warfarin and Neoplasms

Venous thromboembolism (VTE) is a common complication in patients with cancer. Warfarin has largely been replaced by low-molecular-weight heparin (LMWHs) and direct oral anticoagulants (DOACs) as the standard of care in cancer-associated VTE. The survival benefit of these anticoagulants over warfarin in the cancer population was not demonstrated in clinical trials, possibly due to insufficient sample size and limited follow-up duration. There are emerging population-based studies suggesting that warfarin may be associated with improved overall survival in cancers and may have a protective effect against certain types of cancers. Warfarin may exert its anti-neoplastic properties through both coagulation pathway -dependent and -independent mechanisms, the latter of which are mediated by inhibition of the Gas6-AXL signaling pathway. Further research should emphasize on identifying clinical and laboratory predictors of beneficial effects of warfarin. In this review article, we summarize and update the current evidence regarding the potential impact of warfarin on the overall survival of cancer patients and incidence of cancer, as well as review the potential mechanism of such effect and future perspectives.

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

Patients with cancer are at higher risk of atrial fibrillation (AF). Currently there are no definitive data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in cancer patients with AF. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of NOACs compared with warfarin. A search through Pubmed/MEDLINE, Embase, and Cochrane library was done from the databases inception to March 2022. Studies that compared NOACs to warfarin in the setting of AF and cancer were included. The primary outcomes were the incidence of major bleeding and ischemic stroke/systemic embolism (SE). Secondary outcomes were major adverse cardiovascular event (MACE), intracranial bleeding, and Major gastrointestinal bleeding. Risk ratios (RRs) with 95% confidence intervals (CI) were used to report the outcomes. A total of 11 studies were included. We found that NOACs were associated with a lower incidence of major bleeding and combined ischemic stroke/SE in patients with AF and cancer compared with warfarin (RR 0.57; 95% CI 0.44-0.75, P < 0.0001 and RR 0.59; 95% CI 0.47-0.75, P < 0.0001, respectively). Also, there was lower incidence of Intracranial and major gastrointestinal bleeding in patients who received NOACs compared with warfarin (P < 0.0001). Network analyses revealed that apixaban and dabigatran were associated with reduction of major bleeding compared with warfarin. Among patients who diagnosed with AF and cancer, NOACs were associated with lower incidence of major bleeding ischemic stroke/SE compared with warfarin. Furthermore, NOACs were associated with lower gastrointestinal and intracranial bleeding.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Dabigatran; Gastrointestinal Hemorrhage; Humans; Ischemic Stroke; Neoplasms; Network Meta-Analysis; Stroke; Treatment Outcome; Warfarin

The efficacy and safety of direct oral anticoagulants (DOACs), including dabigatran, apixaban, rivaroxaban, and edoxaban, for preventing and treating venous thromboembolism (VTE) in patients with cancer is unclear.. We searched the PubMed, Embase, Web of Science, and Cochrane Library databases from the establishment to November 30, 2021. In the frequency-based network meta-analysis, the odds ratio with a 95% confidence interval was reported. The relative ranking probability of each group was generated based on the surface under the cumulative ranking curve (SUCRA).. We included 15 randomized controlled trials involving a total of 6162 patients. Apixaban reduced the risk of VTE compared with low-molecular heparin [OR = 0.53, 95% CI (0.32, 0.89)]. The efficacy of drugs was ranked from highest to lowest as follows: apixaban (SUCRA, 81.0), rivaroxaban (73.0), edoxaban (65.9), dabigatran (51.4), warfarin (30.8), and low-molecular-weight heparin (LMWH) (27.4). Edoxaban increased the risk of major bleeding compared with LMWH [OR = 1.83, 95% CI (1.04, 3.22)]. The safety of drugs was ranked from highest to lowest as follows: major bleeding-apixaban (SUCRA, 68.5), LMWH (55.1), rivaroxaban (53.0), warfarin (35.9), dabigatran (29.2), edoxaban (16.5) and clinically relevant non-major bleeding-LMWH (73.0), apixaban (57.8), edoxaban (45.8), rivaroxaban (35.3), and warfarin (10.8).. For preventing and treating VTE, in terms of VTE occurrence and major bleeding, apixaban had the lowest risk; in terms of clinically relevant non-major bleeding, LMWH had the lowest risk, followed by apixaban. Generally, apixaban is the most efficient and safest DOAC and presents better efficacy and relatively low bleeding risk among the VTE prevention and treatment drugs for patients with cancer.

Topics: Administration, Oral; Anticoagulants; Dabigatran; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Network Meta-Analysis; Rivaroxaban; Venous Thromboembolism; Warfarin

Data on the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer are limited. Therefore, we conducted a meta-analysis to compare the efficacy and safety between NOACs and warfarin in this population.. A comprehensive search of the PubMed, Embase, and Cochrane databases for articles published through July 2020 was performed. An evaluation of each study was conducted, and data were extracted. Pooled odds ratio (OR) estimates and 95% CIs were calculated.. Eight studies (3 randomized controlled trials (RCTs) and 5 retrospective cohort studies) involving a total of 24,665 patients were included. Among the RCTs, there were no significant differences in the rates of stroke or systemic embolism (OR=0.69; 95% CI, 0.45-1.06; P=0.09), venous thromboembolism (OR=0.91; 95% CI, 0.33-2.52; P=0.86), myocardial infarction (OR=0.74; 95% CI, 0.44-1.23; P=0.24), major bleeding (OR=0.81; 95% CI, 0.61-1.06; P=0.12), or major or nonmajor clinically relevant bleeding (OR= 0.98; 95% CI, 0.82-1.19; P=0.86) between the NOAC and warfarin groups. Among the observational studies, patients who used NOACs had a significantly lower risk than those who used warfarin. The prevalence rates of ischemic stroke (OR=0.51; 95% CI, 0.28-0.92; P=0.02), VTE (OR=0.50; 95% CI, 0.41-0.60; P<0.00001), major bleeding (OR=0.28; 95% CI, 0.14-0.55; P=0.0002), and intracranial or gastrointestinal bleeding (OR=0.59; 95% CI, 0.37-0.92; P=0.02) were significantly reduced in the NOAC group.. Our meta-analysis confirms that NOACs are as safe and effective as warfarin and can be applied in the real world; this data can serve as a reference for clinical doctors for formulating treatment strategies.

Topics: Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; Neoplasms; Observational Studies as Topic; Randomized Controlled Trials as Topic; Stroke; Warfarin

Patients with cancer are at higher risk of atrial fibrillation, thromboembolic complications and bleeding events compared with the general population. The aim of the present meta-analysis was to compare the efficacy and safety of direct oral Xa inhibitor anticoagulants versus warfarin in patients with cancer and atrial fibrillation.. We searched electronic databases for randomized controlled trials comparing direct oral Xa inhibitor anticoagulants and warfarin in cancer patients. The primary efficacy outcome was stroke or systemic embolism. The primary safety outcome was major bleeding. A subgroup analysis was performed to explore the outcome differences between patients with active cancer or history of cancer.. Three trials with a total of 3029 cancer patients were included in the analysis. There was no statistically significant difference in the risk of stroke or systemic embolism [risk ratio (RR) 0.76; 95% confidence interval (CI) 0.52-1.10] between the two therapeutic strategies. Direct oral Xa inhibitors significantly reduced the incidence of major bleeding compared with warfarin (RR 0.79; 95% CI 0.63-0.99; P = 0.04; number needed to treat = 113). These results were consistent both in patients with active cancer and in those with history of cancer.. In patients with cancer and atrial fibrillation, direct oral Xa inhibitors have a similar efficacy and may be safer compared with warfarin. These results are consistent both in patients with active cancer and history of cancer.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Treatment Outcome; Warfarin

Patients with cancer are at high risk of venous thromboembolic events, and this risk can be further increased in patients with certain cancer types and by cancer treatments. Guidelines on the prevention of cancer-associated thrombosis (CAT) recommend thromboprophylaxis for hospitalised patients; however, this is not routinely recommended for ambulatory patients receiving chemotherapy and is limited to specified high-risk patients. Identification of the ambulatory patients at risk of CAT who would most benefit from anticoagulant therapy is therefore critical to reduce the incidence of this complication. For patients receiving thromboprophylaxis for CAT, treatment options include low molecular weight heparin, acetylsalicylic acid, warfarin or direct oral anticoagulants (apixaban or rivaroxaban), dependent on the cancer type and cancer treatment regimen. This review discusses emerging clinical trial data and their potential clinical impact.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Rivaroxaban; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the third update of a review first published in February 2012.. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis, or an active control intervention.. For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references.. Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.. We extracted data on risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence.. We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence). When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence). In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis, but did not report on VTE or major bleeding. When compared with placebo or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence). One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE: RR 0.84, 95% CI 0.41 to 1.73; major bleeding:. In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.

Topics: Adult; Ambulatory Care; Anticoagulants; Antineoplastic Agents; Antithrombins; Bias; Child; Factor Xa Inhibitors; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Primary Prevention; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thromboembolism; Warfarin

Cancer and atrial fibrillation (AF) are common conditions, but for patients affected with both, there is a lack of data about management of anticoagulation and cerebrovascular outcomes. In the first section of this review, we summarize the most relevant studies on stroke risk and management of AF in patients with active cancer, attempting to answer questions of whether to anticoagulate, whom to anticoagulate, and what agents to use. In the second section of the review, we suggest a decision algorithm on the basis of the available evidence and provide practical recommendations for each of the anticoagulant options. In the third section, we discuss the limitations of the available evidence. On the basis of low-quality evidence, we find that patients with cancer and AF have a risk of stroke similar to that of the general population but a substantially higher risk of bleeding regardless of the anticoagulant agent used; this makes anticoagulation-related decisions complex and evidence from the general population not immediately applicable. In general, we suggest stopping anticoagulation in patients with high risk of bleeding and in those with a moderate bleeding risk without a high thromboembolic risk and recommend anticoagulation as in the general population for patients at a low risk for bleeding. However, regardless of initial therapy, we recommend reassessing whether anticoagulation should be given at each point in the clinical course of the disease. High-quality evidence to guide anticoagulation for AF in patients with cancer is needed.

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Neoplasms; Risk Assessment; Risk Factors; Stroke; Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality worldwide. For decades, low molecular weight heparins (LMWH) and vitamin K-antagonists have been the gold standard of anticoagulation for VTE. Recently, direct oral anticoagulants (DOACs) that can be administered in fixed doses, without laboratory monitoring and dose adjustment have revolutionized anticoagulation management in VTE. Here, we report on recent evidence regarding the safety of DOACs compared to traditional anticoagulants in surgical and medical prophylaxis as well as in acute and extended treatments of VTE. Additionally, we provide data on special situations such as elderly, cancer and renal impairment patients. Regarding antithrombotic prophylaxis, data are lacking on DOAC use in general surgical patients, while DOACs appear to be more effective than and as safe as LMWHs in VTE prophylaxis for major orthopedic surgical patients. Whether a medically ill patient may benefit from extended VTE prophylaxis remains unclear. In fact, in these patients, DOACs showed an increased risk of bleeding compared to conventional therapy. In the acute treatment of VTE, DOACs were non-inferior and probably safer than conventional anticoagulation therapy while in the extended VTE treatment DOACs were more effective than placebo or aspirin with a comparable risk of major bleeding. These favorable results were also confirmed in elderly, cancer and renal impairment patients. However, further investigations are needed in order to generalize the safe use of DOACs in these specific subgroups of patients.

Topics: Anticoagulants; Aspirin; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Risk Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Background Several studies have investigated the effect of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer, but the results remain controversial. Therefore, we conducted a meta-analysis to compare the efficacy and safety of NOACs versus warfarin in this population. Methods and Results We systematically searched the PubMed and Embase databases until February 16, 2019 for studies comparing the effect of NOACs with warfarin in AF patients with cancer. Risk ratios (RRs) with 95% CIs were extracted and pooled by a random-effects model. Five studies involving 8908 NOACs and 12 440 warfarin users were included. There were no significant associations between cancer status and risks of stroke or systemic embolism, major bleeding, or death in AF patients. Compared with warfarin, NOACs were associated with decreased risks of stroke or systemic embolism (RR, 0.52; 95% CI, 0.28-0.99), venous thromboembolism (RR, 0.37, 95% CI, 0.22-0.63), and intracranial or gastrointestinal bleeding (RR, 0.65; 95% CI, 0.42-0.98) and with borderline significant reductions in ischemic stroke (RR, 0.63; 95% CI, 0.40-1.00) and major bleeding (RR, 0.73; 95% CI, 0.53-1.00). In addition, risks of efficacy and safety outcomes of NOACs versus warfarin were similar between AF patients with and without cancer. Conclusions In patients with AF and cancer, compared with warfarin, NOACs had lower or similar rates of thromboembolic and bleeding events and posed a reduced risk of venous thromboembolism.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Intracranial Hemorrhages; Neoplasms; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism; Warfarin

Direct oral anticoagulants (DOACs) were developed to compensate for the demerits of warfarin. In Japan, three factor Xa inhibitors are used for the treatment of venous thromboembolism (VTE): edoxaban, rivaroxaban, and apixaban. Despite problems, such as the inability to monitor their effect and the lack of an antidote, these inhibitors have the same efficacy as conventional treatment with warfarin, and they are associated with a significantly high degree of safety in relation to hemorrhagic complications. East Asians, including Japanese, suffer from hemorrhage more frequently; therefore, DOACs are considered to be highly effective. Although there is no evidence to date, DOACs may be effective in a wide variety of ways, including the possibility that they prevent recurrence over the long term, reduce the length of hospitalization, allow treatment to be started on an outpatient basis, and be effective in cancer patients.

Topics: Administration, Oral; Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Humans; Japan; Neoplasms; Outpatients; Platelet Count; Pyrazoles; Pyridines; Pyridones; Recurrence; Rivaroxaban; Thiazoles; Venous Thromboembolism; Warfarin

Anticoagulation may improve survival in patients with cancer through a speculated anti-tumour effect, in addition to the antithrombotic effect, although may increase the risk of bleeding.. To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) a major electronic search (February 2016) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (1946 to February 2016; accessed via OVID) and Embase (1980 to February 2016; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies in trial registries. As part of the living systematic review approach, we are running searches continually and we will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 August, 2017.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding, and quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE handbook).. Of 6947 identified citations, 18 RCTs fulfilled the eligibility criteria. These trials enrolled 9575 participants. Trial registries' searches identified nine registered but unpublished trials, two of which were labeled as 'ongoing trials'. In all included RCTs, the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin appears to have no effect on mortality at 12 months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.93 to 1.03; risk difference (RD) 10 fewer per 1000; 95% CI 35 fewer to 15 more; moderate certainty of evidence) and mortality at 24 months (RR 0.99; 95% CI 0.96 to 1.01; RD 8 fewer per 1000; 95% CI 31 fewer to 8 more; moderate certainty of evidence). Heparin therapy reduces the risk of symptomatic VTE (RR 0.56; 95% CI 0.47 to 0.68; RD 30 fewer per 1000; 95% CI 36 fewer to 22 fewer; high certainty of evidence), while it increases in the risks of major bleeding (RR 1.30; 95% 0.94 to 1.79; RD 4 more per 1000; 95% CI 1 fewer to 11 more; moderate certainty of evidence) and minor bleeding (RR 1.70; 95% 1.13 to 2.55; RD 17 more per 1000; 95% CI 3 more to 37 more; high certainty of evidence). Results failed to confirm or to exclude a beneficial or detrimental effect of heparin on thrombocytopenia (RR 0.69; 95% CI 0.37 to 1.27; RD 33 fewer per 1000; 95% CI 66 fewer to 28 more; moderate certainty of evidence); quality of life (moderate certainty of evidence).. Heparin appears to have no effect on mortality at 12 months and 24 months. It reduces symptomatic VTE and likely increases major and minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy should balance the benefits and downsides, and should integrate the patient's values and preferences.Editorial note:This is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Anticoagulants; Cause of Death; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and antithrombotic effect, yet increase the risk of bleeding.. To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017.. Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. Using a standardized form, we extracted data in duplicate on study design, participants, intervention outcomes of interest and risk of bias. Outcomes of interest included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook).. Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence).The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence).. The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding.Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

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

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

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

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

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012.. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.. For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016.. Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.. We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.. We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau. In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

Topics: Adult; Ambulatory Care; Anticoagulants; Antineoplastic Agents; Antithrombins; Child; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thromboembolism; Warfarin

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Initial treatment for venous thromboembolism (VTE) includes the acute and intermediate phases, usually lasting for 3 months. The choice to extend therapy beyond the initial 3-month window involves assessing a combination of risk factors for VTE recurrence and bleeding, along with weighing patient preferences. In some cases, such as VTE provoked by a reversible surgical risk factor, the recurrence risk is sufficiently low that most patients should not receive extended therapy. In other cases, such as VTE associated with malignancy, the recurrence risk is sufficiently high that treatment should be extended beyond the initial 3 months. However, a large number of patients fall into a grey zone where the decision on extended therapy is less clear-cut. In this review, we summarize the evidence for VTE recurrence risk and the role for extended anticoagulation given a variety of patient-specific factors and laboratory results. We also review the role of VTE risk prediction tools and provide a recommended algorithm for approaching the decision of extended anticoagulation therapy. Various agents available for extended VTE therapy, including warfarin, aspirin and the direct oral anticoagulant agents, are discussed.

Topics: Anticoagulants; Hemorrhage; Humans; Neoplasms; Recurrence; Risk Factors; Time Factors; Venous Thromboembolism; Warfarin

Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino-noscapine, 9-nitronoscapine, 9-bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.

Topics: Alkaloids; Animals; Antineoplastic Agents; Centrosome; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Female; Humans; Male; Microtubules; Neoplasms; Noscapine; Papaver; Plant Extracts; Stroke; Warfarin

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism.. Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding.. Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Female; Hemorrhage; Heparin; Humans; Lung Neoplasms; Male; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012.. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013).. Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants.. Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.. We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo.. In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Topics: Adult; Ambulatory Care; Anticoagulants; Antineoplastic Agents; Antithrombins; Child; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a common complication in cancer patients. This review summarizes some of the most current knowledge of the epidemiology, risk factors, risk models, prophylaxis, and treatment of VTE in cancer patients.. A literature search was conducted using PubMed; the search terms were venous thromboembolism, anticoagulation, and cancer. The bibliographies of pertinent studies and review articles were reviewed for additional references.. Venous thromboembolism is the second leading cause of death in patients with cancer. Cancer patients with VTE have poorer outcomes compared with noncancer patients with VTE. Many risk factors have been identified for VTE in patients with cancer that are patient-related, cancer-related, or treatment-related. Several biomarkers have been identified as potentially predictive of VTE risk. Risk assessment models such as the Khorana Risk Score stratify cancer patients with low, intermediate, and high risk of developing VTE based on baseline clinical and laboratory variables. Currently, enoxaparin is the preferred anticoagulant for initial VTE treatment in cancer patients. Low molecular weight heparin (LMWH) is recommended for both initial and long-term management of cancer-related VTE. Because the optimal duration of anticoagulation in cancer patients with VTE is unknown, the decision to extend anticoagulation requires weighing the risk of recurrent thrombosis against the risk of major bleeding. Patients with recurrent VTE can be bridged with LMWH, transitioned to full-dose LMWH or treated with LMWH dose escalation. While there is insufficient data to determine whether anticoagulation should be held in the setting of thrombocytopenia, full-dose anticoagulation is typically considered unsafe when platelets are < 50 000/μL. Inferior vena cava filters are currently recommended only for patients with acute VTE and contraindications to anticoagulation. Although management of catheter-associated thrombosis has not been well studied in cancer patients, it is recommended that cancer patients with catheter-associated thrombosis be treated with therapeutic anticoagulation for ≥ 3 months. Venous thromboembolism prophylaxis with UFH, LMWH, or fondaparinux is recommended in all hospitalized nonsurgical cancer patients and cancer patients undergoing major cancer surgery. Primary thromboprophylaxis is only currently recommended in high-risk ambulatory cancer patients such as multiple myeloma patients receiving thalidomide- or lenalidomide- based therapy.. Cancer-associated thrombosis is a common problem. As we begin to better understand the risk factors and biomarkers for cancer-associated VTE, we can further refine and develop risk-assessment models to determine those patients who would most likely benefit from anticoagulation. While LMWH products are generally preferred in cancer-related VTE, more research will continue to evolve our understanding of treatment and thrombopprophylaxis in cancer-associated VTE.

Topics: Anticoagulants; Biomarkers; Catheterization; Hemorrhage; Heparin; Hospitalization; Humans; Neoplasms; Prognosis; Recurrence; Risk Assessment; Risk Factors; Vena Cava Filters; Venous Thromboembolism; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2013) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1), MEDLINE (1966 to February 2013; accessed via OVID) and EMBASE(1980 to February 2013; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted data in duplicate on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), arterial thrombosis (e.g. stroke, myocardial infarction), major bleeding, minor bleeding and quality of life.. Of 9559 identified citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 7622 participants for whom follow-up data were available. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin may have a small effect on mortality at 12 months and 24 months (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.92 to 1.01 and RR 0.95; 95% CI 0.90 to 1.00, respectively). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.56; 95% CI 0.42 to 0.74) and a clinically important increase in the risk of minor bleeding (RR 1.32; 95% 1.02 to 1.71). Results failed to show or to exclude a beneficial or detrimental effect of heparin on major bleeding (RR 1.14; 95% CI 0.70 to 1.85) or quality of life. Our confidence in the effect estimates (i.e. quality of evidence) was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for quality of life.. Heparin may have a small effect on mortality at 12 months and 24 months. It is associated with a reduction in venous thromboembolism and a likely increase in minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides, and should integrate the patient's values and preferences.

Topics: Anticoagulants; Cause of Death; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

Thromboembolic events are common among patients with cancer as a consequence of cancer- and treatment-related factors. As these events are the second most frequent cause of death in this population, their prevention and treatment are important. Venous ultrasonography is the technique of choice for diagnosis, with sensitivity and specificity above 95 % in symptomatic thrombosis. Routine prophylaxis is not recommended for ambulatory patients, although it could be useful in selected cases. On the other hand, all inpatients should receive prophylactic therapy unless contraindicated. Therapy of thromboembolic disease is based on anticoagulants. Clinical trials demonstrate that the use of low-weight heparins is associated with a lower incidence of bleeding and recurrent thrombosis as compared with non-fractionated heparin or warfarin. Options for recurrent thrombosis include change to another anticoagulant agent, increasing doses of the same agent and cava filters.

Topics: Anticoagulants; Clinical Trials as Topic; Heparin; Humans; Inpatients; Neoplasms; Risk Factors; Secondary Prevention; Sensitivity and Specificity; Thromboembolism; Ultrasonography; Warfarin

The association of thrombosis with cancer has been recognized since the middle of the nineteenth century. It remains a common and serious complication of the cancer itself, as well as chemotherapy. Thrombosis is the second leading cause of death in cancer patients, second only to the cancer itself. For many years the treatment options for managing thrombosis in cancer had been static, but the past decade has seen significant evolution in the management, with the clear superiority of low molecular weight heparin over warfarin for secondary prevention of thrombosis. This article will review the understanding and management of thrombosis in cancer.

Topics: Animals; Anticoagulants; Heparin, Low-Molecular-Weight; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Neoplasms; Thrombosis; Warfarin

Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.

Topics: Age Factors; Anticoagulants; Chronic Disease; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Male; Neoplasms; Sex Factors; Stroke; Substance-Related Disorders; Thromboembolism; Vitamin K; Warfarin

Venous thromboembolism (VTE) represents a common source of morbidity and mortality among patients with malignant disease. In this specific setting, the treatment of VTE is challenging as cancer patients display a high tendency to develop recurrent VTE, as well as anticoagulant-related bleeding complications. Low-molecular-weight heparins have been demonstrated to be more effective in the long-term prevention of recurrent VTE in cancer patients compared with conventional treatment with vitamin K antagonists. A limitation of this therapeutic approach includes the long-term requirement of daily subcutaneous injections, which may be burdensome to patients. Over the past decade, several novel oral anticoagulants have emerged, which can be administered in fixed doses without the need for monitoring. Clinical trials evaluating these agents for treatment in the general VTE population yielded promising results. This review summarizes the current management of cancer-associated VTE, overviews the trials that investigated the novel anticoagulant drugs for the treatment of acute VTE and discusses the potential of these novel agents for use in cancer patients.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Drug Administration Schedule; Heparin, Low-Molecular-Weight; Humans; Morpholines; Neoplasms; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Treatment Outcome; Venous Thromboembolism; Warfarin

Venous thrombo-embolic events (VTEs) occur in 2.2% to 14% of paediatric cancer patients and cause significant morbidity and mortality. The malignant disease itself, the cancer treatment and the presence of central venous catheters (CVCs) increase the risk of VTE.. The primary objective of this review was to investigate the effects of preventive systemic treatments in paediatric cancer patients with tunnelled CVCs on (a)symptomatic VTE. Secondary objectives of this review were to investigate adverse effects of systemic treatments for the prevention of (a)symptomatic VTE in paediatric cancer patients with tunnelled CVCs; and to investigate the effects of systemic treatments in the prevention of (a)symptomatic VTE with CVC-related infection in paediatric cancer patients with tunnelled CVCs.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8 2012), MEDLINE (1966 to August 2012) and EMBASE (1966 to August 2012). In addition, we searched reference lists from relevant articles and conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2011), the American Society of Clinical Oncology (ASCO) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2011) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the International Standard Randomised Controlled Trial Number (ISRCTN) Register and the National Institute of Health (NIH) Register for ongoing trials (www.controlled-trials.com) (August 2012), and we contacted the authors of eligible studies if additional information was required.. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing systemic treatments to prevent venous thrombo-embolic events (VTEs) in paediatric cancer patients with tunnelled CVCs with a control intervention or no systemic treatment. For the description of adverse events, cohort studies were eligible for inclusion.. Two review authors independently selected studies, extracted data and performed risk of bias assessment of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.. Three RCTs and three CCTs (including 1291 children) investigated the prevention of VTE (low molecular weight heparin (LMWH) n = 134, antithrombin (AT) supplementation n = 37, low-dose warfarin n = 31, cryoprecipitate and/or fresh frozen plasma (FFP) supplementation n = 240, AT supplementation and LMWH n = 41). AT, cryoprecipitate and FFP were supplemented only in cases of AT or fibrinogen deficiency. Of the six included RCTs/CCTs, five investigated the prevention of VTE compared with no intervention (n = 737), and one CCT compared AT supplementation and LMWH with AT supplementation (n = 71). All studies had methodological limitations, and clinical heterogeneity between studies was noted.We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE and no differences in adverse events (such as major and/or minor bleeding; none of the studies reported thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia with thrombosis (HITT), death as a result of VTE, removal of CVC due to VTE, CVC-related infection, and post-thrombotic syndrome (PTS)) between experimental and control groups. Two studies with comparable participant groups and interventions were included for meta-analyses (n = 182). In the experimental group, 1/68 (1.5%) children were diagnosed with symptomatic VTE, as were 4/114 (3.5%) in the control group (best case scenario: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.09 to 4.78). These studies also evaluated asymptomatic CVC-related VTE: In the experimental group, 22/68 (32.4%) were diagnosed with asymptomatic VTE, as were 35/114 (30.7%) in the control group (best case scenario: RR 1.02, 95% CI 0.40 to 2.55). Heterogeneity was substantial for this analysis: I(2) = 73%.The attribution of LMWH to AT supplementation resulted in a significant reduction in symptomatic VTE (Fisher's exact test, two-sided P = 0.028) without bleeding complications; asymptomatic VTE, thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection and PTS were not assessed.Four cohort studies were included for the evaluation of adverse events. Three studies provided information on bleeding episodes: One participant developed an ischaemo-haemorrhagic stroke. One study provided information on other adverse events: None occurred.. We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE in paediatric oncology patients with CVCs. However, this could be a result of the low number of included participants, which resulted in low power. In one CCT, which compared one systemic treatment with another systemic treatment, we identified a significant reduction in symptomatic VTE with the addition of LMWH to AT supplementation.All studies investigated the prevalence of major and/or minor bleeding episodes, and none found a significant difference between study groups. None of the studies reported thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection or PTS among participants.On the basis of currently available evidence, we are not able to give recommendations for clinical practise. Additional well-designed international RCTs are needed to further explore the effects of systemic treatments in preventing VTE. Future studies should aim for adequate power with attainable sample sizes. The incidence of symptomatic VTE is relatively low; therefore, it might be necessary to select participants with thrombotic risk factors or to investigate asymptomatic VTE instead.

Topics: Anticoagulants; Antithrombins; Central Venous Catheters; Child; Controlled Clinical Trials as Topic; Factor VIII; Fibrinogen; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Plasma; Randomized Controlled Trials as Topic; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) often complicates the clinical course of cancer disease. The risk is further increased by chemotherapy but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain.. To assess the efficacy and safety of primary thromboprophylaxis in ambulatory cancer patients receiving chemotherapy.. The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 3 May 2011) and CENTRAL (2011, Issue 2). The authors searched clinical trials registries and reference lists of relevant studies.. Randomised controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), direct thrombin inhibitors, direct factor Xa inhibitors or mechanical intervention to no intervention or placebo; or comparing two different anticoagulants.. Data were extracted on methodological quality, patients, interventions and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.. Nine RCTs with a total of 3538 patients were considered. None of the RCTs tested UFH, fondaparinux, direct factor Xa inhibitors or mechanical interventions. Overall, the risk of bias was low in most of the studies. LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.41 to 0.93) with no evidence of heterogeneity (I(2) = 0%). The number needed to treat to prevent a symptomatic VTE was 60. LMWH was associated with a 60% increase in major bleeding when compared with inactive control, although this was not statistically significant (RR 1.57, 95% CI 0.69 to 3.60; I(2) = 10%). There was a 45% reduction in overall VTE (RR 0.55, 95% CI 0.34 to 0.88; I(2) = 0%) while for symptomatic pulmonary embolism, asymptomatic VTE, minor bleeding and one-year mortality the differences between the LMWH and control groups were not statistically significant. The effect of the vitamin K antagonist warfarin on preventing symptomatic VTE, measured in only one study, was not statistically significant (RR 0.15, 95% CI 0.02 to 1.20). In one RCT of patients with myeloma, LMWH was associated with a 67% reduction in symptomatic VTE (RR 0.33, 95% CI 0.14 to 0.83) compared with warfarin, with no differences in major bleeding. Antithrombin, evaluated in one study on paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control.. Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. However, the lack of power hampers definite conclusions on the effects on major safety outcomes, which mandates additional studies to determine the risk to benefit ratio of LMWH in this setting.

Topics: Adult; Ambulatory Care; Anticoagulants; Antineoplastic Agents; Antithrombins; Child; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pulmonary Embolism; Randomized Controlled Trials as Topic; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a chronic disease with a 30% ten-year recurrence rate. The highest incidence of recurrence is in the first 6 months. Active cancer significantly increases the hazard of early recurrence, and the proportions of time on standard heparin with an APTT ≥ 0.2 anti-X(a) U/mL, and on warfarin with an INR ≥ 2.0, significantly reduce the hazard. The acute treatment duration does not affect recurrence risk after treatment is stopped. Independent predictors of late recurrence include increasing patient age and body mass index, leg paresis, active cancer and other persistent VTE risk factors, idiopathic VTE, antiphospholipid antibody syndrome, antithrombin, protein C or protein S deficiency, hyperhomocysteinemia and a persistently increased plasma fibrin D-dimer. A recommendation for secondary prophylaxis should be individualized based on the risk for recurrent VTE (especially fatal pulmonary embolism) and bleeding. The appropriateness of secondary prophylaxis should be continuously reevaluated, and the prophylaxis stopped if the benefit no longer exceeds the risk.

Topics: Age Factors; Anticoagulants; Antiphospholipid Syndrome; Body Mass Index; Chronic Disease; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Hyperhomocysteinemia; International Normalized Ratio; Neoplasms; Paresis; Protein C Deficiency; Protein S Deficiency; Recurrence; Risk Factors; Time Factors; Venous Thromboembolism; Warfarin

Medicine has always been personalized. For years, physicians have incorporated environmental, behavioural, and genetic factors that affect disease and drug response into patient management decisions. However, until recently, the 'genetic' data took the form of family history and self-reported race/ethnicity. As genome sequencing declines in cost, the availability of specific genomic information will no longer be limiting. Rather, our ability to parse these data and our decision whether to use it will become primary. As our understanding of genetic association with drug responses and diseases continues to improve, clinically useful genetic tests may emerge to improve upon our previous methods of assessing genetic risks. Indeed, genetic tests for monogenic disorders have already proven useful. Such changes may usher in a new era of personalized medicine. In this review, we will discuss the utility and limitations of personal genomic data in three domains: pharmacogenomics, assessment of genetic predispositions for common diseases, and identification of rare disease-causing genetic variants.

Topics: Anticoagulants; Cardiovascular Diseases; Clopidogrel; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genome, Human; Humans; Mutation; Neoplasms; Pharmacogenetics; Platelet Aggregation Inhibitors; Precision Medicine; Risk Adjustment; Ticlopidine; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).. Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

To critically evaluate the benefit/risk ratio of some strategies for venous thromboembolism prophylaxis (VTE) RECENT FINDINGS: A growing body of evidence shows that graduated elastic stockings are not effective in medical patients. Special surgical settings as bariatric surgery deserve attention with a high VTE risk and no evidence-based data with regard to prophylaxis. Extended prophylaxis is being evaluated in these patients, whereas its efficacy has been demonstrated in abdominal and pelvic surgery for cancer. New oral anticoagulants are about to change the clinical landscape but yet some issues are not solved: no antidote, no monitoring, no standardization for the perioperative bridging in patients with therapeutic doses. In addition, they have not been tested in fragile patients in whom an increased bleeding risk could be feared. Finally, a large bunch of guidelines are now available to help the physician in the decision-making process.. Studies evaluating the benefit/risk ratio of graduated elastic stockings should now take place in surgery. Increasing and splitting the anticoagulant dose (mainly low molecular weight heparins) by two injections a day could be recommended in bariatric surgery and morbidly obese patients. New anticoagulant agents should also be tested in special populations, following the European Medicines Agency guidance. The methodology of clinical trials in VTE prophylaxis has to be moved forward, pending the choice of debatable surrogate end-points as asymptomatic venous thrombosis and disputed issues on the assessment of major bleeding.

