; Venous Thromboembolism; Vitamin K

Cancer increases the risk of thromboembolic events in patients including those receiving anticoagulation treatments.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.. We conducted a comprehensive search for studies of anticoagulation in cancer patients including 1. a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL Issue 12, 2012), MEDLINE, and EMBASE; 2. a handsearch of conference proceedings; 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. a search of clinicaltrials.gov for ongoing studies.. We included randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE.. Using a standardized data form, we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.. Of 9559 identified citations, 10 RCTs (11 reports) were eligible and reported data for 1981 patients with cancer. We excluded 14 studies in which patients with cancer constituted study subgroups, but did not report outcome data for them. Meta-analysis of seven RCTs comparing LMWH with VKA found no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). The remaining findings did not exclude a beneficial or harmful effect of LMWH compared with VKA for the outcomes of major bleeding (RR 1.07; 95% CI 0.52 to 2.19), minor bleeding (RR 0.89; 95% CI 0.51 to 1.55), or thrombocytopenia (RR 0.98; 95% CI 0.57 to 1.66). We judged the quality of evidence as low for mortality, major bleeding, and minor bleeding, and as moderate for recurrent VTE.One RCT comparing dabigatran with VKA did not exclude beneficial or harmful effects of one agent over the other. One RCT comparing six months' extension of anticoagulation with 18 months of ximelagatran 24 mg twice daily versus no extended ximelagatran did not exclude beneficial or harmful effects for the outcomes of reduction in VTE, mortality, and minor bleeding. One RCT comparing once-weekly subcutaneous injection of idraparinux for three or six months versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) suggested a reduction in recurrent VTE (HR 0.39; 95% CI 0.14 to 1.11) at six months, but did not exclude beneficial or harmful effects for the outcomes of mortality (HR 0.99; 95% CI 0.66 to 1.48) and major bleeding (RR 1.04; 95% CI 0.39 to 2.83).. For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and harms and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oligosaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

The frequency and case fatality of venous thromboembolism (VTE) and major bleeding during the initial 3 months of therapy in those treated for symptomatic VTE with either direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA) are important clinically relevant outcomes. We sought to measure it during the initial months of anticoagulation for symptomatic VTE.. We searched MEDLINE, EMBASE, and CENTRAL to identify studies that enrolled patients with acute symptomatic VTE treated with DOACs or VKA and reported data on bleeding, VTE recurrence and death. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Single-proportion random-effects models were used to pool estimates.. Of the 2453 citations retrieved, 5 RCTs that enrolled 24,507 patients were included. The rate of major bleeding was 1.8 (95% CI: 1.3-2.5) and 3.1 (95% CI: 2.4-3.9) per 100 patient-years in DOAC and VKA arms, respectively. The rate of VTE recurrence was 3.7 (95% CI: 2.7-4.7) and 4.1 (95% CI: 3.0-5.4) per 100 patient-years of DOAC and VKA, respectively. The case fatality rate of bleeding was significantly higher in the VKA arms 10.4% (95% CI: 6.6-15.4) compared to DOACs 6.1% (95% CI: 2.7-11.7; p value for difference=0.029) with no statistical difference between the case fatalities for recurrent VTE. The rate of death from either definite major bleeding or definite recurrent VTE was 0.27 (95% CI: 0.16-0.40) and 0.46 (95% CI: 0.32-0.63) per 100 patient-years for DOACs and VKAs respectively, resulting in a number needed to treat of 875 for DOACs to prevent one death.. DOACs are attractive alternatives to VKAs for initial treatment of symptomatic VTE, with lower frequency and case fatality for major bleeding. However, the incremental safety benefit of DOACs over VKAs is small, with large numbers needed to treat.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Recurrence; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Warfarin, a vitamin K antagonist, is the most widely used oral anticoagulant in the world. It is cheap and effective, but its use is limited in many patients by unpredictable levels of anticoagulation, which increases the risk of thromboembolic or haemorrhagic complications. It also requires regular blood monitoring and dose adjustment. New classes of drugs, non-vitamin K antagonist oral anticoagulants (NOACs), are now supported as alternatives to warfarin. Three NOACs are licensed: dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, antagonists of factor Xa. NOACs do not require routine blood monitoring or dose adjustment. They have a rapid onset and offset of action and fewer food and drug interactions. Current indications include treatment and prophylaxis of venous thromboembolism and prevention of cardioembolic disease in non-valvular atrial fibrillation. Effective antidotes are lacking and some caution must be used in severe renal impairment, but favourable trial evidence has led to their widespread adoption. Research is ongoing, and an increase in their use and indications is expected in the coming years.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Drug Administration Schedule; Evidence-Based Medicine; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Venous Thromboembolism; Vitamin K; Warfarin

Venous thrombo-embolism is the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke. Recently published landmark trials paved the way for significant progress in the management of the disease and provided the evidence for the ESC Pulmonary Embolism (PE) Guidelines 2014 update. Risk stratification strategies for non-high-risk PE continue to evolve, with an increasing emphasis on clinical prediction rules and right ventricular (RV) assessment on computed tomographic pulmonary angiography. In the field of anticoagulation treatment, pharmacogenetic testing for vitamin K antagonists on top of clinical parameters was not found to offer a significant benefit during the initiation phase; on the other hand, dosing based on the patient's clinical data seems superior to fixed loading regimens. The phase 3 trial programme of new oral anticoagulants in the treatment of venous thrombo-embolism has been completed, and the results indicate that these agents are at least as effective and probably cause less major bleeding than currently standard treatment. A multicentre prospective phase 4 trial will determine whether early discharge and out-of-hospital treatment of low-risk PE with the oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. For intermediate-risk PE defined on the basis of imaging tests and laboratory biomarkers, the bleeding risks of full-dose thrombolytic treatment appear too high to justify its use, unless clinical signs of haemodynamic decompensation appear. Patients in whom PE has resulted in chronic thrombo-embolic pulmonary hypertension and who are not suitable for pulmonary endarterectomy, may be expected to benefit from emerging pharmaceutical and interventional treatment options.

Topics: Administration, Oral; Algorithms; Ambulatory Care; Anticoagulants; Biomarkers; Chronic Disease; Clinical Trials as Topic; Diagnostic Imaging; Early Diagnosis; Humans; Long-Term Care; Pulmonary Embolism; Risk Assessment; Thrombolytic Therapy; Venous Thromboembolism; Vitamin K

This study sought to investigate the relative efficacy and safety of non-vitamin K oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) in cancer patients.. A systematic search of the PubMed, EMBASE, and ClinicalTrials.gov databases identified all multicentre, randomised phase III trials investigating the initial use of NOAC against a vitamin K antagonist (VKA) together with subcutaneous heparin or low molecular weight heparin (upstart) for treatment of VTE. Outcomes of interest were recurrent VTE (deep venous thrombosis or pulmonary embolism), and clinically relevant bleeding.. Four randomised controlled phase III trials were included, comprising a total of 19,060 patients randomised to either NOAC or VKA. For patients with active cancer (N = 759), the analysis on the efficacy outcomes demonstrated a trend in favour of NOAC (OR 0.56, 95% CI 0.28-1.13). Similar, analyses on the safety outcomes comparing NOAC to VKA and enoxaparin demonstrated a trend in favour of NOAC (OR 0.88, 95% CI 0.57-1.35).. Point estimates of the effect size suggest an important estimated beneficial effect of NOAC in the treatment of VTE in cancer, in terms of efficacy and safety, but given the small numbers of patients with cancer in the randomised trials, statistical significance was not achieved.

Topics: Administration, Oral; Anticoagulants; Clinical Trials, Phase III as Topic; Enoxaparin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Before the advent of oral, targeted anticoagulants, physicians had no choice regarding the type of oral anticoagulant prescribed, as every patient received warfarin. The new oral direct thrombin and factor Xa inhibitors give the prescribing physician, as well as the patient, greater choice. Variation in dosing, half-life, elimination, monitoring, and reversal will help the clinician decide on the appropriate anticoagulant for the appropriate patient. Rather than replace warfarin, each anticoagulant will now have a particular niche, and the decision of which agent to prescribe will be determined at the bedside.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Drug Monitoring; Factor Xa Inhibitors; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Medication Adherence; Orthopedic Procedures; Partial Thromboplastin Time; Polysaccharides; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K; Warfarin

In recent years, the significant limitations associated with the use of vitamin K antagonists (VKA) have encouraged the development of new agents. Based upon the central roles played by the serine proteases thrombin and Factor Xa in the blood coagulation cascade, direct thrombin inhibitors and direct Factor Xa inhibitors have been developed. These agents, which include the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitors rivaroxaban and idrabiotaparinux are free from many of the limitations of VKAs. According to the results of available phase III randomized clinical trials, both dabigatran and rivaroxaban are effective and safe enough to qualify as ideal oral anticoagulants for the initial and long-term treatment of patients with acute venous thromboembolism (VTE). Rivaroxaban does not require an initial parenteral treatment and can be given in once daily administrations after the first three weeks. Both of them have limitations for the treatment of patients with severe renal failure, and require further investigations in cancer patients and in pregnant patients with VTE. Both of them lack an antidote.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; Biotin; Dabigatran; Humans; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Thiazoles; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Atrial Fibrillation; Humans; Pulmonary Embolism; Stroke; Venous Thromboembolism; Venous Thrombosis; Vitamin K

To review novel oral anticoagulant (NOAC) trials in the treatment of venous thromboembolism (VTE) and the possible use of risk-stratification tools to guide their use in practice.. MEDLINE and Cochrane databases were searched to identify relevant journal articles published from January 1982 to February 2013. Additional references were obtained from articles extracted during the database search.. NOACs have been developed to optimize VTE management and overcome the limitations of heparin and vitamin K antagonists (VKA). The AMPLIFY and EINSTEIN trials of apixaban and rivaroxaban, respectively, investigated single-drug management of VTE, whereas the edoxaban Hokusai-VTE trial and dabigatran RE-COVER and RE-COVER II trials investigated the use of NOACs with a heparin lead-in. The AMPLIFY and Hokusai-VTE trials are ongoing but the EINSTEIN and RE-COVER trials have demonstrated that rivaroxaban and dabigatran, respectively, are non-inferior to parenteral anticoagulants and warfarin in the management of VTE. Differences in study design complicate the application of study results to clinical practice. There are multiple validated DVT protocols that effectively and safely treat patients in outpatient settings. The pulmonary embolism (PE) severity index (PESI), simplified PESI (sPESI), and other prognostic tools have been used to risk stratify patients with PE by estimating mortality risk to guide outpatient eligibility.. NOACs provide physicians with new therapeutic options in the management of VTE. While heparin and VKAs compose the current standard treatment for VTE, their use will likely disappear as physicians grow comfortable with the adoption of NOACs. As studies have not clearly defined the efficacy of these agents in certain patient populations, further data in special patient populations and risk stratification through the use of VTE severity scores could potentially be adapted to guide anticoagulant management and outpatient treatment eligibility.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor X; Heparin; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

The new oral anticoagulants (NOACs) dabigatran etexilate, rivaroxaban, and apixaban have been extensively studied for prevention and treatment of venous thromboembolic disease and for stroke prevention in atrial fibrillation. Elderly patients have the highest incidence of thrombotic complications but also have the highest risk of anticoagulant associated bleeding. In this review we critically examine the balance between risks and benefits of NOACs compared with vitamin K antagonists in elderly patients enrolled in phase 3 randomized controlled trials for the management of venous thrombosis and stroke prevention in atrial fibrillation. Results show that the favourable balance between risks and benefits of NOACs is preserved in the elderly population.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Administration Schedule; Humans; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism.. Systematic review and network meta-analysis.. Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand.. Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms.. 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available.. All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

Topics: Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K

Vitamin K antagonists, such as warfarin, have been the mainstay in treatment and prophylaxis of venous thromboembolism. However, warfarin has many disadvantages including a narrow therapeutic window, numerous potential drug interactions, modulation of effect by alcohol and foods containing vitamin K and genetic variation in metabolism of warfarin, all of which contribute to the unpredictability of therapy. This has provided the impetus for developing new oral anticoagulants with a rapid onset of action, wide therapeutic window, predictable and reversible action, with few drug or dietary interactions, no requirement for routine coagulation monitoring or dose adjustment and acceptable cost. No single agent incorporates all these characteristics, but new factor Xa and direct thrombin inhibitors are being introduced into clinical practice that fulfil some of these aims. Here, we briefly discuss the current practice with its limitations and pitfalls, and then review important trials that have launched new oral anticoagulants into clinical practice.

Topics: Anticoagulants; Antithrombins; Factor Xa; Humans; Practice Patterns, Physicians'; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

The availability of new oral anticoagulants (NOACs) targeting either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban) for the prevention and treatment of thrombosis has been highly anticipated. NOACs have major pharmacologic advantages over vitamin K antagonists (eg, warfarin), including rapid onset/offset of action, few drug interactions, and predictable pharmacokinetics, eliminating the requirement for regular coagulation monitoring. Regulatory agencies have approved several NOACs for specific indications based on the results of clinical trials demonstrating efficacy and safety that are at least as good, if not better, than warfarin (for stroke prevention in atrial fibrillation and treatment and secondary prevention of venous thromboembolism) or low-molecular-weight heparin, which is injectable (for initial treatment of venous thromboembolism and thromboprophylaxis in patients undergoing hip or knee arthroplasty). However, the adoption of this new therapeutic class into clinical practice has been slower than expected due to several factors including concerns regarding medication adherence without laboratory monitoring, uncertainty about dosing in some patient populations (eg, renal dysfunction, marked extremes of body weight), and higher drug costs compared with warfarin. Other issues are the current absence of specific antidotes for NOACs and assays to measure drug levels at most centers. The indications for NOACs on the market will expand and at least one additional agent (edoxaban) will likely gain approval within the next 2 years. As practitioners gain familiarity with the drugs and healthcare systems adapt to their use, NOAC use will increase substantially over time. Warfarin, however, will continue to be an appropriate anticoagulant choice for many patients.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Stroke; Thrombin; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a major public health concern since the incidence of VTE rises substantially with age. Furthermore, the diagnosis can be elusive since patients can present differently, causing delay in diagnosis and initiation of treatment and resulting in major morbidity and mortality. In addition to accuracy and precision in diagnosis, antithrombotic therapies are the cornerstones of VTE management. In traditional paradigm, vitamin K antagonists (warfarin), indirect factor Xa inhibitors, and heparin are the foundation in management of VTE. Warfarin has been the only available oral anticoagulant therapy for several decades. Although warfarin is effective in both treatment and prophylaxis against VTE, there are several limitations. Therefore, the novel anticoagulation therapies, including rivaroxaban, apixaban, and dabigatran etexilate, have apparent advantages over warfarin in terms of clinical efficacy and adverse effects. The objective of this review is to describe the background and clinical implications of these novel anticoagulants.

Topics: Acute Coronary Syndrome; Administration, Oral; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) and atrial fibrillation are common conditions in Western countries. The mainstay of treatment and prevention for these diseases is fast-acting anticoagulant drugs such as heparins and vitamin K antagonists. The use of these drugs is, however, complex and demanding for both patients and physicians. Recently, new antithrombotic drugs that act directly by inhibiting activated coagulation factors such as factor X or thrombin have been developed and investigated in phase III clinical trials. The aim of this article is to review: (i) the need to develop new drugs; (ii) their efficacy/safety as demonstrated in clinical trials; (iii) the need for laboratory monitoring and (iv) the direction towards the use of these new drugs in the real-life clinical situation.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Dabigatran; Drugs, Investigational; Heparin; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

In patients with unprovoked venous thromboembolism (VTE), the optimal duration of anticoagulation is anchored on estimating the risk of disease recurrence.. We aimed to develop a score that could predict the recurrence risk following a first episode of unprovoked VTE, pooling individual patient data from seven prospective studies.. One thousand eight hundred and eighteen cases with unprovoked VTE treated for at least 3 months with a vitamin K antagonist were available for analysis. Optimism-corrected Cox regression coefficients were used to develop a recurrence score that was subsequently internally validated by bootstrap analysis.. Abnormal D-dimer after stopping anticoagulation, age <50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence and were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy) showing a satisfactory predictive capability (ROC area =0.71). The annualized recurrence risk was 3.1% (95% confidence interval [CI], 2.3-3.9) for a score ≤ 1, 6.4% (95% CI, 4.8-7.9) for a score=2 and 12.3% (95% CI, 9.9-14.7) for a score ≥ 3. By considering at low recurrence risk those patients with a score ≤ 1, life-long anticoagulation might be avoided in about half of patients with unprovoked VTE.. The DASH prediction rule appears to predict recurrence risk in patients with a first unprovoked VTE and may be useful to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at least 3 months.

Topics: Adolescent; Adult; Age Factors; Aged; Anticoagulants; Biomarkers; Contraceptives, Oral, Hormonal; Decision Support Techniques; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Hormone Replacement Therapy; Humans; Male; Middle Aged; Patient Selection; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

Secondary prevention of venous thromboembolism in antiphospholipid syndrome (APS) is usually made using vitamin K antagonists (VKAs) to maintain an international normalized ratio (INR) between 2.0 and 3.0. The optimal intensity of anticoagulation was determined in two prospective randomized controlled trials, both excluding the benefit of more intense anticoagulation. The same regimen is also recommended in patients with APS and arterial thromboembolism as aspirin does not appear to protect against recurrences. The duration of treatment is usually indefinite because of a substantial risk of recurrence.

Topics: Antiphospholipid Syndrome; Humans; Randomized Controlled Trials as Topic; Secondary Prevention; Venous Thromboembolism; Vitamin K

Low molecular weight heparins (LMWHs) and vitamin K antagonists make up the cornerstone of therapy for patients with venous thromboembolism (VTE) but have drawbacks making their use difficult in daily practice. Current research focuses on the development of new anticoagulant drugs that could be administered orally at a fixed dose, with fewer food and drug interactions and no need for monitoring or dose adjustment. Several new drugs are tested in noninferiority trials, either as a single-drug approach treatment (e.g., rivaroxaban or apixaban), or after an initial course of LMWH (e.g., dabigatran or edoxaban). Published clinical trials demonstrate that rivaroxaban and dabigatran are noninferior to conventional treatment in patients with VTE. Several issues remain challenging for physicians, such as the lack of antidote and of routinely available monitoring tests. To what extent new anticoagulant drugs will change clinical practice is not yet well defined. They may facilitate outpatient management of VTE. They might also improve the risk-benefit balance of prolonged anticoagulation and therefore modify the optimal duration of anticoagulation in VTE patients.

Topics: Administration, Oral; Anticoagulants; Drug Administration Schedule; Drug Design; Drug Interactions; Drug Monitoring; Food-Drug Interactions; Heparin, Low-Molecular-Weight; Humans; Time Factors; Venous Thromboembolism; Vitamin K

Due to its specific pharmacokinetic profile, tinzaparin, a low-molecular-weight heparin (LMWH), appears not to be associated with anti-factor Xa accumulation. Our meta-analysis aimed at determining whether long-term curative doses of tinzaparin is a valuable alternative to vitamin K antagonists (VKA) for the treatment of symptomatic venous thromboembolism (VTE), especially in patients with cancer who are at higher risk of recurrence and bleeding.. A systematic literature search identified randomized studies on long-term tinzaparin compared to VKA in patients with VTE. Outcome measures were VTE recurrence, major bleeding, deaths and net clinical benefit combining the three endpoints during the treatment period and at one year. Pooled relative risk was estimated using the logarithm of the relative risk (RR) method based on a fixed-effect model in the overall population and cancer population.. Five randomized controlled studies were eligible. No difference between groups in VTE recurrence was found in the overall population (RR=0.85 [0.55; 1.31]). In cancer patients, a non-significant 38% VTE risk reduction in favor of tinzaparin was observed on treatment (RR=0.62 [0.30; 1.31]). The difference was significant at the end of follow-up at one year (RR=0.40 [0.19; 0.82], p<0.01). The incidence of major bleeding in the tinzaparin group was not significantly different from the VKA group in the overall population and cancer patients.. Tinzaparin appears as a valuable option for long-term treatment of patients in whom VKA are contraindicated or difficult to monitor. Tinzaparin may have a more favorable benefit-risk ratio than VKA in patients with cancer and VTE.

Topics: Adult; Aged; Aged, 80 and over; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

The past decade has witnessed important advances in the diagnosis and treatment of venous thromboembolism with excellent opportunities to apply evidence-based medicine for many of the steps in the management of the disease. This review discusses the clinical prediction rules that should be used to reduce utilization of imaging diagnosis for deep vein thrombosis or pulmonary embolism and the risk stratification for thrombolytic therapy or outpatient management of pulmonary embolism. The treatment options have increased and include low-molecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin - the latter either monitored or not monitored, fondaparinux and rivaroxaban for the initial phase. Thereafter, vitamin K antagonists (VKAs), LMWH, oral factor Xa or thrombin inhibitors are or will soon become available. The VKAs have been subjected to many randomised trial addressing the initiation, intensity, monitoring and self-management. Extended anticoagulation and the selection for that is finally reviewed.

Topics: Anticoagulants; Antithrombins; Clinical Trials as Topic; Diagnostic Imaging; Disease Management; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Morpholines; Radiography; Risk; Rivaroxaban; Thiophenes; Thrombin; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

This review summarizes the current knowledge of the epidemiology, prophylaxis, and treatment of venous thromboembolism (VTE) in patients with lymphoma, multiple myeloma or acute leukemia.. Hematologic malignancies are associated with a high risk of thrombotic complications. The incidence of these events is greatly variable and is influenced by many factors, including the type and the stage of disease, antitumor therapies, and the use of central venous device (CVD). Epidemiological data allow an estimate of the incidence of VTE in acute leukemia, lymphomas, and multiple myeloma. The effect of chemotherapy on the incidence of thrombosis is particularly evident in acute leukemia as it causes the exacerbation of the clotting/bleeding syndrome typical of this disease. The role of chemotherapy is also relevant in lymphoma, and in multiple myeloma, in which the use of immunomodulating agents, in combination with chemotherapy and steroids significantly increases the risk of VTE.. Thrombotic complications have a significant impact on morbidity and mortality of hematological cancer patients, therefore, in this setting, the issue of thromboprophylaxis to prevent VTE is important. However, no clear recommendation in these conditions is available, with the exception of multiple myeloma. Large prospective randomized clinical trials are needed to establish the best practice for prevention and treatment of VTE in these types of malignant diseases.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Incidence; Leukemia; Lymphoma; Multiple Myeloma; Platelet Transfusion; Venous Thromboembolism; Vitamin K

The percentage of time within the target INR range 2.0 to 3.0 (TTR) in patients treated with vitamin K antagonists varies considerably among efficacy-studies of novel anticoagulants. In order to properly asses the quality of anticoagulant control in upcoming cost-effectiveness studies and real life registries this systematic review reports a benchmark of TTR for different treatment durations in patients with venous thromboembolism and discusses ways to calculate TTR.. Medline and Embase were searched for studies published between January 1990 and May 2012. Randomized controlled trials and cohort studies reporting the TTR in patients with objectively confirmed venous thromboembolism treated with vitamin K antagonists (VKA) were eligible. Duplicate reports, studies only reporting INR during initial treatment or with VKA treatment less than 3 months were excluded. Three authors assessed trials for inclusion and extracted data independently. Discrepancies were resolved by discussion between the reviewers. A meta-analysis was performed by calculating a weighted mean, based on the number of participants in each included study, for each time-period in which the TTR was measured since the confirmation of the diagnosis of VTE.. Forty studies were included (26064 patients). The weighted means of TTR were 54.0% in the first month since the start of treatment, 55.6% in months 1 to 3, 60.0% in months 2 to 3, 60.0% in the months 1 to 6+ and 75.2% in months 4 to 12+. Five studies reported TTR in classes. The INR in these studies was ≥ 67% of time in therapeutic range in 72.0% of the patients.. Reported quality of VKA treatment is highly dependent on the time-period since the start of treatment, with TTR ranging from approximately 56% in studies including the 1(st) month to 75% in studies excluding the first 3 months.

Topics: Anticoagulants; Benchmarking; Cost-Benefit Analysis; Databases, Bibliographic; Disease Management; Humans; International Normalized Ratio; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

People with venous thromboembolism (VTE) are generally treated for five days with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (LMWH) followed by three months of vitamin K antagonist treatment. Treatment with vitamin K antagonists requires regular laboratory measurements and some patients have contraindications to treatment. This is an update of a review first published in 2000 and updated in 2002.. To evaluate the efficacy and safety of long term treatment of VTE with LMWH compared to vitamin K antagonists.. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched their Specialised Register (last searched February 2012) and CENTRAL (2012, Issue 1).. Two authors evaluated trials independently for methodological quality.. The review authors extracted data independently. Primary analysis included all trial participants randomised to the allocated treatment groups. Separate analyses were performed according to the quality of the trials and for subgroups such as trials initially using similar treatments in both trial arms and those that did not, trials concerning deep vein thrombosis (DVT) and pulmonary embolism (PE) and the different periods of follow-up.. All 15 trials, with a combined total of 3197 patients, fulfilling our criteria were combined in a meta-analysis. We found a non-statistically significant reduction in the risk of recurrent VTE between the two treatments (odds ratio (OR) 0.82, 95% CI 0.59 to 1.13). Analysis of pooled data for category I trials (those with a high methodological quality) showed a non-significant reduction in the odds of recurrent VTE favouring LMWH treatment (OR 0.80, 95% CI 0.54 to 1.18).For all trials combined, the difference in bleeding significantly favoured treatment with LMWH (OR 0.50, 95% CI 0.31 to 0.79). Considering only category I trials, a non-significant trend favouring LMWH remained (OR 0.62, 95% CI 0.36 to 1.07). No difference was observed in mortality (OR 1.06, 95% CI 0.74 to 1.54).. LMWHs are possibly as effective as vitamin K antagonists in preventing symptomatic VTE after an episode of symptomatic deep venous thrombosis, but are much more expensive. Treatment with LMWH is significantly safer than treatment with vitamin K antagonists. LMWH may result in fewer episodes of bleeding and is possibly a safe alternative in some patients, especially those in geographically inaccessible areas, are reluctant to visit the thrombosis service regularly, or with contraindications to vitamin K antagonists. However, treatment with vitamin K antagonists remains the treatment of choice for the majority of patients.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Odds Ratio; Randomized Controlled Trials as Topic; Venous Thromboembolism; Venous Thrombosis; Vitamin K

For patients with an acute episode of venous thromboembolism (VTE), the optimal starting time of long-term therapy with vitamin K antagonists (VKA) and how much overlap should occur with heparin are unclear and the current guidelines and practice are not based on high-quality data. The objective of this study was to perform a meta-analysis on the evidence comparing early versus late initiation of VKA on the effectiveness and safety of anticoagulation. We searched for randomized controlled trials in Medline, EMBASE, Cochrane CENTRAL, IPA and ClinicalTrials.gov. Studies were included if they compared early initiation of VKA (within approximately 24 h) and late initiation (>4 days) of the onset of heparin therapy. Data were pooled using the Review Manager 5 software and the quality of evidence was appraised with Grading of Recommendations, Assessment, Development and Evaluation profiler. Five studies were included in the review, with a total of 840 patients. Meta-analysis of recurrence of VTE, death and major bleeding revealed no significant differences between the two treatment regimens. Minor bleeding [RR 0.65, 95% confidence interval (CI) 0.43-0.98] and hospital stay (mean difference 3.92 days, 95% CI -4.57 to -3.28) were reduced in the early VKA group (P < 0.05). The quality of evidence for each outcome except hospital stay was low. Results from this meta-analysis favour the early start of VKA (within 24 h of the initiation of heparin) based on minor bleeding and resource utilization. However, these results should be interpreted with caution, as the quality and quantity of evidence is limited.

Topics: Anticoagulants; Blood Coagulation; Early Medical Intervention; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Randomized Controlled Trials as Topic; Secondary Prevention; Survival Rate; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

The therapeutic management of catheter-related thromboembolic events in children is still a challenge due to the large number of potentially effective pharmacological alternatives and the insufficient scientific evidence available. A bibliographic review was performed in order to identify the available pharmacological alternatives for the prophylaxis and therapeutic management of catheter-related thrombosis in children.. A literature search was carried out on MEDLINE using the medical subject heading (MeSH) central venous catheter thrombosis and on Google Scholar. The search was limited to review papers, meta-analyses, clinical practice guidelines, and randomized controlled trials performed on pediatric populations until November 2011.. The different options for anticoagulation include unfractionated heparin, low molecular weight heparin and vitamin K antagonists. Thrombus resolution is stimulated more rapidly with thrombolytic agents than with anticoagulants, but the risk-benefit ratio must be considered. Streptokinase is not considered an optimal alternative due to the risk of anaphylactic reactions and has been replaced by urokinase, alteplase or the newer reteplase. Preventive strategies have been considered and most centers have protocols for routine flushing of the catheter with heparin or normal saline. Intraluminal application of urokinase and alteplase has also been studied.. The wide range of options available for the pharmacotherapeutic management of catheter-related thromboembolism in children and the lack of strong evidence on the comparative efficacy and safety of the different therapeutic options, make its positioning rather difficult. Randomized controlled trials and national plans should be set up urgently.

Topics: Anticoagulants; Catheterization, Central Venous; Child; Fibrinolytic Agents; Humans; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Traditional therapeutic oral anticoagulation strategies often require invasive dosing or monitoring. Vitamin K antagonists (VKAs) have a large number of interactions, delayed onset requires frequent dose monitoring, and they have a small margin between therapeutic dose and bleeding complications. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, are being developed to prevent those VKAs drawbacks. Besides oral bioavailability, those compounds are designed to require minimal to no monitoring and have a favourable safety profile. This review reports efficacy and safety data of these compounds throughout clinical development, as well as new approaches for oral pharmacological management of venous thromboembolism.

Topics: Administration, Oral; Animals; Anticoagulants; Biological Availability; Humans; Monitoring, Physiologic; Venous Thromboembolism; Vitamin K

the development of venous thromboembolism (VTE) in patients with cancer adversely affects their prognosis. Several autopsy- and population-based studies have clearly shown a negative impact of VTE on patient outcome in cancer patients.. an up-to-date review of VTE prophylaxis and treatment in cancer patients is provided with some insights on areas of uncertainty to be answered in the near future. Particular attention is paid to recent cohort studies, randomized clinical trials and consensus guidelines.. cancer patients at a higher risk for VTE may be identified with five variables easily available before initiation of chemotherapy. Long-term treatment with low-molecular-weight heparin (LMWH) demonstrated a superior efficacy over vitamin K antagonists. The intensity and duration of anticoagulant therapy should be tailored to the risk of VTE recurrences or bleeding in an individual patient.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Prognosis; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is associated with a long term risk of recurrence. This risk is at least in part related to the presence of major identifiable risk factors at the time of the index event. It is generally low in the presence of removable risk factors, and very high in the presence of permanent risk factors such as active cancer. This categorization is important because it drives the duration of secondary prevention treatment with anticoagulant drugs. Unfortunately, up to 40-50% of VTE events remain classified as unprovoked. This large group of patients is obviously heterogeneous, with an unpredictable risk of recurrence. Evidences from clinical trials suggest that extending secondary prevention with vitamin K antagonists (VKAs) for 1 or 2 years after an initial course of treatment in patients with unprovoked VTE does not provide additional benefit in terms of reducing the long term risk of recurrence. Prolonging indefinitely the duration of treatment would likely be effective in reducing this risk, but at the cost of unnecessarily expose the majority of patients to several complications, there including major bleeding events, and inconveniences. A number of variables have been identified to predict the individual risk of recurrence in these patients and some clinical prediction rules have been proposed. Improved patients stratification, together with a better understanding of the mechanisms underlying unprovoked VTE, should allow physicians to individually tailor the optimal duration of secondary prevention and to identify those patients (likely the minority) for whom indefinite duration of treatment is warranted.

Topics: Anticoagulants; Clinical Trials as Topic; Humans; Neoplasms; Recurrence; Risk Factors; Venous Thromboembolism; Vitamin K

About half of patients with a first unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) will have a recurrent venous thromboembolism (VTE) within 10 years if they stop treatment, and randomized trials have shown clear benefit from extended anticoagulant therapy in these patients. Although the risk of recurrence varies among patients with a first unprovoked proximal DVT or PE, and a number of factors can identify patients with a lower risk of recurrence, the safety of routinely stopping anticoagulant therapy based on the presence of these factors needs to be established in prospective studies before this is done in clinical practice. As isolated distal DVT is associated with about half the risk of recurrence of proximal DVT or PE, a first episode of unprovoked distal DVT does not justify extended anticoagulation. High risk for bleeding, and patient preference, are good reasons not to treat unprovoked proximal DVT or PE indefinitely. New anticoagulants, because they are easier to use and may be associated with less bleeding that vitamin K antagonists, have the potential to increase the proportion of patients with unprovoked VTE who are candidates for extended anticoagulant therapy.

