vitamin-k-semiquinone-radical and apixaban

Although guidelines give preference to direct oral anticoagulants (DOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF), DOACs are not recommended in those with rheumatic heart disease or mechanical heart valves. The results of the INVICTUS trial (Investigation of Rheumatic AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies), which compared rivaroxaban with a VKA in patients with rheumatic heart disease-associated AF, and the PROACT Xa trial (A Trial to Determine if Participants with an On-X Aortic Valve Can be Maintained Safely on Apixaban), which compared apixaban with warfarin in patients with an On-X valve in the aortic position, support the use of VKAs for these indications. In this paper, we review the results of these trials, provide perspective on why VKAs were superior to DOACs, and discuss future directions for anticoagulation in these disorders.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Fibrinolytic Agents; Humans; Pyridones; Rheumatic Heart Disease; Rivaroxaban; Stroke; Vitamin K; Warfarin

We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF).. A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated.. Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1).. Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Network Meta-Analysis; Rivaroxaban; Stroke; Vitamin K

Patients with end-stage renal disease (ESRD) have high rates of cardiac valvulopathy but can develop contraindications for vitamin K antagonist (VKA) therapy. We explored the evidence for alternative anticoagulation strategies in patients with ESRD with a contraindication for VKA therapy.. A scoping review was completed, searching MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Conference abstracts from inception to March 30, 2021. The study population was patients with ESRD who were on VKA therapy and developed a contraindication to VKA therapy use. All data regarding studies, patient characteristics, anticoagulation strategy, and clinical outcomes were summarized.. Twenty-three articles met inclusion criteria. These articles included 57 patients. Contraindications to VKA therapy included calcific uremic arteriolopathy (CUA) (n = 55) and warfarin-induced skin necrosis (n = 2). All studies were either case reports or case series. There were 10 anticoagulation strategies identified. Continuation of VKA therapy was associated with increased death and decreased rates of CUA resolution (80.0% and 10.0%, respectively), compared to apixaban (24.0% and 70.8%), subcutaneous (SC) low-molecular-weight heparin (LMWH) (14.3%, 85.7%), and SC unfractionated heparin (0.0%, 100.0%). While only 5 patient cases were reported with mechanical heart valves, SC LMWH use has been reported in this context with good outcomes.. In patients with ESRD who develop a contraindication to VKA therapy, several alternative anticoagulation strategies have been reported with superior outcomes to VKA continuation. While outcomes appear superior to continuation of VKA therapy, more data are required before definitive recommendations can be made for the patient with ESRD and a mechanical heart valve.

Topics: Anticoagulants; Contraindications, Drug; Factor Xa Inhibitors; Heart Valve Prosthesis; Heparin; Humans; Kidney Failure, Chronic; Pyrazoles; Pyridones; Renal Dialysis; Vitamin K

The increasing availability of real-world evidence (RWE) about safety and effectiveness of direct non-vitamin K oral anticoagulants (DOACs) for the management of atrial fibrillation (AF) offers the opportunity to better understand the clinical and economic implications of DOACs versus vitamin K antagonists (VKAs). The objective of this study was to compare the economic implications of DOACs and VKAs using data from real-world evidence in patients with AF.. A Markov model simulating the lifetime course of patients diagnosed with non-valvular AF was used to evaluate the cost-effectiveness of DOACs (i.e., rivaroxaban, dabigatran and apixaban) versus VKAs from the Italian National Health System (INHS) perspective. The model was made up of data from the literature and a meta-analysis of RWE on the incidence of stroke/systemic embolism (SE), major bleeding (MB), intracranial haemorrhage (ICH) and all-cause mortality (ACM); direct costs included drug costs, costs for drug monitoring, and management of events from official national lists. One-way and probabilistic sensitivity analyses (PSA) were used to assess the robustness of the results.. Results from the meta-analysis showed that apixaban had a high probability of being the most effective for stroke/SE, MB and ACM. Despite their higher acquisition costs, the cost-effectiveness analysis showed all DOACs involved a saving when compared with VKAs, with per-patient savings ranging between €4647 (rivaroxaban) to €6086 (apixaban). Moreover, all DOACs indicated a gain both in quality-adjusted life-years and life-years. According to PSA, findings related to apixaban were consistent, while for dabigatran and rivaroxaban PSA revealed a higher degree of uncertainty.. The beneficial effect of DOACs on containing events showed in RWE had the potential to offset drug-related costs, thus improving the sustainability of treatment for non-valvular AF in daily clinical practice.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Female; Hemorrhage; Humans; Italy; Male; Pyrazoles; Pyridones; Rivaroxaban; Stroke; 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

This meta-analysis aimed to evaluate the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in secondary stroke prevention in atrial fibrillation (AF) patients.. PubMed and Embase electronic databases were systematically searched from January 2009 to July 2019 for relevant randomized clinical trials and observational studies. A random-effects model was applied in the pooled analysis.. A total of 14 studies (4 randomized clinical trials and 10 observational studies) were included. Based on the randomized clinical trials, compared with VKA use, the use of NOACs was associated with decreased risk of stroke and systemic embolism, major bleeding, and intracranial bleeding. Based on the observational studies, compared with VKAs, the subgroup analysis showed that dabigatran and rivaroxaban were associated with a reduced risk of stroke or systemic embolism, whereas dabigatran and apixaban were associated with a decreased risk of major bleeding.. Based on current data, the use of NOACs is at least non-inferior to the use of VKAs in AF patients for secondary stroke prevention irrespective of NOAC type.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Observational Studies as Topic; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Secondary Prevention; Stroke; Thiazoles; Treatment Outcome; Vitamin K; Warfarin

Ischaemic stroke and systemic embolism are the major potentially preventable complications of atrial fibrillation (AF) leading to severe morbidity and mortality. Anticoagulation using vitamin K antagonists (VKA) or non-vitamin K oral anticoagulants (NOACs) is mandatory for stroke prevention in AF. Following approval of the four NOACs dabigatran, rivaroxaban, apixaban, and edoxaban, the use of VKA is declining steadily. Increasing age with thresholds of 65 and 75 years is a strong risk factor when determining annual stroke risk in AF patients. Current recommendations such as the "2016 Guidelines for the management of atrial fibrillation" of the European Society of Cardiology and the "2019 AHA/ACC/HRS Focused Update" by the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society strengthen the importance of anticoagulation and detection of bleeding risks, of which older age is an important one. While patients aged ≥ 75 years are usually underrepresented in randomised clinical trials, they represent almost 40% of the trial populations in the large NOAC approval studies. Therefore, a sufficient amount of data is available to assess the efficacy and safety for this patient cohort in that specific indication. In this article, the evidence for stroke prevention in AF using either VKA or NOACs is summarised with a special focus on efficacy compared to bleeding risk in patients aged ≥ 75 years. Specifically, we used a model of increased weighing of intracranial bleeding to illustrate the potential benefit of NOACs over VKA in the elderly population. In brief, there are at least two tested strategies with apixaban and edoxaban which even confer an additional clinical net benefit compared with VKA. Furthermore, elderly subgroups of trials for combined antithrombotic treatment following percutaneous coronary interventions in anticoagulated patients are analysed.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Vitamin K; Warfarin

Evidence regarding safety and efficacy of oral anticoagulants for the treatment of atrial fibrillation (AFib) in older adults has been assessed regarding the age appropriateness of oral anticoagulants (OAC) according to the FORTA (Fit fOR The Aged) classification (OAC-FORTA). Three years after its first version (OAC-FORTA 2016), an update was initiated to create OAC-FORTA 2019.. A structured review of randomized controlled clinical trials and summaries of individual product characteristics was performed to detect newly emerged evidence on oral anticoagulants in older patients with AFib. This review was used by an interdisciplinary panel of European experts (N = 10) in a Delphi process to label OACs according to FORTA.. A total of 202 records were identified and 11 studies finally included. We found four new trials providing relevant data on efficacy and safety of warfarin, apixaban, dabigatran or rivaroxaban in older patients with AFib. In the majority of studies comparing the non-vitamin-K oral anticoagulants (NOACs) with warfarin, NOACs were superior to warfarin regarding at least one relevant clinical endpoint. The mean consensus coefficient significantly increased from 0.867 (OAC-FORTA 2016) to 0.931 (p < 0.05) and the proposed FORTA classes were confirmed in all cases during the first round (consensus coefficient > 0.8). Warfarin, dabigatran, edoxaban and rivaroxaban were assigned to the FORTA B label, acenocoumarol, fluindione and phenprocoumon were labeled FORTA C and only apixaban was rated as FORTA A.. OAC-FORTA 2019 confirms that AFib can be successfully treated with positively labeled antithrombotics at advanced age.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Consensus Development Conferences as Topic; Dabigatran; Europe; Female; Humans; Long-Term Care; Male; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Vitamin K; Warfarin

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

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups.

Topics: Administration, Oral; Adult; Age Factors; Anticoagulants; Antithrombins; Atrial Fibrillation; Blood Coagulation; Dabigatran; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Male; Prognosis; Pyrazoles; Pyridines; Pyridones; Risk Assessment; Severity of Illness Index; Sex Factors; Stroke; Survival Analysis; Thiazoles; Vitamin K

To assess the effectiveness of direct oral anticoagulants vs vitamin K antagonists in real-life patients with atrial fibrillation.. A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA statement. The ROBINS-I tool was used to assess risk of bias.. A total of 27 different studies publishing data in 30 publications were included. In the studies with a follow-up up to 1 year, apixaban (HR, 0.93; 95%CI, 0.71-1.20) and dabigatran (HR, 0.95; 95%CI, 0.80-1.13) did not significantly reduce the risk of ischemic stroke vs warfarin, whereas rivaroxaban significantly reduced this risk (HR, 0.83; 95%CI, 0.73-0.94). Apixaban (HR, 0.66; 95%CI, 0.55-0.80) and dabigatran (HR, 0.83; 95%CI, 0.70-0.97) significantly reduced the major bleeding risk vs warfarin, but not rivaroxaban (HR, 1.02; 95%CI, 0.95-1.10), although with a high statistical heterogeneity among studies. Apixaban (HR, 0.56; 95%CI, 0.42-0.73), dabigatran (HR, 0.45; 95%CI, 0.39-0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49-0.88) significantly reduced the risk of intracranial bleeding vs warfarin. Reduced doses of direct oral anticoagulants were associated with a slightly better safety profile, but with a marked reduction in stroke prevention effectiveness.. Data from this meta-analysis suggest that, vs warfarin, the stroke prevention effectiveness and bleeding risk of direct oral anticoagulants may differ in real-life patients with atrial fibrillation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Case-Control Studies; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Observational Studies as Topic; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K; Warfarin

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

The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH).. We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation.. Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted.. Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Topics: Anticoagulants; Antithrombins; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Hematoma; Humans; Mortality; Odds Ratio; Phenprocoumon; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Thiazoles; Vitamin K; Warfarin

Prevention of stroke is a pivotal intervention in the management of patients with atrial fibrillation (AF). Because of the difficulties of safely implementing Vitamin K Antagonists in all patients, there has been a growing interest in improving the pharmacological management of AF with newer antithrombotic agents. The new oral anticoagulants (NOACs) have been developed to overcome the limitations and improve the efficacy of the conventional oral anticoagulant drugs. Among the NOACs, apixaban - a very specific antagonist of activated factor Xa - has pharmacokinetic and pharmacodynamic properties that allow significant efficacy in AF management.. The aim of this review is to summarise the available data on the efficacy of apixaban in patients with AF, with a particular focus on the implications for its clinical management.. Clinical application of apixaban in subgroups of patients with AF is still under investigation and some contraindications should be taken into account. Despite these limitations, apixaban is an effective alternative to warfarin and aspirin for stroke prevention in AF, with encouraging evidence also in terms of adherence to treatment.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridones; Stroke; Vitamin K

The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention in atrial fibrillation.. We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs.. From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared with warfarin, apixaban regular dose was more effective in reducing any thromboembolic event (odds ratio: 0.77; 95% confidence interval: 0.64-0.93), but no significant difference was found for stroke risk. Apixaban was as effective as dabigatran and rivaroxaban in reducing thromboembolic events and stroke. The risk of major bleeding was significantly lower for apixaban compared with warfarin, dabigatran, and rivaroxaban (relative risk reduction, 38%, 35%, and 46%, respectively). Similarly, the risk for intracranial hemorrhage was significantly lower for apixaban than warfarin and rivaroxaban (46% and 54%, respectively) but not dabigatran. The risk of gastrointestinal bleeding was lower with apixaban when compared with all oral anticoagulant agents (. Use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke and any thromboembolic events when compared with warfarin. A better safety profile was found with apixaban compared with warfarin, dabigatran, and rivaroxaban.

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Female; Humans; Intracranial Hemorrhages; Male; Polymers; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Saliva, Artificial; Stroke; Vitamin K; Warfarin

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 Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.. Zusammenfassung. Die zunehmende Lebenserwartung in den westlichen Ländern führt zu einer gleichzeitigen Zunahme chronischer Krankheiten, was mit «Multimorbidität» bezeichnet wird. Viele dieser Patienten leiden an chronischer Niereninsuffizienz (CKD) sowie thrombogenen Komorbiditäten wie z.B. Vorhofflimmern, weshalb eine orale Antikoagulation indiziert ist. Für lange Zeit standen lediglich die Vitamin-K-Antagonisten zur Verfügung. Aufgrund der unter anderem veränderten Pharmakokinetik sowie Bioverfügbarkeit dieser Medikamente bei CKD besteht jedoch gleichzeitig ein deutlich erhöhtes Blutungsrisiko. Die Einführung der direkten oralen Antikoagulanzien als neue und vielversprechende Alternative zu Vitamin-K-Antagonisten wurde daher insbesondere für die Population der CKD-Patienten mit grosser Spannung erwartet. Aufgrund der noch nicht ausreichenden Datenlage insbesondere bei älteren Patienten mit fortgeschrittener Niereninsuffizienz sollte das Risiko-Nutzen-Verhältnis vor Therapiebeginn sorgfältig evaluiert werden.

Topics: Anticoagulants; Arterial Occlusive Diseases; Atrial Fibrillation; Comorbidity; Contraindications; Coronary Disease; Dabigatran; Glomerular Filtration Rate; Kidney Failure, Chronic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Anticoagulation in patients with impaired kidney function can be challenging since drugs' pharmacokinetics and bioavailability are altered in this setting. Patients with chronic kidney disease (CKD) treated with conventional anticoagulant agents [vitamin K antagonist (VKA), low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)] are at high risk of bleeding events (both non-major and major clinically relevant bleeding). While anticoagulation reduces the risk of thromboembolic events, the co-existing bleeding risk and the fact that the most commonly used anticoagulation agents are eliminated via the kidneys pose additional challenges. More recently, two classes of direct oral anticoagulant agents (DOACs) have been investigated for the prevention and management of venous thromboembolic events: the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the direct thrombin inhibitor dabigatran. In this review, we discuss the complex challenges and the practical considerations associated with the management of anticoagulation treatment in patients with CKD, with a special focus on DOACs.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Heparin; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Rivaroxaban; Thrombosis; Vitamin K

Non vitamin-K oral anticoagulants (NOACs) are direct and specific inhibitors of the coagulation factors IIa (dabigatran) and Xa (apixaban, rivaroxaban, edoxaban) which share many pharmacokinetic properties. However, indications are lacking regarding the use of NOACs during thrombolysis, surgery and bleeding events. Areas covered: In this paper, the authors retrospectively analyzed the relevant literature on the NOACs using the PubMed and Google Scholar databases. Expert commentary: Although warfarin is effective in cardioembolic stroke prevention, easier handling and more favorable risk-benefit profile often render NOACs a more preferable therapy choice for neurologists. New evidences have suggested their use in treatment of elderly people, in patients with renal insufficiency or with antiphospholipid antibody syndrome. In addition, the use of antidotes, which rapidly reverse the anticoagulant effect of the NOACs, could be useful in bleeding, during emergency procedures, or in case of overdose.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Humans; Pyrazoles; Pyridones; Stroke; Vitamin K

Many patients under oral anticoagulation therapy need percutaneous or surgical interventions/operations. For vitamin K antagonists (VKA), there are recommendations regarding preoperative or postoperative administration. Management of the new oral anticoagulants (NOAC) was supposed to be easier - but some aspects must be considered. Due to the different pharmacokinetic profiles of substances such as dabigatran, rivaroxaban, apixaban, and edoxaban, different recommendations are given.Upon periprocedural management, thromboembolic risk has to be considered in patients treated with NOACs. NOACS have a pharmacokinetic advantage in terms of a rapid onset and rapid elimination via the liver and kidneys. Impaired renal function results in extended half-life of NOACs considerably.Surgical procedures under NOACS can be scheduled at the beginning of next dosing interval or omitted in low/minimal bleeding risk patients, so that only 2-3 NOAC doses are not administered. In patients with moderate and high risk of bleeding, there should be a NOAC break of 24-48 h prior to surgery in order to allow a corresponding decay of the active metabolite. In patients with low/intermediate risk for thromboembolism, no bridging is necessary if the "unprotected" time (NOAC break) is less than 4-5-(7) days. In patients at high risk of thromboembolism, individual consideration must be taken regarding bridging or extended NOAC break. Whether NOACs can be dispensed or bridging is necessary in these patients must be clarified in randomized trials for periprocedural management of NOACs patients.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Loss, Surgical; Dabigatran; Drug Interactions; Half-Life; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Surgical Procedures, Operative; Thiazoles; Thromboembolism; Vitamin K

The non-vitamin K antagonists (NOAC) are an integral component of our antithrombotic prevention and therapy. For four of the NOAC, their non-inferiority or even superiority versus vitamin K antagonists (VKA) has been proven. Thus, the management of special patient cohorts or the management of active bleeding complications is a focus of current discussion.In addition to prospective trials, numerous retrospective analyses of health insurers or public health provider data have been analyzed and published as "real life" or "real-world evidence" data. In almost all data sets the results of the NOAC approval trials were confirmed, demonstrating their non-inferiority or even superiority versus VKA. Attempts to compare the various NOAC with each other must be viewed critically since the real-world evidence (RWE) analysis provides very divergent results depending on the cohorts analyzed. Thus, a substantial prescriber-bias must be taken into account and never be excluded.In order to improve the management of bleeding complications, NOAC antidotes were developed. While the factors Xa antidote, andexanet alpha, a modified coagulation factor deleted of an intrinsic activity, will not be available before 2018, the dabigatran antidote idarucizumab is already in clinical use. Idarucizumab, a monoclonal antibody fragment directed against dabigatran, is able to completely antagonize the effect of dabigatran within minutes. Therefore, the drug has the potential to terminate life-threatening bleeding complications earlier and make emergency surgical or interventional procedures possible without an elevated bleeding risk.