Topics: Anticoagulants; Bariatric Surgery; Enoxaparin; Guidelines as Topic; Humans; Neoplasms; Perioperative Care; Stockings, Compression; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Anti-Infective Agents; Antineoplastic Agents; Aromatase Inhibitors; Cardiovascular Agents; Clopidogrel; Genome-Wide Association Study; Genomics; Genotype; Humans; Neoplasms; Pharmacogenetics; Polymorphism, Genetic; Ticlopidine; Warfarin

Adverse drug reactions (ADRs) rank as one of the top ten leading causes of death and illness in the developed world. In cancer therapy, more patients are surviving cancer than ever before, but 40% of cancer survivors suffer life-threatening or permanently disabling severe ADRs and are left with long-term sequelae. ADRs are often more frequent and more severe in children, and the consequences for children who experience a severe ADR can be catastrophic. Pharmacogenomics has the potential to improve the safety of these drugs. This review highlights severe ADRs that can occur in cancer therapy that are more frequent and more severe in children, and the pharmacogenomics research that aims to understand, predict, and ultimately prevent these severe reactions.

Topics: Anthracyclines; Antineoplastic Agents; Child; Cisplatin; Humans; Methotrexate; Neoplasms; Peripheral Nervous System Diseases; Pharmacogenetics; Vincristine; Warfarin

Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect.. To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed.. Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL).. Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL.. Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Venous Thromboembolism; Warfarin

Warfarin significantly reduces thromboembolic risk, but perceptions of associated bleeding risk limit its use. The evidence supporting the association between bleeding and individual patient risks factors is unclear. This systematic review aims to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information are prescribed the drug. A systematic literature search of MEDLINE and Cochrane CENTRAL was conducted to identify studies reporting multivariate relationships between prespecified covariates and the risk of bleeding in patients receiving warfarin. The prespecified covariates were identified based on patient characteristics for bleeding listed in the warfarin package insert. Each covariate was evaluated for its association with specific types of bleeding. The quality of individual evaluations was rated as 'good', 'fair' or 'poor' using methods consistent with those recommended by the Agency for Healthcare Research and Quality (AHRQ). Overall strength of evidence was determined using the Grading of Recommendations Assessment, Development (GRADE) criteria and categorised as 'insufficient', 'very low', 'low', 'moderate' or 'high'. Thirty-four studies, reporting 134 multivariate evaluations of the association between a covariate and bleeding risk were identified. The majority of evaluations had a low strength of evidence for the association between covariates and bleeding and none had a high strength of evidence. Malignancy and renal insufficiency were the only two covariates that had a moderate strength of evidence for their association with major and minor bleeding respectively. The associations between covariates listed in the warfarin prescribing information and increased bleeding risk are not well supported by the medical literature.

Topics: Alcohol Drinking; Anemia; Anticoagulants; Drug Labeling; Heart Diseases; Hemorrhage; Humans; Liver Diseases; Medication Adherence; Mental Disorders; Neoplasms; Prescription Drugs; Renal Insufficiency; Risk Factors; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Time Factors; Warfarin

The relation of cancer to thromboembolism has been described since the mid 1800s. Different studies in animal and in vitro models have confirmed the link between the haemostatic system and both tumor stroma formation and metastasis. Although the mechanisms of warfarin effects on cancer are not elucidated, but are based on hypothesis, various studies have reported interesting results in this setting. But does warfarin added to recommended anti-tumour therapy improve survival of cancer patients? For the time being it is difficult to answer this question. Data from the literature are few and sometimes contradictory. Trials are characterized by important differences in studied cohorts, histological types of cancers evaluated, and in the treatment protocols. Most studies show that there is benefit from the addition of warfarin to chemotherapy in the tumour development, expansion and on the patient survival, especially in particular types of cancers. These data, although fascinating, do not rationalize the use of anticoagulation in the routine prophylaxis of cancer, however, they call for efforts in preparing large scale randomized trials to elucidate the effect of anticoagulation in the setting of neoplastic disease.

Topics: Animals; Anticoagulants; Clinical Trials as Topic; Humans; Neoplasms; Thromboembolism; Vitamin K; Warfarin

Acutely ill medical patients are at moderate to high risk of venous thromboembolism (VTE): approximately 10-30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Medical conditions associated with a high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, rheumatological and infectious diseases. Pre-disposing risk factors in medical patients include a history of VTE, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility and obesity. Hence active cancer and a history of cancer are both strongly related to VTE in medical (non-surgical) patients. Heparins, both unfractionated (UFH) and low molecular weight (LMWH) and fondaparinux have been shown to be effective agents in prevention of VTE in this setting. However, it has not yet been possible to demonstrate a significant effect on mortality rates in this population. In medical patients, unfractionated heparin has a higher rate of bleeding complications than low molecular weight heparin. Thromboprophylaxis has been shown to be effective in medical patients with cancer and may have an effect on cancer outcomes. Thromboprophylaxis in patients receiving chemotherapy remains controversial and requires further investigation. There is no evidence for the use of aspirin, warfarin or mechanical methods. We recommend either low molecular weight heparin or fondaparinux as safe and effective agents in the thromboprophylaxis of medical patients.

Topics: Anticoagulants; Aspirin; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Neoplasms; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Warfarin

Involutional osteoporosis is one of common diseases related to ageing. However, it is essential for physicians to exclude possibilities that it is caused by certain background diseases or disorders, such as hypercortisolism, hyperthyroidism and type 1 diabetes mellitus. In addition, there are several diseases other than osteoporosis, that are known to be associated with low bone mineral density, although osteoporosis is usually diagnosed according to bone mineral density measurements. Thus, physicians should be prepared to appropriately evaluate how bone metabolism is impaired in the face of patients with low bone mineral density.

Topics: Anticonvulsants; Antidepressive Agents; Bone and Bones; Bone Density; Cushing Syndrome; Diabetes Mellitus, Type 1; Glucocorticoids; Humans; Hyperthyroidism; Neoplasms; Osteoporosis; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect.. To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding.. Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74).. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a common complication of malignancy, and is associated with significant morbidity and mortality. Anticoagulant therapy, in the form of heparin and warfarin, plays an important role in the prevention of recurrent VTE. Recent studies have demonstrated that long-term therapy with low molecular weight heparin (LMWH) is more effective than warfarin in patients with cancer. In addition, accumulating clinical evidence suggests that LMWH significantly improves overall survival in cancer patients without VTE. Intriguingly, however, this improved survival cannot simply be explained by a reduction in fatal pulmonary embolism. Furthermore, the beneficial effects persist long after the LMWH has been discontinued, suggesting that LMWH can directly influence tumour cell biology. This hypothesis is entirely plausible, given the complex feedback mechanisms that exist between tumour cells, coagulation proteases, and vascular endothelial cells. Furthermore, an accumulating body of in vitro experimental evidence suggests that both heparin and warfarin have direct antineoplastic effects. Further large randomized controlled trials will be required in order to validate these exciting preliminary data, and to define whether anticoagulant therapy may constitute a useful adjunctive therapy in the management of cancer patients without VTE.

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

Cancer is a frequent finding in patients with thrombosis, and thrombosis is much more prevalent in patients with cancer, with important clinical consequences. Thrombosis is the second most common cause of death in cancer patients. Venous thromboembolism (VTE) in cancer is also associated with a high rate of recurrence, bleeding, a requirement for long-term anticoagulation, and worsened quality of life. Risk factors for cancer-associated VTE include particular cancer types, chemotherapy (with or without antiangiogenic agents), the use of erythropoietin-stimulating agents, the presence of central venous catheters, and surgery. Novel risk factors include platelet and leukocyte counts and tissue factor. A risk model for identifying cancer patients at highest risk for VTE has recently been developed. Anticoagulant therapy is safe and efficacious for prophylaxis and treatment of VTE in patients with cancer. Available anticoagulants include warfarin, heparin, and low-molecular weight heparins (LMWHs). LMWHs represent the preferred therapeutic option for VTE prophylaxis and treatment. Their use may be associated with improved survival in cancer, although this issue requires further study. Despite the significant burden imposed by VTE and the availability of effective anticoagulant therapies, many oncology patients do not receive appropriate VTE prophylaxis as recommended by practice guidelines. Improved adherence to guidelines could substantially reduce morbidity, decrease resource use, enhance quality of life, and improve survival in these patients.

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Publishing; Thrombosis; Venous Thromboembolism; Warfarin

Venous thromboembolism is common in patients with cancer. However, no management guidelines exist for venous thromboembolism specific to patients with advanced progressive cancer. To help develop recommendations for practice, we have done a comprehensive review of anticoagulation treatment in patients with cancer, with particular focus on studies that included patients with advanced disease. Data from 19 publications, including randomised, prospective, and retrospective studies suggest that: long-term full-dose low-molecular-weight heparin (LMWH) is more effective than warfarin in the secondary prophylaxis of venous thromboembolism in patients with cancer of any stage, performance status, or prognosis; warfarin should not be used in patients with advancing progressive disease; and in patients at high risk of bleeding, full-dose LMWH for 7 days followed by a long-term decreased fixed dose long term can be considered. The optimum treatment duration is unclear, but because the prothrombotic tendency will persist in patients with advanced cancer, indefinite treatment is generally recommended. For patients with contraindications to anticoagulation, inferior-vena-caval filters can be considered, but their use needs careful patient selection. Ultimately, the decision to initiate, continue, and stop anticoagulation will need to be made on an individual basis, guided by the available evidence, the patient's circumstances, and their informed preferences.

Topics: Anticoagulants; Disease Progression; Drug Administration Schedule; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasm Staging; Neoplasms; Patient Selection; Practice Guidelines as Topic; Risk Assessment; Vena Cava Filters; Venous Thromboembolism; Warfarin

Cancer has been shown to be an independent risk factor for the development of venous thromboembolism (VTE; deep vein thrombosis and pulmonary embolism). Thromboprophylaxis reduces the incidence of VTE in patients with cancer; however, active cancer places patients at high risk for recurrent VTE, necessitating extended prophylactic regimens. Extended prophylaxis in patients with cancer can be problematic because of increased risk for bleeding. Oral anticoagulants, such as warfarin, have been the standard of care for extended prophylaxis, but maintaining a clinically effective level of anticoagulation can be difficult because of a wide range of drug interactions, a narrow therapeutic window, and an increased risk of bleeding complications, particularly in patients with cancer. Recent evidence indicates that long-term prophylaxis with low-molecular-weight heparins (LMWHs) is an effective and safe alternative to oral anticoagulation in patients with VTE and cancer, reducing the risk for recurrent VTE by up to 52%. LMWHs can also be seen as cost-effective for long-term prophylaxis, because higher drug acquisition costs are offset by the potential for reduced hospital stays, reduced need for coagulation monitoring, and fewer bleeding complications. Some studies suggest that LMWHs may also have direct antitumor effects and improve survival rates, most notably in patients with non-metastatic disease. Further clinical research is needed to evaluate the potential survival benefits of LMWH therapy in patients with cancer.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Recurrence; Risk Factors; Thrombosis; Warfarin

Management of venous thromboembolism (VTE) in patients with cancer is challenging. In addition, cancer-associated thrombosis (CAT) is becoming an increasingly prevalent condition because of the aging population, the aggressiveness of anticancer therapies, and the improved survival of patients with cancer. Diagnosis of CAT can be difficult because many cancer patients without acute thrombosis often have with signs and symptoms that mimic those of deep vein thrombosis or pulmonary embolism, while others are found to have clinically silent VTE incidentally on routine staging investigations for their cancer. Prevention of CAT is important for reducing the burden of disease but it has received very little attention from clinicians and researchers. Treatment of CAT is also challenging because oncology patients have a high risk of recurrent thrombosis and major bleeding even while receiving anticoagulant therapy. This review will focus on the current standards of practice for the diagnosis, prevention and treatment of VTE in patients with cancer.

Topics: Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Venous Thromboembolism; Warfarin

Patients with cancer, particularly those with metastatic cancer, are at high risk of venous thromboembolism (VTE), which places a huge burden on healthcare resources and can adversely affect patients' prognosis. In addition, VTE can have a negative impact on quality of life and increase the management challenges faced by physicians and nurses. Conventional long-term treatment using vitamin K antagonists, such as warfarin, presents many practical problems for cancer patients including frequent monitoring and dose adjustment, drug interactions, and disruption of anticoagulation for invasive procedures. The aim of this article is to review the potential advantages of using low molecular weight heparin (LMWH) in the treatment of cancer-related VTE in comparison to conventional therapy with warfarin or standard heparin. The potential advantages were determined via a literature review. LMWH is at least as effective as standard heparin or warfarin, and has been shown to have several benefits over warfarin in cancer patients. The simplicity of this therapy enables patients to be treated at home, and has been shown to have a positive impact on overall quality of life. The use of LMWH provides a treatment alternative to patients with cancer offering them hope and optimism regarding their care.

Topics: Anticoagulants; Attitude to Health; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Evidence-Based Practice; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Oncology Nursing; Patient Selection; Practice Guidelines as Topic; Prevalence; Quality of Life; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Cancer is linked with hypercoagulability and risk of thrombosis and this close association was recognized by Armand Trousseau in 1865. The relation between cancer and blood coagulation is reciprocal: cancer induces a hypercoagulable state and predisposes to thrombosis and activation of platelets, blood coagulation and fibrinolysis interfere with tumor cell biology, tumor growth, angiogenesis and metastatic process. In the present article, we analyze the clinical trials which assessed the influence of anticoagulant treatment on the survival of patients with cancer. The available data show that low-molecular-weight heparins (LMWHs) tend to be more effective and safer than vitamin K antagonists (VKA) in improving survival in patients with cancer. The beneficial effect of anticoagulation with either LMWHs or VKA is not universal for all patients with cancer. There are some histological types of cancers which, at early stages, appear to be more sensitive than others to the effect of anticoagulant treatment. The available clinical trials, although limited, are encouraging for the beneficial effect of anticoagulant treatment on the survival of cancer patients. More clinical trials are needed, targeting groups of patients homogenous regarding the type of cancer, the stage of the disease and life expectancy. The forthcoming clinical trials have to address some issues regarding the optimal dose, the timing and the duration of treatment with LMWH in relation to chemotherapy or other anticancer therapies.

Topics: Animals; Anticoagulants; Clinical Trials as Topic; Double-Blind Method; Drug Screening Assays, Antitumor; Fibrinolytic Agents; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Mice; Multicenter Studies as Topic; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic; Research Design; Survival Analysis; Thrombophilia; Thrombosis; Vitamin K; Warfarin

Venous thromboembolism (VTE) occurs frequently in patients with cancer. It can be difficult to manage, sometimes delay cancer therapy and predicts for a worse prognosis. Hence, effective methods to prevent and treat VTE can reduce morbidity and mortality. Prophylaxis with anticoagulants is recommended for patients hospitalized for surgery or medical conditions, but is not routinely administered in the ambulatory setting. Traditional anticoagulation with a heparin followed by vitamin K antagonist therapy for cancer patients with acute VTE is associated with a high frequency of treatment failure and bleeding complications. Low molecular weight heparins (LMWHs) have simplified and improved the management of VTE, and recent studies suggest these agents may improve survival in patients with limited or early stage disease. This brief review will provide an update on the primary prevention and treatment of VTE and discuss the evidence for the survival advantage associated with LMWH use in patients with malignancy.

Topics: Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Warfarin

The association of cancer and venous thromboembolism (VTE) becomes increasingly important. VTE has been recognised as an increasingly frequent complication in cancer care. Furthermore, recent clinical trials have shown that therapy and prophylaxis of VTEs with low-molecular weight heparin (LMWH) is, in general, superior to oral anticoagulation with warfarin. Also, prolonged therapy of or prophylaxis for VTE in cancer patients seems to be associated with an improved outcome.. Research on patient preferences for therapy and prophylaxis of VTE is still rare; but it seems clear that, as in other areas, cancer patients wish to be involved in the decision-making process. Patients seem to accept LMWH over oral anticoagulation despite the need for subcutaneous injections.. Cancer and thrombosis/hypercoagulability is an increasingly important association. The use of antithrombotics in cancer patients warrants increased attention since it's importance seems underrecognized.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Primary Prevention; Prognosis; Quality of Life; Venous Thrombosis; Warfarin

It was the aim of the review to determine the risks and benefits of primary thromboprophylaxis with anticoagulants in cancer patients with central venous devices. Medline, Central and Google Scholar databases were searched for randomized controlled trials (RCTs) in June 2006. Two reviewers extracted data and appraised the quality of RCTs. Results were expressed as relative risk (RR) with 95% confidence intervals (CI) using random effects model for the outcomes of catheter-related thrombosis, bleeding and thrombocytopenia. Eight RCTs (1,428 patients) were included. There was no statistically significant difference in the risk of catheter-related thrombosis for the use of warfarin versus placebo (3 trials, 425 patients, RR 0.75, 95% CI 0.24-2.35, p = 0.63), heparin versus placebo (4 trials, 886 patients, RR 0.46 95% CI 0.18-1.20, p = 0.06) or warfarin, unfractionated heparin or low-molecular-weight heparin versus placebo (7 trials, 1,311 patients, RR 0.59, 95% CI 0.31-1.13, p = 0.11). Substantial statistical heterogeneity was noted among these trials (I(2) > 50%). The use of anticoagulants showed no statistically significant difference in the risk of overall bleeding (5 trials, 1,193 patients, RR 1.24, 95% CI 0.84-1.82, p = 0.28), and thrombocytopenia for heparin versus placebo (4 trials, 958 patients, RR 0.85, 95% CI 0.49, 1.46, p = 0.55) without any statistical heterogeneity (I(2) = 0%). In cancer patients with central venous devices, thromboprophylaxis has no significant effect on the risk of catheter related thrombosis or bleeding. The use of primary thromboprophylaxis in cancer patients with central venous catheters while not causing any harm provides no benefit.

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Catheters, Indwelling; Drug Delivery Systems; Hemorrhage; Heparin; Humans; Neoplasms; Odds Ratio; Patient Selection; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thrombocytopenia; Thrombosis; Warfarin

Venous thromboembolism (VTE) disease, as defined by the occurrence of deep venous thrombosis or pulmonary embolism, occurs among 4 to 20% of patients with cancer and is a leading cause of death among these patients. Use of classical anticoagulation to treat VTE in a cancer patient is associated with a higher risk of major bleeding and of VTE recurrence as compared to noncancer patients. Updated comprehensive and systematic review of current data from the medical literature allows to reconsider the classical approach used for anticoagulant treatment in cancer patients and to implement adapted recommendations. In 2008, the use of daily subcutaneous low-molecular-weight heparin (LMWH) for at least three to six months is recommended as first line therapy to treat VTE disease in cancer patients. If LMWH are contra-indicated (renal insufficiency), other therapeutic approaches are warranted, such as use of unfractionated heparin (UFH) with early introduction of anti-vitamin K for at least three months or venous cava filter in case of absolute contra-indications to anticoagulation. VTE prophylaxis in cancer patients relies on the same therapeutic approaches as currently used for noncancer patients at high risk of VTE. The definition of more specific prophylactic approaches for patients with cancer considered at higher risks of VTE, will be the subject of many clinical trials in the forthcoming years.

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

Venous thromboembolism is a serious complication in patients with cancer. The seriousness of venous thromboembolism as a complication in cancer patients is becoming recognized as an important medical issue. Venous thromboembolism is a multifactorial disease associated with vascular endothelial damage, stasis of blood flow, and hypercoagulation. Preexisting morbidity, mutations of factor V Leiden or prothrombin 20210A, type of cancer, presence of metastases, use of central venous access, surgery, anesthesia, etc., increase the risk of venous thromboembolism. The patients with malignancies have a 7-fold increase in the risk of venous thromboembolism compared with individuals without cancer. Venous thromboembolism is the second most common cause of mortality in cancer patients. Venous thromboembolism is the most common cause of death at 30 days after surgery in patients undergoing surgery for cancer. Venous thromboembolism caused death in 46.3% of the cases after surgery for cancer. The Geneva prognostic index identified predictive factors for an adverse outcome, and the American College of Chest Physicians (ACCP) has suggested the guidelines for the prevention of venous tromboembolism in cancer patients. Cancer patients should receive appropriate venous thromboembolism prophylaxis. The methods used for venous thromboembolism prophylaxis are mechanical, pharmacological, or a combination of both. Well-timed thromboprophylaxis may protect patients from venous thromboembolism, early lethal outcome and even influence survival.

Topics: Adult; Age Factors; Anticoagulants; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk; Risk Factors; Time Factors; Venous Thromboembolism; Warfarin

Cancer patients, especially those undergoing surgery for cancer, are at extremely high risk for developing venous thromboembolism (VTE), even with appropriate thromboprophylaxis. Anticoagulant prophylaxis in cancer surgery patients has reduced the incidence of VTE events by approximately one-half in placebo-controlled trials, and extended prophylaxis (for up to 1 month) has also significantly reduced out-of-hospital VTE events in clinical trials in this population. Clinical trials show no difference between low-molecular-weight heparin (LMWH) and unfractionated heparin in VTE prophylaxis efficacy or bleeding risk in this population, although the incidence of heparin-induced thrombocytopenia is lower with LMWH. The risk-benefit profile of low-dose anticoagulant prophylaxis appears to be favorable even in many cancer patients undergoing neurosurgery, for whom pharmacologic VTE prophylaxis has been controversial because of bleeding risks.

Topics: Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Postoperative Complications; Risk Assessment; Risk Factors; Risk Reduction Behavior; Venous Thromboembolism; Warfarin

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.

Topics: Adenocarcinoma, Clear Cell; Adolescent; Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Antiphospholipid Syndrome; Carboplatin; Cerebral Hemorrhage; Cerebral Infarction; Docetaxel; Fatal Outcome; Female; Humans; Male; Middle Aged; Neoplasms; Neoplasms, Unknown Primary; Ovarian Neoplasms; Palliative Care; Paraneoplastic Syndromes; Protein C Deficiency; Protein S Deficiency; Pulmonary Embolism; Taxoids; Thrombophilia; Thrombophlebitis; Warfarin

Several in vitro and in vivo studies have shown that low molecular weight heparin and warfarin may directly inhibit tumour cell growth and prevent metastatic spread. However, the clinical evidence in support of an anti-cancer effect is less conclusive. We summarize the evidence from clinical studies that examine the effect of these anticoagulants on cancer development and briefly describe the current understanding of the potential mechanisms by which anticoagulants may exert an anti-cancer effect.. English-language articles reporting on warfarin, coumarin or low molecular weight heparin for the treatment or prevention of cancer were selected from PUBMED. All randomized clinical trials, case-control studies, cohort studies, and meta-analyses were retrieved. Detailed data review and abstraction was performed according to pre-specified criteria.. Of ninety-nine articles retrieved, 12 warfarin and 17 low molecular weight heparin articles were included in the review. We found no consistent evidence that warfarin may improve cancer survival, though there is indirect evidence that prolonged warfarin use may decrease the risk of urogenital cancer. Low molecular weight heparin may improve survival of patients with small cell lung cancer and those with advanced malignancy who have more favorable prognoses.. Clinical evidence exists in support of an anti-neoplastic effect of anticoagulants. However, more research is needed to further define which cancer type and stage would most benefit from low molecular weight heparin, as well as to explore the role of warfarin in urogenital tumour development.

Topics: Anticoagulants; Antineoplastic Agents; Clinical Trials as Topic; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Warfarin

Topics: Analgesics, Non-Narcotic; Anemia; Anticoagulants; Antineoplastic Agents; Dietary Supplements; Female; Gastrointestinal Diseases; Humans; International Normalized Ratio; Middle Aged; Neoplasms; Thrombocytopenia; Warfarin

A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect.. To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.. Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.. Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype.. Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Thromboembolism; Warfarin

Topics: Animals; Biomarkers, Tumor; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Prognosis; Pulmonary Embolism; Venous Thrombosis; Warfarin

Preclinical evidence suggests that anticoagulants, in particular the low-molecular-weight heparins (LMWH), exert an antitumor effect, whereas clinical trials have reported conflicting results. The authors conducted a comprehensive, systematic review and meta-analysis of the evidence from randomized controlled trials (RCTs), to evaluate the impact of anticoagulants on survival and safety in cancer patients without venous thromboembolism.. A comprehensive systematic literature review of RCTs was performed without language restrictions through May 2006 with subsequent updates to the end of 2006, including an exhaustive search of electronic databases, major conference proceedings, article references, and content experts. Two reviewers extracted data independently. Primary study outcomes were 1-year overall mortality and all bleeding complications. Major and fatal bleeding complications were secondary outcomes.. Across all 11 studies that were identified, anticoagulation significantly decreased 1-year overall mortality with a relative risk (RR) of 0.905 (95% confidence interval [95% CI], 0.847-0.967; P = .003). The RR for mortality was 0.877 (95% CI, 0.789-0.975; P = .015) for LMWH, compared with an RR of 0.942 (95% CI, 0.854-1.040; P = .239) for warfarin, resulting in an absolute risk difference (ARD) of 8% for LMWH and an ARD of 3% for warfarin. Improved survival with anticoagulation may be dependent on tumor type. Major bleeding episodes occurred less frequently in patients who received LMWH (ARD, 1%) compared with patients who received warfarin (ARD, 11.5%; P < .0001). Overall, fatal bleeding occurred rarely (ARD, 0.32%; P = .542).. Anticoagulants, particularly LMWH, significantly improved overall survival in cancer patients without venous thrombosis while increasing the risk for bleeding complications. However, given the limitations of available data, the use of anticoagulants as antineoplastic therapy cannot be recommended until additional RCTs confirm these results.

Topics: Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Warfarin

Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect.. To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer.. A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed.. We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest.. Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.. Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38).. Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

Topics: Anticoagulants; Carcinoma, Small Cell; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

To evaluate the effectiveness and safety of oral anticoagulants in improving survival of cancer patients. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We extracted data on methodological quality, participants, interventions and outcomes using a standardized form. Five RCTs fulfilled the inclusion criteria and all compared warfarin to either placebo or no intervention. Their overall methodological quality was acceptable. The effect of warfarin on mortality was not statistically significant at 6 months (RR = 0.96; 95% CI 0.80-1.16), at 1 year (RR = 0.95; 95% CI 0.86-1.05), at 2 years (RR = 0.97; 95% CI 0.87-1.08) or at 5 years (RR 0.91; 95% CI 0.83-1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at 6 months (RR = 0.69; 95% CI 0.50-0.96) but not at 1 year (RR = 0.88; 95% CI 0.77-1.01). This 6 months mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45-0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36-1.28). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85-9.68) and minor bleeding (RR = 3.34; 95% CI 1.66-6.74). The evidence suggests a survival benefit from warfarin in patients with extensive SCLC, but not in other patient groups. This survival benefit should be weighed against the increased risk for hemorrhage.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Warfarin

Venous thromboembolism (VTE) occurs more frequently in cancer patients than in non-cancer patients and outcomes are poor in patients with both cancer and thrombosis. Patients with cancer who develop thrombosis are more likely to experience a recurrence of VTE and have increased bleeding complications while receiving oral anticoagulant treatment. The purpose of this paper is to discuss the causes and outcomes of thrombosis in cancer patients, the limitations of warfarin therapy, the guidelines and data for the use of low-molecular-weight heparins (LMWHs) in the treatment and secondary prevention of thrombosis in cancer patients, and emerging data regarding survival with the use of LMWH in cancer patients.. Literature for this paper has been collected using multiple sources, including primary, secondary, and tertiary references. Online searches have been conducted utilizing the PubMed and OVID databases, and abstracts from the Proceedings of the American Society of Clinical Oncology and the American Society of Hematology Annual Meeting and Exhibition. The following key terms were used in the search: cancer, deep vein thrombosis, pulmonary embolism, anticoagulation, LMWHs, guidelines, survival, cost.. The long-term use of LMWHs in the settings of cancer and thrombosis are supported by recent clinical trial evidence that demonstrate their equivalent safety and improved efficacy when compared to oral anticoagulants resulting in their inclusion in current guidelines. Finally, newer studies offer further evidence of improved outcomes with dalteparin and nadroparin, including possible survival benefits.. Treatment with LMWHs has been shown to be more effective than warfarin in the extended treatment of VTE in patients with cancer and is safe in this setting. Use of a LMWH for at least the first 3-6 months of long-term treatment is now considered the standard of care for patients with cancer and is recommended in numerous guidelines. Additionally, further evaluation of the survival benefits of LMWH in cancer patients is warranted.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Survival Analysis; Thromboembolism; Treatment Outcome; Venous Thrombosis; Warfarin

To determine whether the use of low-dose warfarin could reduce the incidence of thrombosis in patients with cancer who have a central venous catheter (CVC).. MEDLINE, CINAHL, CANCERLIT, EMBASE, and the Cochrane Library.. Meta-analysis of four studies (N = 1,236 patients) revealed that 6.4% of warfarin-treated patients experienced a thrombotic event compared with 7.5% in the control (no treatment) group. The risk difference for thrombus formation was not significant (2.0%, confidence interval = -9.0% to 5.0%).. The administration of warfarin did not reduce the incidence of symptomatic or asymptomatic CVC-associated thrombosis in patients with cancer.. Using research findings to inform clinical nursing practice is important in caring for patients and providing optimal and improved patient outcomes. Prophylactic use of low-dose warfarin may not prevent thrombus formation and is associated with potentially adverse patient outcomes.

Topics: Anticoagulants; Catheterization, Central Venous; Humans; Neoplasms; Venous Thrombosis; Warfarin

Pathology studies of human cancers suggested to early investigators that the hemostatic system may play an important role in cancer metastasis. Subsequent studies in animal models have demonstrated a reduction of tumor metastasis and improved animal survival with systemic anticoagulation. In many of these experiments, vitamin K antagonists (VKAs) were utilized. Although warfarin was effective in reducing metastasis in a majority of these animal models, effects on the growth of the primary tumor and on animal survival have been less consistent. Clinical studies on the effect of warfarin in human malignancy are limited and less than conclusive. Several small, uncontrolled and controlled clinical studies have been reported but do not definitively suggest a benefit in most malignancies. However, none of the studies of VKAs in humans are adequately designed or sufficiently powered to definitively exclude an impact of oral anticoagulants on cancer survival. Because of the difficulties in managing VKA oral anticoagulation in cancer patients and recent studies suggesting a positive effect on cancer survival with low-molecular-weight heparins, it unlikely that further studies on the use of VKAs in cancer patients will be undertaken.

Topics: Animals; Anticoagulants; Disease Progression; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Survival Rate; Vitamin K; Warfarin

Topics: Anticoagulants; Antineoplastic Agents; Catheterization; Catheters, Indwelling; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Venous Thrombosis; Warfarin

Recent literature has highlighted the unique challenges facing professionals involved with the management of venous thromboembolism (VTE) in cancer patients. Although research favours the use of low molecular weight heparin (LMWH) rather than warfarin, no studies have been conducted exclusively in the palliative care population. Likewise, active treatment may not always be appropriate in the advanced cancer patient. This paper highlights the issues to be considered when facing a palliative care patient and suspected VTE. In particular, consideration must be given to the practicalities and acceptability of investigating suspected VTE, the dose and length of anticoagulation, and management of the patient nearing death. An understanding of the current evidence must be applied to the individual patient, taking into account their needs and wishes.

Topics: Anticoagulants; Drug Monitoring; Evidence-Based Medicine; Heparin, Low-Molecular-Weight; Humans; Incidence; International Normalized Ratio; Neoplasms; Palliative Care; Paternalism; Patient Advocacy; Patient Selection; Prevalence; Risk Factors; Time Factors; Treatment Outcome; Ultrasonography, Doppler; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) constitutes an important health problem in developed countries. Owing to their underlying malignancies, people with cancer are at particularly high risk of VTE. The level of this risk is influenced by several factors, including type of cancer and the presence or absence of metastases. However, different types of oncology treatment can also further increase the thrombotic risk. Consequently, primary and secondary thromboprophylaxis in people with cancer should be considered as part of any integrated oncology treatment. Moreover, recent exciting studies have suggested that low molecular weight heparins (LMWH) may also influence overall survival in people with cancer. Clearly, these findings raise the likelihood that the use of LMWH in oncology practice may increase significantly in the near future. However, it is important to appreciate that the use of thromboprophylaxis in people with cancer is complicated by a number of specific problems. In this overview, we have systematically addressed the difficult clinical issues that are involved in the selection of appropriate primary and secondary thromboprophylaxis for people with cancer.

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

The risk of cancer-associated thrombosis can be substantial, depending on tumor type, extent of cancer, and type of treatment. Unfractionated heparin and warfarin have been used in the prevention of cancer-associated thrombosis, but low-molecular-weight heparin (LMWH) is widely used for the prevention of venous thromboembolism in high-risk patients. Long-term management with warfarin is associated with close monitoring, an increased risk of drug interactions, and bleeding. LMWHs may offer an alternative outpatient treatment strategy for prophylactic treatment because of their simpler dosing, more predictable anticoagulant activity, and improved safety profile. Clinical trials examining the treatment of venous thromboembolism with LMWH in patients with cancer suggest a survival advantage for the treated groups. Subtle differences in the pharmacokinetics of available LMWHs exist, and each LMWH should be regarded as a distinct drug. Pharmacists should be aware of the US Food and Drug Administration-approved uses for each LMWH, dosing options, and the advantages and disadvantages of available delivery systems for various patient populations. Pharmacists can play a major role in educating patients and other health care professionals on risk factor recognition, patient risk stratification, and proper agent selection for prevention and treatment of cancer-associated thrombosis.