Topics: Anticoagulants; Hemorrhage; Humans; Pulmonary Embolism; Recurrence; Time Factors; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet-drug interactions, and has fewer clinically significant drug-drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Interactions; Heparinoids; Humans; Pulmonary Embolism; Pyridines; Stroke; Venous Thromboembolism; Vitamin K

Deep vein thrombosis and pulmonary embolism-the components of venous thromboembolism (VTE)-are significant causes of morbidity and mortality and are a major burden on US healthcare systems. Current VTE prevention strategies are often suboptimal after total hip or total knee arthroplasty, possibly due to drawbacks of the established anticoagulants, resulting in residual VTE and associated (or related) costs of care. New anticoagulant agents under development may address some of the limitations of current options and possibly increase adherence to guidelines for thromboprophylaxis. This article will review the characteristics of the new oral anticoagulants, which may potentially translate into cost savings for the healthcare system.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Cost Savings; Dabigatran; Health Care Costs; Humans; Medication Adherence; Morpholines; Rivaroxaban; Thiophenes; United States; Venous Thromboembolism; Vitamin K

Cancer increases the risk of thromboembolic events even while on anticoagulation.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science.. Randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively-confirmed VTE.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.. Of 8187 identified citations, nine RCTs were eligible and reported data for 1908 patients with cancer. Meta-analysis of seven RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). Other results did not exclude a beneficial or harmful effect of LMWH compared to VKA for the outcomes of major bleeding (RR 1.05; 95% CI 0.53 to 2.10) or thrombocytopenia (RR 1.02; 95% CI 0.60 to 1.74). The quality of evidence was low for mortality, major bleeding and minor bleeding and moderate for recurrent VTE. One RCT comparing six months extension of anticoagulation with 18 months ximelagatran 24 mg twice daily versus placebo found a reduction in VTE (HR 0.16; 95% CI 0.09 to 0.30) but did not exclude beneficial or harmful effects for the outcomes of mortality and bleeding. One RCT, comparing dabigatran to VKA, did not exclude beneficial or harmful effect of one agent over the other.. For the long-term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

The risk of venous thromboembolic events (VTE) in cancer patients is higher than in the general population. Treatment may also increase this risk in these patients. Based on the appropriate criteria (of which the most important are the current ministerial guidelines) thrombosis prophylaxis should be started (given that there is no contraindication) on these patients and be continued while they are at risk. In the event of permanent risk thrombosis prophylaxis should be given lifelong. The drug of choice is low-molecular-weight heparin (LMWH) which is safer and more effective than the oral vitamin K antagonists. Platelet aggregation inhibitors have proved unsuccessful in this patient group. The evidence so far suggests that LMWH (during VTE prophylaxis) can have a positive impact on the course of cancer and perhaps it will be registered under the indication section for cancer patients in the future.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Assessment; Risk Factors; Thromboembolism; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Anticoagulant prophylaxis for preventing venous thrombembolism (VTE) is a worldwide established procedure in hip (HR) and knee replacement (KR) surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Hemostasis and Thrombosis, the Italian Society of Orthopedics and Traumatology, the association of Orthopedic Traumatology of Italian Hospitals, together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care have set down easy and quick suggestions for VTE prophylaxis in HR and KR surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and thus at improving its proper application. Special focus is given to fragile patients, those with high bleeding risk, and on those receiving chronic antiplatelet and vitamin K antagonists treatment. A special chapter is dedicated to regional anesthesia and VTE prophylaxis.

Topics: Anesthesia; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Consensus; Femoral Neck Fractures; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Patient Safety; Polysaccharides; Postoperative Complications; Postoperative Hemorrhage; Risk; Stockings, Compression; Thrombosis; Venous Thromboembolism; Vitamin K

Dabigatran is an oral direct thrombin inhibitor with a rapid onset. Patients on dabigatran do not require coagulation monitoring. Recent prospective randomized trials have shown the efficacy of dabigatran for the prevention of venous thromboembolism after knee or hip arthroplasty and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Because dabigatran is cleared principally by the kidneys, dosage adjustments are required in the setting of renal dysfunction. There currently is no reversal agent for dabigatran although hemodialysis can facilitate its rapid removal in life-threatening circumstances. The management of severe bleeding associated with dabigatran also may include the administration of a procoagulant, such as recombinant activated factor VII. Based on recent guidelines, regional anesthesia should be used cautiously in patients taking this novel oral thrombin inhibitor.

Topics: Anesthesia, Conduction; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Chemistry, Pharmaceutical; Dabigatran; Fondaparinux; Heart Valve Prosthesis Implantation; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Randomized Controlled Trials as Topic; Thrombin; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Infusions, Intravenous; Injections, Subcutaneous; Long-Term Care; Neoplasms; Patient Acceptance of Health Care; Randomized Controlled Trials as Topic; Secondary Prevention; Survival Analysis; Thrombin; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a major therapeutic issue in cancer patients. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines in the management of VTE in cancer patients according to the SOR (Standards, Options and Recommendations) methodology. A literature review of the studies published on this topic between 1999 and 2007 was performed. The guidelines were developed from the analysis of 38 out of 418 publications selected. They were peer-reviewed by 65 independent experts. The treatment of VTE in patients with cancer, including those with intracranial malignancies, should be based on low-molecular-weight heparins administered at therapeutic doses for at least 3 months. In the event of recurrent VTE, pulmonary embolism with hemodynamic failure or contra-indication to anticoagulant treatment, the indications and usages of vena cava filters and thrombolytic drugs should be the same as in non-cancer patients.

Topics: Antineoplastic Agents; France; Heparin; Humans; Neoplasms; Practice Guidelines as Topic; Venous Thromboembolism; Vitamin K

We evaluated whether the incidence of recurrent venous thromboembolic events (VTEs) during and after therapy differs for patients treated with full or reduced doses of low-molecular-weight heparin (LMWH) used long term compared with vitamin K antagonists (VKAs).. We identified randomized studies of long-term treatment with LMWH or VKA by searching MEDLINE, EMBASE, BIOSIS, and PASCAL. Seventeen studies were included, with 4,002 patients.. In the assessment at 12 months of 1,957 patients without cancer, the recurrence rates of VTE in the LMWH/VKA groups were 8.3%/7.6% in the studies using full doses and 12.3%/12.1% in those using prophylactic doses. However, combined analysis after treatment to 1 year showed a nonsignificant (NS) trend to lower recurrent symptomatic VTE in favor of VKA (RR = 1.46, 95% CI 0.96-2.23). In 1,292 patients with cancer the recurrence rates of VTE in the LMWH/VKA groups were 6.5%/17.9% (p = 0.005) in the studies using full doses, 7.1%/13.4% (p = 0.002) in the studies using intermediate doses, and 14.3%/19.1% (p = NS) in the studies using prophylactic doses. Furthermore, the recurrences of VTE after discontinuation of treatment in the LMWH/VKA groups were 1.6%/9.5% (RR = 0.25, 95% CI 0.06-1.1) in 252 patients with full doses and 12%/7.4% (RR = 1.49, 95% CI 0.3-7.48) in 52 patients with prophylactic doses. In this population with cancer, the full-treatment LMWH regimen did not produce more major bleeding events than intermediate or prophylactic doses (5.1% vs. 6.3% or 8.1%, respectively).. Full-dose LMWH for 3-6 months is as safe as intermediate and prophylactic doses for the long-term treatment of deep vein thrombosis. In patients with cancer it appears that there is an excess of VTE recurrence after treatment with prophylactic doses that does not occur with full therapeutic doses.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Evidence-Based Medicine; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Current evidence-based guidelines provide recommendations for prophylaxis and treatment of venous thromboembolism (VTE) in a variety of surgical patients.. A systematic Ovid Medline search (from 1950 to the present) was conducted for relevant articles using the following search terms: "venous thromboembolism," "thrombophlebitis," "thromboembolism," "pulmonary embolism," "heparin," "low-molecular-weight heparin," "postoperative complications," and "anticoagulants.". Pharmacologic and mechanical approaches are available for VTE prophylaxis, including low-dose unfractionated heparin, low-molecular-weight heparin, vitamin K antagonists, fondaparinux, intermittent pneumatic compression devices, and graduated compression stockings. Permanent inferior vena cava filters are not recommended for primary VTE prophylaxis, although they do have a role in the prevention of pulmonary embolism in patients with recent VTE who cannot have surgery delayed. Retrievable inferior vena cava filters are under investigation for primary VTE prophylaxis in trauma patients. New anticoagulants that inhibit factor Xa and thrombin will soon be available for the prevention and treatment of VTE in surgical patients.

Topics: Anticoagulants; Contraindications; Heparin; Humans; Intermittent Pneumatic Compression Devices; Patient Care Team; Postoperative Complications; Practice Guidelines as Topic; Renal Insufficiency; Risk Factors; Stockings, Compression; Surgical Procedures, Operative; Venous Thromboembolism; Vitamin K

Patients who have undergone total hip or knee replacement (THR, TKR) have a high risk of developing venous thromboembolism (VTE) following surgery, despite appropriate anticoagulation with warfarin or low molecular weight heparin (LMWH). New anticoagulants are under investigation.. To examine the efficacy and safety of prophylactic anticoagulation with direct thrombin inhibitors (DTIs) versus LMWH or vitamin K antagonists in the prevention of VTE in patients undergoing THR or TKR.. The Cochrane Peripheral Vascular Disease Group searched their Specialized Register (last searched 12 March 2010) and CENTRAL (last searched 2010, Issue 2).. Randomised controlled trials.. Three reviewers independently assessed methodological quality and extracted data in pre-designed tables. The reported follow-up events were included. We included 14 studies included involving 21,642 patients evaluated for efficacy and 27,360 for safety. No difference was observed in major VTE in DTIs compared with LMWH in both types of operations (odds ratio (OR) 0.91; 95% confidence interval (CI) 0.69 to 1.19), with high heterogeneity (I(2) 71%). No difference was observed with warfarin (OR 0.85; 95% CI 0.63 to 1.15) in TKR, with no heterogeneity (I(2) 0%).More total bleeding events were observed in the DTI group (in ximelagatran and dabigatran but not in desirudin) in patients subjected to THR (OR 1.40; 95% CI 1.06, 1.85; I(2) 41%) compared with LMWH. No difference was observed with warfarin in TKR (OR 1.76; 95% CI 0.91 to 3.38; I(2) 0%). All-cause mortality was higher in the DTI group when the reported follow-up events were included (OR 2.06; 95% CI 1.10 to 3.87).Studies that initiated anticoagulation before surgery showed less VTE events; those that began anticoagulation after surgery showed more VTE events in comparison with LMWH. Therefore, the effect of the DTIs compared with LMWH appears to be influenced by the time of initiation of coagulation more than the effect of the drug itself.The results obtained from sensitivity analysis, did not differ from the analysed results; this strengthens the value of the results.. Direct thrombin inhibitors are as effective in the prevention of major venous thromboembolism in THR or TKR as LMWH and vitamin K antagonists. However, they show higher mortality and cause more bleeding than LMWH. No severe hepatic complications were reported in the analysed studies. Use of ximelagatran is not recommended for VTE prevention in patients who have undergone orthopedic surgery. More studies are necessary regarding dabigatran.

Topics: Anticoagulants; Antifibrinolytic Agents; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzimidazoles; Benzylamines; Contraindications; Dabigatran; Heparin, Low-Molecular-Weight; Humans; Pyridines; Randomized Controlled Trials as Topic; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Warfarin is a commonly used medication for the prevention and treatment of venous thromboembolism. It can be challenging for both the patient and the prescriber to manage at times.. To describe the mechanism of action of warfarin, and to discuss the indications for warfarinisation, the risks associated with warfarin use, and some of its drug interactions.. The common indications for warfarinisation are atrial fibrillation, venous thromboembolism and prosthetic heart valves. Contraindications include absolute and relative contraindications, and an individualised risk-benefit analyses is required for each patient. There are many interactions with warfarin, including pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions can be monitored by using International Normalised Ratio levels. Pharmacodynamic interactions require knowledge by the prescriber to predict any interactions with warfarin, and International Normalised Ratio monitoring assists.

Topics: Anticoagulants; Atrial Fibrillation; Cytochrome P-450 Enzyme System; Drug Interactions; Heart Valve Prosthesis; Humans; International Normalized Ratio; Risk Factors; Venous Thromboembolism; Vitamin K; Warfarin

Both prophylaxis and treatment of venous thromboembolism (VTE: deep venous thrombosis (DVT) and pulmonary emboli (PE)) with anticoagulants are associated with significant risks of major and fatal hemorrhage. Anticoagulation treatment of VTE has been the standard of care in the USA since before 1962 when the U.S. Food and Drug Administration began requiring randomized controlled clinical trials (RCTs) showing efficacy, so efficacy trials were never required for FDA approval. In clinical trials of 'high VTE risk' surgical patients before the 1980s, anticoagulant prophylaxis was clearly beneficial (fatal pulmonary emboli (FPE) without anticoagulants = 0.99%, FPE with anticoagulants = 0.31%). However, observational studies and RCTs of 'high VTE risk' surgical patients from the 1980s until 2010 show that FPE deaths without anticoagulants are about one-fourth the rate that occurs during prophylaxis with anticoagulants (FPE without anticoagulants = 0.023%, FPE while receiving anticoagulant prophylaxis = 0.10%). Additionally, an FPE rate of about 0.012% (35/28,400) in patients receiving prophylactic anticoagulants can be attributed to 'rebound hypercoagulation' in the two months after stopping anticoagulants. Alternatives to anticoagulant prophylaxis should be explored.. The literature concerning dietary influences on VTE incidence was reviewed. Hypotheses concerning the etiology of VTE were critiqued in relationship to the rationale for dietary versus anticoagulant approaches to prophylaxis and treatment.Epidemiological evidence suggests that a diet with ample fruits and vegetables and little meat may substantially reduce the risk of VTE; vegetarian, vegan, or Mediterranean diets favorably affect serum markers of hemostasis and inflammation. The valve cusp hypoxia hypothesis of DVT/VTE etiology is consistent with the development of VTE being affected directly or indirectly by diet. However, it is less consistent with the rationale of using anticoagulants as VTE prophylaxis. For both prophylaxis and treatment of VTE, we propose RCTs comparing standard anticoagulation with low VTE risk diets, and we discuss the statistical considerations for an example of such a trial.. Because of (a) the risks of biochemical anticoagulation as anti-VTE prophylaxis or treatment, (b) the lack of placebo-controlled efficacy data supporting anticoagulant treatment of VTE, (c) dramatically reduced hospital-acquired FPE incidence in surgical patients without anticoagulant prophylaxis from 1980 - 2010 relative to the 1960s and 1970s, and (d) evidence that VTE incidence and outcomes may be influenced by diet, randomized controlled non-inferiority clinical trials are proposed to compare standard anticoagulant treatment with potentially low VTE risk diets. We call upon the U. S. National Institutes of Health and the U.K. National Institute for Health and Clinical Excellence to design and fund those trials.

Topics: Animals; Anticoagulants; Diet; Fishes; Humans; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

For a majority of patients with venous thromboembolism (VTE), initial treatment is straightforward and necessitates the immediate initiation of a parenteral anticoagulant (eg, heparin or low molecular weight heparin), simultaneous initiation of long-term therapy (eg, vitamin K antagonist), and discontinuation of the parenteral anticoagulant after 5 days assuming that the vitamin K antagonist is therapeutic. This standardized approach is based on numerous pivotal clinical trials completed over the past 3 decades. Yet, advances in standardized VTE treatment continue to evolve and include issues related to the selection and dosing of parenteral anticoagulants (eg, relative efficacy and dosing in the obese patient, patients with renal impairment, and pregnant patients), optimal location of initial care delivery, use of dosing initiation nomograms for vitamin K antagonists with the potential of gene-based dosing, and demonstration that longterm low molecular weight heparin therapy may be optimal for some patient populations (eg, those with active cancer). Further, in parallel with the evolution of VTE treatment, there have been remarkable advances in our understanding of heparin-induced thrombocytopenia, a prothrombotic complication of parenteral anticoagulant use.

Topics: Heparin; Heparin, Low-Molecular-Weight; Humans; Thrombocytopenia; Venous Thromboembolism; Vitamin K; Warfarin

Patients with malignancy have a 4-fold increase in the risk of developing a venous thrombosis and a 3-fold increase in risk of bleeding. Both low-molecular-weight-heparin (LMWH) and vitamin K antagonists (VKA) have been used for treatment of cancer-associated thrombosis. However, the best anticoagulation approach remains a matter of debate.. In adult patients with cancer and an acute venous thromboembolic event we sought to determine the rates of recurrent venous thromboembolism (VTE) and major hemorrhage when treated with prolonged LMWH therapy compared to vitamin-K antagonists.. A systematic literature search strategy was used to identify potential trials on MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Medline in-process using an OVID interface. Risk assessment of bias of randomized controlled trials (RCTs) was performed according to the Cochrane Collaboration-Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome measure was symptomatic VTE recurrence rate during the anticoagulation period. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated using random -effects and fixed-effects model.. Five articles met our inclusion criteria. All compared LMWH and VKA for secondary prevention of VTE. The pooled RR of VTE recurrence was 0.53 (95% CI: 0.36-0.76; p=0.007). The pooled RR of major bleeding was 0.98 (95% CI: 0.49-1.93, p=0.95). Minor bleeding events and all cause mortality were similar between the 2 intervention arms.. The results of our review suggest that the long term use of LMWH after the acute first week of treatment is superior to VKAs for secondary prevention of venous thromboembolism in adult patients with cancer.

Topics: Adult; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Drug Therapy, Combination; Evidence-Based Medicine; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; Polysaccharides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

We have made great strides in the diagnosis, treatment and prevention of venous thromboembolism (VTE). Despite these advances, however, questions remain. Perhaps the most important unmet need is the development and implementation of strategies to increase the uptake of guidelines for thromboprophylaxis. VTE is largely preventable with appropriate prophylaxis. New oral anticoagulants have the potential to further streamline VTE prevention and treatment. Although heparin, low molecular weight heparins or fondaparinux are frequently used for thromboprophylaxis in hospitalized medical or surgical patients, these agents are not ideal for out-of-hospital use. There is now good evidence that patients undergoing major orthopaedic surgery require extended thromboprophylaxis. Medical patients may also benefit from extended prophylaxis. The new oral anticoagulants will be more convenient than existing agents for this purpose and will help physicians and patients to adhere to optimal preventive strategies. VTE treatment also may be simplified with the new oral anticoagulants. With a rapid onset of action, these drugs may obviate the need for a parenteral anticoagulant for initial therapy. In addition, the new agents have the potential to streamline extended VTE therapy because, unlike vitamin K antagonists, they can be given in fixed doses without the need for coagulation monitoring.

Topics: Administration, Oral; Anticoagulants; Drugs, Investigational; Guideline Adherence; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Patient Selection; Practice Guidelines as Topic; Predictive Value of Tests; Recurrence; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

The treatment of choice for acute venous thromboembolism is anticoagulant therapy with fast-acting drugs (unfractionated or low-molecular-weight heparin or fondaparinux) aimed at preventing thrombus extension, followed by extended prophylaxis with vitamin K antagonists aimed at preventing recurrence. Experience accumulated over the years has demonstrated that strict laboratory monitoring is required for unfractionated heparin and vitamin K antagonists, making use of these drugs problematic for patients and physicians and prompting researchers to develop new anticoagulants equally effective but without the requirement for laboratory monitoring. The results of clinical trials to date, albeit limited, suggest that these new drugs will probably keep their promise. However, the definitive answer will come subsequent to these clinical trials, when clinicians will start to use these drugs to treat patients in the real world. It is likely that some sort of laboratory monitoring will be required at least for selected categories of patients. Accordingly, clinical laboratories should still be prepared to monitor patients, although the numbers may hopefully decrease sharply in the next decade or so.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; International Normalized Ratio; Monitoring, Physiologic; Morpholines; Polysaccharides; Prothrombin Time; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Topics: Adult; Aged; Anticoagulants; Antineoplastic Agents; Child; Clinical Trials as Topic; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Multicenter Studies as Topic; Neoplasms; Quality of Life; Recurrence; Thrombolytic Therapy; Venous Thromboembolism; Vitamin K

The use of aspirin for venous thromboembolism (VTE) prophylaxis after major orthopaedic surgery is controversial. The hypothesis of the present study is that aspirin will decrease the rate of operative site bleeding without increasing thromboembolic events when aspirin is used for VTE prophylaxis after major orthopaedic surgery. A pooled analysis of 14 randomized controlled trials (RCTs) cited by the American College of Chest Physicians (ACCP) guidelines was performed to determine pooled rates of symptomatic deep vein thromboses, pulmonary emboli (PE), fatal PE, and operative site bleeding rates. The VTE rates with aspirin were not significantly different than the rates for vitamin K antagonists (VKA), low molecular weight heparins (LMWH), and pentasaccharides. The operative site bleeding relative risks of VKA, LMWH, and pentasaccharides versus aspirin, are 4.9, 6.4, and 4.2, respectively. A pooled analysis of RCTs supports the use of aspirin for VTE prophylaxis after major orthopaedic surgery.

Topics: Anticoagulants; Aspirin; Heparin, Low-Molecular-Weight; Humans; Orthopedic Procedures; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Heparins, either unfractionated or low-molecular-weight (UFH and LMWHs), and vitamin K antagonists (VKAs) are currently the anticoagulants of choice for the prevention of post-operative venous thromboembolism (VTE) and for the treatment of acute venous and arterial thromboembolism. While VKAs are widely used in the US, LMWHs are the standard of care in the EU. Although efficacious, these agents are associated with a number of drawbacks, such as the risk of heparin-induced thrombocytopenia, the need for frequent coagulation monitoring in the case of UFH and VKAs, and the parenteral mode of administration in the case of heparins, which can lead to problems associated with patient compliance. There is a need for new anticoagulants that overcome these limitations. Direct, small-molecule inhibitors of coagulation proteins targeting a single enzyme in the coagulation cascade - particularly thrombin or Factor Xa - have been developed in recent years. Two agents, the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitor rivaroxaban, have recently been approved in the EU and several other countries for the prevention of VTE after total hip or knee replacement surgery. Here we will review data that suggest that the antithrombin-independent mechanism of action of these agents, particularly that of direct Factor Xa inhibitors, leads to increased efficacy with similar safety profiles compared with the antithrombin-dependent heparins. Although the end of the heparins era is not to be expected, the new anticoagulants presented in this review potentially represent the future of anticoagulation.

Topics: Anticoagulants; Antithrombin III; Blood Coagulation Factors; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Factor V; Factor Xa; Factor Xa Inhibitors; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Molecular Weight; Postoperative Complications; Purpura, Thrombocytopenic, Idiopathic; Thrombophilia; Venous Thromboembolism; Vitamin K

Oral anticoagulation (OAC) with vitamin K antagonists is commonly used for long-term prevention or treatment of arterial or venous thromboembolism. In the USA alone, approximately 250,000 patients will require temporary interruption of OAC annually. Managing anticoagulation in those patients on chronic OAC who require invasive procedures continues to be a major clinical dilemma. This article summarizes the existing evidence in light of the recommendations of the American College of Chest Physicians. Management of anticoagulation in the perioperative period will continue to be an important clinical challenge and an evolving area of research. If new oral anticoagulants are successful in replacing warfarin, the entire perioperative anticoagulation scene will change.

Topics: Administration, Oral; Anticoagulants; Blood Loss, Surgical; Evidence-Based Medicine; Heparin; Humans; Perioperative Care; Practice Guidelines as Topic; Risk Factors; Venous Thromboembolism; Vitamin K

Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of approximately 50 to 60 x 10(9) platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

Topics: Anticoagulants; Arginine; Autoantibodies; Contraindications; Disseminated Intravascular Coagulation; Fondaparinux; Heparin; Hirudins; Humans; Pipecolic Acids; Platelet Count; Platelet Factor 4; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombocytopenia; Thrombophilia; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Cancer and its therapies increase the risk of venous thromboembolism. Compared to patients without cancer, patients with cancer anticoagulated for venous thromboembolism are more likely to develop recurrent thrombotic events and major bleeding. Addressing all important outcomes including harm is of great importance to make evidence based health care decisions. The objective of this study was to compare low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism in patients with cancer.. A systematic review of the medical literature. We followed the Cochrane Collaboration methodology for conducting systematic reviews. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.. Eight randomized controlled trials (RCTs) were eligible and reported data for patients with cancer. The quality of evidence was low for death and moderate for recurrent venous thromboembolism. LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in venous thromboembolism (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74).. For the long term treatment of venous thromboembolism in patients with cancer, LMWH compared to VKA reduces venous thromboembolism but not death.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

To discuss new features that were published during the past few years on diagnosis and treatment of venous thromboembolism (VTE). Progress has been made in assessing clinical probability of pulmonary embolism (PE), in addressing the particular aspects of PE diagnosis in the elderly, in evaluating the diagnostic performance of single- and multi-detector row helical computed tomography (hCT), and in looking at the role of D-dimer measurement and lower limb venous compression ultrasonography in the diagnostic work-up of PE. New therapeutic options have also been proposed. Diagnosing VTE depends upon several, mainly non-invasive diagnostic tools that must be used sequentially, depending on the clinical situation and the local expertise. In the vast majority of patients, a noninvasive work-up is feasible and the diagnostic algorithms are becoming simpler. We focused on new developments of clinical probability assessment, PE in the elderly, potential new uses of D-dimer measurement, advent of multidetector row helical computed tomography and utility of ultrasonography to detect deep vein thrombosis in PE suspected patients. Treatment of acute venous thromboembolism consists of parenteral administration of heparin (usually low-molecular-weight heparin or, more recently, fondaparinux) overlapped and followed by oral vitamin K antagonists that will be administered for a certain period of time (usually 3 to 12 months), depending upon the estimated risks of recurrence and bleeding in each individual patient. Contemporary features include the controversial possibility of reducing the intensity of oral anticoagulant treatment (INR 1.5-2) after an initial full-intensity treatment (INR 2-3) period of 3 to 12 months, and the emergence of new anticoagulant drugs such as direct oral synthetic inhibitors of thrombin or factor Xa.

Topics: Administration, Oral; Age Factors; Anticoagulants; Biomarkers; Blood Coagulation; Drug Administration Schedule; Fibrin Fibrinogen Degradation Products; Health Status Indicators; Humans; Predictive Value of Tests; Pulmonary Embolism; Risk Assessment; Tomography, Spiral Computed; Ultrasonography; Venous Thromboembolism; Vitamin K

Vitamin K antagonists are the mainstay for the treatment for venous thromboembolism. The optimum (VTE) course of oral anticoagulant therapy is determined according to the risk of recurrent VTE after stopping anticoagulant therapy and the risk of anticoagulant-related bleeding while on antivitamin K. The risk of recurrent VTE is low when the initial episode is provoked by a reversible major-risk factor (surgery), whereas this risk is high when VTE is not provoked or associated with a persistent-risk factor (cancer). Conversely, the influence of biochemical and morphological tests is uncertain. The optimum balance of the benefits and the risks of oral anticoagulant therapy is based on the frequency as well as the consequences of the risk of recurrent VTE and anticoagulant-related bleeding. After VTE provoked by a major reversible-risk factor, three months of anticoagulation is optimal, whereas after unprovoked VTE, anticoagulation should be extended. However, given the number of unresolved issues, a randomised trial comparing different durations of anticoagulation is needed.

Topics: Anticoagulants; Hemorrhage; Humans; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K

Topics: Aerospace Medicine; Aircraft; Anticoagulants; Drug Therapy, Combination; Humans; Pulmonary Embolism; Risk Factors; Time Factors; Travel; Treatment Outcome; Venous Thromboembolism; Vitamin K

Cancer increases the risk of thromboembolic events and the risk of recurrent thromboembolic events while on anticoagulation.. To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism (VTE) in patients with cancer.. A comprehensive search was undertaken including a January 2007 search of electronic databases; Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2007, Issue 1). MEDLINE (1966 onwards; accessed via OVID), EMBASE (1980 onwards; accessed via OVID) and ISI the Web of Science. Hand search of the proceedings of the American Society of Clinical Oncology and of the American Society of Hematology. Checking of references of included studies, relevant papers and related systematic reviews. Use of "related article" feature in PubMed; and (5) search of ISI the Web of Science for papers citing landmark studies.. Randomized controlled trials (RCTs) comparing long term treatment with LMWH versus oral anticoagulants (VKA or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome.. Of 3986 identified citations, eight RCTs were eligible and reported data for patients with cancer. Their overall methodological quality was moderate. Meta-analysis of six RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in VTE (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74). One RCT compared tinzaparin and dalteparin and showed no differences in the outcomes of interest. One RCT compared a six months extension of anticoagulation with 18 months Ximelagatran 24mg twice daily versus placebo. It showed a reduction in VTE (HR = 0.16; 95% CI 0.09 to 0.30) with no apparent effect on survival or bleeding.. For the long term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Topics: Anticoagulants; Azetidines; Benzylamines; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

During the past two decades well designed randomized controlled trials have addressed every important aspect of prophylaxis against venous thromboembolism (VTE) and treatment of established VTE. In addition, systematic reviews and meta-analyses have been performed in most of these areas. The most important advances are the widely accepted and effective VTE prophylaxis in major orthopedic surgery and the shift from in-hospital to outpatient treatment of a majority of patients with established VTE. The major hurdles at this point are efficient selection of the appropriate medically ill patients for prophylaxis and the inconvenience of long-term secondary prophylaxis with vitamin K antagonists. Although new, orally available anticoagulants without need for monitoring or dose adjustments have been in clinical trials for a decade, none is approved yet, and will not be discussed in this review.

Topics: Ambulatory Care; Anticoagulants; Drug Monitoring; Humans; Orthopedic Procedures; Patient Selection; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) in patients with cancer follows an aggressive course, and it is often resistant to traditional regimens of pharmacological prophylaxis and treatment. Anticoagulant-related bleeding is also common and can complicate VTE treatment as well as cancer therapy. Consequently, the most effective approach to reducing the burden of VTE and its associated morbidity and mortality is to provide appropriate prophylaxis. Few clinical trials have focused on the prevention of VTE in this high-risk patient population, and they consistently demonstrate the efficacy and safety of anticoagulant prophylaxis in reducing thrombotic complications. Currently, low-molecular-weight heparins and oral vitamin K antagonists are the most commonly used anticoagulants for primary prevention in patients with cancer, but compliance with consensus guidelines is poor. Novel anticoagulants with a convenient and favorable risk/benefit profile may help to improve prophylaxis utilization and treatment. This review will provide a summary of the evidence on the primary prevention of VTE in patients with cancer.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages.. The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease.. Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis.. a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy.. From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels.. In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).

Topics: Adult; Anticoagulants; Child; Fibrinolytic Agents; Heart Diseases; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Pyridones; Quality of Life; Venous Thromboembolism; Vitamin K

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent recurrence of PE and secondary in situ thrombus formation. Warfarin, a vitamin K antagonist, is commonly used for anticoagulation in CTEPH based on historical experience and evidence. The anticoagulant activity of warfarin is affected by food and drug interactions, requiring regular monitoring of prothrombin time. The lability of anticoagulant effect often results in haemorrhagic and thromboembolic complications. Thus, lifelong warfarin is a handicap in terms of safety and convenience. Currently, the use of direct oral anticoagulants (DOACs) in CTEPH has increased with the advent of four DOACs. The safety of DOACs is superior to warfarin, with less intracranial bleeding in patients with non-valvular atrial fibrillation and venous thromboembolism. Edoxaban, the latest DOAC, also has proven efficacy and safety for those diseases in two large clinical trials; the ENGAGE-AF trial and HOKUSAI-VTE trial. The present trial seeks to evaluate whether edoxaban is non-inferior to warfarin in preventing worsening of CTEPH.. The KABUKI trial (is an investigator-initiated, multicentre, phase 3, randomised, single-blind, parallel-group, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban versus warfarin (vitamin K Antagonist) in subjects with chronic thromBoembolic pUlmonary hypertension taking warfarin (vitamin K antagonIst) at baseline) is designed to prove the non-inferiority of edoxaban to warfarin in terms of efficacy and safety in patients with CTEPH.. This study is approved by the Institutional Review Board of each participating institution. The findings will be published in a peer-reviewed journal, including positive, negative and inconclusive results.. NCT04730037.. This paper was written per the study protocol V.4.0, dated 29 January 2021.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Hypertension, Pulmonary; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Single-Blind Method; Stroke; Venous Thromboembolism; Vitamin K; Warfarin

 Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved..  We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial..  A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding..  The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365)..  In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.

Topics: Adult; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Double-Blind Method; Female; Hemorrhage; Humans; International Normalized Ratio; Linear Models; Male; Middle Aged; Recurrence; Research Design; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

The prospective, non-interventional XALIA study investigated the safety and effectiveness of rivaroxaban and standard anticoagulation for the treatment of deep vein thrombosis (DVT). XALIA-LEA was conducted in regions not included in XALIA (Latin America, Eastern Europe, the Middle East, Africa, and the Asia-Pacific), and enrolled patients with isolated pulmonary embolism (PE).. Adult patients with acute venous thromboembolism (VTE) indicated for ≥3 months' anticoagulant treatment were eligible; treatment strategies were at the physician's discretion. Patients receiving rivaroxaban or standard anticoagulation (unfractionated or low-molecular weight heparin/fondaparinux alone or overlapping with and followed by a vitamin K antagonist [VKA]) were included in the safety analysis. "Early switchers" to rivaroxaban (i.e. after receiving heparin/fondaparinux for >2-14 days and/or a VKA for 1-14 days) were not included in the safety analysis set.. Of the 1972 eligible patients, 1285 received rivaroxaban, 402 received standard anticoagulation, and 285 were early switchers. Most patients who received rivaroxaban were appropriately selected, received the correct dosing schedule, reported few adverse effects. Outcomes were similar to previously published results, with rivaroxaban associated with a low rate of major bleeding (1.6%), recurrent VTE (1.4%) and all-cause mortality (2.3%). Including early switchers, relatively fewer patients with index isolated PE received rivaroxaban (14.4%) versus standard anticoagulation therapy (20.9%). Some regional variations and differences in outcomes by VTE subtype were apparent with standard anticoagulation treatment.. XALIA-LEA reaffirms the safety and effectiveness of rivaroxaban for VTE treatment for countries not included in XALIA.