Topics: Aged; Antibodies, Monoclonal, Humanized; Anticoagulants; Antidotes; Dabigatran; Factor Xa; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Stroke; Thromboembolism; Vitamin K; Warfarin

Stroke is the most serious clinical consequence of atrial fibrillation, which is the most common cardiac arrhythmia. Non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as efficacious, safe and convenient stroke prevention agents. This updated network meta-analysis focused on the relative efficacy and safety of apixaban compared with dabigatran, rivaroxaban and edoxaban for stroke prevention in (i) patients with CHADS2 score ≥ 2, (ii) secondary stroke prevention, and (iii) patients with high quality anticoagulation control with warfarin.. A fixed-effects network meta-analysis was conducted, including data from four Phase III randomised controlled trials (> 70,000 patients with non-valvular atrial fibrillation). The results of the base-case analysis comparing NOACs with warfarin were broadly in line with the results from the individual trials. Results from the three subgroup analyses were broadly similar to the base case results. For example in patients with CHADS2 score ≥ 2, apixaban, high-dose dabigatran, rivaroxaban, and high-dose edoxaban had significantly lower hazards of stroke/systemic embolism compared with low-dose edoxaban. Apixaban and low-dose edoxaban were associated with significantly lower hazards of major bleeding compared with rivaroxaban and dabigatran 150 mg. However, several treatment comparisons that were significant in the base-case analysis were not significant in the patient subgroups, due to the reduced sample size of the subgroups compared with the overall population.. Among the NOACs, apixaban offered the most favourable efficacy and safety profile in the overall patient population as well as in the three subgroups investigated.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiazoles; Vitamin K

Anticoagulation in catheter ablation (CA) of atrial fibrillation (AF) is of paramount importance for prevention of thromboembolic events, and recent studies favor uninterrupted vitamin K antagonists (VKAs). We aimed to compare the efficacy and safety of new oral anticoagulants (NOACs) to uninterrupted VKAs for anticoagulation in CA by performing a meta-analysis. PubMed, EMBASE, the Cochrane Library, and Clinicaltrials.gov databases were searched for studies comparing NOACs with uninterrupted VKAs in patients who underwent CA for AF from January 1, 2000, to August 31, 2015. Odds ratio (OR) and Peto's OR (POR) were used to report for event rates >1% and <1%, respectively. A total of 11,686 patients with AF who underwent CA in 25 studies were included in this analysis. There was no significant difference between NOACs and uninterrupted VKAs in occurrence of stroke or transient ischemic attacks (POR 1.35, 95% CI 0.62 to 2.94) and major bleeding (POR 0.87, 95% CI 0.58 to 1.31), which were consistent in subgroup analysis of interrupted and uninterrupted NOACs. A lower risk of minor bleeding was observed with NOACs (OR 0.80, 95% CI 0.65 to 1.00), and no major differences were observed for the risk of thromboembolic events, cardiac tamponade or pericardial effusion requiring drainage, and groin hematoma. NOACs, whether interrupted preprocedure or not, were associated with equal rates of stroke or TIA and major bleeding complications and less risk of minor bleeding compared with uninterrupted VKAs in CA for AF.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Dabigatran; Factor Xa Inhibitors; Humans; Ischemic Attack, Transient; Observational Studies as Topic; Prothrombin; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Atrial fibrillation (AF) is associated with an increased risk of stroke. AF-related strokes cause greater disability and mortality than those in patients without AF, and are associated with a significant clinical and economic burden in Mexico. Antithrombotic therapy reduces stroke risk in patients with AF and is recommended for all patients except those classified as having a low stroke risk. However, its use is suboptimal all around the world; one study showed that only 4 % of Mexican patients with AF who presented with ischemic stroke were in the therapeutic range for anticoagulation. Vitamin K antagonists (VKAs) such as warfarin or acenocoumarin have long been the only oral anticoagulants for stroke prevention in AF. Although effective, VKAs have disadvantages, including the need for regular coagulation monitoring and dose adjustment. Interactions with numerous common medications and foods contribute to the risk of serious bleeding and thrombotic events in VKA-treated patients. Thus novel oral anticoagulants (NOACs), more properly called direct oral anticoagulants (DOACs), such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban (not available in Mexico), have been developed. These offer the convenience of fixed-dose treatment without the need for monitoring, and have few drug or food interactions. Pivotal phase III trials have demonstrated that these agents are at least as effective as warfarin in preventing stroke and are associated with a reduced risk of intracranial hemorrhage. With apixaban approved in Mexico in April 2013, clinicians now have the choice of three novel DOACs as alternatives to warfarin. However, it is yet to be established which of these agents should be the first choice, and treatment decisions are likely to depend on the individual patient's characteristics.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Drug Administration Schedule; Drugs, Investigational; Evidence-Based Medicine; Humans; Mexico; Practice Guidelines as Topic; Precision Medicine; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Vitamin K

The aim of this network meta-analysis was to evaluate the comparative efficacy and safety of dabigatran, rivaroxaban, apixaban, interrupted vitamin K antagonist (I-VKA), and continuous VKA (C-VKA) in patients undergoing radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF).. PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify clinical trials comparing dabigatran, rivaroxaban, or apixaban with I-VKA or C-VKA, or against each other, in AF patients undergoing RFCA. A network meta-analysis was conducted to directly and indirectly compare the efficacy and safety of competitive anticoagulation regimens with a Bayesian random-effects model.. A total of 39 studies enrolling 27,766 patients were included. C-VKA demonstrated significant superiority over I-VKA in reducing thromboembolic events (risk difference [RD] -0.0068, 95 % confidence interval [CI] -0.0106 to -0.0032) and major bleeding complications (RD -0.0044, 95 % CI -0.0098 to -0.0006). Rivaroxaban compared with I-VKA was associated with a lower risk of thromboembolism (RD -0.0073, 95 % CI -0.0134 to -0.0012), being at the best ranking position among all of the compared anticoagulation regimens in terms of both the efficacy and safety. None of the remaining comparisons reached statistically significant difference in the rate of thromboembolism or major bleeding.. The present study suggests that C-VKA is superior to I-VKA for AF patients undergoing RFCA. Rivaroxaban is the highest probability to be the optimal alternative to C-VKA among the three non-VKA oral anticoagulants in AF ablation.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Causality; Comorbidity; Dabigatran; Female; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thromboembolism; Treatment Outcome; Vitamin K

The high risk of both stroke and major bleeding in atrial fibrillation (AF) patients with chronic kidney disease (CKD) defines an important population for whom the assessment of the balance between the risk of ischemic stroke and of bleeding is essential. The use of novel oral anticoagulants (NOACs) may be a viable option in this population due to their greater net clinical benefit than warfarin, as demonstrated by the results of the clinical phase III trials. NOACs have been found to have a greater net clinical benefit than warfarin in patients at high risk of either stroke (CHADS2≥1 or CHA2DS2-VASc score≥2) or bleeding (HAS-BLED≥3). Noteworthy, it has been found also a positive net clinical benefit with apixaban and dabigatran 110mg BID in patients with CHADS2 score=0 and HAS-BLED score≥3. At CHA2DS2-VASc score=1, apixaban and both doses of dabigatran were superior to warfarin in terms of the net clinical benefit. Available scientific evidence might help in clinical decision-making regarding the use of NOACs in patients with CKD who are at high risk for both stroke and bleeding. Overall, current findings provide a rationale for the choice of apixaban or rivaroxaban over dabigatran in patients with AF and stage III CKD. Out of the NOACs, only apixaban has been recently approved for the use in patients with end-stage renal dysfunction on hemodialysis (the recommended dose of 5mg twice daily should be halved in patients with body weight of ≤60kg and or age≥80years).

Topics: Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Humans; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Severity of Illness Index; Treatment Outcome; 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

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

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzamides; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostatics; Heparin; Humans; Infusions, Parenteral; Intracranial Hemorrhages; Polysaccharides; Protamines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombosis; Vitamin K

Modern direct-acting anticoagulants are rapidly replacing vitamin K antagonists (VKA) in the management of millions of patients worldwide who require anticoagulation. These drugs include agents that inhibit activated factor X (FXa) (such as apixaban and rivaroxaban) or thrombin (such as dabigatran), and are collectively known today as non-VKA oral anticoagulants (NOACs). Since bleeding is the most common and most dangerous side effect of long-term anticoagulation, and because NOACs have very different mechanisms of action and pharmacokinetics compared with VKA, physicians are naturally concerned about the lack of experience regarding frequency, management and outcome of NOAC-associated bleeding in daily care. This review appraises trial and registry (or "real-world") data pertaining to bleeding complications in patients taking NOACs and VKA and provides practical recommendations for the management of acute bleeding situations.

Topics: Antithrombins; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Outcome Assessment, Health Care; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thromboembolism; Vitamin K

This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date.. We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.. A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban.. Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Odds Ratio; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

Thrombo-embolic prophylaxis is a key element within the therapy of atrial fibrillation/atrial flutter. Besides new oral anticoagulants the concept of left atrial appendage occlusion has approved to be a good alternative option, especially in patients with increased risk of bleeding.

Topics: Anticoagulants; Atrial Appendage; Atrial Fibrillation; Atrial Flutter; Benzimidazoles; beta-Alanine; Combined Modality Therapy; Contraindications; Dabigatran; Hemorrhage; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

More and more patients are being treated with direct oral anticoagulants (DOAC). Under treatment with DOACs gastrointestinal bleeding appears to occur more frequently, particularly in the lower gastrointestinal tract, compared to treatment with vitamin K antagonists (e.g. warfarin).. A possible approach should now be elaborated in a joint effort by gastroenterologists and cardiologists.. A selective literatue search was carried out and own experiences were also included.. The decision to perform procoagulant therapy by slowly injecting 30-50 IU prothrombin complex concentrate (PPSB) per kg body weight intravenously depends on various factors and should be assessed critically. Specific antidotes are awaiting approval. After a bleeding episode potentially controllable and reversible triggers must be excluded (e.g. drug interactions and renal impairment). The risk of recurrent bleeding and the risk of thromboembolic events have to be weighed against each other before deciding to readminister an anticoagulant and its form. Dose reduction and changing to apixaban (in reduced dosage) are options for risk reduction and vitamin K antagonists can also be considered.. It is still unclear what role specific antidotes will play.

Topics: Administration, Oral; Anticoagulants; Critical Care; Drug Substitution; Gastrointestinal Hemorrhage; Humans; Injections, Intravenous; Prothrombin; Pyrazoles; Pyridones; Recurrence; Risk Factors; Thromboembolism; Vitamin K

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Vitamin K

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Elective Surgical Procedures; Emergencies; Factor Xa Inhibitors; Hemorrhage; Humans; Kidney Diseases; Morpholines; Orthopedic Procedures; Postoperative Complications; Premedication; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Risk; Rivaroxaban; Thiophenes; Thrombophilia; 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

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

Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Vitamin K

For the prevention of thromboembolic events in patients with atrial fibrillation and a high thrombotic risk, the standard treatment is warfarin, an anticoagulant. Dabigatran, a thrombin inhibitor, is the alternative when warfarin fails to maintain the INR within the therapeutic range. Patients with a moderate thrombotic risk may receive either warfarin or low-dose aspirin. Apixaban, a factor Xa inhibitor anticoagulant, has been authorised in the European Union for use in patients with non-valvular atrial fibrillation and a moderate or high risk of thrombosis. In a double-blind, randomised non-inferiority trial versus warfarin in 18 201 patients, the incidence of stroke or systemic embolism was lower in the apixaban group (average 1.3 versus 1.6 events per 100 patient-years; p = 0.01). This difference was mainly due to a lower incidence of haemorrhagic stroke and did not result in a clear decline in mortality. In addition, these results are undermined by multiple methodological flaws. Clinical evaluation included no trials comparing apixaban with dabigatran; any indirect comparison would be risky given the poor quality of the clinical assessment of both drugs in atrial fibrillation. A double-blind, randomised trial including 5598 patients compared apixaban with aspirin but provided little information on these options in patients with a moderate risk of thrombosis, as most patients were at high risk. In clinical trials, major bleeding events were less frequent with apixaban than with warfarin (average 2.1 versus 3.1 events per 100 patient-years), but they were more frequent with apixaban than with aspirin (1.4 versus 0.9 events per 100 patient-years). In 2013, there is no way of monitoring the anticoagulant activity of apixaban in routine clinical practice, and there is no antidote in case of overdose; the same is true for dabigatran. Apixaban is a substrate for various cytochrome P450 isoenzymes and for P-glycoprotein, creating a risk of multiple drug-drug interactions. In addition, the anticoagulant action of apixaban is increased by renal failure, meaning that renal function must be regularly monitored. In practice, the antithrombotic treatment of choice for patients with atrial fibrillation is warfarin when the risk of thrombosis is high, and warfarin or aspirin when the thrombotic risk is moderate. When the INR cannot be maintained within the desired therapeutic range, it is best to stick with dabigatran.

Topics: Atrial Fibrillation; Clinical Trials as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Pyrazoles; Pyridones; 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

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Embolism; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K; Warfarin

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

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

The approval of the oral direct thrombin inhibitor dabigatranetexilat and the oral factor Xa inhibitors rivaroxaban and apixaban as thromboprophylaxis challenges the position of the vitamin K antagonists (VKA). Predictable pharmacodynamics gives the new oral anticoagulants an advantageous profile. Unlike VKAs there is no specific reversal agent available for the new oral anticoagulants. Experience with haemostatic products for the emergency management of critical bleeding caused by these agents is limited.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation Factors; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Plasma; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Non-valvular atrial fibrillation is one of the most important risk factor for embolic cerebral infarcts. Besides vitamin K antagonists, recently developed novel oral anticoagulants are gaining an increasing role in its treatment. Dabigatran, rivaroxaban and apixaban are novel oral anticoagulants available in the routine clinical practice. This review summarizes their use and the corresponding guidelines in the secondary prevention of ischemic stroke, by answering questions raised in relation of a hypothetical case report.. A nem valvularis eredetű pitvarfibrilláció az embóliás agyi infarktusok egyik legfontosabb kockázati tényezője. Kezelésében a K-vitamin-antagonisták mellett az elmúlt években megjelenő új típusú orális antikoagulánsok egyre nagyobb teret kapnak. A dabigatran, a rivaroxaban és az apixaban a klinikai gyakorlatban elérhető új típusú orális antikoagulánsok. Az összefoglaló ezek alkalmazásának irányelveit, tulajdonságaikat tekinti át ischaemiás stroke szekunder prevenciójában, hipotetikus esetismertetés kapcsán felmerülő kérdéseket tárgyalva. Orv. Hetil., 2014, 155(42), 1655–1660.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Vitamin K; Warfarin

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Tests; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Vitamin K

Disadvantages with traditional anticoagulants (vitamin K antagonists and heparinoids) have led to the development on non-vitamin K antagonist oral anticoagulants (NOACs). These agents are set to replace the traditional anticoagulants in situations such as following orthopaedic surgery, in atrial fibrillation, and in the prevention and treatment of venous thromboembolism. Although superior to vitamin K antagonists and heparinoids in several aspects, NOACs retain the ability to cause haemorrhage and, despite claims to the contrary, may need monitoring. This review aims to summarise key aspects of the NOACs of relevance to the laboratory.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Dose-Response Relationship, Drug; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Thrombosis; Treatment Outcome; Vitamin K

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

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

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Morpholines; Prodrugs; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Vitamin K; Warfarin

Vitamin K antagonists have been in wide use for over 70 years. Warfarin, the most commonly used vitamin K antagonist, has been shown to be highly effective in treating and preventing thrombosis. Despite this, warfarin has many disadvantages, which has led to the development of a new class of oral anticoagulants targeted to specific coagulation factors designated as target-specific oral anticoagulants (TSOAs). TSOAs include the thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban). This chapter reviews the disadvantages of warfarin and evaluates both the advantages and disadvantages of the new oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Dosage Calculations; Drug Interactions; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; 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

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Infarction; Dabigatran; Humans; Intracranial Embolism; Ischemic Attack, Transient; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Treatment with vitamin K antagonists are subject to a common iatrogenic mainly characterized by hemorrhagic stroke. Their narrow therapeutic range associated with variability largely explains this phenomenon. New oral anticoagulants (NOAC) are now available. dabigatran (Pradaxa®) is a direct and specific thrombin inhibitor. It is excreted mainly by the kidney and is the only which can be dialyzed. Rivaroxaban (Xarelto®) and apixaban (Eliquis®) are factor X activated direct inhibitors. They are highly bound to plasma proteins and are metabolized mainly by the liver, via CYP3A4. All NOAC are substrates of P-glycoprotein (P-gp). Due to pharmacological changes, some populations at risk were identified: patients with hepatic impairment, renal impairment, elderly patients or low weight. Some pharmacokinetic or pharmacodynamic drug interactions alter the concentration and the expected impact of NOAC. The NOAC does not require biological monitoring. They interfere with the routine coagulation tests which should be interpreted with caution. Specific tests exist and can be used in case of emergencies. Currently, no antidote is available. The new oral anticoagulant look promising in the elderly. However, certain rules must be followed to reduce the risk of iatrogenic.

Topics: Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Infarction; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drugs, Investigational; Humans; Iatrogenic Disease; Intracranial Hemorrhages; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Atrial fibrillation treatment relies on anticoagulation therapy that reduces the risk of stroke. Vitamin K antagonists (VKA) were the only oral anticoagulant drugs for more than 50 years, but they are difficult to manage especially in the elderly. In France, VKA are the main cause of iatrogenic hospitalizations with about 17,000 hospitalizations per year and around 4,000 to 5,000 deaths per year. Pharmacologic properties of VKA, especially the narrow therapeutic margin explain the complexity of their management. Several studies have shown that patients treated with VKA were on average only 50% of the time with an INR in the therapeutic range. In other words, patients are, half of the time, either-under treated or over-treated. Within this framework, development of new oral anticoagulant drugs appeared necessary, in order to obtain drugs with larger therapeutic margin and a better risk/benefit profile than VKA. Three large randomized clinical trials including almost 50,000 patients with 20,000 subjects over 75 years old and 8,000 over 80 years old, show a better risk/benefit profile of the new oral anticoagulants (NOAC) than VKA, characterized by a 50% reduction of cerebral hemorrhages, 22% reduction of stroke and 12% reduction of total mortality. Meanwhile, their renal elimination and the lack of control of the biological efficacy need to be taken into account for their prescription. Renal failure (estimated glomerular filtration rate according to Cockcroft formula < 30 mL/min) contraindicates their use. Their half-life is shorter than that of VKA and the biological monitoring is not available, thus a good adherence to the treatment is important. Studies specifically conducted among geriatric older population with poly-pathologies and frail are therefore needed to evaluate tolerance of NOAC in real life conditions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Drugs, Investigational; Half-Life; Humans; Intracranial Embolism; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Vitamin K

Prevention of atrial fibrillation (AF)-related stroke and thromboembolism is an important part of AF management. However, stroke risk varies considerably with associated morbidities and risk factors. Several stroke risk stratification schemes have been developed, and categorize patients' stroke risk into categories based on the presence and combination of risk factors. Based on the perceived level of risk, current guidelines recommend that patients with AF receive some form of antithrombotic therapy. Despite guideline recommendations, however, many patients with AF do not receive adequate thromboprophylaxis. This review will discuss some of the reasons why guidelines are not adhered to in clinical practice and current gaps in knowledge. Low adherence to guidelines is in part related to the drawbacks associated with vitamin K antagonist therapy and to the imperfection of current schemes for stratification of both thromboembolic and bleeding risks. Such drawbacks have highlighted the need for new anticoagulants for the prevention of stroke in patients with AF. The novel oral anticoagulants in development, four of which - dabigatran, rivaroxaban, apixaban and edoxaban - have completed or are completing phase III testing, may overcome some of the limitations of vitamin K antagonist therapy and address the underuse and safety concerns associated with current antithrombotic therapies in patients with AF.