Topics: Anticoagulants; Clinical Trials as Topic; Economics, Pharmaceutical; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Patient Selection; Pharmacists; Practice Guidelines as Topic; Prognosis; Risk Factors; Survival; Thrombosis; Warfarin

In the nearly 130 years since Trousseau first described migratory thrombophlebitis in cancer patients, thromboembolism has become a well-established presenting sign and complication of cancer. The coagulation system is activated in cancer and is further amplified by treatment with chemotherapy, radiation or surgery. Hypercoagulation is documented in virtually all cancer types, albeit at different rates, and is the second leading cause of death in cancer patients. The relationship between clotting activation and carcinogenesis supports the view of cancer as a hypercoagulable state and holds implications for the development of thrombosis, enhancement of tumor growth and risk of poor clinical outcomes. Although it is well recognized that cancer can activate the coagulation cascade, it is less well known that activation of the coagulation system may also support tumor progression. Additionally, platelet activation in cancer patients and its impact on tumor progression and metastasis further expand the role of the hemostatic system in malignancy. The problem of thrombosis in patients with metastatic diseases is a serious concern for clinicians. This review explores the mechanisms and clinical implications of coagulation and platelet activation in cancer. The prevention and treatment of venous thromboembolism in cancer will also be discussed by reviewing data from key clinical investigations. Finally, the emerging role of low-molecular-weight heparin as an antineoplastic agent will be explored. Warfarin and unfractionated heparin have been in clinical use for more than 50 years. Both are effective anticoagulants, but their use is associated with a number of impediments, including the need for intensive coagulation monitoring, wide variation in dose-response relationships, multiple drug interactions (in the case of warfarin), and serious immune-mediated thrombocytopenia (in the case of heparin). The introduction of low-molecular weight heparin advanced anticoagulation therapy by enhancing efficacy and eliminating the need for intensive coagulation monitoring. Fondaparinux, the first selective factor Xa inhibitor, represents yet another improvement in anticoagulation therapy. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Additionally, efficient inhibition of factor Xa act

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Drug Administration Schedule; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Polysaccharides; Randomized Controlled Trials as Topic; Thrombin; Thrombosis; Warfarin

The association between cancer and venous thromboembolism (VTE) is well established. Importantly, VTE is a significant cause of mortality in cancer patients. Although long-term warfarin (Coumadin(trade mark); Bristol-Myers Squibb; New York, NY) therapy is the mainstay of treatment for cancer patients with VTE, there are many practical problems with its use in this population. In particular, achieving therapeutic drug levels is difficult in cancer patients due to the increased risk of drug interactions, malnutrition, vomiting, and liver dysfunction in these patients. Moreover, cancer patients are at an increased risk of adverse effects of warfarin therapy. In contrast, low-molecular-weight heparins (LMWHs) are associated with a lower risk of adverse events compared with warfarin in patients with cancer. These agents also offer practical advantages compared with warfarin, including more predictable anticoagulant effects and ease of administration in addition to possible antineoplastic effects. Several LMWHs have demonstrated superior efficacy to warfarin in the secondary prevention of VTE. In particular, the LMWH, dalteparin (Fragmin; Pfizer; New York, NY), has recently been shown to have superior efficacy to warfarin in a large trial of patients with cancer and VTE without increasing the risk of bleeding. A randomized trial of dalteparin has also shown improved response rates and survival in patients with small cell lung cancer. In view of the availability of more effective and reliable alternatives to warfarin therapy in cancer patients, it is appropriate to reassess the role of warfarin therapy in patients with cancer and VTE. Further evaluation of the LMWHs for effects on cancer outcome is indicated.

Topics: Administration, Oral; Anticoagulants; Drug Interactions; Heparin, Low-Molecular-Weight; Humans; Malnutrition; Neoplasms; Risk Factors; Thromboembolism; Vomiting; Warfarin

Several proofs of principle have established that pharmacogenetic testing for mutations altering expression and functions of genes associated with drug disposition and response can decrease the "trial-and-error" dosing and reduce the risk of adverse drug reactions. These proofs of principle include thiopurine methyltransferase and thiopurine therapy, dihydropyrimidine dehydrogenase/thymidylate synthase and 5-fluorouracil therapy, folate enzyme MTHFR and methotrexate therapy, UGT1A1 and irinotecan therapy and CYP450 2C9 and S-warfarin therapy. These evidences advocate for the prospective identification of mutations associated with drug response, serious adverse reactions and treatment failure. More recent evidence with the HLA basis of hypersensitivity to the retroviral agent abacavir demonstrates the potential of pharmacogenetic testing and its pharmacoeconomic implications. With the convergence of rising drug costs and evidence supporting the clinical benefits of pharmacogenetic testing, it will be important to demonstrate the improved net health outcomes attributed to the additional costs for this testing.

Topics: Antineoplastic Agents; Cytochrome P-450 Enzyme System; Dideoxynucleosides; Histocompatibility Testing; Humans; Mutation; Neoplasms; Pharmacogenetics; Warfarin

Thromboembolism affects many patients with solid tumors and clonal hematologic malignancies. Thromboprophylaxis with low-molecular-weight heparin (LMWH) is indicated for surgery and other high-risk situations, but not routinely for central venous catheters or nonsurgical, ambulatory management. Thrombotic events require full anticoagulation for the duration of active disease and/or the prothrombotic stimulus. LMWHs are safe and more effective than both unfractionated heparin for initial therapy and warfarin for secondary prevention. Anti-inflammatory and antiangiogenic properties might account for this advantage and for a survival benefit of chronic LMWH in subgroups of cancer patients. Ongoing studies are characterizing the cost-effectiveness and antitumor mechanisms of LMWHs, the potential utility of newer anticoagulants, and the ability of predictive models to identify high-risk candidates for thromboprophylaxis.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Postoperative Complications; Preoperative Care; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Surgical Procedures, Operative; Survival Analysis; Thromboembolism; Thrombolytic Therapy; Treatment Outcome; Warfarin

To provide oncology nurses with an understanding of therapeutic options for cancer-associated thrombosis, strategies to prevent recurrence, and practical issues in patient management.. Primary and tertiary literature and the author's clinical experience.. Oncology nurses monitor patients throughout the care continuum for signs and symptoms indicating vascular thromboembolism and need to know the steps to take to expedite an accurate diagnosis and ensure prompt treatment.. Oncology nurses must keep informed about the evolving evidence that leads to practice changes. They should be able to teach patients about therapeutic options and their potential for improving outcomes.

Topics: Anticoagulants; Hemorrhage; Humans; Neoplasms; Oncology Nursing; Risk Factors; Vena Cava Filters; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Clinical Trials as Topic; Humans; Immobilization; Neoplasms; Risk Factors; Venous Thrombosis; Warfarin

Central venous catheters (CVCs), such as the tunneled catheters and the totally implanted ports, play a major role in general medicine and oncology. Aside from the complications (pneumothorax, hemorrhage) associated with their initial insertion, all of these CVCs are associated with the long-term risks of infection and thrombosis. Despite routine flushing with heparin or saline, 41% of CVCs result in thrombosis of the blood vessel, and this markedly increases the risk of infection. Only one-third of these clots are symptomatic. Within days of insertion, almost all CVCs are coated with a fibrin sheath, and within 30 days, most CVC-related thrombi arise. Aside from reducing the function of the catheter, these CVC-related thrombi can cause postphlebitic syndrome in 15%-30% of cases and pulmonary embolism in 11% (only half of which are symptomatic). Risk factors for CVC thrombosis include the type of malignancy, type of chemotherapy, type of CVC, and locations of insertion site and catheter tip, but not inherited thrombophilic risk factors. Efforts to reduce CVC thrombosis with systemic prophylactic anticoagulation with low-molecular-weight heparin have failed. Low-dose warfarin prophylaxis remains controversial; all studies are flawed, with older studies, but not newer ones, showing benefit. Currently, less than 10% of patients with CVCs receive any systemic prophylaxis. Although its general use cannot be recommended, low-dose warfarin may be a low-risk treatment in patients with good nutrition and adequate hepatic function. Clearly, additional studies are required to substantiate the prophylactic use of low-dose warfarin. Newer anticoagulant treatments, such as pentasaccharide and direct thrombin inhibitors, need to be explored to address this major medical problem.

Topics: Anticoagulants; Catheterization; Catheterization, Central Venous; Catheters, Indwelling; Costs and Cost Analysis; Heparin; History, 17th Century; Humans; Neoplasms; Risk Factors; Thrombosis; Venous Thrombosis; Warfarin

Experimental and clinical studies have shown an anticancer effect of anticoagulant drugs. The aim of this study is to review the mechanisms by which the common types of anticoagulants influence the primary tumor and metastatic processes of solid tumors. The review evaluates the interference of unfractionated heparin (UFH), low molecular weight heparin (LMWH) and warfarin on the growth of primary tumors and on the development of metastases. The first part of the review evaluates the effect on the growth and development of primary tumors. Attention is paid to the interference with proliferation of cancer cells, tumor angiogenesis and to the interference with the immune system. The second part of the review describes the metastatic process and the effect of anticoagulants on the cell motility and cancer cell adhesion. The third part refers to the outcomes of clinical studies with anticoagulant treatment in patients with cancer. The problem of thromboembolic disease in patients with advanced cancer is also mentioned. The anticoagulants are more effective in inhibition of stages of the metastatic cascade than in the influence on primary tumors. They can interfere with tumor angiogenesis, immunity system, cancer cell motility and adhesion. The first clinical trials showed an effect on the development of primary tumors and survival of patients namely with lung cancer.

Topics: Anticoagulants; Antineoplastic Agents; Clinical Trials as Topic; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Warfarin

Topics: Anticoagulants; Bed Rest; Blood Coagulation; Blood Coagulation Factors; Female; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Prognosis; Pulmonary Embolism; Risk; Thrombectomy; Thrombolytic Therapy; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; Vena Cava Filters; Venous Thrombosis; Warfarin

Central venous catheters (CVCs) are used in a wide variety of patients. Associated complications are thrombosis and infection. It is a matter of debate whether thromboprophylaxis is beneficial.. We performed a systematic review of 3 different patient populations to render the available information in the literature more accessible to clinical practice: patients receiving parenteral nutrition (PN), patients with cancer, and patients admitted to intensive care units.. Prophylaxis with heparin added to PN was found to give a nonsignificant reduction in the incidence of catheter-related thrombosis (pooled relative risk of randomized studies, 0.77; 95% confidence interval [CI], 0.11-5.48). In cancer patients, both low-dose warfarin and low-molecular-weight heparin significantly reduced the incidence of catheter-related thrombosis (relative risk of randomized studies, 0.25 [95% CI, 0.09-0.70] and 0.10 [95% CI, 0.01-0.71], respectively). So far, intensive care patients have hardly been studied with respect to thromboprophylaxis and the incidence of CVC thrombosis. Any effect of the type of catheter could not be established because of small numbers. There was no apparent increase in bleeding events with prophylactic anticoagulation in patients with CVCs.. In the small number of patients studied, the addition of heparin to PN did not significantly decrease the risk of catheter-related thrombosis, whereas warfarin and dalteparin did decrease the thrombosis risk in cancer patients with CVCs. There is no apparent increase in bleeding events with prophylactic anticoagulants in patients with CVCs.

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Critical Illness; Dalteparin; Heparin; Humans; Intensive Care Units; Neoplasms; Parenteral Nutrition; Randomized Controlled Trials as Topic; Risk Factors; Venous Thrombosis; Warfarin

Venous thromboembolism (VTE) and particularly idiopathic VTE may be paraneoplastic phenomena. The merits of screening patients with idiopathic VTE for occult cancer are still under debate, and randomized studies are required to establish its potential cost-effectiveness. Cancer and its related surgery greatly increase the risk of VTE. Thromboprophylaxis using agents such as low-molecular-weight heparin (LMWH) has proved to be safe and effective in reducing the incidence of postoperative VTE. The ENOXACAN II study has shown that prolonging the standard 1-week regimen of the LMWH enoxaparin to 4 weeks may further reduce the incidence of postoperative VTE. Enoxaparin has also shown potential benefits in the secondary prevention of VTE and the reduction of bleeding complications. Emerging data indicate that LMWH may improve survival rates in cancer patients with VTE, making this a very important area for future research.

Topics: Antineoplastic Agents; Double-Blind Method; Enoxaparin; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Meta-Analysis as Topic; Multicenter Studies as Topic; Neoplasms; Paraneoplastic Syndromes; Postoperative Complications; Prospective Studies; Randomized Controlled Trials as Topic; Risk; Thromboembolism; Thrombophilia; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Antiphospholipid Syndrome; Azetidines; Benzylamines; Blood Coagulation; Glycine; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Recurrence; Thrombin; Thrombosis; Treatment Failure; Warfarin

Although pharmacologic prophylaxis against venous thromboembolism has become the standard of care following total hip and knee replacement, prophylaxis among patients undergoing surgery for hip fracture and other lower extremity trauma remains underutilized. Available experience consistently supports the view that low-molecular-weight heparins are more effective than unfractionated heparin for prevention of proximal deep vein thrombosis (DVT) with no additional hemorrhagic risk and more effective than oral anticoagulants for prevention of in-hospital (mostly distal) venous thrombosis at the price of a higher surgical site bleeding and wound hematoma. The choice between low-molecular-weight heparin and warfarin should be tailored to the individual patients based on the clinical assessment of postoperative thrombosis and bleeding risk as well as the prophylaxis-specific cost and convenience. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. The overall incidence of postoperative DVT in patients with cancer is about twice as high as that of patients free of malignancy. Accordingly, they require prophylactic measures comparable with those usually recommended for major orthopedic surgery. In this setting, dermatan sulfate shows promise. In contrast to surgical patients, prevention of venous thromboembolism is less well studied in hospitalized medical patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients.

Topics: Anesthesia, Conduction; Anticoagulants; Arthroplasty, Replacement, Hip; Comorbidity; Heart Diseases; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Neoplasms; Postoperative Complications; Spinal Cord Injuries; Venous Thrombosis; Warfarin

Venous thromboembolism is a common complication in patients with cancer. The management of deep-vein thrombosis and pulmonary embolism can be a considerable challenge in these patients. Diagnosing venous thrombosis requires objective testing, and noninvasive investigations may be less accurate in patients who have cancer than in those who do not. Treatment of acute venous thrombosis at home with low-molecular-weight heparin is an attractive option in patients with malignant disease, in whom quality of life is especially important. Comorbid conditions, warfarin resistance, difficult venous access, and a potentially high bleeding risk are some of the factors that often complicate the prolonged course of anticoagulant therapy needed in this group. In addition, the use of central venous catheters is increasing, but the optimal treatment of catheter-related thrombosis remains controversial. This article reviews the current diagnostic and treatment approaches to venous thromboembolism in patients with cancer and provides several clinical scenarios to illustrate and discuss some common management problems.

Topics: Adult; Aged; Anticoagulants; Catheterization, Central Venous; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Venous Thrombosis; Warfarin

The microsomal mixed function oxidase system metabolizes xenobiotics (Phase I) to products that, if not activated and conjugated for excretion (Phase II), are capable of forming conjugates with cellular macromolecules, including DNA, resulting in toxic, mutagenic, or carcinogenic events. Benzo(a)pyrene (BP), a polycyclic aromatic hydrocarbon, is a model carcinogen for this system. Vitamin K1 (phylloquinone) is a regulator of BP metabolism. These studies demonstrate that K1 is capable of increasing Phase I metabolism and decreasing glutathione transferase activity (Phase II) in chick embryo liver; that deprivation of K1 reduces BP/DNA adducts in mouse liver and reduces tumor formation in mice given intraperitoneal BP; and that K1 supplementation increases BP induced tumor formation in mice. However, epidemiologic studies indicate that children of mothers who smoke during pregnancy may not be at increased risk of cancer. It is known that the placentas from these pregnancies exhibit markedly increased levels of arylhydrocarbon hydroxylase induced by the polycyclic aromatic hydrocarbons in tobacco smoke, but there is no corresponding increase in this enzyme activity in the fetus in such pregnancies. We suggest that the low vitamin K level is a secondary protective mechanism for xenobiotics, such as BP, that may escape the primary placental screen. The recently described role of vitamin K-dependent Gla protein as ligands for receptor tyrosine kinases, also establishes K as a link in cell growth and transformation. It is proposed that the small total body pool of K1 in the adult, which is sufficient only to meet continuing needs, and the even smaller pool in the fetus are protective. This protective effect of low K1 levels is particularly important in the presence of the high mitotic rates and rapid cell turnover in the avian embryo and mammalian fetus.

Topics: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; Adult; Animals; Biotransformation; Carcinogens; Chick Embryo; Cocarcinogenesis; DNA Adducts; Female; Fetal Diseases; Fetus; Humans; Infant, Newborn; Liver; Maternal Exposure; Maternal-Fetal Exchange; Mice; Mice, Inbred ICR; Microsomes, Liver; Mixed Function Oxygenases; Neoplasms; Neoplasms, Experimental; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Smoking; Vitamin K; Vitamin K 1; Vitamin K Deficiency; Warfarin; Xenobiotics

The relationship between cancer and abnormalities of blood coagulation has been recognized for well over a century. Deep venous thrombosis of the lower extremities is most common, but pulmonary embolism, upper extremity vein thrombosis, disseminated intravascular coagulation, and other, more unusual, clinical events may occur. Chemotherapy also has been linked to thrombotic episodes. Anticoagulant therapy is appropriate in many patients with venous or arterial thrombosis. Prophylaxis of venous thrombosis is particularly important in hospitalized cancer patients who are at bed rest or undergoing surgery.

Topics: Antineoplastic Agents; Drug Monitoring; Heparin; Humans; Neoplasms; Recurrence; Thromboembolism; Warfarin

Metastases formation involves platelets activation and coagulation cascade. Drugs interfering with such mechanisms have shown promising activity in controlling neoplastic spread. Particularly, combined treatment with coumarins and the most recent antiplatelet agents could open interesting therapeutic perspectives.

Topics: Administration, Oral; Drug Therapy, Combination; Humans; Neoplasm Metastasis; Neoplasms; Platelet Aggregation Inhibitors; Warfarin

Clinical and experimental observations have firmly established the concept of a two-way interaction between malignancy and the hemostatic system. On the one hand, certain tumors can activate platelets and the coagulation mechanism in vivo, on the other, a convincing case has been made for the involvement of platelets and fibrin in tumor growth and metastasis. A large number of clinical and experimental studies have been conducted in order to test the efficacy of platelet inhibitors and anticoagulants as adjuvants in the treatment of cancer. Antiplatelet drugs gave variable results, depending on the drug and the tumor system tested. Prostaglandin synthetic pathways by both the host and tumor seem to be an important determinant in the response to platelet function inhibitors. Of the various anticoagulants tested, the coumarin derivatives gave somewhat consistent antitumor effect in certain human and experimental cancer. The antitumor effect of oral anticoagulants does not appear to be a primary drug effect and seems related to their role as vitamin K antagonists. It should be emphasized that although the antitumor potential of antithrombotic agents is a subject of keen interest at the present, their use in treating human cancer is still controversial.

Topics: Anticoagulants; Blood Coagulation Factors; Blood Platelets; Growth Substances; Hemostasis; Heparin; Humans; Neoplasm Metastasis; Neoplasms; Warfarin

Plasminogen activator activity (PAA) has been detected in various tumor cells or in their excretion products. In some cell systems PAA is a symptom of cell transformation, but its amount is questionably correlated with the invasiveness of the tumor cells. Procoagulant and aggregation activities on platelets, have been demonstrated in various tumor cells. There are weakly correlated with the metastatic potential of these cells. In vivo, the treatment of animals by modifiers of the hemostasis, or of the fibrinolysis systems provides contradictory results. Some reduction of metastatic diffusion and increase of life span have been noted with Warfarin. Clinical trials are scarce and their methodology is debatable. When conclusive, a lengthening of the life span has been observed, but not a reduction of the metastatic spread as metastases were still present.

Topics: Animals; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Factors; Blood Vessels; Cell Adhesion; Cell Aggregation; Cell Line; Clinical Trials as Topic; Endothelium; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Indomethacin; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plasminogen Activators; Warfarin

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Topics: Animals; Anti-Inflammatory Agents; Antigens; Blood Coagulation; Blood Coagulation Factors; Cell Line; Factor V; Factor VII; Factor X; Factor Xa; Fibrin; Fibrin Fibrinogen Degradation Products; Guinea Pigs; Humans; Hypersensitivity, Delayed; Immunologic Deficiency Syndromes; Infections; Inflammation; Lipopolysaccharides; Macrophages; Mice; Monocytes; Neoplasms; Neutrophils; Rabbits; Rats; T-Lymphocytes; Thromboembolism; Thromboplastin; Warfarin

Topics: Animals; Aspirin; Blood Vessels; Capillaries; Endothelium; Fibrin; Heparin; Lung Neoplasms; Microcirculation; Neoplasm Metastasis; Neoplasms; Platelet Aggregation; Warfarin

Topics: Animals; Blood Coagulation; Blood Platelets; Coumarins; Disease Models, Animal; Fibrin; Fibrinolysis; Hemostasis; Humans; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Platelet Aggregation; Warfarin

Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy.

Topics: Animals; Blood Coagulation; Cell Adhesion; Clinical Trials as Topic; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Research Design; Warfarin

Topics: Animals; Anticoagulants; Female; Fibrinolysin; Fibrinolysis; Fibrinolytic Agents; Heparin; Humans; Immunosuppression Therapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Peptide Hydrolases; Uterine Neoplasms; Warfarin

Of the four major biological mechanisms of cancer spread, hematogenous dissemination is perhaps the most significant, as it usually heralds a fatal outcome for the patient. Recent experimental approaches have shown ways of altering the metastatic process and even totally inhibiting it in some animal models. It appears that these models may be applicable to certain human cancers. To prevent hematogenous metastasis formation the process must be inhibited at any one of four levels: 1) growth of the primary; 2) invasion of vessel walls; 3) release of viable tumor cells; or 4) entrapment and growth in distant organs. Judicious handling of the primary can decrease metastasis by minimizing the shedding of tumor cells. New experimental agents prevent the release of tumor cells from the primary by normalizing the blood vessels of the tumor. Warfarin, heparin, and fibrinolytic agents inhibit the entrapment of circulating tumor cells, presumably by their effect on coagulative mechanisms. A better understanding of the benefits of combined approaches to cancer using chemotherapy, irradiation, and immunotherapy, alone and as adjuncts to surgery, offers new opportunity to study methods of controlling metastatic disease.

Topics: Animals; Antineoplastic Agents; Biopsy; Cell Adhesion; Cell Movement; Detergents; Formaldehyde; Heparin; Humans; Immunotherapy; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Pharmaceutic Aids; Piperazines; Polyethylene Glycols; Propane; Rats; Rats, Inbred Strains; Warfarin

Topics: Animals; Blood Coagulation; Capillaries; Embolism; Heparin; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Thrombin; Warfarin

Topics: Animals; Benz(a)Anthracenes; Cell Movement; Culture Techniques; Ear; Fibrinolysin; Histological Techniques; Humans; Leukocytes; Lung Neoplasms; Lymphatic Metastasis; Mice; Motion Pictures; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Prothrombin Time; Rabbits; RNA; Thrombosis; Time Factors; Warfarin

We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6).. This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75-mg dose on Day 1 of run-in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28-day cycle after the run-in period in both cohorts.. The geometric means ratios [90% confidence interval] for (S)-warfarin with and without sonidegib were: area under the concentration-time curve from time 0 to infinity (AUC. Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration-approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).

Topics: Administration, Oral; Area Under Curve; Biphenyl Compounds; Bupropion; Drug Interactions; Humans; Neoplasms; Pyridines; Warfarin

Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug-drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug-drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.. A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9-21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.. Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC. Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug-drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Nifedipine; Pyridines; Warfarin; Young Adult

Pulmonary embolism (PE) is a life-threatening disease. Target-specific anticoagulant rivaroxaban is a direct factor Xa inhibitor that can be safely used without laboratory monitoring.. To investigate the efficacy and safety of rivaroxaban versus warfarin for the treatment of acute pulmonary thromboembolism in real-world clinical practice.. This was a semiretrospective, semiprospective, and real-world trial involving 128 patients with acute symptomatic pulmonary embolism with or without active tumor or frailty. We compared rivaroxaban to the standard therapy consisting of low-molecular-weight heparin combined with warfarin. The primary efficacy outcome was absorption of thrombus. The principal safety outcome was bleeding episode.. There was no significant difference in thrombus absorption between rivaroxaban and standard therapy after 3-month treatment (. In this real-world study, the efficacy and safety of rivaroxaban alone was not different to standard therapy for pulmonary emboli absorption. With an extension in treatment duration, the rivaroxaban regimen had a higher efficacy and safety than standard therapy and there was no decline in treatment efficacy when the rivaroxaban dose was reduced to 10 mg once daily.

Topics: Female; Frailty; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Risk Factors; Rivaroxaban; Treatment Outcome; Warfarin

The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer.. ROCKET AF randomized 14 264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban vs. warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior vitamin K antagonist (VKA) use and had higher rates of overall bleeding [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.16-1.47; P < 0.0001] and non-cardiovascular death (HR 1.47, 95% CI 1.04-2.07; P = 0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban vs. warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction P-value = 0.21).. In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischaemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.Clinical trial registration: ClinicalTrials.gov: NCT00403767.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Australia; Dose-Response Relationship, Drug; Double-Blind Method; Europe; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Neoplasms; Risk Factors; Rivaroxaban; Stroke; Treatment Outcome; United States; Warfarin

This phase 1, open-label, crossover study sought to evaluate drug-drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein.. The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily.. The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89-1.05) for caffeine, 0.88 (0.76-1.02) for S-warfarin, 0.89 (0.60-1.31) for omeprazole, 0.83 (0.67-1.02) for midazolam, and 0.69 (0.51-0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60-0.95).. The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Caffeine; Chromatography, High Pressure Liquid; Cross-Over Studies; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Midazolam; Middle Aged; Neoplasms; Omeprazole; Proto-Oncogene Proteins c-met; Pyrrolidinones; Quinolines; Tandem Mass Spectrometry; Warfarin

Essentials Cancer patients receiving anticoagulants for venous thromboembolism have an elevated bleeding risk. This secondary analysis of CATCH assessed characteristics of clinically relevant bleeding (CRB). CRB occurs in 15% of cancer patients with thrombosis using therapeutic doses of anticoagulation. After multivariate analysis, risk factors for CRB were age >75 years and intracranial malignancy.. Background Cancer patients with acute venous thromboembolism (VTE) receiving anticoagulant treatment have an increased bleeding risk. Objectives We performed a prespecified secondary analysis of the randomized, open-label, Phase III CATCH trial (NCT01130025) to assess the rate and sites of and the risk factors for clinically relevant bleeding (CRB). Patients/Methods Patients with active cancer and acute, symptomatic VTE received either tinzaparin 175 IU kg

Topics: Aged; Anticoagulants; Drug Monitoring; Female; Hemorrhage; Humans; Incidence; International Normalized Ratio; Male; Middle Aged; Neoplasms; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Warfarin

This article assesses the impact of renal impairment (RI) on the efficacy and safety of anticoagulation in patients with cancer-associated thrombosis from the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) study (NCT01130025).. Renal function was assessed using the Modification of Diet in Renal Disease equation in patients with cancer-associated thrombosis who received either tinzaparin (175 IU/kg) once daily or warfarin for 6 months, in an open-label, randomized, multi-centre trial with blinded adjudication of outcomes. Associations between baseline RI (glomerular filtration rate [GFR] <60 mL/min/1.73m. Baseline-centralized GFR data were available for 864 patients (96% of study population). RI was found in 131 patients (15%;. RI in patients with cancer-associated thrombosis on anticoagulation was associated with a statistically significant increase in recurrent VTE and major bleeding, but no significant increase in CRB or mortality. No differences were observed between long-term tinzaparin therapy and warfarin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Female; Fibrinolytic Agents; Glomerular Filtration Rate; Hemorrhage; Humans; Incidence; Kidney; Kidney Diseases; Male; Middle Aged; Neoplasms; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Time Factors; Tinzaparin; Treatment Outcome; Venous Thromboembolism; Warfarin; Young Adult

Belinostat is a potent small molecule inhibitor that exerts its antitumor effect through inhibition of histone deacetylase. The purpose of this study was to evaluate the pharmacokinetics and pharmacodynamics of warfarin (as a reference drug metabolized by CYP2C9) in the presence and absence of belinostat.. We conducted a phase I, single-center, open-label, drug-drug interaction study between belinostat and warfarin. In part I, patients were given warfarin 5 mg orally (day-14 and 3) and belinostat 1000 mg/m(2) (days 1 through 5). Patients receiving benefit continued belinostat on days 1 through 5 every 21 days until disease progression, unacceptable toxicity, or per patient preference.. A total of 18 patients were treated. With belinostat, the least-squared means for maximum concentration (C max), area under the curve0-∞, and area under the curve0-t of R-warfarin were slightly increased. However, for the more potent S-warfarin isomer, the same parameters were primarily contained within the pre-specified equivalence limits of 0.80 and 1.25, indicating there was no statistically significant interaction between S-warfarin and belinostat. The most common adverse events were nausea, vomiting, and fatigue. Three grade 3 adverse events (diarrhea 5.6 %, nausea 5.6 %, and vomiting 5.6 %) were thought to be treatment related. Progression-free survival ranged from 0.2 to 13.8 months in all patients.. Belinostat did not significantly affect the pharmacokinetics and pharmacodynamics of warfarin, indicating no clinically relevant effect on the enzymatic activity of CYP2C9.

Topics: Adult; Aged; Anticoagulants; Area Under Curve; Cytochrome P-450 CYP2C9; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Interactions; Fatigue; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Middle Aged; Neoplasms; Sulfonamides; Treatment Outcome; Vomiting; Warfarin

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

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

In cancer patients, the chest computer tomography (CT) can be used to identify asymptomatic pulmonary embolism (APE). In most cases, these patients are treated with anticoagulant drugs for at least 3 months. The American College of Physicians recommend treatment of these patients as patients with symptomatic pulmonary embolism. In this study, we evaluated and compared the efficacy and safety of fondaparinux vs warfarin in the prevention of unsuspected pulmonary embolism in patients with active cancer.. A prospective and parallel group study was performed on 64 cancer patients (29 males and 35 females) with APE. A multidetector CT angiography with high spatial and temporal resolution and quality of arterial opacification was used to make the diagnosis. Lung scintigraphy was reserved to selected patients only. Patients were randomized to either the warfarin (Group A) or the fondaparinux (Group B) for 90 days. The first end point of efficacy was the persistence, reduction, or disappearance of thrombosis after 90 days. The second end point was the reappearance of thrombosis after 1 year. The first end point of safety was the development of major bleeding.. We enrolled 32 patients into each treatment group. We reached the first end point of efficacy and safety in Group B which showed that fondaparinux was able to induce the disappearance of thrombotic pulmonary with a lower incidence of major bleeding events compared with warfarin. No difference in the secondary end point was recorded.. We suggest that the treatment of cancer patients with APE can be oriented with the administration of a standard dose of fondaparinux until the next CT lung control (3 months). However, the lack of a randomized clinical trial, including a larger patient cohort, does not allow formulation of final recommendations in these patients. A broader study would be desirable, involving a larger number of patients and a longer follow-up period.

Topics: Anticoagulants; Antineoplastic Agents; Female; Fondaparinux; Humans; Male; Neoplasms; Polysaccharides; Pulmonary Embolism; Warfarin

Venous thromboembolism (VTE) is a common complication in patients with cancer. Previous randomized studies have demonstrated that the rates of recurrent VTE are lower in patients treated with low-molecular-weight heparin compared to warfarin. We performed a retrospective analysis of 236 patients with cancer managed by a dedicated oncology anticoagulation management service to compare "real-world" rates of recurrent VTE and bleeding in patients treated with warfarin versus parenteral anticoagulants. Initial anticoagulant regimen included a parenteral agent with transition to warfarin in 132 (55.9%) patients, enoxaparin in 53 (22.5%), dalteparin in 37 (15.7%), and fondaparinux in 14 (5.9%). Taking into account the competing risk of death, cumulative incidence of VTE recurrence at 6 months was 4.0% with warfarin, 10.3% with enoxaparin, 3.0% with dalteparin, and 7.7% with fondaparinux (P = .004). Bleeding complications occurred in 10.6% of patients on warfarin, 17.0% on enoxaparin, 27.0% on dalteparin, and 14.3% on fondaparinux (P = .089). In a dedicated anticoagulation clinic, specific for patients with cancer, warfarin may be an acceptable treatment for first thrombotic events in patients with cancer.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Recurrence; Venous Thromboembolism; Warfarin

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

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

Low-molecular-weight heparin is recommended over warfarin for the treatment of acute venous thromboembolism (VTE) in patients with active cancer largely based on results of a single, large trial.. To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute, symptomatic VTE in patients with active cancer.. A randomized, open-label study with blinded central adjudication of study outcomes enrolled patients in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013. Adult patients with active cancer (defined as histologic diagnosis of cancer and receiving anticancer therapy or diagnosed with, or received such therapy, within the previous 6 months) and objectively documented proximal deep vein thrombosis (DVT) or pulmonary embolism, with a life expectancy greater than 6 months and without contraindications for anticoagulation, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data.. Tinzaparin (175 IU/kg) once daily for 6 months vs conventional therapy with tinzaparin (175 IU/kg) once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio within the therapeutic range (2.0-3.0) for 6 months.. Primary efficacy outcome was a composite of centrally adjudicated recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and overall mortality.. Nine hundred patients were randomized and included in intention-to-treat efficacy and safety analyses. Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89 [95% CI, 0.40-1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin; HR, 1.08 [95% CI, 0.85-1.36]; P = .54). A significant reduction in clinically relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004).. Among patients with active cancer and acute symptomatic VTE, the use of full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did not significantly reduce the composite measure of recurrent VTE and was not associated with reductions in overall mortality or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding. Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE.. clinicaltrials.gov Identifier: NCT01130025.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Recurrence; Survival Analysis; Tinzaparin; Venous Thromboembolism; Venous Thrombosis; Warfarin

The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute venous thromboembolism (VTE).. To perform a subgroup analysis to compare the efficacy and safety of apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY.. Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively.. Of the 5395 patients randomized, 169 (3.1%) had active cancer at baseline, and 365 (6.8%) had a history of cancer without active cancer at baseline. Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk [RR] 0.56, 95% confidence interval [CI] 0.13-2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively (RR 0.45, 95% CI 0.08-2.46). Among patients with a history of cancer, recurrent VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (RR 0.17, 95% CI 0.04-0.78); major bleeding occurred in 0.5% and 2.8% of treated patients, respectively (RR 0.20, 95% CI 0.02-1.65).. The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with low molecular weight heparin in these patients.