Topics: Adult; Africa; Aged; Anticoagulants; Asia; Europe, Eastern; Factor Xa Inhibitors; Female; Humans; Latin America; Male; Middle Aged; Middle East; Prospective Studies; Rivaroxaban; Venous Thromboembolism; Vitamin K

Unfavorable fibrin clot features have been observed in patients with venous thromboembolism (VTE). We investigated whether rivaroxaban, a direct factor Xa inhibitor, and vitamin K antagonists (VKAs) can improve plasma clot viscoelastic properties. We studied four age- and sex-matched groups: 25 healthy controls, 15 VTE patients taking rivaroxaban 20 mg/day (blood concentration, 145 (67 - 217) ng/ml), 15 VTE patients taking VKA (INR: 2 - 3), and 15 VTE patients who stopped oral anticoagulant therapy (OAT). Using a hybrid rheometier the storage (G') and loss (G") moduli were evaluated in citrated plasma after addition of 5 pmol/l tissue factor. Fiber thickness within clots was assessed using scanning electron microscopy. Higher G' but not G" was observed for VTE patients taking rivaroxaban (+34%; post hoc, P = 0.029) compared to controls. As reflected by lower G' and G", patients taking rivaroxaban (-19% and -30%; post hoc, P = 0.0013 and P < 0.0001, respectively) formed less stiff and viscous clots compared to VTE patients after OAT withdrawal, also after adjustment for fibrinogen. VTE patients treated with rivaroxaban and VKA had similar clot viscoelastic properties (post hoc, P = 0.85 for G' and P = 0.29 for G"). G' and G" correlated with plasma rivaroxaban concentrations (r = -0.67, P = 0.005 and r = -0.59, P = 0.021, respectively), and the time from the last dose of rivaroxaban intake (r = 0.59, P = 0.02 and r = 0.58, P = 0.022, respectively). G' and G" showed no association with INR in patients on VKAs. G' or G" were not associated with fibrin diameter on scanning electron microscopy images in either group. Our preliminary study shows that both rivaroxaban and VKA improve clot viscoelastic properties in VTE patients, which might contribute to their antithrombotic effects. G' and G" may reflect specific clot physical features, beyond key plasma clot characteristics, which highlights benefits from comprehensive plasma clot analysis in patients with thrombotic diseases.

Topics: Acenocoumarol; Adult; Anticoagulants; Elasticity; Factor Xa Inhibitors; Female; Fibrin; Humans; Male; Middle Aged; Rivaroxaban; Thrombosis; Venous Thromboembolism; Viscosity; Vitamin K; Warfarin

The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear.. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE.. From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3).. Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Transfusion; Female; Hemorrhage; Hemostatics; Humans; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Treatment Outcome; Venous Thromboembolism; Vitamin K

Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.

Topics: Aged; Anticoagulants; Blood Coagulation; Decision Support Techniques; Double-Blind Method; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Predictive Value of Tests; Pyridines; Risk Assessment; Risk Factors; Thiazoles; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

To quantify thromboembolic and bleeding events in patients with low thromboembolic risk, who were chronically receiving vitamin K antagonists and undergoing elective surgery.. A descriptive, prospective, single-center study was conducted between December 2010 and July 2014. Patients aged over 18 years old, chronically anticoagulated with vitamin K antagonists and admitted for elective surgery were included in the study. We excluded patients with a creatinine clearance<30ml/min, a body weight>120kg, heparin-induced thrombocytopenia, pregnant women, carriers of an epidural catheter for analgesia, patients who underwent unscheduled surgery and high thromboembolic risk-patients. Vitamin K antagonists were discontinued 5 days prior to the procedure without administering anticoagulant enoxaparin. The NIR was measured 24h before the procedure. A single dose of 3mg of vitamin K was administered in cases of a NIR>1.5. Vitamin K antagonists was resumed according to the surgical bleeding risk. Events were registered between 5 days prior to the procedure until 30 days after it.. A total of 75 procedures were included in the study. Fifty-six patients (74.7%) received vitamin K antagonists for atrial fibrillation, 15 suffered from venous thromboembolism (20%) and 4 had mechanical heart valves (5.3%). Twenty-six patients (34.5%) underwent high-bleeding risk surgeries and 49 (65.5%) underwent low risk procedures. No thromboembolic event was recorded. Four bleeding events (5.3%) were reported, 3 of which were considered major bleeding events (2 fatal).. Suspending vitamin K antagonists with no bridging therapy performed in patients with a low thromboembolic risk does not expose such patients to a significant risk of embolic events.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Loss, Surgical; Drug Administration Schedule; Elective Surgical Procedures; Female; Humans; Longitudinal Studies; Male; Middle Aged; Perioperative Care; Postoperative Hemorrhage; Prospective Studies; Risk; Treatment Outcome; Venous Thromboembolism; Vitamin K

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Black or African American; Blood Coagulation; Data Interpretation, Statistical; Enoxaparin; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemoglobins; Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasms; Platelet Aggregation Inhibitors; Prognosis; Proportional Hazards Models; Regression Analysis; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Pre-defined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30-1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32-1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.

Topics: Administration, Oral; Anticoagulants; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Pyridines; Risk Factors; Thiazoles; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (VTE) is a common and serious complication in patients with cancer; treatment guidelines recommend extended therapy of ≥6 months with low-molecular-weight heparin (LMWH) for treatment and prevention of recurrent VTE (rVTE) in this population. This post hoc analysis used data from the CLOT study-a phase III, randomized, open-label, controlled study (N = 676)-to compare the efficacy and safety of dalteparin, a LMWH, versus vitamin K antagonist (VKA) for prevention of rVTE in patients with cancer and renal impairment (creatinine clearance <60 ml/min). Overall, 162/676 (24 %) patients had renal impairment at baseline. Patients received subcutaneous dalteparin 200 IU/kg once daily during month 1, followed by 150 IU/kg once daily for months 2-6; or VKA once daily for 6 months, with initial overlapping subcutaneous dalteparin 200 IU/kg once daily for ≥5 days until international normalized ratio was 2.0-3.0 for 2 consecutive days. Endpoints included the rates of rVTE (primary) and bleeding events. Overall, fewer dalteparin-treated patients (2/74 [2.7 %]) experienced ≥1 adjudicated symptomatic rVTE compared with VKA-treated patients (15/88 [17.0 %]; hazard ratio = 0.15 [95 % confidence interval 0.03-0.65]; p = 0.01). Bleeding event rates for both treatments were similar (p = 0.47). In summary, compared with VKA, dalteparin significantly reduced risk of rVTE in patients with cancer and renal impairment (p = 0.01) while exhibiting a comparable safety profile. This analysis supports dosing patients with renal impairment in accordance with patients with normal renal function; however, anti-Xa monitoring could be considered to further support safety in selected patients, particularly those with very severe renal impairment.

Topics: Acenocoumarol; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dalteparin; Female; Humans; Kidney Diseases; Male; Middle Aged; Neoplasms; Venous Thromboembolism; Vitamin K; Warfarin

In a randomized trial (ie, Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer [CLOT]) that evaluated secondary prophylaxis of recurrent venous thromboembolism (VTE) in patients with cancer, dalteparin reduced the relative risk by 52% compared to oral vitamin K antagonists (VKAs; hazard ratio = 0.48, P = .002). A recent subgroup analysis in patients with moderate to severe renal impairment also revealed lower absolute VTE rates with dalteparin (3% vs 17%; P = .011). To measure the economic value of dalteparin in these populations, a pharmacoeconomic analysis was conducted from the Dutch health-care system perspective.. Resource utilization data contained within the CLOT trial database were extracted and converted into direct cost estimates. Univariate analysis was then conducted to compare the total cost of therapy between patients randomized to dalteparin or VKA therapy. Health state utilities were then measured in 24 members of the general public using the time trade-off technique.. When all of the cost components were combined for the entire population (n = 676), the dalteparin group had significantly higher overall costs than the VKA control group (dalteparin = €2375 vs VKA = €1724; P < .001). However, dalteparin was associated with a gain of 0.14 (95% confidence interval [CI]: 0.10-0.18) quality-adjusted life years (QALYs) over VKA. When the incremental cost was combined with the utility gain, dalteparin had a cost of €4,697 (95% CI: €3824-€4951) per QALY gained.. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cost-Benefit Analysis; Dalteparin; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Recurrence; Renal Insufficiency; Venous Thromboembolism; Vitamin K; Young Adult

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Enoxaparin; Female; Humans; Male; Middle Aged; Recurrence; Rivaroxaban; Venous Thromboembolism; Vitamin K; Young Adult

In the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment.. To evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3-month incidence of recurrent VTE, and the 14-day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin.. Of the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction  = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction  = 0.68) prestudy heparin.. Although the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it.

Topics: Adult; Aged; Anticoagulants; Enoxaparin; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Morpholines; Rivaroxaban; Safety; Thiophenes; Venous Thromboembolism; Vitamin K

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Postthrombotic Syndrome; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Direct oral anticoagulants have been evaluated for their efficacy and safety in the treatment of venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism. The randomized, double-blind Hokusai-VTE trial demonstrated that 60 mg of edoxaban once daily following initial heparin treatment is non-inferior to heparin overlapped with and followed by warfarin for the treatment of VTE, and is associated with significantly fewer bleeding events.. To assess the efficacy and safety of edoxaban versus warfarin among East Asian patients enrolled in the Hokusai-VTE trial.. The Hokusai-VTE trial enrolled 8292 patients from 439 centers worldwide, including 1109 patients from Japan, China, Korea, and Taiwan. The primary efficacy and safety outcomes were symptomatic recurrent VTE and clinically relevant bleeding, respectively.. In the overall East Asian population, the primary efficacy outcome of symptomatic recurrent VTE occurred in 16 of 563 (2.8%) patients in the edoxaban group versus 24 of 538 (4.5%) patients in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34-1.19; P = 0.1601). The primary safety outcome of clinically relevant bleeding occurred in 56 of 563 (9.9%) patients in the edoxaban group versus 93 of 538 (17.3%) patients in the warfarin group (HR 0.56; 95% CI 0.40-0.78; P < 0.001).. Edoxaban is an effective and safer alternative to warfarin in East Asian patients with acute VTE who require anticoagulant therapy, consistent with overall study findings from the Hokusai-VTE trial.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Asia, Eastern; Asian People; Double-Blind Method; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Pulmonary Embolism; Pyridines; Recurrence; Therapeutic Equivalency; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin; Young Adult

Vitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03-3.49), active cancer at baseline (OR=1.52; CI1.05-2.19), secondary VTE (OR=1.42; CI1.20-1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09-1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06-3.63 and OR=1.95; CI1.36-2.80, respectively). ORs of early (≤ 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31-2.80) and instability (OR=1.55; CI1.07-2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09-1.69) and instability (OR=1.25; CI1.01-1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57-2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

Topics: Acenocoumarol; Administration, Oral; Aged; Anticoagulants; Drug Therapy, Combination; Enoxaparin; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Prognosis; Recurrence; Risk Factors; Thrombophilia; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

The Prolong study shows that continuing vitamin K antagonists (VKA) in patients with abnormal D-dimer (evaluated by a qualitative assay, Clearview Simplify D-dimer) results in a significant reduction of venous thromboembolism (VTE) recurrence. The present study retrospectively analyzes a subgroup of patients enrolled in the Prolong study with a view to calculate cut-off values for six quantitative D-dimer methods to predict the risk of VTE recurrence. We measured D-dimer levels by VIDAS D-dimer Exclusion (bioMerieux), STA Liatest D-dimer (DiagnosticaStago), HemosIL D-dimer and HemosIL D-dimer HS (Instrumentation Laboratory), Innovance D-dimer (Siemens) and AutoDimer (Trinity Biotech) in frozen plasma aliquots sampled 30 ± 10 days after VKA cessation in 390 patients enrolled in the Prolong study. During follow-up (562.7 years), 28 patients had recurrent VTE (7.2%, 5.0% person-years). Since D-dimer levels are positively correlated with age and significantly lower in men, we calculated method-specific cut-off values according to age and gender. The HRs for VTE recurrence calculated using method-specific cut-off values based on age and gender are higher than those using cut-off values indicated by the manufacturers for VTE exclusion in symptomatic outpatients. These data suggest that method-specific cut-off values calculated according to patient age and gender can be more accurate in identifying patients at a higher risk for VTE recurrence. These method-specific cut-off values are being evaluated in the ongoing prospective management multicenter DULCIS study.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Male; Middle Aged; Predictive Value of Tests; Recurrence; Retrospective Studies; Risk Factors; Sex Factors; Venous Thromboembolism; Vitamin K; Young Adult

The optimal duration of anticoagulation after recurrent venous thromboembolism(VTE) is poorly established [1,2]. Recent studies suggested that D-dimer may identify patients at low risk of recurrence after a first VTE [3,4]. In a pilot, prospective, cohort study we aimed to assess the negative predictive value of D-dimer in patients with recurrent VTE. Patients with negative D-dimer while on treatment stopped anti coagulation and underwent repeated testing after 7, 15, and 30 days; treatment was resumed if D-dimer turned positive and permanently stopped if it remained negative. The study was interrupted after the enrolment of 75 patients. At that time, treating physicians decided treatment resumption in 12.2% of the patients, but the majority of events were distal or superficial vein thromboses. The rate of objectively documented recurrent proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) was 2.56% (95% CI 0.13, 15.07%) in the 39 patients with persistently negative D-dimer at 30 days, for an annual incidence of VTE of 5.65 events/100 patient/years. These preliminary findings suggest that negative D-dimer may identify patients with history of previous VTE at low risk of recurrences, but this approach should be tested in larger trials in highly selected patients.

Topics: Aged; Anticoagulants; Cohort Studies; Drug Monitoring; Early Termination of Clinical Trials; Female; Fibrin Fibrinogen Degradation Products; Follow-Up Studies; Humans; Incidence; Italy; Male; Middle Aged; Pilot Projects; Pulmonary Embolism; Risk Factors; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K

About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown.. In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome.. Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.. Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA ClinicalTrials.gov number, NCT00222677.).

Topics: Aged; Anticoagulants; Aspirin; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Pulmonary Embolism; Secondary Prevention; Venous Thromboembolism; Venous Thrombosis; Vitamin K

The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no-RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9-9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis.

Topics: Acenocoumarol; Adult; Aged; Anticoagulants; Drug Administration Schedule; Female; Hemorrhage; Humans; Lower Extremity; Male; Middle Aged; Prospective Studies; Recurrence; Risk Factors; Ultrasonography; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

Evaluation of the risk of recurrent venous thromboembolism (VTE) is required to determine the optimal duration of secondary prophylaxis. Application of global assays reflecting the pro- versus anti-coagulant balance in vivo would be desirable. We aimed at investigating the relationship between recurrent VTE and the Protac-induced coagulation inhibition (PICI) assay, which is based on tissue factor-induced thrombin generation measured by a chromogenic substrate. One-hundred-ninety patients were followed-up after a first episode of unprovoked, objectively documented VTE for 2.7 years after stopping treatment with vitamin K antagonists (VKA). PICI was measured 1 month after stopping treatment as the percentage of the OD values recorded without or with Protac. The lower the PICI%, the greater the pro- versus anti-coagulant imbalance. The study outcome was objectively-documented symptomatic recurrent VTE. Patients with PICI% 87%. After adjustment for age, gender, type of index event, VKA duration and normal/abnormal D-Dimer, HR (95% CI) were substantially unchanged [2.91 (1.01-8.38)]. The corresponding values after further adjustment for the above variables plus the absence/presence of the most frequent thrombophilic alterations were 3.38 (1.16-9.84). These HR values compare favorably with those obtained in a previous study investigating the thrombin generation test performed in the presence of thrombomodulin. In conclusion, the measurement of PICI helps to identify patients at higher risk of VTE recurrence. Advantages of PICI over thrombin generation tests are easy performance in general clinical laboratories, easy standardization and no special equipment.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Biomarkers; Blood Coagulation; Blood Coagulation Tests; Chromogenic Compounds; Drug Administration Schedule; Female; Fibrinolytic Agents; Humans; Intercellular Signaling Peptides and Proteins; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Peptides; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Protein C; Recurrence; Risk Assessment; Risk Factors; Thrombin; Thromboplastin; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring.. We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.. The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).. Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

Topics: Acenocoumarol; Acute Disease; Administration, Oral; Aged; Anticoagulants; Double-Blind Method; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Injections, Subcutaneous; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Pulmonary Embolism; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin

After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT.. A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients.. This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Topics: Anticoagulants; Chi-Square Distribution; Data Interpretation, Statistical; Double-Blind Method; Hemorrhage; Humans; Placebos; Practice Guidelines as Topic; Prognosis; Pulmonary Embolism; Recurrence; Risk Assessment; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

The assessment of the risk of recurrent venous thromboembolism (VTE) is important to determine the optimal duration of secondary prophylaxis. The risk can be estimated by measuring individual parameters reflecting hypercoagulability. Because of the large numbers of such putative parameters, the assessment in individual patients is complex. Application of global assays reflecting the pro-/anti-coagulant balance in vivo would be desirable.. To investigate the relationship between recurrent VTE and thrombin generation (TG).. Two hundred and fifty-four patients were followed-up after a first episode of unprovoked, objectively documented VTE for a period of 2.7 years after discontinuation of treatment with vitamin K antagonists. TG was measured 1 month after discontinuation of treatment as endogenous thrombin potential (ETP), peak thrombin and lag-time in the presence or absence of thrombomodulin. The study outcome was objectively documented symptomatic recurrent VTE.. Patients with ETP or peak (measured in the presence of thrombomodulin) of >960 nm(*)min or >193 nm had hazard ratios (HR) (95% CI) for recurrent VTE of 3.41 (1.34-8.68) or 4.57 (1.70-12.2) as compared with those with an ETP <563 nm(*)min or peak <115 nm. Patients with lag-time <14.5 min had HR of 3.19 (1.29-7.89) as compared with those with lag-time >20.8 min. HR for ETP, peak or lag-time measured in the absence of thrombomodulin were smaller than those measured in the presence of thrombomodulin.. The measurement of TG helps to identify patients at higher risk of VTE recurrence. The increased risk may be better appreciated if the test is performed in the presence of thrombomodulin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Recurrence; Risk Factors; Thrombin; Thrombomodulin; Venous Thromboembolism; Vitamin K

The SAMe-TT

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Humans; International Normalized Ratio; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Humans; Registries; Veins; Venous Thromboembolism; Vitamin K

Anticoagulant therapy is the cornerstone of treatment and prevention of arterial and venous thromboembolism. Taking a historical perspective, starting in the 1960s, and progressing through to 2022, we discuss key clinical trials of anticoagulants that have changed clinical practice, and examine obstacles encountered in bringing these anticoagulants to the clinic. The design of some of the early studies that shaped clinical practice was poor by current standards, but their results were influential because nothing better was available. Both heparin and vitamin K antagonists had been in clinical use for several decades before well-designed trials in the 1980s optimized their dosing and enhanced their safety and efficacy. Low-molecular-weight heparin then replaced unfractionated heparin because it had a more predictable dose-response and a longer half-life, thereby allowing it to be used conveniently in out-of-hospital settings. More recently, direct oral anticoagulants became the oral anticoagulants of choice for most indications because they were shown to be at least as safe and effective as vitamin K antagonists when used in fixed doses without the need for laboratory monitoring. The design of the trials that led to the approval of the direct oral anticoagulants was excellent, but further studies are required to optimize their dosing in selected patients who were underrepresented in these trials.

Topics: Anticoagulants; Fibrinolytic Agents; Heparin; Heparin, Low-Molecular-Weight; Humans; Venous Thromboembolism; Vitamin K

Topics: Aged; Aged, 80 and over; Anticoagulants; Cost-Effectiveness Analysis; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Registries; Rivaroxaban; Venous Thromboembolism; Vitamin K

The use of direct oral anticoagulants (DOACs) is increasing in patients needing treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (SPAF). This is due to the net clinical benefit in comparison to vitamin K antagonists (VKAs). The rise in DOAC use is accompanied by a remarkable reduction in heparin and VKA prescriptions. However, this rapid change in anticoagulation patterns brought new challenges to patients, prescribers, laboratories, and emergency physicians. Patients have new liberties concerning nutritional habits and comedication and no longer need frequent monitoring or dose adjustments. Still, they have to comprehend that DOACs are potent anticoagulants that may cause or contribute to bleeding. Challenges for the prescriber include decision pathways for choosing the right anticoagulant and dosage for a specific patient and to change bridging practice in case of invasive procedures. Laboratory personnel are challenged by DOAC due to limited 24/7 availability of specific DOAC quantification tests and by the impact of DOAC on routine coagulation assays and thrombophilia tests. Challenges for the emergency physician result from the increasing age of DOAC anticoagulated patients, the difficulties to establish last intake of DOAC type and dosage, to interpret coagulation test results in emergency situations, and to make decisions for or against DOAC reversal strategies in acute bleeding or urgent surgery. In conclusion, although DOACs make long-term anticoagulation safer and more convenient for patients, DOACs pose challenge to all healthcare providers involved in anticoagulation decisions. The key to correct patient management and optimal outcome therefore lies in education.

Topics: Administration, Oral; Anticoagulants; Antidotes; Atrial Fibrillation; Hemorrhage; Heparin; Humans; Laboratories; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) are widely used for the treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). However, evidence in obese and underweight patients is limited. We assessed the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients  ≥ 120 kg or ≤ 50 kg enrolled in an observational prospective cohort study, the START-Register.. Adult patients started on anticoagulant therapy were followed up for a median of 1.5 years (IQR 0.6-2.8). Primary efficacy outcome was the occurrence of VTE recurrence, stroke and systemic embolism. Primary safety outcome was major bleeding (MB).. 10,080 AF and VTE patients were enrolled between March 2011 and June 2021, 295 patients weighted  ≤ 50 kg and 82 patients ≥ 120 kg. Obese patients were significantly younger than underweight patients. Rates of thrombotic events were low and similar between DOACs and VKAs in underweight patients (1 event on DOACs therapy [0.9% 95% CI 0.11-5.39] and 2 on VKAs [1.1% 95% CI 0.01-47.68]) and in overweight patients (0 events on DOACs, 1 on VKAs [1.6%, 95% CI 0.11-5.79]. Two MB events occurred on DOACs (1.9%, 95% CI 0.38-6.00) and 3 on VKAs (1.6%, 95% CI 0.04-22.06) in the underweight group; 1 MB on DOACs (5.3% 95% CI 0.33-16.68) and 2 on VKAs (3.3%, 95% CI 0.02-130.77) in the overweight group.. DOACs seem to be effective and safe also for the treatment of patients with extreme body weights, both underweight and overweight. Further prospective studies are needed to support these findings.

Topics: Administration, Oral; Adult; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Obesity; Overweight; Prospective Studies; Stroke; Thinness; Venous Thromboembolism; Vitamin K

Chronic thromboembolic pulmonary hypertension (CTEPH) remains an underdiagnosed disease. Anticoagulation is essential in its therapy to prevent recurrent venous thromboembolism (VTE). According to some international guidelines, vitamin K antagonists (VKA) remain the gold standard. Nevertheless, direct oral anticoagulants (DOAC) are widely used, partly because of numerous advantages. The objective of this study was to determine if DOAC is an effective and safe alternative to VKA in CTEPH patients.. A retrospective observational study was conducted between 2001 and 2021 in a CTEPH Clinic of a tertiary care hospital. We recorded demographic characteristics, anticoagulant therapies and pulmonary hypertension treatments received. Safety outcomes were bleeding events and deaths while efficacy outcomes were recurrent VTE events.. Among the study population (N = 205), the distribution of anticoagulant used transitioned from majority on VKA to majority on DOAC. In 2020, 23 (19 %) were on VKA and 97 (78 %) on DOAC. Among 11 VTE events occurring during follow-up, 7 were in the VKA group (1.10 %/person-year) and 1 in the DOAC group (0.32 %/person-year). Rates of VTE recurrence were not significantly different in those treated with DOAC compared to VKA (P = 0.21). Total bleeding rate on VKA (2.52 %/person-year) and DOAC (2.52 %/person-year) were the same (P = 1.00). Among 27 patients who died, no deaths occurred as a consequence of bleeding or VTE events.. Bleeding and VTE events were not higher in CTEPH patients receiving DOAC compared to VKA which adds confidence to considering DOAC as an effective and safe alternative for long term anticoagulation in CTEPH patients.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension, Pulmonary; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a common cardiovascular disease that seriously threatens human lives. Anticoagulant therapy is considered to be the cornerstone of VTE treatment. An increasing number of studies has been updated in the VTE anticoagulation field. However, no bibliometric analyses have assessed these publications comprehensively. Therefore, our study aimed to analyze the global status, hotspots, and trends of anticoagulant therapy for VTE.. The relevant literature on VTE anticoagulation published between 2012 and 2021 was retrieved and collected from the Web of Science Core Collection database. VOSviewer, Cooccurrence Matrix Builder, gCLUTO, and some online visualization tools were adopted for bibliometric analysis.. A total of 15,152 related articles were retrieved. In recent years, the research output of VTE anticoagulation gradually increased. The United States was the most productive country. International cooperation is concentrated in North America and Europe; the most influential documents, journals, authors, and organizations were also from these two continents. Research hotspots mainly focus on clinical guidelines, VTE in special populations, non-vitamin K oral anticoagulants (NOACs), and parenteral anticoagulation. The research frontiers and trends include the assessment of NOACs and the antithrombotic management of VTE complicated with coronavirus disease 2019 (COVID-19).. This bibliometric analysis provides a systematic overview of the VTE anticoagulation research, which will facilitate researchers to better understand the situation of VTE anticoagulation. Future studies should be dedicated to NOACs application and VTE-combined COVID-19 patients.

Topics: Administration, Oral; Anticoagulants; COVID-19; Humans; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Child; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Risk Factors; Rivaroxaban; Venous Thromboembolism; Vitamin K

The purpose of this study was to investigate first trimester anticoagulant exposure and risks of adverse pregnancy-related and fetal outcomes.. Using Danish nationwide registries, we identified all pregnant women with preconception venous thromboembolism, 2000-2017, and linked data on exposure to low-molecular-weight heparin (LMWH), vitamin K antagonist (VKA), or non-VKA oral anticoagulant (NOAC) during pregnancy. We assessed pregnancy-related and fetal outcomes associated with first trimester anticoagulant exposure.. Among 4490 pregnancies in women with preconception venous thromboembolism (mean age 31 years, 40% nulliparous) during the first trimester, 63.1% were unexposed, 25.9% were exposed to LMWH, 10.4% VKA, and 0.6% NOAC. Adverse outcomes were lowest in unexposed and LMWH exposed. Compared with unexposed, VKA was associated with higher risks of preterm (adjusted odds ratio [OR] 2.26; 95% confidence interval [CI], 1.70-2.99) and very preterm birth (adjusted OR 3.78; 95% CI, 1.91-7.49), shorter mean gestational age was associated with VKA (-7.5 days; 95% CI, -9.1 to -5.9 days) or NOAC (-2.3 days; 95% CI, -8.4-3.8), and lower mean birthweight with VKA (-55 g; 95% CI, -103.1 to -8.5) or NOAC (-190 g; 95% CI, -364.1 to -16.4). Adjusted ORs for small-for-gestational-age infants were 1.07 (95% CI, 0.77-1.50) with VKA, and 3.29 (95% CI, 1.26-7.95) with NOAC. Mean 5-minute Apgar score (9.8) and congenital defect prevalence (8.4%-10%) varied little across exposure groups.. Fetal risk was lowest in unexposed and LMWH-exposed pregnancies, supporting the recommendation of LMWH during pregnancy. NOAC safety during pregnancy is unclear due to the rarity of NOAC exposure.

Topics: Adult; Anticoagulants; Cohort Studies; Female; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Premature Birth; Venous Thromboembolism; Vitamin K

Polypharmacy, including use of inhibitors of CYP3A4 and P-glycoprotein (P-gp), is common in patients with venous thromboembolism (VTE) and is associated with increased bleeding.. In 8246 patients included in the EINSTEIN-VTE studies for acute VTE, we evaluated the effect of polypharmacy on bleeding and on the relative differences between rivaroxaban and enoxaparin/vitamin K antagonist (VKA). We assessed the incidence of clinically relevant bleeding (major and clinically relevant nonmajor bleeding) by number of comedications (none, 1-3, ≥4) at baseline, and by use of CYP3A4 and/or P-gp inhibitors. Interaction between rivaroxaban versus enoxaparin/VKA and comedication was assessed by Cox regression analysis with p. We conclude that fixed-dose rivaroxaban as compared with enoxaparin followed by dose-adjusted VKA is not associated with an increased bleeding risk in patients with VTE administered polypharmacy in general and CYP3A4 and/or P-gp inhibitors specifically. This implies that the observed increased bleeding risks with polypharmacy and use of CYP3A4 and/or P-gp inhibitors are likely explained by comorbidities and frailty, and not by pharmacokinetic interactions.

Topics: Anticoagulants; Cytochrome P-450 CYP3A; Enoxaparin; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Polypharmacy; Rivaroxaban; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Polypharmacy; Rivaroxaban; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Polypharmacy; Rivaroxaban; Venous Thromboembolism; Vitamin K

Vitamin K antagonist (VKA) remains an essential option for venous thromboembolism (VTE), although direct oral anticoagulants have become available. However, there is a paucity of data on the optimal intensity and quality of control for VKA in Japanese.. The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1938 patients who received VKA with prothrombin time-international normalized ratio (PT-INR) measurement >5 times. The primary outcome measure was a composite of symptomatic VTE recurrence or major bleeding at 1 year. The presumed optimal quality of VKA therapy was defined as the combination of PT-INR range and time in therapeutic range (TTR) with the numerically lowest event rate.. The group with TTR ≥70 % based on PT-INR range ≥1.5 and <2.0 showed the lowest cumulative incidence rate. The cumulative 1-year incidence and the adjusted risk for the primary outcome measure were significantly lower in the optimal quality group than in the non-optimal quality group (5.2 % vs. 11.7 %, p = 0.001, and HR 0.49, 95%CI 0.28-0.81). Similarly, the cumulative 1-year incidences of a recurrent VTE, major bleeding, and all-cause death were significantly lower in the optimal quality group (recurrent VTE: 2.5 % vs. 6.0 %, p = 0.02; major bleeding: 2.8 % vs. 7.0 %, p = 0.008; and all-cause death: 2.8 % vs. 12.6 %, p < 0.0001). The lower risk of the optimal quality group relative to non-optimal quality group for the clinical outcomes was consistent regardless of the etiology of VTE (active cancer, transient risk factor, and unprovoked).. The current VTE registry showed the optimal intensity of VKA therapy was target PT-INR range ≥1.5 and <2.0, which could support the current Japanese guideline recommendation, and the good quality of control for VKA therapy of TTR ≥70 % was independently associated with better outcomes.

Topics: Anticoagulants; Fibrinolytic Agents; Hemorrhage; Humans; Japan; Recurrence; Venous Thromboembolism; Vitamin K

Limited data exist in large, representative populations about whether the risk of thromboembolic events varies after receiving four-factor human prothrombin complex concentrate (4F-PCC) versus treatment with human plasma for urgent reversal of oral vitamin K antagonist therapy. We conducted a multicenter observational study to compare the 45-day risk of thromboembolic events in adults with warfarin-associated major bleeding after treatment with 4F-PCC (Kcentra®) or plasma. Hospitalized patients in two large integrated healthcare delivery systems who received 4F-PCC or plasma for reversal of warfarin due to major bleeding from January 1, 2008 to March 31, 2020 were identified and were matched 1:1 on potential confounders and a high-dimensional propensity score. Arterial and venous thromboembolic events were identified up to 45 days after receiving 4F-PCC or plasma from electronic health records and adjudicated by physician review. Among 1119 patients receiving 4F-PCC and a matched historical cohort of 1119 patients receiving plasma without a recent history of thromboembolism, mean (SD) age was 76.7 (10.5) years, 45.6% were women, and 9.4% Black, 14.6% Asian/Pacific Islander, and 15.7% Hispanic. The 45-day risk of thromboembolic events was 3.4% in those receiving 4F-PCC and 4.1% in those receiving plasma (P = 0.26; adjusted hazard ratio 0.76; 95% confidence interval 0.49-1.16). The adjusted risk of all-cause death at 45 days post-treatment was lower in those receiving 4F-PCC compared with plasma. Among a large, ethnically diverse cohort of adults treated for reversal of warfarin-associated bleeding, receipt of 4F-PCC was not associated with an excess risk of thromboembolic events at 45 days compared with plasma therapy.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Factor IX; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Retrospective Studies; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Registries; Venous Thromboembolism; Vitamin K

Venous thromboembolic disease (VTD) is currently the second leading cause of death in cancer patients with a prevalence of approximately 20% compared with that of 5% in the entire adult population. Cancer patients are a heterogeneous group with significant differences in the risk of VTD which is, in particular, determined by the type of tumour, its extent, location, and the presence of metastases. Some tumours represent a mean 3- to 5-fold increase in risk, while in others the risk of developing VTD is even several times higher. In comparison with non-cancer patients, those with a tumour are not only at an increased risk of an initial thromboembolic event, but also of its recurrence, regardless of ongoing anticoagulation which is associated with a higher risk of bleeding, particularly in mucosal involvement. Venous thrombosis and its treatment may interfere with the ongoing diagnosis and treatment. In cancer patients, VTD is a frequent incidental finding on imaging studies. Primary thromboprophylaxis (apixaban, rivaroxaban, LMWH) is currently recommended in selected groups of cancer patients who are either hospitalized for acute internal disease or immobilized and have an active malignancy, undergo outpatient systemic chemotherapy for a tumour with a high risk of VTD (a Khorana score of 2) or surgery and are not at high risk of bleeding. DOACs should be administered six months after the initiation of chemotherapy. If there is a risk of drug interactions or mucosal bleeding, LMWHs are recommended. At present, DOACs (apixaban, edoxaban, rivaroxaban) and LMWHs are the first-choice drugs in treating VTD. LMWHs are preferred in mucosal tumours, when there is a high risk of bleeding, in progressive malignancy, concomitant emetogenic therapy, and dyspeptic difficulties. In severe renal insufficiency (CrCl < 15 ml/min), vitamin K antagonists may be of value. Individualized treatment should take into consideration the patients general condition, prognosis, and personal preferences.