Topics: Atrial Fibrillation; Fibrinolytic Agents; Humans; Pyrazoles; Pyridones; Vitamin K

For more than 60 years, vitamin K antagonists have been the only available oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation (AF). Several new molecules, with a favorable pharmacokinetic profile and avoiding routine monitoring, have been recently developed, opening a new era in anticoagulation. The oral direct thrombin inhibitor, dabigatran, and the oral activated factor X inhibitors, rivaroxaban and apixaban, are the novel oral anticoagulants with data from large randomized clinical trials showing that these drugs are noninferior to warfarin in the prevention of stroke and thromboembolic complications of AF, with the advantage of less hemorrhagic stroke and intracranial bleeding. While these trial data are extremely encouraging, several practical issues (e.g., lack of specific antidote, safety of long-term treatment or cost-effectiveness in "real-life" clinical practice) still need to be elucidated.

Topics: Anticoagulants; Atrial Fibrillation; Drugs, Investigational; Factor X; Fibrinolytic Agents; Humans; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Thromboembolism; Vitamin K; Warfarin

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

The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high risk of bleeding. Currently, several drugs are being developed as possible substitutes for VKA that have many advantages such as the lack of monitoring requirement and scarce pharmacologic and food interactions. The present article provides an update on the new oral anticoagulants that are in a more advanced stage of clinical research, their pharmacologic properties, advantages and disadvantages and their results in recent clinical trials.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; beta-Alanine; Clinical Trials as Topic; Dabigatran; Drug Monitoring; Drugs, Investigational; Hemorrhage; Humans; Morpholines; Multicenter Studies as Topic; Patient Care Planning; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombophilia; Vitamin K

New oral anticoagulant drugs are emerging as alternatives to warfarin for the prevention of stroke in patients with non-valvular atrial fibrillation. Two agents are direct factor Xa inhibitors (rivaroxaban and apixaban), and the third is a direct thrombin inhibitor (dabigatran). They have been separately compared to warfarin in large randomised trials. Our objective was to indirectly compare the three agents to each other for major efficacy and safety outcomes. Studies were assessed for comparability and the odds ratios of selected outcomes for each anticoagulant versus one another were estimated indirectly. The three cohorts differed significantly in terms of CHADS(2) score and the number of individuals with a past history of stroke, transient ischemic attack or systemic embolism. The estimated odds ratio of stroke or systemic embolism was 1.35 for rivaroxaban vs dabigatran 150 mg (p=0.04), 0.97 for rivaroxaban versus dabigatran 110 mg (p=0.81), 1.22 for apixaban versus dabigatran 150 mg (p=0.18), 0.88 for apixaban versus dabigatran 110 mg (p=0.34) and 0.90 for apixaban versus rivaroxaban (p=0.43). The estimated odds ratio of major bleeding was 1.10 for rivaroxaban versus dabigatran 150 mg (p=0.36), 1.28 for rivaroxaban versus dabigatran 110 mg (p=0.02), 0.74 for apixaban versus dabigatran 150 mg (p=0.004), 0.87 for apixaban versus dabigatran 110 mg (p=0.17) and 0.68 for apixaban versus rivaroxaban (p<0.001). In conclusion, the available data indicate no significant difference in efficacy between dabigatran 150 mg and apixaban for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. It appears however that apixaban is associated with less major bleeding than dabigatran 150 mg or rivaroxaban and that rivaroxaban is less effective than dabigatran 150 mg in preventing stroke or systemic embolism. Such an indirect comparison should be used only to generate hypotheses which need to be tested in a dedicated randomised trial comparing the three drugs directly.

Topics: Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Heart Valve Diseases; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Morpholines; Multicenter Studies as Topic; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Secondary Prevention; Severity of Illness Index; Stroke; Thiophenes; Thrombophilia; Vitamin K; Warfarin

For many decades Vitamin K antagonists were the standard orally given medication for primary and secondary prevention of thromboembolism in patients with atrial fibrillation and stroke. Three compounds, dabigatran, rivaroxaban, and apixaban, are now challenging this well established prescription, as they showed similar effect in preventing thromboembolism with a lower bleeding rate in recently published well designed, controlled randomised, non-inferiority trials. Their advantages of each are to have a fixed dosage, no need to monitor coagulation factors, and fewer interactions with food and other drug intake. The therapeutic effect is estimated overall similar between the three compounds. Who is a candidate for one of the new drugs: Patients with atrial fibrillation and the clear indication to get a future oral anticoagulation are potential candidates to receive one of the new drugs. Further this may be patients where the treatment with Vit K antagonists was difficult to optimise, patients who are not willing to have blood controls done regularly or where blood controls are difficult to obtain. This will also be an option in patients who had a stroke due to atrial fibrillation and had no history of cerebral bleeding. Who should not receive the new anticoagulants: patients who present stable blood coagulation values in the treatment range and no complications should not be merged to the new drugs. Patients with severe renal insufficiency or receiving a medication that interacts with the new drugs (e. g. ketoconazole) or with synthetic heart valves will not be candidates to receive the new drugs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Thromboembolism; Vitamin K

The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS(2) score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest : rivaroxaban in the ROCKET AF trial and apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Kidney; Morpholines; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Vitamin K

New oral anticoagulants such as the factor Xa inhibitors rivaroxaban and apixaban or the thrombin inhibitor dabigatran lack some of the limitations of the well-known vitamin K-antagonists. Although routine monitoring is not required, large variations in overall exposure can be seen under certain circumstances. Dabigatran is primarily eliminated in unchanged form in the urine and dose has to be adapted according to renal function. The factor Xa inhibitors are CYP3A4-substrates and combination with potent CYP3A4-inhibitors is not allowed. In cases of bleeding or thromboembolic events under treatment, targeted monitoring of drug concentration or anti-FXa- or anti-FIIa-activity may be helpful to identify the underlying cause. In contrast to vitamin K antagonists or heparin, no antidotes are available for the new anticoagulants and the optimal procedure in cases of life-threatening bleeding has not yet been defined. For certain indications such as prophylaxis of venous thromboembolism in acutely ill medical patients study data are (not yet) available. Concerning localization of bleeding sites the new compounds may display a different profile compared to vitamin K-antagonists (less intracranial bleedings). Experience with long-term use (> 5 years) is limited. Therefore careful clinical monitoring of patients considering co-medication and co-morbidity is necessary to allow safe therapy with the new oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dabigatran; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Humans; Metabolic Clearance Rate; Morpholines; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Topics: Acute Coronary Syndrome; Amidines; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Treatment Outcome; Vitamin K

Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF.. The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug.. Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Drug Design; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Vitamin K

Vitamin K antagonists and heparins have been standard anticoagulation drugs over the past decades. They are effective and safe but they have several drawbacks which has led to the development of new oral anticoagulants. Dabigatran etexilate is a specific oral thrombin inhibitor and rivaroxaban and apixaban are oral inhibitors of factor Xa. These agents produce a predictable anticoagulant response after fixed-dose administration so that routine coagulation monitoring is unnecessary. Currently, dabigatran etexilate, rivaroxaban and apixaban are licensed for thromboprophylaxis after elective total hip or knee replacement surgery. Since august 2011, dabigatran etexilate is licensed for patients with atrial fibrillation, rivaroxaban will follow. However, indications will be expanded e.g. for therapy of venous thromboembolism. It is important to be aware of the pharmacokinetic and pharmacodynamic profiles of these new agents. The drugs considerably influence the global test of coagulation thus making an interpretation of test results difficult. Currently, there is a lack of suitable coagulation tests to monitor anticoagulation in emergency cases, such as bleeding. Specific antidotes are not yet available.

Topics: Administration, Oral; Antithrombins; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Benzimidazoles; Blood Coagulation Tests; Critical Care; Dabigatran; Drug Approval; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombophilia; Vitamin K

Many years of practical use and intensive scientific research have allowed vitamin K antagonists to become a cornerstone of treatment of internal diseases. Nevertheless, limitations in pharmacokinetics and -dynamics of vitamin K antagonists and the availability of new drugs in regard to a targeted anticoagulation therapy ask for a new review of the situation. Proof of effectiveness for the perioperative prophylaxis of venous thrombosis after hip and knee replacement has already been achieved for the direct thrombin inhibitor dabigatran etexilate as well as for the factor Xa inhibitors rivaroxaban und apixaban compared to low molecular weight heparins. These new drugs are now also investigated in patients with internal diseases. For the long-term application (6 or 12 months) concerning the treatment of venous thrombosis and/or stroke prophylaxis in patients with atrial fibrillation data is already available for the direct thrombin inhibitor dabigatran etexilate. Depending on its dosage its effectiveness in comparison with vitamin K antagonists is equal or even better without disadvantages in safety. However, vitamin K antagonists will remain the standard oral anticoagulation until open questions regarding e.g. insufficient therapy adherence (with termination rates up to 20%) or problems with drug interactions of the new competitive products have been completely answered.

Topics: Anticoagulants; Antithrombin Proteins; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; Dabigatran; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thrombosis; Vitamin K

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

Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Benzimidazoles; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; 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

Managing antithrombotic therapy in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is challenging and can be affected by prior oral anticoagulant (OAC) treatment. We examined the relationship between prior OAC use and outcomes in the AUGUSTUS trial.. This prespecified secondary analysis is from AUGUSTUS, an open-label, 2-by-2 factorial, RCT to evaluate the safety of apixaban versus vitamin K antagonist (VKA) and aspirin versus placebo in patients with AF and ACS and/or PCI. The primary endpoint, major or clinically relevant non-major bleeding and clinical outcomes were compared in patients receiving (n=2262) or not receiving (n=2352) an OAC prior to enrolment.. Patients with prior OAC use had more comorbidities, higher CHA. In AUGUSTUS, prior OAC use was associated with fewer ischaemic events but not more bleeding. In patients with AF and ACS and/or undergoing PCI, clinicians can be assured that the trial results can be applied to patients regardless of their prior OAC status.. NCT02415400.

Topics: Acute Coronary Syndrome; Aspirin; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Ischemia; Male; Medication Therapy Management; Middle Aged; Outcome and Process Assessment, Health Care; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Preoperative Period; Pyrazoles; Pyridones; Vitamin K

Subclinical obstructive valve thrombosis after transcatheter aortic valve replacement (TAVR) is of uncertain frequency and clinical impact.. The aim of this study was to determine the effects of apixaban vs standard of care on post-TAVR valve thrombosis detected by 4-dimensional (4D) computed tomography.. The randomized ATLANTIS (Anti-Thrombotic Strategy to Lower All Cardiovascular and Neurologic Ischemic and Hemorrhagic Events After Trans-Aortic Valve Implantation for Aortic Stenosis) trial demonstrated that apixaban 5 mg twice daily was not superior to standard of care (vitamin K antagonists or antiplatelet therapy) after successful TAVR and was associated with similar safety but with more noncardiovascular deaths. Three months after randomization, 4D computed tomography was proposed to all patients to determine the percentage of patients with ≥1 prosthetic valve leaflet with grade 3 or 4 reduced leaflet motion or grade 3 or 4 hypoattenuated leaflet thickening (the primary endpoint) in the intention-to-treat population.. Seven hundred sixty-two participants had complete multiphase datasets and were included in the 4D computed tomographic analysis. The primary endpoint occurred in 33 (8.9%) and 51 (13.0%) patients in the apixaban and standard-of-care groups, respectively. It was reduced with apixaban vs antiplatelet therapy (OR: 0.51; 95% CI: 0.30-0.86) but not vs vitamin K antagonists (OR: 1.80; 95% CI: 0.62-5.25) (P. Apixaban reduced subclinical obstructive valve thrombosis in the majority of patients who underwent TAVR without having an established indication for anticoagulation. This study was not powered for clinical outcomes. (Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis [ATLANTIS]; NCT02664649).

Topics: Anticoagulants; Aortic Valve; Aortic Valve Stenosis; Fibrinolytic Agents; Four-Dimensional Computed Tomography; Heart Valve Prosthesis; Humans; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Factors; Thrombosis; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K

Current guidelines recommend anticoagulation with a vitamin K antagonist to treat left ventricular (LV) thrombus after myocardial infarction (MI). Data on the use of direct oral anticoagulants (DOACs) in this setting are limited. The aim of the study was to assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI.. We conducted a prospective, randomized, multicentre open-label clinical trial including patients with LV thrombus detected by 2D transthoracic echocardiography 1-14 days after acute MI. Thirty-five patients were enrolled in three medical centres; 17 patients were randomized to warfarin and 18 patients to apixaban. The primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation. Secondary outcomes were major bleeding, stroke or systemic embolism, re-hospitalization, and all-cause mortality. Mean LV thrombus size at enrolment was 18.5 mm × 12.3 mm in the warfarin group and 19.9 mm × 12.4 mm in the apixaban group (P = NS). Thirty-two patients completed 3 months follow-up. In the warfarin group, two patients withdrew, and in the apixaban group one patient died. Thrombus completely resolved in 14 of 15 patients in the warfarin group and in 16 of 17 patients in the apixaban group (P = NS and P = 0.026 for non-inferiority). Two patients had major bleeding in the warfarin group, while no major bleeding events were recorded in the apixaban group. There was one stroke in the warfarin group and one death in the apixaban group.. Our results suggest that apixaban is non-inferior to warfarin for treatment of patients with LV thrombus after acute MI with a 20% non-inferiority margin.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Myocardial Infarction; Prospective Studies; Pyrazoles; Pyridones; Stroke; Thrombosis; Vitamin K; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Coronary Artery Disease; Coronary Thrombosis; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Percutaneous Coronary Intervention; Pyrazoles; Pyridones; Risk Factors; Stents; Time Factors; Treatment Outcome; Vitamin K

Mechanical thrombectomy (MT) is one of the main treatments for acute ischemic stroke (AIS) in patients on effective anticoagulation. The use of direct oral anticoagulants (DOA) has increased, given their efficacy and safety profile compared to vitamin K antagonists (VKA). We compared procedural and clinical outcomes of MT in patients on DOA and VKA treatment before stroke onset. We analyzed 2 groups from the Endovascular Treatment in Ischemic Stroke prospective registry: patients on DOA and patients on VKA treated by MT without thrombolysis. Generalized linear mixed models including center as random effect were used to compare angiographic (rates of reperfusion at end of procedure, number of passes >2, procedural complications) and clinical (favorable and excellent outcome, 90-day all-cause mortality, and hemorrhagic complications) outcomes according to anticoagulation subgroups. Comparisons were adjusted for prespecified confounders (age, admission NIH Stroke Scale score) as well as for meaningful baseline between-group differences. Among 221 patients included, more DOA-treated patients (n = 115, 52%) achieved successful (modified Thrombolysis in Cerebral Infarction score [mTICI] 2b/3) or near complete (mTICI 2c/3) reperfusion at the procedure end than did VKA-treated patients, with an adjusted odds ratio (OR) for DOA vs VKA of 3.27 (95% confidence interval [CI], 1.40-7.65) and 2.00 (95% CI, 1.08-3.73), respectively. DOA-treated patients had a lower 90-day mortality risk with an adjusted OR of 0.47 (95% CI, 0.24-0.89) and a better excellent outcome OR of 2.40 (1.10-5.27). There was no significant between-group difference in hemorrhagic or procedural complications. The study highlights the benefits of DOA compared to VKA. Regarding mortality, excellent outcomes, and recanalization rate, DOA appears to provide a favorable setting for MT treatment in AIS.

Topics: Aged; Anticoagulants; Dabigatran; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Reperfusion; Rivaroxaban; Stroke; Thrombectomy; Treatment Outcome; Vitamin K

Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice.. To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice.. Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea's nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin.. Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA2DS2-VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54-0.71; 0.60, 0.53-0.69; and 0.71, 0.56-0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51-0.66 and 0.75, 0.60-0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69-1.04), showed a significantly lower MB risk than warfarin.. Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Female; Hemorrhage; Humans; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring.. We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF).. Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks.. In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3-89.7), 85.2% (95% CI 81.5-88.2), and 87.8% (95% CI 83.4-91.1). Serious adverse events were similar across groups.. High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits.. This study is registered at ClinicalTrials.gov [NCT01884350].

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Female; Fibrinolytic Agents; Humans; Male; Medication Adherence; Pyrazoles; Pyridones; Risk Factors; Stroke; Vitamin K

Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.

Topics: Adolescent; Anticoagulants; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Factor Xa Inhibitors; Female; Heart Defects, Congenital; Heart Diseases; Heparin, Low-Molecular-Weight; Humans; Infant; Male; Multicenter Studies as Topic; Prospective Studies; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Sample Size; Vitamin K

The safety and efficacy of antithrombotic regimens may differ between patients with atrial fibrillation who have acute coronary syndromes (ACS), treated medically or with percutaneous coronary intervention (PCI), and those undergoing elective PCI.. Using a 2×2 factorial design, we compared apixaban with vitamin K antagonists and aspirin with placebo in patients with atrial fibrillation who had ACS or were undergoing PCI and were receiving a P2Y. An antithrombotic regimen consisting of apixaban and a P2Y. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02415400.

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Agents; Combined Modality Therapy; Disease Management; Drug Therapy, Combination; Elective Surgical Procedures; Female; Fibrinolytic Agents; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Treatment Outcome; Vitamin K

Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear.. In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y. Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group.. In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Vitamin K

It is recommended to perform atrial fibrillation ablation with continuous anticoagulation. Continuous apixaban has not been tested.. We compared continuous apixaban (5 mg b.i.d.) to vitamin K antagonists (VKA, international normalized ratio 2-3) in atrial fibrillation patients at risk of stroke a prospective, open, multi-centre study with blinded outcome assessment. Primary outcome was a composite of death, stroke, or bleeding (Bleeding Academic Research Consortium 2-5). A high-resolution brain magnetic resonance imaging (MRI) sub-study quantified acute brain lesions. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) at baseline and at end of follow-up. Overall, 674 patients (median age 64 years, 33% female, 42% non-paroxysmal atrial fibrillation, 49 sites) were randomized; 633 received study drug and underwent ablation; 335 undertook MRI (25 sites, 323 analysable scans). The primary outcome was observed in 22/318 patients randomized to apixaban, and in 23/315 randomized to VKA {difference -0.38% [90% confidence interval (CI) -4.0%, 3.3%], non-inferiority P = 0.0002 at the pre-specified absolute margin of 0.075}, including 2 (0.3%) deaths, 2 (0.3%) strokes, and 24 (3.8%) ISTH major bleeds. Acute small brain lesions were found in a similar number of patients in each arm [apixaban 44/162 (27.2%); VKA 40/161 (24.8%); P = 0.64]. Cognitive function increased at the end of follow-up (median 1 MoCA unit; P = 0.005) without differences between study groups.. Continuous apixaban is safe and effective in patients undergoing atrial fibrillation ablation at risk of stroke with respect to bleeding, stroke, and cognitive function. Further research is needed to reduce ablation-related acute brain lesions.