Topics: Aged; Anticoagulants; Chi-Square Distribution; Double-Blind Method; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Neoplasms; Odds Ratio; Pyrazoles; Pyridones; Recurrence; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment.. We performed a phase III prospective, open-label randomized trial. After the insertion of a central venous access device, consecutive patients with planned chemotherapy for cancer were randomized to no anticoagulant prophylaxis, low molecular weight heparin [low molecular weight heparin (LMWH); with isocoagulation doses], or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90, respectively, or sooner in case of clinical presumption of thrombosis.. A total of 420 patients were randomized, and 407 were evaluable. Forty-two catheter-related deep vein thrombosis (DVT) occurred (10.3 %), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Nine additional non-related catheter deep vein thrombosis (CDVT) occurred. Anticoagulation significantly reduced the incidence of catheter-related DVT (p = 0.035) and catheter non-related DVT (p = 0.007), with no difference between warfarin and LMWH. Safety was good (3.4 % of attributable events) but compliance with randomized prophylaxis was lower than expected.. Prophylaxis showed a benefit regarding catheter-related and non-catheter-related DVT with no increase in serious side effects.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antineoplastic Agents; Central Venous Catheters; Female; France; Heparin, Low-Molecular-Weight; Humans; Incidence; Intention to Treat Analysis; Lost to Follow-Up; Male; Medication Adherence; Middle Aged; Neoplasms; Severity of Illness Index; Upper Extremity Deep Vein Thrombosis; Venous Thrombosis; Warfarin; Young Adult

Low-molecular-weight heparin (LMWH) is recommended and commonly used for extended treatment of cancer-associated thrombosis (CAT), but its superiority over warfarin has been demonstrated in only one randomised study. We report here the rationale, design and a priori analysis plans of Comparison of Acute Treatments in Cancer Haemostasis (CATCH; NCT01130025), a multinational, Phase III, open-label, randomised controlled trial comparing tinzaparin with warfarin for extended treatment of CAT.. The primary objective is to assess the efficacy of tinzaparin in preventing recurrent venous thromboembolism (VTE) in patients with active cancer and acute, symptomatic proximal deep vein thrombosis and/or pulmonary embolism. The secondary objectives are to determine: safety of tinzaparin given over 6 months; clinical and laboratory markers for recurrent VTE and/or major bleeding; 6-month overall mortality; incidence and severity of post-thrombotic syndrome; patient-reported quality of life; and healthcare resource utilisation. Nine hundred patients are randomised to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5-10 days and dose-adjusted warfarin (target INR 2.0-3.0) for 6 months. The primary composite outcome is time to recurrent VTE, including incidental VTE and fatal pulmonary embolism. All patients are followed up to 6 months or death, whichever comes sooner. Blinded adjudication will be performed for all reported VTE, bleeding events and causes of death. Efficacy will be analysed using centrally adjudicated results of all patients according to intention-to-treat analysis. An independent Data Safety Monitoring Board is reviewing data at regular intervals and an interim analysis is planned after 450 patients have completed the study.. The results will add significantly to the knowledge of the efficacy, safety and cost effectiveness of tinzaparin in the prevention of recurrent VTE in patients with cancer and thrombosis. Prospective data will emerge on the clinical significance of incidental VTE and risk stratification in patients with CAT. Results on post-thrombotic syndrome, quality of life and healthcare resource utilisation will inform decision makers on how to secure better patient care. If tinzaparin is shown to be more effective than warfarin, CATCH will provide valuable confirmatory data to support the use of the LMWH tinzaparin for extended treatment of CAT.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Follow-Up Studies; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Quality of Life; Tinzaparin; Venous Thromboembolism; Warfarin; Young Adult

No data are available regarding the management of cancer patients requiring interruption of long-term vitamin-K antagonist (VKA) therapy. For this purpose, we tested the efficacy and safety of fixed doses of low-molecular weight heparin (LMWH) in substitution of VKA because of invasive procedures or chemotherapy-induced thrombocytopenia. In cancer patients on VKA, therapy was discontinued 5 ± 1 days before surgery or chemotherapy. Heparin was given at prophylactic dosage in patients at low risk and at fixed subtherapeutic doses (3,800 or 4,000 UI anti-FXa, b.i.d.) in those at high-risk for thrombosis. LMWH was reinitiated 12 hr after surgery and VKA the day after. In patients receiving chemotherapy, LMWH was reinitiated 12/24 hr after obtaining a stable platelet count ≥ 30,000 mmc(3) and VKA after a stable platelet count ≥ 50,000 mmc(3) . Thromboembolism and major bleeding events were recorded from the time of VKA suspension to 30 ± 2 days postprocedure or until the next chemotherapy. Overall, 156 patients (56.4% at low risk and 43.5% at high risk for thrombosis) were enrolled; 34.6% underwent major surgery, 40.4% nonmajor surgery, and 25% chemotherapy. Thrombotic events occurred in five patients [3.2%, 95% confidence interval (CI): 1.41-7.27], four belonging to the high-risk and one to the low-risk group. Major bleeding occurred in five patients (3.2%, 95 CI: 1.41-7.27), all belonging to the high-risk group (three during major surgery and two during chemotherapy). In conclusion, LMWH given at fixed subtherapeutic is a feasible and relatively safe approach for bridging therapy in cancer patients on long-term VKA.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antineoplastic Agents; Atrial Fibrillation; Female; Heart Valve Prosthesis; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Middle Aged; Neoplasms; Postoperative Complications; Prospective Studies; Risk; Thrombocytopenia; Thromboembolism; Thrombophilia; Warfarin

Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.

Topics: Adult; Aged; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Interactions; Epothilones; Female; Humans; Male; Middle Aged; Neoplasms; Warfarin; Young Adult

The role and dose of anticoagulants in thromboprophylaxis for patients with cancer receiving chemotherapy through central venous catheters (CVCs) is controversial. We therefore assessed whether warfarin reduces catheter-related thrombosis compared with no warfarin and whether the dose of warfarin determines the thromboprophylactic effect.. In 68 clinical centres in the UK, we randomly assigned 1590 patients aged at least 16 years with cancer who were receiving chemotherapy through CVCs to no warfarin, fixed-dose warfarin 1 mg per day, or dose-adjusted warfarin per day to maintain an international normalised ratio between 1.5 and 2.0. Clinicians who were certain of the benefit of warfarin randomly assigned patients to fixed-dose or dose-adjusted warfarin groups. The primary outcome was the rate of radiologically proven, symptomatic catheter-related thrombosis. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN 50312145.. Compared with no warfarin (n=404), warfarin (n=408; 324 [79%] on fixed-dose and 84 [21%] on dose-adjusted) did not reduce the rate of catheter-related thromboses (24 [6%] vs 24 [6%]; relative risk 0.99, 95% CI 0.57-1.72, p=0.98). However, compared with fixed-dose warfarin (n=471), dose-adjusted warfarin (n=473) was superior in the prevention of catheter-related thromboses (13 [3%] vs 34 [7%]; 0.38, 0.20-0.71, p=0.002). Major bleeding events were rare; an excess was noted with warfarin compared with no warfarin (7 vs 1, p=0.07) and with dose-adjusted warfarin compared with fixed-dose warfarin (16 vs 7, p=0.09). A combined endpoint of thromboses and major bleeding showed no difference between comparisons. We did not note a survival benefit in either comparison.. The findings show that prophylactic warfarin compared with no warfarin is not associated with a reduction in symptomatic catheter-related or other thromboses in patients with cancer and therefore we should consider newer treatments.. Medical Research Council and Cancer Research UK.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Meta-Analysis as Topic; Middle Aged; Neoplasms; Venous Thrombosis; Warfarin

Clinical management of warfarin therapy is complex, and dosing algorithms do not include genetic factors or interactions with other drugs for warfarin dose determinations. We evaluated the interaction of warfarin and CYP2C9 polymorphisms and concomitant corticosteroids in 29 children with cancer. Children with heterozygous polymorphisms of CYP2C9 achieved target INR sooner and more frequently had INR above the target level, compared to children without mutations. Children on concomitant steroids had significantly lower warfarin requirements. Thus, awareness of CYP2C9 genotype and steroid-induced responsiveness to warfarin may be important when administrating oral anticoagulation in children.

Topics: Adolescent; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Aryl Hydrocarbon Hydroxylases; Catheterization, Central Venous; Child; Child, Preschool; Cytochrome P-450 CYP2C9; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Female; Genotype; Humans; Infant; International Normalized Ratio; Male; Neoplasms; Polymorphism, Genetic; Prednisone; Thrombophilia; Thrombosis; Warfarin

Recent guidelines do not recommend antithrombotic prophylaxis (AP) to prevent catheter-related thrombosis in cancer patients with a central line.. This study assessed the management of central lines in cancer patients, current attitude towards AP, catheter-related and systemic venous thromboses, and survival.. Of 1410 patients enrolled, 1390 were seen at least once in the 6-month median follow-up. Continuous AP, mainly low-dose warfarin, was given to 451 (32.4%); they were older, with a more frequent history of venous thromboembolism (VTE), and more advanced cancer. There was no difference in catheter-related thrombosis in patients given AP or not (2.8% and 2.2%, odds ratio 1.29, 95% confidence interval 0.64-2.6). The median time to first catheter-related complication was 120 days. Systemic VTE including deep and superficial thromboses and pulmonary embolism, were less frequent with AP (4% versus 8.2%, P = 0.005). Mortality was also lower (25% versus 44%, P = 0.0001). Multiple logistic regression analysis found only advanced cancer and no AP significantly associated with mortality. No major bleeding was recorded with AP.. Current AP schedules do not appear to prevent catheter-related thrombosis. Systemic VTE and mortality, however, appeared lower after prophylaxis.

Topics: Catheterization, Central Venous; Catheters, Indwelling; Female; Fibrinolytic Agents; Humans; Italy; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Neoplasms; Odds Ratio; Prospective Studies; Pulmonary Embolism; Risk Assessment; Time Factors; Treatment Outcome; Venous Thrombosis; Warfarin

Central venous lines (CVLs) are essential in the care of children with malignancies, but are associated with venous thromboembolism (VTE) and infections. Effective and safe prophylactic approaches are deficient.. To perform a study of adjusted low-dose warfarin for the prevention of CVL-related VTE in children with malignancies.. Children with newly diagnosed cancer, a CVL in a jugular vein and an expected treatment period of over 6 mo were eligible for the study. Participants were randomized to low-dose warfarin, with intended international normalized ratio (INR) 1.3-1.9, or to a control group. Primary outcome was VTE in a jugular vein diagnosed by ultrasonography at 1, 3 and 6 mo after inclusion. Secondary outcome was CVL-related infections, mainly measured as days on antibiotics or positive blood cultures.. The study enrolled 73 children, and 62 completed it fully. Asymptomatic CVL-related VTE was frequent (42%), but often transient. Regardless of severity, timing and duration, CVL-related VTE was equally frequent among children on warfarin as compared to controls (p=0.44). Low-dose warfarin (p=0.59) or jugular CVL-related VTE (p=0.91) did not have any impact on days on antibiotics, but we observed a tendency towards an association between CVL-related VTE and positive blood cultures (p=0.15).. Our randomized study of low-dose oral anticoagulation for the prevention of CVL-related asymptomatic VTE in children with cancer did not show any benefit of warfarin adjusted to maintain INR between 1.3 and 1.9.

Topics: Anticoagulants; Catheterization, Central Venous; Catheters, Indwelling; Child; Child, Preschool; Female; Humans; Jugular Veins; Male; Neoplasms; Venous Thrombosis; Warfarin

This study evaluated enoxaparin alone versus initial enoxaparin followed by warfarin in secondary prevention of venous thromboembolic events in adults with active malignancy. Cancer patients (n = 122) with acute symptomatic venous thromboembolic events were randomly allocated to receive subcutaneous enoxaparin 1.0 mg/kg every 12 hours for 5 days, followed by 1.0 mg/kg daily (group 1a) or 1.5 mg/kg daily (group 1b) for 175 days, or subcutaneous enoxaparin 1.0 mg/kg every 12 hours for at least 5 days and until a stable international normalized ratio of 2 to 3 was achieved on oral warfarin begun on day 2 and continued to day 180 (group 2). There were no significant differences in major and minor bleeding rates between treatment groups. No bleeding events were intracranial or fatal. Enoxaparin treatment was feasible, generally well tolerated, and effective for a 180-day period in the secondary prevention of venous thromboembolic events in patients with active malignancy.

Topics: Adult; Aged; Anticoagulants; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enoxaparin; Humans; Middle Aged; Neoplasms; Safety; Survival Analysis; Thromboembolism; Warfarin

In this multicenter, randomized, placebo-controlled clinical trial, we studied whether warfarin 1 mg daily reduces the incidence of symptomatic central venous catheter (CVC) -associated thrombosis in patients with cancer.. Two hundred fifty-five patients with cancer who required a CVC for at least 7 days were randomly assigned to receive warfarin 1 mg or placebo.. There were 11 (4.3%) symptomatic CVC-associated thromboses among 255 patients, with no difference in the incidence of symptomatic CVC-associated thrombosis between patients taking warfarin 1 mg daily (six of 130 patients; 4.6%) and patients taking placebo (five of 125 patients; 4.0%; hazard ratio, 1.20; 95% CI, 0.37 to 3.94). Warfarin had no effect on CVC life span (84 days v 63 days in control and warfarin groups, respectively; 95% confidence limit, -16 to 55 days; P = .09), and it did not affect the number of premature CVC removals (23.2% v 25.4% in control and warfarin groups, respectively; 95% confidence limit of difference -8.34 to 12.71; P = .68) or the frequency of major bleeding episodes (2% v 0% in control and warfarin groups, respectively; P = .5, Fisher's exact test).. Symptomatic CVC-associated thrombosis in patients with cancer, although significant, is less common than previously reported. In this study, the administration of warfarin 1 mg daily did not reduce the incidence of symptomatic CVC-associated thrombosis in patients with cancer. However, the low rate of symptomatic CVC-associated thrombosis means that a much larger trial is required to address this issue definitively.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Catheterization, Central Venous; Catheters, Indwelling; Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasms; Placebos; Radiography; Treatment Outcome; Venous Thrombosis; Warfarin

Outpatient treatment of deep vein thrombosis (DVT) has become a common practice in uncomplicated patients. Few data are still present in patients with comorbidity (such as cancer) or concomitant symptomatic pulmonary embolism. Cancer patients with DVT are often excluded from home treatment because they have a higher risk of both bleeding and recurrent DVT. We tested the feasibility and safety of the Home Treatment (HT) program for acute DVT a PE in cancer patients. Patients were treated as outpatients unless they required admission for other medical problems, were actively bleeding or had pain that requires parenteral narcotics. Outpatient treatment was with low molecular weight heparin (LMWH) followed by warfarin or with LMWH alone. An educational program for patients was implemented. Two-hundred and seven patients with cancer were evaluated, 36 (17.4%) of whom had metastatic disease. Treatment with LMWH and warfarin was prescribed to 106 (51.2%) and LMWH alone to 102 (48.8%). One hundred and twenty-seven patients (61.3%) were entirely treated at home. There were no differences between patients treated at home and hospitalized patients with regard to gender, mean age, site of cancer, presence of metastases, and treatment. After 6 months, recurrent thrombo-embolism occurred in 8.7% of patients treated at home and in 5.6% of hospitalized patients (P=0.58); major bleeding in 2.0% and 1.5%, respectively (P=0.06). Twenty-seven patients (33%) in the hospitalized, and 33 (26%) in the home-treatment group, died after a follow-up of 6 months. These results indicate that, regarding cancer patients with acute DVT and/or PE, there is no difference between hospitalised and home-treated patients in terms of major outcomes.

Topics: Adult; Aged; Aged, 80 and over; Feasibility Studies; Female; Follow-Up Studies; Heparin, Low-Molecular-Weight; Home Care Services; Home Nursing; Hospitalization; Humans; Male; Middle Aged; Neoplasms; Patient Compliance; Patient Education as Topic; Pulmonary Embolism; Recurrence; Self Administration; Venous Thrombosis; Warfarin

Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.

Topics: Adult; Aged; Anticoagulants; Dalteparin; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Thromboembolism; Warfarin

Topics: Anticoagulants; Catheterization, Central Venous; Humans; Nadroparin; Neoplasms; Pilot Projects; Prospective Studies; Venous Thrombosis; Warfarin

Upper extremity thrombosis is a major complication of central venous catheters implanted for chemotherapy in cancer patients. Vitamin K antagonists and low-molecular-weight heparins have been recommended in this setting, but their relative benefit-to-risk ratios have never been compared.. A prospective, randomized, open, parallel-group, multicenter trial was performed comparing the antithrombotic efficacy and safety of warfarin and the low-molecular-weight heparin, nadroparin, in cancer patients who had undergone central venous catheter implantation. Warfarin was given orally at a fixed daily dose of 1 mg and nadroparin was injected subcutaneously at a fixed daily dose of 2,850 IU for 90 days, or until venographically-confirmed thrombosis occurred. The primary efficacy outcome was the occurrence of upper extremity thrombosis confirmed by venography performed 90 days after insertion of the catheter, or earlier if symptoms of thrombosis had appeared. Safety end-points were bleeding and thrombocytopenia.. Fifty-nine patients were included in the study. A total of 21 and 24 patients in the nadroparin and warfarin groups, respectively, were evaluable for primary efficacy. Six out of the 21 patients in the nadroparin group (28.6%) and 4 out of the 24 patients in the warfarin group (16.7%) had venographically-documented upper extremity thrombosis at day 90 (p=0.48). Safety was satisfactory and similar with both treatments.. Warfarin at a fixed, very low dose and nadroparin at a fixed, prophylactic dose had comparable benefit-to-risk ratios in the prevention of thrombosis associated with central venous catheters in cancer patients.

Topics: Aged; Anticoagulants; Catheterization, Central Venous; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Nadroparin; Neoplasms; Pilot Projects; Prospective Studies; Therapeutic Equivalency; Thrombosis; Treatment Outcome; Upper Extremity; Warfarin

Warfarin induction is accomplished by titrating dosage to coagulation test results. Algorithms can guide this process but not identify the starting dose. We hypothesized that an initial warfarin dose approximating the maintenance value would safely enhance rapidity of induction. In a randomized trial we compared a fixed-dose to a maintenance-dose strategy for beginning warfarin therapy. To predict the maintenance dose among patients with differing warfarin requirements we performed regression analysis on clinical factors derived from chart review. Four community hospitals supplied records for retrospective analysis. The prospective trial was conducted in one, a 350-bed teaching institution. A sample of inpatients anticoagulated during 1998 formed the development set for retrospective study; a 1999 sample formed the validation set. A one year trial recruited consecutive eligible inpatients initiated on warfarin. We randomly assigned patients to a first warfarin dose calculated using our regression formula or fixed at 5 mg. All patients' subsequent doses were determined (as a percentage of initial) from coagulation testing. We compared days to anticoagulation, hospitalized hours, complications, and activity of factor II and protein C in a patient sample at intervals after induction. Weight, age, serum albumin, and presence of malignancy explained 25-30% of variance in maintenance dose. Ninety patients (44 calculated-dose and 46 standard-dose) evaluated in the clinical trial. Mean time to anticoagulation (among patients achieving anticoagulation) was 4.2 and 5.0 days, respectively (p = 0.007). We observed no significant differences in other endpoints. Individualized initial dosing may safely hasten warfarin induction.

Topics: Adult; Aged; Algorithms; Anticoagulants; Comorbidity; Dose-Response Relationship, Drug; Female; Hemorrhage; Humans; International Normalized Ratio; Length of Stay; Male; Middle Aged; Neoplasms; Prospective Studies; Protein C; Prothrombin; Retrospective Studies; Thrombosis; Warfarin

Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer.. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months).. During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group.. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.

Topics: Acenocoumarol; Administration, Oral; Anticoagulants; Dalteparin; Drug Therapy, Combination; Female; Hemorrhage; Humans; Injections, Subcutaneous; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Secondary Prevention; Survival Analysis; Thromboembolism; Venous Thrombosis; Warfarin

The purpose of this study was to establish the safety and efficacy of sodium warfarin in the secondary prophylaxis of venous thrombosis in patients with cancer. This was an inception cohort study of patients enrolled in an anticoagulation clinic between July 1991 and October 1996. The rates of bleeding and recurrent thrombosis were evaluated in all the patients, and the results in patients with cancer (n = 104) were compared with those without cancer (n = 208). The rate of major hemorrhage was 0.4% and 0.3% per treatment month in the patients with cancer and those without cancer, respectively. The rates of recurrent thrombosis were 1.2% and 0.2% per treatment month in the patients with cancer compared with those without cancer, respectively. We conclude that warfarin is safe when used for the secondary prophylaxis of patients with cancer who have had a venous or arterial thrombosis, and the risk of major hemorrhage is not significantly different when compared with the risk in patients without cancer. The rate of recurrent thrombosis is approximately sixfold higher in patients with cancer being treated with warfarin for secondary prophylaxis of thrombosis compared with patients without cancer. Nonetheless, the rate of recurrent thrombosis is not overly excessive, and warfarin can be viewed as a relatively effective form of therapy for these patients.

Topics: Anticoagulants; Female; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Venous Thrombosis; Warfarin

The length of time after an episode of venous thromboembolism during which the risk of newly diagnosed cancer is increased is not known, and whether vitamin K antagonists have an antineoplastic effect is controversial.. In a prospective, randomized study of the duration of oral anticoagulation (six weeks or six months) after a first episode of venous thromboembolism, patients were questioned annually about any newly diagnosed cancer. After a mean follow-up of 8.1 years, we used the Swedish Cancer Registry to identify all diagnoses of cancer and causes of death in the study population. The observed numbers of cases of cancer were compared with expected numbers based on national incidence rates, and the standardized incidence ratios were calculated.. A first cancer was diagnosed in 111 of 854 patients (13.0 percent) during follow-up. The standardized incidence ratio for newly diagnosed cancer was 3.4 (95 percent confidence interval, 2.2 to 4.6) during the first year after the thromboembolic event and remained between 1.3 and 2.2 for the following five years. Cancer was diagnosed in 66 of 419 patients (15.8 percent) who were treated for six weeks with oral anticoagulants, as compared with 45 of 435 patients (10.3 percent) who were treated for six months (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The difference was mainly due to the occurrence of new urogenital cancers, of which there were 28 cases in the six-week group (6.7 percent) and 12 cases in the six-month group (2.8 percent) (odds ratio, 2.5; 95 percent confidence interval, 1.3 to 5.0). The difference in the incidence of cancer between the treatment groups became evident only after two years of follow-up, and it remained significant after adjustment for sex, age, and whether the thromboembolism was idiopathic or nonidiopathic. Older age at the time of the venous thrombosis and an idiopathic thromboembolism were also independent risk factors for a diagnosis of cancer. No difference in the incidence of cancer-related deaths was detected.. The risk of newly diagnosed cancer after a first episode of venous thromboembolism is elevated during at least the following two years. Subsequently, the risk seems to be lower among patients treated with oral anticoagulants for six months than among those treated for six weeks.

Topics: Administration, Oral; Age Factors; Anticoagulants; Drug Administration Schedule; Humans; Incidence; Neoplasms; Prospective Studies; Pulmonary Embolism; Retrospective Studies; Risk Factors; Thromboembolism; Time Factors; Urogenital Neoplasms; Venous Thrombosis; Vitamin K; Warfarin

To compare the complication rate (bleeding and thrombosis) of oral anticoagulation in a cohort of patients with cancer to a cohort without cancer.. Prospective cohort study.. Outpatient anticoagulation clinic in a community hospital.. Consecutive patients enrolled in an anticoagulation clinic: 44 with cancer, 64 without cancer.. Patients received prophylactic doses of Warfarin (target INR 2-3 in the majority of instances) and complication rates were assessed.. Major bleeding (strictly defined), minor bleeding, recurrent thrombosis, proportion of time with therapeutic INR, frequency of clinic visits.. The rates of major bleeding, minor bleeding, and recurrent thrombosis were not statistically significantly different in the two groups of patients. Therapeutic INR's were more difficult to sustain in the cancer patients as compared to the non-cancer patients (43.3% vs 56.9%, p < 0.0001). There was a non significant trend towards more frequent monitoring for the cancer patients compared with the non-cancer patients (4.6 vs 3.5 visits per treatment month, p = 0.14).. Oral anticoagulation is safe and effective in the patient with cancer. It is more difficult to sustain a therapeutic INR in the cancer patients and they may need more frequent monitoring to achieve a low complication rate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Thrombosis; Warfarin

Plasma warfarin and its R,S enantiomer concentrations, one-stage prothrombin times, and mean daily warfarin doses were analyzed in 196 patients given warfarin. These individuals were part of a controlled clinical trial that examined the effect of warfarin as an adjuvant to "standard" treatment in a variety of malignancies. Neither the plasma warfarin concentration nor the daily warfarin dose required to produce a given degree of prothrombin-time prolongation was influenced by age or body weight in these subjects. When the data were analyzed by performance status, we noted several variations of interest. Individuals with different tumor types demonstrated disparities in warfarin disposition. Patients with colorectal cancer, for example, required lower mean daily warfarin doses to achieve a given degree of one-stage prothrombin time prolongation. Analysis of warfarin enantiomers (R,S) in a selected group of patients demonstrated a lower-than-normal ratio (2:1) for the colorectal cancer group (1.42:1) because of an apparent decrease in the plasma R component. In contrast, patients with head and neck cancer demonstrated a ratio of 2.85:1, and the R component was elevated. Warfarin disposition and the effect of warfarin on vitamin K-dependent clotting factor production were altered in the patients with cancer reported in this study. The mechanisms for these alterations are complex and not completely understood.

Topics: Aging; Body Weight; Colorectal Neoplasms; Head and Neck Neoplasms; Humans; Neoplasms; Prospective Studies; Prothrombin Time; Psychomotor Performance; Stereoisomerism; United States; United States Department of Veterans Affairs; Warfarin

Bleeding complications from warfarin anticoagulants were analyzed in 431 patients with carcinoma of the lung, colon, prostate and head and neck who were admitted to a randomized, controlled therapeutic trial of this agent. A total of 215 patients were randomized to the warfarin-treated group and 216 to the control groups. The mean prothrombin time was significantly prolonged (p = 0.0001) for warfarin-treated patients. The duration of warfarin administration was 64.9% of the total followup period providing 101 patient-years of experience with warfarin in cancer. Both the overall incidence of bleeding episodes (58% of warfarin-treated versus 30% of control) and the incidence of major bleeding episodes (42% versus 14%, respectively) were significantly increased in the warfarin-treated group (p = less than 0.001). The incidence of major bleeding was 1.86 per patient-year on warfarin. The most common sites of bleeding (in descending order) were the gastointestinal tract, the urinary tract, the nasal passages and skin. Hemorrhage occurred in association with the terminal event in 10 warfarin-treated and 12 control patients. Warfarin anticoagulation may have contributed to terminal bleeding in 3 (1.4%) patients. There was no difference in mean hemoglobin or hematocrit values for patients with versus patients without bleeding episodes.

Topics: Clinical Trials as Topic; Double-Blind Method; Hemorrhage; Humans; Middle Aged; Neoplasms; Prothrombin Time; Random Allocation; Warfarin

As more potent antibacterial drugs are used to combat infections and as more patients with impaired defenses against infection are treated, other organisms, like fungi, have become important pathogens. Fungi of all types may appear in this setting, but Candida species are the most common, usually beginning as an infection in the oropharynx. Although oropharyngeal candidiasis usually remains localized, it may spread elsewhere, leading to a fatal outcome. Controversy still exists regarding the best drug to prevent or treat oropharyngeal candidiasis, but clotrimazole given as a troche may be the best choice at the moment owing to its high clinical success rate, safety, cost effectiveness, and high patient acceptability. There remains a need for more randomized and controlled studies comparing the efficacy of nystatin, ketoconazole, and clotrimazole in high-risk patients in whom invasive candidiasis remains a frequent problem.

Topics: Adolescent; Adult; Aged; Aspergillosis; Candidiasis; Child; Child, Preschool; Clinical Trials as Topic; Clotrimazole; Drug Synergism; Half-Life; Humans; Infant; Ketoconazole; Middle Aged; Neoplasms; Pharyngeal Diseases; Placebos; Suppositories; Tablets; Warfarin

Plasminogen activator activity (PAA) has been detected in various tumor cells or in their excretion products. In some cell systems PAA is a symptom of cell transformation, but its amount is questionably correlated with the invasiveness of the tumor cells. Procoagulant and aggregation activities on platelets, have been demonstrated in various tumor cells. There are weakly correlated with the metastatic potential of these cells. In vivo, the treatment of animals by modifiers of the hemostasis, or of the fibrinolysis systems provides contradictory results. Some reduction of metastatic diffusion and increase of life span have been noted with Warfarin. Clinical trials are scarce and their methodology is debatable. When conclusive, a lengthening of the life span has been observed, but not a reduction of the metastatic spread as metastases were still present.

Topics: Animals; Antifibrinolytic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Factors; Blood Vessels; Cell Adhesion; Cell Aggregation; Cell Line; Clinical Trials as Topic; Endothelium; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Heparin; Humans; Indomethacin; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Plasminogen Activators; Warfarin

Anticoagulants have been demonstrated to reduce tumor growth in certain experimental animal systems. Inhibition of clot formation interferes with tumor growth and spread while enhancement of coagulation promotes tumor growth and spread. The fact that the coagulation mechanism is commonly activated in human malignancy together with preliminary reports of therapeutic efficacy of anticoagulants suggests that the coagulation mechanism may be of pathophysiologic significance also in the growth of human tumors. A VA Cooperative Study has been established to test the hypothesis that warfarin anticoagulation will modify the course of malignancy in man. The purpose of this paper is to present the rationale and experimental design for this study with emphasis on management of anticoagulant administration in cancer patients. This paper serves as the basis for forthcoming reports of toxicity and therapeutic efficacy of warfarin in human malignancy.

Topics: Animals; Blood Coagulation; Cell Adhesion; Clinical Trials as Topic; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Research Design; Warfarin

The value of the oral anticoagulant warfarin sodium and fibrinolytic agents is discussed in relation to cancer surgery. A controlled trial of 128 patients showed that in a variety of recurrent cases the addition of warfarin to chemotherapy doubled the 2-year survival rate. The best results were obtained in postmenopausal patients with breast cancer. Warfarin depresses cellular immune responses which might militate against its use for cases undergoing "curative" surgery. Instead, induction of fibrinolysis by streptokinase or Brinase is suggested, because it increases the activity of the cellular immune mechanism. The results to date of an ongoing controlled randomized trial of streptokinase with surgery of tumors of the large bowel are presented, showing that the trends are in favor of streptokinase therapy; however, insufficient time has elapsed to make it, as yet, statistically significant. The action of streptokinase-induced plasmin and Brinase on lymphocytes is described.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Agents; Aspergillus; Breast Neoplasms; Colonic Neoplasms; Drug Evaluation; Female; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity, Cellular; Lymphoma, Non-Hodgkin; Male; Neoplasms; Ovarian Neoplasms; Peptide Hydrolases; Rectal Neoplasms; Streptokinase; Warfarin

Topics: Animals; Anticoagulants; Blood Coagulation; Carcinoma 256, Walker; Cecal Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fibrinolysin; Fibrinolytic Agents; Heparin; Humans; Lung Neoplasms; Lymphoma; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Ovarian Neoplasms; Pelvic Neoplasms; Rabbits; Stomach Neoplasms; Swine; Thrombosis; Vena Cava, Superior; Warfarin

Topics: Administration, Oral; Anticoagulants; Antineoplastic Agents; Breast Neoplasms; Busulfan; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia, Myeloid; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Warfarin

In patients with renal cell carcinoma (RCC) on cabozantinib, venous thromboembolism (VTE) management remains challenging due to limited safety data regarding direct oral anticoagulants (DOACs) use in conjunction with cabozantinib. We investigated the safety of cabozantinib with different anticoagulants in patients with RCC.. In this retrospective multicenter study (9 sites), patients with advanced RCC were allocated into 4 groups: (1) cabozantinib without anticoagulation, cabozantinib with concomitant use of (2) DOACs, (3) low molecular weight heparin (LMWH), or (4) warfarin. The primary safety endpoint was the proportion of major bleeding events (defined per International Society on Thrombosis and Hemostasis criteria). The primary efficacy endpoint was the proportion of new/recurrent VTE while anticoagulated.. Between 2016 and 2020, 298 patients with RCC received cabozantinib (no anticoagulant = 178, LMWH = 41, DOAC = 64, and warfarin = 15). Most patients had clear cell histology (78.5%) and IMDC intermediate/poor disease (78.2%). Cabozantinib was first, second, or ≥ third line in 21.8%, 31.9%, 43.3% of patients, respectively. Overall, there was no difference in major bleeding events between the no anticoagulant, LMWH, and DOAC groups (P = .088). Rate of new/recurrent VTE was similar among anticoagulant groups. Patients with a VTE had a statistically significantly worse survival than without a VTE (HR 1.48 [CI 95% 1.05-2.08, P = .02]).. This real-world cohort provides first data on bleeding and thrombosis complications in patients with RCC treated with cabozantinib with or without concurrent anticoagulation. DOACs appear safe for VTE treatment for patients with RCC on cabozantinib, but optimized anticoagulation management, including individualized risk-benefit discussion, remains important in clinical practice.