Topics: Administration, Oral; Adult; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Patients with cancer have increased risks of venous and arterial thromboembolism and/or atrial fibrillation, for which anticoagulation is commonly used. For these indications, three main types of anticoagulants are recommended or used: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and vitamin K antagonists (VKAs), all have different advantages and disadvantages. Drug-drug interactions (DDIs) with anticoagulation are often cautioned against by major guidelines, but evidence remains scarce regarding the best management approach for specific drug combinations, particularly with DOACs. Significant DDIs might affect the efficacy and safety of anticoagulants and/or anticancer therapies as well as other interfering medications, and more studies are needed. This paper will review the available evidence and guidelines on DDIs with anticoagulants, focusing on the cancer population whenever possible, and propose directions for future research.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Vitamin K

The article is an opinion on the problem of venous thromboembolic (VTE) complications in patients with chronic kidney disease (CKD), which is significant and urgent for Russia. Signs of CKD are noted in more than 1/3 of patients with chronic heart failure; a decrease in kidney function is observed in 36% of people over the age of 60, in people of working age, a decrease in function is noted in 16% of cases, and in the presence of cardiovascular diseases increases to 26%. Clinical research data convincingly show that CKD is an independent risk factor for the development of VTE complications. The last decade has given us the opportunity to observe a kind of "revolution" in VTE therapy, which is associated with the appearance on the market of direct oral anticoagulants, including inhibitors of factor IIa (thrombin) and factor Xa. These drugs are approved by the Food and Drug Administration for the treatment of acute thromboembolism. Nevertheless, patients with severe CKD (estimated glomerular filtration rate 30 ml/min) are still limited to the use of unfractionated heparin and vitamin K antagonists, as there is insufficient data to support the use of direct oral anticoagulants in this population.. Статья представляет собой обсуждение проблемы венозных тромбоэмболических осложнений (ВТЭО) у больных хронической болезнью почек (ХБП), которая для нашей страны является значимой и насущной. Признаки ХБП отмечаются более чем у 1/3 пациентов с хронической сердечной недостаточностью; снижение функции почек наблюдается у 36% лиц в возрасте старше 60 лет, у лиц трудоспособного возраста снижение функции отмечается в 16% случаев, а при наличии сердечно-сосудистых заболеваний возрастает до 26%. Данные клинических исследований убедительно показывают, что ХБП является независимым фактором риска развития ВТЭО. Последнее десятилетие дало нам возможность наблюдать некую революцию в терапии ВТЭО, которая связана с появлением на рынке прямых пероральных антикоагулянтов, включающих ингибиторы фактора IIa (тромбина) и фактора Ха. Эти препараты одобрены Управлением по контролю пищевых продуктов и лекарств в США для лечения острой тромбоэмболии. Тем не менее пациенты с тяжелой ХБП (расчетная скорость клубочковой фильтрации 30 мл/мин) по-прежнему ограничены использованием нефракционированного гепарина и антагонистов витамина К, так как недостаточно данных в поддержку использования прямых пероральных антикоагулянтов в этой популяции.

Topics: Anticoagulants; Factor Xa; Heparin; Humans; Prevalence; Renal Insufficiency, Chronic; Thrombin; Venous Thromboembolism; Vitamin K

The effectiveness of direct oral anticoagulants (DOAC) is non-inferior to vitamin K antagonists (VKA) to treat atrial fibrillation and venous thromboembolism (VTE). In this cross-sectional study, we compared older persons taking DOACs to those taking VKAs. We included ambulatory individuals ≥80 years, affiliated to Mutualité Sociale Agricole of Burgundy, who were refunded for a medical prescription in September 2017. The demographic conditions, registered chronic diseases (RCD), and number and types of prescribed drugs were compared in the DOAC group and VKA group. Of the 3190 included individuals, 1279 (40%) were prescribed DOACs and 1911 (60%) VKAs. Individuals taking VKAs were older than those taking DOACs (87.11 vs. 86.35 years). In the DOAC group, there were more women (51.92% vs. 48.25%) (

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Female; Humans; Venous Thromboembolism; Vitamin K

 In elderly patients with venous thromboembolism (VTE), the decision to extend anticoagulation beyond 3 months must be weighed against the bleeding risk. We compared the predictive performance of 10 clinical bleeding scores (VTE-BLEED, Seiler, Kuijer, Kearon, RIETE, ACCP, OBRI, HEMORR.  In a multicenter Swiss cohort study, we analyzed 743 patients aged ≥65 years who received extended treatment with vitamin K antagonists after VTE. The outcomes were the time to a first major and clinically relevant bleeding. For each score, we classified patients into two bleeding risk categories (low/moderate vs. high). We calculated likelihood ratios and the area under the receiver operating characteristic (ROC) curve for each score..  Over a median anticoagulation duration of 10.1 months, 45 patients (6.1%) had a first major and 127 (17.1%) a clinically relevant bleeding. The positive likelihood ratios for predicting major bleeding ranged from 0.69 (OBRI) to 2.56 (Seiler) and from 1.07 (ACCP) to 2.36 (Seiler) for clinically relevant bleeding. The areas under the ROC curves were poor to fair and varied between 0.47 (OBRI) and 0.70 (Seiler) for major and between 0.52 (OBRI) and 0.67 (HEMORR.  The predictive performance of most clinical bleeding risk scores does not appear to be sufficiently high to identify elderly patients with VTE who are at high risk of bleeding and who may therefore not be suitable candidates for extended anticoagulation.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Clinical Decision-Making; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Risk Assessment; Risk Factors; Switzerland; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, few data exist on the safety and efficacy of vitamin K antagonists (VKAs) in CTEPH and none for direct oral anticoagulants (DOACs).. To evaluate outcomes and complication rates in CTEPH following pulmonary endarterectomy (PEA) for individuals receiving VKAs or DOACs.. Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Postoperative outcomes, recurrent venous thromboembolism (VTE), and bleeding events were obtained from patient medical records.. Seven hundred ninety-four individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (standard deviation: 702) days. Significant improvements in hemodynamics and functional status were observed in both groups following PEA (P < .001). Major bleeding events were equivalent (P = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). The VTE recurrence was proportionately higher (P = .008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ.. Post-PEA functional and hemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH.

Topics: Administration, Oral; Anticoagulants; Humans; Hypertension, Pulmonary; Retrospective Studies; Venous Thromboembolism; Vitamin K

Despite controversies, direct oral anticoagulants (DOACs) are increasingly used in antiphospholipid syndrome (APS). We investigated the safety and efficacy of DOACs versus vitamin K antagonists (VKAs) in real-life consecutive APS patients.. In a cohort study of 176 APS patients, which included 82 subjects who preferred DOACs or had unstable anticoagulation with VKAs, we recorded venous thromboembolism (VTE), cerebrovascular ischemic events or myocardial infarction, along with major bleeding or clinically relevant non-major bleeding (CRNMB).. APS patients were followed for a median time of 51 (interquartile range 43-63) months. Patients on DOACs and those on VKAs were similar with regard to baseline characteristics. APS patients treated with DOACs had increased risk of recurrent thromboembolic events and recurrent VTE alone compared with those on VKAs (hazard ratio (HR) = 3.98, 95% confidence interval (CI): 1.54-10.28,. During long-term follow-up of real-life APS patients, DOACs are less effective and less safe as VKAs in the prevention of thromboembolism.

Topics: Adult; Antiphospholipid Syndrome; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Vitamin K

Evidence for guideline recommendations for the treatment of venous thromboembolism (VTE) during anticoagulant therapy is scarce. We aimed to observe and to describe the management of VTE occurring during anticoagulant therapy.. This prospective multi-center, observational study included patients with objectively confirmed VTE during anticoagulant therapy (breakthrough event), with a follow-up of 3 months, after the breakthrough event.. We registered 121 patients with a breakthrough event, with a mean age of 56 years (range, 19 to 90); 61 were male (50%). Fifty-eight patients (48%) had an active malignancy. At the time of the breakthrough event, 57 patients (47%) were treated with a vitamin K antagonist (VKA), 53 patients (44%) with low-molecular-weight heparin (LMWH) and 11 patients (9%) with direct oral anticoagulants, unfractionated heparin, or VKA plus LMWH. A total of 21 patients (17%) were receiving a subtherapeutic dose of an anticoagulant. The main regimens to treat recurrence in patients on VKA were: switch to LMWH (33%), temporary double treatment with LMWH and VKA (23%), and VKA with a higher target INR (19%). In patients with a breakthrough on LMWH, the most frequently chosen regimen was a permanent dose increase (74%). During 3-month follow-up, 7% of patients had a second breakthrough event and 8% experienced major or clinically relevant non-major bleeding.. There is wide variation in the management of VTE during anticoagulant treatment, reflecting a heterogeneous and complex clinical situation. Despite intensifying anticoagulation, the risk of a second breakthrough event in this population is 7%.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Venous Thromboembolism; Vitamin K; Young Adult

Bleeding is the most concerning complication associated with anticoagulant therapy but poorly characterized and important for risk/benefit assessment. We developed a risk stratification score to predict vitamin K antagonist (VKA)-associated bleeding in venous thromboembolism (VTE) using the UK Clinical Practice Research Datalink. Significant bleeding events in outpatients consisted of major bleeding and clinically relevant non-major bleeding requiring hospitalisation (CRNMB-H) within 90 days of VKA initiation. A scoring scheme for predicting bleeding was developed from subhazard ratios, validated using cross-validation and expressed by the C-statistic. The study cohort consisted of 10,010 patients with first VTE receiving initial VKA treatment, mean age 62·2 years. Between 2008 and 2016, 167 significant bleeding events were recorded (1·7%), i.e. incidence rate was 7·4/100 person-years. Independent predictors for community-acquired significant bleeding included active cancer, trauma/surgical procedure, male gender, dementia, liver disease, anaemia, history of bleeding, cerebrovascular, renal and chronic pulmonary disease, VTE presenting as pulmonary embolism and age over 75. The overall C-statistic was 0·68 (95% CI, 0·60-0·76), 0·75 (0·60-0·88) for major bleeding and 0·65 (0·55-0·75) for CRNMB-H, and higher than in other risk schemes applied to our study population. The developed risk score may identify patients having a significant bleeding risk, in particular major bleeding events, in outpatients.

Topics: Female; Hemorrhage; Humans; Male; Middle Aged; Outpatients; Venous Thromboembolism; Vitamin K

Topics: Heparin, Low-Molecular-Weight; Humans; Venous Thromboembolism; Vitamin K

Anticoagulant therapy has undergone a significant change since direct oral anticoagulants (DOACs) introduction. Their obvious advantages including the fixed dose, the few interactions and less frequent controls, have made them the first choice anticoagulant therapy. More and more patients have therefore switched from therapy with vitamin K antagonists (VKAs) to DOACs. Aim of our study was to assess the satisfaction, quality of life (QoL) and therapy adherence of patients who switched from VKA to DOACs therapy. This single center study evaluated satisfaction and QoL of 107 patients who switched from VKA to DOACs therapy through Anti-Clot Treatment Scale and SF-36 respectively. The questionnaires were administered before therapy change, after 3 months of DOACs therapy and then annually. We also evaluated DOACs therapy adherence with a questionnaire administered each visit and through the measures of DOACs plasma levels. Patients' satisfaction and QoL were high during VKA therapy, but with DOACs we observed an improvement after the first 3 months and then maintained over the time of DOACs therapy. DOACs adherence was excellent, also confirmed by DOACs plasma levels.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Patient Compliance; Patient Satisfaction; Quality of Life; Venous Thromboembolism; Vitamin K

Anticoagulation therapy is the cornerstone of treatment in acute vein thrombosis (DVT) and it aims to reduce symptoms, thrombus extension, DVT recurrences, and mortality. The treatment for DVT depends on its anatomical extent, among other factors. Anticoagulation therapy for proximal DVT is clearly recommended (at least for 3 months), while AT for isolated distal DVT should be considered, especially in the presence of high thromboembolic risk factors. The optimal anticoagulant and duration of therapy are determined by the clinical assessment, taking into account the thromboembolic and bleeding risk in each patient in a case-by-case decision making. Non-Vitamin K antagonists oral anticoagulants (NOACs) were a revolution in the anticoagulation management of DVT. Nowadays, NOACs are considered as first-line therapy in the anticoagulation therapy for DVT and are recommended as the preferred anticoagulant agents by most scientific societies. NOACs offer a simple route of administration (oral agents), a rapid onset-offset of their action along with a good efficacy and safety profile in comparison with Vitamin K Antagonists (VKAs). However, there are issues about their efficacy and safety profile in specific populations with high thromboembolic and bleeding risks, such as renal failure patients, active-cancer patients, and pregnant women, in which VKAs and heparins were the standard care of treatment. Since the available data are promising for the use of NOACs in end-stage chronic kidney disease and cancer patients, several ongoing randomized trials are currently trying to solve that issues and give evidence about the safety and efficacy of NOACs in these populations.

Topics: Administration, Oral; Anticoagulants; Female; Humans; Pregnancy; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Topics: 4-Hydroxycoumarins; Adult; Aftercare; Anticoagulants; Antiphospholipid Syndrome; England; Factor Xa Inhibitors; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Incidence; Indenes; International Normalized Ratio; Neoplasms; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; State Medicine; Systematic Reviews as Topic; Thrombophilia; Vena Cava Filters; Venous Thromboembolism; Vitamin K

Intracranial hemorrhage (ICH) is associated with severe prognosis and recurrent risk. This impacts on the decision to resume anticoagulation in atrial fibrillation (AF) or venous thromboembolism (VTE) patients. Purpose of our study is to evaluate the incidence rate of recurrent ICH in patients with AF or VTE resuming anticoagulation after a first ICH episode.. We report data of two cohorts of AF or VTE after a first ICH. The Vitamin K antagonist (VKA) cohort (166 patients) derives from CHIRONE Study, the direct oral anticoagulant (DOAC) cohort (178 patients) derives from START2-Register RESULTS: The clinical characteristics of the two cohort are similar with the exception of more prevalence of history of previous stroke/TIA in DOAC patients with respect to VKA (p = 0.02) and serum creatinine levels>1.5 mg/dL in VKA patients with respect to DOAC(p = 0.0001). The index ICH was spontaneous in 66.4% and in 33.7% among DOAC and VKAs cohort respectively (p = 0.0001). During follow-up, 14 recurrent ICH were recorded; 9 (rate 2.5 × 100 patient-years) in VKA and 5 (rate 1.3 × 100 patient-years) in DOAC (Relative Risk 1.9; 95% CI 0.6-7.4; p = 0.2). The univariate logistic regression analysis showed that patients with recurrent ICH were more frequently males, hypertensive, with a history of previous Stroke/TIA and older than patients without recurrence. VKA patients showed a higher risk of recurrence with respect to DOAC patients (OR 1.9;95% CI 0.7-6.7).. A trend toward fewer ICH recurrences was detected among DOACs patients in comparison to the previously reported rate of patients on warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Intracranial Hemorrhages; Male; Venous Thromboembolism; Vitamin K

Treatment with vitamin K antagonists (VKA) requires a high proportion of time in the therapeutic range (TTR) and a low international normalised ratio (INR) variability to be maximally safe and effective. Switching from short-acting acenocoumarol to long-acting phenprocoumon could improve VKA control.. We assessed whether switching from acenocoumarol to phenprocoumon improves the time in the therapeutic range (TTR) and INR variability.. In a retrospective cohort with data on 236,957 patients-years of VKA management from two first-line anticoagulation clinics in the Netherlands, we identified 124 patients in target range 2-3, 269 patients in target range 2-3.5 and 98 patients in target range 2.5-3.5 who switched from acenocoumarol to phenprocoumon. They were matched in a 1:2 ratio to non-switching controls using propensity score matching. Over the first 180 days after a switch, switchers' TTR declined 5 (95% CI 1 to 10), 10 (95% CI 7 to 13) and 5 (95% CI 0 to 11) percentage points relative to non-switchers, in target ranges 2-3, 2-3.5 and 2.5-3.5. Anticoagulation was more often supra-therapeutic in switchers, and switchers had a higher INR variability. In the following 180 days, TTR in switchers became 1 (95% CI -4 to 6), 4 (95% CI 0 to 7) and 6 (95% CI 1 to 12) percentage points better than in non-switchers. Switchers' INRs were much more stable than non-switchers'.. Eventually, a switch from acenocoumarol to phenprocoumon leads to a higher TTR and a lower INR variability. However, this is preceded by a transition period with opposite effects. An improved conversion algorithm could possibly shorten the transition period. Until then, physicians and patients should decide whether switching is worth the increased risk during the transition phase.

Topics: Acenocoumarol; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Retrospective Studies; Risk; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: 4-Hydroxycoumarins; Administration, Oral; Anticoagulants; Clinical Trials as Topic; Dalteparin; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Indenes; Medical Oncology; Neoadjuvant Therapy; Neoplasms; Prognosis; Pyrazoles; Pyridones; Risk Assessment; Venous Thromboembolism; Vitamin K

The time in therapeutic range (TTR) of patients with venous thromboembolism (VTE) treated with vitamin K antagonists (VKA) is usually below recommended, leading to higher frequency of vascular events, bleeding and mortality. The SAMe-TT2R2 prediction score discriminates those patients with high or low probability of obtaining poor INR control and its use is recommended in patients with atrial fibrillation. Its usefulness has been evaluated in patients with VTE, with conflicting results.. We included consecutive patients enrolled in Registro Informatizado Enfermedad TromboEmbolica (RIETE), a prospective multicenter VTE registry, treated with VKA for >90 days and a minimum of 3 INR determinations. We analyzed the relationship between the SAMe-TT. 3893 patients were included and classified in high (1411 patients) or low (2482 patients) probability of obtaining poor INR control according to the total score obtained (0-1 points versus 2 points, respectively). TTR, calculated by direct method and Rosendaal method, was 51.2 (±23.4) and 55.4 (±25.9) in the high probability group; and 54.4 (±23.0) and 58.2 (±25.6) in the low probability group, respectively (p < 0.001 for both comparisons). The outcomes were similar between groups. The predictive capacity of the SAMe-TT2R2 score showed an area under the ROC curve of 0.54 (CI 95% 0.52-0.56) and 0.53 (CI 95% 0.51-0.55).. In patients with VTE treated with VKA, the SAMe-TT2R2 score discriminated those patients with high probability of obtaining poor INR control, but with a low predictive capacity. Further studies are required to assess the usefulness of the score in clinical decision-making.

Topics: Anticoagulants; Atrial Fibrillation; Humans; International Normalized Ratio; Prospective Studies; Registries; Venous Thromboembolism; Vitamin K

BACKGROUND COVID-19 was declared a pandemic in March 2020 in the United States. It has been associated with high mortality and morbidity all over the world. COVID-19 can cause a significant inflammatory response leading to coagulopathy and this hypercoagulable state has been associated with worse clinical outcomes in these patients. The published data regarding the presence of lupus anticoagulant in critically ill COVID-19-positive patients is limited and indicates varying conclusions so far. CASE REPORT Here, we present a case of a 31-year-old man who was admitted to the hospital with COVID-19 pneumonia, complicated with superadded bacterial empyema and required video-assisted thoracoscopic surgery with decortication. This patient also had prolonged prothrombin time on preoperative labs, which was not corrected with mixing study. Further workup detected positive lupus anticoagulant and anti-cardiolipin IgM along with alteration in other coagulation factor levels. The patient was treated with fresh frozen plasma and vitamin K before surgical intervention. He had an uneventful surgical course. He received prophylactic-dose low molecular weight heparin for venous thromboembolism prophylaxis and did not experience any thrombotic events while hospitalized. CONCLUSIONS COVID-19 infection creates a prothrombotic state in affected patients. The formation of micro-thrombotic emboli results in significantly increased mortality and morbidity. Routine anticoagulation with low molecular weight heparin can prevent thrombotic events and thus can improve patient outcomes. In patients with elevated prothrombin time, lupus anticoagulant/anti-cardiolipin antibody-positivity should be suspected, and anticoagulation prophylaxis should be continued perioperatively for better outcomes.

Topics: Adult; Antifibrinolytic Agents; Betacoronavirus; Cardiolipins; Chest Tubes; Coronavirus Infections; COVID-19; Empyema, Pleural; Humans; Immunoglobulin M; International Normalized Ratio; Lupus Coagulation Inhibitor; Male; Pandemics; Partial Thromboplastin Time; Plasma; Pneumonia, Viral; Prothrombin Time; SARS-CoV-2; Tomography, X-Ray Computed; Venous Thromboembolism; Vitamin K

Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post-thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty-five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16-2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10-4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post-thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2-year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47-0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2-year risk of VTE recurrence after anticoagulant discontinuation.

Topics: Administration, Oral; Adult; Factor Xa Inhibitors; Female; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Prospective Studies; Recurrence; Thrombophilia; Venous Thromboembolism; Vitamin K

The proportion and characteristics of Italian patients affected by venous thromboembolism (VTE) treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs), and complications occurring during follow-up.. A prospective cohort of 2728 VTE patients included in the Survey on anticoagulaTed pAtients RegisTer (START2-Register) from January 2014 to June 2018 was investigated. Characteristics of patients, type of treatment and complications occurring during 2962 years of follow-up were analysed.. About 60 Italian anticoagulation and thrombosis centres participated in the observational START2-Register PARTICIPANTS: 2728 adult patients with VTE of a lower limb and/or pulmonary embolism (PE), with a follow-up after the initial phase treatment.. Patients could receive DOACs or VKAs; both prescribed by the National and Regional Health Systems for patients with VTE.. Efficacy: rate of VTE recurrence (all thrombotic complications were also recorded).. the rate of major and clinically relevant non-major bleeding events.. Almost 80% of patients were treated with DOACs. The prevalence of symptomatic PE and impaired renal function was higher in patients receiving VKAs. Duration of anticoagulation was >180 days in approximately 70% of patients. Bleeding events were similar in both treatment groups. The overall eventuality of recurrence was significantly higher in DOAC cohorts versus VKA cohorts (HR 2.15 (1.14-4.06), p=0.018); the difference was almost completely due to recurrences occurring during extended treatment (2.73% DOAC vs 0.49% VKA, p<0.0001). All-cause mortality was higher in VKA-treated (5.9%) than in DOAC-treated patients (2.6%, p<0.001).. Italian centres treat most patients with VTE with DOACs and prefer VKA for those with more serious clinical conditions. Recurrences were significantly more frequent in DOAC-treated patients due to increased incidence after 180 days of treatment, probably due to reduced adherence to treatment. These results underline the importance of structured surveillance of DOAC-treated patients with VTE to strengthen treatment adherence during extended therapy.

Topics: Administration, Oral; Anticoagulants; Hemorrhage; Humans; Male; Prospective Studies; Thrombosis; Venous Thromboembolism; Vitamin K

To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs).. PubMed was searched using terms "venous thromboembolism," "cancer," and "anticoagulation." This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations.. English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer.. Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered.. DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Prospective Studies; Retrospective Studies; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Fibrinolytic Agents; Humans; Prospective Studies; Venous Thromboembolism; Vitamin K

To retrospectively review the efficacy and safety of novel direct oral anticoagulants (DOACs) and compare the results with those of vitamin K antagonists (VKA) when used in clinical practice to treat venous thromboembolism (VTE) because there is insufficient evidence regarding its use in patients with gynecological cancers.. A study was conducted of patients diagnosed with gynecological cancers at Osaka University Hospital between January 2010 and December 2017. The medical records of those who suffered from deep venous thrombosis (DVT) and/or pulmonary embolism (PE) were retrospectively reviewed.. Among the 1698 cases of gynecological cancers, 107 (6.3%) cases were diagnosed as having VTE. A total of 34 (31.8%) patients presented DVT plus PE and 73 (68.2%) patients had DVT alone. Fifty-four cases were treated with DOACs and 53 with VKA. Although 3 of the 53 patients (5.7%) in the VKA group developed recurrent VTE, only 1 (1.9%) patient in the DOAC group showed clinically relevant bleeding from a tumor penetrating the rectum. DOACs were non-inferior to VKA with respect to the composite outcome, including recurrent venous thrombosis and relevant bleeding (hazard ratio 0.31, 95% confidence interval 0.03-3.12, P=0.363).. DOACs can be effectively and safely used in VTE patients with gynecological cancers.

Topics: Administration, Oral; Aged; Anticoagulants; Female; Genital Neoplasms, Female; Heparin; Humans; Middle Aged; Retrospective Studies; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is an important cause of morbidity and mortality in Western countries. The incidence rate of VTE is estimated at 1-2 cases per 1000 annually. This study was a population-based cohort study of previously treatment naïve patients with a first occurrence of venous thromboembolism (VTE), using data from the administrative health data register of the Stockholm Region 2011-2018. Data on anticoagulant treatment was taken from the Swedish Prescribed Drug Register. We also analyzed all VTE events between 2011 and 2018. Altogether 14,849 naïve incident VTE cases were identified. In 2011 the majority of patients with a first episode of VTE were prescribed warfarin versus non-vitamin K antagonist oral anticoagulants (NOACs), 1144 versus 5. In contrast in 2018, the majority of patients were treated with NOACs, 1049 versus 59 treated with warfarin. Treatment with low molecular weight heparin only decreased from 814 to 683 patients. The frequency of all VTE events in the population increased over time from 1.88/1000 to 1.93/1000 (p = 0.072), and PE diagnoses increased from 0.69/1000 to 0.76/1000 (p = 0.003). In conclusion, during 2011-2018 there has been a shift of prescription of warfarin to a clear predominance of NOACs in the treatment of VTE in the Stockholm Region, in line with current recommendations. In the clinical situation, treatment has been simplified as monitoring of warfarin has decreased substantially. PE events increased during the time period in the population even if the increase was rather modest, while all VTE events did not increase significantly.

Topics: Administration, Oral; Anticoagulants; Demography; Drug Prescriptions; Female; Heparin, Low-Molecular-Weight; Humans; Male; Pulmonary Embolism; Registries; Sweden; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (VTE), which includes pulmonary embolism and deep vein thrombosis, is a leading cause of morbidity and mortality worldwide. Based on new evidence, the management and treatment of VTE have changed over the years. For several decades, low molecular weight heparin and vitamin K antagonists have been the two cornerstones of anticoagulant therapy for VTE. Recently, the introduction in clinical practice of the new oral anticoagulants has radically changed the management of VTE for their easy use and their better efficacy and safety profile. Here, we report on recent evidence of 10 still controversial clinical questions concerning common diagnostic and therapeutic aspects of VTE.

Topics: Anticoagulants; Humans; Pulmonary Embolism; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Most invasive procedures require the interruption of oral anticoagulation. In 2015, an international randomised trial demonstrated that perioperative bridging caused more harm than benefit in most anticoagulated patients with atrial fibrillation, leading to a more restrictive Dutch national guideline in April 2016. The objective of the present study was to analyse the integration of the 2016 Dutch guideline for perioperative antithrombotic management from after publication until update of hospital protocols.. This is a retrospective cohort study of patients on vitamin K antagonists undergoing a surgical procedure between April 2016 and June 2017.. The proportion of high-risk patients with venous thromboembolism or atrial fibrillation receiving bridging therapy decreased from 91% and 77%, respectively at the start of the study to 33% in both groups in the last months. In high-risk patients with a mechanical heart valve, the bridging rate remained stable at 70-80% for 12 months and increased to 100% in the last 3 months. Protocol adherence for high-risk patients decreased from 80% to below 43%. The 30-day incidence of major bleeding was 4.1% (15.2% in bridged patients and 0.7% in non-bridged patients) and 10.3% for clinically relevant non-major bleeding (23.9% in bridged patients and 6.0% in non-bridged patients). The incidence of thrombo-embolism was 0.5%.. New evidence from the Dutch national guideline on perioperative bridging was adopted by physicians before the local hospital protocol was updated. Low incidence of thromboembolism in non-bridged patients and high incidence of bleeding in bridged patients support a more restrictive bridging policy.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Atrial Fibrillation; Female; Guideline Adherence; Guidelines as Topic; Humans; Male; Middle Aged; Netherlands; Perioperative Care; Retrospective Studies; Thromboembolism; Venous Thromboembolism; Vitamin K

The safety and efficacy of direct oral anticoagulants in cancer patients is currently unclear. Low-molecular-weight heparin remains the standard of care for cancer patients with venous thromboembolism, with warfarin, a vitamin K antagonist, as an alternative. Clear recommendations do not exist for patients with both active cancer and non-valvular atrial fibrillation. The objectives of this study were to report safety and efficacy outcomes of direct oral anticoagulants, low-molecular-weight heparin, and vitamin K antagonist in cancer patients with venous thromboembolism or non-valvular atrial fibrillation.. Retrospective chart review of adult cancer patients from 2012 to 2015 who received an antineoplastic agent and an anticoagulant.. A total of 258 patients were reviewed: 80 patients in direct oral anticoagulant group, 95 patients in low-molecular-weight heparin group, and 83 patients in vitamin K antagonist group. Sixty-seven percent of patients were on an anticoagulant for acute or chronic venous thromboembolism. Major bleeding events were similar across the groups (15% direct oral anticoagulant vs 17% low-molecular-weight heparin vs 18% vitamin K antagonist). The most common type of major bleeding event was gastrointestinal bleeding. A total of five fatal bleeding events occurred. Venous thromboembolism recurrence rates were higher in both direct oral anticoagulant (18%) and low-molecular-weight heparin (12%) groups while lower in vitamin K antagonist group (10%) compared to previous studies.. Cancer patients receiving direct oral anticoagulants, low-molecular-weight heparin, or vitamin K antagonist had similar rates of major bleeding events, with gastrointestinal bleeding being the most common event. Venous thromboembolism recurrence rates were higher in direct oral anticoagulant and low-molecular-weight heparin groups than prior studies. Randomized trials are warranted to establish clear safety and efficacy in this population.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Treatment Outcome; United States; Venous Thromboembolism; Vitamin K; Warfarin

The strategies of perioperative bridging anticoagulation in orthopedic surgical patients during oral anticoagulation (OAC) therapy with vitamin K antagonists (VKA) vary from center to center.. The aim of this single-center study was to assess the risk of bleeding and thromboembolic events (TEs) in bridged patients on VKA who underwent orthopedic surgery due to trochanteric or hip fracture.. The retrospective study included 64 patients (mean age: 80 years) who received VKA for at least 3 months prior to orthopedic procedure. All subjects were bridged with enoxaparin (40 mg once a day). The control group (n = 69) comprised of age-, sexand procedure-matched patients operated on for the same indications, but with neither a history of VKA therapy nor perioperative bridging anticoagulation.. Severe postoperative bleeding occurred in 19 (29.7%) patients from the VKA group and in 13 (18.8%) controls (p = 0.16). Within the VKA group, intertrochanteric fractures (52.6%) and femoral neck fractures (47.4%) occurred more often in patients with bleeding than other lower extremity fractures (0%; p = 0.03). Severe adverse events (SAEs) were more common in the VKA group than in the controls (12.5% vs 1.5%; p = 0.01). Patients from the VKA group did not differ from the controls in the incidence of TEs (6.3% vs 8.9%; p = 0.31). No intrahospital mortality was documented.. Prophylactic administration of enoxaparin is a common strategy of bridging anticoagulation in a hospital setting. This approach does not seem to be associated with an increase in thromboembolic risk nor higher risk of bleeding in orthopedic patients who received VKA preoperatively.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Loss, Surgical; Female; Heparin, Low-Molecular-Weight; Hip Fractures; Humans; Male; Perioperative Care; Retrospective Studies; Treatment Outcome; Venous Thromboembolism; Vitamin K

Although dabigatran has a favorable risk-benefit profile compared with vitamin K antagonist therapy for venous thromboembolism and nonvalvular atrial fibrillation, major bleeding events, including gastrointestinal (GI) bleeding, may occur. Therefore, our aim was to provide insights into the efficacy and safety of idarucizumab for urgent dabigatran reversal in patients with major GI bleeding.. Patients with uncontrollable GI bleeding requiring reversal were enrolled from June 2014 through July 2016 in the RE-VERSE AD study (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab), a prospective, multicenter, open-label study of idarucizumab, and were followed up for 90 days for primary and secondary outcomes. Patients were to receive a 5-g dose of intravenous idarucizumab, administered as 2 bolus infusions of 2.5 g no more than 15 minutes apart. The primary end point was the maximum reversal of dabigatran anticoagulation within 4 hours after administration of idarucizumab as measured by the dabigatran-specific assays diluted thrombin time and ecarin clotting time. Further end points included investigator-reported bleeding cessation within the first 24 hours and incidence of rebleeding, thromboembolic events, or mortality.. GI bleeding occurred in 137 patients enrolled in RE-VERSE AD, of which 84% was adjudicated as major or life-threatening, 48 (35.0%) was upper GI tract in origin, 43 (31.4%) was lower GI in origin, and 46 (33.6%) was either both or unknown. Complete reversal of dabigatran was observed in 118 of 121 patients (97.5%) with an elevated diluted thrombin time at presentation and 95 of 131 patients (72.5%) with an elevated ecarin clotting time and was similar for upper and lower GI bleeding. Bleeding cessation within 24 hours was reported in 92 of 134 evaluable patients (68.7%) after a median duration of 2.4 hours (interquartile range, 2.0-3.9 hours). During the 90-day follow-up, 6 patients (4.4%) had a postreversal thromboembolic event, and 20 patients (14.6%) died.. Idarucizumab showed a rapid and complete reversal of dabigatran activity in nearly all patients presenting with GI bleeding, facilitating emergency patient care without the additional presence of anticoagulation.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02104947.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Anticoagulants; Dabigatran; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Risk Assessment; United States; Venous Thromboembolism; Vitamin K

Non-vitamin K antagonist oral anticoagulants (NOACs) have been included in international guidelines as important alternatives to vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) and stroke prevention in non-valvular atrial fibrillation (NVAF). Meanwhile, in the Netherlands, NOACs are widely used next to VKAs. The objective of this study is to estimate the cost-effectiveness of treatment with rivaroxaban compared to VKAs in NVAF and VTE patients in the Netherlands, using data from international prospective observational phase IV studies.. Two models were developed to represent NVAF and VTE patients, populated with patients from the XANTUS (NCT01606995) and XALIA (NCT01619007) international prospective observational studies. The 1-year cost-effectiveness of rivaroxaban use, compared to VKAs, was explored in a population consisting of NVAF and VTE patients (base case) as well as for four scenarios with sub-populations: NVAF patients only, VTE patients only, NVAF patients with unstable international normalized ratio (INR), and NVAF patients using an INR self-measuring device.. In the base case, rivaroxaban saved €72,350 and gained 21 quality-adjusted life-years (QALYs) in a simulation of 2,000 patients over the use of VKAs. Ergo, rivaroxaban was dominant over VKAs. The probabilistic sensitivity analysis showed a probability of 85% for rivaroxaban being dominant and 100% at a willingness-to-pay threshold of €20,000/QALY. Rivaroxaban appeared to be dominant in all scenarios as well, except for the NVAF-patients-only scenario where the incremental cost-effectiveness ratio (ICER) was €157/QALY.. In patients with NVAF or VTE, rivaroxaban treatment is likely to be cost-effective and a potentially cost-saving alternative to VKA in the Netherlands.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Cost-Benefit Analysis; Female; Health Expenditures; Health Resources; Humans; Male; Models, Econometric; Netherlands; Prospective Studies; Rivaroxaban; Severity of Illness Index; Venous Thromboembolism; Vitamin K

Dialysis patients manifest both an increased thrombotic risk and a haemorrhagic tendency. A great number of patients with chronic kidney disease requiring dialysis have cardiovascular comorbidities (coronary artery disease, atrial fibrillation or venous thromboembolism) and different indications for treatment with antithrombotics (primary or secondary prevention). Unfortunately, few randomized controlled trials deal with antiplatelet and/or anticoagulant therapy in dialysis. Therefore cardiology and nephrology guidelines offer ambiguous recommendations and often exclude or ignore these patients. In our opinion, there is a need for an expert consensus that provides physicians with useful information to make correct decisions in different situations requiring antithrombotics. Herein the European Dialysis Working Group presents up-to-date evidence about the topic and encourages practitioners to choose among alternatives in order to limit bleeding and minimize atherothrombotic and cardioembolic risks. In the absence of clear evidence, these clinical settings and consequent therapeutic strategies will be discussed by highlighting data from observational studies for and against the use of antiplatelet and anticoagulant drugs alone or in combination. Until new studies shed light on unclear clinical situations, one should keep in mind that the objective of treatment is to minimize thrombotic risk while reducing bleeding events.