Topics: Aged; Atrial Fibrillation; Brain; Catheter Ablation; Cognition; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Risk Factors; Stroke; Treatment Outcome; Vitamin K

Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 ± 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Body Mass Index; Dabigatran; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Obesity; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Registries; Rivaroxaban; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

The primary objective was to compare apixaban to heparin/vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and ≤48 h anticoagulation prior to randomization undergoing cardioversion.. One thousand five hundred patients were randomized. The apixaban dose of 5 mg b.i.d. was reduced to 2.5 mg b.i.d. in patients with two of the following: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 133 µmol/L. To expedite cardioversion, at the discretion of the investigator, imaging and/or a loading dose of 10 mg (down-titrated to 5 mg) was allowed. The endpoints for efficacy were stroke, systemic embolism (SE), and death. The endpoints for safety were major bleeding and clinically relevant non-major (CRNM) bleeding.. There were 1038 active and 300 spontaneous cardioversions; 162 patients were not cardioverted. Imaging was performed in 855 patients, and 342 received a loading dose of apixaban. Comparing apixaban to heparin/VKA in the full analysis set, there were 0/753 vs. 6/747 strokes [relative risk (RR) 0; 95% confidence interval (95% CI) 0-0.64; nominal P = 0.015], no SE, and 2 vs. 1 deaths (RR 1.98; 95% CI 0.19-54.00; nominal P > 0.999). In the safety population, there were 3/735 vs. 6/721 major (RR 0.49; 95% CI 0.10-2.07; nominal P = 0.338) and 11 vs. 13 CRNM bleeding events (RR 0.83; 95% CI 0.34-1.89; nominal P = 0.685). On imaging, 60/61 with thrombi continued randomized treatment; all (61) were without outcome events.. Rates of strokes, systemic emboli, deaths, and bleeds were low for both apixaban and heparin/VKA treated AF patients undergoing cardioversion.. NCT02100228.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cause of Death; Drug Administration Schedule; Echocardiography, Transesophageal; Electric Countershock; Embolism; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Stroke; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K

Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF.. The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF.. At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA. In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status.. clinicaltrials.gov Identifier: NCT01701817.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K; Warfarin

Catheter ablation is the most efficacious rhythm control therapy in atrial fibrillation (AF) patients. There is growing evidence that catheter ablation procedures are best performed during continuous oral anticoagulation, but outcomes are variable depending on the anticoagulation strategy or agent chosen. Specifically, there is a need to evaluate the peri-procedural use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients undergoing catheter ablation of AF. The AXAFA-AFNET 5 trial will test whether peri-procedural anticoagulation therapy using apixaban is a safe alternative to vitamin K antagonist (VKA) therapy for patients undergoing catheter ablation of AF.. AXAFA-AFNET 5 is a randomized, prospective multi-centre study conducted in Europe and the USA. A total of 650 patients scheduled for AF ablation will be randomized 1:1 to undergo AF ablation on continuous treatment with the NOAC apixaban or with a VKA. Patients can undergo AF ablation after at least 30 days of continuous effective anticoagulation or after exclusion of atrial thrombi by transoesophageal echocardiogram. The trial includes a post-ablation magnetic resonance imaging substudy that will quantify silent brain lesions that can occur in neurologically asymptomatic patients after AF ablation. Patients will be followed on continuous anticoagulation for 3 months after the ablation. The primary outcome parameter of AXAFA-AFNET 5 is a composite of all-cause death, stroke, and major bleeding events.. The results of AXAFA-AFNET 5 will provide evidence informing about the safety of apixaban in ablation patients and on its efficacy including effects on silent brain lesions. AXAFA - AFNET 5 is an investigator-initiated trial sponsored by AFNET. The trial is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) and by Bristol-Myers Squibb/Pfizer Alliance.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Catheter Ablation; Drug Administration Schedule; Echocardiography, Transesophageal; Europe; Factor Xa Inhibitors; Hemorrhage; Humans; Magnetic Resonance Imaging; Prospective Studies; Pyrazoles; Pyridones; Research Design; Risk Factors; Stroke; Time Factors; Treatment Outcome; United States; Vitamin K

Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombosis, pregnancy morbidity, and the presence of characteristic antibodies. Current therapy for patients having APS with a history of thrombosis necessitates anticoagulation with the vitamin K antagonist warfarin, a challenging drug to manage. Apixaban, approved for the treatment and prevention of venous thrombosis with a low rate of bleeding observed, has never been studied among patients with APS.. We report study rationale and design of Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome (ASTRO-APS), a prospective randomized open-label blinded event pilot study that will randomize patients with a clinical diagnosis of APS receiving therapeutic anticoagulation to either adjusted-dose warfarin or apixaban 2.5 mg twice a day. We aim to report our ability to identify, recruit, randomize, and retain patients with APS randomized to apixaban compared with warfarin. We will report clinically important outcomes of thrombosis and bleeding. All clinical outcomes will be adjudicated by a panel blinded to the treatment arm. A unique aspect of this study is the enrollment of patients with an established clinical diagnosis of APS. Also unique is our use of electronic medical record interrogation techniques to identify patients who would likely meet our inclusion criteria and use of an electronic portal for follow-up visit data capture.. ASTRO-APS will be the largest prospective study to date comparing a direct oral anticoagulant with warfarin among patients with APS for the secondary prevention of thrombosis. Our inclusion criteria assure that outcomes obtained will be clinically applicable to the routine management of patients with APS receiving indefinite anticoagulation.

Topics: Administration, Oral; Adult; Antiphospholipid Syndrome; Female; Humans; Male; Middle Aged; Pilot Projects; Pregnancy; Pregnancy Complications, Hematologic; Pyrazoles; Pyridones; Thrombosis; Vitamin K; Warfarin

The AVERROES double-blinded, randomized trial demonstrated that apixaban reduces the risk of stroke or systemic embolism (SSE) by 55% compared with aspirin without an increase in major bleeding in patients with atrial fibrillation either who previously tried but failed vitamin K antagonists (VKA) therapy or who were expected to be unsuitable for VKA therapy. In this pre-specified analysis, we explored the consistency of the results in the subgroup of patients who tried but failed VKA therapy.. Of 5599 patients, 2216 (40%) had previously failed VKA treatment [main reasons: poor international normalized ratio (INR) control 42%, refusal 37%, bleeding on VKA 8%]. Compared with those expected to be unsuitable for VKA therapy, those who had previously failed were older, more often male, had higher body mass index, more likely to have moderate renal impairment and a history of stroke and less likely to have heart failure or to be medically undertreated. The effects of apixaban compared with aspirin were consistent in those who previously failed and those who were expected to be unsuitable, for both SSE (P interaction 0.13) and major bleeding (P interaction 0.74) and were also consistent among different subgroups of patients who had previously failed VKA therapy defined by reasons for unsuitability, age, sex, renal function, CHADS2 score, aspirin dose, duration, indication, and quality of INR control of prior VKA use.. The efficacy and safety of apixaban compared with aspirin is consistent in subgroups of patients who have previously attempted but failed VKA therapy, irrespective of the reason for discontinuation.

Topics: Aged; Aspirin; Atrial Fibrillation; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Risk Factors; Stroke; Treatment Outcome; Vitamin K

D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases.. To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin.. In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization.. Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14-2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06-5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77-3.45, P < 0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS2 score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level.. In anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Embolism; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Hemorrhage; Humans; Incidence; Male; Middle Aged; Predictive Value of Tests; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin.. The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding.. The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category.. Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Contraindications; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Factors; Stroke; Vitamin K; Warfarin

Many patients with atrial fibrillation (AF) at moderate or high risk for stroke are not treated with a vitamin K antagonist (VKA). Presently, the only alternative to a VKA with a labeled indication for AF is antiplatelet therapy with acetylsalicylic acid (ASA), which is much less effective than a VKA for prevention of stroke. The novel oral factor Xa inhibitor, apixaban, is being developed for prevention of stroke in AF. A noninferiority trial of apixaban versus a VKA (warfarin) is being conducted but does not address the large unmet need of AF patients at risk of stroke who are unsuitable for or unwilling to take a VKA. Apixaban may be an attractive alternative to ASA for prevention of stroke in patients with AF who cannot or will not take a VKA.. AVERROES is a double-blind, double-dummy superiority trial of apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) compared with ASA 81 to 324 mg once daily in patients with AF and at least 1 risk factor for stroke who have failed or are unsuitable for VKA therapy. The primary outcome is stroke or systemic embolism, and the primary safety outcome is major bleeding. The trial is event driven and is expected to enroll at least 5,600 patients.. By evaluating the use of apixaban as a replacement for ASA in AF patients who are not treated with a VKA, the AVERROES study is addressing an important unmet clinical need. The results of AVERROES will be complementary to those of a parallel noninferiority trial comparing apixaban with VKA therapy in patients with AF who are able to receive a VKA.

Topics: Aged; Aged, 80 and over; Aspirin; Atrial Fibrillation; Double-Blind Method; Drug Administration Schedule; Fibrinolytic Agents; Hemorrhage; Humans; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Research Design; Retreatment; Stroke; Treatment Failure; Vitamin K; Warfarin

Apixaban, an oral potent reversible direct inhibitor of activated factor X, has shown promise in the prevention of venous thromboembolism following major orthopedic surgery. We conducted a dose-ranging study in patients with deep vein thrombosis.. Consecutive patients with symptomatic deep vein thrombosis were included and randomized to receive 84-91 days of apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily, or low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan. The principal safety outcome was the composite of major and clinically relevant, non-major bleeding.. The mean age of the 520 included patients was 59 years, and 62% were male. The primary outcome occurred in 17 of the 358 apixaban-treated patients [4.7%, 95% confidence interval (CI) 2.8-7.5%] and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI 1.4-9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable without evidence of a dose response. The principal safety outcome occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/VKA-treated patients. No dose response for apixaban was observed.. These observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Recurrence; Safety; Treatment Outcome; Venous Thrombosis; Vitamin K

BACKGROUND Left ventricular thrombus is a serious complication of numerous cardiovascular conditions. Anticoagulation with oral vitamin K antagonists such as warfarin is a standard treatment for left ventricular thrombus and is recommended to reduce the risk of embolization. Patients with cardiac conditions share comorbidities with patients with end-stage renal disease, and patients with advanced kidney disease are predisposed to atherothrombotic and thromboembolic complications. The efficacy of direct oral anticoagulants in patients with left ventricular thrombus has not been well studied. CASE REPORT A 50-year-old man had prior myocardial infarction, heart failure with reduced ejection fraction, diabetes, hypertension, atrial fibrillation, treated hepatitis B infection, and end-stage renal disease on hemodialysis. On regular outpatient follow-up with the cardiology clinic, a transthoracic echocardiogram was requested and revealed akinesia of the mid to apical anterior wall, mid to apical septum, and left ventricular apex, and large apical thrombus measuring 20×15 mm. Apixaban 5 mg orally twice daily was started. A transthoracic echocardiogram was done after 3 months and after 6 months, and the thrombus did not resolve. The apixaban was shifted to warfarin. The international normalized range was maintained at the therapeutic range (INR 2.0-3.0). After 4 months of receiving warfarin, echocardiography showed a resolution of the left ventricular thrombus. CONCLUSIONS We report a case of left ventricular thrombus that was successfully dissolved by warfarin after treatment with apixaban failed. This case challenges the general assumption of apixaban's effectiveness in patients with end-stage renal disease on dialysis.

Topics: Anticoagulants; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Thrombosis; Vitamin K; Warfarin

The aim of the study was to compare the real-world effectiveness and safety in atrial fibrillation (AF) patients treated with edoxaban versus other oral anticoagulants (OACs) (apixaban, dabigatran, rivaroxaban, and vitamin K antagonists [VKA]) in Germany.. Using a representative database of 3.5 million statutory health-insured lives in Germany, a retrospective cohort study was conducted to examine ischemic stroke (IS) or systemic embolism (SE) and major bleeding in AF patients initiating anticoagulant therapy from January 2014 through June 2017. Inverse probability of treatment weighting using propensity score was applied for baseline covariate adjustment. Cox proportional hazards models were used to estimate the adjusted risk (hazard ratio [HR]) of each outcome comparing edoxaban versus other OACs. Among 21,038 patients treated with OACs, 1236 edoxaban, 6053 apixaban, 1306 dabigatran, 7013 rivaroxaban, and 5430 VKA patients were included. The adjusted combined risks of IS or SE were lower (p < 0.05) for each edoxaban pairwise comparison with other OACs (HR: 0.83 vs. apixaban, 0.60 vs. dabigatran, 0.72 vs. rivaroxaban, 0.64 vs. VKA). Edoxaban favored lower risks of major bleeding compared with rivaroxaban (HR: 0.74) and VKA (HR: 0.47). No differences in the risk of major bleeding were found between edoxaban and apixaban (p = 0.33), and between edoxaban and dabigatran (p = 0.06).. Edoxaban was associated with better effectiveness compared with other OACs in AF patients from Germany. Edoxaban also demonstrated a favorable safety profile.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Humans; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; Vitamin K

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.

Topics: Adult; Aged; Aged, 80 and over; Antithrombins; Creatinine; Cystatin C; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population.. This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin.. This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB.. Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55-0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72-0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57-0.66) and dabigatran (HR: 0.79, 95% CI: 0.70-0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08-1.21) was associated with a higher risk vs warfarin.. Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cause of Death; Dabigatran; Frail Elderly; Hemorrhage; Humans; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; United States; Vitamin K; Warfarin

In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y. In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial.. Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min. The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Kidney; Male; Middle Aged; Percutaneous Coronary Intervention; Pyrazoles; Pyridones; Vitamin K

Our aim was to compare adverse drug reactions (ADRs) associated with direct-acting oral anticoagulants and vitamin K antagonists from the European EudraVigilance (EV) database. The EV database is the system for the analysis of information on suspected ADRs that are authorised, or being evaluated in clinical trials, in the European Economic Area. Registered ADRs (from the groups "Gastrointestinal disorders", "General disorders and administration site conditions", "Injury, poisoning and procedural complications", "Nervous system (NS) disorders" and "Vascular disorders") for apixaban, rivaroxaban, dabigatran and vitamin K antagonists (VKA) were collected by age group (< 65 years; 65-85 years and > 85 years) and by sex. The proportional reporting ratio (PRR) was used to compare ADRs in relation to the anticoagulants tested. A total of 274,693 ADRs were analysed. For gastrointestinal ADRs, patients treated with rivaroxaban and dabigatran (PRR 2.17 and 2.51, respectively) were at significantly higher risks than those treated with apixaban and VKA (PRR 1.27 and 1.47, respectively), while risks for vascular disorders were increased by all anticoagulants that were tested. Lastly, none of the anticoagulants significantly increased the risk of ADRs within the NS group. Rivaroxaban and dabigatran were associated with a significantly higher risk of gastrointestinal ADR than apixaban or VKA. All anticoagulants increased the risk of vascular pathology while none of them demonstrated significant increased risk of ADR to NS.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Pharmacovigilance; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K; Young Adult

Empirically, a significant proportion of patients using direct oral anticoagulation (DOAC) take off-label reduced doses. We aimed to investigate the prevalence, indications, dosages, and bleeding complications of oral anticoagulants on admission to the emergency department.. In this retrospective analysis, patients presenting to our emergency department between January 1 and December 31, 2018, with therapeutic oral anticoagulation were included (ie, vitamin-K antagonists, rivaroxaban, apixaban, edoxaban, and dabigatran). A detailed chart review was performed for each case concerning characteristics, indication, and bleeding complications.. A total of 19,662 consecutive cases in the emergency department were reported: 1721 (9%) had therapeutic oral anticoagulation. Vitamin-K antagonists (41%), rivaroxaban (36%), and apixaban (19%) were the most common. Stroke prophylaxis in patients with atrial fibrillation (63.2%) and venous thromboembolism (24.1%) were the most common indications. In 27 cases (1.6%), no indication could be identified; further, 32% of patients were classified to have either off-label doses of DOACs or an international normalized ratio (INR) out of range (in vitamin-K antagonists), whereas 20% were classified as off-label underdosed and 12% as overdosed. No difference in the likelihood of bleeding on admission could be found between the respective drugs. Only concomitant use of aspirin was significantly associated with presence and higher severity of bleeding.. Vitamin-K antagonists are still the most widely used drug followed by rivaroxaban. A significant proportion of patients are being prescribed off label-doses. While no difference was found for the respective anticoagulants with respect to bleeding, concomitant aspirin use was a significant predictor for bleeding in our collective.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Emergency Service, Hospital; Female; Hemorrhage; Humans; Male; Off-Label Use; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Thiazoles; 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

Topics: Administration, Oral; Anticoagulants; Blood Volume; Chromatography, Liquid; Dabigatran; Dried Blood Spot Testing; Humans; Pyrazoles; Pyridones; Rivaroxaban; Tandem Mass Spectrometry; Vitamin K

With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran).. Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging.. Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4-5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04).. We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.

Topics: Accidental Falls; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Antithrombins; Blood Coagulation Factors; Coagulants; Dabigatran; Disease Progression; Factor Xa Inhibitors; Female; Glasgow Outcome Scale; Humans; Intracranial Hemorrhage, Traumatic; Length of Stay; Male; Middle Aged; Mortality; Neurosurgical Procedures; Plasma; Platelet Transfusion; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Thiazoles; Vitamin K; Warfarin

In AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), patients with atrial fibrillation and a recent acute coronary syndrome and those undergoing percutaneous coronary intervention had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin. However, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo.. In AUGUSTUS, 4614 patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention on a P2Y. Compared with VKA, apixaban had either a lower or a similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference, 0.97% [95% CI, 0.23-1.70]) and fewer severe ischemic events (absolute risk difference, -0.91% [95% CI, -1.74 to -0.08]) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference, 1.25% [95% CI, 0.23-2.27]), whereas the risk of severe ischemic events was similar (absolute risk difference, -0.17% [95% CI, -1.33 to 0.98]).

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Coronary Thrombosis; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Ischemia; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K

The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials.. An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting.. This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiologists; Clinical Trials, Phase III as Topic; Consensus; Dabigatran; Disease Management; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Vitamin K; Warfarin

Evidence for the efficacy of direct oral anticoagulants (DOACs) to prevent cardiovascular (CV) events and mortality in older individuals with a low estimated glomerular filtration rate (eGFR) is lacking. We sought to characterize the association of oral anticoagulant use with CV morbidity in elderly patients with or without reductions in eGFRs, comparing DOACs with vitamin K antagonists (VKAs).. Population-based retrospective cohort study.. All individuals 66 years or older with an initial prescription for oral anticoagulants dispensed in Ontario, Canada, from 2009 to 2016.. DOACs (apixaban, dabigatran, and rivaroxaban) compared with VKAs by eGFR group (≥60, 30-59, and<30mL/min/1.73m. The primary outcome was a composite of a CV event (myocardial infarction, revascularization, or ischemic stroke) or mortality. Secondary outcomes were CV events alone, mortality, and hemorrhage requiring hospitalization.. High-dimensional propensity score matching of DOAC to VKA users and Cox proportional hazards regression.. 27,552 new DOAC users were matched to 27,552 new VKA users (median age, 78 years; 49% women). There was significantly lower risk for CV events or mortality among DOAC users compared with VKA users (event rates of 79.78 vs 99.77 per 1,000 person-years, respectively; HR, 0.82 [95% CI, 0.75-0.90]) and lower risk for hemorrhage (event rates of 10.35 vs 16.77 per 1,000 person-years, respectively; HR, 0.73 [95% CI, 0.58-0.91]). There was an interaction between eGFR and the association of anticoagulant class with the primary composite outcome (P<0.02): HRs of 1.01 [95% CI, 0.92-1.12], 0.83 [95% CI, 0.75-0.93], and 0.75 [95% CI, 0.51-1.10] for eGFRs of≥60, 30 to 59, and<30mL/min/1.73m. Retrospective observational study design limits causal inference; dosages of DOACs and international normalized ratio values were not available; low event rates in some subgroups limited statistical power.. DOACs compared with VKAs were associated with lower risk for the composite of CV events or mortality, an association for which the strength was most apparent among those with reduced eGFRs. The therapeutic implications of these findings await further study.