Topics: Administration, Oral; Anticoagulants; Carcinoma, Renal Cell; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Kidney Neoplasms; Neoplasms; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a life-threatening complication occurring in cancer patients. Direct oral anticoagulants (DOACs) or warfarin are widely prescribed for treating cancer-associated VTE. However, data are sparse as to the effectiveness and bleeding complications associated with these medications in elderly patients. The purpose of this study was to compare effectiveness and safety profiles between DOACs and warfarin in elderly cancer patients undergoing chemotherapy.. Using the Diagnosis Procedure Combination inpatient database, we retrospectively identified cancer patients aged ≥75 years who developed VTE during chemotherapy (n = 4,278, January 2016 to March 2020). Eligible patients were divided into those receiving warfarin (n = 557) and DOACs (n = 3,721). We conducted a 1:4 propensity score matching analysis to adjust for measured confounders. The primary outcome was VTE recurrence requiring hospitalization. Secondary outcomes were major bleeding requiring hospitalization and inhospital death from all causes within 6 months.. The propensity-matched cohort included 557 patients in the warfarin group and 2,278 patients in the DOACs group. The proportion of VTE recurrence requiring hospitalization was lower in the DOACs group (5.3% vs. 7.5%; odds ratio [OR], 0.69; 95% confidence interval [CI], 0.48-0.98). The proportion of recurrent deep vein thrombosis was 6.3% and 4.4%, while that of recurrent pulmonary emboli was 1.3% and 1.3% in the warfarin and DOACs groups, respectively. No statistically significant differences were found in the proportion of major bleeding events requiring hospitalization (1.6% vs. 1.1%; OR, 1.47; 95% CI, 0.62-3.50) or all-cause inhospital mortality (11.1% vs. 9.9%; OR, 1.14; 95% CI, 0.84-1.56) between the DOACs and warfarin groups.. Our findings suggest that DOACs may be more effective than warfarin in terms of VTE recurrence requiring hospitalization and that these medications may be equivalent in terms of safety.

Topics: Aged; Anticoagulants; Hemorrhage; Humans; Inpatients; Neoplasms; Retrospective Studies; Venous Thromboembolism; Warfarin

Patients with cancer are at an increased risk of developing atrial fibrillation (AF) and often need to undergo procedures or surgery that requires periprocedural interruption of anticoagulation. Anticoagulated patients with cancer might be at increased risk of postprocedural thromboembolic and bleeding complications. Data on postprocedural outcomes among patients with concurrent active cancer and AF are sparse.. To assess the 30-day risk of postoperative thromboembolic and major bleeding complications after the periprocedural interruption of anticoagulation among patients with AF and active cancer.. We conducted a single-center retrospective cohort study in patients with active cancer and AF who required periprocedural interruption of anticoagulation for invasive procedures between August 2015 and May 2019. The primary endpoints were the 30-day postoperative risks of arterial thromboembolism (ATE) and major bleeding. The secondary endpoints included the 30-day risks of venous thromboembolism, clinically relevant nonmajor bleeding, and overall mortality.. Two hundred sixty-four patients undergoing 302 periprocedural interruptions were included in our study. The 30-day risk of ATE was 0.7% (95% CI, 0.1%-2.4%), and the 30-day risk of major bleeding was 1.7% (95% CI, 0.6%-3.9%). The 30-day risks of venous thromboembolism and clinically relevant nonmajor bleeding were 0.7% (95% CI, 0.1%-2.4%) and 4.3% (95% CI, 2.5%-7.3%), respectively. The overall risk of mortality at 30 days was 1.3% (95% CI, 0.4%-3.4%). There was one fatal postoperative stroke.. Patients with AF and active cancer in this study were at relatively low risk for ATE and postoperative bleeding complications when patients were managed according to commonly applied perioperative management recommendations.

Topics: Anticoagulants; Atrial Fibrillation; Humans; Neoplasms; Postoperative Complications; Postoperative Hemorrhage; Retrospective Studies; Risk Factors; Thrombosis; Treatment Outcome; Venous Thromboembolism; Warfarin

Patients with venous thromboembolism (VTE) are commonly classified by the presence or absence of provoking factors at the time of VTE to guide treatment decisions. This approach may not capture the heterogeneity of the disease and its prognosis.. To evaluate clinically important novel phenotypic clusters among patients with VTE without cancer and to explore their association with anticoagulant treatment and clinical outcomes.. Latent class analysis was performed with 18 baseline clinical variables in 3062 adult patients with VTE without active cancer participating in PREFER in VTE, a noninterventional disease registry. The derived latent classes were externally validated in a post hoc analysis of Hokusai-VTE (n = 6593), a randomized trial comparing edoxaban with warfarin. The associations between cluster membership and anticoagulant treatment, recurrent VTE, bleeding, and mortality after initial treatment were studied.. The following 5 clusters were identified: young men cluster (n = 1126, 37%), young women cluster (n = 215, 7%), older people cluster (n = 1106, 36%), comorbidity cluster (n = 447, 15%), and history of venous thromboembolism cluster (n = 168, 5%). Patient characteristics varied by age, sex, medical history, and treatment patterns. Consistent clusters were evident on external validation. In Cox proportional hazard models, recurrence risk was lower in the young women cluster (hazard ratio [HR], 0.27; 95% CI, 0.12-0.61) compared with the comorbidity cluster, after adjusting for extended anticoagulation. The risk of bleeding was lower in young men, young women, and older people clusters (HR, 0.50; 95% CI, 0.38-0.66; HR, 0.23; 95% CI, 0.11-0.46; and HR, 0.55; 95% CI 0.41-0.73, respectively).. The heterogeneity of VTE cases extends beyond the distinction between provoked and unprovoked VTE.

Topics: Anticoagulants; Female; Hemorrhage; Humans; Latent Class Analysis; Neoplasms; Recurrence; Venous Thromboembolism; Warfarin

Patients with brain cancer are at a high risk of developing venous thromboembolism (VTE) and are underrepresented in clinical trials. This study compared the risk of recurrent VTE (rVTE), major bleeding (MB), and clinically relevant non-major bleeding (CRNMB) among VTE cancer patients initiating apixaban, low molecular weight heparin (LMWH), or warfarin stratified by patients with brain vs other cancer types.. Active cancer patients initiating apixaban, LMWH, or warfarin within 30 days after VTE diagnosis were identified from 4 US commercial and the Medicare databases. Inverse probability of treatment weights (IPTW) was used to balance patient characteristics. Cox proportional hazards models were used to evaluate the interaction between brain cancer status and treatment on outcomes (rVTE, MB, and CRNMB), with a p-value <0.1 indicating a significant interaction.. Of 30,586 patients with active cancer (5 % had brain cancer), apixaban (vs. LMWH and warfarin) was associated with lower risk of rVTE, MB, and CRNMB. Generally, no significant interactions (P > 0.1) were found between brain cancer status and anticoagulant treatment across outcomes. The exception was MB for apixaban [vs LMWH (p-value for interaction = 0.091)] with a higher reduction among those with brain cancer (HR = 0.32) than those with (HR = 0.72) other cancer.. Among VTE patients with all types of cancer, apixaban (vs LMWH and warfarin) was associated with a lower risk of rVTE, MB, and CRNMB. In general, anticoagulant treatment effects were not significantly different between VTE patients with brain cancer and those with other cancer.

Topics: Aged; Anticoagulants; Brain Neoplasms; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Medicare; Neoplasms; United States; Venous Thromboembolism; Warfarin

To date, evidence on optimal anticoagulant options in patients with AF who concurrently have active cancer remains elusive. To describe anticoagulant patterns and clinical outcomes among patients with a concomitant diagnosis of AF and cancer. Data were obtained from the University of Utah and Huntsman Cancer Institute (HCI) Hospitals. Patients were included if they had diagnosis of AF and cancer. Outcome was type and pattern of anticoagulant. Clinical outcomes were stroke, bleeding and all-cause mortality. From October 1999 to December 2020, there were 566 AF patients who concurrently had active cancer. Mean age ± standard deviation was 76.2 ± 10.7 and 57.6% were males. Comparing to warfarin, patients who received direct oral anticoagulant (DOACs) were associated with similar risk of stroke (adjusted hazard ratio, aHR 0.8, 95% confidence interval [CI] 0.2-2.7, P = 0.67). On contrary, those who received low-molecular-weight heparin (LMWH) were associated with significantly higher risk of stroke comparing to warfarin (aHR 2.4, 95% CI 1.0-5.6, P = 0.04). Comparing to warfarin, DOACs and LMWH was associated with similar risk of overall bleeding with aHR 1.1 (95% CI 0.7-1.6, P = 0.73) and aHR 1.1 (95% CI 0.6-1.7, P = 0.83), respectively. Patients who received LMWH but not DOACs were associated with increased risk of death as compared to warfarin, aHR 4.5 (95% CI 2.8-7.2, P < 0.001) and 1.2 (95% CI 0.7-2.2, P = 0.47). In patients with active cancer and AF, LMWH, compared to warfarin, was associated with an increased risk of stroke and all-cause mortality. Furthermore, DOACs was associated with similar risk of stroke, bleeding and death as compared to warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Stroke; Warfarin

Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored.. To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting.. This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021.. The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin.. Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs.. This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs.. In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.

Topics: Anticoagulants; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Neoplasms; Retrospective Studies; Thrombosis; Venous Thromboembolism; Warfarin

Data on outcomes for patients with atrial fibrillation (AF) and active cancer are scarce. The effect of active cancer on thrombosis and bleeding risks in elderly (≥75 years) patients with non-valvular AF (NVAF) enrolled in the All Nippon AF In the Elderly (ANAFIE) Registry were prospectively analyzed.Methods and Results:In this subanalysis of the ANAFIE Registry, a prospective, multicenter, observational study conducted in Japan, we compared the incidence rates of clinical outcomes between active cancer and non-cancer groups. Relationships between primary outcomes and anticoagulation status were evaluated. Of the 32,725 patients enrolled in the Registry, 3,569 had active cancer at baseline; 92.0% of active cancer patients received anticoagulants (23.7%, warfarin; 68.2%, direct oral anticoagulants [DOACs]). Two-year probabilities of stroke/systemic embolic events (SEE) were similar in the cancer (3.33%) and non-cancer (3.16%) groups. Patients with cancer had greater incidences of major bleeding (2.86% vs. 2.04%), all-cause death (10.95% vs. 6.77%), and net clinical outcomes (14.63% vs. 10.00%) than those without cancer. In patients without cancer, DOACs were associated with a decreased risk of stroke/SEE, major bleeding, all-cause death, and net clinical outcome compared with warfarin. No between-treatment differences were observed in patients with active cancer.. Active cancer had no effect on stroke/SEE incidence in elderly NVAF patients, but those with cancer had higher incidences of major bleeding events and all-cause death than those without cancer.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Humans; Neoplasms; Prospective Studies; Registries; Stroke; Treatment Outcome; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Thromboembolism; Warfarin

Data on the use of oral anti-coagulants (OAC) for stroke prevention in cancer patients with atrial fibrillation (AF) are sparse. Nationwide cohort study of patients with AF (2012-2018) and an indication for OAC who were diagnosed with cancer at least one year later (N = 12 756). We identified treatment with OAC at cancer diagnosis and the following year and described the incidence of discontinuing or switching between warfarin and direct oral anti-coagulants (DOACs). We also described baseline characteristics associated with OAC non-persistence. One third of the cancer patients received no OAC therapy, whereas 42% received warfarin and 24% received DOAC treatment. Switching incidence between OACs was higher for those receiving warfarin treatment (8.6%) than DOAC treatment (1.7%) within one year. Treatment discontinuation was 61% for warfarin and 26% for DOAC. Females were less likely to discontinue DOAC than males (ratio 0.77, 95% confidence interval: 0.66, 0.90). Increasing cancer stage was associated with discontinuation of DOAC, but not warfarin. OAC for stroke prevention in AF was used by two thirds of patients with newly diagnosed cancer. Switching between OACs and discontinuation was more common for warfarin than DOAC, and females had higher persistence with DOACs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cohort Studies; Denmark; Female; Humans; Male; Neoplasms; Stroke; Warfarin

Anticoagulation among patients with cancer and atrial fibrillation is challenging due to elevated risk of bleeding and stroke. We characterized use of oral anticoagulants among patients with cancer and non-valvular atrial fibrillation (NVAF).. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data and included patients with cancer aged ≥66 years with an incident diagnosis of NVAF from 2010 to 2016. We used a Cox proportional hazard model and multivariable logistic regression to identify factors associated with anticoagulant use versus no use and direct oral anticoagulants (DOACs) versus warfarin use, respectively.. Of 27,702 patients with cancer and NVAF, 4469 (16.1%) used DOACs and 3577 (12.9%) used warfarin. Among 8046 anticoagulant users, DOACs use increased from 21.8% in 2011 to 76.2% in 2016, with a corresponding decline in warfarin use from 78.2% to 23.8%. Nearly 7 out of 10 patients with cancer and NVAF did not initiate anticoagulation in 2016. Anticoagulant use was more likely among those with higher CHA₂DS₂-VASc scores (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.27-1.90 for score ≥6 vs. 1) or with lower HAS-BLED scores (HR 1.96, 95% CI 1.67-2.30 for score 1 vs. ≥6). Among anticoagulant users, DOAC use was less likely than warfarin in those with higher CHA₂DS₂-VASc scores (odds ratio [OR] 0.53, 95% CI 0.33-0.84 for score ≥6 vs. 1).. Nearly 7 out of 10 patients with cancer and NVAF did not receive anticoagulation. Use of DOACs increased from 2010 to 2016, with a corresponding decline in warfarin use. DOACs are used less than warfarin among those at higher risk of stroke.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Medicare; Neoplasms; Retrospective Studies; Stroke; United States; Warfarin

Direct oral anticoagulants (DOACs) have comparable efficacy with low-molecular-weight heparin (LMWH) for the treatment of cancer-associated venous thromboembolism (VTE). Whether there is a mortality benefit of DOACs compared with warfarin in the management of VTE in cancer is not established.. Utilizing the United States' Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases from 2012 through 2016, we analyzed overall survival in individuals diagnosed with a primary gastric, colorectal, pancreas, lung, ovarian, or brain cancer and VTE who received a prescription of DOAC or warfarin within 30 days of VTE diagnosis. Patients were matched 1:2 (DOAC to warfarin) through exact matching for cancer stage and propensity score matching for age, cancer site, cancer stage, and time interval from cancer to VTE diagnosis. The analysis identified 4,274 patients who received a DOAC or warfarin for the treatment of VTE within 30 days of cancer diagnosis (1,348 in DOAC group and 2,926 in warfarin group). Patients were of median age 75 years and 56% female. Within the DOAC group, 1,188 (88%) received rivaroxaban, and 160 (12%) received apixaban. With a median follow-up of 41 months, warfarin was associated with a statistically significantly higher overall survival compared to DOACs (median overall survival 12.0 months [95% confidence interval (CI): 10.9 to 13.5] versus 9.9 months [95% CI: 8.4 to 11.2]; hazard ratio (HR) 0.85; 95% CI: 0.78 to 0.91; p < 0.001). Observed differences in survival were consistent across subgroups of cancer sites, cancer stages, and type of VTE. The study limitations include retrospective design with potential for unaccounted confounders along with issues of generalizability beyond the cancer diagnoses studied.. In this analysis of a population-based registry, warfarin was associated with prolonged overall survival compared to DOACs for treatment of cancer-associated VTE.

Topics: Administration, Oral; Aged; Anticoagulants; Cohort Studies; Female; Heparin, Low-Molecular-Weight; Humans; Male; Medicare; Neoplasms; Retrospective Studies; United States; Venous Thromboembolism; Warfarin

The increasing volume of the data and experience with direct oral anticoagulants (DOACS) in the primary and secondary prevention of venous thromboembolism in oncologic patients (CAVTE) has recently lead to changes in several international guidelines. We reflect these changes within the conditions in Slovak republic. In the primary prevention of CAVTE we recognise oncosurgical patients and nonsurgical patients: hospitalised and out patients. Low molecular weight heparins are still dominant in the primary prevention of CAVTE. Regarding the treatment and the secondary prevention of CAVTE, we recommend always to consider the possibility to use DOACs as they proved to be non inferior to LMWH. However, LMWH should be prefered over DOACs as well as over warfarin (VKA) in all patients who are in a clinically unstable condition with the high risk of bleeding and/or interaction with the systemic treatment. Primarily in the patients with intraluminal tumours of the upper part of the gastrointestinal tract and genitourinary tumours with the high risk of bleeding. As for the lack of data, LMWH are still preferd also in patients with primary tumours and metastatic disease of the central nervous system and in hemato oncology.

Topics: Anticoagulants; Consensus; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thromboembolism; Warfarin

While clinical guidelines recommend direct-acting oral anticoagulants (DOAC) over warfarin to treat isolated nonvalvular atrial fibrillation, guidelines are silent regarding nonvalvular atrial fibrillation treatment among individuals with cancer, reflecting the paucity of evidence in this setting. We quantified relative risk of ischemic stroke or systemic embolism and major bleeding (primary outcomes), and all-cause and cardiovascular death (secondary outcomes) among older individuals with cancer and nonvalvular atrial fibrillation comparing DOACs and warfarin.. This retrospective cohort study used Surveillance, Epidemiology, and End Results cancer registry and linked US Medicare data from 2010 through 2016, and included individuals diagnosed with cancer and nonvalvular atrial fibrillation who newly initiated DOAC or warfarin. We used inverse probability of treatment weighting to control confounding. We used competing risk regression for primary outcomes and cardiovascular death, and Cox proportional hazard regression for all-cause death.. Among 7675 individuals included in the cohort, 4244 (55.3%) received DOACs and 3431 (44.7%) warfarin. In the inverse probability of treatment weighting analysis, there was no statistically significant difference among DOAC and warfarin users in the risk of ischemic stroke or systemic embolism (1.24 versus 1.19 events per 100 person-years, adjusted hazard ratio 1.41 [95% CI, 0.92-2.14]), major bleeding (3.08 versus 4.49 events per 100 person-years, adjusted hazard ratio 0.90 [95% CI, 0.70-1.17]), and cardiovascular death (1.88 versus 3.14 per 100 person-years, adjusted hazard ratio 0.82 [95% CI, 0.59-0.1.13]). DOAC users had significantly lower risk of all-cause death (7.09 versus 13.3 per 100 person-years, adjusted hazard ratio 0.81 [95% CI, 0.69-0.94]) compared to warfarin users.. Older adults with cancer and atrial fibrillation exposed to DOACs had similar risks of stroke and systemic embolism and major bleeding as those exposed to warfarin. Relative to warfarin, DOAC use was associated with a similar risk of cardiovascular death and a lower risk of all-cause death.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Humans; Ischemic Stroke; Medicare; Neoplasms; Retrospective Studies; Stroke; Treatment Outcome; United States; Warfarin

There are clinical issues of special importance and practice variation in the management of venous thromboembolism (VTE) and in the use of anticoagulants among hematologists who practice in Asia. In Asian-inherited thrombophilia, coagulation is disturbed due to loss-of-function mutations of protein S and protein C causing protein S and protein C deficiencies, whereas the gain-of-function factor V Leiden and prothrombin G20210A mutations are almost absent. Thrombophilia screening is not recommended in patients with VTE patients who have major provoking factors. However, it can be considered in unprovoked young patients with VTE who have a strong family history of VTE. Cancer is the most important acquired risk factor for VTE in Asians. Limited cancer screening at the initial presentation of unprovoked VTE is appropriate, especially in the elderly. Direct oral anticoagulants have been shown to have similar efficacy and reduce risk of major bleeding, including intracranial hemorrhage and bleeding requiring hospitalization, compared with warfarin. Most clinical trials evaluating therapies for treatment and prevention of VTE have included small numbers of Asian patients. Despite this lack of evidence, direct oral anticoagulants have been increasingly used in Asia for cancer-associated thrombosis. Individualized assessment of thrombotic and bleeding risks should be used for all hospitalized Asian patients when deciding on pharmacologic thromboprophylaxis. More research is needed to understand the factors that contribute to risks of VTE and anticoagulant-associated bleeding in Asian patients as these may differ from Western populations.

Topics: Aged; Anticoagulants; Blood Coagulation; Hemorrhage; Humans; Neoplasms; Risk Factors; Thrombosis; Venous Thromboembolism; Warfarin

This study audited prescribing practices for patients with acute venous thromboembolism (VTE) prior to and after being seen in an outpatient VTE clinic. This retrospective chart review conducted between June 2018 through May 2019 included patients with confirmed acute VTE, seen for an initial appointment. Exclusion criteria were patients with additional indications for anticoagulation, lack of information to determine primary outcome and active cancer. To assess practices, the time taken to be seen in clinic, anticoagulant therapies (prior to/following clinic) used and concordance of anticoagulant use with product monographs were assessed. Of the 325 (40.6%) patients included, the median age was 57.7 years, most were referred with pulmonary embolism (PE) (54.5%) and the majority of referrals came through the emergency department (45.2%). The median time to be seen in clinic was 13 days, with no differences in time between type of VTE or proximity of clot. Prior to being seen in VTE clinic, most were prescribed direct oral anticoagulants (DOACs) (81.9%), with a small portion receiving low molecular weight heparin (LMWH) (12.9%) and warfarin (5.2%). Most received anticoagulants concordant with product monographs (87.7%), with more discordance with warfarin (52.9%) and LMWH (14.3%) compared to DOACs (9.4%) (P < 0.001). At the initial VTE clinic visit, 70 (21.5%) patients had therapy changes, with most being from LMWH/warfarin to a DOAC (47.1%). Our data reflects high uptake of DOACs for acute VTE treatment with most prescribed in accordance with product monographs.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Neoplasms; Referral and Consultation; Retrospective Studies; Venous Thromboembolism; Warfarin

When compared with warfarin, low-molecular-weight heparin (LMWH) reduces the incidence of recurrent venous thromboembolism (VTE) in cancer. However, a survival benefit of LMWH over warfarin for the treatment of cancer-associated VTE has not been established.. Using the Surveillance, Epidemiology and End Results and Medicare linked database from 2007 through 2016, we identified Medicare beneficiaries (aged ≥66 years) who were: (1) diagnosed with primary gastric, colorectal, pancreatic, lung, ovarian, or brain cancer; (2) diagnosed with cancer-associated VTE; and (3) prescribed LMWH or warfarin within 30 days. The primary outcome was overall survival (OS). Patients were matched 1:1 using exact matching for cancer stage and propensity score matching for cancer diagnosis, age, year of VTE, and time from cancer diagnosis to index VTE. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).. A total of 9706 patients were included. Warfarin was associated with a significant improvement in OS compared with LMWH (median OS, 9.8 months [95% CI, 9.1-10.4] vs. 7.2 months [95% CI, 6.8-7.8]; HR, 0.86; 95% CI 0.83-0.90; p < .001). The survival advantage was most pronounced in pancreatic (HR 0.82 [95% CI, 0.74-0.90], p < .001) and gastric cancers (HR 0.82 [95% CI, 0.68-0.98], p = .03). The observed differences in survival were consistent across subgroups including cancer stage, age, comorbidity burden, and year of VTE.. In this population-based study, warfarin was associated with improved OS compared with LMWH for the treatment of cancer-associated VTE.

Topics: Aged; Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Medicare; Neoplasms; Thrombosis; United States; Venous Thromboembolism; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Thrombosis; Venous Thrombosis; Warfarin

 This study primarily evaluates the risk of recurrent venous thromboembolism (VTE) and major bleeding (MB) among patients with VTE and active cancer prescribed apixaban, low-molecular-weight heparin (LMWH), or warfarin, with claims data..  Four U.S. commercial insurance claims databases were used to identify patients with VTE and active cancer who initiated apixaban, LMWH, or warfarin within 30 days following the first VTE event. Stabilized inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate risk of recurrent VTE and MB..  All eligibility criteria were fulfilled by 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients. After IPTW, all patient characteristics were balanced. When the follow-up was censored at 6 months, apixaban patients had a lower risk of recurrent VTE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.47-0.81) and MB (HR: 0.63; 95% CI: 0.47-0.86) versus LMWH. Apixaban patients had a lower risk of recurrent VTE (HR: 0.68; 95% CI: 0.52-0.90) and similar risk of MB (HR: 0.73; 95% CI: 0.53-1.00) versus warfarin. Warfarin patients had a similar risk of recurrent VTE (HR: 0.91; 95% CI: 0.72-1.15) and MB (HR: 0.87; 95% CI: 0.68-1.12) versus LMWH. The trends were similar for the entire follow-up; however, apixaban patients had a lower risk of MB versus warfarin patients..  Patients with VTE and active cancer who initiated apixaban had a lower risk of recurrent VTE and MB compared with LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared with warfarin patients.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Factor Xa Inhibitors; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridones; United States; Venous Thromboembolism; Warfarin; Young Adult

Cancer associated thrombosis (CAT) is a leading cause of death among patients with cancer. It is not clear if non-clinical factors are associated with anticoagulation receipt. We conducted a retrospective cohort study of Optum's de-identified Clinformatics® Database of adults with cancer diagnosed between 2009 and 2016 who developed CAT, treated with an outpatient anticoagulant (warfarin, low molecular weight heparin (LMWH), or a direct oral anticoagulant (DOAC)). Of 12,622 patients, three months after an episode of CAT, 1,485 (12%) were on LMWH, 1,546 (12%) on DOACs, and 9,591 (76%) were on warfarin. When controlling for other factors, anticoagulant use was significantly associated with socioeconomic factors, region, co-morbidities, type of thrombosis, and cancer subtype. Patients with a bachelor's degree or greater level of education were less likely to receive warfarin (OR: 0.77; 95% CI: [0.59, 0.99]; p < 0.046) or DOACs (OR: 0.67; 95% CI: [0.55, 0.82]; p < 0.001) compared to LMWH. Patients with higher income levels were more likely to receive LMWH or DOACs compared to warfarin, while patients across all income levels were equally likely to receive LMWH or DOACs. Non-clinical factors including income, education, and region, are associated with anticoagulation receipt three months after an episode of CAT. Sociodemographic factors may result in some patients receiving suboptimal care and contribute to non-guideline concordant care for CAT.

Topics: Administration, Oral; Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Retrospective Studies; Sociodemographic Factors; Thrombosis; Venous Thromboembolism; Warfarin

Cancer patients, especially active cancer patients have high risk of cancer-associated venous thromboembolism(VTE). Virchow's triad, hyper-coagulability, endothelial cell damage, and blood stasis are often found during cancer treatment. Tissue factor expressed on tumor cells activate coagulation, and decrease in antithrombotic activity by topical inflammation and platelet activation increase the risk of VTE. The risk of VTE is further enhanced by surgical intervention and chemotherapy. Anticoagulation is the most important treatment, however warfarin is not suitable for active cancer patients due to drug- drug interaction and gastrointestinal toxicity. In the Western countries, low molecular weight heparin (LMWH) is the standard choice for cancer-associated VTE. During anticoagulation, risk of recurrence of VTE and major bleeding is very high. Recently, direct oral anticoagulant(DOAC)has been introduced and widely used in Japan after the evidence of DOACs in cancer patients. Gastrointestinal bleeding is one of the frequent adverse events during DOAC treatment. Drug-drug interaction such as P-glycoprotein and CYP3A4 must be considered for safety treatment.

Topics: Anticoagulants; Heparin, Low-Molecular-Weight; Humans; Japan; Neoplasms; Venous Thromboembolism; Warfarin

Available classification tools and risk factors predicting bleeding events in elderly patients after mechanical valve replacement may not be suitable in Asian populations. Thus, we aimed to identify an accurate model for predicting bleeding in elderly patients receiving warfarin after mechanical valve replacement in a Korean population. In this retrospective cohort study, a random forest model was used to determine factors predicting bleeding events among 598 participants. Twenty-two descriptors were selected as predictors for bleeding. Steroid use was the most important predictor of bleeding events, followed by labile international normalized ratio, history of stroke, history of myocardial infarction, and cancer. The random forest model was sensitive (80.77%), specific (87.67%), and accurate (85.86%), with an area under the curve of 0.87, suggesting fair prediction. In the elderly, drug interactions with steroids and overall physical condition had a significant effect on bleeding. Elderly patients taking warfarin for life require lifelong management.

Topics: Adrenal Cortex Hormones; Aged; Anticoagulants; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; Machine Learning; Myocardial Infarction; Neoplasms; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Warfarin

Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer.. In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups.. There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50–0.80]; P=0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24–0.70]; P=0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23–0.61]; P<0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56–0.94]; P=0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer (P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years (P interaction <0.05).. Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Cohort Studies; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Propensity Score; Retrospective Studies; Stroke; Taiwan; Treatment Outcome; Venous Thrombosis; Vitamin K; Warfarin

Topics: Anticoagulants; Factor Xa Inhibitors; Humans; Neoplasms; Patient Reported Outcome Measures; Rivaroxaban; Venous Thromboembolism; Warfarin

Low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are among the recommended treatment options for cancer-associated thrombosis (CAT) in the 2019 National Comprehensive Care Network guidelines. Little is known about the current utilization of DOACs in CAT patients, particularly on the inpatient to outpatient therapy transition. This study assessed real-world treatment patterns of CAT in hospital/ED in adult cancer patients (≥ 18 years) diagnosed with CAT during a hospital visit in IQVIA's Hospital Charge Data Master database between July 1, 2015 and April 30, 2018, and followed their outpatient medical and pharmacy claims to evaluate the initial inpatient/ED and outpatient anticoagulants received within 3 months post-discharge. Results showed that LMWH and unfractionated heparin (UFH) were the most common initial inpatient/ED CAT treatments (35.2% and 27.4%, respectively), followed by DOACs (9.6%); 20.8% of patients received no anticoagulants. Most DOAC patients remained on DOACs from inpatient/ED to outpatient settings (71.4%), while 24.1%, 43.5%, and 0.1% of patients treated with LMWH, warfarin, or UFH respectively, remained on the same therapy after discharge. In addition, DOACs were the most common initial post-discharge outpatient therapy. Outpatient treatment persistence and adherence appeared higher in patients using DOACs or warfarin versus LMWH or UFH. This study shows that DOACs are used as an inpatient/ED treatment option for CAT, and are associated with less post-discharge treatment switching and higher persistence and adherence. Further research generating real-world evidence on the role of DOACs to help inform the complex CAT clinical treatment decisions is warranted.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Anticoagulants; Databases, Factual; Drug Substitution; Drug Utilization; Factor Xa Inhibitors; Female; Heparin; Humans; Inpatients; Male; Medication Adherence; Middle Aged; Neoplasms; Patient Discharge; Practice Patterns, Physicians'; Retrospective Studies; Time Factors; Treatment Outcome; United States; Venous Thrombosis; Warfarin

The efficacy and bleeding complications of direct oral anticoagulant (DOAC) therapy for cancer-associated venous thromboembolism (VTE) in routine clinical practice remain unclear. Moreover, data on long-term outcomes in patients with cancer-associated VTE who received DOAC therapy are limited.Methods and Results:This retrospective study enrolled 1,096 consecutive patients with acute VTE who received warfarin or DOAC therapy between April 2014 and May 2017. The mean follow-up period was 665±490 days. The number of cancer-associated VTE patients who received DOAC therapy was 334. Patients who could not be followed up and those prescribed off-label under-dose DOAC were excluded. Finally, 303 patients with cancer-associated VTE were evaluated. The number of cases of major bleeding and VTE recurrence was 54 (17.8%) and 26 (8.6%), respectively. In the multivariate analysis, the factors correlated with major bleeding were high cancer stage, high performance status, liver dysfunction, diabetes mellitus, and stomach cancer; those correlated with recurrent VTE were initial diagnosis of pulmonary embolism, uterine cancer, and previous cerebral infarction. Major bleeding was an independent risk factor of all-cause death. In the Kaplan-Meier analysis, those who received prolonged DOAC therapy had lower composite major bleeding and recurrent VTE risks than those who did not.. In DOAC therapy for cancer-associated VTE, major bleeding prevention is important because it is an independent risk factor of death.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Neoplasms; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

There is limited evidence to support the use of direct-acting oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and active cancer. This study aimed to assess the effectiveness of DOACs versus warfarin for the prevention of recurrent VTE and major bleeding events in patients with VTE and active cancer.. We identified patients with incident VTE and active cancer who newly initiated treatment with DOACs or warfarin from Truven Health MarketScan Commercial Claims and Medicare supplemental databases. Patients were followed up from treatment initiation (index date) until the occurrence of >7-day gap in treatment, the start of the study comparator, an outcome of interest (recurrent VTE or major bleeding), inpatient death, disenrollment, or end of the study period, whichever occurred first. We controlled for confounders via propensity score matching and estimated the hazard ratios (HRs) using Cox proportional hazards regression models.. A total of 9952 patients were included in the matched cohort (4976 DOACs users and 4976 warfarin users). Patient characteristics were well balanced after matching. We observed a lower incidence of recurrent VTE (3 vs 5 per 100 person-years) and major bleeding events (2 vs 3 per 100 person-years) in the DOAC group compared to warfarin group, respectively. In Cox regression models, use of DOACs (vs warfarin) was associated with a lower risk of recurrent VTE (hazard ratio (HR), 0.59; 95% CI, 0.42-0.82) and major bleeding events (HR, 0.64; 95% CI, 0.44-0.94).. On the basis of our findings, among patients with VTE and active cancer, DOACs offer superior effectiveness with a lower risk of bleeding when compared with warfarin for the secondary prevention of VTE.