Topics: Algorithms; Anticoagulants; Atrial Fibrillation; Coronary Artery Disease; Drug Therapy, Combination; Evidence-Based Medicine; Fibrinolytic Agents; Hemorrhage; Humans; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Secondary Prevention; Thrombosis; Venous Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD), yet the optimal pharmacologic anticoagulant is unknown.. A retrospective single-institution cohort study of patients with SCD complicated by first VTE from January 2009 through July 2017 was performed using ICD 9/10 codes. Data collected included the anticoagulant used, VTE recurrence, and incidence of bleeding.. 109 patients with VTE were identified. SCD genotypes included HbSS in 92 (84%), HbSC in 13 (12%), and HbS-β+ thalassemia in 4 (4%). After the initial VTE event, 32 patients received a vitamin K antagonist (VKA), 34 for low-molecular-weight heparin (LMWH), and 43 for direct oral anticoagulants (DOACs). 16 patients (15%) experienced a clinically significant bleeding event, including 9 on VKA, 5 on LMWH, and 2 on DOACs. At a median follow-up of 11.8 (range, 3.4-60) months, 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH, and 13 on DOACs (p = 0.833). Bleeding incidence was least with the DOACs, which were associated with fewer bleeding events (OR 0.22), and greatest with VKA (OR 1.55) (p < 0.05).. There was no difference between VTE recurrence and choice of anticoagulation in SCD patients with VTE. Bleeding events were lower for DOACs compared to VKA or LMWH.

Topics: Administration, Oral; Adult; Anemia, Sickle Cell; Anticoagulants; beta-Thalassemia; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Venous Thromboembolism; Vitamin K

Low-molecular-weight heparins (LMWH) are the drug of choice for treatment of cancer-associated thrombosis (CAT), however non-vitamin K antagonist oral anticoagulants (NOAC) seem to be a reasonable alternative. We investigated the safety and efficacy of NOAC versus LMWH in patients with a history of CAT.. In a prospective cohort study 128 consecutive patients with active cancer who experienced CAT were enrolled following LMWH treatment for ≥3 months. Symptomatic recurrent venous thromboembolism (VTE), bleeding and death were recorded during follow-up.. 65 (50.8%) patients were switched to NOAC and 63 (49.2%) continued with LMWH. During a median follow-up of 17 (interquartile range, 15-21) months, recurrent VTE was observed in 6 (9.2%) patients on NOAC and in 12 (19.0%) on LMWH (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.16-1.16). The rate of major bleeding was 9.2% and 4.8%, respectively (HR 2.00, 95% CI 0.50-8.00). The median time to bleeding was shorter in patients on NOAC (3 [2.25-5.5] months) versus on LMWH (9 [6.5-13.0] months). The mortality rates were similar in both groups (15.4% versus 15.9%, respectively, HR 0.76, 95% CI 0.32-1.84).. In patients following CAT, extended treatment with NOAC, compared with LMWH, appears to be associated with similar effectiveness and safety.

Topics: Administration, Oral; Aged; Anticoagulants; Antithrombins; Comparative Effectiveness Research; Dabigatran; Drug Administration Schedule; Enoxaparin; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

The primary study objective is to compare the outcomes of patients taking oral anticoagulant medications in two distinct populations treated according to different management models (comprehensive vs. usual care). (Design: regional prospective cohort study; setting: hospital admission data from two regions). Eligible partecipants were patients taking oral anticoagulant drugs (vitamin K antagonist or direct oral anticoagulants), residents in the Vicenza and Cremona districts from February 1st, 2016 to June 30th, 2017. Patients were identified by accessing the administrative databases of patient drug prescriptions. The primary study outcome was admission to the Emergency Department for stroke, systemic arterial embolism, recurrence of venous thromboembolism or major bleeding. The study evaluated outcomes in 14,226 patients taking oral anticoagulants, of whom 6725 being followed in Cremona with a comprehensive management model. There were 19 and 45 thromboembolic events over 6205 and 6530 patient-years in the Cremona and Vicenza cohort, respectively (IRR 0.44, 95% CI 0.24-0.77). The reduction of events in the Cremona cohort was almost entirely explained by a decrease of events in patients taking VKA (IRR 0.41, 95% CI 0.20-0.78) but not DOACs (IRR 1.08, 95% CI 0.25-5.24). The rate of major bleeding was non-significantly higher in Cremona than in Vicenza (IRI 1.32; 95% CI 0.74-2.40). Across the two cohorts, the risk of bleeding was lower in patients being treated with DOACs rather than warfarin (10/4574 vs. 42/8161 event/person-years, respectively, IRR 0.42 95% CI 0.19-0.86). We conclude that a comprehensive management model providing centralized dose prescription and follow-up may significantly reduce the rate of thromboembolic complications, without substantially increasing the number of bleeding complications. Patients treated with direct oral anticoagulants appear to have a rate of thromboembolic complications comparable to VKA patients under the best management model, with a reduction of major bleeding.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Disease Management; Ecology; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Thrombolytic Therapy; Venous Thromboembolism; Vitamin K

D-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anticoagulants (DOACs) are frequently used in venous thromboembolism treatment; however, their pharmacokinetics and pharmacodynamics characteristics are completely different than vitamin K antagonists. The present study aimed at comparing the results of D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with DOACs or warfarin.. D-dimer levels were measured in 527 patients ("cases") during DOACs treatment (T0) and after 15 (T15), 30 (T30), 60 (T60) and 90 (T90) days after their discontinuation and in 527 patients ("controls") enrolled in the DULCIS study (all treated with warfarin), matched for sex, age (+/-3 y), type of D-dimer assay and site of venous thromboembolism. Both cases and controls received anticoagulant treatment after a first venous thromboembolism event that was unprovoked or associated with weak risk factors.. The rate of positive D-dimer results was significantly higher in cases than in controls at T0 (10.8% vs 5.1%, p = 0.002) and at T30 (18.8% vs 11.8%, p = 0.019), as well as at the other time-points, though not statistically significant.. D-dimer levels during and after stopping an anticoagulant treatment for a venous thromboembolism episode differ between patients treated with a DOAC than in those treated with warfarin. Specifically designed prospective studies are warranted to reassess the use of D-dimer as predictor of the risk of recurrent venous thromboembolism in patients treated with DOACs.

Topics: Administration, Oral; Aged; Anticoagulants; Case-Control Studies; Clinical Laboratory Techniques; Clinical Trials as Topic; Female; Fibrin Fibrinogen Degradation Products; Humans; Italy; Male; Middle Aged; Retrospective Studies; Risk; Rivaroxaban; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Anemia, Sickle Cell; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Incidence; Venous Thromboembolism; Vitamin K

Studies from several countries show that self-management of vitamin K antagonist (e.g., warfarin) therapy reduce the risk of complications compared with conventional management.. The aim of this study was to investigate the quality of warfarin management when patients were transferred from conventional management to self-management in Norway. In addition, quality of life (QoL) before and after 2 years of warfarin self-management was investigated.. The study was longitudinal with a retrospective and prospective design where 126 patients on conventional management of long-term warfarin therapy underwent a 21-week training program of warfarin self-management followed by 2 years of self-management. The outcomes of the study were time in therapeutic range (TTR), the variance of international normalized ratio (INR) values, extreme INR values (INR ≤ 1.5 and ≥ 5), complications, and QoL, comparing the 2-year period of the conventional management with the 2-year period with the self-management.. The median TTR was higher during self-management compared with conventional management (78.1% vs. 65.9%, respectively,. We used five different measures and found improved quality of warfarin self-management 2 years after patients were transferred from the conventional management.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Drug Monitoring; Female; Heart Valve Prosthesis; Humans; International Normalized Ratio; Longitudinal Studies; Male; Middle Aged; Patient Education as Topic; Prospective Studies; Quality of Life; Retrospective Studies; Self-Management; Venous Thromboembolism; Vitamin K; Warfarin

Low-molecular-weight heparin (LMWH) is the treatment of choice in cancer patients with venous thromboembolism. However, data on continuing LMWH treatment beyond 6 months remain scanty.. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the rate of venous thromboembolism recurrences and major bleeding appearing beyond the first 6 months of anticoagulant therapy in cancer patients with venous thromboembolism, according to therapy with LMWH or vitamin K antagonists (VKA). We performed a propensity score-matched cohort study.. After propensity matching, 482 cancer patients continued to receive LMWH and 482 switched to VKA. During the course of anticoagulant therapy (mean 275.5 days), 57 patients developed venous thrombosis recurrences (recurrent pulmonary embolism 26, recurrent deep vein thrombosis 29, both 2), 28 had major bleeding, 38 had nonmajor bleeding, and 129 died. No patient died of recurrent venous thrombosis, and 5 patients died of bleeding (2 were on LMWH, 3 on VKA). Patients who continued with LMWH had a similar rate of deep vein thrombosis recurrences (relative risk [RR] 1.41; 95% confidence interval [CI], 0.68-2.93), pulmonary embolism recurrences (RR 0.73; 95% CI, 0.34-1.58), major bleeding (RR 0.96; 95% CI, 0.51-1.79), or nonmajor bleeding (RR 1.15; 95% CI, 0.55-2.40), compared with those who switched to VKA, but a higher mortality rate (RR 1.58; 95% CI, 1.13-2.20).. In cancer patients with venous thromboembolism who completed 6 months of LMWH therapy, switching to VKA was associated with a similar risk of venous thrombosis recurrences or bleeding when compared with patients who continued LMWH.

Topics: Aged; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Propensity Score; Recurrence; Registries; Retrospective Studies; Venous Thromboembolism; Vitamin K

Single nucleotide polymorphisms (SNP) in genes encoding proteins involved in metabolism and action of vitamin K antagonists (VKA) affect anticoagulation stability. We investigated how those polymorphisms influence bleeding rates in patients following venous thromboembolism (VTE).. In 324 patients following unprovoked VTE, 143 (44%) on warfarin and 181 (56%) on acenocoumarol, we recorded bleeds within the preceding 24 months. We assessed eight SNP, including those in cytochrome P450 isoform 2C9 (CYP2C9) and isoform 4F2 (CYP4F2), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), apolipoprotein E (APOE) and multidrug resistance gene 1 (MDR1).. Within 48 months before enrolment, bleeding events occurred in 80 (25%) patients, including 14 (4%) major bleeds. Patients with bleeds had 16.2% lower median time in therapeutic range (TTR) and were more often carriers of CYP2C9*3 variant (26 [33%] vs. 19 [8%], p < 0.001) compared with the remainder. Bleeding occurred more frequently in patients with ≥4 SNP compared with the remainder (27 [34%] vs. 47 [19%], p = 0.009) with no intergroup differences of TTR. Number of SNP was one of the predictors of any bleeding. The regression model for major bleeding including factors such as CYP2C9*3 c. 1075 C, VKORC1 c. -1639 A and APOE c. 388 C showed good predictive ability (area under the curve - 0.79).. In VTE patients on the maintenance treatment with VKA, bleeding episodes are associated with CYP2C9 gene variations and increased number of SNP of genes involved in the action and metabolism of VKA.

Topics: Acenocoumarol; Adult; Anticoagulants; Apolipoproteins E; Cytochrome P-450 CYP2C9; Female; Gene Frequency; Genetic Predisposition to Disease; Hemorrhage; Humans; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Venous Thromboembolism; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

The uninterrupted use of oral anticoagulation (OAC) with vitamin K antagonists (VKAs) for electrophysiology procedures has been more and more recommended. The clinical practice in our service recommends the continuous use of these drugs for atrial flutter ablation. There is little evidence as to the uninterrupted use of non-vitamin K antagonist oral anticoagulants (NOACs) in this scenario.. To compare the rates of complications related with the uninterrupted use of different types of oral anticoagulants in patients referred to atrial flutter (AFL) ablation.. Historical, single-center cohort of ablation procedures by AFL conducted from November 2012 to April 2016. The primary outcome was the occurrence of hemorrhagic or embolic complication during the procedure. The secondary outcome was the occurrence of stroke or transient ischemic attack (TIA) in follow-up. The statistical significance level was 5%.. There were 288 ablations per AFL; 154 were carried out with the uninterrupted use of OAC (57.8% with VKA and 42.2% with NOAC). Mean age was 57 ± 13 years. The rate of hemorrhagic complication during the procedure was 3% in each group (p = NS). The rate of stroke/TIA was, respectively, of 56/1,000 people-year in the VKA group against zero/1,000 people-year in the NOAC group (p = 0.02).. In our population there were no hemorrhagic complications regarding the procedure of OAC use uninterruptedly, including NOACs. There was higher occurrence of stroke/TIA in the follow-up of the group of patients undergoing VKAs; however, this difference may not only be a result of the type of OAC used.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Flutter; Catheter Ablation; Cohort Studies; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Middle Aged; Risk Factors; Stroke; Venous Thromboembolism; Vitamin K

Defective clot contraction has been postulated to contribute to thrombosis. We aimed to evaluate the association of residual vein obstruction (RVO) with erythrocyte compression within the whole-blood clot. We studied 32 patients with venous thromboembolism (VTE) taking vitamin K antagonists (VKAs) for at least 3 months (median time in therapeutic range 60%), including 12 (37.5%) with RVO, and 32 age- and sex-matched controls. In all study participants we evaluated whole blood clot retraction, expressed as the erythrocyte compression index (ECI), defined as a ratio of mean polyhedrocyte area to mean native erythrocyte area, along with clot area covered by polyhedrocytes, plasma clot permeability (Ks), clot lysis time (CLT), and thrombin generation. In both groups higher ECI, indicating impaired clot contraction, increased with older age, higher body mass index, red blood cell distribution width, and lower platelet count (all p < 0.05), but not with red blood cell count. In VTE patients ECI was 15.8% higher than in controls (median 63.6 vs. 54.9%, p = 0.021). Subjects with RVO had 20% higher ECI and 155% lower clot area covered by polyhedrocytes. RVO patients had also prolonged CLT by 41%, but not Ks, and elevated peak thrombin generation by 33%, as compared to those without RVO (all p < 0.05). This study is the first to show impaired compression of erythrocytes in RVO patients despite VKA anticoagulation. Altered ECI coexisted with hypolysability and increased thrombin generation. ECI might be useful in the diagnostic process of RVO or post-thrombotic syndrome and can help optimize the anticoagulant therapy.

Topics: Adult; Anticoagulants; Case-Control Studies; Clot Retraction; Erythrocyte Indices; Female; Fibrin Clot Lysis Time; Humans; Male; Middle Aged; Postthrombotic Syndrome; Thrombin; Venous Thromboembolism; Vitamin K

Kuperman et al. found that patients with anemia had a higher risk of major bleeding (RR 2.84; 95% CI 2.52-3.39) in RIETE database. Anemia appeared to be an independent predictive factor for major bleeding [hazard ratio (HR) 1.95; 95% CI 1.72-2.20] in this registry. Unfortunately, selection bias due to enrolled patients does not allowed us to use these major results in ambulatory care. The aim of SCORE study was to refine bleeding risk estimation in French vitamin K antagonist (VKA) treated patients and to identifying one or several parameters of prognostic significance. We conducted a prospective, multi-center cohort study of 962 consecutive outpatients from private angiologic offices, clinics and hospitals enrolled in grenoble angiologic network for thromboembolic diseases between May 2009 and December 2010, followed during 1 year by their general practitioner. Main outcome was the occurrence of major bleeding or clinically non major relevant bleeding (CNMRB). Incidence rates major bleeding and CNMRB were 2.86 (95% CI 1.95-4.2) events per 100 patient-years and 12% (95% CI 9.89-14.11) respectively. Cox multivariate analyses showed that only anemia was strongly associated with a risk of major bleeding (HR 6.1; 95% CI 2.7-13.8; p = 0.001). Logistic regression analyses performed in CNMRB showed that anemia, prior gastro-intestinal bleeding and antiplatelet drug use were strongly associated with a risk of CNMRB at 1 year, respectively OR 2.53, 95% CI (1.4-4.56); p = 0.002, OR 3.32, 95% CI (1.51-7.31); p = 0.003 and OR 1.77, 95% CI (1.1-2.83); p = 0.017. These new data were consistent between major and CRNM bleeding in VKA treated patients. The key role of anemia should be confirmed in other prospective cohort studies, with different anticoagulants use such as direct oral anticoagulant in ambulatory care settings.

Topics: Aged; Anemia; Anticoagulants; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Risk Assessment; Venous Thromboembolism; Vitamin K

Essentials Factor Xa inhibitors cause more abnormal menstrual bleeding (AUB) than vitamin-K antagonists (VKA). We analyzed data of AUB in women, evaluating dabigatran versus VKA. We observed a 41% lower risk of AUB in women on dabigatran compared to those on VKA. Our findings of lower AUB risk on dabigatran should be corroborated in future studies.. Introduction Although direct oral anticoagulants (DOACs) are associated with a better safety profile than warfarin in patients with acute venous thromboembolism (VTE), direct factor Xa inhibitors involve a higher risk of abnormal uterine bleeding (AUB). We aimed to determine the risk of AUB during anticoagulation with dabigatran compared with warfarin. Methods Post-hoc analysis of the pooled RE-COVER studies and the RE-MEDY trial. Incidences of AUB, based on a defined preferred terms search for adverse events, in female patients aged 18-50 years treated with dabigatran, were compared with those in women treated with warfarin. Results Of the 2964 women included in the above-mentioned trials, 1280 women were in the relevant age category (18-50 years) and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 8.1%, 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an odds ratio for dabigatran-treated patients of 0.59 (95% confidence interval [CI], 0.39-0.90; P = 0.015). In the dabigatran-treated patients, three (0.5%) suffered major bleeding (MB) vs. five (0.8%) in the warfarin-treated patients (HR, 0.65; 95% CI, 0.15-2.72). MB or non-major relevant bleeding occurred in 30 (4.7%) patients randomized to receive dabigatran and 57 (8.9%) randomized to receive warfarin (HR, 0.53; 95% CI, 0.34-0.83). None of the bleeding events was fatal. Conclusion Dabigatran treatment was associated with a significantly (41%) lower risk of AUB than warfarin. Future studies in daily practice are needed to corroborate these findings.

Topics: Adolescent; Adult; Anticoagulants; Clinical Trials as Topic; Contraceptives, Oral, Hormonal; Dabigatran; Factor Xa Inhibitors; Female; Humans; Incidence; Menorrhagia; Middle Aged; Multicenter Studies as Topic; Uterine Hemorrhage; Venous Thromboembolism; Vitamin K; Warfarin; Young Adult

Essentials The risk of bleeding influences the duration of anticoagulation (AC) after venous thromboembolism. We assessed the ACCP bleeding risk score in an inception-cohort of patients receiving AC. 53% were categorized at high-risk, but their bleeding rate was low during long-term AC. ACCP score had low predictive value for bleeding.. Background The American College of Chest Physicians (ACCP) guideline proposes a score to decide on extended anticoagulation after an unprovoked venous thromboembolism (VTE). Methods We investigated the ACCP score to predict bleeding risk in an inception cohort of 2263 patients on long-term anticoagulation (1522 treated with vitamin K antagonists [VKAs] and the remaining with direct oral anticoagulants [DOACs]) belonging to the Italian START2 Register. Results More than half the patients were categorized as high risk; nevertheless, a higher proportion received anticoagulation for > 1 year compared with those in the low-risk category. For 3130 years (median 12 [interquartile range 6, 24] months), 48 bleeding outcomes occurred (1.53%/year) in the cohort (1.7%/year and 0.95%/year in high- and low-risk categories, respectively). The c-statistic of the ACCP score was 0.55 (0.48-0.63), 0.50 (0.42-0.58) and 0.56 (0.48-0.64) in low-, moderate- and high-risk categories, respectively. The bleeding incidence was higher during the first 90 days of treatment (3.0%/year) than afterwards (1.2%/year; relative risk (RR), 2.5 [1.3-4.7]), and similar among the three categories. The bleeding rate was not different during the initial 3 months of treatment in patients receiving VKAs or DOACs; it was, however, lower in the latter patients in the subsequent period (0.5%/year vs. 1.4%/year, respectively). Conclusion The bleeding rate during extended treatment was rather low in our patients. ACCP score had insufficiently predictive value for bleeding and cannot be used to guide decisions on extended treatment. New prediction tools for bleeding risk during anticoagulant treatments (including DOACs) are required.

Topics: Administration, Oral; Aged; Anticoagulants; Blood Coagulation; Decision Support Techniques; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Predictive Value of Tests; Prospective Studies; Registries; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE).. These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made.. ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.. The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants.. Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti-factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding.

Topics: Administration, Oral; Anticoagulants; ATP Binding Cassette Transporter, Subfamily B; Cytochrome P-450 Enzyme System; Evidence-Based Medicine; Heparin; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Medication Adherence; Point-of-Care Systems; Venous Thromboembolism; Vitamin K

The correlation between chronic direct oral anticoagulants (DOACs) intake and the incidence of intracranial complications after minor head injury (MHI) is still not well defined. This study examined the incidence of complications in patients receiving vitamin K antagonists (VKA) or DOACs observed in the emergency department (ED) for MHI.. Two hundred twenty-five patients affected by MHI and receiving oral anticoagulants were recorded between January and December 2016, distinguishing those treated with VKA (118) from those receiving DOACs (107). All patients underwent a CT scan and were observed for 24h in the ED. Follow-up was performed up to 1month after the head trauma.. The rate of intracranial hemorrhage was significantly lower in patients treated with DOACs than in patients treated with VKA. We recorded 2 deaths among the 12 patients who experienced intracranial complications in the VKA group.. DOACs seem to have a more favorable safety profile than VKA in patients affected by MHI. This observation is important in light of the increasing number of elderly patients who are receiving anticoagulant therapy.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Craniocerebral Trauma; Female; Humans; Intracranial Hemorrhage, Traumatic; Italy; Male; Middle Aged; Prospective Studies; Risk Factors; Tomography, X-Ray Computed; Venous Thromboembolism; Vitamin K

Essentials Low-molecular-weight-heparins (LMWH) kinetics differ which may result in different bleeding risks. A cohort of 12 934 venous thrombosis patients on LMWH was followed until major bleeding. The absolute major bleeding risk was low among patients registered at the anticoagulation clinic. Once-daily dosing was associated with a lower bleeding risk as compared with twice-daily.. Background Low-molecular-weight heparins (LMWHs) are considered members of a class of drugs with similar anticoagulant properties. However, pharmacodynamics and pharmacokinetics between LMWHs differ, which may result in different bleeding risks. As these agents are used by many patients, small differences may lead to a large effect on numbers of major bleeding events. Objectives To determine major bleeding risks for different LMWH agents and dosing schedules. Methods A cohort of acute venous thrombosis patients from four anticoagulation clinics who used an LMWH and a vitamin K antagonist were followed until they ceased LMWH treatment or until major bleeding. Exposures were classified according to different types of LMWHs and for b.i.d. and o.d. use. Cumulative incidences for major bleeding per 1000 patients and risk ratios were calculated and adjusted for study center. Results The study comprised 12 934 patients with a mean age of 59 years; 6218 (48%) were men. The cumulative incidence of major bleeding was 2.5 per 1000 patients (95% confidence interval [CI], 1.7-3.5). Enoxaparin b.i.d. or o.d. was associated with a relative bleeding risk of 1.7 (95% CI, 0.2-17.5) compared with nadroparin o.d. In addition, a nadroparin b.i.d. dosing schedule was associated with a 2.0-fold increased major bleeding risk (95% CI, 0.8-5.1) as compared with a nadroparin o.d. dosing schedule. Conclusions Absolute major bleeding rates were low for all LMWH agents and dosing schedules in a large unselected cohort. Nevertheless, twice-daily dosing with nadroparin appeared to be associated with an increased major bleeding risk as compared with once-daily dosing, as also suggested in a meta-analysis of controlled clinical trials.

Topics: Acute Disease; Adult; Aged; Anticoagulants; Cohort Studies; Drug Administration Schedule; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Nadroparin; Pulmonary Embolism; Risk; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Vitamin K antagonist (VKA) treatment requires routine monitoring using the international normalized ratio (INR). However, different INR assays may vary in their results. The aim of this study was to assess the agreement of three different INR methods, compared with thrombin generation, in patients on VKA treatment.. Sixty patients attending the Anticoagulation Clinic at Mater Dei Hospital (Msida, Malta) for VKA monitoring between August and September 2015 were enrolled. The INR was tested using a point-of-care (POC) device (CoaguChek XS Plus, Roche Diagnostics) for both capillary and venous blood samples, a photo-optical (Sysmex CS-2100i/CA-1500, Siemens) and a mechanical clot detection system (Thrombolyzer XRC, Behnk Elektronik). All assays used human recombinant thromboplastin as reagent. Thrombin generation was performed using the calibrated automated thrombogram.. There was a negative curvilinear correlation between the endogenous thrombin potential and different INR assays (r≤-.75) and a strong positive linear correlation between the CoaguChek XS Plus on capillary samples and the other INR methodologies (r≥.96).. All different INR assays showed good correlation with the thrombin generation potential. The POC INR showed one of the highest correlation coefficients with thrombin generation, confirming the POC devices as an accurate, valid alternative to laboratory INR in VKA patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Female; Humans; International Normalized Ratio; Male; Middle Aged; Point-of-Care Systems; Reproducibility of Results; Thrombin; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Antithrombins; Dabigatran; Humans; Practice Guidelines as Topic; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Review Literature as Topic; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Danish nationwide registries were used to investigate temporal trends in initiation of rivaroxaban or apixaban or dabigatran versus vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Patients treated with one of the NOACs (rivaroxaban, dabigatran, apixaban) or VKA were identified between February 2012 and September 2016. A total of 19,578 patients were included of which 10,844 (55.4%) were treated with VKA and 8,734 (44.6%) were treated with NOACs (rivaroxaban 7,572, apixaban 1,066, and dabigatran 96). Temporal trends showed a decrease in the initiation of VKA (p-value for decreasing trend, p < 0001) and an increase in the initiation of rivaroxaban and apixaban (p-value for increasing trend, p < 0001). By September 2016, 12%, 70%, 16%, and 2% of patients with VTE were initiated on VKA, rivaroxaban, apixaban, and dabigatran. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with one of the NOACs. In conclusion the initiation of rivaroxaban and apixaban is increasing significantly over time in patients with VTE. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with rivaroxaban or apixaban.

Topics: Aged; Antithrombins; Denmark; Drug Utilization; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Registries; Venous Thromboembolism; Vitamin K

The international guidelines recommend the use of direct oral anticoagulants (DOACs) over vitamin K antagonists for anticoagulation long-term therapy in patients diagnosed with venous thromboembolism (VTE), and for stroke prevention in patients with non-valvular atrial fibrillation (AF). Efficacy and safety of DOACS have been extensively evaluated in large phase III trials. According to the product label, dose reductions of DOACs are recommended for patients with AF and renal impairment, low body weight and concomitant use of interfering medications. Except for Edoxaban, dose reductions of DOACs are not recommended in patients with VTE based on the same indications for AF patients. The aim of this article is to discuss the indication of a lower DOAC dose in some patients with VTE. Observational studies and randomized control trials (RCTs) show that patients with AF are usually older, more often have chronic diseases, and more often are treated with several concomitant medications, potentially increasing their haemorrhagic risk. Furthermore, many VTE patients need a shorter period of anticoagulation therapy than AF patients. In real-life studies, VTE patients treated with inappropriate DOAC doses present a higher rate of VTE recurrence, and the same risk of bleeding compared to those treated with the correct dose. In light of this evidence, the use of lower DOAC dose in patients with VTE does not appear reasonable and may be potentially dangerous.

Topics: Administration, Oral; Anticoagulants; Evidence-Based Medicine; Humans; Pyridines; Thiazoles; Venous Thromboembolism; Vitamin K

The effect of direct oral anticoagulants (DOACs) on the risk of bleeding after tooth extraction remains unclear. This study aimed to evaluate the incidence of postextraction bleeding among patients who received DOAC and vitamin K antagonists (VKAs), such as warfarin.. This study was a retrospective cohort analysis. Incidence rates and propensity score-matched regression models were used to compare the risks of bleeding after tooth extractions involving DOACs and VKAs.. The study took place in a single university hospital in Japan.. Between April 2013 and April 2015, 543 patients underwent a total of 1196 simple tooth extractions.. The primary outcome measure was the occurrence of postextraction bleeding, which was defined as bleeding that could not be stopped by biting down on gauze and required medical treatment between 30 min and 7 days after the extraction.. A total of 1196 tooth extractions (634 procedures) in 541 patients fulfilled the study criteria, with 72 extractions (41 procedures) involving DOACs, 100 extractions (50 procedures) involving VKAs and 1024 extractions (543 procedures) involving no anticoagulants. The incidences of postextraction bleeding per tooth for the DOAC, VKA and no anticoagulant extractions were 10.4%, 12.0% and 0.9%, respectively. The incidences of postextraction bleeding per procedure for DOACs, VKAs and no anticoagulants were 9.7%, 10.0% and 1.1%, respectively. In comparison to the VKA extractions, the DOAC extractions did not significantly increase the risk of postextraction bleeding (OR 0.69, 95% CIs 0.24 to 1.97; p=0.49).. The risk of postextraction bleeding was similar for DOAC and VKA extractions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Female; Hospitals, University; Humans; Japan; Logistic Models; Male; Multivariate Analysis; Postoperative Hemorrhage; Propensity Score; Retrospective Studies; Risk Assessment; Risk Factors; ROC Curve; Tooth Extraction; Venous Thromboembolism; Vitamin K; Warfarin

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only.. Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

Topics: Age Factors; Aged; Anticoagulants; Blood Coagulation; Cytochrome P-450 CYP2C9; Female; Hemorrhage; Humans; Male; Pharmacogenetics; Pharmacogenomic Variants; Prospective Studies; Recurrence; Risk Factors; Switzerland; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Vitamin K Epoxide Reductases

Since several trials have demonstrated that low-molecular-weight-heparin (LMWH) is superior to vitamin K antagonist (VKA) in preventing recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, guidelines now recommend LMWH monotherapy in this setting. We evaluated whether this shift resulted in improved outcomes in routine clinical practice. We performed a cohort study of consecutive patients with cancer-associated VTE during 2001 and 2010. We compared the risks for recurrent VTE, major bleeding and mortality between patients diagnosed before and after 2008 during a 6-month routine follow-up. A total of 381 patients were included, of which 234 (61.4%) were diagnosed before 2008. Before 2008, 23% of the patients were treated with LMWH; thereafter, this percentage was higher: 67%. The 6-month incidence for recurrent VTE was 8.6% in patients diagnosed before 2008 versus 7.5% for patients diagnosed after 2008 (risk difference [RD]: -1.1%; 95% confidence interval [CI]: -6.3, 5.3). The respective risks for major bleeding were 6.4 versus 4.8% (RD: -1.6%; 95% CI: -3.8 to 5.8), and 39.7 versus 41.5% (RD: 1.8%; 95% CI: -8.8, 12) for overall mortality. The mean time in therapeutic range (TTR) of patients treated with VKA was 61%. Despite a clear shift toward LMWH as agent of choice for cancer-associated VTE, we did not observe a clear improvement in terms of recurrent VTE and bleeding complications.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation; Clinical Decision-Making; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Netherlands; Recurrence; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Factor Xa (fXa)-inhibitors are as effective and safer than vitamin-K-antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35% and 48% of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95% CI 0.36-0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22% of the fXa inhibitor and 25% of the VKA associated bleeds (OR 0.83, 95% CI 0.47-1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Disease Progression; Factor Xa Inhibitors; Female; Gastrointestinal Diseases; Hemorrhage; Humans; Intracranial Hemorrhages; Male; Middle Aged; Odds Ratio; Venous Thromboembolism; Vitamin K

Topics: 4-Hydroxycoumarins; Anticoagulants; Atrial Fibrillation; Combined Modality Therapy; Humans; Indenes; Intraoperative Period; Observational Studies as Topic; Postoperative Hemorrhage; Risk Factors; Surgical Procedures, Operative; Venous Thromboembolism; Vitamin K

: Activated protein C resistance (APC-R) is assessed as part of thrombophilia screening, preferably in patients not taking oral anticoagulants. Rivaroxaban is known to alter some APC-R assays. To our knowledge, there have been no reports on the effect of rivaroxaban on the Russell viper venom time (RVVT)-based APC-R assay in real-life patients. In 168 consecutive outpatients suspected of having venous thromboembolism because of thrombophilia, APC-R was determined using the RVVT-based ProC Ac R assay (Siemens, Marburg, Germany). Patients receiving rivaroxaban or vitamin K antagonists were eligible. We measured rivaroxaban concentrations using the anti-Xa Biophen DiXal assay (Hyphen Biomed, Neuville-Sur-Oise, France) and factor V Leiden using the real-time PCR. APC-R was detected in 23 (28%) patients on rivaroxaban (n = 81) administrated 2-48 h since the blood draw, 15 (28%) patients on vitamin K antagonists (n = 54), and in four (12%) patients off anticoagulation (n = 33). Compared with nonanticoagulated patients, APC-R ratios were similar in patients on rivaroxaban, without any correlation with rivaroxaban concentrations (from 0 to 303 μg/l). None of the patients on rivaroxaban were found to have false-negative or false-positive APC-R ratios. Rivaroxaban concentrations up to 300 μg/l do not affect results of the ProC Ac R RVVT-based assay, which could be recommended in patients referred to a clinic for thrombophilia screening in whom the time since the last dose of rivaroxaban is uncertain.