Topics: Aged; Aged, 80 and over; Antithrombins; Brain Ischemia; Cause of Death; Comorbidity; Dabigatran; Female; Glomerular Filtration Rate; Hemorrhage; Humans; Male; Mortality; Myocardial Infarction; Myocardial Revascularization; Ontario; Procedures and Techniques Utilization; Propensity Score; Proportional Hazards Models; Pyrazoles; Pyridones; Renal Insufficiency, Chronic; Retrospective Studies; Rivaroxaban; Thrombophilia; Vitamin K

To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs.. We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted.. In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.

Topics: Administration, Oral; Administrative Claims, Healthcare; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Dabigatran; Electronic Health Records; Female; Hemorrhage; Humans; Japan; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Stroke; Thiazoles; Time Factors; Treatment Outcome; Vitamin K; Warfarin

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

Topics: Acute Coronary Syndrome; Acute Disease; Aspirin; Atrial Fibrillation; Clopidogrel; Combined Modality Therapy; Cyclophosphamide; Dabigatran; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stents; Stroke; 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 evidence of effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) among elderly East Asians is limited.. We aimed to describe the effectiveness and safety outcomes associated with NOACs and warfarin among elderly Koreans aged ≥80 years.. Using the Korean Health Insurance Review and Assessment service database, patients with atrial fibrillation (AF) who were naïve to index oral anticoagulant between 2015 and 2017 were included in this study (20,573 for NOACs and 4086 for warfarin). Two treatment groups were balanced using the inverse probability of treatment weighting (IPTW) method. The clinical outcomes including ischemic stroke, major bleeding including intracranial hemorrhage (ICH) and gastrointestinal bleeding (GIB), and a composite of these outcomes were evaluated.. Compared to warfarin, NOACs were associated with lower risks of ischemic stroke (hazard ratio 0.74 [95% confidence interval 0.62-0.89]), and composite outcome (0.78 [0.69-0.90]). NOACs showed nonsignificant trends towards to lower risks of GIB and major bleeding than warfarin. The risk of ICH of NOAC group was comparable with the warfarin group. Among NOACs, apixaban and edoxaban showed better composite outcomes than warfarin. Among the clinical outcomes, only ischemic stroke and the composite outcome had a significant interaction with age subgroups (80-89 years and ≥90 years, P-for-interaction = .097 and .040, respectively).. NOACs were associated with lower risks of ischemic stroke and the composite outcome (ischemic stroke and major bleeding) compared to warfarin in elderly East Asians. Physicians should be more confident in prescribing NOACs to elderly East Asians with AF.

Topics: Aged, 80 and over; Atrial Fibrillation; Brain Ischemia; Databases, Factual; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Republic of Korea; Stroke; Thiazoles; Vitamin K; Warfarin

The purpose of the study was to examine the association between the type of preceding oral anticoagulant use (warfarin or direct oral anticoagulants [DOACs]) and in-hospital mortality among patients admitted with gastrointestinal bleeding.. In this observational cohort study, all patients admitted with a first-time gastrointestinal bleeding from January 2011 to March 2017 while receiving any oral anticoagulant therapy prior to admission were identified using data from Danish nationwide registries. The risk of in-hospital mortality according to type of oral anticoagulation therapy was examined by multivariable logistic regression models.. Among 5,774 patients admitted with gastrointestinal bleeding (median age, 78 years [25th-75th percentile, 71-85 years]; 56.8% men), 2,038 (35.3%) were receiving DOACs and 3,736 (64.7%) were receiving warfarin prior to admission. The unadjusted in-hospital mortality rates were 7.5% for DOAC (7.2% for dabigatran, 6.4% for rivaroxaban, and 10.1% for apixaban) and 6.5% for warfarin. After adjustment for baseline demographic and clinical characteristics, there was no statistically significant difference in in-hospital mortality between prior use of any DOAC and warfarin (unadjusted odds ratio [OR] 1.18 [95% CI 0.95-1.45], adjusted OR 0.97 [95% CI 0.77-1.24]). Similar results were found for each individual DOAC as compared with warfarin (dabigatran: unadjusted OR 1.12 [95% CI 0.84-1.49], adjusted OR 0.96 [95% CI 0.71-1.30]); rivaroxaban: unadjusted OR 0.98 [95% CI 0.71-1.37], adjusted OR 0.84 [95% CI 0.59-1.21]; and apixaban: unadjusted OR 1.62 [95% CI 0.84-1.49], adjusted OR 1.22 [95% CI 0.83-1.79]).. Among patients admitted with gastrointestinal bleeding, there was no statistically significant difference in in-hospital mortality between prior use of DOAC and warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Cohort Studies; Dabigatran; Denmark; Female; Gastrointestinal Hemorrhage; Hospital Mortality; Humans; Logistic Models; Male; Pyrazoles; Pyridones; Rivaroxaban; United States; Vitamin K; Warfarin

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Agents; Combined Modality Therapy; Drug Therapy, Combination; Elective Surgical Procedures; Female; Fibrinolytic Agents; Hemorrhage; Hospitalization; Humans; Length of Stay; Male; Middle Aged; Multicenter Studies as Topic; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Vitamin K

Vitamin K antagonists (VKA) continue to be the standard of long-term anticoagulation. Direct oral anticoagulants(DOAC) are increasingly used. In many trials DOAC were at least as effective as VKA. In this study we evaluate the bleeding profiles, frequencies and etiologies of patients receiving DOAC versus VKA in a real-life setting. All patients presenting with suspected gastrointestinal bleeding (GIB) in the emergency department of the University Hospital Erlangen in one year were enrolled in this study. They were looked up for the intake of either DOAC (dabigatran, rivaroxaban and apixaban) or VKA. The results showed that 406 patients with suspected GIB were admitted to the emergency unit of the University Hospital Erlangen. In 228 of those patients GIB could be verified (56.2%). Fifty four of those patients (23.7%) were administered either VKA or DOAC. In 35 of those 54 patients (64.8%) GIB was classified as 'major bleeding'. In 27 patients with administration of VKA upper GIB was recorded and lower GIB was detected four times. In 16 patients with administration of DOAC upper GIB was found and lower GIB was found in 7 patients. The presented data do not show higher GIB rates for DOAC (mainly dabigatran and rivaroxaban), but do also not indicate a significantly higher safety of DOAC concerning GIB than VKA. This finding represents a clear contrast to the reduced bleeding rates of DOAC for intracerebral bleeding and other non-GIB events. According to our study, the absolute number of DOAC-associated GIB events is lower than in the VKA group.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Vitamin K; Young Adult

Several comparative real-world effectiveness studies on direct oral anticoagulants (DOACs) have been conducted, but an overview of the available evidence remains to be developed, which could provide a better understanding of the value of DOACs relative to vitamin K antagonists (VKAs).. A systematic literature review was conducted on the available real-world evidence (RWE) of three DOACs (rivaroxaban, dabigatran, and apixaban) compared with VKAs (e.g. warfarin), in patients with nonvalvular atrial fibrillation (NVAF).This systematic literature review included RWE published up to December 2016. Studies with > 50 patients reporting on incident and prevalent NVAF cases were included. The following databases were searched: Medline, Embase, and the Cochrane Library. Outcomes of interest included thromboembolic events, all-cause mortality, bleeding events, and nonpersistence. Of the 562 RWE DOACs articles retrieved, 49 presented results for rivaroxaban versus VKAs, 79 for dabigatran versus VKAs, and 18 for apixaban versus VKAs. Substantial heterogeneity was found across patient population, outcome definition, and follow-up period. Major bleeding, ischemic stroke, and intracranial hemorrhage were the most frequent outcomes analyzed.. Overall, the RWE studies were aligned with the Phase 3 trials. However, conflicting results were reported for several outcomes of interest.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

Patients with non-valvular atrial fibrillation (NVAF) have a five times higher stroke risk. For more than 50 years, vitamin K antagonists (VKAs) have been the primary medication for stroke prevention. Apixaban, a non-vitamin K oral anticoagulant (NOAC), has demonstrated better efficacy and safety characteristics than the VKA warfarin in the ARISTOTLE trial. This study aims to quantify the potential societal effects of using apixaban instead of VKA in the German NVAF population from 2017 to 2030.. Using an existing Markov model and a dynamic population approach, we modelled the health benefits of apixaban in patients with NVAF compared to VKA therapy in the German population from 2017 to 2030.. The results represent the extrapolated direct long-term health benefits of apixaban over VKA therapy for the German NVAF population. From 2017 until 2030, the use of apixaban instead of a VKA could avoid 52,185 major clinical events. This includes 15,383 non-fatal strokes or SEs, 22,483 non-fatal major bleeds, and 14,319 all-cause deaths, which correspond to 109,887 life years gained.. This study demonstrated that using apixaban instead of VKA for stroke prevention can lead to considerable reduction in cardiovascular events.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Female; Germany; Hemorrhage; Humans; Male; Markov Chains; Models, Theoretical; Pyrazoles; Pyridones; Stroke; Time Factors; Vitamin K; Warfarin

The correlation between direct oral anticoagulants (DOACs) or Vitamin K Antagonist (VKAs) intake and the incidence of intracranial complications after minor head injury (MHI) is still object of debate: preliminary observation seems to demonstrate lower incidence in intracranial bleeding complications (ICH) in patients taking DOACs than VKA. METHODS. This prospective and observational study was performed to clarify the incidence of ICH in patients in DOACs compared to VKAs. Between January 2016 and April 2018 we have recorded in our ED patients with MHI taking oral anticoagulants. Their hemorragic risk score was calculated and recorded for each patient (Has Bled, Atria and Orbit). RESULTS A total of 402 patients with MHI taking anticoagulant were collected: 226 were receiving one of the four DOACs (dabigatran, rivaroxaban, apixaban or edoxaban) while 176 patients were in therapy with VKA. The rate of intracranial complications was significantly lower in patients receiving DOACs than in patients treated with VKA (p < 0.01). In the VKA group two patients died because of intracranial bleeding. No deaths were recorded in the DOACs group. DISCUSSION patients with MHI who take DOACs have a significant lower incidence of intracranial bleeding complications than those treated with vitamin k antagonists. This statement is supported by the observation that the hemorrhagic risk, measured according to the chosen scores, was similar between the two groups.

Topics: Aged; Aged, 80 and over; Anticoagulants; Craniocerebral Trauma; Dabigatran; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridines; Pyridones; Risk; Rivaroxaban; Thiazoles; Vitamin K; Warfarin

There is a high degree of uncertainty regarding optimum care of patients with potential or known intake of oral anticoagulants and traumatic brain injury (TBI). Anticoagulation therapy aggravates the risk of intracerebral hemorrhage but, on the other hand, patients take anticoagulants because of an underlying prothrombotic risk, and this could be increased following trauma. Treatment decisions must be taken with due consideration of both these risks. An interdisciplinary group of Austrian experts was convened to develop recommendations for best clinical practice. The aim was to provide pragmatic, clear, and easy-to-follow clinical guidance for coagulation management in adult patients with TBI and potential or known intake of platelet inhibitors, vitamin K antagonists, or non-vitamin K antagonist oral anticoagulants. Diagnosis, coagulation testing, and reversal of anticoagulation were considered as key steps upon presentation. Post-trauma management (prophylaxis for thromboembolism and resumption of long-term anticoagulation therapy) was also explored. The lack of robust evidence on which to base treatment recommendations highlights the need for randomized controlled trials in this setting.

Topics: Administration, Oral; Anticoagulants; Austria; Brain Injuries, Traumatic; Consensus; Dabigatran; Deamino Arginine Vasopressin; Humans; Interdisciplinary Communication; Partial Thromboplastin Time; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thromboembolism; Tomography, X-Ray Computed; Tranexamic Acid; Treatment Outcome; Vitamin K

Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs.. In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations.. We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA₂DS₂-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use.. In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.

Topics: Administration, Oral; Aged; Anticoagulants; Asian People; Atrial Fibrillation; Dabigatran; Drug Labeling; Female; Humans; Male; Medication Adherence; Middle Aged; Prospective Studies; Pyrazoles; Pyridines; Pyridones; Republic of Korea; Risk Factors; Rivaroxaban; Thiazoles; Vitamin K

Atrial fibrillation (AF) is associated with an increased risk of thromboembolic events.. This study compared the long-term efficacy and safety of apixaban with that of uninterrupted vitamin K antagonist (VKA) therapy in patients with AF scheduled for transesophageal echocardiogram (TEE)-guided direct current cardioversion (DCC) from June 2014 to September 2016.. We enrolled consecutive patients with persistent nonvalvular AF scheduled to undergo DCC. Patients received apixaban 5 mg or 2.5 mg twice daily (bid) or VKA at therapeutic doses for at least 3 weeks before and 4 weeks after DCC. All patients underwent anamnestic, clinical, electrocardiographic, and echocardiographic evaluation at each follow-up visit and were followed-up for 12 months. The primary efficacy endpoint was the composite of stroke/transient ischemic attack and systemic embolism. The primary safety endpoint was major bleeding.. After propensity score matching, comparative treatment groups comprised 182 (75.8%) patients receiving apixaban 5 mg bid and 182 receiving VKA. A low incidence of atrial thrombus (0.5%) at TEE was found in both groups. The acute cardioversion success rate was 86.1% in the apixaban group (156/181) and 83.9% in the VKA group (152/181). During the follow-up period, a similarly low incidence of thromboembolic events (1.1%) was reported in both groups; the bleeding safety profile tended to favor apixaban over VKA (1.1 vs. 1.6%; p = 0.3).. Newly initiated anticoagulation with apixaban in patients with nonvalvular AF scheduled for TEE-guided DCC seems to be as effective and safe as uninterrupted VKA therapy during 12 months of follow-up.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Electric Countershock; Embolism; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Propensity Score; Prospective Studies; Pyrazoles; Pyridones; Stroke; Thromboembolism; Vitamin K

Topics: Atrial Fibrillation; Dabigatran; Humans; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

 This study assessed changes in anticoagulation therapy over time in patients with atrial fibrillation (AF)..  Analyses were performed on a claims-based dataset of 4 million health-insured individuals. The study population consisted of patients newly initiating a non-vitamin-K oral anticoagulants (NOACs) or vitamin K antagonist (VKA) for AF between 2013 and 2016. The study outcomes consisted of the proportion of patients who had (1) discontinued OAC treatment, (2) switched from VKA to NOAC, (3) switched from NOAC to VKA or (4) switched from one NOAC to another. Predictors of discontinuation or switching of OAC treatment were determined by Cox proportional hazards regression models with time-independent and time-dependent covariates..  The study population comprised 51,606 AF patients initiating VKA (.  Overall discontinuation rates of VKA and NOACs are comparable over the first year of therapy, while switching from VKA to NOAC was more common than from NOAC to VKA. The majority of treatment changes were associated with clinical events.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug Substitution; Female; Follow-Up Studies; Germany; Hemorrhage; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Vitamin K; Withholding Treatment

Geriatric characteristics such as high age, multi-morbidity, polypharmacy and frailty are common in patients with atrial fibrillation (AF). In a retrospective study using a German claims database, effectiveness (ischaemic stroke/systemic embolism) and safety (intracerebral, gastrointestinal and major extracranial bleeding) were compared in patients with non-valvular AF starting non-vitamin K oral antagonists (NOACs) (apixaban, dabigatran and rivaroxaban) and phenprocoumon. Cox proportional hazards models were used to calculate adjusted hazard ratios, and interaction terms of the treatment group and geriatric status (defined by age ≥75 years, frailty, ≥ 4 co-morbidities and polypharmacy) were entered into the model. A total of 42,562 and 27,939 patients initiated NOAC and phenprocoumon treatment (mean age 74 years ± 11, 51% male) with a follow-up time of 147,785 person-years. Note that 52.9% of patients were elderly, 50.8% were frail, 37.0% were co-morbid and 46.5% had polypharmacy. NOAC use was not associated with effectiveness and gastrointestinal bleeding, neither in geriatric nor in non-geriatric patients. The hazard of major extracranial and intracranial bleeding was significantly decreased for NOAC use, with similar risk reduction in geriatric and non-geriatric patients: major extracranial bleeding 0.70 (95% confidence interval [CI], 0.56-0.87) to 0.73 (95% CI, 0.60-0.89) for the geriatric groups and 0.71 (95% CI, 0.56-0.93) to 0.76 (0.59-0.98) for the non-geriatric groups (

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Geriatrics; Germany; Humans; Middle Aged; Phenprocoumon; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Vitamin K