Topics: Administration, Oral; Aged; Anticoagulants; Cohort Studies; Databases, Factual; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Medicare; Middle Aged; Neoplasms; Retrospective Studies; Secondary Prevention; United States; Venous Thromboembolism; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation; Humans; Neoplasms; Risk Factors; Stroke; Warfarin

Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. In Brazil, even though low-molecular-weight heparin (LMWH) is the gold standard of care for the management of cancer-associated thrombosis (CAT), its cost limits its use and therefore warfarin is commonly prescribed. Direct oral anticoagulants (DOACs), such as edoxaban, have been introduced as an alternative in this setting.. The aim of this study was to compare the cost-effectiveness of edoxaban with LMWH (Model 1) and warfarin (Model 2) to support clinicians and hospitals when choosing an anticoagulant to manage CAT.. Cost-effectiveness analyses were performed using Markov state-transition models over a timeframe of 5 years, in a hypothetical, 64 years-old patients cancer population with an index VTE event. Transition probabilities, costs, quality-adjusted life years (QALYs) and risk reductions were either derived from the literature, estimated or calculated. A willingness-to-pay limit of 3 Gross Domestic Product (GDP) per head was used. Deterministic and probabilistic sensitivity analyses were performed for robustness. The main outcome of this study was the incremental cost-effectiveness ratio (ICER), expressed as cost per QALY gained.. Model 1 base case analysis demonstrated dominance of edoxaban compared to LMWH, with an ICER of $5204.46, representing cost saved per QALY lost. In Model 2, edoxaban was associated with a $736.90 cost increase vs. warfarin, with an ICER of $2541.03. Sensitivity analyses confirmed base-case results.. Edoxaban represents a cost-saving alternative to LMWH for the management of CAT and is cost-effective vs. warfarin.

Topics: Anticoagulants; Brazil; Cost-Benefit Analysis; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Pyridines; Quality-Adjusted Life Years; Thiazoles; Thrombosis; Warfarin

Animal and epidemiologic studies suggest that the use of warfarin might reduce cancer incidence. The antitumor potential of warfarin is demonstrated in different experimental cancer models. Specifically, studies in murine cancer models have shown that warfarin blocks AXL receptor tyrosine kinase by inhibiting a vitamin K-dependent protein called GAS6, thereby may halt the spread of cancer cells. An off-target effect of the anticoagulant warfarin is inhibition of GAS6-AXL signaling, which enhances antitumor immunity and blocks tumorigenesis independently of anticoagulation. Hence, the observed association between warfarin use and lower cancer incidence is likely due to an enhanced antitumor immune surveillance of early cancer. The large observational study also showed a reduction in cancer incidence among regular warfarin users. The study data indicate that warfarin provides a possible cancer protection. Despite some limitations, the results of this study give further support for the hypothesis that warfarin use decreases cancer incidence, which warrants continued investigation. This finding may have important implications for choosing medications in patients who need anticoagulant therapy.

Topics: Animals; Anticoagulants; Axl Receptor Tyrosine Kinase; Humans; Incidence; Intercellular Signaling Peptides and Proteins; Mice; Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Warfarin

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

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

Direct oral anticoagulants (DOACs) are not recommended for venous thromboembolism (VTE) treatment in patients with cancer because their safety and efficacy have not been compared to low molecular weight heparin (LMWH) in large trials. Routine anti-Xa monitoring in cancer patients on LMWH is also not recommended due to limited data correlating anti-Xa levels and outcomes.. Compare the safety and efficacy of DOACs to LMWH and warfarin and assess the relationship of anti-Xa monitoring and outcomes in patients with cancer taking LMWH in an urban university setting.. This retrospective, cohort study analyzed the recurrence of VTE and number of bleeding events in patients with cancer.. There were 131 patients included in the analysis. There was no difference seen in the rate of recurrent VTEs between the LMWH, warfarin and DOAC groups (9.3%, 5.9%, 9.1%, p = 0.89). There was also no difference in the rate of bleeding between groups (10.5%, 14.7%, 9.1%, p = 0.576). There was an increased rate of mortality seen in the LMWH group (26.7% vs. 2.9% vs. 18.2%, p = 0.006). There was no difference seen in recurrent VTE (10.3% vs. 8.5%, p = 0.53) or bleeding (10.3% vs. 10.7%, p = 0.661) between the monitored and unmonitored LMWH patients.. Results of this analysis suggest DOACs may be as safe and effective as LMWH and warfarin for the treatment of VTE in patients with cancer, and there may be no clinical benefit to routine anti-Xa monitoring in patients on LMWH treatment. However, larger studies are needed to confirm these observations.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Venous Thromboembolism; Warfarin

Topics: Aged; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Insurance; Middle Aged; Neoplasms; Recurrence; Risk; Rivaroxaban; Venous Thromboembolism; Warfarin

Treatment on organized stroke units (SUs) improves survival after stroke, and stroke mortality has decreased worldwide in recent decades; however, little is known of survival trends among SU patients specifically. This study investigates changes in survival and characteristics of older stroke patients receiving SU treatment.. We compared 3-year all-cause mortality and baseline characteristics in two cohorts of stroke patients aged ≥60 consecutively admitted to the same comprehensive SU in 1994 (n = 271) and 2012 (n = 546).. Three-year survival was 53.9% in 1994 and 56.0% in 2012, and adjusted hazard ratio (HR) was 0.99 (95% CI: 0.77-1.28). Adjusted 30-day case fatality was slightly higher in 2012, 18.9% versus 16.2%, HR 1.68 (95% CI: 1.14-2.47). There were no significant between-cohort differences in survival beyond 30 days. Patients in 2012 were older (mean age: 78.8 vs. 76.7 years) and more often admitted from nursing homes. There were higher rates of atrial fibrillation (33.7% vs. 21.4%) and malignancy (19.2% vs. 8.9%), and prescription of antiplatelets (46.9% vs. 26.2%) and warfarin (16.3% vs. 5.5%) at admission. Stroke severity was significantly milder in 2012, proportion with mild stroke 66.1% versus 44.3%.. Three-year survival in older Norwegian stroke patients treated on an SU remained stable despite improved treatment in the last decades. Differences in background characteristics may explain this lack of difference; patients in 2012 were older, more often living in supported care, and had higher prestroke comorbidity; however, their strokes were milder and risk factors more often treated.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Comorbidity; Female; Hospital Units; Humans; Male; Middle Aged; Neoplasms; Norway; Proportional Hazards Models; Risk Factors; Severity of Illness Index; Stroke; Survival Analysis; Warfarin

 Many patients on warfarin therapy often present with supratherapeutic international normalized ratio (INR) levels, resulting from the influence of several patient-specific factors, which have been associated with adverse outcomes..  This article aims to identify risk factors for over-anticoagulation (INR levels ≥4) in a cohort of patients taking warfarin..  A cohort of warfarin users aged 18 to 85 years from January 2005 to April 2013 was identified in The Health Improvement Network U.K. primary care database (.  Among the factors examined, the strongest predictors of over-anticoagulation were warfarin indication (in particular, valvular atrial fibrillation and valve replacement), renal failure (with the risk increasing steeply with decreasing estimated glomerular filtration rate), cancer, anaemia, respiratory infections treated with antibiotics, chronic obstructive pulmonary disease treated with β2-agonists, polypharmacy (≥10 medications), low socio-economic status and residency in rural areas. Similar results were obtained when supratherapeutic levels were defined as INR ≥5 or, alternatively, as INR > 3..  Predictors of supratherapeutic INR levels found in this study might help physicians identify patients where closer INR monitoring is warranted.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Anticoagulants; Blood Coagulation; Case-Control Studies; Databases, Factual; Female; Glomerular Filtration Rate; Humans; International Normalized Ratio; Male; Medical Overuse; Middle Aged; Neoplasms; Odds Ratio; Poverty; Primary Health Care; Pulmonary Disease, Chronic Obstructive; Regression Analysis; Renal Insufficiency; Respiratory Tract Infections; Rural Population; United Kingdom; Warfarin; Young Adult

Objective Oral anticoagulants (OACs), which include direct oral anticoagulants (DOACs) and warfarin, are widely used for the prevention of thromboembolic events in patients with atrial fibrillation (AF). Cancer is associated with a prothrombotic state as well as an increased bleeding risk. Few data are available on the efficacy and safety of OACs in Japanese cancer patients with AF. We sought to investigate the efficacy and safety of OACs in this population. Methods This retrospective cohort study included active cancer patients in whom AF was recorded by electrocardiography in our hospital from January 2014 to December 2016 and who were treated with DOACs or warfarin. Patients were followed for 1 year. The study outcomes were stroke or systemic embolism and major bleeding. Result A total of 224 patients with AF and active cancer were treated with OACs (DOACs, n=127; warfarin, n=97). Overall, stroke or systemic embolism and major bleeding occurred in seven (3.8%/year) and eight (4.9%/year) patients, respectively. Stroke or systemic embolism occurred in three patients in the DOAC group (2.8%/year) and four patients in the warfarin group (5.4%/year). Major bleeding occurred in four patients in the DOAC group (4.0%/year) and four patients in the warfarin group (6.5%/year). Conclusion The rates of stroke or systemic embolism and major bleeding events were not negligible among Japanese cancer patients with AF receiving OACs. Further investigations on the optimal management of Japanese patients with AF and cancer are needed.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Comorbidity; Female; Humans; Japan; Male; Middle Aged; Neoplasms; Retrospective Studies; Treatment Outcome; Warfarin

Topics: Aged; Databases, Factual; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Neoplasms; Risk Factors; Rivaroxaban; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Female; Health Expenditures; Health Resources; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Insurance Claim Review; Male; Middle Aged; Neoplasms; Patient Acceptance of Health Care; Retrospective Studies; Rivaroxaban; Venous Thromboembolism; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Pulmonary Embolism; Venous Thromboembolism; Warfarin

Background There is increasing evidence indicating oral factor Xa inhibitors can be used for secondary prevention of venous thromboembolism. Studies are needed to compare oral factor Xa inhibitors, low molecular weight heparins, and warfarin in the oncology population. The purpose of this study is to evaluate the recurrent venous thromboembolism incidence in oncology patients utilizing oral Xa inhibitors, low molecular weight heparins, or warfarin. Methods Using retrospectively collected data, we compared the recurrent venous thromboembolism incidence in oncology patients taking rivaroxaban/apixaban, enoxaparin, or warfarin with at least three months of follow-up. Patients were included if they had an active cancer, venous thromboembolism, and taking warfarin, enoxaparin, or rivaroxaban/apixaban. The primary endpoint was the first episode of recurrent venous thromboembolism at three months. Secondary endpoints included recurrent venous thromboembolism after six months, major bleeding, and mortality. Results Of 127 venous thromboembolism patients, 48 received rivaroxaban or apixaban, 23 received enoxaparin, and 56 received warfarin. The three most common cancer diagnoses were lung (21%), colorectal (14%), and breast (14%). There was no difference in venous thromboembolism recurrence at three months between the rivaroxaban/apixaban (0%), warfarin (3.6%), and the enoxaparin cohorts (4.4%) (p = 0.8319). Major bleeding at three months was only seen in one patient in the enoxaparin arm (4.2%). Mortality at three months was 0%, 3.6%, and 17.4% in the rivaroxaban/apixaban, warfarin, and enoxaparin cohorts, respectively. Conclusion The results of this retrospective study suggest that oral factor Xa inhibitors are potential options for cancer patients with venous thromboembolism. However, randomized, controlled trials are needed to confirm these results.

Topics: Aged; Aged, 80 and over; Anticoagulants; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridones; Recurrence; Retrospective Studies; Rivaroxaban; Secondary Prevention; Venous Thromboembolism; Warfarin

Cancer is a known hypercoagulable state that leads to an increased risk of venous thromboembolism (VTE). Low molecular weight heparin remains the preferred anticoagulant for VTE in patients with cancer over vitamin K antagonist. However, the preferred anticoagulant in prevention of stroke and systemic embolism in atrial fibrillation (AF) in patients with cancer has yet to be determined. The direct oral anticoagulants (DOACs) are increasingly being utilized; however their role in cancer has only recently been investigated. The objective of this retrospective cohort was to describe real-world anticoagulation prescribing patterns in cancer patients at a large academic medical center between January 1, 2013 and October 31, 2016. We sought to assess the safety, tolerability, and efficacy of DOACs in patients with cancer for either VTE and/or AF. Patient demographic, clinical characteristics, as well as bleeding and thrombotic events were collected. There were 214 patients in our analysis, of which 71 patients (33%) received a DOAC [apixaban (n = 22), dabigatran (n = 17), and rivaroxaban (n = 32)]. There were fewer bleeding events and/or discontinuations in the DOAC group compared to enoxaparin (13 vs. 27, p = 0.022). There was no difference in major or minor bleeds or thromboembolic events in comparing DOAC to enoxaparin or DOAC to warfarin. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs compared to warfarin or enoxaparin in patients with cancer. DOACs may represent an alternative to warfarin or enoxaparin in patients with cancer for VTE and/or stroke reduction in AF.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Dabigatran; Enoxaparin; Hemorrhage; Humans; Middle Aged; Neoplasms; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Thrombosis; Treatment Outcome; Venous Thromboembolism; Warfarin

Randomized clinical trials comparing direct oral anticoagulants (DOACs) to warfarin in cancer patients have not been performed. We evaluated the effectiveness and associated risk of DOACs vs warfarin, as well as comparisons of DOACs, in a large population of cancer patients with nonvalvular atrial fibrillation (AF). Using the MarketScan databases, we identified 16 096 AF patients (mean age, 74 years) initiating oral anticoagulant and being actively treated for cancer between 2010 and 2014. Anticoagulant users were matched by age, sex, enrollment date, and drug initiation date. Study end points were identified with diagnostic codes and included ischemic stroke, severe bleeding, other bleeding, and venous thromboembolism (VTE). Cox regression was used to estimate associations of anticoagulants with study end points. Compared with warfarin, rates of bleeding (hazard ratio [95% confidence interval]) were similar in rivaroxaban (1.09 [0.79, 1.39]) and dabigatran (0.96 [0.72, 1.27]) users, whereas apixaban users experienced lower rates (0.37 [0.17, 0.79]). Rates of ischemic stroke did not differ among anticoagulant users. Compared with warfarin, rate of VTE (hazard ratio [95% confidence interval]) was lower among rivaroxaban (0.51 [0.41, 0.63]), dabigatran (0.28 [0.21, 0.38]), and apixaban (0.14 [0.07, 0.32]) users. In head-to-head comparisons among DOACs, dabigatran users had lower rates of VTE than rivaroxaban users; apixaban users had lower rates of VTE and severe bleeding than rivaroxaban users. In this population of patients with AF and cancer, DOAC users experienced lower or similar rates of bleeding and stroke compared with warfarin users, and a lower rate of incident VTE.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Databases, Factual; Hemorrhage; Humans; Middle Aged; Neoplasms; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Venous Thromboembolism; Warfarin; Young Adult

Anticoagulation is used to treat venous thromboembolism (VTE) in cancer patients, but may be associated with an increased risk of bleeding. VTE recurrence and major bleeding were assessed in cancer patients treated for VTE with the most currently prescribed anticoagulants in clinical practice. Newly diagnosed cancer patients (first VTE 1/1/2013-05/31/2015) who initiated rivaroxaban, low-molecular-weight heparin (LMWH), or warfarin were identified from Humana claims data and observed until end of eligibility or end of data availability. VTE recurrence was a hospitalization with a primary diagnosis of VTE ≥7 days after first VTE. Major bleeding events on treatment were identified using validated criteria. Cohorts were compared using Kaplan-Meier rates at 6 and 12 months and Cox proportional hazards models. Cohorts were adjusted for their differences at baseline. A total of 2428 patients (rivaroxaban: 707; LMWH: 660; warfarin: 1061) met inclusion criteria. Patient characteristics were well balanced after weighting. There was a trend for lower VTE recurrence rates in rivaroxaban users compared to LMWH users at 6 months (13.2% vs. 17.1%; P = .060) and significantly lower at 12 months (16.5% vs. 22.2%; P = .030) [HR: 0.72, 95% CI: (0.52-0.95); P = .024]. VTE recurrence rates were also lower for rivaroxaban than warfarin users at 6 months (13.2% vs. 17.5%; P = .014) and 12 months (15.7% vs. 19.9%; P = .017) [HR: 0.74, 95% CI: (0.56-0.96); P = .028]. Major bleeding rates were similar across cohorts. This real-world analysis suggests cancer patients with VTE treated with rivaroxaban had significantly lower risk of recurrent VTE and similar risk of bleeding compared to those treated with LMWH or warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Factor Xa Inhibitors; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Recurrence; Rivaroxaban; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Bias; Humans; Incidence; Neoplasms; Time Factors; Warfarin

Topics: Bias; Humans; Incidence; Neoplasms; Time Factors; Warfarin

Topics: Bias; Humans; Incidence; Neoplasms; Time Factors; Warfarin

Essentials Bleeding risk by anticoagulant choice for cancer-associated venous thrombosis (CA-VTE) is unknown. 26 894 people with CA-VTE were followed for bleeding in a claims database in the United States. Hospitalized bleeding risk was similar with direct acting oral anticoagulants vs. warfarin. Relative hospitalized bleeding risk varied by cancer type and anticoagulant choice. SUMMARY: Background Direct acting oral anticoagulants (DOACs) are associated with less bleeding than traditional venous thromboembolism (VTE) treatments in the general population but are little studied in cancer-associated VTE (CA-VTE). Objective To determine whether different anticoagulation strategies for CA-VTE have different hospitalized bleeding rates. Patients/Methods We conducted a retrospective study of patients with CA-VTE, diagnosed between 2011 and 2015, in a large administrative database. Using validated algorithms, we identified 26 894 CA-VTE patients treated with anticoagulants and followed them for hospitalized severe bleeding. Cox models were used to assess bleeding risk, adjusted for age, sex, high dimensional propensity score and frailty. Results Over 27 281 person-years of follow-up (median 0.6 years), 1204 bleeding events occurred, for a bleeding rate of 4.4% per patient-year. Bleeding rates varied by cancer type, with the highest rate for upper gastrointestinal cancers (8.6%) and the lowest for breast cancer (2.9%). In Cox models (hazard ratio [HR]; 95% confidence interval [CI]), compared with warfarin, DOACS and low-molecular-weight heparin (LMWH) had similar hazards of bleeding (HR, 0.88; 95% CI, 0.69-1.11 and 0.98; 0.85-1.13). Compared with LMWH, there was no difference in hazard of bleeding with DOACs (0.86; 0.66-1.12). There was heterogeneity in bleeding risk with DOACs by cancer type, with a higher risk of bleeding in upper gastrointestinal cancers and lower risk of bleeding in prostate cancer and hematologic cancers. Conclusions In this practice-based sample of CA-VTE patients, DOACs were associated with similar bleeding risks to warfarin and LMWH. These findings suggest a complex association of bleeding risk with anticoagulant choice in cancer patients.

Topics: Administration, Oral; Administrative Claims, Healthcare; Aged; Anticoagulants; Blood Coagulation; Clinical Decision-Making; Databases, Factual; Drug Utilization; Female; Hemorrhage; Hospitalization; Humans; Inpatients; Male; Middle Aged; Neoplasms; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Advances in cancer therapy have led to a significant improvement of survival in most types of malignancies over the past few decades. As a result, there is a growing population of cancer survivors, expected to reach 18 million people in 2030 in the US and a similar number in Europe. Interestingly, cancer survivor studies have shown that although about half of these patients eventually die of cancer, one third of them actually die of cardiovascular disease. Arrhythmias represent a significant part of cardiovascular complications and atrial fibrillation is the main arrhythmia occurring in cancer patients.Antithrombotic therapy is a challenge: the optimal international normalized ratio (INR) level in patients on therapy with vitamin K antagonists is achieved in only 12% of them; in these patients, direct oral anticoagulants seem to be effective and safe for the prevention of stroke and systemic embolic events compared to warfarin and have similar risk of major bleeding. Among the trials, ENGAGE AF-TIMI 48 provides more data on the efficacy and safety of edoxaban in cancer patients.

Topics: Anticoagulants; Atrial Fibrillation; Cancer Survivors; Cardiovascular Diseases; Embolism; Factor Xa Inhibitors; Hemorrhage; Humans; International Normalized Ratio; Neoplasms; Pyridines; Stroke; Thiazoles; Warfarin

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Embolism; Factor Xa Inhibitors; Female; Gastrointestinal Neoplasms; Hemorrhage; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Prostatic Neoplasms; Pyridines; Stroke; Thiazoles; Warfarin

Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.. The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer.. There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.53-2.26) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, 0.64-0.93) (P interaction = .37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, 0.11-0.83) versus without cancer (HR, 0.86; 95% CI, 0.78-0.95), but not in remote cancer (HR, 1.46; 95% CI, 1.01-2.10) (interaction P = .0028).. Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Neoplasms; Pyrazoles; Pyridones; Stroke; Thromboembolism; Treatment Outcome; Warfarin

In cancer models, warfarin inhibits AXL receptor tyrosine kinase-dependent tumorigenesis and enhances antitumor immune responses at doses not reaching anticoagulation levels. This study investigates the association between warfarin use and cancer incidence in a large, unselected population-based cohort.. To examine the association between warfarin use and cancer incidence.. This population-based cohort study with subgroup analysis used the Norwegian National Registry coupled with the Norwegian Prescription Database and the Cancer Registry of Norway. The cohort comprised all persons (N = 1 256 725) born between January 1, 1924, and December 31, 1954, who were residing in Norway from January 1, 2006, through December 31, 2012. The cohort was divided into 2 groups-warfarin users and nonusers; persons taking warfarin for atrial fibrillation or atrial flutter were the subgroup. Data were collected from January 1, 2004, to December 31, 2012. Data analysis was conducted from October 15, 2016, to January 31, 2017.. Warfarin use was defined as taking at least 6 months of a prescription and at least 2 years from first prescription to any cancer diagnosis. If warfarin treatment started after January 1, 2006, each person contributed person-time in the nonuser group until the warfarin user criteria were fulfilled.. Cancer diagnosis of any type during the 7-year observation period (January 1, 2006, through December 31, 2012).. Of the 1 256 725 persons in the cohort, 607 350 (48.3%) were male, 649 375 (51.7%) were female, 132 687 (10.6%) had cancer, 92 942 (7.4%) were classified as warfarin users, and 1 163 783 (92.6%) were classified as nonusers. Warfarin users were older, with a mean (SD) age of 70.2 (8.2) years, and were predominantly men (57 370 [61.7%]) as compared with nonusers, who had a mean (SD) age of 63.9 (8.6) years and were mostly women (613 803 [52.7%]). Among warfarin users and compared with nonusers, there was a significantly lower age- and sex-adjusted incidence rate ratio (IRR) in all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) and in prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). There was no observed significant effect in colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In a subgroup analysis of patients with atrial fibrillation or atrial flutter, the IRR was lower in all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65) and in prevalent sites (lung, 0.39 [95% CI, 0.33-0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]; and colon, 0.71 [95% CI, 0.63-0.81]).. Warfarin use may have broad anticancer potential in a large, population-based cohort of persons older than 50 years. This finding could have important implications for the selection of medications for patients needing anticoagulation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Atrial Flutter; Female; Humans; Incidence; Male; Middle Aged; Neoplasms; Norway; Registries; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Embolism; Gastrointestinal Hemorrhage; Humans; Neoplasms; Stroke; Warfarin

Prolonged prothrombin time is observed in patients taking warfarin (WF) with a fluoropyrimidine, such as S-1. When WF is combined with S-1, the prothrombin time-international normalized ratio (PT-INR) and dose adjustment of WF should be closely monitored. To date, no clinical data have been reported in terms of the relation between temporal variation of PT-INR and its therapeutic range. In this study, we retrospectively collected patients' clinical data including PT-INR. We identified 21 patients receiving WF therapy before the start of S-1 treatment. Patient characteristics were male/female: 18/3, median age: 69 (range 48-81) years old, cancer of gastric/lung/pancreatic/other: 8/5/4/4, and history of deep vein thrombosis (DVT)/atrial fibrillation (AF)/cerebral infarction (CI)/other: 11/6/2/2. The PT-INR of 16 patients exceeded normal upper limits after taking S-1 with WF. The median time to exceed the PT-INR upper therapeutic range is 25 (range 3-77) days. Patients receiving WF anticoagulant therapy concomitant with S-1 should have their PT-INR closely monitored and WF doses adjusted accordingly.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antimetabolites, Antineoplastic; Drug Combinations; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Oxonic Acid; Prothrombin Time; Retrospective Studies; Tegafur; Warfarin

Phenotyping cytochrome P450 (CYP) 2C9 activity using S-warfarin has routinely required extensive blood sampling over at least 96 hours after dose to estimate the area under the concentration time curve from zero to infinity (AUC). Alternatively, S-warfarin limited sampling models (LSMs) using one or 2 concentration timepoints have been proposed to estimate AUC. This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced-stage cancer patients.. Plasma S-warfarin concentrations from healthy adults (n = 92) and in advanced-stage cancer patients (n = 22) were obtained from 6 published studies where a single 10 mg dose of oral warfarin was administered at CYP2C9 baseline and induction conditions. S-warfarin observed AUC was determined by noncompartmental analysis, whereas estimated AUC was calculated from the LSMs. Bias and precision were assessed by percent mean prediction error, percent mean absolute error, and percent root mean square error.. Different results were observed for S-warfarin LSMs in estimating CYP2C9 baseline activity, with most studies resulting in unacceptable bias and precision. The percent mean prediction error, percent mean absolute error, and/or percent root mean square error exceeded acceptable limits for LSMs in patients with advanced-stage cancer and during CYP2C9 induction with lopinavir/ritonavir.. The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs.

Topics: Administration, Oral; Adult; Aged; Anticoagulants; Area Under Curve; Bias; Blood Specimen Collection; Case-Control Studies; Cytochrome P-450 CYP2C9; Drug Monitoring; Enzyme Induction; Female; Humans; Male; Middle Aged; Models, Theoretical; Neoplasms; Phenotype; Retrospective Studies; Time Factors; Warfarin; Young Adult

Antithrombotic therapy could trigger diffuse alveolar hemorrhage (DAH), and there are several case reports of DAH that occurred during antithrombotic therapy (DAH-AT). However, little is known about the clinical features and outcomes of DAH-AT. The purpose of this study was to clarify the features and mortality of DAH-AT.. 76 consecutive patients with DAH who were admitted to our hospital between January 2003 and April 2014 were retrospectively reviewed to identify the clinical features and outcomes of DAH-AT. The primary outcome was 90-day mortality.. Of the 76 patients with DAH, 39 patients (51 %) had DAH-AT, and 37 patients (49 %) had DAH that occurred with no antithrombotic therapy (DAH-NAT). Of the patients with DAH-AT, 25 (64 %) were taking aspirin, 14 (36 %) were taking warfarin, 5 (13 %) were taking clopidogrel sulfate, and 4 (10 %) were taking cilostazol. Pre-existing cardiac disease was present in 23 (59 %) DAH-AT cases and 5 (14 %) DAH-NAT cases. Logistic regression analysis was used to assess the effect of antithrombotic therapy on the mortality of DAH patients, and no significant difference in survival was seen with antithrombotic therapy (OR 1.18, 95 % CI 0.38-3.78).. Antithrombotic therapies had no effect on the 90-day mortality of DAH patients.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Cilostazol; Clopidogrel; Connective Tissue Diseases; Female; Fibrinolytic Agents; Heart Failure; Hemorrhage; Humans; Infections; Lung Diseases; Male; Middle Aged; Neoplasms; Pneumonia; Pulmonary Alveoli; Retrospective Studies; Survival Rate; Tetrazoles; Ticlopidine; Vasculitis; Warfarin

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

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

Whilst the term cancer associated thrombosis (CAT) offers an overarching term for all thrombotic events encountered during the cancer journey, the reality is that this is a far too simplistic reflection of a complex multifactorial process occurring within a heterogeneous population. The management of CAT needs to consider factors beyond the thrombus itself: patients must be treated as individuals within the context of their own cancer journey and their preferences for different treatment options. The breath of pathological, pharmacological and psychosocial variants means it is highly unlikely that one treatment regime will be appropriate for all patients. It is inevitable that regimes may need to be modified and anticoagulant agents changed according to clinical and patient preference needs. There is strong evidence supporting the use of low molecular weight heparin first line in the treatment of acute CAT. The evidence for warfarin and the direct acting oral anticoagulants is not as strong but, as oral agents, may be preferred by some patients. This paper shall identify the various treatment options available, factors which will influence the decision making process and when it is justifiable to treat patients differently to the established protocol.

Topics: Anticoagulants; Clinical Decision-Making; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Precision Medicine; Thrombosis; Warfarin

A two-fold prolongation of activated partial thromboplastin time (APTT) is established as therapeutic range for therapy with unfractionated heparin, hirudin and argatroban. The international normalized ratio (INR) of 2 to 3 is required to maintain anticoagulation in the therapeutic range of vitamin K antagonists. The therapeutic range of anti-factor Xa activity during therapy with low-molecular weight heparins and danaparoid are less well and of direct oral anticoagulants (DOAC) poorly defined. The relation of aPTT and INR values to thrombotic and bleeding events are well established despite a large variation of values in affected patients. The relation of coagulation values of the other anticoagulants to clinical events is open. The value of determination in cancer patients is higher because of the increased risk for thrombotic and bleeding events of this patient group. Several activities are currently undertaken to certify methods for in vitro diagnostic testing for DAOCs.

Topics: Anticoagulants; Blood Coagulation Tests; Dabigatran; Drug Monitoring; Factor Xa Inhibitors; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Partial Thromboplastin Time; Pyrazoles; Pyridones; Rivaroxaban; Thrombosis; Warfarin

A new cancer diagnosis adds significant complexity and uncertainty to the management of pre-existing warfarin therapy.. To determine how new-onset cancer affects anticoagulation control and outcomes among patients who had been receiving warfarin for atrial fibrillation (AF) compared to patients who had been receiving warfarin for venous thromboembolism (VTE) prior to cancer diagnosis.. This cohort study started with 122,875 veterans who had been receiving warfarin for at least six months from a VA Medical Center between 10/1/06 and 9/30/08. We identified patients with incident cancer during this interval, and excluded those with a prior cancer history. We analyzed percent time in therapeutic range (TTR) at 6 and 12-month intervals after cancer diagnosis compared to pre-cancer baseline, as well as crude rates of warfarin-relevant outcomes (stroke, major bleeding, mortality) between patients with AF and VTE.. Among patients with new-onset cancer, patients anticoagulated for AF outnumbered those anticoagulated for VTE more than 2.5-fold. There were no significant differences in TTR by indication for warfarin in months 0-6 or 7-12 following cancer diagnosis, but TTR decreased significantly compared to the pre-cancer baseline for both groups in months 0-6. As expected, cancer patients with VTE had significantly worse mortality at six months and one year compared to cancer patients with AF.. Patients receiving chronic warfarin therapy who are newly diagnosed with cancer experience a significant decrease in TTR in the first 6months after diagnosis, regardless of indication for anticoagulation. This effect appears to attenuate in months 7-12.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome; Venous Thromboembolism; Veterans; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Pulmonary Embolism; Warfarin

Data on efficacy and safety of using low molecular weight heparin in cancer patients with catheter-related upper extremity deep vein thrombosis is scarce and the risk of recurrent venous thromboembolism after discontinuation of anticoagulation is unknown.. We conducted a retrospective cohort study including consecutive cancer outpatients assessed for the management of symptomatic central venous catheter-associated proximal upper extremity deep vein thrombosis.. Of 99 included patients, 89 were treated with one month of full therapeutic weight-adjusted dose of low molecular weight heparin followed by an intermediate dose. Median duration of anticoagulation was 124 days (range 40 to 1849). No recurrent venous thromboembolism and two major bleeding episodes occurred during the first 3 months of treatment. Eighty patients were followed-up after anticoagulation discontinuation for a median of 632 days (range 6 to 2495). Central venous line was pulled in all patients in remission and in 26 of the 29 patients (89.6%) with active cancer. Five recurrences were observed during follow-up. The cumulative probability of recurrent venous thromboembolism was higher in patients whose cancer was active at the time of anticoagulation discontinuation as compared with those in remission (22.2% (95% CI: 0 to 40.6) vs. 2.3% (95% CI: 0 to 6.7)).. The risk of venous thromboembolism recurrence in patients whose central venous catheter has been pulled out and cancer is in remission appears low following anticoagulation discontinuation and after a minimum of 3 months of full/intermediate dose.

Topics: Central Venous Catheters; Cohort Studies; Female; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Treatment Outcome; Upper Extremity Deep Vein Thrombosis; Venous Thromboembolism; Warfarin

The efficacy and safety of dabigatran for treatment of venous thromboembolism (VTE) were demonstrated in two trials. It is unclear if the results pertain to patients with cancer and VTE. Data from two randomised trials comparing dabigatran and warfarin for acute VTE were pooled. Primary efficacy outcome was symptomatic recurrent VTE and related death from randomisation to the end of the treatment period. Safety outcomes were major, major and clinically relevant non-major, and any bleeding during the oral-only treatment period. Patients with active cancer (=within 5 years) at baseline or diagnosed during the study were analysed. Compared with 4,772 patients without cancer, recurrent VTE occurred more frequently in 335 patients with cancer at any time (hazard ratio [HR] 3.3; 95 % confidence interval [CI], 2.1-5.3) and more often in 114 with cancer diagnosed during the study compared to 221 with cancer at baseline (HR 2.6; 95 % CI, 1.1-6.2). There was no significant difference in efficacy between dabigatran and warfarin for cancer at baseline (HR 0.75; 95 % CI, 0.20-2.8) or diagnosed during the study (HR 0.63; 95 % CI, 0.20-2.0). Major bleeding (HR 4.1; 95 % CI, 2.2-7.5) and any bleeding (HR 1.5; 95 % CI, 1.2-2.0) were more frequent in patients with cancer than without, but with similar incidence in cancer with dabigatran or warfarin. In conclusion, in cancer patients, dabigatran provided similar clinical benefit as warfarin. VTE recurrence or bleeding were similar in patients on dabigatran or warfarin. The efficacy of dabigatran has not been assessed in comparison with low-molecular-weight heparin.