Topics: Activated Protein C Resistance; Adult; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Prothrombin Time; Rivaroxaban; Thrombophilia; Venous Thromboembolism; Vitamin K

Treatment of venous thromboembolism (VTE) is classically based on oral vitamin K antagonists (VKAs). Due to the disadvantages and side effects of these drugs, monitoring the quality of anticoagulation by assessing time within therapeutic range (TTR) is recommended. Variables altering the TTR in patients with VTE are yet to be determined. The aim of this study was to analyze the quality of anticoagulation in patients with VTE treated with VKAs and to identify factors associated with poor-quality anticoagulation.. A retrospective observational study was performed in a cohort of 94 patients diagnosed with VTE undergoing treatment with VKAs. The TTR at 6 months was analyzed by the Rosendaal method. Univariate and a multivariate logistic regression analyses were performed to unravel factors that increase risk of poor-quality anticoagulation.. The TTR at 6 months in this cohort was 60.5%; 54 patients had a TTR < 65%. In the univariate analysis, female sex, age ≥ 65 years, and renal impairment were significantly associated with poor-quality anticoagulation. However, in the multivariate logistic regression model, only renal impairment was independently associated with poor-quality anticoagulation (odds ratio = 3.31, 95% confidence interval [1.049, 10.486], p = .041).. The average quality of anticoagulation was 60.5%, and a high percentage of patients had a quality of anticoagulation below recommended levels. Study findings indicate that renal impairment is an independent risk factor for poor-quality anticoagulation in patients with VTE treated with VKAs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

The clinical and economic benefits associated with apixaban treatment have been established in clinical trials and published economic evaluations. The benefits associated with apixaban could extend to improving hospital efficiencies, potentially influencing hospital resource use, and bed days. The objective of this study is to estimate the impact of 6-month treatment with apixaban vs low molecular weight heparin/vitamin k antagonist (LMWH/VKA) on hospital resource use among patients with venous thromboembolism (VTE).. A model was developed to assess the impact of apixaban vs LMWH/VKA for treatment of VTE and prevention of recurrences on hospital resource use and costs. Resource use items included total hospitalizations, length of stay (LOS), and emergency department (ED) visits, estimated for all incident VTE patients in the UK over a 5-year time horizon. Rates of hospitalizations, ED visits, and LOS associated with recurrent VTE, major, and clinically relevant non-major bleeding were obtained from the AMPLIFY trial; costs were obtained from UK published sources.. Over a 5-year time horizon, the model predicted that, compared to 6 months of LMWH/VKA, 6 months of apixaban led to 3,954 fewer hospitalizations (consisting of 2,341 fewer new admissions and 1,613 fewer re-admissions) and 32,214 fewer bed days, among 332,607 incident VTE patients. ED visits were reduced by 1,582. The reduction in hospital resource use led to a cost saving of ∼£4.5 million in a market of patients treated with apixaban as compared to a market treated with LMWH/VKA. Sensitivity analysis indicated these findings were robust over a wide range of inputs.. 6-month treatment with apixaban for treatment of VTE and prevention of recurrences on hospital resource use led to a reduction in hospitalizations and LOS in comparison to LMWH/VKA. These findings can help the efforts in reducing the growing burden of preventable re-admissions to hospitals.

Topics: Anticoagulants; Antifibrinolytic Agents; Databases, Factual; Emergency Service, Hospital; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Hospital Costs; Hospitalization; Humans; Length of Stay; Models, Economic; Pyrazoles; Pyridones; United Kingdom; Venous Thromboembolism; Vitamin K

Limited data are available on major bleeding (MB) occurring during treatment with vitamin K (VKAs) or direct oral anticoagulants (DOACs) outside clinical trials.. Patients hospitalized for MB while on treatment with VKAs or DOACs were included in a multicenter study to compare clinical presentation, management and outcome of bleeding. The primary study outcome was death at 30days.. Between September 2013 and September 2015, 806 patients were included in the study, 76% on VKAs and 24% on DOACs. MB was an intracranial hemorrhage in 51% and 21% patients on VKAs or DOACs, respectively (Odds Ratio [OR] 3.79; 95% confidence interval [CI] 2.59-5.54) a gastrointestinal bleeding in 46% and 25% patients on DOACs and VKAs, respectively (OR 2.62; 95% CI 1.87-3.68). Death at 30days occurred in 130 patients (16%), 18% and 9% of VKA and DOAC patients (HR 1.95; 95% CI 1.19-3.22, p=0.008). The rate of death at 30days was similar in VKA and DOAC patients with intracranial hemorrhage (26% and 24%; HR 1.05, 95% CI 0.54-2.02) and gastrointestinal bleeding (11% and 7%; HR 1.46, 95% CI 0.57-3.74) and higher in VKA than DOAC patients with other MBs (10% and 3%; HR 3.42, 95% CI 0.78-15.03).. Admission for ICH is less frequent for DOAC patients compared with VKA patients. Admission for gastrointestinal MB is more frequent for DOAC as compared to VKA patients. Mortality seems lower in patients with MBs while on DOACs than VKAs but this finding varies across different types of MBs.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Stroke; Survival Rate; Venous Thromboembolism; Vitamin K

The therapeutic management of venous thromboembolism (VTE) is rapidly evolving. Following the positive results of pivotal large-scale randomised trials, the non-vitamin K antagonist oral anticoagulants (NOACs) represent an important alternative to standard anticoagulation. In phase III studies, dabigatran was as effective as, and significantly safer than warfarin. Additional information on real-world data of dabigatran is now warranted. RE-COVERY DVT/PE is a multi-centre, international, observational (i. e. non-interventional) study enrolling patients with acute DVT and/or PE within 30 days after objective diagnosis. The study is designed with two phases. Phase 1 has a cross-sectional design, enrolling approximately 6000 patients independently of treatment choice, with the aim of providing a contemporary picture of the management of VTE worldwide. Phase 2 has a prospective cohort design, with follow-up of one year, enrolling 8000 patients treated with dabigatran or vitamin K antagonists (VKAs) with the aim of comparing their safety, defined by the occurrence of major bleeding, and effectiveness, defined by the occurrence of symptomatic recurrent VTE. RE-COVERY DVT/PE will complement both the results of other observational studies in this field and the results of phase III studies with dabigatran, in particular by assessing its clinical benefit in various patient subgroups treated in routine clinical practice.

Topics: Acute Disease; Anticoagulants; Antithrombins; Blood Coagulation; Cross-Sectional Studies; Dabigatran; Hemorrhage; Humans; Prospective Studies; Pulmonary Embolism; Research Design; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Prior analyses beyond clinical trials are yet to evaluate the projected lifetime benefit of apixaban treatment compared to low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) for treatment of venous thromboembolism (VTE) and prevention of recurrences. The objective of this study is to assess the cost-effectiveness of initial plus extended treatment with apixaban versus LMWH/VKA for either initial treatment only or initial plus extended treatment.. A Markov cohort model was developed to evaluate the lifetime clinical and economic impact of treatment of VTE and prevention of recurrences with apixaban (starting at 10 mg BID for 1 week, then 5 mg BID for 6 months, then 2.5 mg BID for an additional 12 months) versus LMWH/VKA for 6 months and either no further treatment or extended treatment with VKA for an additional 12 months. Clinical event rates to inform the model were taken from the AMPLIFY and AMPLIFY-EXT trials and a network meta-analysis. Background mortality rates, costs, and utilities were obtained from published sources. The analysis was conducted from the perspective of the United Kingdom National Health Service. The evaluated outcomes included the number of events avoided in a 1000-patient cohort, total costs, life-years, quality-adjusted life-years (QALYs), and cost per QALY gained.. Initial plus extended treatment with apixaban was superior to both treatment durations of LMWH/VKA in reducing the number of bleeding events, and was superior to initial LMWH/VKA for 6 months followed by no therapy, in reducing VTE recurrences. Apixaban treatment was cost-effective compared to 6-month treatment with LMWH/VKA at an incremental cost-effectiveness ratio (ICER) of £6692 per QALY. When initial LMWH/VKA was followed by further VKA therapy for an additional 12 months (i.e., total treatment duration of 18 months), apixaban was cost-effective at an ICER of £8528 per QALY gained. Sensitivity analysis suggested these findings were robust over a wide range of inputs and scenarios for the model.. In the UK, initial plus extended treatment with apixaban for treatment of VTE and prevention of recurrences appears to be economical and a clinically effective alternative to LMWH/VKA, whether used for initial or initial plus extended treatment.

Topics: Anticoagulants; Cost-Benefit Analysis; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Recurrence; Secondary Prevention; State Medicine; Treatment Outcome; United Kingdom; Venous Thromboembolism; Vitamin K

The risk of venous thromboembolic event (VTE) in multiple myeloma is particularly increased. Current guidelines recommend systematic VTE prophylaxis with vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on treatment received [e.g. use of IMiDs (thalidomide, lenalidomide and pomalidomide), alkylating agents or erythropoietin] and individual risk factors (e.g. history of VTE). The aim of this study was to describe strategy of VTE prophylaxis and prescribing of other antithrombotic agents during the first 6 months of multiple myeloma therapy, with stratification on IMiD-based regimens and drug and disease-related risk factors.. A retrospective cohort study of French beneficiaries from the health insurance database (SNIIRAM, Système National d'Information Inter-Régime de l'Assurance Maladie) was designed in the Midi-Pyrénées area (South West France). Patients starting a treatment for multiple myeloma in the period 2011-2014 were identified through hospital and chronic disease diagnoses.. Among the 236 incident multiple myeloma patients, 56% male (n = 133), 67% >65 years (n = 159) and 47% (n = 110) patients received an IMiD-based regimen. In these patients, 63% (n = 69) were identified as high-risk patients with indication for low molecular weight heparin or equivalent, and 37% (n = 41) were identified as low-risk with aspirin recommended. Among the high-risk IMiDs patients, 43% (30/69) currently received a VTE prophylaxis after starting their first regimen: 70% LWMH (21/30), 40% VKA (12/30), 10% UFH (3/30) and 13% (4/30) other drugs (rivaroxaban and fondaparinux); 33% of the patients (23/69) received an antiplatelet drug only, and 23% (16/69) did not receive any antithrombotic drug.. These results revealed lack of implementation of VTE prophylaxis in one out of high-risk multiple myeloma patients with IMiD. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Cohort Studies; Databases, Factual; Female; France; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Multiple Myeloma; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Retrospective Studies; Risk Factors; Venous Thromboembolism; Vitamin K

International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146-53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR = 0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates = 3% vs. 17%; p = 0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives.. Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained.. The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin = €2687 vs. VKA = €2012; France: dalteparin = €2053 vs. VKA = €1352: p < 0.001). However, when the incremental costs were combined with the utility gain, dalteparin had a cost of €6600 and €4900 per QALY gained in Austria and France, respectively. The analyses in patients with renal impairment suggested an even better economic profile, with the cost per QALY gained being less than €4000 in both countries.. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

Topics: Anticoagulants; Austria; Cost-Benefit Analysis; Dalteparin; Female; France; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Recurrence; Venous Thromboembolism; Vitamin K

Direct oral anticoagulants (DOACs) are an alternative for vitamin K antagonists (VKA) in the treatment and prevention of venous thromboembolism (VTE). Patient preferences for treatment options have not been extensively explored.. A random sample of 200 patients was obtained from those treated with VKA for deep vein thrombosis, pulmonary embolism or both at the Thrombosis Service Amsterdam. Preference for DOACs relative to VKA was assessed using a treatment trade-off technique administered as a questionnaire sent to all patients. The trade-off consisted of four consecutive scenarios: 1 (no need for laboratory control), 2 (decreased bleeding risk), 3 (less interactions with food and other drugs), 4 (higher efficacy).. The response rate was 68%. In scenario 1, 36% of patients would switch to a DOAC. This proportion rises to 57% (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.6-3.3) for scenario 2. Scenario 3 resulted in 64% of patients preferring a DOAC (OR 3.2; 95%CI 2.2-4.6). The advantage of greater efficacy did not result in a noteworthy change in the preference. Patients who were less satisfied with their current treatment, who were younger and those with higher education were more likely to prefer a DOAC over a VKA. The variables gender, treatment duration, and type of VKA were not significantly associated with DOAC preference.. Almost two-thirds of patients preferred DOACs over VKA. Patients considered the lack of regular laboratory monitoring, the lower risk of serious bleeding and less interactions with food and other drugs the most important arguments to switch to a DOAC.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Drug Monitoring; Drug Substitution; Educational Status; Female; Hemorrhage; Humans; Male; Middle Aged; Patient Preference; Risk Assessment; Risk Factors; Surveys and Questionnaires; Venous Thromboembolism; Vitamin K

Given the qualitative differences in the role of VKORC1 and CYP2C9 polymorphisms in Vitamin K antagonists (VKA) dosing variation between adults and children, we were interested in determining at what age these polymorphism begin to play a more significant role.. A prospective cohort study of 190 patients aged 1-86years receiving VKA for treatment of venous thromboembolism. Blood samples were collected beyond the acute thrombotic event when patients were on stable targeted INR (2-3) for plasma testing and VKORC1/CYP2C9 genotyping. Patient demographics including VKA dose were collected. Simple and multiple linear regression was used to assess the relationship of VKA dose with polymorphisms and weight, adjusted for quality of anticoagulation (INR, D-Dimer), liver (AST, ALT) and renal function.. In subjects 1-19years of age, weight explained 39.0% of dosing variation with VKORC1 and CYP2C9 playing a minor role. In contrast, in subjects 20-40years weight contributed 23%, VKORC1 44% and CYPC29 49% of the VKA dose variation.. Until the age of 19, weight has a far greater effect on VKA dosing variation than VKORC1 and CYP2C9 polymorphisms. During the age of 20-40years, VKORC1 and CYP2C9 play a significant role.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Child; Child, Preschool; Cytochrome P-450 CYP2C9; Drug Dosage Calculations; Female; Genotype; Humans; Infant; Male; Middle Aged; Polymorphism, Genetic; Prospective Studies; Venous Thromboembolism; Vitamin K; Vitamin K Epoxide Reductases; Young Adult

The approval of rivaroxaban has changed the landscape of treatment of venous thromboembolism (VTE). Little is known about the effect of rivaroxaban compared with vitamin K antagonists (VKA), when used in the everyday clinical practice. The aim of this study was to investigate the safety and effectiveness of rivaroxaban compared with VKAs among patients with VTE, using the Danish nationwide registries. All patients diagnosed with VTE and treated with either rivaroxaban or VKAs between 2013 and 2015 were included. A total of 12,318 patients were diagnosed with VTE and treated with VKAs [n=6,907] or rivaroxaban [n=5,411.]. Combined Cox regression analyses showed that the standardised absolute six-month risk of recurrent VTE was 3.03 % [95 % CI: 2.57 % to 3.48 %] in the rivaroxaban group and 3.13 % [95 % CI: 2.70 % to 3.56 %] in the VKA group (absolute risk difference of -0.11 % [95 % CI: -0.76 % to 0.54 %]). The standardised absolute six-months risk of bleeding was 2.28 % [95 % CI: 1.87 % to 2.67 %] for patients in the rivaroxaban group and 2.10 % [95 % CI: 1.78 % to 2.43 %] in the VKA group (absolute risk difference of 0.18 % [95 % CI: -0.34 % to 0.67]). In conclusion, rivaroxaban was associated with similar risk of recurrent VTE and bleeding compared with VKA.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Comorbidity; Denmark; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Recurrence; Registries; Risk; Rivaroxaban; Venous Thromboembolism; Vitamin K; Young Adult

ESSENTIALS: We performed a pooled analysis of 926 patients with cancer-associated incidental pulmonary embolism (IPE). Vitamin K antagonists (VKA) are associated with a higher risk of major hemorrhage. Recurrence risk is comparable after subsegmental and more proximally localized IPE. Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE.. Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. We aimed to provide the best available evidence on IPE management.. Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6-month follow-up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed.. In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6-month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval [CI] 3.7-8.3%), 4.7% (95% CI 3.0-6.8%), and 37% (95% CI 28-47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio [HR] 0.9; 95% CI 0.3-3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91-7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6-10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50-2.4).. These results support the current recommendation to anticoagulate cancer-associated IPE with LMWH and argue against different management of subsegmental IPE.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Data Interpretation, Statistical; Female; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Recurrence; Registries; Risk Factors; Tomography, X-Ray Computed; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

Outpatient treatment of acute venous thromboembolism (VTE) requires the selection of patients with a low risk of bleeding during the first few weeks of anticoagulation. The accuracy of four systems, originally derived for predicting bleeding in VTE treated with vitamin K antagonists (VKAs), was assessed in VTE patients treated with rivaroxaban.. All patients treated with rivaroxaban in the multinational EINSTEIN deep vein thrombosis (DVT) and pulmonary embolism (PE) trials were included. Major bleeding was defined as ≥2 g/dL drop in hemoglobin or ≥2-unit blood transfusion, bleeding in critical area, or bleeding contributing to death. The authors examined the incidence of major bleeding in patients with low-risk assignment by the systems of Ruiz-Gimenez et al. (score = 0 to 1), Beyth et al. (score = 0), Kuijer et al. (score = 0), and Landefeld and Goldman. (score = 0). For clinical relevance, the definition of low risk for all scores except Kuijer includes all patients < 65 years with no prior bleeding history and no comorbid conditions (current cancer, renal insufficiency, diabetes mellitus, anemia, prior stroke, or myocardial infarction).. A total of 4,130 patients (1,731 with DVT only, 2,399 with PE with or without DVT) were treated with rivaroxaban for a mean (±SD) duration of 207.6 (±95.9) days. Major bleeding occurred in 1.0% (40 of 4,130; 95% confidence interval [CI] = 0.7% to 1.3%) overall. Rates of major bleeding for low-risk patients during the entire treatment period were similar: Ruiz-Gimenez et al., 12 of 2,622 (0.5%; 95% CI = 0.2% to 0.8%); Beyth et al., nine of 2,249 (0.4%; 95% CI = 0.2% to 0.8%); Kuijer et al., four of 1,186 (0.3%; 95% CI = 0.1% to 0.9%); and Landefeld and Goldman, 11 of 2,407 (0.5%; 95% CI = 0.2% to 0.8%). At 30 days, major bleed rates for low-risk patients were as follows: Ruiz-Gimenez et al., five of 2,622 (0.2%; 95% CI = 0.1% to 0.4%); Beyth et al., five of 2,249 (0.2%; 95% CI = 0.1% to 0.5%); Kuijer et al., three of 1,186 (0.3%; 95% CI = 0.1% to 0.7%); and Landefeld and Goldman, seven of 2,407 (0.3%; 95% CI = 0.1% to 0.6%). No low-risk patient had a fatal bleed.. Four scoring systems that use criteria obtained in routine clinical practice, derived to predict low bleeding risk with VKA treatment for VTE, identified patients with less than a 1% risk of major bleeding during full-course treatment with rivaroxaban.

Topics: Aged; Anticoagulants; Clinical Decision-Making; Emergency Service, Hospital; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Predictive Value of Tests; Pulmonary Embolism; Risk Assessment; Rivaroxaban; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Point-of-care (POC) international normalized ratio (INR) monitoring by healthcare professionals could eliminate the need for venous blood sampling in non-self-monitoring (NSM) patients on vitamin K antagonists (VKA). However, few studies have investigated the impact of POC INR monitoring on the quality of treatment in these patients and real-world data on this issue are lacking.. To investigate the safety, efficacy and quality of anticoagulant control during POC INR monitoring as compared with laboratory INR monitoring in NSM patients.. We performed a retrospective cohort study using data from the anticoagulation clinic of the Star-Medical Diagnostic Center (Rotterdam, the Netherlands). Patients who received treatment with VKA between 29 May 2012 and 29 May 2014 were eligible. Percentage of time in therapeutic range (TTR) and incidence rates of major clinical events (all-cause mortality, hospitalization, major bleeding and ischemic stroke) were compared for the year before and year after introduction of POC monitoring. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals for major clinical events between exposure groups.. In total, 1973 patients during the 1-year laboratory-monitoring observation period and 1959 patients during the 1-year POC-monitoring observation period were included. Median TTR was significantly lower during POC monitoring (77.9%; 95% CI, 67.2-87.4) than during laboratory INR monitoring (81.0%; 95% CI, 71.1-90.5). Adjusted hazard ratios for major clinical events were all around unity.. Although associated with lower TTR, POC INR monitoring is a safe and effective alternative to laboratory INR monitoring in NSM patients on VKA.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Female; Follow-Up Studies; Heart Valve Prosthesis; Humans; International Normalized Ratio; Kaplan-Meier Estimate; Male; Middle Aged; Monitoring, Physiologic; Point-of-Care Systems; Proportional Hazards Models; Quality of Health Care; Reproducibility of Results; Retrospective Studies; Treatment Outcome; Venous Thromboembolism; Vitamin K

The SAMe-TT2R2 score has recently been proposed to predict the quality of vitamin K antagonist (VKA) anticoagulation control in patients with atrial fibrillation. We aimed at investigating whether the score is effective also in patients with venous thromboembolism (VTE). Patients included in the START-Register because started VKA therapy for a recent VTE episode and with > 3 months follow-up were analyzed. The score was calculated using the baseline patient's characteristics present in the electronic database of the registry, where all INR results were also available and analysed to calculate the time in therapeutic range (TTR). A total of 1308 patients (53.4 % female, median age 68 years) were analysed. During 998 patient-years follow-up, the median TTR was 63 %. The maximum score in the patients was 4, with 70 % of them having 0-1. INR controls within range (2.0-3.0) were significantly less prevalent in patients with score ≥ 2 vs 0-1 score (58.5 ± 20 % vs 61.5 ± 19 %, respectively, p = 0.046). Patients with score ≥ 2 vs 0-1 had a highly significant lower TTR during the first 3 months of therapy (53 ± 26 % and 61 ± 26 %, respectively; p=0.0001), difference mainly due to more time spent below 2.0 INR (38 ± 28 % vs 31.3 ± 26.7 %, respectively; p=0.0001). In conclusion, the study proved, for the first time, that the SAMe-TT2R2 score is useful to predict among VTE patients those who will have good (score 0-1) or less good (score ≥ 2) VKA anticoagulation control. The score can help decision-making in everyday clinical practice, especially when choosing between VKA and non-vitamin K antagonists direct anticoagulants.

Topics: Aged; Anticoagulants; Blood Coagulation; Cohort Studies; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Risk Factors; Thrombosis; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Vitamin K antagonists (VKA) are widely prescribed throughout the world. Patients on VKA therapy require international normalized ratio (INR) monitoring of venous blood to ensure the response remains within the therapeutic window. Point-of-care devices (POC-INR) can safely and easily monitor VKA efficacy but need to be evaluated in practice. The aim of this study was to assess the precision and accuracy of a new POC-INR (Qlab) compared to the laboratory plasma technique and the CoaguChek-XS system.. Consecutive patients on VKA referred to our institution were included. The study was designed to analyze 75 patients divided equally in the following subgroups: INR<2; INR=2-3; INR>3. INR was measured with an established laboratory method (INRREF) with an international sensitivity index of 1.0 and by two different POC-INRs: the Qlab (INRQlab) and the CoaguChek-XS systems (INRXS).. 82 patients treated mainly for atrial fibrillation or venous thromboembolism disease were included. Precision in therapeutic range (INR=2-3) of both POC-INRs was satisfactory with a coefficient of variation of 4.6% for the Qlab and 4.3% for the CoaguChek-XS. INRRef was 2.70 ± 1.36, INRQlab 2.59 ± 1.25 and INRXS 2.89 ± 1.37. Accuracy was low with the Qlab (R(2)=0.64) and higher with the CoaguChek-XS (R(2)=0.94). The mean relative difference from the INRRef was higher for the Qlab (18.4%) than for the CoaguChek-XS (12.9%). Clinical concordance was lower with the Qlab (78.2%) than with the CoaguChek-XS (90.0%).. This study suggests that the Qlab has accuracy limitations with clinical consequences. New POC-INR devices require careful evaluation prior to clinical implementation.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Drug Monitoring; Female; Humans; International Normalized Ratio; Male; Middle Aged; Point-of-Care Systems; Prothrombin Time; Venous Thromboembolism; Vitamin K

There has been a concern that major bleeding events (MBE) on direct-acting oral anticoagulants (DOACs) will be more difficult to manage than on vitamin K antagonists. Patients with cancer and DOAC-associated bleeding may be even more of a challenge to manage. We therefore reviewed the literature on bleeding in patients with cancer on DOACs. In addition, we performed an analysis of individual patient data from 5 phase III trials on treatment with dabigatran with focus on those with cancer. In 6 randomized trials the risk of MBE in patients with cancer was similar on treatment with DOACs compared to vitamin K antagonists. Bleeding was in the majority of patients managed with supportive therapy alone. In the individual patient data analysis there were no significant differences in use of hemostatic products, transfusion of red cells, effectiveness of management, bleeding-related mortality or 30-day all-cause mortality between patients with cancer treated with dabigatran or with warfarin. Local hemostatic therapy, including resection of the cancer site was more common in patients with gastrointestinal bleeding with cancer than among those without cancer. We conclude that management of bleeding in patients with cancer and on a DOAC does not pose a greater challenge than management of bleeding in patients without cancer.

Topics: Anticoagulants; Dabigatran; Hemorrhage; Humans; Neoplasms; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Humans; Long-Term Care; Pulmonary Embolism; Pyrazoles; Pyridones; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Essentials Vitamin K antagonists (VKA) in venous thromboembolism (VTE) lower the risk of recurrences. 41 841 VKA-treated VTE patients had 1242 recurrent VTEs on therapy or early after cessation. An increased risk of recurrence was found in the first 120 days after VKA cessation. Patient education for the early detection of recurrent VTE after VKA cessation is recommended.. Background The standard treatment for venous thromboembolism (VTE) and the prevention of recurrent VTE (rVTE) consists of anticoagulant therapy. The optimal duration of anticoagulation depends on the presence of risk factors for rVTE. Objectives To estimate the risk of rVTE in association with time since discontinuation of vitamin K antagonist (VKA) treatment. Methods From the UK Clinical Practice Research Datalink with linked information on hospitalization and cause of death, a cohort of patients with a first VTE receiving initial VKA treatment between 2001 and 2013 was formed. With a nested case-control approach, patients with incident rVTE (cases) were matched to patients with VTE but without rVTE (controls). Adjusted rate ratios (RRs) of rVTE associated with time since VKA discontinuation relative to current VKA use were estimated from conditional logistic regression. Results The VTE cohort comprised 41 841 patients with 1242 rVTEs and 6205 matched controls. The RR of rVTE was increased within 60 days following VKA discontinuation (RR 2.23, 95% confidence interval [CI] 1.71-2.91) and within 61-120 days following VKA discontinuation (RR 1.49, 95% CI 1.08-2.05) relative to current VKA use. The increased RR corresponded to excess incidence rates of 6.72 (95% CI 3.90-10.06) rVTE cases per 100 person-years within 60 days, and of 2.68 (95% CI 0.42-5.58) rVTE cases per 100 person-years within 61-120 days after VKA discontinuation. Conclusions VKA discontinuation results in a transient increased risk of rVTE, which peaks within 60 days and lasts for up to 120 days after VKA discontinuation. Specific patient education for increased vigilance for signs and symptoms of recurrences is recommended in this period.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Body Mass Index; Case-Control Studies; Cohort Studies; Female; Fibrinolytic Agents; Humans; Incidence; Male; Middle Aged; Patient Education as Topic; Recurrence; Regression Analysis; Risk Factors; United Kingdom; Venous Thromboembolism; Vitamin K; Young Adult

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow Neoplasms; Cohort Studies; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myeloproliferative Disorders; Premedication; Pulmonary Embolism; Recurrence; Retrospective Studies; Venous Thromboembolism; Vitamin K

Cost-effectiveness analysis of a 6-month treatment of apixaban (10 mg/12h, first 7 days; 5 mg/12h afterwards) for the treatment of the first event of venous thromboembolism (VTE) and prevention of recurrences, versus low-molecular-weight heparins/vitamin K antagonists treatment (LMWH/VKA).. A lifetime Markov model with 13 health states was used for describing the course of the disease. Efficacy and safety data were obtained from AMPLIFY and AMPLIFY-EXT clinical trials; health outcomes were measured as life years gained (LYG) and quality-adjusted life years (QALY). The chosen perspective of this analysis has been the Spanish National Health System (NHS). Drugs, management of VTE and complications costs were obtained from several Spanish data sources (€, 2014). A 3% discount rate was applied to health outcomes and costs. Univariate and probabilistic sensitivity analyses (SA) were performed in order to assess the robustness of the results.. Apixaban was the most effective therapy with 7.182 LYG and 5.865 QALY, versus 7.160 LYG and 5.838 QALYs with LMWH/VKA. Furthermore, apixaban had a lower total cost (€13,374.70 vs €13,738.30). Probabilistic SA confirmed dominance of apixaban (led to better health outcomes with less associated costs) in 89% of the simulations.. Apixaban 5 mg/12h versus LMWH/VKA was an efficient therapeutic strategy for the treatment and prevention of recurrences of VTE from the NHS perspective.. Objetivo: Analizar la relación coste-efectividad de 6 meses de tratamiento con apixaban (10 mg/12 h, 7 primeros días; 5 mg/12 h después) para el primer evento de tromboembolismo venoso (TEV) y prevención de recurrencias, frente a heparinas de bajo peso molecular/antagonistas de vitamina K (HBPM/ AVK). Material y métodos: Se ha empleado un modelo de Markov con 13 estados de salud que describen la evolución de la enfermedad a lo largo de la vida de los pacientes. Los datos de eficacia y seguridad se han obtenido de los ensayos clínicos AMPLIFY y AMPLIFY- EXT, calculándose los años de vida ganados (AVG) y los años de vida ajustados por calidad (AVAC) de las opciones terapéuticas evaluadas. En este análisis se adoptó la perspectiva del Sistema Nacional de Salud (SNS). El coste de la medicación, de las complicaciones y del manejo del TEV se obtuvo de distintas fuentes españolas (€, 2014). Se aplicó una tasa de descuento anual del 3% a costes y beneficios en salud. Se realizaron análisis de sensibilidad univariante y probabilístico (ASP) para evaluar la robustez de los resultados. Resultados: Apixaban generó mejores resultados en salud con 7,182 AVG y 5,865 AVAC, frente a 7,160 AVG y 5,838 AVAC para HBPM/AVK, y con menor coste total (13.374,70 € versus 13.738,30 €). El ASP confirmó la dominancia de apixaban (produce mejores resultados con menores costes asociados) en el 89% de las simulaciones. Conclusiones: Apixaban 5 mg/12 h versus HBPM/AVK fue una estrategia eficiente para el SNS en el tratamiento y prevención de recurrencias de TEV.