In the treatment of non-valvular atrial fibrillation (AF) with oral anticoagulants (OAC), medical adherence is a relevant factor for stroke prevention.. To evaluate the one-year persistence of vitamin K antagonists (VKA) and direct oral anticoagulants (DOAC) in patients suffering from AF and already treated with OACs.. Information from the National Health Insurance Fund of Hungary prescriptions database on pharmacy claims between June 1, 2015 and December 31, 2015 was analysed. Authors identified patients who filled prescriptions for OACs (VKAs or DOACs) prescribed for AF who have already received OACs therapy during one year before. Apparatus of survival analysis was used, where 'survival' was the time to abandon the medication.. 196 016 patients met the inclusion criteria. 181 810 patients received VKA and 14 206 patients were treated with DOACs. The one-year persistence rate in patients taking VKA was 52.9% whereas it was 66.8% in those on the DOACs. The persistence rates after 360 days were 67.5% for rivaroxaban, 63.6% for apixaban and 63.4% for dabigatran. The mean duration of persistence was 311 days for rivaroxaban, 308 days for apixaban and 284 days for dabigatran. The actual rate of discontinuation was 14% (HR = 1.14 [95% CI 1.05-1.24]), p = 0.0015) for apixaban, 15% (HR = 1.15 [95% CI 1.08-1.23], p = 0.003) for dabigatran and 62% (HR = 1.62 [95% CI 1.56-1.69], p<0.0001) for VKA compared to rivaroxaban (reference).. The authors have confirmed that the one-year persistence of DOAKs was significantly higher compared to KVA therapy in AF. The one-year persistence of rivaroxaban was more favoured than apixaban and dabigatran. Orv Hetil. 2019; 160(13): 509-515.. Absztrakt: Bevezetés: A nonvalvularis pitvarfibrilláció (PF) orális antikoagulánssal (OAK) történő kezelésekor a terápiahűség igen jelentős tényező a stroke prevenciójában. Célkitűzések: A szerzők célja a már OAK-terápiában részesülő PF-ban szenvedő betegeknél a K-vitamin-antagonista (KVA) és a direkt orális antikoagulánsok (DOAK) egyéves perzisztenciájának vizsgálata. Módszer: A Nemzeti Egészségbiztosítási Alapkezelő adatbázisából a vényforgalmi adatokra támaszkodva pitvarfibrilláció indikációjában, 2015 második félévében valamely orális antikoaguláns (OAK = KVA/DOAK) receptjét kiváltó olyan betegeket választottak ki, akiknek a vizsgálati időszakot megelőzően – a vizsgálati időszakban történt kiváltási dátumhoz képest – 12 hónappal korábban volt (DOAK/KVA összes) vénykiváltásuk. A perzisztencia modellezésére a túlélés-analízis klasszikus eszköztárát alkalmazták, ahol a „túlélési” idő a gyógyszer szedésének abbahagyásáig eltelt idő volt, 60 napos ’grace’ periódussal. Eredmények: A bevonási kritériumoknak 196 016 beteg felelt meg. A betegek közül 181 810 szedett KVA-t, míg 14 206 beteg kapott DOAK-ot. A KVA-k egyéves perzisztenciája 52,9%, a DOAK-ot szedőké 66,8% volt. A DOAK-terápián belül a rivaroxaban egyéves perzisztenciája 67,5%, az apixabané 63,6%, a dabigatrané 63,4% volt. A 360 napra korlátozott átlagos gyógyszerszedési idő 311 nap volt a rivaroxaban, 308 nap az apixaban, 303 nap a dabigatran, míg 284 nap a KVA-k esetén. A gyógyszerelhagyás kockázatának pillanatnyi rátája az apixaban esetén 14%-kal (HR = 1,14 [95% CI 1,05–1,24]), p = 0,0015), a dabigatrannál 15%-kal (HR = 1,15 [95% CI 1,08–1,23], p = 0,003), a KVA-t szedőknél 62%-kal (HR = 1,62 [95% CI 1,56–1,69], p<0,0001) volt magasabb a rivaroxabanhoz képest. Következtetés: A szerzők igazolták, hogy PF-ban a KVA-terápiához képest a DOAK-ok egyéves perzisztenciája szignifikánsan magasabb volt. A DOAK-ok közül a rivaroxaban egyéves perzisztenciája előnyösebbnek bizonyult az apixabanhoz és a dabigatranhoz képest. Orv Hetil. 2019; 160(13): 509–515.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Humans; Hungary; Pyrazoles; Pyridones; Rivaroxaban; Treatment Outcome; 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

Scarce data comparing real-world outcomes between apixaban and vitamin K antagonist (VKA) users with nonvalvular atrial fibrillation (NVAF) are available. We sought to assess the effectiveness and safety of newly-initiated apixaban vs. VKA in German NVAF patients.. We performed a retrospective analysis in German outpatients using IMS Disease Analyzer data. Adults newly-initiated on apixaban or a VKA from January 2013 to March 2015 with a diagnosis of NVAF on the day of the first qualifying oral anticoagulant (OAC) prescription (index date) or any time during 1 year prior, and at least 1 year of follow-up were included. Patients experiencing a prior event in the composite endpoint, receiving an OAC before the index date, >1 OAC on the index date or switched to another OAC during follow-up were excluded. Apixaban and VKA users were 1:1 propensity-score matched. We evaluated the composite of ischaemic stroke, transient ischaemic attack (TIA), myocardial infarction (MI) or intracranial haemorrhage (ICH) in the year after OAC initiation. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).. In total, 835 apixaban and 835 VKA users were matched. Forty-one composite events were identified. Hazard of the composite endpoint did not differ between apixaban and VKA users (HR=0.87, 95%CI=0.47-1.60). Ischaemic stroke and MI occurred at dissimilar (albeit not statistically significant) rates between apixaban and VKA therapy (HR=1.51, 95%CI=0.54-4.24) and (HR=0.33, 95%CI=0.11-1.03). Only two patients (both in the apixaban cohort) experienced an ICH.. Apixaban and VKA therapy were associated with a similar impact on the composite endpoint in real-world German practice. Additional investigation is needed to evaluate the numeric trends of ischaemic stroke and decreased number of MIs observed with apixaban, as well as the high rate of reduced dose apixaban use found in this analysis.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Stroke; Treatment Outcome; Vitamin K

After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations.. Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%).. In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Denmark; Drug Substitution; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Rivaroxaban; Stroke; Vitamin K

Atrial fibrillation (AF) is the most common arrhythmia worldwide, and its prevalence is expected to increase with population ageing. The use of vitamin K antagonists (VKAs) for the prevention of stroke and/or systemic embolism in patients with non-valvular atrial fibrillation (NVAF) was recently challenged by non-VKA oral anticoagulants (NOACs), demonstrating a favourable risk-benefit profile, with reductions in stroke, intracranial haemorrhage and mortality, similar major bleeding, but increased gastrointestinal bleeding. Nevertheless, data on their use in a "real-life" setting are scarce for France.. To compare the characteristics of patients with AF newly anticoagulated with either VKAs or NOACs, to describe the reasons for discontinuing the previous anticoagulant strategy and/or choosing the newly initiated anticoagulant treatment, and to precisely describe the prescriptions of patients newly initiated with apixaban.. This is a nationwide multicentre non-interventional cross-sectional study conducted in patients with AF by a representative stratified sample of cardiologists in France. Over a 12-month accrual period, consecutive patients aged ≥18 years with NVAF, for whom anticoagulant treatment (VKAs or NOACs) has been initiated within the last three months before the index consultation, will be included. The primary outcome will be the comparison of anticoagulant-naïve patient characteristics, co-morbidities and treatment history among the anticoagulant subgroups. Secondary endpoints will include a description of the reasons for discontinuing the previous anticoagulant strategy and/or for initiating and choosing the newly initiated anticoagulant treatment, as well as the prescription conditions of apixaban.. The PAROS study will provide real-life data on the characteristics of NVAF patients and their anticoagulant prescription in France.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cross-Sectional Studies; Drug Prescriptions; Drug Substitution; Embolism; Factor Xa Inhibitors; France; Hemorrhage; Humans; Pyrazoles; Pyridones; Research Design; Risk Factors; Stroke; Time Factors; Treatment Outcome; Vitamin K

Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension.. A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study.. Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall.. Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.

Topics: Administration, Oral; Adult; Aged; Antithrombins; Chronic Disease; Dabigatran; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyridones; Reproducibility of Results; Treatment Outcome; Vitamin K

Topics: Anticoagulants; Atrial Fibrillation; Electric Countershock; Heparin; Humans; Intention; Pyrazoles; Pyridones; Vitamin K

The safety of direct oral anticoagulants (DOACs) in oldest old patients with nonvalvular atrial fibrillation (NVAF) in daily clinical practice has not been systematically assessed. This study examined the safety of DOACs and dicumarol (a vitamin K antagonist) in NVAF geriatric patients.. Prospective study from January 2010 through June 2015, with follow-up through January 2016.. Geriatric medicine department at a tertiary hospital.. A total of 554 outpatients, 75 years or older, diagnosed of NVAF and starting oral anticoagulation.. The main outcome was bleeding, which was classified into major (including those life-threatening) and nonmajor episodes. Statistical analyses were performed with Cox regression.. A total of 351 patients received DOACs and 193 dicumarol. Patients on DOACs were older, with more frequent comorbidities, mobility limitation and disability in activities of daily living, as well as higher mortality, than those treated with dicumarol. The incidence of any bleeding was 19.2/100 person-years among patients on DOACs and 13.7/100 person-years on dicumarol; corresponding figures for major bleeding were 5.2 for those on DOACs, and 3.3 for those on dicumarol. In crude analyses, hazard ratios (95% confidence intervals) for any bleeding, and for mayor bleeding in patients on DOACs vs dicumarol were 1.60 (1.04-2.44) and 2.22 (0.88-5.59), respectively. Excess risk of bleeding associated with DOACs vs dicumarol disappeared after adjustment for clinical characteristics, so that corresponding figures were 1.19 (0.68-2.08) and 1.01 (0.35-2.93). Results did not vary across subgroups of high-risk patients.. In very old patients with NVAF, the higher risk of bleeding associated with DOACs vs dicumarol could be mostly explained by the worse clinical profile of patients receiving DOACs. Risk of bleeding was rather high, and warrants close clinical monitoring.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Chronic Disease; Comorbidity; Dabigatran; Dementia; Dicumarol; Disabled Persons; Follow-Up Studies; Hemorrhage; Humans; Mobility Limitation; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

This study aimed to evaluate the risk of major bleeding among two cohorts of nonvalvular atrial fibrillation patients newly initiating a vitamin K antagonist (VKA) or apixaban in a real-world setting in Italy.. A retrospective study using a large administrative database of Italian local health units was performed, using data from ten local health units and patients were included from the date of new initiation of apixaban or VKAs from January 2012 to June 2015.. Risk of major bleeding was calculated using an adjusted Cox regression model. Compared with VKA, apixaban had a significantly lower risk of major bleeding (hazard ratio = 0.44 [95% CI: 0.12-0.97]).. In this analysis, apixaban was associated with a lower risk of major bleeding compared with VKA.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Databases, Factual; Evidence-Based Medicine; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Italy; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyridones; Retrospective Studies; Risk; Vitamin K

Limited real-world data are available regarding the comparative safety of non-vitamin K antagonist oral anticoagulants (NOACs). The objective of this retrospective claims observational cohort study was to compare the risk of bleeding among non-valvular atrial fibrillation (NVAF) patients prescribed apixaban, dabigatran, or rivaroxaban. NVAF patients aged ≥18 years with a 1-year baseline period were included if they were new initiators of NOACs or switched from warfarin to a NOAC. Cox proportional hazards modelling was used to estimate the adjusted hazard ratios of any bleeding, clinically relevant non-major (CRNM) bleeding, and major inpatient bleeding within 6 months of treatment initiation for rivaroxaban and dabigatran compared to apixaban. Among 60,227 eligible patients, 8,785 were prescribed apixaban, 20,963 dabigatran, and 30,529 rivaroxaban. Compared to dabigatran or rivaroxaban patients, apixaban patients were more likely to have greater proportions of baseline comorbidities and higher CHA2DS2-VASc and HAS-BLED scores. After adjusting for baseline clinical and demographic characteristics, patients prescribed rivaroxaban were more likely to experience any bleeding (HR: 1.35, 95% confidence interval [CI]: 1.26-1.45), CRNM bleeding (HR: 1.38, 95% CI: 1.27-1.49), and major inpatient bleeding (HR: 1.43, 95% CI: 1.17-1.74), compared to patients prescribed apixaban. Dabigatran patients had similar bleeding risks as apixaban patients. In conclusion, NVAF patients treated with rivaroxaban appeared to have an increased risk of any bleeding, CRNM bleeding, and major inpatient bleeding, compared to apixaban patients. There was no significant difference in any bleeding, CRNM bleeding, or inpatient major bleeding risks between patients treated with dabigatran and apixaban.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Hemorrhage; Humans; Inpatients; Male; Middle Aged; Outpatients; Proportional Hazards Models; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Vitamin K; Warfarin

Novel oral anticoagulants (NOACs) are alternatives to vitamin-K antagonists (VKAs) for the prevention of thromboembolism. It is unclear how NOACs have been adopted in the UK since first introduced in 2008. The present study was conducted to describe the trends in the prescription of NOACs in the UK, including dabigatran, rivaroxaban and apixaban.. Using the UK's Clinical Practice Research Datalink, the rates of new use of NOACs and VKAs from 2009 to 2015 were calculated using Poisson regression. Patient characteristics associated with NOAC initiation were identified using multivariate logistic regression.. The overall rate of oral anticoagulant initiation increased by 58% over the study period [rate ratio (RR) 1.58; 95% confidence interval (CI) 1.23, 2.03], even as the rate of new VKA use decreased by 31% (RR 0.69; 95% CI 0.52, 0.93). By contrast, the rate of initiation of NOAC increased, particularly from 2012 onwards, with a 17-fold increase from 2012 to 2015 (RR 17.68; 95% CI 12.16, 25.71). In 2015, NOACs accounted for 56.5% of oral anticoagulant prescriptions, with rivaroxaban prescribed most frequently, followed by apixaban and then dabigatran. Compared to VKAs, new NOAC users were less likely to have congestive heart failure, coronary artery disease and peripheral vascular disease, and more likely to have a history of ischaemic stroke.. In the UK, the rate of initiation of NOACs has increased substantially since 2009, and these agents have now surpassed VKAs as the anticoagulant of choice. Moreover, the characteristics of patients initiated on NOACs have changed over time, and this should be accounted for in future studies comparing NOACs and VKAs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Drug Utilization; Female; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Primary Health Care; Pyrazoles; Pyridones; Rivaroxaban; United Kingdom; Vitamin K

The use of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prophylaxis in atrial fibrillation (AF) is increasing rapidly. We compared characteristics of AF patients initiated on NOACs versus vitamin K antagonists (VKAs).. Using Danish nationwide registry data, we identified AF patients initiating either a VKA or a NOAC from 22 August 2011 until 30 September 2016. We compared patient characteristics including age, gender, comorbidities, concomitant pharmacotherapy and CHA. The study population comprised 51 981 AF patients of whom 19 989 (38.5%) were initiated on a VKA, 13 242 (25.5%) on dabigatran, 8475 (16.3%) on rivaroxaban and 10 275 (19.8%) on apixaban. Those patients initiated on apixaban had higher mean ± SD CHA. Atrial fibrillation patients who were initiated on apixaban had higher stroke risk scores than patients initiated on VKAs. Interestingly, opposite results were found for dabigatran.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; 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

Data evaluating the impact of the periprocedural administration of novel oral anticoagulants (NOACs) on complications in the setting of pulmonary vein (PV) isolation using cryoballoon (CB) is limited. In the present study, our aim was to analyze procedural characteristics and incidence of complications in those patients who underwent CB ablation for atrial fibrillation and the impact of NOACs on adverse events compared with vitamin K antagonists (VKAs). Consecutive patients with drug resistant atrial fibrillation who underwent PV isolation by CB as index procedure were retrospectively included in our analysis. In group I, 290 of 454 patients (63.9%) received VKAs (warfarin: n = 222 and acenocoumarol: n = 68), and in group II, 164 of 454 patients (36.1%) were treated with NOACs (rivaroxaban: n = 71; dabigatran: n = 60; and apixaban: n = 33). Age was significantly higher in the group II (62.8 ± 9.7 vs 58.6 ± 11.3; p <0.001). During the study period, 454 consecutive patients (male 71%, age 60.1 ± 10.9 years) were enrolled. Major complications occurred in 9 patients (2.0%): peripheral vascular complications were observed in 6 patients (1.3% per procedure), persistent phrenic nerve palsy occurred in 2 (0.4%), and transient ischemic attacks in 1 (0.2%). In both groups, the incidence of major complications was similar (group I [VKAs]: 7 patients [2.4%] vs group II [NOACs]: 2 patients [1.2%]; p = 0.5). In conclusion, CB ablation is a safe procedure for PV isolation and is associated with low complication rates. The incidence of adverse events in PV isolation using the second-generation CB with the periprocedural administration of NOACs is not significantly different than VKA treatment.

Topics: Ablation Techniques; Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Belgium; Cryosurgery; Dabigatran; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Intraoperative Period; Italy; Male; Middle Aged; Postoperative Complications; Prognosis; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Survival Rate; Thiazoles; Time Factors; Vitamin K

Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk, whereas dose reductions without a firm indication may decrease the effectiveness of stroke prevention.. The goal of this study was to investigate NOAC dosing patterns and associated outcomes, i.e., stroke (ischemic stroke and systemic embolism) and major bleeding in patients treated in routine clinical practice.. Using a large U.S. administrative database, 14,865 patients with AF were identified who initiated apixaban, dabigatran, or rivaroxaban between October 1, 2010, and September 30, 2015. We examined use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication is not present (potential underdosing). Cox proportional hazards regression was performed in propensity score-matched cohorts to investigate the outcomes.. Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.. In routine clinical practice, prescribed NOAC doses are often inconsistent with drug labeling. These prescribing patterns may be associated with worse safety with no benefit in effectiveness in patients with severe kidney disease and worse effectiveness with no benefit in safety in apixaban-treated patients with normal or mildly impaired renal function.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Pyrazoles; Pyridones; Renal Insufficiency; Retrospective Studies; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; United States; Vitamin K; Young Adult

Topics: Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Intracranial Hemorrhages; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Vitamin K; Warfarin

Data are limited on the safety of periprocedural anticoagulation with novel oral anticoagulants (NOACs) in patients undergoing pulmonary vein isolation (PVI) using the second-generation cryoballoon (CB) for the treatment of atrial fibrillation.. We hypothesized that the incidence of acute periprocedural complications in patients undergoing PVI do not differ between patients treated with VKA compared to NOACs.. In 200 consecutive patients (mean age, 64.3 _ 10.6 years; female, n = 83) with symptomatic atrial fibrillation, PVI using the second-generation 28-mm CB was performed. In patients treated with NOACs, the medication was stopped the day of the procedure and continued the evening after the procedure with a reduced dosage. Patients treated with phenprocoumon were continued on uninterrupted phenprocoumon with a target INR of 2 to 3. If INR was <2, bridging with low-molecular-weight heparin was performed.. Forty-seven of 200 patients (23.5%) were treated with a vitamin K antagonist (VKA) and 55 (27.5%) were treated with apixaban, 67 (33.5%) with rivaroxaban, and 31 (15.5%) with dabigatran. Seven (3.5%) major complications occurred in the overall population. Major bleeding complications did not differ significantly between the 2 groups (P = 0.23). One patient taking VKA had a pericardial tamponade at the end of the procedure; 2 patients treated with apixaban developed a groin hematoma requiring surgical intervention. Transient ischemic attack occurred in 1 patient of the apixaban and rivaroxaban group.. Apixaban, rivaroxaban, and dabigatran, compared with uninterrupted VKA, did not show a higher risk for major bleeding or ischemic complications in patients undergoing PVI using the second-generation CB.