Topics: Adult; Aged; Anticoagulants; Antithrombins; Dabigatran; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Odds Ratio; Proportional Hazards Models; Randomized Controlled Trials as Topic; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

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

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

Venous limb gangrene (VLG) can occur in cancer patients, but the clinical picture and pathogenesis remain uncertain. We identified 10 patients with metastatic cancer (7 pathologically proven) who developed severe venous limb ischemia (phlegmasia/VLG) after initiating treatment of deep-vein thrombosis (DVT); in 8 patients, cancer was not known or suspected at presentation. The patients exhibited a novel, clinically distinct syndrome: warfarin-associated supratherapeutic international normalized ratio (INR; median, 6.5) at onset of limb ischemia, rising platelet count during heparin anticoagulation, and platelet fall after stopping heparin. Despite supratherapeutic INRs, patient plasma contained markedly elevated thrombin-antithrombin (TAT) complex levels (indicating uncontrolled thrombin generation) and protein C (PC) depletion; this profile resembles the greatly elevated TAT/PC activity ratios reported in patients with warfarin-associated VLG complicating heparin-induced thrombocytopenia. Analyses of vitamin K-dependent factors in 6 cancer patients with available serial plasma samples showed that variations in the INR corresponded most closely with changes in factor VII, with a highly collinear relationship between VII and PC. We conclude that venous limb ischemia/gangrene is explained in some cancer patients by profoundly disturbed procoagulant-anticoagulant balance, whereby warfarin fails to block cancer-associated hypercoagulability while nonetheless contributing to severe PC depletion, manifest as a characteristic supratherapeutic INR caused by parallel severe factor VII depletion.

Topics: Aged; Anticoagulants; Antithrombin III; Blood Coagulation Factors; Blood Platelets; Female; Follow-Up Studies; Gangrene; Heparin; Humans; International Normalized Ratio; Ischemia; Leg; Male; Middle Aged; Neoplasms; Peptide Hydrolases; Prognosis; Protein C Deficiency; Syndrome; Venous Thrombosis; Vitamin K; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used in the prevention and treatment of venous thromboembolism and in the prevention of stroke in patients with non-valvular atrial fibrillation. In phase III clinical trials and meta-analyses, the NOACs were at least as effective as vitamin K antagonists (VKAs) and were associated with a similar or lower incidence of major bleeding, including consistent and significant decreases in intracranial bleeding, although with an increase in gastrointestinal bleeding for some agents compared with VKAs. Subsequent real-world evidence supports these outcomes. Despite this, physicians have concerns about serious bleeding or emergencies because there are no specific reversal agents for the NOACs. However, in clinical trials, patients receiving NOACs generally had similar or better outcomes after these events than those taking VKAs. As with any bleeding, anticoagulant-related bleeding should first be stratified according to severity and location; risk can be minimised by ongoing assessment. Management protocols for NOAC-related bleeding are similar to those for VKAs but should take into account the pharmacological profile of the specific drug. Because of their short half-lives, NOAC-related mild bleeding can often be controlled by temporarily withholding treatment. More severe bleeding requires standard escalating haemodynamic support measures, and non-specific reversal agents can be considered in life-threatening situations, based on limited clinical data. Specific and rapid reversal agents are not currently available for any oral anticoagulant and restoration of coagulation may not necessarily lead to better outcomes. Nevertheless, specific NOAC reversal agents are in development and show promise in healthy volunteers.

Topics: Aged; Antidotes; Antithrombins; Atrial Fibrillation; Blood Coagulation Factors; Blood Transfusion; Clinical Protocols; Clinical Trials, Phase III as Topic; Disease Management; Drug Design; Factor Xa Inhibitors; Hemorrhage; Hemostatic Techniques; Humans; Intracranial Hemorrhages; Kidney Failure, Chronic; Meta-Analysis as Topic; Neoplasms; Perioperative Care; Postoperative Hemorrhage; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Assessment; Thrombophilia; Vulnerable Populations; Warfarin

In this issue of Blood, Warkentin et al describe a novel clinical syndrome of warfarin-associated severe venous limb ischemia occurring in a series of 10 patients with malignancy after initiating treatment of deep venous thrombosis. Patients in this series also demonstrated a decline in platelet counts after stopping heparin, warfarin-associated supratherapeutic international normalized ratios (INRs), and evidence of persistent thrombin generation despite anticoagulation.

Topics: Anticoagulants; Female; Gangrene; Humans; Ischemia; Leg; Male; Neoplasms; Venous Thrombosis; Warfarin

Topics: Acute Disease; Age Factors; Ambulatory Care; Anticoagulants; Antithrombins; Comorbidity; Dabigatran; Disease Management; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Hospitalization; Humans; Male; Neoplasms; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thrombolytic Therapy; Tissue Plasminogen Activator; Vena Cava Filters; Warfarin

Periprocedural management of patients on long-term warfarin therapy remains a common and important clinical issue, with little high-quality data to guide this complex process. The current accepted practice is cessation of warfarin five days preoperatively, but this is not without risk and can be complicated, particularly if bridging is required. An alternative method utilising low-dose intravenous vitamin K the day before surgery has been shown previously to be efficacious, safe and convenient in an elective surgical population receiving chronic warfarin therapy. The efficacy and utility of this 'fast-track' warfarin reversal protocol in surgical patients with cancer, who were at high risk of both thromboembolism and bleeding was investigated in a prospective, single-arm study at a dedicated cancer centre. Seventy-one patients underwent 82 episodes of fast-track warfarin reversal (3 mg intravenous vitamin K 18 to 24 hours before surgery). No patient suffered an adverse reaction to intravenous vitamin K, all but one achieved an International Normalized Ratio =1.5 on the day of surgery, and no surgery was deferred. Assays of vitamin K-dependent factor levels pre- and post-vitamin K demonstrated restoration of functional activity to within an acceptable range for surgical haemostasis. While this alternative method requires further validation in a larger prospective randomised study, we have now extended our use of fast-track warfarin reversal using vitamin K to patients with cancer, on the basis of our experience of its safety, convenience, reliability and efficacy.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Elective Surgical Procedures; Female; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Vitamin K; Warfarin

Nowadays, anticoagulant therapy belongs to the most commonly used forms of pharmacotherapy in modern medicine. The most important representatives of anticoagulants are heparins (unfractionated heparin and low-molecular-weight heparin) and coumarin derivatives (vitamin K antagonists--VKA). Next to the many advantages of traditional oral anticoagulants may also have disadvantages. In Poland most often used two VKA: acenocoumarol and warfarin. The aim of the work is the analysis of the causes of the occurrence of bleeding disorders and symptoms of overdose VKA in patients to be hospitalized. In the years 2012 to 2014 were hospitalized 62 patients with overdose VKA (40 women and 22 men). The average age of patients was 75.3 years) and clotting disturbances and/or bleeding. At the time of the admission in all patients a significant increase in the value of the INR was stated, in 22 patients INR result was " no clot detected", on the remaining value of the INR were in the range of 7 to 13.1. On 51 patients observed different severe symptoms of bleeding (hematuria, bleeding from mucous membranes of the nose or gums ecchymoses on the extremities, bleeding from the gastrointestinal tract--as in 5 patients has led to significant anemia and transfusion of concentrated red blood cells. Up on 33 patients kidney function disorder were found--exacerbated chronic renal failure and urinary tract infection. 8 diagnosed inflammatory changes in the airways. On 13 patients, it was found a significant degree of neuropsychiatric disorders (dementia, cognitive impairment), which made impossible the understanding the sense of treatment and cooperation with the patient. In 6 patients the symptoms of overdose were probably dependent on the interaction with the congestants at the same time (change the preparation of anticoagulant, NSAIDs, antibiotics). In 2 cases, the overdose was a suicide attempt in nature. In addition to the above mentioned disorders, on two of those patients diagnosed with a malignant disease. Two patients died, the other has been improving and anticoagulant therapy with VKA was continued, in 4 VKA were changed to low-molecular-weight heparin, and on 4 commissioned new generation anticoagulant (rivaroxaban).

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Cognition Disorders; Dementia; Drug Interactions; Drug Overdose; Female; Humans; Male; Neoplasms; Poland; Suicide, Attempted; Vitamin K; Warfarin

While a considerable amount is known about which patient-level factors predict poor anticoagulation control with warfarin, measured by percent time in therapeutic range (TTR), less is known about predictors of time above or below target.. To identify predictors of different patterns of international normalized ratio (INR) values that account for poor control, including 'erratic' patterns, where more time is spent both above and below INR target, and unidirectional patterns, where time out of range is predominantly in one direction (low or high).. We studied 103 897 patients receiving warfarin with a target INR of 2-3 from 100 Veterans Health Administration sites between October 2006 and September 2008. Our outcomes were percent time above and below the target range. Predictors included patients' demographics, comorbidities, and other clinical data.. Predictors of erratic patterns included alcohol abuse (5.2% more time below and 3.7% more time above, P < 0.001 for all results), taking > 16 medications (4.6% more time below and 1.8% more time above compared to taking seven or fewer medications), and four or more hospitalizations during the study (6.6% more time below and 2% more time above compared to no hospitalization). In contrast, predictors like cancer, non-alcohol drug abuse, dementia, and bipolar disorder were associated with more time below the target range (3.4%, 5.2%, 2.6%, and 3.2%, respectively) and less (or similar) time above range.. Different patient-level factors predicted unidirectional below-target and 'erratic' patterns of INR control. Distinct interventions are necessary to address these two separate pathways to poor anticoagulation.

Topics: Adult; Aged; Alcoholism; Anticoagulants; Atrial Fibrillation; Bipolar Disorder; Blood Coagulation; Dementia; Female; Hospitalization; Humans; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Neoplasms; Substance-Related Disorders; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs; Venous Thromboembolism; Warfarin; Young Adult

Topics: Aged; Female; Heart Valve Prosthesis; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Warfarin

Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer-related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk.

Topics: Aged; Anticoagulants; Cohort Studies; Comorbidity; Female; Hemorrhage; Humans; Incidence; Leg; Male; Middle Aged; Minnesota; Multivariate Analysis; Neoplasm Staging; Neoplasms; Paresis; Population Surveillance; Prognosis; Proportional Hazards Models; Recurrence; Risk Assessment; Risk Factors; Venous Thromboembolism; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Australia; Chest Pain; Female; Heart Diseases; Hospital Mortality; Humans; Hypoxia; Male; Neoplasms; Neurodegenerative Diseases; Nursing Homes; Pulmonary Embolism; Retrospective Studies; Sex Distribution; Syncope; Warfarin

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Periodicals as Topic; Pharmacogenetics; Warfarin

Topics: Anticoagulants; Creatinine; Female; Fibrinolytic Agents; Heparin; Humans; International Normalized Ratio; Neoplasms; Platelet Count; Pregnancy; Pulmonary Embolism; Venous Thrombosis; Warfarin

There is no consensus in the oncology community about the optimal model for anticoagulation management of ambulatory cancer patients. To understand oncologists' preferences regarding anticoagulation management, we compared the characteristics of patients referred to an oncology-oriented anticoagulation management service with "usual care" patients managed by the patient's primary oncologist.. We performed a retrospective medical record review of ambulatory oncology patients' anticoagulation care at a comprehensive cancer center. We examined the characteristics of 33 patients anticoagulated before implementation of a dedicated oncology anticoagulation management service. We compared this group with 33 patients managed by the anticoagulation management service and with 39 usual care patients managed by the primary oncologist after the anticoagulation management service was created. We also examined differences in laboratory test utilization, time in the therapeutic range (for patients anticoagulated with warfarin), and anticoagulation-related adverse events during a 3-month assessment period.. Anticoagulation management service patients were more likely to be treated for hematologic malignancies, use erythropoietin stimulating agents, and require warfarin management for previous venous thromboembolic disease compared to usual care patients. In contrast, oncologists were more likely to manage anticoagulation care of patients with advanced solid tumors undergoing active chemotherapy. Anticoagulation management service and usual care patients on warfarin therapy had comparable time in the therapeutic range and complication rates.. Oncologists selectively referred patients to the anticoagulation management service. Anticoagulation management service patients' warfarin control and complication rates were comparable to care provided by the primary oncologist, suggesting that an oncology-specific anticoagulation management service may be a feasible and effective option for anticoagulation management of ambulatory oncology patients.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Anticoagulants; Blood Coagulation Tests; Erythropoietin; Female; Humans; Male; Middle Aged; Neoplasms; Oncology Service, Hospital; Physicians; Practice Patterns, Physicians'; Retrospective Studies; Warfarin

Long term anticoagulant therapy is recommended for treatment and secondary prevention of venous thromboembolism in cancer patients. We assessed outpatient anticoagulants [warfarin, low molecular weight heparins (LMWHs), fondaparinux and unfractionated heparin (UFH)] use in adult, cancer patients, 20years of age or older, who incurred a venous thromboembolism (primary or secondary in-hospital diagnosis) in Quebec, Canada between 2007 and 2009.. Data were obtained from the Quebec Health Insurance Agency. Patients with an in-hospital cancer diagnosis between April 2007 and June 2009 and an in-hospital venous thromboembolism diagnosis either concurrently or consequently were eligible at the date of discharge (index date). Those patients registered with the provincial drug plan and discharged to the community were included in the study and followed for 6months.. Among 2,070 study patients, 72.4% received anticoagulant therapy at index date, 60% of whom were persistent with therapy and received it for ≥80% of follow-up days. Outpatient anticoagulant use was more likely in those with primary versus secondary diagnosis of venous thromboembolism and less likely in patients with cerebrovascular disease, peptic ulcer disease or previous anticoagulant use. The small number of patients who used either UFH (n=11) or fondaparinux (n=5) at index date were included in the LMWH group. Warfarin use was less likely than LMWH use in corticosteroid users, previous anticoagulant users, patients with metastatic cancer and those with catheter or chemotherapy in the previous three months. Warfarin use was more likely than LMWH use in: older patients, those residing in rural areas, those with lower income and those suffering from ischemic heart disease, atrial fibrillation or chronic kidney disease. Patients with ischemic heart disease were more likely to have used a non-dalteparin LMWH versus dalteparin (currently, the only LMWH approved by health Canada for chronic treatment of VTE), while those residing in rural areas and those with catheter/chemotherapy were less likely to have used them. A primary (versus secondary) discharge diagnosis of venous thromboembolism [Odds Ratio 1.42; 95% confidence interval (1.14, 1.76)], and metastatic cancer 1.27 (1.00, 1.60) were associated with persistence on anticoagulant treatment.. Guideline recommended outpatient use of anticoagulant in cancer patients hospitalized with venous thromboembolism was influenced by cancer status, old age and low income. Risk factors for bleeding prevented outpatient anticoagulant use in some patients.

Topics: Adult; Aged; Anticoagulants; Cohort Studies; Female; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Odds Ratio; Polysaccharides; Retrospective Studies; Time Factors; Venous Thromboembolism; Warfarin

Evidence-based treatment guidelines recommend low molecular weight heparin (LMWH) monotherapy for cancer-associated venous thromboembolism (VTE). This analysis assessed the first-line treatment strategies for VTE in patients with advanced solid tumors.. Using administrative data from advanced lung, prostate, colon, or breast cancer patients diagnosed between January 2000 and December 2007 at four HMOs with integrated delivery systems, patients with an inpatient or outpatient VTE diagnosed within 2 years after cancer diagnosis and an outpatient purchase of warfarin, LMWH, and/or fondaparinux anticoagulant within 7 days of the VTE diagnosis were identified. First-line outpatient VTE pharmacological treatment and factors independently associated with receipt/non-receipt of LMWH monotherapy were assessed.. Overall, 25% of the 1,089 eligible patients received LMWH monotherapy as primary VTE treatment. The percentage increased steadily over time from 18% among patients diagnosed in 2000 to 31% among those diagnosed in 2007. Factors associated with LMWH monotherapy included VTE diagnosis year, chemotherapy within 60 days prior to VTE diagnosis, history of VTE prior to cancer diagnosis, and invasive surgery in the 90 days following VTE diagnosis. Colorectal and prostate cancer patients versus lung cancer patients and stage III versus stage IV patients were less likely to be treated with LMWH monotherapy.. Adoption of LMWH monotherapy as initial treatment for cancer-associated VTE was low but increased steadily over the study period. Future studies should explore reasons underlying the underutilization of this preferred evidence-based treatment as well as the comparative effectiveness of LMWH versus warfarin-based anticoagulation in real-world cancer patients with VTE.

Topics: Aged; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Outpatients; Risk Factors; Treatment Outcome; Venous Thromboembolism; Warfarin

Patients with active cancer are often on chronic anticoagulation and frequently require interruption of this treatment for invasive procedures. The impact of cancer on periprocedural thromboembolism (TE) and major bleeding is not known.. Two thousand one hundred and eighty-two consecutive patients referred for periprocedural anticoagulation (2484 procedures) using a standardized protocol were followed forward in time to estimate the 3-month incidence of TE, major bleeding and survival stratified by anticoagulation indication. For each indication, we tested active cancer and bridging heparin therapy as potential predictors of TE and major bleeding.. Compared with patients without cancer, active cancer patients (n=493) had more venous thromboembolism (VTE) complications (1.2% versus 0.2%; P=0.001), major bleeding (3.4% versus 1.7%; P=0.02) and reduced survival (95% versus 99%; P<0.001). Among active cancer patients, only those chronically anticoagulated for VTE had higher rates of periprocedural VTE (2% versus 0.16%; P=0.002) and major bleeding (3.7% versus 0.6%; P<0.001). Bridging with heparin increased the rate of major bleeding in cancer patients (5% versus 1%; P=0.03) without impacting the VTE rate (0.7% versus 1.4%, P=0.50).. Cancer patients anticoagulated for VTE experience higher rates of periprocedural VTE and major bleeding. Periprocedural anticoagulation for these patients requires particular attention to reduce these complications.

Topics: Aged; Anticoagulants; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Prospective Studies; Venous Thromboembolism; Warfarin

Thrombotic risk is increased in patients with cancer and there are important implications for those who suffer a venous thromboembolism (VTE). We undertook this study to determine the frequency, clinical patterns, and outcome of VTE in Saudi patients with cancer.. Cancer (solid tumors and lymphoma) patients who developed VTE from January 2004 to January 2009 were studied retrospectively. Demographics and clinical characteristics related to thrombosis and cancer were evaluated.. A total of 701 patients with cancer were seen during the study period. VTE was diagnosed in 47 (6.7%) patients (median age 52, range 18-80 years). Lower limb DVT was the most common type, seen in 47% patients, followed by PE in 19%, and 19% patients had both DVT and PE. Thrombosis was symptomatic in 72% patients while it was an incidental finding on routine workup in 28% . Cancer and VTE were diagnosed at the same time in 38% of patients, and 47% patients developed VTE during the course of disease after the cancer diagnosis. The majority of VTE post cancer diagnoses occurred during the first year (median 4 months, range 1-14). Additional risk factors for VTE were present in 22 (47%) patients and 14 (30%) of these patients were receiving chemotherapy at the time of thrombosis. Only 5 (10.6%) patients were receiving thrombo-prophylaxis at the time of VTE diagnosis. Most common types of tumors associated with thrombosis were breast cancer, non-Hodgkin's lymphoma and lung cancer. The majority of the affected patients (79%) had advanced stage of cancer. After a median follow-up of 13 (range 0.5-60) months, 38 (81%) patients had died. There was no difference in the mortality of patients with symptomatic or asymptomatic thrombosis (82% vs 78.6%).. Thrombotic complications can develop in a significant number of patients with cancer, and almost half of the patients have additional risk factors for VTE. Thrombosis is usually associated with advanced disease and can be asymptomatic in more than a quarter of cases. Thromboprophylaxis in cancer patients is under-utilized. Community based studies are needed to accurately define the extent of this problem and to develop effective prophylactic strategies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Lymphoma; Male; Middle Aged; Neoplasm Staging; Neoplasms; Pulmonary Embolism; Retrospective Studies; Saudi Arabia; Venous Thromboembolism; Venous Thrombosis; Warfarin; Young Adult

Approximately 6 million Americans are treated with chronic anticoagulation. Of these, 10% of patients will require temporary anticoagulation interruption for an invasive procedure each year. Anticoagulation management during this period requires a formal strategy in order to limit both bleeding and thromboembolic complications. This article will give health care providers a stepwise approach to this process. The first step is to determine whether warfarin discontinuation is necessary for the planned procedure. For procedures requiring warfarin discontinuation, the second step is to determine the appropriate timing. The third step is to identify the patient-specific thromboembolic risk in order to determine which patients require bridging therapy with parenteral anticoagulants. The fourth step is both the most complicated and most critical step in this management strategy. This decision-making step involves choosing the appropriate anticoagulant regimen, dose, and timing of reinitiation that is best tailored to a specific patient, as well as determining procedural variables, in order to limit bleeding and thrombotic complications.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Coronary Restenosis; Dabigatran; Heart Valve Prosthesis; Hemorrhage; Humans; Morpholines; Neoplasms; Perioperative Care; Risk Assessment; Rivaroxaban; Stents; Thiophenes; Venous Thromboembolism; Warfarin

Topics: Aged; Altitude Sickness; Anticoagulants; Cholesterol, HDL; Clinical Trials as Topic; Enoxaparin; Female; Humans; Male; Neoplasms; Popliteal Vein; Pulmonary Embolism; Risk Factors; Sex Factors; Ultrasonography; Venous Thromboembolism; Warfarin; Young Adult

Topics: Anticoagulants; Antineoplastic Agents; Humans; Neoplasms; Precision Medicine; Terminology as Topic; Warfarin

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

Topics: Anticoagulants; Antineoplastic Agents; Catheterization, Central Venous; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Neoplasms; Randomized Controlled Trials as Topic; Venous Thrombosis; Vitamin K; Warfarin

Topics: Anticoagulants; Blood Coagulation Disorders; Endocarditis; Gangrene; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Risk Factors; Venous Thromboembolism; Warfarin

Infections in cancer patients after implantation of a central venous device (CVD) are not infrequent and are potentially serious. The possibility of limiting this complication with antithrombotic drugs is still debated. For this observational study, we recorded the routine management of CVD in cancer patients in 18 oncology centers in Lombardy (northern Italy), assessing the effect of antithrombotic prophylaxis on catheter-related infections. Out of 1410 patients enrolled, 451 received antithrombotic prophylaxis continuously after implantation of the central line. During a median follow-up of 30 months, 57 catheter-related infections were reported in the 1390 patients seen at least once at follow-up visits (4.1% of the whole series), giving an overall incidence of 0.10 infections per 1000 catheter days. This complication was significantly more frequent among patients with an indwelling central venous catheter, or peripherally inserted catheter, than among those with a port device, and the group not given antithrombotic prophylaxis had 0.14 infective complications/1000 CVD days compared with 0.05/1000 CVD days (odds ratio 2.4; 95% confidence interval 1.7-5.0) for those treated. Antithrombotic prophylaxis protected against infections at the catheter exit site and track but not against systemic infections. Confirming earlier evidence, this study found a reduction in catheter-related infections in patients given antithrombotic prophylaxis. However, this reduction, reflecting local infections, seems unlikely to be one of the mechanisms explaining the lower mortality among our patients treated with anticoagulants.

Topics: Antineoplastic Combined Chemotherapy Protocols; Catheterization, Central Venous; Cohort Studies; Female; Fibrinolytic Agents; Follow-Up Studies; Heparin, Low-Molecular-Weight; Humans; Italy; Male; Middle Aged; Neoplasm Staging; Neoplasms; Prospective Studies; Prosthesis-Related Infections; Regression Analysis; Treatment Outcome; Warfarin

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

Cancer patients at the end of life often take many medications and are at risk for drug interactions. The purpose of this study was to describe the epidemiology of potential drug interactions in cancer patients receiving supportive care exclusively. We retrospectively reviewed the charts of consecutive adult cancer outpatients attending palliative care clinics at the Princess Margaret Hospital, Toronto, Canada. Drugs were screened for interactions by the Drug Interaction Facts software, which classifies interactions by levels of severity (major, moderate, and minor) and scientific evidence (1-5, with 1=the strongest level of evidence). Among 372 eligible patients, 250 potential drug interactions were identified in 115 patients (31%, 95% confidence interval 26%-36%). The most common involved warfarin and phenytoin. Most interactions were classified as being of moderate severity (59%) and 42% of them were supported by Levels 1-3 of evidence. In multivariable analysis, increasing age (P<0.001), presence of comorbidity (P=0.001), cancer type (brain tumors, P<0.001), and increasing number of drugs (P<0.001) were associated with risk of drug interactions. Potential drug interactions are common in palliative care and mostly involve warfarin and anticonvulsants. Older patients, those with comorbid conditions, brain tumor patients, and those taking many medications are at greater risk of drug interactions.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Anticonvulsants; Cohort Studies; Cross-Sectional Studies; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Retrospective Studies; Warfarin

Among patients treated with warfarin for venous thromboembolism (VTE), cancer patients have more thrombotic and hemorrhagic events than patients without cancer. Is this also the case when cancer patients are anticoagulated for other indications?. The objective of the study is to evaluate the effectiveness of warfarin, given for any indication, among patients with cancer in a community setting.. We identified patients with cancer from a larger prospective cohort of 6,761 patients from 101 clinical sites in the United States, matched to controls without cancer. The proportion of time spent in the therapeutic range, international normalized ration (INR) variability, and the rate of thromboembolic and major hemorrhagic events were compared between the two groups.. Ninety-five patients undergoing treatment for cancer were matched to 283 patients without cancer. The cancer group spent less time in the target INR range (54 vs 66%, P < .001) and had more variable INR values (standard deviation around the mean INR value 1.30 vs 0.71, P < .001). There were more thrombotic events in the cancer group than in the control group (5 vs 0 events, P < .001). These analyses were repeated after excluding all of the patients anticoagulated for VTE; the results were unchanged.. Compared to matched controls, cancer patients receiving warfarin spend less time in the target INR range, have more variable INR values, and have more thrombotic events. These effects are not dependent on whether the patient is anticoagulated for VTE or another indication.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Neoplasms; Prospective Studies; Treatment Outcome; Venous Thrombosis; Warfarin

Central venous catheters in patients with cancer are associated with development of deep vein thrombosis (DVT); however, there is no accepted standard treatment.. To assess the safety and effectiveness of a management strategy for central venous catheter-related DVT in cancer patients consisting of dalteparin and warfarin without the need for line removal.. Patients older than 18 years of age with an active malignancy and who had symptomatic, acute, objectively documented UEDVT were eligible. Patients were treated with dalteparin 200 IU kg(-1) per day for 5-7 days and warfarin with a target International Normalized Ratio of 2.0-3.0. Patients were followed for 3 months for recurrent venous thromboembolism, major hemorrhage and survival of the central venous catheter.. There were 74 patients (48 males). The average age was 58 years. There were no episodes of recurrent venous thromboembolism and three (4%) major bleeds. No lines were removed because of infusion failure or recurrence/extension of DVT.. Treatment of UEDVTs secondary to central catheters in cancer patients with standard dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT.

Topics: Aged; Anticoagulants; Catheterization, Central Venous; Cohort Studies; Dalteparin; Female; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Pilot Projects; Treatment Outcome; Venous Thrombosis; Warfarin

Oral anticoagulants present multiple practical problems for patients undergoing chemotherapy. To assess the practice implications of anticoagulation therapy, a review was carried out.. A review of all patients with cancer treated with warfarin for venous thromboembolism (VTE) over a 1-year-period was carried out. Adverse events and therapeutic efficacy were assessed and the extra volume of work involved in monitoring was quantified.. Fifty-five patients with cancer and VTE were treated with warfarin from 07/04 to 06/05. Twenty-one invasive interventions required disruption of anticoagulation. There were eight admissions for haemorrhage. Nine patients died while on warfarin. A total of 1,379 coagulation tests were performed. There were 382 extra dayward visits attributable to warfarin monitoring. On treatment, 13 patients (24%) were changed from warfarin therapy to low molecular weight heparin (LMWH).. This study identifies and quantifies the extra resource utilization with warfarin therapy in patients undergoing chemotherapy.

Topics: Anticoagulants; Comorbidity; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Retrospective Studies; Superior Vena Cava Syndrome; Venous Thromboembolism; Warfarin

The aim was to identify risk factors for postoperative bleeding following skin cancer surgery.. This was a prospective study of 5950 skin lesions excised in 2394 patients. No patient stopped taking aspirin or warfarin unless the international normalized ratio (INR) exceeded 3.0.. The rate of postoperative bleeding was 0.7 per cent overall and 2.5 per cent in the 320 patients taking warfarin. The rate of bleeding was 1.0 per cent for skin flap repairs, 0.4 per cent for simple excision and closure, and 5.0 per cent for skin grafts. Diabetic patients and smokers were not at increased risk of bleeding. There were four independent factors for bleeding: age 67 years or older (odds ratio (OR) 4.7 (95 per cent confidence interval 1.8 to 12.2); P = 0.002), warfarin therapy (OR 2.9 (1.4 to 6.3); P = 0.006), surgery on or around the ear (OR 2.6 (1.2 to 5.7); P = 0.012) and closure with a skin flap or graft (OR 2.7 (1.4 to 5.3); P = 0.004). Aspirin therapy was not an independent risk factor for bleeding.. Most postoperative bleeds were inconvenient but not life threatening, unlike the potential risk of thromboembolism after stopping warfarin or aspirin. There was no case for discontinuing aspirin before skin surgery, but the INR should be monitored in patients taking warfarin.

Topics: Aged; Anticoagulants; Aspirin; Female; Hematoma; Humans; Male; Neoplasms; Platelet Aggregation Inhibitors; Postoperative Hemorrhage; Prospective Studies; Risk Factors; Warfarin

Topics: Anticoagulants; Comorbidity; Drug Administration Schedule; Fibrinolytic Agents; Heart Valve Prosthesis; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Thrombosis; Warfarin

The incidence of thrombosis and bleeding is higher in patients with cancer receiving warfarin compared with low molecular weight heparins. Despite these findings, warfarin remains a commonly used treatment strategy for anticoagulation in patients with cancer secondary to several factors that limit the use of low molecular weight heparins. Determining the appropriate warfarin dose in cancer patients is challenging. The objective of our study is to compare the weekly warfarin dose in patients with and without cancer. In a retrospective analysis, the average weekly warfarin dose was compared for 63 subjects who 1) were treated for cancer while receiving warfarin (n = 21), 2) completed treatment for their cancer before starting warfarin (n = 21), and 3) received warfarin with no diagnosis of cancer (n = 21). The data were abstracted from the medical record from the date the subject started taking a stable dose of warfarin after the initial titration until the discontinuation of warfarin. No significant differences were observed in the mean weekly warfarin dose, but the dose demonstrated greater intrasubject variability for subjects in group 1 (group 1, 31 +/- 22% vs. 2, 19 +/- 11% and 3, 15 +/- 10%, P = 0.003). Subjects in group 1 also spent more time above their goal International Normalized Ratio (group 1, 30 +/- 21% vs. 2, 21 +/- 16% and 3, 15 +/- 16%, P = 0.038). The average weekly warfarin dose was similar for the three groups, but the results of this study suggest that patients with cancer receiving treatment for their cancer and anticoagulation with warfarin are more difficult to appropriately anticoagulate.

Topics: Aged; Anticoagulants; Drug Administration Schedule; Drug Monitoring; Female; Humans; Illinois; International Normalized Ratio; Male; Medical Records; Middle Aged; Neoplasms; Retrospective Studies; Thromboembolism; Warfarin

Topics: Anticoagulants; Antimetabolites, Antineoplastic; Drug Interactions; Fluorouracil; Humans; International Normalized Ratio; Neoplasms; Thrombosis; Warfarin

Patients with a central venous catheter (CVC) undergoing high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell transplantation (PBSCT) for malignancies are at high risk of thrombosis, but the use of anti-coagulant prophylaxis remains debatable in this setting of patients. We analyzed the efficacy and the safety of minidose warfarin in 228 patients in whom CVCs had been placed and who had received 292 HDC courses of therapy. The catheters remained in place for a mean of 173 (range 40-298) days. All patients received prophylactic oral warfarin in the fixed dose of 1 mg/day starting on the day of CVC insertion. Prophylaxis was interrupted during aplasia when platelet counts fell below 50,000/dL. There were no toxic deaths related to the prophylaxis. Overall there were 4 thrombotic events. Three occurrences were directly related to the catheter, while the remaining event was a deep saphenous-vein thrombosis. A number of potential predictive factors were analyzed for their impact on thrombotic events without finding any significant correlation. Four episodes of bleeding occurred, with each of these individuals having a normal INR but a platelet count below 50,000/dL. Minidose warfarin is effective and safe to use for preventing thrombotic events in this setting of patients.