Topics: Anticoagulants; Cost-Benefit Analysis; Heparin, Low-Molecular-Weight; Humans; Markov Chains; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Secondary Prevention; Spain; Treatment Outcome; Venous Thromboembolism; Vitamin K

Cancer and venous thrombo-embolic disease (VTE) are closely related. Indeed, cancer can reveal VTE and VTE can be the first sign of cancer. Low molecular weight heparin (LWMH) is now the first line treatment in cancer patients. Compliance with marketing authorizations and guidelines are crucial for patient-centered decision-making. This work deals with the prescription of LWMH in patients who develop VTE during cancer in order to better recognize what should or should not be done. The patient's wishes must be taken into consideration when making the final therapeutic decision. The other treatments are discussed: vitamin K antagonists and direct oral anticoagulants (DOACs) may be useful.

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Risk Factors; Venous Thromboembolism; Venous Thrombosis; Vitamin K

D-dimer levels are closely related to the clinical status of deep vein thrombosis (DVT). This study aimed to investigate the factors which were associated with the normalization of D-dimer level by vitamin K antagonist (VKA) therapy, the maintenance of normal D-dimer levels for 6 months during VKA therapy, and the recurrent elevations of D-dimer above normal level after VKA withdrawal, in DVT of the legs.. The 469 consecutive patients with first-episode leg swelling were examined. All blood tests were measured from the initially sampled blood before the administration of medications.. Of the 469 patients, 288 (61.4%) showed positive D-dimer test. Radiologic examinations, including Doppler ultrasound and computed tomography venography, of the 288 patients revealed positive DVT of the legs in 135 (46.9%) patients and of these, 122 with total follow-up durations of >6 months were enrolled in this study. Linear regression analysis of 100 patients who experienced D-dimer normalization revealed initial D-dimer levels were positively correlated with D-dimer normalization time during VKA therapy (P = 0.010). Logistic regression analysis showed initial D-dimer level was negatively associated with the normalization of D-dimer levels by VKA therapy (P = 0.045), and being a woman (P = 0.005) and having lower protein C (P = 0.002) level had negative impacts on the maintenance of normal D-dimer levels for 6 months during VKA therapy. Finally, after VKA withdrawal, the recurrent elevations of D-dimer above normal level were more likely to occur in women than in men (P = 0.004).. From these observations, it is suggested that higher initial D-dimer level, lower protein C level, and female gender may be the adverse risk factors for the treatment of DVT of the legs using VKA.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Biomarkers; Chi-Square Distribution; Computed Tomography Angiography; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Humans; Linear Models; Logistic Models; Lower Extremity; Male; Middle Aged; Perfusion Imaging; Phlebography; Predictive Value of Tests; Protein C; Retrospective Studies; Risk Factors; Sex Factors; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ultrasonography, Doppler; Up-Regulation; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Warfarin; Young Adult

Previous studies have shown that, despite the higher risk of bleeding, the elderly still benefit from taking anticoagulants if they have a stringent indication. However, owing to the relatively low number of patients older than 90 years in these studies, it is unknown whether this benefit is also seen with the eldest patients.. To determine how the risk of bleeding and thrombosis is associated with age in patients older than 70 years who were treated with a vitamin K antagonist (VKA).. A matched cohort study was conducted of patients at a thrombosis service who were treated with a VKA between January 21, 2009, and June 30, 2012. All 1109 patients 90 years or older who were treated with a VKA were randomly matched 1:1:1 with 1100 patients aged 80 to 89 years and 1104 patients aged 70 to 79 years based on duration of VKA treatment. Data analysis was conducted from April 2015 to April 2016.. The primary outcome was a composite of clinically relevant nonmajor and major bleeding. Secondary outcomes included thromboses and quality of VKA control.. During 6419 observation-years, 713 of the 3313 patients (1394 men and 1919 women) had 1050 bleeding events. The risk of bleeding was not significantly increased in patients aged 80 to 89 years (event rate per 100 patient-years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89-1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05-1.50) compared with patients aged 70 to 79 years (ER, 14.8). The point estimates for major bleeding (including fatal) were comparable for patients aged 80 to 89 years (ER, 1.0; HR, 1.09; 95% CI, 0.60-1.98) and those 90 years or older (ER, 1.1; HR, 1.20; 95% CI, 0.65-2.22) compared with those aged 70 to 79 years (ER, 0.9). The increase in bleeding risk was sharper in men than in women. Eighty-five patients (2.6%) developed a thrombotic event. Risk of thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22-3.75) and 80s (HR, 1.75; 95% CI, 1.002-3.05) than for patients in their 70s. Vitamin K antagonist control became significantly poorer with rising age, which partly explained the increased bleeding risk in patients 90 years or older, but most of the increased risk of thrombosis was not mediated by VKA control.. These clinical practice data of patients considered eligible for anticoagulation show that the bleeding risk with a VKA only mildly increases after the age of 80 years, while there is a sharp increase in the risk of thrombosis in the same age group.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cohort Studies; Female; Hemorrhage; Humans; Male; Proportional Hazards Models; Risk Factors; Venous Thromboembolism; Vitamin K

Currently available anticoagulants have limitations for long-term treatment of venous thromboembolism (VTE). We have evaluated the efficacy and safety of direct oral anticoagulants (DOACs) for extended treatment of VTE. Four randomized controlled trials (RCTs) comparing DOACs (apixaban, rivaroxaban, and dabigatran) with placebo or warfarin for extended treatment of VTE were published. Primary efficacy outcome was recurrent VTE or VTE-related death, and primary safety outcome was major bleeding. DOACs significantly lower the risk of recurrent VTE or VTE-related death compared to placebo/warfarin, as well as all-cause mortality. Risk of major bleeding is not different with DOACs compared to placebo/warfarin. However, DOACs are associated with a significantly higher rate of the composite of major and clinically relevant bleeding compared to placebo. In conclusion, DOACs are effective and safe for the extended treatment of VTE, and may reduce the risk of all-cause mortality.

Topics: Administration, Oral; Anticoagulants; Aspirin; Dabigatran; Humans; Italy; Pyrazoles; Pyridones; Rivaroxaban; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

The SAMe-TT. We included all consecutive patients with VTE treated with VKA for >90days. We collected all variables included in the score (female sex, age<60years, medical history [>2 comorbidities], treatment [interacting drugs: e.g. amiodarone], tobacco [doubled], race [doubled]) and analyzed the relationship between the SAMe-TT. 135 patients were treated with VKA for >90days, with a median TTR 65%. No differences in INR controls within range were found between patients with score 0-1 vs ≥2 (64.7±19.5% vs 66.0±20.5%, p=0.728). No differences were found in INR controls above (21.5±18.1% vs 21.2±21.3%, p=0.605) or below (3.9±14% vs 2.9±15.9%, p=0.517) the therapeutic range.

Topics: Acenocoumarol; Algorithms; Anticoagulants; Blood Coagulation; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; ROC Curve; Venous Thromboembolism; Vitamin K; Warfarin

Anticoagulants increase the risk of heavy menstrual bleeding (HMB). We sought to investigate the incidence, predictors and management of HMB in women on rivaroxaban compared to those on vitamin K antagonists (VKA). We addressed the issue as to whether HMB is associated with VTE recurrences. We performed a single-center prospective study in menstruating women aged 18-55years treated with rivaroxaban or VKA≥3months since the index VTE episode. Seventy six women on rivaroxaban and 45 patients on VKA were included. Patients on rivaroxaban more commonly reported HMB compared with those on VKA (31 [41%] vs. 8 [18%], p=0.009). Women treated with rivaroxaban more frequently needed interventions to reduce menstruation compared with those on VKA (29 [38%] vs. 6 [13%], p=0.004). During the median follow-up time of 13months, there were 8 (11%) recurrent VTE on rivaroxaban and 3 (7%) on VKA (p=0.5). Rivaroxaban treatment predisposed to HMB (odds ratio [OR] 3.2, 95% [confidence interval] CI 1.4-8.2, p=0.007) and the interruption of anticoagulant treatment for 2-3days (OR 3.2, 95% CI 1.1-11.6, p=0.033). HMB during the rivaroxaban treatment predisposed to recurrent VTE (OR 5.3, 95% CI 1.1-33.3, p=0.038). In menstruating women following VTE, rivaroxaban is associated with a two-fold higher risk of HMB compared with VKA. HMB predisposes to recurrent VTE episode, most likely due to the short interruptions of anticoagulation.

Topics: Adult; Anticoagulants; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Middle Aged; Prospective Studies; Recurrence; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Vitamin K; Young Adult

Polypharmacy, defined as the concomitant use of multiple medications, is very common in the elderly and may trigger drug-drug interactions and increase the risk of falls in patients receiving vitamin K antagonists.. To examine whether polypharmacy increases the risk of bleeding in elderly patients who receive vitamin K antagonists for acute venous thromboembolism (VTE).. We used a prospective cohort study.. In a multicenter Swiss cohort, we studied 830 patients aged ≥ 65 years with VTE.. We defined polypharmacy as the prescription of more than four different drugs. We assessed the association between polypharmacy and the time to a first major and clinically relevant non-major bleeding, accounting for the competing risk of death. We adjusted for known bleeding risk factors (age, gender, pulmonary embolism, active cancer, arterial hypertension, cardiac disease, cerebrovascular disease, chronic liver and renal disease, diabetes mellitus, history of major bleeding, recent surgery, anemia, thrombocytopenia) and periods of vitamin K antagonist treatment as a time-varying covariate.. Overall, 413 (49.8 %) patients had polypharmacy. The mean follow-up duration was 17.8 months. Patients with polypharmacy had a significantly higher incidence of major (9.0 vs. 4.1 events/100 patient-years; incidence rate ratio [IRR] 2.18, 95 % confidence interval [CI] 1.32-3.68) and clinically relevant non-major bleeding (14.8 vs. 8.0 events/100 patient-years; IRR 1.85, 95 % CI 1.27-2.71) than patients without polypharmacy. After adjustment, polypharmacy was significantly associated with major (sub-hazard ratio [SHR] 1.83, 95 % CI 1.03-3.25) and clinically relevant non-major bleeding (SHR 1.60, 95 % CI 1.06-2.42).. Polypharmacy is associated with an increased risk of both major and clinically relevant non-major bleeding in elderly patients receiving vitamin K antagonists for VTE.

Topics: Aged; Aged, 80 and over; Anticoagulants; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Polypharmacy; Prospective Studies; Risk Factors; Switzerland; Venous Thromboembolism; Vitamin K

After 6months, little is known about the optimal anticoagulant strategy for an acute episode of VTE in cancer patients.. The objective was to determine the risk of recurrent VTE and anticoagulant-related bleeding at 6months of follow-up and after 6months, in cancer patients who received tinzaparin during at least 3months for an acute episode of VTE. We conducted a multicenter retrospective cohort study from January 2004 to March 2011.. Two hundred fifty patients were included. Stopping anticoagulation before 6months in patients considered at low risk by physicians (i.e.; patients who had prior cancer surgery) and for another reason than bleeding or death was the only factor associated with a significant increased risk of recurrent VTE (OR 7.2 95%CI, 2.0-25.7; p=0.002). The type of anticoagulation did not influence the risk of recurrent VTE. We found a trend towards an increased risk of recurrent VTE when anticoagulation was stopped because of major bleeding while on anticoagulant therapy and patients with metastatic cancer (OR 2.3, 95%CI, 0.9-5.4; p=0.07; and OR 1.8 95%CI, 1.0-3.3; p=0.07; respectively). No factors were found to increase the risk of major bleeding at 6months and after. The overall mortality was 42.8%.. The risk of recurrent VTE was mainly related to early discontinuation of anticoagulation in patients considered at low risk of recurrence (after surgery). When the anticoagulation was stopped before the sixth month, the risk was eight fold higher. After 6month, the risks of recurrent VTE, major bleeding and death were similar in patients with either VKA or tinzaparin when patients were treated according to the guidelines.

Topics: Anticoagulants; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasm Metastasis; Neoplasms; Recurrence; Retrospective Studies; Risk Factors; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKA) are widely used in atrial fibrillation and venous thromboembolism (VTE). Their efficacy and safety depend on individual time in the therapeutic range (iTTR). Due to the variable dose-response relationship within patients, also patients with initially stable VKA treatment may develop extreme overanticoagulation (EO). EO is associated with an immediate bleeding risk, but it is unknown whether VKA treatment will subsequently restabilise. We evaluated long-term quality of VKA treatment and clinical outcome after EO. EO was defined as international normalized ratio (INR) ≥ 8.0 and/or unscheduled vitamin K supplementation. We included a consecutive cohort of initially stable atrial fibrillation and venous thromboembolism patients. In EO patients, the 90 days pre- and post-period were compared. In addition, patients with EO were compared with patients without EO using a matched 1:2 cohort. Of 14,777 initially stable patients, 800 patients developed EO. The pre-period was characterised by frequent overanticoagulation, and half of EO patients had an inadequate iTTR (< 65 %). After EO, underanticoagulation became more prevalent. Although the mean time between INR-measurements decreased from 18.6 to 13.2 days, after EO inadequate iTTR became more frequent (62 %), p-value < 0.001. A 2.3 times (95 % confidence interval [CI] 2.0-2.5) higher risk for iTTR< 65 % after EO, was accompanied by increased risk of bleeding (hazard ratio [HR] 2.1;CI 1.4-3.2), VKA-related death 17.0 (HR 17.0;CI 2.1-138) and thrombosis (HR 5.7;CI 1.5-22.2), compared to the 1600 controls. In conclusion, patients continuing VKA after EO have long-lasting inferior quality of VKA treatment despite intensified INR-monitoring, and an increased risk of bleeding, thrombosis and VKA-related death.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Dose-Response Relationship, Drug; Drug Monitoring; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Netherlands; Predictive Value of Tests; Quality of Health Care; Retrospective Studies; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) impacts ∼900,000 individuals annually in the US, causing up to 100,000 deaths. Patients experiencing VTE have heightened risk of recurrence. Initial parenteral anti-coagulation is standard therapy for acute VTE followed by ≥3 months of warfarin, which introduces the risk of major bleeding. Balancing increased risks of bleeding and recurrent VTE remains challenging. Recent clinical trials suggest that rivaroxaban, an oral direct inhibitor of factor Xa, provides an effective, safe, simplified approach to treatment. This study considers the economic implications of these data.. This study modeled inpatient, acute, and 1-year VTE costs for a hypothetical commercial plan with 1 million members. At baseline, all VTE patients receive standard therapy. Alternatively, 25% are instead treated with rivaroxaban. Model inputs are trial- and literature-based.. Standard therapy for VTE consumes 9474 inpatient days ($31.6 million). Added to that is treatment for 74 recurrences ($1.4 million); major and non-major bleed events ($1 million); and direct costs of anti-coagulation ($5.3 million). Alternatively, a 25% shift to oral anti-coagulation with rivaroxaban reduces inpatient days (by 5%); associated acute-care costs (by 2%); recurrences and costs (by 6%). Four major bleeding events are prevented, at the cost of one additional non-major bleeding event, which, taken together, reduce net utilization by 9%. Direct costs of anti-coagulation increase by 5%.. The reduction in inpatient utilization, recurrences, and major bleeding resulting from a 25% shift from standard therapy to rivaroxaban following acute VTE would conserve ∼$860,475 for every 1 million commercial health plan enrollees.

Topics: Anticoagulants; Computer Simulation; Cost-Benefit Analysis; Drug Therapy, Combination; Enoxaparin; Hemorrhage; Hospitalization; Humans; Models, Econometric; Pulmonary Embolism; Recurrence; Rivaroxaban; United States; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Female; Humans; Male; Quality of Health Care; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Humans; Incidence; Myocardial Infarction; Thromboembolism; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Recommendations for management of cancer-related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low-quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies.. Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression.. We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low-molecular-weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11-0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45-2.63). The bleeding rate did not increase significantly with dose escalation.. Morbidity and mortality are high after recurrence of cancer-related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Topics: Aged; Anticoagulants; Chi-Square Distribution; Drug Substitution; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Prospective Studies; Recurrence; Registries; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Blood Coagulation; Fibrinolytic Agents; Hemorrhage; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Retrospective Studies; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Hemorrhage; Humans; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Venous Thromboembolism; Vitamin K

Topics: Adolescent; Adult; Aged; Anticoagulants; Antiphospholipid Syndrome; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Rivaroxaban; Venous Thromboembolism; Vitamin K; Young Adult

The initial management or venous thromboembolism (VTE) corresponds to the first 3 months of treatment. Pulmonary embolism (PE) are mostly hospitalized. Serious PE associated with hemodynamic instability has to be admitted in intensive care unit due to the need for fibrinolytics. PE without any risk factor for VTE recurrences or death could be followed as outpatient. Conversely, deep vein thrombosis (DVT), including proximal DVT are not hospitalized with the xception of patients with serious risk factors. The therapeutic strategy is identical between DVT and PE treatment with an acute phase with either parenteral anticoagulants, especially low molecular weight heparins or fondaparinux, or by an intensive dose of direct oral anticoagulant such as rivaroxaban or apixaban. Then maintenance therapy has to be prescribed either with vitamin K antagonists with overlapping parenteral anticoagulants for at least 72 hours, or with a maintenance dose of apixaban or rivaroxaban.

Topics: Anticoagulants; Blood Coagulation Tests; Fibrinolytic Agents; Humans; Pulmonary Embolism; Risk Assessment; Venous Thromboembolism; Vitamin K

Venous thromboembolism occurs in up to 10% of patients with cancer. The incidence of thrombosis is varying with the nature, the histologic type and the stage of the disease. The risk of thrombosis is also increased by most of anticancer treatments and supportive care. Although long-term prophylactic treatment is able to decrease the rate of venous thromboembolism in patients with cancer, the absolute reduction is too low to give long-term prophylaxis, except for some rare exceptions. The treatment of cancer associated thrombosis is based on the use of low-molecular weight heparin for at least three to six months. In most cases, anticoagulation should be given for a longer period but the choice of the drug should be indi- vidualized on the basis of the evolution of the underlying cancer, overall prognosis, tolerance of injections and patient's preference. Recurrent venous thromboembolism during treatment with low-molecular weight heparin can be treated with a 10% dose escalation. Dose should be adjusted during periods of thrombocytopenia. Finally, the direct oral anticoagulants have not been compared with low-molecular weight heparins for the treatment of cancer associated thrombosis.

Topics: Anticoagulants; Humans; Neoplasms; Pulmonary Embolism; Venous Thromboembolism; Vitamin K

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.

Topics: Aged; Aged, 80 and over; Anticoagulants; Drug Prescriptions; Female; Fibrinolytic Agents; Follow-Up Studies; Guideline Adherence; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Time Factors; Venous Thromboembolism; Vitamin K

The percentage of time in therapeutic range (TTR) is a measure of anticoagulation quality with vitamin K antagonists (VKAs). The method most commonly used in clinical trials is the Rosendaal TTR. However, the application of this method in daily practice for clinical decision lacks appropriate instruments. We aimed to evaluate the percentage of tests within the target international normalized ratio (INR) (tests ratio) as a surrogate of Rosendaal TTR. We performed an observational and retrospective study to evaluate the TTR according to the Rosendaal method and tests ratio. We included all outpatients who attended the cardiology anticoagulation clinic of a Portuguese hospital (2011-2013), whose target INR was 2.0-3.0. Three hundred and seventy-seven VKA-treated patients followed for a mean 1.3 years were evaluated. Rosendaal methold and tests ratio significantly correlated (Rho Spearman 0.88, P < 0.001), but the Bland-Altman plot evaluation showed a clinically relevant data dispersion [95% confidence interval (95% CI) -12.9 to 23.1] around a mean difference in TTR -5.1% using the tests ratio method. The linear regression Passing-Bablok confirmed the existence of significant data dispersion and systematic differences. The tests ratio less than 60% had a sensitivity of 91.6%, specificity of 72.3%, positive predictive value (PPV) of 72.2% and negative predictive value (NPV) of 91.6%, for the diagnosis of patients inadequately anticoagulated (Rosendaal TTR <60%). Tests ratio had a c-statistics of 0.94 (95% CI 0.91-0.96). Number of tests in 6 months had a c-statistics of 0.70 (95% CI 0.65-0.75). Tests ratio underestimated TTR in 5% and was not considered equivalent to Rosendaal TTR due to the high variability between methods. Nevertheless, the use of tests ratio less than 60% may be a reasonable option to detect inadequate anticoagulation, as it is a sensitive method and excluded most of the patients with adequate control.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Diabetes Mellitus; Female; Heart Failure; Humans; Hypertension; International Normalized Ratio; Linear Models; Male; Outpatients; Predictive Value of Tests; Retrospective Studies; Stroke; Venous Thromboembolism; Vitamin K

We report the case of a woman who developed unexplained warfarin hypersensitivity after undergoing surgery to remove her ovaries. Presurgery, the patient's international normalised ratios (INR) control was stable and uneventful but 11 days after her operation she presented with extremely high (frequently ≥10) INR. Warfarin was discontinued on day 24 postoperation but 11 days later the plasma warfarin concentration was high at 4.8 mg/l (therapeutic range 0.7-2.3 mg/l). After cessation of warfarin, she required frequent doses of oral and intravenous vitamin K1 (totalling 48 mg) as well as two doses of prothrombin complex concentrate to normalise the INR. The patient was switched from warfarin to heparin, then to dabigatran with no further thrombosis or bleeding. While on heparin, the kinetics of warfarin elimination and vitamin K status were found to be normal and the reason for the onset of the extreme sensitivity to warfarin remains unknown.

Topics: Anticoagulants; Blood Coagulation Factors; Dabigatran; Drug Hypersensitivity; Drug Substitution; Female; Heparin; Humans; International Normalized Ratio; Middle Aged; Ovariectomy; Venous Thromboembolism; Vitamin K; Warfarin

Rivaroxaban is a convenient oral anticoagulant for patients with venous thromboembolism (VTE). The impact of rivaroxaban and vitamin K antagonists (VKAs) on abnormal uterine bleeding (AUB) in real life has not been previously explored.. We performed a single-center retrospective study on AUB in female VTE patients of reproductive age who were treated with either rivaroxaban or VKAs.. Questionnaire results were available for 52 patients in each treatment group. Approximately two thirds of all women reported AUB after initiation of anticoagulant therapy. Patients using rivaroxaban were more likely to experience prolonged (>8days) menstrual bleeding (27 % vs. 8.3%, P=0.017). Rivaroxaban treatment increased the duration of menstrual bleeding from median 5 (IQR 3.5-6.0) days before start of treatment to 6 (IQR 4.1-8.9) days (P<0.001). VKA treatment did not lead to significant prolongation of the menstrual period. Patients on rivaroxaban more frequently reported an unscheduled contact with a physician for AUB than women using VKAs (41% vs. 25%, P=0.096). They also reported increased need for menorrhagia-related medical or surgical intervention (25% vs. 7.7%, P=0.032) and had more adaptations of anticoagulant therapy (15% vs. 1.9%, P=0.031).. AUB is frequent after initiation of anticoagulant therapy for acute symptomatic VTE. Compared to VKAs, rivaroxaban was associated with prolonged menstrual bleeding and more medical interventions and adaptation of anticoagulant treatment for AUB. These data can guide proactive discussion with patients starting anticoagulant therapy.

Topics: Adult; Anticoagulants; Female; Humans; Retrospective Studies; Risk Factors; Rivaroxaban; Uterine Hemorrhage; Venous Thromboembolism; Vitamin K; Young Adult

The outcome of patients with acute venous thromboembolism (VTE) and abnormal platelet count (PlC) at baseline has not been consistently studied. In real-world clinical practice, a number of patients with abnormal PlC receive vitamin K antagonists (VKAs) to treat acute VTE despite their higher risk of bleeding.We used the Registro Informatizado de Enfermedad TromboEmbólica registry database to compare the rate of major bleeding in patients receiving VKA for long-term therapy of acute VTE according to PlC levels at baseline. Patients were categorized as having very low (<100,000/μL), low (100,000-150,000/μL), normal (150,000-300,000/μL), high (300,000-450,000/μL), or very high (>450,000/μL) PlC at baseline.Of 55,369 patients recruited as of January 2015, 37,000 (67%) received long-term therapy with VKA. Of these, 611 patients (1.6%) had very low PlC, 4006 (10.8%) had low PlC, 25,598 (69%) had normal PlC, 5801 (15.6%) had high PlC, and 984 (2.6%) had very high PlC at baseline. During the course of VKA therapy (mean, 192 days), there were no differences in the duration or intensity (as measured by international normalized ratio levels) of treatment between subgroups. The rate of major bleeding was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, 0.34%, and 0.50%, respectively. Patients with very low or very high PlC levels were more likely to have severe comorbidities.We found a nonlinear "U-shaped" relationship between PlC at baseline and major bleeding during therapy with VKA for VTE. Consistent alteration of PlC values at baseline suggested a greater frailty.

Topics: Aged; Anticoagulants; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Platelet Count; Registries; Treatment Outcome; Venous Thromboembolism; Vitamin K

Although risk factors for MI have been described in the general population, there is a lack of data on the assessment of risk factors associated with MI in venous thromboembolism (VTE) patients.. The purpose of this study was to identify risk factors associated with MI in VTE patients.. Health insurance claims between January 2004 and September 2008 from the Ingenix IMPACT database were analyzed. Patients aged ≥18 years were identified as of the date of their first VTE diagnosis with ≥1 year of continuous insurance coverage before the index VTE. The risk of MI for VTE patients with 1, 2, and ≥3 major risk factors as identified by published guidelines was calculated. Multivariate Cox proportional hazard models were conducted to identify the most predictive risk factors associated with MI.. A total of 177,885 VTE patients were identified; 4412 (2.5%) developed an MI during a mean follow-up period of 1.3 years. Previous MI, age (≥65 years), and coronary artery disease were the most predictive risk factors of MI with adjusted hazard ratios (HRs; 95% CI) of 5.47 (5.01-5.97), 1.78 (1.66-1.91), and 1.60 (1.48-1.74), respectively. Adjusted HRs (95% CI) for VTE patients with 1, 2, and ≥3 major risk factors relative to no major risk factor were 2.34 (1.94-2.81), 3.21 (2.67-3.85), and 6.93 (5.85-8.22), respectively.. These included possible inaccuracies or omissions in diagnoses, classification bias such as the identification of false-positive MI events, and the likely undercoding of some risk factors such as social issues.. Traditional major cardiovascular risk factors are also predictive of MI in VTE patients. Having multiple major risk factors significantly increases the probability of developing MI events in VTE patients.

Topics: Anticoagulants; Antihypertensive Agents; Cohort Studies; Coronary Artery Disease; Female; Humans; Insurance, Health; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Risk Factors; Stroke; Venous Thromboembolism; Vitamin K

Topics: Atrial Fibrillation; Female; Humans; Male; Venous Thromboembolism; Vitamin K

Topics: Atrial Fibrillation; Female; Humans; Male; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3-6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.

Topics: Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Postoperative Complications; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Thrombocytopenia; Venous Thromboembolism; Vitamin K

Bleeding is a common and feared complication of oral anticoagulant therapy. Several prediction models have been recently developed, but there is a lack of evidence in patients with venous thromboembolism (VTE). The aim of this study was to validate currently available bleeding risk scores during long-term oral anticoagulation for VTE. We retrospectively included adult patients on vitamin K antagonists for VTE secondary prevention, followed by five Italian Anticoagulation Clinics (Cuneo, Livorno, Mantova, Napoli, Varese), between January 2010 and August 2012. All bleeding events were classified as major bleeding (MB) or clinically-relevant-non-major-bleeding (CRNMB). A total of 681 patients were included (median age 63 years; 52.0% female). During a mean follow-up of 8.82 (± 3.59) months, 50 bleeding events occurred (13 MB and 37 CRNMB), for an overall bleeding incidence of 9.99/100 patient-years. The rate of bleeding was higher in the first three months of treatment (15.86/100 patient-years) than afterwards (7.13/100 patient-years). The HAS-BLED showed the best predictive value for bleeding complications during the first three months of treatment (area under the curve [AUC] 0.68, 95% confidence interval [CI] 0.59-0.78), while only the ACCP score showed a modest predictive value after the initial three months (AUC 0.61, 95%CI 0.51-0.72). These two scores had also the highest sensitivity and the highest negative predictive value. None of the scores predicted MB better than chance. Currently available bleeding risk scores had only a modest predictive value for patients with VTE. Future studies should aim at the creation of a new prediction rule, in order to better define the risk of bleeding of VTE patients.

Topics: Aged; Anticoagulants; Cohort Studies; Female; Follow-Up Studies; Hemorrhage; Humans; Italy; Male; Middle Aged; Predictive Value of Tests; Research Design; Retrospective Studies; Skin Tests; Time Factors; Venous Thromboembolism; Vitamin K

In many countries, new oral anticoagulants are only covered for patients with suboptimal anticoagulation control on vitamin K antagonists (VKAs). The quality of VKA management is often reported using the time in therapeutic range (TTR). We sought to predict a TTR 65% or less using a surrogate measure [number of changes in VKA dose and number of international normalized ratio (INR) tests] that could be easily determined by primary care physicians. This cross-sectional study included consecutive patients whose VKA therapy was managed in a specialized anticoagulation clinic. Patients were dichotomized according to their TTR in the past 6 months (TTR > or ≤ 65%). The ability of the number of INR tests and VKA dose changes to predict TTR group was assessed using receiver-operating characteristics (ROC) curve analysis. The analyses included 1381 patients with a median age of 63 years. The mean TTR was 81% (interquartile range 70-90) and 17.4% of patients had a TTR 65% or more. Based on the ROC curve, patients were stratified according to whether they had either 3 or more dose changes or 9 or more INR tests within the last 6 months. The sensitivity to identify patients with TTR 65% or less was 87% and the specificity was 63%. The number of dose changes and the number of INR tests might be used as indicators of TTR; they could offer a simple way for clinicians to identify patients who are good candidates for the new oral anticoagulants. However, external validation studies in different clinical settings are needed to confirm these findings.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Blood Coagulation Tests; Cross-Sectional Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Outpatients; ROC Curve; Venous Thromboembolism; Vitamin K; Warfarin

Few studies have assessed treatment patterns of acute venous thromboembolism (VTE) in a real-world population. We aimed to describe anticoagulant treatment patterns for acute VTE using healthcare databases of Québec, Canada.. We used linked healthcare databases of the province of Québec, Canada to identify all incident cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) between 2000 and 2009. We formed two patient cohorts, one with definite cases (definite VTE cohort, N=40,776) and the other including cases with definite or probable VTE (any VTE cohort, N=54,803) that were followed until death, end of health coverage, or end of study (December 31, 2009).. In the definite cohort, 73.6% of subjects were dispensed an anticoagulant following the diagnosis of VTE. Of those who were dispensed a vitamin K antagonist (VKA), median duration of use was 61days (interquartile range 89). VKA initiation was more likely in patients with pulmonary embolism than deep vein thrombosis alone (HR 1.62, 95% CI (1.58-1.66)). Among outpatients, those managed initially in the outpatient setting were less likely to initiate VKA therapy (HR 0.75, 95% CI (0.68-0.77)), while those requiring admission to hospital for VTE management were more likely to initiate (HR 1.81, 95% CI (1.76-1.87)). Findings were similar in the any VTE cohort.. Our study describes VTE treatment patterns in a real-world setting and suggests that there may be important gaps. These may include significant numbers of patients who did not initiate oral anticoagulant therapy, particularly in the outpatient setting, and shorter duration of oral anticoagulant use than recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Male; Middle Aged; Pulmonary Embolism; Quebec; Venous Thromboembolism; Vitamin K; Young Adult

Topics: Anticoagulants; Humans; International Normalized Ratio; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Female; Humans; Male; Venous Thromboembolism; Vitamin K

Rivaroxaban is a direct factor Xa inhibitor, which is rapidly absorbed in the upper gastrointestinal (GI) tract. In large trials, it has been shown to be effective and safe in VTE treatment. However, in these trials patients with morbid obesity were not reported and it is unknown if the standard dosage of 20 mg rivaroxaban is sufficient for bariatric patients, especially after bariatric surgery, which may impact the resorption of rivaroxaban. We report the case of a bariatric patient with high venous thromboembolism risk and instable INR after recent bariatric surgery, who was switched from Vitamin-K antagonists to rivaroxaban. After intake of 20 mg rivaroxaban, plasma concentration were repeatedly measured until 3 h after the second dose using a commercially available chromogenic aXa-assay. Furthermore, INR and aPTT were measured. Peak concentrations of 224.22 ng/ml were observed. After 6 h, plasma concentration decreased to 86.9 ng/ml and remained stable until 12 h (86.32 ng/ml). After 24 h, a trough level of 35.54 ng/ml was observed. The patients INR did immediately increase and remained significantly elevated throughout the day with a slow decrease. Since peak values of rivaroxaban plasma concentrations were in the expected range of published data, we conclude that resorption of rivaroxaban was immediate and not significantly impaired by bariatric surgery of the upper GI tract. Consequently, no dose adjustments seem to be necessary in this high-risk population.