Topics: Administration, Oral; Aged; Antithrombins; Atrial Fibrillation; Cardiac Catheters; Cerebrovascular Disorders; Cryosurgery; Dabigatran; Drug Administration Schedule; Drug Monitoring; Equipment Design; Factor Xa Inhibitors; Female; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Phenprocoumon; Postoperative Hemorrhage; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; Vitamin K

This study examined characteristics and treatment persistence among patients prescribed oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). We identified 15,244 patients (51.8% male, 72.7% aged ≥70) with NVAF and no prior OAC therapy who were prescribed apixaban (n = 1,303), rivaroxaban (n = 5,742), dabigatran (n = 1,622) or vitamin-K antagonists (VKAs, n = 6,577) between 1-Dec-2012 and 31-Oct-2014 in German primary care (IMS® Disease Analyzer). We compared OAC persistence using Cox regression over patients' entire follow-up and using a data-driven time-partitioned approach (before/after 100 days) to handle non-proportional hazards. History of stroke risk factors (stroke/transient ischaemic attack [TIA] 15.2%; thromboembolism 14.1%; hypertension 84.3%) and high bleeding risk (HAS-BLED score≥3 68.4%) was common. Apixaban-prescribed patients had more frequent history of stroke/TIA (19.7%) and high bleeding risk (72.6%) than other OACs. 12-month persistence rates were: VKA 57.5% (95% confidence interval (CI) 56.0-59.0%), rivaroxaban 56.6% (54.9-58.2%), dabigatran 50.1% (47.2-53.1%), apixaban 62.9% (58.8-67.0%). Over entire follow-up, compared to VKA, non-persistence was similar with apixaban (adjusted hazard ratio 1.08, 95% CI 0.95-1.24) but higher with rivaroxaban (1.21, 1.14-1.29) and dabigatran (1.53, 1.40-1.68). Using post-hoc time-partitioned approach: in first 100 days, non-persistence was higher with apixaban (1.37, 1.17-1.59), rivaroxaban (1.41, 1.30-1.53) and dabigatran (1.91, 1.70-2.14) compared to VKA. Compared to apixaban, rivaroxaban non-persistence was similar (1.03, 0.89-1.20), dabigatran was higher (1.39, 1.17-1.66). After 100 days, apixaban non-persistence was lower than VKA (0.66, 0.52-0.85); rivaroxaban (0.97, 0.87-1.07) and dabigatran (1.10, 0.95-1.28) were similar to VKA. Furthermore, rivaroxaban (1.46, 1.13-1.88) and dabigatran (1.67, 1.26-2.19) non-persistence was higher than apixaban. This study describes real-world observations on OAC use, particularly early apixaban use following approval for NVAF, in Germany. We identified potential differential OAC prescribing and higher persistence with apixaban than other OACs after 100 days' treatment. Larger studies are needed with longer follow-up to establish long-term patterns.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Female; Germany; Hemorrhage; Humans; Hypertension; Ischemic Attack, Transient; Male; Primary Health Care; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Thromboembolism; Vitamin K

The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention.. Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA. In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Topics: Acute Disease; Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Dabigatran; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hemorrhage; Humans; Incidence; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Recurrence; Rivaroxaban; Survival Rate; Time Factors; Treatment Outcome; Vitamin K

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are widely used as stroke prophylaxis in non-valvular atrial fibrillation (AF), but comparative data are sparse.. To compare dabigatran, rivaroxaban, and apixaban vs. VKA and the risk of stroke/thromboembolism (TE) and intracranial bleeding in AF.. Using Danish nationwide registries (2011-15), anticoagulant-naïve AF patients were identified when initiating VKA or an NOAC. Outcomes were stroke/TE and intracranial bleeding. Multiple outcome-specific Cox regression was performed to calculate average treatment effects as standardized differences in 1-year absolute risks.. Overall, 43 299 AF patients initiated VKA (42%), dabigatran (29%), rivaroxaban (13%), and apixaban (16%). Mean CHA2DS2-VASc (SD) score was: VKA 2.9 (1.6), dabigatran 2.7 (1.6), rivaroxaban 3.0 (1.6), and apixaban 3.1 (1.6). Within patient-specific follow-up limited to the first 2 years, 1054 stroke/TE occurred and 261 intracranial bleedings. Standardized absolute risk (95% CI) of stroke/TE at 1 year after initiation of VKA was 2.01% (1.80% to 2.21%). In relation to VKA, the absolute risk differences were for dabigatran 0.11% (-0.16% to 0.42%), rivaroxaban 0.05% (-0.33% to 0.48%), and apixaban 0.45% (-0.001% to 0.93%). For the intracranial bleeding outcome, the standardized absolute risk at 1 year was for VKA 0.60% (0.49% to 0.72%); the corresponding absolute risk differences were for dabigatran -0.34% (-0.47% to - 0.21%), rivaroxaban -0.13% (-0.33% to 0.08%), and apixaban -0.20% (-0.38% to - 0.01%).. Among anticoagulant-naïve AF patients, treatment with NOACs was not associated with significantly lower risk of stroke/TE compared with VKA, but intracranial bleeding risk was significantly lower with dabigatran and apixaban.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cohort Studies; Dabigatran; Denmark; Female; Hospitalization; Humans; Intracranial Hemorrhages; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Vitamin K; Warfarin

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

The aims of this study were to assess the impact of atrial fibrillation (AF) on outcome in transfemoral aortic valve replacement (TAVR) and to evaluate the safety and efficacy of apixaban compared with a vitamin K antagonist (VKA) in patients with AF after TAVR.. Non-VKA oral anticoagulant agents have not been systematically used in patients with AF after TAVR.. Of the 617 patients enrolled, 55.9% (n = 345) were in sinus rhythm and 44.1% (n = 272) in AF. Clinical follow-up was performed after 30 days and 12 months.. The early safety endpoint at 30 days was significantly more frequent in patients with AF compared with those in sinus rhythm (23.2% vs. 11.0%; p < 0.01). During 12-month follow-up, the secondary endpoint of all-cause mortality and stroke was significantly higher in patients with AF (20.6% vs. 9.7%; p = 0.02), driven by a significantly higher rate of all-cause mortality (19.1% vs. 7.8%; p = 0.01). Among patients with AF, 141 (51.8%) were treated with apixaban and 131 (48.2%) with a VKA. There was a significantly lower rate of the early safety endpoint in patients with AF treated with apixaban compared with patients treated with a VKA (13.5% vs. 30.5%; p < 0.01), with a numerically lower stroke rate (2.1% vs. 5.3%; p = 0.17) at 30 days and 12 months (1.2% vs. 2.0%; p = 0.73) of follow-up.. In patients undergoing TAVR, AF was associated with a significantly higher rate of all-cause mortality throughout 12 months follow-up. The early safety endpoint in patients with AF on apixaban was significantly less frequent compared with patients receiving a VKA.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Disease-Free Survival; Factor Xa Inhibitors; Female; Femoral Artery; Humans; Kaplan-Meier Estimate; Male; Phenprocoumon; Proportional Hazards Models; Prospective Studies; Punctures; Pyrazoles; Pyridones; Registries; Risk Factors; Stroke; Time Factors; Transcatheter Aortic Valve Replacement; Treatment Outcome; Vitamin K

Antiphospholipid syndrome (APS) is a common acquired thrombophilia associated with a high thrombotic risk, in which vitamin K antagonists (VKA) represent the mainstay of therapy. Case series involving up to 35 patients with APS suggested limited efficacy and safety of direct oral anticoagulants (DOACs).. In the prospective case series we followed 56 consecutive patients with APS (44 women and 12 men, aged from 22 to 64years), including 33 (60%) associated with systemic lupus erythematosus (SLE) and 16 (28.6%) with triple APS who were treated with DOACs due to their preferences or unstable anticoagulation with VKA. DOACs were started at least 3months since the thromboembolic event in patients with D-dimer below 500ng/ml.. Forty-nine (87.5%) patients were treated with rivaroxaban, 4 (7.3%) with dabigatran and 3 (5.4%) with apixaban. During follow-up of 2 to 43 (mean 22) months, 6 (10.7%, 5.8 per 100 patient-years) patients (4 women and 2 men, 4 with triple positive APS) experienced recurrent thrombosis, including deep vein thrombosis (n=4, including 2 episodes preceded by nonadherence), superficial vein thrombosis (n=1) and non-ST elevation myocardial infarction (n=1). The recurrence rate of VTE on DOACs was 5.8 per 100 patient-years. Two patients (3.6%) experienced severe bleeding.. This case-series suggests that DOACs are safe in patients with APS. These findings need to be confirmed in larger studies.

Topics: Administration, Oral; Adult; Anticoagulants; Antiphospholipid Syndrome; Dabigatran; Female; Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis; Vitamin K; Young Adult

Monitoring non-vitamin K antagonist oral anticoagulants (NOAC) is usually not necessary; however, in some patients it may prove beneficial.. Patient subgroups who may profit from monitoring were identified, and methods of monitoring (including assessment of which coagulation parameters are affected by NOAC) are described.. We searched the PubMed database for each of the search terms, "NOAC", "DOAC", "rivaroxaban", "dabigatran", and "apixaban", in combination with one of the terms, "monitoring", "measurement", "measuring", or "assessment". The results were compiled and reviewed.. Monitoring is most advantageous in emergency cases with severe bleeding where drug activity needs to be assessed. It can also help in deciding for or against lysis therapy after acute stroke in patients taking NOAC. Furthermore, it can also identify compliance problems and help in planning periprocedural management. There are quantitative measurement methods which measure plasma concentrations exactly and qualitative methods which only allow for a rough estimate or a general confirmation of drug activity. Recommended quantitative measurement methods are diluted thrombin time for dabigatran, and anti-factor Xa activity (calibrated) for rivaroxaban and apixaban.. Several patient subgroups may profit from monitoring of NOAC plasma concentration. One should, however, take several issues into consideration before measurements, such as the objective of each individual measurement, possible consequences (e. g., dose adjustment), and which measurement method to pick.

Topics: Administration, Oral; Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Coagulation Tests; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Emergency Service, Hospital; Hemorrhage; Humans; Intensive Care Units; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thromboembolism; 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

Persistence to treatment affects clinical outcomes in patients with chronic disease such as atrial fibrillation (AF).. This prospective cohort study included consecutive non-valvular AF patients prescribed with non-vitamin K oral anticoagulants (NOACs) and investigated for any permanent discontinuation at 1-year of this therapy, as well as any reasons for discontinuation.. Overall, 1305 patients were prescribed with dabigatran (N=473), rivaroxaban (N=425) or apixaban (N=407). Of these, 201 patients (15.4%) discontinued NOACs during the first year of treatment. More than 60% of these discontinuations occurred during the first 6months. Reasons for discontinuation included: dyspepsia or abdominal pain in 38 patients (2.9%) and bleeding in 59 (4.5%). Discontinuation for the former occurred earlier (50% within 2months) compared to the latter (66% after the first 4months). The prescription of reduced NOAC doses resulted being an independent predictor of discontinuation (OR 1.74, 95% CI 1.23-2.45, p=0.002). Regarding the use of dabigatran, rivaroxaban and apixaban, the following were observed: discontinuers were 22.0% (95% CI 18.5-25.9), 14.4% (95% CI 11.3-18.0) and 8.8% (95% CI 6.5-12.0), the risk of discontinuation associated with bleeding was 20.2%, 44.3% and 30.6% and dyspepsia or abdominal pain was 35.6%, 1.6% and 0%, respectively.. Discontinuation of NOACs in AF patients was relatively common and more than often occurred in the first six months after prescription. Patients treated with reduced doses of NOACs had a higher probability to discontinue compared to those who were prescribed conventional doses.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Dabigatran; Dyspepsia; Female; Follow-Up Studies; Hemorrhage; Humans; Italy; Male; Medication Adherence; Middle Aged; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Since first used in 2009, non-vitamin K oral anticoagulants (NOAC) have gained world-wide acceptance. Two groups of NOAC are currently used: the direct thrombin antagonist dabigatran and three direct factor  Xa antagonists apixaban, edoxaban, and ricaroxaban. With their increasing use for prevention of thromboembolism, the probability increases that NOAC-pretreated patients are admitted to emergency departments or intensive care units.The clinical challenge in NOAC preanticoagulated patients is to adequately cope with the given anticoagulated status of such patients. Because of their short half-life, many patients will be adequately treated with a "wait and see" approach, and surgeries and interventions are postponed until anticoagulant activities have totally subsided. In the few cases where immediate action is mandated, based on appropriate risk assessments it can be decided either to take the increased hemorrhagic risk of early intervention or to transfuse factor concentrates like PPSB or FEIBA which can safely reverse the anticoagulant activities of the three factor Xa antagonists (and potentially also of dabigatran). Recently a humanized Fab antibody fragment for dabigatran, idarucizumab, has been introduced onto the market, that can immediately reverse the anticoagulant effects of dabigatran. For the reversal of dabigatran, idarucizumab is therefore the drug of choice.In addition, in some specific indications of emergency and intensive care medicine, the primary use of a NOAC can be considered advantageous. Such indications are early cardioversion in patients admitted for new episodes of atrial fibrillation and patients with acute pulmonary embolism. For the widespread use of low-molecular-weight heparins in such indications, however, the decision to use a NOAC for anticoagulant therapy is frequently postponed to the treatment phase when the stabilized patient is already treated on the general ward.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Dabigatran; Electric Countershock; Emergency Service, Hospital; Factor Xa Inhibitors; Hemorrhage; Humans; Intensive Care Units; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thrombin; Thromboembolism; Vitamin K

Apixaban, dabigatran and rivaroxaban are three new direct oral anticoagulants (DOACs) used in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) in Spain.. To assess the relative cost-utility of the three DOACs compared with vitamin K antagonists.. A Markov model with 3-month cycles was used to simulate NVAF patients starting with treatment and followed up for their lifetime from the perspective of the National Health System. The model included 36 health states including treatment combinations, disability and events history and considered a hypothetical cohort of 10,000 NVAF patients. Relative efficacy was calculated from a formal indirect treatment comparison using data from the pivotal trials of each DOAC.. Dabigatran was associated with the highest number of quality-adjusted life years (QALY) (8.40 QALY), followed by apixaban (8.33 QALY), rivaroxaban (8.15 QALY) and acenocoumarol (8.03 QALY). Patients taking acenocoumarol had the lowest total costs (€22,230), followed by dabigatran (€24,564), apixaban (€24,655) and rivaroxaban (€25,900). Incremental cost-utility ratios compared to vitamin K antagonists, were €6,397, €8,039 and €29,957/QALY for dabigatran, apixaban and rivaroxaban, respectively. If compared together, dabigatran dominated apixaban and rivaroxaban. Sensitivity analyses confirmed the robustness of the baseline case.. All three direct anticoagulants are cost-effective against acenocoumarol. Dabigatran is economically dominant over rivaroxaban and apixaban in the Spanish setting, as it is more effective and cheaper.. Comparacion del coste-utilidad de los anticoagulantes orales de accion directa en la prevencion de ictus en la fibrilacion auricular no valvular en España.. Introduccion. El apixaban, el dabigatran y el rivaroxaban son tres anticoagulantes orales de accion directa (ACOD) indicados para la prevencion del ictus y la embolia sistemica en pacientes con fibrilacion auricular no valvular (FANV) en España. Objetivo. Comparar el coste-utilidad de los tres ACOD frente a los antivitamina K. Pacientes y metodos. Se utilizo un modelo Markov con ciclos trimestrales para simular pacientes con FANV desde que inician su tratamiento hasta el resto de su vida desde la perspectiva del Sistema Nacional de Salud. El modelo incorporo 36 estados de salud, incluyendo combinaciones de tratamientos, discapacidad y antecedentes de eventos, y considero una cohorte hipotetica de 10.000 pacientes con FANV. La eficacia relativa se calculo a partir de una comparacion indirecta formal de los tratamientos segun los datos de los ensayos pivotales de cada ACOD. Resultados. El dabigatran se asocio al valor maximo de años de vida ajustados por calidad (AVAC) (8,40 AVAC), seguido del apixaban (8,33 AVAC), el rivaroxaban (8,15 AVAC) y el acenocumarol (8,03 AVAC). Los costes totales fueron menores con el acenocumarol (22.230 €), seguido del dabigatran (24.564 €), el apixaban (24.655 €) y el rivaroxaban (25.900 €). La ratio coste-utilidad incremental frente a los antivitamina K fue de 6.397, 8.039 y 29.957 €/AVAC para el dabigatran, el apixaban y el rivaroxaban, respectivamente. Comparados entre ellos, el dabigatran domino al apixaban y al rivaroxaban. Los analisis de sensibilidad confirmaron la robustez del caso base. Conclusiones. Los tres ACOD son coste-efectivos frente al acenocumarol. El dabigatran es economicamente dominante frente al rivaroxaban y al apixaban en España, al ser mas efectivo y menos costoso.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cost-Benefit Analysis; Dabigatran; Female; Humans; Male; Markov Chains; Pyrazoles; Pyridones; Rivaroxaban; Spain; Stroke; Vitamin K

To examine the long-term persistence and safety of the non-vitamin-K-antagonist oral anticoagulants (NOACs) dabigatran (D), rivaroxaban (R) and apixaban (A) in patients with non-valvular atrial fibrillation (AF) treated in the framework of a well structured, nurse-based AF unit for initiation and follow-up of NOAC.. Retrospective clinical data were collected for 766 consequent patients from a single cardiology outpatient clinic incorporating the AF unit.. The follow-up time, median (q1-q3), was 367 days (183-493) for D patients (n = 233), 432 days (255-546) for R patients (n = 282) and 348 days (267-419) for A patients (n = 251). No significant differences were found between the three groups with regard to age, sex, renal function, or CHA2DS2-VASc score. For all bleeding events the incidence rates per 100 patient-years of follow-up (95% confidence interval [CI], p-value) were reported more often for treatment with R (17.2, 12.7-22.8) than for D (7.0, 4.0-11.3, p = 0.001) and A (8.7, 5.2-13.6, p = 0.013). The differences remained significant after adjustment for clinically relevant variables. Discontinuation rates (n = 167) were lower for A (11.5, 7.5-16.8) than for D (30, 23.4-37.9, p < 0.001) and R (23.9, 18.6-30.1, p = 0.001), and were mainly attributed to drug-specific side effects and bleedings. The majority of discontinued patients (n = 142, 85%) proceeded with other types of oral anticoagulants.. The main limitation of the study is the small patient population with a short follow-up time.. In a retrospective study at a single AF clinic, NOACs showed significantly different bleeding rates and varied discontinuation rates when compared to each other, related mainly to agent-specific side effects and bleedings. The majority of patients that discontinued proceeded with other types of oral anticoagulant.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Dabigatran; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K

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

Current guidelines recommend vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with non-valvular atrial fibrillation (AF).. We compared the clinical features of consecutive in- and out-patients with non-valvular AF newly-treated with NOACs or on treatment with VKAs.. Overall, 1314 patients newly-treated with NOACs and 1024 on treatment with VKAs were included in the study. The mean CHA2DS2-VASc score was 4.3±1.5 and 4.0±1.5 and the mean HAS-BLED score was 2.8±1.2 and 2.2±1.1 in the two groups, respectively (both p<0.001). Hypertension, previous stroke, female gender, vascular diseases and previous bleeding were more prevalent in NOACs patients. Renal failure, age ≥75years and congestive heart failure were more prevalent in VKAs patients. Among NOACs patients, 438 were given dabigatran, 463 rivaroxaban and 413 apixaban (33%, 35% and 31%, respectively). The mean CHA2DS2-VASc and HAS-BLED scores were higher in rivaroxaban or apixaban patients compared with dabigatran (both p<0.001) and VKAs patients (both p<0.001). A lower mean age was observed in patients newly-treated with dabigatran. Patients newly-treated with reduced doses of NOACs (599 patients, 45.5%) had a higher CHA2DS2-VASc (4.8±1.4 vs. 3.9±1.5 vs. 4.0±1.5) and HAS-BLED (2.9±1.1 vs. 2.8±1.2 vs. 2.2±1.1) scores compared with those treated with regular doses of NOACs or VKAs.. Patients given rivaroxaban and apixaban in clinical practice have a higher thrombotic and hemorrhagic risk in comparison with patients given dabigatran or VKAs. A considerable proportion of patients receive reduced doses of NOACs.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Female; Fibrinolytic Agents; Hemorrhage; Humans; Italy; Logistic Models; Male; Middle Aged; Pyrazoles; Pyridones; Rivaroxaban; Severity of Illness Index; Vitamin K

Apixaban is a novel oral anticoagulation agent that exerts its effect through direct factor Xa inhibition. We present a case of multi-drug overdose including apixaban with associated apixaban concentrations.. A 53 year-old man presented to our metropolitan hospital following a deliberate self-poisoning with 200 mg apixaban, 35 mg ramipril, 105 mg bisoprolol, 280 mg atorvastatin, 6 mg colchicine, 37.4 mg magnesium, 4 × 500 mg paracetamol/9.5 mg codeine/5 mg phenylephrine and alcohol. He developed hypotension that was treated with noradrenaline. His initial and peak apixaban concentration was 1022.6 ng/ml and was associated with only minor bleeding from his femoral central line insertion site, which improved with local compression. Vitamin K 10 mg (at 9 h post-ingestion) and Prothrombinex-VF 2000 units (at 13 h post-ingestion) were also administered without any observed effect on coagulation studies. Apixaban elimination appeared to display first-order kinetics with an elimination half-life of 7.4 h. His plasma apixaban concentration was within the therapeutic dose range 10 h post-ingestion and he recovered uneventfully.. A case of apixaban overdose with associated apixaban concentrations is presented. There was rapid resolution of anticoagulation with no demonstrable benefit of currently available clotting factor replacement.

Topics: Administration, Oral; Antifibrinolytic Agents; Blood Coagulation Factors; Drug Overdose; Factor Xa; Factor Xa Inhibitors; Half-Life; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Vitamin K

Previous trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria.. This was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed.. Ninety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P= .01) and major surgery within 14 days (P= .02), as well as the presence of >6 thrombotic risk factors (P= .01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K.. 4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cardiac Surgical Procedures; Dabigatran; Emergencies; Female; Gastrointestinal Hemorrhage; Heart Transplantation; Hemorrhage; Hemostatics; Heparin; Humans; Incidence; International Normalized Ratio; Intracranial Hemorrhages; Laparotomy; Male; Middle Aged; Preoperative Care; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Surgical Procedures, Operative; Thrombocytopenia; Thromboembolism; Vitamin K; Warfarin

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

Although several non-vitamin K oral anticoagulants have been developed to prevent cardiogenic thrombosis, the status of hemorrhagic complications in the clinical setting among Asian populations, including Japan, remains unclear. We conducted this retrospective cohort study to clarify the current status of hemorrhagic events during antithrombotic therapy with non-vitamin K oral anticoagulants, with particular focus on gastrointestinal bleeding.. Medical charts of 475 patients prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and September 2014 were reviewed to examine whether any hemorrhagic events occurred, compared with 135 patients who received warfarin between April 2009 and March 2011.. Incidences of total and actionable hemorrhage in patient taking non-vitamin K oral anticoagulants were 13.8% per year and 4.6% per year, respectively, showing no significant differences from those in warfarin users (9.3% per year and 5.0% per year, respectively). In addition, actionable gastrointestinal hemorrhage occurred at similar rates in non-vitamin K oral anticoagulants users (2.1% per year) and warfarin users (1.5% per year). Most hemorrhages were from the lower gastrointestinal tract, and considerable events involved perianal bleeding. Multiple regression analysis showed that age, concomitant dual antiplatelet therapy, and concomitant nonsteroidal anti-inflammatory drug therapy were significant factors related to actionable gastrointestinal bleeding.. Risk of gastrointestinal hemorrhage in patients taking non-vitamin K oral anticoagulants was similar to that in patients taking warfarin. The dominant bleeding site was the lower gastrointestinal tract.
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Topics: Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Dabigatran; Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Humans; Incidence; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Vitamin K; Warfarin

Topics: Anticoagulants; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Pyrazoles; Pyridones; Reference Standards; Risk Factors; Rivaroxaban; Vitamin K

Gastrointestinal bleeding during treatment with non -vitamin K antagonist oral anticoagulants (NOACs) may be caused by malignant lesions Gastrointestinal bleeding due to underlying malignancy may not be uncommon in real life patients on non vitamin K antagonist oral anticoagulants (NOACs) like dabigatran, rivaroxaban or apixaban. We performed a small pilot study in patients referred to endoscopy due to suspected gastrointestinal bleeding. In twenty NOAC-treated patients, we found four cases of manifest malignant colon tumors, one premalignant colon adenoma, and one gastric B-cell lymphoma. All lesions were previously unknown and non-symptomatic apart from suspected gastrointestinal bleeding. Endoscopy should be performed in patients on NOACs with signs or suspicions of gastrointestinal bleeding. Whether a fecal occult blood test should be incorporated in the follow-up of patients on NOAC treatment deserves to be investigated in future studies.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Colonoscopy; Dabigatran; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Humans; Male; Pilot Projects; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Vitamin K

Topics: Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Vitamin K; Warfarin

We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE.. At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug.. Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial.. The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether ≥2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation.

Topics: Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Risk Assessment; Stroke; Vitamin K; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) are approved for several indications for prophylaxis of thromboembolism at fixed oral doses. The analysis of NOAC activity/concentration may be required in special patient populations. Heptest coagulation assay determines both factor Xa and thrombin inhibitors. The objective of investigations is to analyze the effects of both groups of NOACs on this assay.. The performance of a modified Heptest-STAT clotting assay was compared with specific chromogenic substrate assays for factor Xa (Coamatic, HemosIL) and thrombin (direct thrombin inhibitor assay and S2238 chromogenic assays) for the determination of rivaroxaban, apixaban, and dabigatran in plasma from patients on treatment.. For rivaroxaban (n = 74), the concentrations (mean and SD) of Heptest-STAT versus Coamatic and HemosIL assays were 179.3 ± 85.8 ng/mL versus 199.3 ± 105.7 ng/mL and 212.4 ± 115.9 ng/mL (P < 0.0001), and for apixaban (n = 26) 232.8 ± 10.0 ng/mL versus 178.4 ± 64.4 ng/mL (P < 0.0001) and 182.1 ± 73.1 ng/mL (P = 0.0002). For dabigatran (n = 74), the values of Heptest-STAT were 92.3 ± 65.0 ng/mL versus 124.3 ± 85.6 ng/mL (direct thrombin inhibitor assay, P < 0.0001) and 107.5 ± 59.7 ng/mL (S2238 assay, P = 0.0015), respectively. The values of the intraclass coefficient of correlation ranged from 0.64 to 0.91 (Bland-Altman analysis).. The objective of the study was achieved by demonstrating a high correlation of the Heptest-STAT coagulation assay with chromogenic assays for factor Xa inhibiting NOACs and acceptably good correlation with thrombin inhibiting NOACs in plasma samples of patients on treatment.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Blood Coagulation; Dabigatran; Dipeptides; Enzyme Assays; Factor Xa Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K; Whole Blood Coagulation Time

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Dose-Response Relationship, Drug; Echocardiography, Transesophageal; Electric Countershock; Female; Humans; Pyrazoles; Pyridones; Recurrence; Risk Factors; Thrombosis; Treatment Outcome; Vitamin K

The non-vitamin K antagonist oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban are being administered in fixed doses without routine monitoring of anticoagulant activities. Despite this key advantage over vitamin K antagonists (VKAs), assessment of anticoagulant intensities is required in various clinical circumstances. We developed a multi-analyte approach for mass spectrometric analysis of NOACs in human plasma.. Plasma samples were precipitated with acetonitrile. Separation was achieved by liquid chromatography using a C18 column and a gradient elution within a run time of 2.5 min. Positive electrospray ionization was used and ion transitions monitored by a triple quadrupole mass spectrometer. Stable-isotope-labeled analogues of analytes were employed as internal standards for quantitative analysis. Certified external quality control samples were obtained for external validation.. For all analytes, linearity could be demonstrated over the concentration range of 1-500 μg/L (R2>0.999), and the calculated limits of quantification were <1 μg/L. Results for inter- and intra-day assay precision and trueness were obtained using internal quality control samples and remained within the acceptance criterion of ±15%. External quality control samples were measured at the specified nominal values with inter- and intra-day precisions <14%. Matrix effects were fully compensated by co-eluting internal standards, which in turn did not relevantly influence ionization efficiency.. The method enables rapid and reliable simultaneous determination of NOAC concentrations in human plasma. It was successfully introduced into clinical practice; a case with rivaroxaban overdose is presented to exemplify the method's applicability.

Topics: Administration, Oral; Anticoagulants; Chromatography, Liquid; Dabigatran; Humans; Pyrazoles; Pyridones; Quality Control; Rivaroxaban; Tandem Mass Spectrometry; Vitamin K

Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention.

Topics: Anticoagulants; Antithrombins; Factor Xa Inhibitors; Hemorrhage; Humans; Medication Therapy Management; Oral Medicine; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K

Although vitamin K antagonists (VKAs) have been the backbone of thromboprophylaxis in nonvalvular atrial fibrillation, their limitations have encouraged the development of a new generation of oral anticoagulants. This review compares the different designs and procedures used to conduct four phase III trials that tested dabigatran, rivaroxaban, apixaban, and edoxaban versus VKAs. Although pharmacologic characteristics and results of the main trials are briefly discussed, this review mainly focuses on study designs, enrollment criteria, populations studied, quality metrics, and transition strategies between oral anticoagulants. While each of the trials was of high quality, performed independently, and led by independent academic groups, substantial differences exist in terms of drug pharmacology and trial characteristics. Caution is advised when comparing results across trials as practicing clinicians strive to personalize anticoagulation treatments for their individual patients. We believe that the differences in the pharmacokinetic and pharmacodynamic profiles of the available novel oral anticoagulants (NOACs), coupled with substantial heterogeneity in the trial populations and designs and procedures used to conduct the trials, support an important role for each of the NOACs dependent upon the specific clinical scenario faced by the practicing clinician.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Thiazoles; Thiophenes; Vitamin K; Warfarin

Warfarin, a vitamin K antagonist (VKA), has been the standard of care for stroke prevention in patients with atrial fibrillation (AF). Aspirin is recommended for low-risk patients and those unsuitable for warfarin. Apixaban is an oral anticoagulant that has demonstrated better efficacy than warfarin and aspirin in the ARISTOTLE and AVERROES studies, respectively, and causes less bleeding than warfarin. We evaluated the potential cost-effectiveness of apixaban against warfarin and aspirin from the perspective of the UK payer perspective.. A lifetime Markov model was developed to evaluate the pharmacoeconomic impact of apixaban compared with warfarin and aspirin in VKA suitable and VKA unsuitable patients, respectively. Clinical events considered in the model include ischaemic stroke, haemorrhagic stroke, intracranial haemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, cardiovascular hospitalization and treatment discontinuations; data from the ARISTOTLE and AVERROES trials and published mortality rates and event-related utility rates were used in the model. Apixaban was projected to increase life expectancy and quality-adjusted life years (QALYs) compared with warfarin and aspirin. These gains were expected to be achieved at a drug acquisition-related cost increase over lifetime. The estimated incremental cost-effectiveness ratio was £11 909 and £7196 per QALY gained with apixaban compared with warfarin and aspirin, respectively. Sensitivity analyses indicated that results were robust to a wide range of inputs.. Based on randomized trial data, apixaban is a cost-effective alternative to warfarin and aspirin, in VKA suitable and VKA unsuitable patients with AF, respectively.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cost-Benefit Analysis; Drug Costs; Factor Xa Inhibitors; Female; Hemorrhage; Hospitalization; Humans; Male; Markov Chains; Middle Aged; Multicenter Studies as Topic; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Vitamin K; Warfarin

Topics: Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Clopidogrel; Dabigatran; Drug Therapy, Combination; Humans; Morpholines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Ticlopidine; Vitamin K

Dabigatran, rivaroxaban, and apixaban have been approved for use in patients with atrial fibrillation based upon randomized trials demonstrating their comparable or superior efficacy and safety relative to warfarin. Little is known about their adoption into clinical practice, whether utilization is consistent with the controlled trials on which their approval was based, and how their use has affected health spending for patients and insurers.. We used medical and prescription claims data from a large insurer to identify patients with nonvalvular atrial fibrillation who were prescribed an oral anticoagulant in 2010-2013. We plotted trends in medication initiation over time, assessed corresponding insurer and patient out-of-pocket spending, and evaluated the cumulative number and cost of anticoagulants. We identified predictors of novel anticoagulant initiation using multivariable logistic models. Finally, we estimated the difference in total drug expenditures over 6 months for patients initiating warfarin versus a novel anticoagulant.. There were 6893 patients with atrial fibrillation that initiated an oral anticoagulant during the study period. By the end of the study period, novel anticoagulants accounted for 62% of new prescriptions and 98% of anticoagulant-related drug costs. Female sex, lower household income, and higher CHADS2, CHA2DS2-VASC, and HAS-BLED scores were significantly associated with lower odds of receiving a novel anticoagulant (P <.001 for each). Average combined patient and insurer anticoagulant spending in the first 6 months after initiation was more than $900 greater for patients initiating a novel anticoagulant.. This study demonstrates rapid adoption of novel anticoagulants into clinical practice, particularly among patients with lower CHADS2 and HAS-BLED scores, and high health care cost consequences. These findings provide important directions for future comparative and cost-effectiveness research.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Databases, Factual; Drug Utilization Review; Factor Xa Inhibitors; Fees, Pharmaceutical; Female; Humans; Income; Male; Middle Aged; Morpholines; Multivariate Analysis; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Severity of Illness Index; Sex Factors; Stroke; Thiophenes; United States; Vitamin K; Warfarin; Young Adult

Edoxaban recently proved non-inferior to warfarin for prevention of thromboembolism in patients with non-valvular atrial fibrillation (AF). We conducted an imputed-placebo analysis with estimates of the proportion of warfarin effect preserved by each non vitamin K antagonist oral anticoagulant (NOAC) and indirect comparisons between edoxaban and different NOACs.. We performed a literature search (up to January 2014), clinical trials registers, conference proceedings, and websites of regulatory agencies. We selected non-inferiority randomised controlled phase III trials of dabigatran, rivaroxaban, apixaban and edoxaban compared with adjusted-dose warfarin in non-valvular AF. Compared to imputed placebo, all NOACs reduced the risk of stroke (ORs between 0.24 and 0.42, all p<0.001) and all-cause mortality (ORs between 0.55 and 0.59, all p<0.05). Edoxaban 30 mg and 60 mg preserved 87% and 112%, respectively, of the protective effect of warfarin on stroke, and 133% and 121%, respectively, of the protective effect of warfarin on all-cause mortality. The risk of primary outcome (stroke/systemic embolism), all strokes and ischemic strokes was significantly higher with edoxaban 30 mg than dabigatran 150 mg and apixaban. There were no significant differences between edoxaban 60 mg and other NOACs for all efficacy outcomes except stroke, which was higher with edoxaban 60 mg than dabigatran 150 mg. The risk of major bleedings was lower with edoxaban 30 mg than any other NOAC, odds ratios (ORs) ranging between 0.45 and 0.67 (all p<0.001).. This study suggests that all NOACs preserve a substantial or even larger proportion of the protective warfarin effect on stroke and all-cause mortality. Edoxaban 30 mg is associated with a definitely lower risk of major bleedings than other NOACs. This is counterbalanced by a lower efficacy in the prevention of thromboembolism, although with a final benefit on all-cause mortality.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Meta-Analysis as Topic; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Vitamin K; Warfarin

Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban is a novel oral anticoagulant associated with significantly lower hazard rates for stroke, major bleedings and treatment discontinuations, compared to VKAs.. To estimate the cost-effectiveness of apixaban compared to VKAs in non-valvular AF patients in the Netherlands.. Previously published lifetime Markov model using efficacy data from the ARISTOTLE and the AVERROES trial was modified to reflect the use of oral anticoagulants in the Netherlands. Dutch specific costs, baseline population stroke risk and coagulation monitoring levels were incorporated. Univariate, probabilistic sensitivity and scenario analyses on the impact of different coagulation monitoring levels were performed on the incremental cost-effectiveness ratio (ICER).. Treatment with apixaban compared to VKAs resulted in an ICER of €10,576 per quality adjusted life year (QALY). Those findings correspond with lower number of strokes and bleedings associated with the use of apixaban compared to VKAs. Univariate sensitivity analyses revealed model sensitivity to the absolute stroke risk with apixaban and treatment discontinuations risks with apixaban and VKAs. The probability that apixaban is cost-effective at a willingness-to-pay threshold of €20,000/QALY was 68%. Results of the scenario analyses on the impact of different coagulation monitoring levels were quite robust.. In patients with non-valvular AF, apixaban is likely to be a cost-effective alternative to VKAs in the Netherlands.

Topics: 4-Hydroxycoumarins; Aged; Atrial Fibrillation; Cost of Illness; Cost-Benefit Analysis; Decision Support Techniques; Female; Fibrinolytic Agents; Humans; Indenes; Male; Netherlands; Pyrazoles; Pyridones; Stroke; Vitamin K

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa; Humans; Pyrazoles; Pyridones; Recombinant Proteins; Vitamin K; Warfarin

Atrial fibrillation is the most common form of cardiac arrhythmia with an age-dependent increase in prevalence. It is common clinical practice to treat patients with atrial fibrillation and who have a high risk for thromboembolic stroke with vitamin K antagonists. However, due to the many problems with vitamin K antagonist therapy many high risk patients are either not treated at all or receive insufficient anticoagulation treatment. The new oral anticoagulants, e.g. dabigatran as a direct thrombin antagonist or rivaroxaban and apixaban as factor Xa antagonists were tested in large scale clinical trials with respect to the efficacy in stroke prevention in atrial fibrillation patients. The therapeutic superiority over warfarin could be impressively proven either with respect to the efficacy in stroke prevention and/or to the safety of therapy with a significant decrease in cerebral bleeding complications.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; 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

For more than a decade, the only treatments available for the prevention of recurrent venous thromboembolism, were vitamin K inhibitors, or low molecular weight heparins (LMWH). Both have been very useful for this purpose; however, with the inconvenience of required frequent laboratory tests and the risk of provoking major hemorrhages. LMWH also carry the risk for immune reactions and the high cost of using it for an extended period of time. With the advent of the new anticoagulants, there is no need for laboratory tests, but there is no way to individualize the dose, or to neutralize their effect. They are also very expensive. Several recent articles have shown that aspirin, as the only treatment for the prevention of recurrent venous thromboembolism, gave good results in comparison to placebo. It has also been found that, after hip replacement surgery, the frequency of thromboembolism was similar in those patients treated with aspirin and those treated with LMWH. These results could open a new path in the search for the ideal treatment for the prevention of recurrent venous thromboembolism.

Topics: Anticoagulants; Antithrombins; Aspirin; Clinical Trials as Topic; Factor Xa Inhibitors; Heparin, Low-Molecular-Weight; Humans; Multicenter Studies as Topic; Pyrazoles; Pyridones; Recurrence; Thromboembolism; Thrombophilia; Venous Thrombosis; Vitamin K

Topics: Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Vitamin K

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

Topics: Anticoagulants; Antithrombin Proteins; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Guideline Adherence; Hemorrhage; Humans; Intracranial Embolism; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Vitamin K