Topics: Adult; Anticoagulants; Bariatric Surgery; Female; Humans; International Normalized Ratio; Morpholines; Obesity, Morbid; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K

The optimal duration of anticoagulant treatment after venous thromboembolism (VTE) should be evaluated in relation to bleeding risk. This assessment is particularly difficult with elderly patients, because of their increased risk of both recurrences and hemorrhages. Bleeding risk stratification models have been proposed, but their predictive ability in very elderly patients is unknown. We aimed to assess six bleeding stratification models in this setting, by using information available in our dataset.. Patients aged ≥ 80 years receiving vitamin K antagonists (VKAs) for the secondary prevention of VTE were eligible for this prospective cohort study. All patients were followed at Italian anticoagulation clinics for monitoring of VKA treatment. Risk factors for bleeding were collected, and major bleeding events and mortality were documented during follow-up. The association of bleeding events with the available risk factors was tested by means of Cox regression analysis; the c-statistic was used to quantify the predictive validity of the classification schemes.. A total of 1078 patients (37.2% males; mean age, 84 years) were enrolled in the study, for a total observation period of 1981 patient-years. The rate of major bleeding was 2.4 per 100 patient-years (47 events; one was fatal). The mortality rate was 5.2 per 100 patient-years. None of the considered risk factors were significantly associated with bleeding events. The predictive validity of the risk stratification models was low, and the most accurate model was not specifically developed for VTE patients (HEMORR2 HAGES, c-statistic 0.60, 95% confidence interval 0.49-0.70).. Bleeding risk stratification models appear to have little accuracy in very elderly VTE patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Risk Assessment; Risk Factors; Venous Thromboembolism; Vitamin K

Oral anticoagulants block the coagulation cascade either by an indirect mechanism (e.g., vitamin K antagonists) or by a direct one (e.g., the novel oral anticoagulants). Vitamin K antagonists are widely used as treatment of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. Although low molecular weight heparin remains the first line in venous thromboembolism prophylaxis, more recently the novel oral anticoagulants such as dabigatran (initial dose of 110 mg within 1-4 h after surgery, followed by the full dose of 220 mg once daily), rivaroxaban (dose of 10 mg once daily, with the first dose administered 6-10 h after the surgery), and apixaban (dose of 2.5 mg twice daily, starting 12-24 h after surgery, but available only in Europe) are approved for prophylaxis in patients undergoing major orthopedic surgery. The period in which thromboembolic risk abates remains uncertain, and trials of extended therapy are still ongoing. After showing at least noninferiority to warfarin in RE-LY, ROCKET-AF, and ARISTOTLE trials, dabigatran (110 or 150 mg twice daily), rivaroxaban (20 or 15 mg once daily), and apixaban (5 mg twice daily), respectively, were approved also for stroke prevention in patients with atrial fibrillation. While awaiting long-term safety data, the choice among all these available therapies should be based on patient preferences, compliance, and ease of administration, as well as on local factors affecting cost-effectiveness.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cost-Benefit Analysis; Dabigatran; Humans; Morpholines; Orthopedic Procedures; Practice Guidelines as Topic; Prognosis; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K

Injectable anticoagulation therapy is indicated for several months following diagnosis of venous thromboembolic disease (VTE) in a context of active neoplasia. Certain studies have shown an improvement in patient compliance using self-injections.. Allow patients to safely make their own injections of anticoagulants after checking their aptitude and motivation.. At the prescribing physician's request, the GRANTED network provided patients and/or the resource person with specific education and training. The educational program was proposed to patients with an indication for a treatment for at least 3 months. After becoming familiar with the injection material and its manipulation, the patient and/or resource person performed sham injections on test materials. Patients were then allowed to decide for themselves whether or not to participate in the self-injection protocol. The prescribing physician received a report from the training team.. From November 2010 to July 2012, 39 patients participated in the educational program, generally in a context of vitamin K antagonist prescriptions. Sixteen of these patients had a neoplasia. The educational program corrected erroneous or imprecise points of information, particularly concerning syringe purging.. The education program proved to be interesting for points other than those initially foreseen and allowed the team to rectify a certain number of erroneous messages unrecognized by the prescribing physicians. This result goes in line with the need for accompanying patients who have a prescription for self-injections and also emphasizes the need for careful follow-up.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Feasibility Studies; Female; Humans; Injections; Male; Middle Aged; Neoplasms; Patient Education as Topic; Self Administration; Venous Thromboembolism; Vitamin K

Information on recurrent venous thromboembolic events (VTEs) and major bleeding risks during anticoagulant treatment in patients with cancer-associated VTEs and chronic kidney disease (CKD) is scarce, although it is of relevance in establishing better tailored management strategies in these patients.. We compared risks of recurrent VTEs and major bleeds in cancer-associated VTE patients with and without CKD.. A total of 1684 patients diagnosed with a cancer-associated VTE between 2001 and 2011 were followed for 180 days after VTE diagnosis. Patients were treated mainly with low-molecular-weight heparin (LMWH) or vitamin-K antagonists (VKA). Primary outcomes were recurrent VTE and major bleeding. Secondary outcome was fatal bleeding.. Recurrent VTEs occurred in 15.9/100 patient years (py) in patients without CKD (eGFR > 60 mL min(-1) ), 19.5/100 py in those with CKD stage 3A (eGFR 45-60 mL min(-1) ), 14.9/100 py in those with CKD 3B (eGFR 30-45 mL min(-1) ), and 6.8/100 py in patients with CKD 4-5 (eGFR < 30 mL min(-1) ). Major bleeding occurred in 11.4/100 py in patients without CKD, 18.5/100 py in those with CKD stage 3A, 16.0/100 py in those with CKD 3B, and 40.8/100 py in patients with CKD 4-5. Fatal bleeding occurred in 1.1/100 py, 3.4/100 py, 6.3/100 py and 15.7/100 py, respectively. These increased bleeding risks in CKD patients were mainly observed in those on LMWH treatment, not VKA.. The risk of major bleeding was increased in CKD patients with VTE and cancer, and was most prominent in those treated with LMWH and an eGFR < 30 mL min(-1) . These results indicate that LMWH should be used with caution in this specific population.

Topics: Aged; Anticoagulants; Cohort Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Recurrence; Registries; Risk; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

The aim of this study is to evaluate the frequency of protein C deficiency in venous thromboembolism in black African patients of Benin. It is a descriptive study. Inclusion criteria were: acceptance- having a venous thromboembolism. No exlusion criteria was retained. Protein C deficiency was diagnosed by quantitative technic with a Minividas materiel in the blood. Protein C dosage has been done before antivitamin k therapy and a second dosage has been done if the first one demonstrated a low level of protein C. Acuired aetiology have been research. For the 54 patients of this study mean age was 52.7±14.1 and sex-ratio 1.08. The frequency of protein C deficiency was 9.3% in all patients and 12.5% in those with clinical thrombophily (p=1). No acquired deficit has been found.

Topics: Adult; Aged; Benin; Black People; Cross-Sectional Studies; Developing Countries; Female; Humans; Male; Middle Aged; Prospective Studies; Protein C Deficiency; Risk Factors; Venous Thromboembolism; Vitamin K

Long-term risk of venous thromboembolism (VTE) following total hip or knee replacement (THR/TKR) compared with controls has not been studied extensively, and the long-term influence of outpatient anticoagulant use on VTE risk remains unknown. The objectives were to evaluate long-term VTE risk following THR/TKR compared with matched controls, and to investigate effect modification by prolonged outpatient vitamin K antagonist use.. A Danish retrospective nationwide cohort study was conducted. All patients undergoing primary THR/TKR (n = 95,227) between 1998 and 2007 were selected, each matched by age, sex and region with three controls (no THR/TKR). Patients were stratified by prolonged outpatient vitamin K antagonist use in the previous 3 months (in a time-dependent manner). All subjects were followed for VTE, and Cox models were used to calculate disease and medication history adjusted hazard ratios (HRs).. Within 6 weeks following surgery, a 13-fold increased risk of VTE was found for THR (adj. HR 12.9; 95% CI 11.2-14.7), and a 14-fold elevated risk for TKR (adj. HR 13.6; 95% CI 11.0-16.7), compared with matched controls. The risk remained substantially increased for at least 4 months following THR/TKR. Within this period, prolonged outpatient vitamin K antagonist use reduced the increase in VTE risk by 69% for THR and 54% for TKR.. The risk of VTE remains substantially elevated for at least 4 months following THR/TKR; this is well beyond the recommended duration of anticoagulant use. The increase in VTE risk is less pronounced in prolonged outpatient vitamin K antagonist users.

Topics: Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Case-Control Studies; Female; Humans; Male; Middle Aged; Outpatients; Retrospective Studies; Risk Factors; Venous Thromboembolism; Vitamin K

Acute venous thromboembolism (VTE) is treated with parenteral administration of heparin or derivatives, in conjunction with oral vitamin K antagonists (VKAs) to reach and maintain INR values between 2.0 and 3.0 for at least 3 months; the duration of a further period of treatment for secondary prevention of recurrences is still matter of debate. If bleeding occurs during treatment the decision will be based on: a) type of bleeding (major or minor), and b) thrombotic risk if anticoagulation is withheld (characteristics of patients and time elapsed from the index VTE). In case of major bleeding anticoagulation should be stopped and reversed. A first but insufficient measure is i.v. vitamin K administration. Fresh frozen plasma is widely used; however, large volumes are needed (at least 15 mL/kg body weight) with risk for fluid overload. Prothrombin complex concentrate infusion, with 3 or (better) the 4 pro-coagulant factors, is a more efficient (fast and safe) measure. In patients at high thrombotic risk (first month or other conditions) and absolute contraindication for anticoagulation a caval filter is recommended, to avoid as much as possible life-threatening pulmonary embolism.

Topics: Anticoagulants; Antifibrinolytic Agents; Hemorrhage; Humans; Venous Thromboembolism; Vitamin K

Topics: 4-Hydroxycoumarins; Acenocoumarol; Anticoagulants; Contraindications; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Drug Utilization; Drugs, Investigational; Heparin; Humans; Indenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Female; Hemorrhage; Humans; Male; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKA) therapy is increasingly used in elderly for prevention of venous thromboembolism (VTE) and of stroke in atrial fibrillation (AF). Glomerular filtration rate (GFR), usually estimated from different equations, decreases progressively with age and it is a risk factor for bleeding. In the frame of the EPICA study, a multicentre prospective observational study including 4,093 patients ≥80 years naïve to VKA treated for AF or after VTE, we performed this ancillary study to evaluate the prevalence of chronic kidney diseases (CKD) by estimated GFR (eGFR). Incidence of bleedings was recorded and bleeding risk was evaluated in relation to eGFR calculated by Cockroft-Gault (C-G); Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas. In addition, the agreement among the three eGFR formulas was evaluated. We recorded 179 major bleedings (rate 1.87 x100 patient-years [py]), 26 fatal (rate 0.27 x100 py). Moderate CKD was detected in 69.3%, 59.3% and 47.0% and severe CKD in 5.8%, 7.4% and 10.0% of cases by C-G, MDRD and CKD-EPI, respectively. Bleeding risk was higher in patients with severe CKD irrespective of the applied equation. This study confirms that CKD represents an independent risk factor for bleeding and that a wide proportion of elderly on VKA had severe or moderate CKD, suggesting the need for frequent monitoring. Although the different available equations yield different eGFR, all appear to similarly predict the risk of major bleeding.

Topics: Age Factors; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Chronic Disease; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Incidence; Italy; Kidney; Kidney Diseases; Male; Odds Ratio; Prevalence; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Atrial Fibrillation; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Kidney; Kidney Diseases; Male; Stroke; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Drug Administration Schedule; Evidence-Based Medicine; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Practice Guidelines as Topic; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Secondary Prevention; Venous Thromboembolism; Vitamin K

Bleeding is the main complication of oral anticoagulants, anti-vitamin K or new drugs such as anti-factor Xa or anti-thrombin agents. Risk factors associated with bleeding during warfarin therapy are discussed. For the new drugs no published data is available yet. Comparative frequencies of major bleeding during anticoagulation in atrial fibrillation and venous thromboembolism are shown. Beyond the intrinsic properties of the classic and new agents, patients characteristics and co-morbidities and an appropriate management of the antithrombotic therapy will be the factors associated with bleeding incidence in real life.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Incidence; Risk Assessment; Risk Factors; Venous Thromboembolism; Vitamin K; Warfarin

New oral anticoagulants are already or will be soon available. They have shown good efficacy and safety in various studies (prevention and treatment of venous thromboembolism, atrial fibrillation). Their arrival will probably modify the prescription of the current anticoagulant agents. However some precaution should be given in their use pending post marketing studies. Although these new drugs are intended to replace mostly vitamin K antagonists, a place will remain for "old" anticoagulants during the next years.

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Evidence-Based Medicine; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Venous Thromboembolism; Vitamin K

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K

Vitamin K antagonist (VKA) therapy is increasingly being used for the prevention of venous thromboembolism and stroke in atrial fibrillation. Bleeds are the major concern for VKA prescription, especially in very old patients who carry many risk factors for bleeding. We performed a large multicenter prospective observational study that enrolled very old patients to evaluate the quality of anticoagulation and the incidence of bleedings.. The study included 4093 patients ≥80 years of age who were naïve to VKA for thromboprophylaxis of atrial fibrillation or after venous thromboembolism. Patients' demographic and clinical data were collected, and the quality of anticoagulation and the incidence of bleeding were recorded. The follow-up was 9603 patient-years; median age at the beginning of follow-up was 84 years (range, 80 to 102 years). We recorded 179 major bleedings (rate, 1.87 per 100 patient-years), 26 fatal (rate, 0.27 per 100 patient-years). The rate of bleeding was higher in men compared with women (relative risk, 1.4; 95% confidence interval, 1.12 to 1.72; P=0.002) and among patients ≥85 years of age compared with younger patients (relative risk, 1.3; 95% confidence interval, 1.0 to 1.65; P=0.048). Time in therapeutic range was 62% (interquartile range, 49% to 75%). History of bleeding, active cancer, and history of falls were independently associated with bleeding risk in Cox regression analysis.. In this large study on very old patients on VKA carefully monitored by anticoagulation clinics, the rate of bleedings was low, suggesting that age in itself should not be considered a contraindication to treatment. Adequate management of VKA therapy in specifically trained center allows very old and frail patients to benefit from VKA thromboprophylaxis.

Topics: Age Distribution; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cooperative Behavior; Female; Hemorrhage; Humans; Incidence; Italy; Male; Proportional Hazards Models; Prospective Studies; Risk Factors; Stroke; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Female; Hemorrhage; Humans; Male; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKA) are the only registered oral anticoagulants for the treatment of venous thromboembolism (VTE). VKA have an unpredictable and highly variable effect on coagulation, with a high risk of under- and over-treatment. Novel anticoagulants, such as dabigatran and rivaroxaban, could be a very welcome replacement for VKA, as they show a predictable anticoagulant effect. Results of several phase II and III studies have shown the efficacy and safety of dabigatran and rivaroxaban in the prophylaxis and treatment of VTE, and for the prevention of stroke in atrial fibrillation. It remains to be shown whether these new anticoagulants have the same safety profile in daily clinical practice, where more vulnerable patients will be treated. Lack of information on the proper monitoring method or antidote in case of bleeding may also hinder the translation from science to clinical practice.

Topics: Acute Coronary Syndrome; Anticoagulants; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Diet; Drug Interactions; Factor VIIa; Factor Xa Inhibitors; Humans; Kidney; Life Style; Monitoring, Physiologic; Morpholines; Recombinant Proteins; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K

Venous thromboembolism (VTE) complicates ~ 1 to 2 of 1000 pregnancies, with pulmonary embolism being a leading cause of maternal mortality and deep vein thrombosis an important cause of maternal morbidity, also on the long term. However, a strong evidence base for the management of pregnancy-related VTE is missing. Management is not standardized between physicians, centers, and countries. The management of pregnancy-related VTE is based on extrapolation from the nonpregnant population, and clinical trial data for the optimal treatment are not available. Low-molecular-weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists postpartum) should be continued until 6 weeks after delivery with a minimum total duration of 3 months. Use of LMWH or vitamin K antagonists does not preclude breastfeeding. Whether dosing should be based on weight or anti-Xa levels is unknown, and practices differ between centers. Management of delivery, including the type of anesthesia if deemed necessary, requires a multidisciplinary approach, and several options are possible, depending on local preferences and patient-specific conditions.

Topics: Adult; Anticoagulants; Delivery, Obstetric; Female; Heparin, Low-Molecular-Weight; Humans; Infant, Newborn; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Venous Thromboembolism; Vitamin K

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Risk; Stroke; Venous Thromboembolism; Vitamin K

Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients.. Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule.. Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg.. In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

Topics: Administration, Oral; Adult; Age Factors; Aged; Ambulatory Care; Anticoagulants; Blood Coagulation; Body Weight; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Female; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Nomograms; Phenotype; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Blood Loss, Surgical; Casts, Surgical; Evidence-Based Medicine; Fibrinolytic Agents; Guideline Adherence; Heparin; Hip Fractures; Humans; Knee; Lower Extremity; Orthopedic Procedures; Postoperative Hemorrhage; Practice Guidelines as Topic; Practice Patterns, Physicians'; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Antidotes; Hemorrhage; Humans; Venous Thromboembolism; Vitamin K; Warfarin

ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting) study in 2006, was a multinational cross-sectional survey designed to assess the prevalence of venous thromboembolism (VTE) risk in the acute hospital care setting, and to determine the proportion of at-risk patients who receive appropriate prophylaxis. From the 358 randomly selected hospitals across 32 countries in the global registry, 9 Hungarian centers were included. According to the Hungarian results, the use of appropriate prophylaxis was more common in surgical patients but much less common in medical patients comparing to the worldwide average. ENDORSE 2-HUNGARY was a local survey to compare the prophylactic habits after two years and two months time period. In both surveys, the 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess venous thromboembolism risk and to determine whether patients were receiving recommended prophylaxis. The one day survey ENDORSE 2-HUNGARY was repeated beside seven already audited hospitals, and in two newly recruited hospitals. A total of 886 patients were assessed for thrombosis risk on the basis of hospital chart review. Of these patients 59.0% (N=523) were judged at risk for VTE, including 100% (N=327) surgical and 35.1% (N=196) medical patients. 67.9% (N=355) of the total at-risk patients received ACCP-recommended VTE prophylaxis. Among surgical patients, 84.4% (N=276) received recommended prophylaxis compared with 40.3% (N=79) of medical patients. Results of the ENDORSE in 2006 and 2009 were compared, as well. The rate of appropriate prophylaxis use in at-risk patients did not changed significantly in surgical patients, however, a significant, 43.9% increase was found in medical patients (p=0.002), that proves the success of lectures presenting the facts and focusing to increase medical prophylaxis during the time period between the two studies. 59.7% of at-risk medical patients and 15.6% of surgical patients were unprotected against thrombosis in 2009. We should further increase the rate of at-risk patients receiving appropriate prophylaxis. We should reinforce the rationale for the increase of awareness of VTE risk in hospitalized medical patients, and to enhance the prophylaxis practice among healthcare professionals.

Topics: Adult; Aged; Anticoagulants; Cross-Sectional Studies; Female; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Hospitals; Humans; Hungary; Inpatients; International Cooperation; Male; Middle Aged; Polysaccharides; Prevalence; Risk Assessment; Risk Factors; Stockings, Compression; Venous Thromboembolism; Vitamin K

Topics: Europe; General Surgery; Heparin, Low-Molecular-Weight; Humans; Incidence; Neoplasms; Prognosis; Risk Factors; Secondary Prevention; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Antithrombin III Deficiency; Disease-Free Survival; Genetic Predisposition to Disease; Hemorrhage; Humans; Incidence; Pedigree; Protein C Deficiency; Protein S Deficiency; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Hereditary deficiencies of protein S, protein C and antithrombin are known risk factors for first venous thromboembolism. We assessed the absolute risk of recurrence, and the contribution of concomitant thrombophilic defects in a large cohort of families with these deficiencies. Annual incidence of recurrence was estimated in 130 deficient patients, with separate estimates for those with each of protein S, protein C, and antithrombin deficiency, and in eight non-deficient patients with prior venous thromboembolism. All patients were also tested for factor V Leiden, prothrombin G20210A, high levels of factors VIII, IX and XI, and hyperhomocysteinemia. There were 81 recurrent events among 130 deficient patients. Median follow-up was 4.6 years. Annual incidences (95% confidence interval) of recurrent venous thromboembolism were 8.4% (5.8-11.7) for protein S deficiency, 6.0% (3.9-8.7) for protein C deficiency, 10.0% (6.1-15.4) for antithrombin deficiency, and overall 7.7% (6.1-9.5). Relative risk of recurrence in patients with a spontaneous versus provoked first event was 1.5 (0.95-2.3). Cumulative recurrence rates at 1, 5 and 10 years were 15%, 38% and 53%. Relative risk of recurrence with concomitant defects was 1.4 (0.7-2.6) (1 defect) and 1.4 (0.8-2.7) (> or =2 defects). Annual incidence was 1.0% (0.03-5.5) in eight non-deficient patients. Annual incidence of major bleeding in deficient patients on oral anticoagulant treatment was 0.5% (0.2-1.0). We conclude that patients with a hereditary protein S, protein C or antithrombin deficiency appear to have a high absolute risk of recurrence. This risk is increased after a first spontaneous event, and by concomitance of other thrombophilic defects.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombin III Deficiency; Disease-Free Survival; Female; Genetic Predisposition to Disease; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pedigree; Protein C Deficiency; Protein S Deficiency; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K; Young Adult

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Double-Blind Method; Enoxaparin; Female; Fondaparinux; Hemorrhage; Heparin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasms; Polysaccharides; Proportional Hazards Models; Pulmonary Embolism; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Secondary Prevention; Time Factors; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis; Vitamin K; Young Adult

The balance between the efficacy and safety of anticoagulant therapy in patients aged >/=90 years with venous thromboembolism (VTE) is uncertain. RIETE is an ongoing, prospective registry of consecutive patients with acute, objectively confirmed, symptomatic VTE. We evaluated the efficacy and safety of anticoagulant therapy during the first three months in all patients aged >/=90 years. In addition, we tried to identify those at a higher risk for VTE. Of 21,873 patients enrolled from March 2001 to February 2008, 610 (2.8%) were aged >/=90 years. Of these, 307 (50%) presented with pulmonary embolism (PE), 240 (39%) had immobility >/=4 days, and 271 (44%) had abnormal creatinine levels. During the first three months of therapy, 140 patients aged >/=90 years (23%) died. Of these, 45 (32%) died of PE (34 of the initial episode, 11 of recurrent PE), 18 (13%) had fatal bleeding. Recent immobility >/=4 days was the most common risk factor for VTE (240 of 610 patients, 39%), but only 54 of them (22%) had received thromboprophylaxis. The most frequent causes for immobility were senile dementia, acute infection, trauma or decompensated heart failure. The duration of immobility was <4 weeks in 126 patients (52%), and most of them were bedridden at home. In conclusion, one in every four VTE patients aged >/=90 years died during the first three months of therapy. Of these, one in every three died of PE, one in every eight had fatal bleeding. Identifying at-risk patients may help to prevent some of these deaths.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Child; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Registries; Risk Factors; Spain; Survival Rate; Treatment Outcome; Venous Thromboembolism; Vitamin K

Initiation of warfarin therapy is a clinical challenge. A 10-mg warfarin initiation nomogram was recently validated in a randomized controlled trial. We sought to determine the efficacy and safety of this 10-mg warfarin initiation nomogram in 'real-life' daily practice. A retrospective cohort including all outpatients beginning concurrent treatment with warfarin and low-molecular-weight heparin over a 24-month period in our Thrombosis Unit was reviewed. Eight hundred and forty-one patients were included; of them, 640 (76.1%) were started on the nomogram. The nomogram was entirely followed in 324 patients (38.5%). The efficacy and safety profile was similar to that observed in the original clinical trial; 86% of patients managed according to the nomogram reached the international normalized ratio target of 2.0-3.0 within 5 days. Mean duration of low-molecular-weight heparin treatment was 6.0 +/- 1.9 days, and 3.7% of patients had an international normalized ratio of at least 5.0 in the first 4 weeks of treatment. The 10-mg nomogram effectively results in an early therapeutic international normalized ratio with a good safety profile in 'real-life' daily practice.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Nomograms; Outpatients; Retrospective Studies; Treatment Outcome; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Adult; Aged; Anticoagulants; Breath Tests; Dose-Response Relationship, Drug; Female; Humans; Intestinal Diseases; Intestine, Small; Lactulose; Male; Middle Aged; Venous Thromboembolism; Vitamin K; Warfarin

Limitations of vitamin K antagonists (VKAs) include frequent monitoring, dietary restrictions and drug interactions. This study conducted an indepth exploration of perspectives of VKA therapy in respondents with atrial fibrillation or venous thromboembolism.. A total of 60 respondents, recruited from the UK, USA and Spain, were interviewed on their experiences and views of VKA therapy. Thematic analysis was conducted on the data.. Although there were some differences between the countries and some small differences between atrial fibrillation and venous thromboembolism respondents, many respondents found various aspects of VKA to be burdensome, including the international normalized ratio monitoring and dietary considerations.. Atrial fibrillation and venous thromboembolism respondents accept the limitations of VKAs and the adjustments to their lifestyles, but recognize a lack of alternative treatment.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Data Collection; Diet; Drug Monitoring; Female; Humans; International Normalized Ratio; Male; Middle Aged; Patient Satisfaction; Spain; United Kingdom; United States; Venous Thromboembolism; Vitamin K

Topics: Acute Disease; Anticoagulants; Cardiovascular Diseases; Chronic Disease; Fibrinolytic Agents; Humans; Hungary; Internal Medicine; Mass Screening; Neoplasms; Nervous System Diseases; Platelet Aggregation Inhibitors; Primary Prevention; Risk Assessment; Risk Factors; Secondary Prevention; Surgical Procedures, Operative; Thromboembolism; Venous Thromboembolism; Vitamin K

Low international normalized ratio (INR;

Topics: Aged; Ambulatory Care Facilities; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Interactions; Female; Heart Valve Diseases; Humans; International Normalized Ratio; Male; Medication Adherence; Prospective Studies; Risk Factors; Sex Factors; United States; Venous Thromboembolism; Vitamin K; Warfarin

Extremely elderly patients are being treated with anticoagulant therapy with increasing frequency. We sought to assess the rates of bleeding in such patients and to carefully examine risk factors that might predict this bleeding. This was a prospective cohort study conducted from 1 January 2007 to 29 February 2008 at an anticoagulation clinic in Modena, Italy. Ninety patients, 90 years or older, among 1635 patients with nonvalvular atrial fibrillation were studied; 69 (77%) were women with a median age of 91.71 years (range 90-98). During the enrolment period, all the patients were interviewed during an ambulatory visit and were followed in the outpatient setting. Hemorrhagic, thromboembolic and fatal events over 1 year of follow-up were monitored. Six (7%) patients discontinued vitamin K antagonists (three due to bleeding, two due to noncompliance, two due to physician recommendation). Twenty-one (23%) patients died, and 35 (39%) were admitted to hospital. One patient had an intracranial hemorrhage [1%, 95% confidence interval (CI) 0.27-6.0], two patients had a major extracranial hemorrhage (2%, 95% CI 0.7-8.0). One patient had an ischemic stroke (1%, 95% CI 0.27-6.0), two patients had embolic arterial ischemia (2%, 95% CI 0.7-8.0). All the events occurred when the international normalized ratio was outside the target range, or after oral anticoagulation had been stopped. In our study of extremely elderly anticoagulated patients, we found low rates of bleeding and thromboembolism. These findings support the use of oral anticoagulants in such patients.

Topics: Age Factors; Aged, 80 and over; Aging; Anticoagulants; Atrial Fibrillation; Cohort Studies; Female; Hemorrhage; Humans; Male; Prospective Studies; Risk Factors; Treatment Outcome; Venous Thromboembolism; Vitamin K

Topics: Anticoagulants; Female; Follow-Up Studies; Humans; Male; Neoplasms; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Topics: Anticoagulants; Brain Ischemia; Evidence-Based Medicine; Fondaparinux; Hemorrhage; Heparin, Low-Molecular-Weight; Hirudins; Humans; International Normalized Ratio; Myocardial Infarction; Polysaccharides; Risk Factors; Severity of Illness Index; Thrombolytic Therapy; Treatment Outcome; Venous Thromboembolism; Vitamin K

This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the "Grades of Recommendation" chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A). For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC). For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and th

Topics: Anticoagulants; Drug Therapy, Combination; Evidence-Based Medicine; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Polysaccharides; Postoperative Complications; Risk Assessment; Venous Thromboembolism; Vitamin K

This article discusses the management of venous thromboembolism (VTE) and thrombophilia, as well as the use of antithrombotic agents, during pregnancy and is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that benefits do, or do not, outweigh risks, burden, and costs. Grade 2 recommendations are weaker and imply that the magnitude of the benefits and risks, burden, and costs are less certain. Support for recommendations may come from high-quality, moderate-quality or low-quality studies; labeled, respectively, A, B, and C. Among the key recommendations in this chapter are the following: for pregnant women, in general, we recommend that vitamin K antagonists should be substituted with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1A], except perhaps in women with mechanical heart valves. For pregnant patients, we suggest LMWH over UFH for the prevention and treatment of VTE (Grade 2C). For pregnant women with acute VTE, we recommend that subcutaneous LMWH or UFH should be continued throughout pregnancy (Grade 1B) and suggest that anticoagulants should be continued for at least 6 weeks postpartum (for a total minimum duration of therapy of 6 months) [Grade 2C]. For pregnant patients with a single prior episode of VTE associated with a transient risk factor that is no longer present and no thrombophilia, we recommend clinical surveillance antepartum and anticoagulant prophylaxis postpartum (Grade 1C). For other pregnant women with a history of a single prior episode of VTE who are not receiving long-term anticoagulant therapy, we recommend one of the following, rather than routine care or full-dose anticoagulation: antepartum prophylactic LMWH/UFH or intermediate-dose LMWH/UFH or clinical surveillance throughout pregnancy plus postpartum anticoagulants (Grade 1C). For such patients with a higher risk thrombophilia, in addition to postpartum prophylaxis, we suggest antepartum prophylactic or intermediate-dose LMWH or prophylactic or intermediate-dose UFH, rather than clinical surveillance (Grade 2C). We suggest that pregnant women with multiple episodes of VTE who are not receiving long-term anticoagulants receive antepartum prophylactic, intermediate-dose, or adjusted-dose LMWH or intermediate or adjusted-dose UFH, followed by postpartum anticoagulants (Grade 2C). For those pregnant women with prior VTE who are receiving l

Topics: Antibodies, Antiphospholipid; Antithrombin III Deficiency; Aspirin; Evidence-Based Medicine; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Risk Assessment; Risk Factors; Thrombophilia; Venous Thromboembolism; Vitamin K

Topics: Dose-Response Relationship, Drug; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Perioperative Care; Practice Guidelines as Topic; Societies, Medical; Venous Thromboembolism; Vitamin K

Coumarin or anti-vitamin K oral anticoagulants have been used in anticoagulation therapy for more than 50 years. Well-designed studies have demonstrated the effectiveness of these drugs in the primary and secondary prevention of venous thromboembolic disease (VTD). Because of greater life expectancy and the increase in the indications for oral anticoagulation therapy (OAT), more and more patients are receiving this type of treatment. In Spain, approximately 1% of the population receives OAT. The mechanism of action of coumarin anticoagulants is based on inhibition of the interconversion of vitamin K and its 2,3-epoxide (vitamin K epoxide, which modulates gamma-carboxylation of the glutamic acid residues in the N-terminal regions of vitamin-K-dependent factors, namely, II, VII, IX, X, protein C, protein S and protein Z). Due to the lack of gamma-carboxylation, these factors lose their procoagulant activity. Major hemorrhagic complications of OAT in VTD after 3-6 months of treatment, with an INR of 2-3, occur in nearly 2% of patients. The hemorrhagic complications of OAT are related to the intensity of anticoagulation, patient characteristics, the concomitant use of drugs that interfere with hemostasis, and treatment duration. The risk of VTD recurrence after 3-6 months of OAT is high and can be more than 10% in patients with idiopathic thromboembolism or irreversible risk factors such as thrombophilia, cancer and other situations conferring permanent risk. The risk of recurrence is more frequent in men, in patients with thrombophilia especially in antithrombin deficiency, and in patients with cancer, residual venous obstruction, or elevated D dimer.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Coumarins; Drug Interactions; Female; Hemorrhage; Humans; Male; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Sex Factors; Spain; Thrombophilia; Time Factors; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Heparin; Humans; Pulmonary Embolism; Recurrence; Venous Thromboembolism; Venous Thrombosis; Vitamin K

The PROLONG study showed that patients with venous thromboembolism who had qualitatively abnormal results in a D-dimer assay (Clearview Simplify D-dimer) after discontinuation of vitamin K antagonism benefit from resumption of treatment with vitamin K antagonism. The objective of this study was to evaluate the possible advantage of using quantitative D-dimer assays.. VIDAS D-dimer Exclusion (bioMerieux), Innovance D-DIMER (Dade Behring), HemosIL D-dimer HS (Instrumentation Laboratory) and STA Liatest D-dimer (Diagnostica Stago) assays were performed in plasma aliquots sampled 30+/-10 days after cessation of vitamin K antagonism in 321 patients enrolled in the PROLONG study.. During the follow-up without vitamin K antagonism, 25 patients had recurrent venous thromboembolism. The cut-off levels of the quantitative assays giving results most comparable with those of the qualitative test were: VIDAS = 800 ng/mL; Innovance = 800 ng/mL; HemosIL HS = 300 ng/mL; STA Liatest = 700 ng/mL. When the effect of the patients' age (< or = 70 vs. >70 years) was analyzed, it was found that only in younger patients was the rate of recurrence of venous thromboembolism significantly higher in patients with abnormal D-dimer levels. However, using the quantitative assays and age-specific cut-off levels it was possible to determine statistically significant hazard ratios also in elderly patients (VIDAS = 600 and 1200 ng/mL, Innovance = 500 and 900 ng/mL, HemosIL HS = 250 and 450 ng/mL, STA Liatest = 700 and 1000 ng/mL, in patients aged < or = 70 and >70 years, respectively).. Quantitative D-dimer assays may provide information useful for evaluating the individual risk of recurrent venous thromboembolism. They seem particularly advantageous since they allow the selection of different cut-off levels according to the age or other characteristics of the patients.

Topics: Adult; Aged; Aged, 80 and over; Blood Chemical Analysis; Clinical Trials as Topic; Female; Fibrin Fibrinogen Degradation Products; Humans; International Normalized Ratio; Male; Middle Aged; Recurrence; Risk; Venous Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Venous Thromboembolism; Vitamin K