Topics: Administration, Oral; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Catheterization, Central Venous; Cytarabine; Female; Hemorrhage; Humans; Male; Melphalan; Neoplasms; Peripheral Blood Stem Cell Transplantation; Platelet Count; Podophyllotoxin; Retrospective Studies; Risk Factors; Transplantation, Homologous; Venous Thrombosis; Warfarin

Topics: Administration, Oral; Anticoagulants; Electric Countershock; Heart Valve Prosthesis; Hemoglobinuria; Heparin, Low-Molecular-Weight; Humans; Medical Audit; Neoplasms; Perioperative Care; Self Administration; Thromboembolism; Thrombophilia; Thrombosis; Vitamin K; Warfarin

The extent and complications of the interaction between capecitabine and warfarin are not fully known.. A retrospective study of 77 patients who received capecitabine was performed to analyze coagulation abnormalities with or without warfarin.. Twenty-one patients received warfarin with capecitabine. Twelve were on an average warfarin dosage of 19.4 mg per week (range, 7-35 mg) before capecitabine treatment, with a stable international normalized ratio (INR; range, 0.9-3.3). The dose of capecitabine ranged from 1.6 g/m2 to 2 g/m2 per day. Thirteen patients (11 on warfarin) had an INR > 3 (range, 3.23-11.5), resulting in a probability of an INR > 3 of 32% in the warfarin group versus 4% for those not on warfarin (P = 5.1 x 10(-14)) at 130 days. Six patients required a warfarin dose reduction (1-2.5 mg decrease). There were 7 episodes of bleeding (all gastrointestinal; 5 with warfarin). Seven patients who experienced bleeding had INRs ranging from 1.06 to 8 (average, 3.31) at the time bleeding occurred. Of the 7 bleeding episodes, 5 patients required transfusions, averaging 3.25 units of red blood cells and 2.4 units of fresh frozen plasma. The incidence of bleeding at 130 days of treatment with capecitabine was 18% with warfarin versus 2% without (P = 4 x 10(-13)). Bleeding episodes were not significantly different between patients with or without liver involvement (4 of 40 episodes vs. 3 of 37 episodes, respectively; P = 0.12). Patients with an INR > 3 were evenly distributed between those with or without liver involvement (6 of 40 patients vs. 7 of 37 patients, respectively). No INR increases persisted after discontinuation of capecitabine.. This study confirms a clinically significant interaction between warfarin and capecitabine-based chemotherapy akin to that already known for 5-fluorouracil. In addition to altered coagulation parameters, bleeding can be a complication. These events occurred in patients with and without liver metastases. We recommend weekly monitoring of coagulation parameters for all patients receiving concomitant warfarin and capecitabine, with an appropriate adjustment of warfarin dose. The nature and extent of this interaction requires further investigation.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antimetabolites, Antineoplastic; Blood Coagulation Disorders; Capecitabine; Deoxycytidine; Drug Interactions; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Polypharmacy; Retrospective Studies; Warfarin

Deep venous thrombosis (DVT) is a common complication of thalidomide treatment. There is little information to guide clinicians in selecting effective preventive treatments and physician practice varies. We sought to determine whether prophylactic anticoagulation with warfarin prevents DVT related to thalidomide treatment.. We reviewed the records of 131 patients receiving thalidomide for a variety of indications. Fifty-five patients were prescribed warfarin with the intent of preventing DVT. Thirty-seven patients received warfarin at a dose of 1-2 mg per day (low dose) and 18 received a dose intended to raise the INR to 2-3 (high dose).. Twenty-one of the 131 patients developed venous thrombosis during thalidomide treatment. Eighteen of the 76 patients (23.7%) who were not prescribed prophylactic anticoagulation developed DVT compared to 3 of the 55 patients (5.5%) who were prescribed any dose of prophylactic warfarin (P = 0.010). Only 1 of the 37 patients who received low-dose warfarin developed DVT (P = 0.011). Bleeding complications occurred in 4 patients, all of whom were receiving high-dose warfarin.. Prophylactic anticoagulation with warfarin reduces the risk of thrombosis during thalidomide treatment. Low-dose warfarin may be as effective as higher dose treatment and may result in fewer bleeding complications.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Anticoagulants; Cohort Studies; Female; Hemorrhage; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Thalidomide; Venous Thrombosis; Warfarin

In a recent randomised trial (CLOT [Comparison of Low molecular weight heparin versus Oral anticoagulant Therapy for long term anticoagulation in cancer patients with venous thromboembolism]), which evaluated secondary prophylaxis of venous thromboembolism (VTE) in cancer patients, dalteparin reduced the relative risk of recurrent VTEs by 52% compared with oral anticoagulation therapy (p = 0.002). A Canadian pharmacoeconomic analysis was conducted to measure the economic value of dalteparin for this indication.. The study was conducted from the Canadian healthcare system. The first part of this study utilised the CLOT trial database, from which resource utilisation data were converted into Canadian cost estimates (Can dollars, year 2005 values). Univariate and multivariate regression analyses were conducted to compare the total cost of therapy between patients randomised to treatment with dalteparin or oral therapy. Health state utilities and treatment preferences were then measured in 24 oncology care providers using the time trade-off technique.. When all of the cost components were combined for the entire population (n = 676), patients in the dalteparin group had significantly higher overall costs than the control group (Can dollars 4162 vs Can dollars 2003; p < 0.001). The preference assessment revealed that 23 of 24 respondents (96%) selected dalteparin over warfarin, with an associated gain of 0.157 QALYs. When the incremental cost of dalteparin (Can dollars 2159 per patient) was combined with the QALY gain, the findings revealed that dalteparin was associated with a cost of approximately Can dollars 13,800 (95% CI 12,400, 15,100) per QALY gained.. Given the practical advantages of dalteparin in terms of convenience, improved efficacy and the acceptable economic value, this analysis suggests that long-term dalteparin therapy is a sound alternative to warfarin for the prevention of recurrent VTEs in patients with cancer.

Topics: Adult; Anticoagulants; Canada; Dalteparin; Female; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Secondary Prevention; Thromboembolism; Warfarin

Approximately one third of children with malignancy and central venous lines develop catheter-related thrombosis, with the reported sequelae including death, pulmonary embolism, chylothoraces, superior vena cava syndrome and post-thrombotic syndrome. These complications prompt the design and completion of randomized, controlled trials to determine a safe and efficacious therapy to prevent these thromboses. The authors Ruud et al. have presented a well-designed, randomized, controlled trial which demonstrates the lack of utility of using low-dose warfarin to prevent catheter-related thrombosis in children with central lines and acute lymphoblastic leukaemia. The difficulties with warfarin in children are again demonstrated in this study.. Further studies are warranted using other thromboprophylactic agents with less or no monitoring and fewer drug interactions, including the newer anticoagulant agents such as direct thrombin inhibitors.

Topics: Anticoagulants; Catheterization, Central Venous; Catheters, Indwelling; Child; Humans; Neoplasms; Venous Thrombosis; Warfarin

Although extended secondary prophylaxis with low-molecular-weight heparin was recently shown to be more effective than warfarin for cancer-related venous thromboembolism, its cost-effectiveness compared to traditional prophylaxis with warfarin is uncertain. We built a decision analytic model to evaluate the clinical and economic outcomes of a 6-month course of low-molecular-weight heparin or warfarin therapy in 65-year-old patients with cancer-related venous thromboembolism. We used probability estimates and utilities reported in the literature and published cost data. Using a US societal perspective, we compared strategies based on quality-adjusted life-years (QALYs) and lifetime costs. The incremental cost-effectiveness ratio of low-molecular-weight heparin compared with warfarin was 149,865 dollars/QALY. Low-molecular-weight heparin yielded a quality-adjusted life expectancy of 1.097 QALYs at the cost of 15,329 dollars. Overall, 46% (7108 dollars) of the total costs associated with low-molecular-weight heparin were attributable to pharmacy costs. Although the low-molecular-weigh heparin strategy achieved a higher incremental quality-adjusted life expectancy than the warfarin strategy (difference of 0.051 QALYs), this clinical benefit was offset by a substantial cost increment of 7,609 dollars. Cost-effectiveness results were sensitive to variation of the early mortality risks associated with low-molecular-weight heparin and warfarin and the pharmacy costs for low-molecular-weight heparin. Based on the best available evidence, secondary prophylaxis with low-molecular-weight heparin is more effective than warfarin for cancer-related venous thromboembolism. However, because of the substantial pharmacy costs of extended low-molecular-weight heparin prophylaxis in the US, this treatment is relatively expensive compared with warfarin.

Topics: Cost-Benefit Analysis; Decision Making, Computer-Assisted; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Premedication; Quality-Adjusted Life Years; Thromboembolism; United States; Venous Thrombosis; Warfarin

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Hemostasis; Humans; Incidence; Leucovorin; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Platelet Aggregation Inhibitors; Warfarin

Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin.. Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61.. During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC(0-infinity)) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t(1/2); 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance.. There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.

Topics: Adult; Anticoagulants; Antimetabolites, Antineoplastic; Capecitabine; Deoxycytidine; Drug Synergism; Factor VII; Fluorouracil; Half-Life; Humans; Middle Aged; Neoplasms; Prothrombin Time; Vitamin K 1; Warfarin

Topics: Anticoagulants; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Venous Thrombosis; Warfarin

One of the standard treatments for cancer-associated thrombosis has been initial therapy with unfractionated heparin (UFH) followed by long-term therapy with an oral anticoagulant (i.e., warfarin). However, characteristics associated with these two agents may make them suboptimal for many cancer patients. This article will explore some of the considerations and limitations when using UFH and warfarin in the cancer population and will also utilize case studies to emphasize the importance of individualized care.. UFH is an effective anticoagulant when doses are adjusted to maintain the activated partial thromboplastin time (aPTT) within a specified therapeutic range. However, due to the complex pharmacokinetics of this agent, patients must undergo frequent monitoring to maintain a therapeutic aPTT. In addition, UFH can be associated with serious adverse events including osteoporosis, heparin-induced thrombocytopenia, and bleeding. Similar to UFH, warfarin requires frequent monitoring and dose adjustments to maintain the International Normalized Ratio (INR) within the therapeutic range of 2.0 to 3.0. Warfarin also has numerous drug-herbal, drug-food, and drug-drug interactions, including interactions with many commonly used anti-tumor therapies. Complications related to UFH and warfarin in the treatment of cancer-associated thrombosis have gradually been minimized with the increased use of low molecular weight heparins (LMWHs), which are associated with reduced incidence of bleeding, heparin-induced thrombocytopenia, and drug interactions. In addition, LMWHs allow for convenient daily dosing without requiring routine monitoring and the option of home therapy.. When deciding on the optimal anticoagulant strategy, pharmacists must take into account the unique characteristics and needs of each individual patient as well as the specifics of the various anticoagulant therapies. Future strategies for the initial and long-term treatment of cancer-associated thrombosis may increasingly incorporate LMWHs because of factors related to safety and convenience.

Topics: Anticoagulants; Bone Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Fatigue; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Thrombosis; Warfarin

Topics: Humans; Neoplasms; Patient Selection; Research Design; Vitamin K; Warfarin

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antineoplastic Agents; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Drug Design; Humans; Neoplasms; Trastuzumab; Warfarin

Topics: Anticoagulants; Antimetabolites, Antineoplastic; Catheterization, Central Venous; Catheters, Indwelling; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Interactions; Fluorouracil; Humans; International Normalized Ratio; Neoplasms; Organoplatinum Compounds; Oxaliplatin; Thrombosis; Warfarin

To correlate the concentration of plasma coagulation markers at baseline and during follow-up in patients with solid tumors and venous thromboembolic disease with the risk of recurrence and death.. Patients (N = 223) with first episode of venous thromboembolic disease received oral anticoagulation with warfarin for a target international normalized ratio of 2 to 3. Plasma coagulation markers were measured before instituting warfarin and at 3 monthly intervals, thereafter.. The median duration of oral anticoagulation was 6.7 months (range 2 weeks to 11 months). Major bleeding episodes occurred in 18 patients (8%), and minor hemorrhagic events occurred in 15 (6.7%) patients. Patients with advanced malignancy (P = 0.032), history of surgery (P = 0.057), and those with poor performance status (P = 0.001) were more likely to encounter major bleeding episodes. Recurrence of venous thromboembolic disease was diagnosed in 31 patients (14%). At univariate analysis, advanced stage of cancer (P = 0.03), performance status > 1 (P = 0.001), treatment with chemotherapy (P = 0.01), the presence of metastatic liver disease (P = 0.03), higher d-dimer (P = 0.001), and thrombin antithrombin complex levels (P = 0.01) were features predictive of recurrent venous thromboembolic disease. At multivariate analysis, poor performance status (P = 0.01) and d-dimer levels (P = 0.001) were predictors of recurrent venous thromboembolic disease. Persistent activation of coagulation as indicated by an upward trend in d-dimer (P = 0.001) and antithrombin (P = 0.001) was observed in patients who developed recurrent thrombosis. Similar upward trends in d-dimer (P = 0.001), antithrombin (P = 0.001), and prothrombin fragment F1 + 2 (P = 0.001) was observed in the 76 patients who died during the study period and in the patients who received chemotherapy.. Successful oral anticoagulation with warfarin in patients with cancer and venous thromboembolic disease is more likely to be achieved in patients with early stage tumors and good performance status. The persistence of activation of hemostasis as shown by plasma coagulation markers is a strong predictor of recurrence and poor outcome.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Female; Fibrin Fibrinogen Degradation Products; Humans; International Normalized Ratio; Liver Diseases; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoplasms; Recurrence; Thromboembolism; Time Factors; Treatment Outcome; Warfarin

The use of prophylactic low-dose oral warfarin in cancer patients with a central venous catheter (CVC) in place has an established role in the prevention of thrombotic complications and is associated with a low hemorrhagic risk. Despite the literature indicating an adverse interaction between warfarin and fluorouracil (FU), the frequency of this interaction and whether it occurs when minidose warfarin is used is unknown. We analyzed the incidence of alterations in the International Normalized Ratio (INR) and bleeding in cancer patients given minidose warfarin during treatment with continuous-infusion FU-based regimens.. Between July 1999 and August 2001, 95 cancer patients were evaluated. Forty-one patients (43%) had liver metastases. Seventy-nine patients (83%) had a Groshong CVC (Bard Access System, Salt Lake City, UT), and 16 (17%) had a Port-a-Cath device (Bard Access System). All patients received oral warfarin at a dose of 1 mg/daily as prophylaxis beginning the day after the catheter was positioned. An INR of more than 1.5 was considered significantly elevated.. INR elevation occurred in 31 patients (33%), with 18 patients (19%) having an INR more than 3.0. Twelve (39%) of the 31 patients had liver metastases. Bleeding was observed in eight patients (8%); seven of these patients had elevated INR levels. We observed INR elevations in 12 of 21 patients treated with a FU, folinic acid, and oxaliplatin (FOLFOX) regimen, 11 of 40 treated with a de Gramont regimen (FU and folinic acid), and five of 19 treated with a FU, folinic acid, and irinotecan (FOLFIRI) regimen.. A high incidence of INR abnormalities was observed in our cohort of patients, especially those treated with FOLFOX regimen. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time in patients receiving warfarin and FU.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Catheterization, Central Venous; Drug Interactions; Female; Fluorouracil; Humans; Infusions, Intravenous; International Normalized Ratio; Liver Neoplasms; Male; Neoplasms; Retrospective Studies; Thrombosis; Warfarin

The role of prophylactic vena cava filters (VCF) in patients with cancer is debated. Although VCF are often placed in patients with cancer after recurrence of venous thromboembolic events (VTE), identification of this subset of patients has not been well-defined. This study was undertaken to assess factors associated with increased risk for recurrent VTE.. All patients with a history of thromboembolism or malignant disease and who required a VCF because of failure of or contraindication to anticoagulation therapy were abstracted from the Michigan Filter Registry. Univariate analysis of potential risk factors for recurrent VTE and logistic regression models were used to identify associations between these variables and recurrent VTE.. Ninety-nine patients (49 men, 50 women) with a mean age of 58 years were included in the study. New metastases occurred in 55% of patients, and 12% of patients had a history of VTE before cancer diagnosis. Corticosteroid agents were used during therapy in 48% of patients. Acute VTE was present in 52% of patients at cancer diagnosis, and in 34% of patients VTE was associated with new metastases. Recurrent VTE occurred in 40% of patients, and significant risk factors included presence of new metastases (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.16-9.09; P =.02) and history of VTE (OR, 10.6; CI, 1.98-57.2; P =.006). Whereas a single episode of neutropenia did not reach significance (OR, 1.1; CI, 0.97-1.35; P =.11), multiple neutropenic episodes were significantly associated with recurrent VTE (P =.04). Smoking, hormone replacement therapy, decreased mobility, post-surgical state, and obesity were not independently associated with increased risk. Mean survival in this series was 30 months, and was significantly worse in patients with VTE at cancer diagnosis and with inability to tolerate anticoagulant therapy in conjunction with VCF.. Patients with malignant disease may be at increased risk for recurrent VTE after development of new metastases or multiple episodes of neutropenia, especially those patients with a history of VTE. VCF may be a reasonable alternative to long-term anticoagulation therapy in this subgroup of patients at high risk patients, provided their quality of life is reasonable.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Vessel Prosthesis Implantation; Cause of Death; Female; Heparin; Humans; Incidence; Male; Michigan; Middle Aged; Neoplasms; Neutropenia; Partial Thromboplastin Time; Recurrence; Risk Factors; Survival Analysis; Thromboembolism; Time Factors; Vena Cava Filters; Venous Thrombosis; Warfarin

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Embolism; Endpoint Determination; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Survival Analysis; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Embolism; Endpoint Determination; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Recurrence; Survival Analysis; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Embolism; Endpoint Determination; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Male; Middle Aged; Neoplasms; Recurrence; Survival Analysis; Treatment Outcome; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Confounding Factors, Epidemiologic; Hemorrhage; Humans; International Normalized Ratio; Neoplasms; Pulmonary Embolism; Secondary Prevention; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Controlled Clinical Trials as Topic; Dalteparin; Fibrinolytic Agents; Heparin; Humans; Neoplasms; Placebos; Prospective Studies; Retrospective Studies; Risk Factors; Thrombosis; Time Factors; Warfarin

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Neoplasms; Survival Rate; Vitamin K; Warfarin

To assess the outcome of deep vein thrombosis in patients with malignancy after 6 months of oral anticoagulant therapy, and to compare it with international normalized ratio (INR).. Thirty-one patients with malignancy (13 with hematological and 18 with solid tumors) and deep vein thrombosis (29 leg thrombosis and 2 upper extremity thrombosis) were included into a prospective cohort study that lasted from March 2000 until May 2001. The presence of malignant tumors was histologically proved and documented, and deep vein thrombosis was proved by ultrasound or venography. Patients were treated with heparin during the acute phase, and with oral anticoagulant therapy during further 6 months. INRs and ultrasound examination performed during the acute event were repeated one month and 6 months afterwards for the needs of analysis.. Twenty-four patients concluded the study. Clot resolution was achieved in 13 patients after 6 months of therapy. The patients with INR>2 (n=10) had better clot resolution than those with INR<2 (n=3); p=0.012. There was no statistically significant difference in the outcome of thrombosis with regard to the INR level after a month of therapy (p=0.555). Three patients experienced bleeding, one patient had recurrent thrombosis, and two patients suffered pulmonary embolism.. Appropriate anticoagulation during 6 months after the acute deep vein thrombosis enhances the rate of the complete clot resolution. The INR values can be used as predictive of complete recovery from the thrombosis. Complications are comparable with those reported for patients without malignancy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Chi-Square Distribution; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Probability; Prospective Studies; Risk Assessment; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Ultrasonography; Venous Thrombosis; Warfarin

Topics: Administration, Oral; Anticoagulants; Dicumarol; Embolism; Follow-Up Studies; Humans; Incidence; Neoplasms; Pulmonary Embolism; Risk Factors; Thrombosis; Time Factors; Warfarin

Topics: Anticoagulants; Humans; International Normalized Ratio; Neoplasms; Thromboembolism; Vitamin K; Warfarin

An elevated international normalized ratio (INR) increases the risk for major hemorrhage during warfarin therapy. Optimal management of patients with asymptomatic elevations in INR is hampered by the lack of understanding of the time course of INR decay after cessation of warfarin therapy.. To identify predictors of the rate of INR normalization after excessive anticoagulation.. Retrospective cohort study.. Outpatient anticoagulant therapy unit.. Outpatients with an INR greater than 6.0 were identified from August 1993 to September 1998. Patients in whom two doses of warfarin were withheld and a follow-up INR was obtained on the second calendar day were enrolled. No patient received vitamin K(1).. The INR was measured 2 days after an INR greater than 6.0 was recorded.. Of 633 study patients with an initial INR greater than 6.0, 232 (37%) still had an INR of 4.0 or greater after two doses of warfarin were withheld. Patients who required larger weekly maintenance doses of warfarin were less likely to have an INR of 4.0 or greater on day 2 (adjusted odds ratio per 10 mg of warfarin, 0.87 [95% CI, 0.79 to 0.97]). Other risk factors for having an INR of 4.0 or greater on day 2 included age (odds ratio per decade of life, 1.18 [CI, 1.01 to 1.38]), index INR (odds ratio per unit, 1.25 [CI, 1.14 to 1.37]), decompensated congestive heart failure (odds ratio, 2.79 [CI, 1.30 to 5.98]), and active cancer (odds ratio, 2.48 [CI, 1.11 to 5.57]).. Steady-state warfarin dose, advanced age, and extreme elevation in INR are risk factors for prolonged delay in return of the INR to within the therapeutic range. Decompensated congestive heart failure and active cancer greatly increase this risk.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Cohort Studies; Female; Half-Life; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Logistic Models; Male; Neoplasms; Retrospective Studies; Risk Factors; Time Factors; Vitamin K 1; Warfarin

The optimal management of patients who have recurrent thromboembolism while being treated with oral anticoagulation therapy is unknown. This study reports managing such patients with extended duration low molecular weight heparin therapy.. This study was a retrospective review of the prospective databases of three tertiary care teaching hospitals over a 27-month period. All patients who had recurrent symptomatic thromboembolism while being treated with warfarin were identified. All patients were treated with low molecular weight heparin (dalteparin), 200 U/kg daily. Data were collected for recurrent venous thromboembolism, bleeding, and survival.. Eight hundred eighty-seven patients were managed for acute thromboembolism. In 32 patients, symptomatic, objectively documented thromboembolism recurred while they were taking warfarin; 63% of the patients with recurrence had cancer, compared with 30% of patients without recurrence. All recurrences were treated with dalteparin. In 3 patients (9% [95% confidence interval: 2% to 25%]), symptomatic recurrence developed while they were being treated with low molecular weight heparin. Nineteen patients (59%) died while receiving anticoagulation therapy; all deaths but 1 were due to malignancy, and none was due to pulmonary embolism or bleeding.. These results suggest that recurrent venous thromboembolism is more likely to develop in cancer patients while being treated with warfarin and that long-term therapy with low molecular weight heparin may be effective in managing warfarin-failure thromboembolic disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Female; Heparin, Low-Molecular-Weight; Humans; Male; Middle Aged; Neoplasms; Outpatients; Recurrence; Retrospective Studies; Thromboembolism; Treatment Outcome; Warfarin

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Cohort Studies; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Male; Neoplasms; Retrospective Studies; Risk Factors; Time Factors; Vitamin K 1; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Thromboembolism; Warfarin

There is an established benefit of prophylactic warfarin in cancer patients with central venous catheters. This study assessed the compliance rate of prophylactic low-dose warfarin prescription in cancer patients with central venous catheters at a single institution.. Oncology patients with central venous catheters were identified by a retrospective chart review. Information retrieved included whether prophylactic warfarin had been prescribed and whether the patient had suffered a thrombotic or bleeding event. After the initial chart review, physicians were notified of the benefits of warfarin prophylaxis, and subsequently, a physician-independent mechanism of prescribing prophylactic warfarin was instituted. After each of these interventions, we retrospectively reviewed a further two cohorts of patients to assess compliance with warfarin prophylaxis.. During the baseline study, only 10% of patients were prescribed prophylactic warfarin. After physician notification, the compliance rate increased to only 20% (P =.3). After instituting the physician-independent mechanism of prescribing prophylactic warfarin, the compliance rate increased to 95% (P <.001). The rate of catheter-related thrombosis was 11% for patients who were prescribed warfarin compared with 21% in those who were not anticoagulated (P =.2).. At our institution, the rate of prescribing prophylactic warfarin was low in this patient population, and there was a reluctance of treating physicians to change their prescribing practice. Mechanisms exist to improve the rate of anticoagulant prophylaxis in this clinical setting. We recommend that institutions review their rate of compliance with prophylactic anticoagulation for patients with central venous catheters and solid tumors.

Topics: Anticoagulants; Catheterization, Central Venous; Guideline Adherence; Humans; Neoplasms; Practice Patterns, Physicians'; Premedication; Retrospective Studies; Thromboembolism; Warfarin

Topics: Anticoagulants; Humans; Neoplasms; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Humans; Incidence; Neoplasms; Thromboembolism; Time Factors; Warfarin

Topics: Anticoagulants; Data Interpretation, Statistical; Humans; Neoplasms; Thromboembolism; Warfarin

Topics: Anticoagulants; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasms; Thromboembolism; Warfarin

Lupus anticoagulant (LA) is an antibody that interferes with phospholipid-dependent coagulation tests. We investigated the usefulness of the ratio of factor V activity determined by the Simplastin auto test (PT assay) to factor V activity determined by the Platelin Excel LS test (APTT assay) for detection of LA in plasma samples obtained from 276 patients with haematological and non-haematological disorders and 73 healthy subjects. This ratio was significantly higher in the 15 LA-positive (4.82 +/- 3.34) than in samples from healthy subjects (1.09 +/- 0.10) and was > 1.4 in 10 of the remaining 261 patient samples. The ratio was particularly low in the 54 samples from warfarin-treated patients. These findings suggest that determination of this ratio may be useful as a routine laboratory test for detection of LA. This test requires no specific antigens and can be applied in patients receiving anticoagulants such as warfarin and heparin.

Topics: Adult; Biomarkers; Factor V; False Positive Reactions; Female; Hematologic Diseases; Humans; Lupus Coagulation Inhibitor; Male; Neoplasms; Partial Thromboplastin Time; Prothrombin Time; Warfarin

Markers of thrombotic risk--fibrinogen, factor VIII and immunoglobulin G (IgG) anticardiolipin titres--were measured, and the presence of lupus anticoagulant and factor V Leiden were assessed in 84 patients with a solid or haematological malignancy. These patients were monitored, following the insertion of an indwelling venous catheter, for thrombosis. Fifty-five were given prophylactic low-dose warfarin. Over a mean of 15 weeks there were 10 (12%) thrombotic events in 10 patients. Seven were on warfarin. Haemorrhagic problems occurred in three (5%), all on warfarin. Of the 84 patients, 86% had raised fibrinogen levels, 37% elevated factor VIII and 44% raised anticardiolipin levels. Lupus anticoagulant was present in five and three were heterozygous for factor V Leiden. A high prevalence of a range of prothrombotic changes was confirmed and the frequent presence of low-titre anticardiolipin antibody in subjects with malignancy demonstrated. However, none of these parameters predicted the development of thrombosis (P > 0.05).

Topics: Anticoagulants; Antineoplastic Agents; Biomarkers; Catheterization, Central Venous; Humans; Neoplasms; Thrombosis; Warfarin

Current guidelines suggest that all patients with acute deep venous thrombosis should be treated with intravenous heparin for at least 5 days, overlapping with warfarin sodium for 4 to 5 days.. Using linked state of California hospital discharge records from 1991 to 1994 we identified patients with acute deep venous thrombosis without pulmonary embolism, and determined the 6-month cumulative incidence of rehospitalization for recurrent thromboembolism. Coding was validated by reviewing the charts of 218 patients matched with the statewide data from 4 local hospitals.. A total of 36924 linked records met study criteria. In the validation group, objectively confirmed thrombosis that was treated with intravenous heparin followed by warfarin was noted in 20%, 65%, 94%, and 95% of the patients who were hospitalized for 2 or fewer days or 3, 4, or 5 or more days, respectively. Statewide, among patients hospitalized for 3, 4, 5, and 6 days, the 6-month cumulative incidence of hospitalization for recurrent thromboembolism was 5.4%, 5.1%, 5.4%, and 6.0%, respectively. Multivariate modeling of patients hospitalized for 3 to 10 days revealed that recurrent thromboembolism was associated with the length of hospitalization (odds ratio [OR], 1.06 each additional day; 95% confidence interval [CI], 1.04-1.08), presence of malignancy (OR, 1.58; 95% CI, 1.46-1.68), age (OR, 0.85 each 10 years; 95% CI, 0.84-0.86), dementia (OR, 0.38; 95% CI, 0.26-0.49), hospitalization for multiple injuries within 3 months (OR, 0.46; 95% CI, 0.32-0.60), and surgery within 3 months (OR, 0.84; 95% CI, 0.78-0.90).. We found no evidence that a stay of 4 days for treatment of deep venous thrombosis was associated with a higher rate of recurrent thromboembolism compared with hospitalization for 5 or more days. Although the evidence was not as strong, the incidence of recurrent thromboembolism after a stay of 3 days appeared comparable with that after a stay of 5 days. These findings suggest that fewer than 5 days of intravenous heparin overlapping with warfarin may provide effective initial treatment for deep venous thrombosis among patients deemed ready for hospital discharge.

Topics: Anticoagulants; Female; Humans; Incidence; Length of Stay; Logistic Models; Male; Middle Aged; Neoplasms; Recurrence; Thrombophlebitis; Warfarin

This postal survey among 174 UK palliative physicians, aimed to assess current practice and perceived problems within the management of venous thromboembolism (VTE) in patients with advanced cancer. The questionnaire was returned by 131 out of 174 (74%) of the doctors surveyed. The most common estimated incidence of patients with VTE was 1-5%. The diagnosis of VTE is usually confirmed by further investigation and in general, outpatients are more likely to be anticoagulated than inpatients. Problems with anticoagulation include bleeding, international normalized ratio instability, appropriateness of anticoagulation, practical difficulties associated with monitoring, and recurrent VTE. Although probably less effective, 77 out of 128 (60%) of respondents use subtherapeutic regimes in order to minimize the risks. Patients with advanced malignancy and VTE are anticoagulated, if considered appropriate, by the vast majority of palliative physicians in the UK. Warfarin has been abandoned in favour of low-molecular-weight heparin (LMWH) by 26%. LMWH provides anticoagulation with no need for monitoring, has no significant drug interactions and is not affected by liver dysfunction. Theoretically, LMWH is more effective than warfarin in the secondary prevention of VTE with less risk of bleeding.

Topics: Anticoagulants; Decision Making; Health Surveys; Heparin; Heparin, Low-Molecular-Weight; Humans; Neoplasms; Palliative Care; Pilot Projects; Practice Patterns, Physicians'; Surveys and Questionnaires; Thromboembolism; Warfarin

Human cytochrome P4501A1 (CYP1A1) occurs extrahepatically and is polymorphic, the common form having Ile at position 462 and the rare form having Val. The rare allele has been associated with enhanced susceptibility to lung cancer. To resolve its role in cancer we have constructed CYP1A1-Val462 cDNA by site-directed mutagenesis from CYP1A1-Ile462, as confirmed by sequencing and allele-specific PCR. Both alleles were expressed in Escherichia coli, and CYP1A1-Ile462 and -Val462 were purified to electrophoretic homogeneity. The secondary structures of both forms were virtually identical, with high alpha helix content, as assessed by circular dichroism. The P450s stereoselectively and regioselectively catalyzed the metabolism of (R)- and (S)- warfarin, in reconstituted systems, with very similar profiles. Both P450s produced (R)-6- and 8-hydroxy-warfarin with Km values of 0.40 +/- 0.06 and 0.43 +/- 0.05 mM, respectively, and Vmax values of 84.0 +/- 6.8 and 137.7 +/- 8.9 pmol/min/nmol CYP1A1-Val462, respectively, 1.0 +/- 0.1 and 1.0 +/- 0.1 mM, respectively, and 46.7 +/- 2.5 and 80.0 +/- 4.4 pmol/min/nmol CYP1A1-Ile462, respectively. Reconstituted CYP1A1-Val462 catalyzed ethoxyresorufin metabolism at a slightly but significantly higher rate than did CYP1A1-Ile462; Vmax values were 4.4 +/- 0.6 and 3.1 +/- 0.3 nmol/min/nmol CYP1A1, respectively. However, with the carcinogen benzo(a) pyrene as substrate, reconstituted CYP1A1-Ile462 together with epoxide hydrolase produced 7,8- and 9,10-dihydrodiols at comparable rates than did CYP1A1-Val462. Thus, the apparently greater susceptibility of the CYP1A1-Val462 genotype to lung cancer is probably not related to greater extents of carcinogen bioactivation.

Topics: Alleles; Base Sequence; Cytochrome P-450 Enzyme System; DNA, Complementary; Escherichia coli; Humans; Isoenzymes; Isoleucine; Molecular Sequence Data; Mutagenesis, Site-Directed; Neoplasms; Plasmids; Recombinant Proteins; Valine; Warfarin

Patients with pulmonary embolism may have no definitive predisposing factors for thrombi. The clinical entity of chronic pulmonary embolism is also uncertain. This study clarified the clinical characteristics of pulmonary embolism without definitive predisposing factors. During the last 10 years, 36 consecutive patients were diagnosed as having pulmonary embolism (mean age 61 years, female 75%). Twenty-four patients (67%) had definitive predisposing factors ("definitive" group). Patients without definitive predisposing factors had the following characteristics. The onset of symptoms was out-hospital and insidious. The main symptom was exertional dyspnea without acute episode compatible with an embolism. In four patients (33%) there was a delay of over 2 years form the onset of symptoms to the diagnosis. Three patients had been treated for depression. Thrombolytic therapy caused an inadequate fall in mean pulmonary artery pressure from 41 +/- 11 to 24 +/- 8 mmHg and in three patients it remained over 30 mmHg. Deep vein thrombosis were found in four of nine patients in whom venography were performed 10 days after thrombolytic therapy, but only one patient showed thrombus in the "definitive" group. During the convalescent stage, all patients were treated with prophylactic warfarin. Home oxygen therapy was indicated in three patients and an inferior vena caval filter was implanted in two patients. One third of patients with pulmonary embolism in our institute had no definitive predisposing factors. In these patients, even with thrombolytic therapy, recovery of pulmonary hypertension was often insufficient and deep vein thrombosis persisted. Clinicians should be aware of this disease to avoid undue delay in its diagnosis.

Topics: Aged; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Neoplasms; Obesity; Prognosis; Pulmonary Embolism; Thrombolytic Therapy; Thrombophlebitis; Warfarin

Previous studies, mainly autopsy-based, suggest that the spectrum of stroke in cancer patients differs from that of the general population. These studies also suggest that cerebrovascular events frequently are a manifestation of hypercoagulability. However, no studies that address this question in the adult oncological population from a clinical perspective are available. We therefore assessed the clinical impact of cerebral ischemic events in cancer patients and attempted to determine whether their occurrence represents a manifestation of Trousseau's syndrome.. A computerized database that records all neurological admissions and consultations at a tertiary medical center was used to retrospectively identify all patients with cerebral ischemic events and cancer.. Thirty-three patients representing 3.5% of all stroke consultations and admissions seen at the University of Massachusetts Medical Center were identified during the period 1988 through 1992. Large-vessel atherosclerosis was the most frequent cause of stroke. Furthermore, although 30% were determined to have hypercoagulability as a cause using clinical criteria, in only one of nine patients in whom tests were done was sufficient evidence present to make a presumptive diagnosis of disseminated intravascular coagulation. Irrespective of therapy, recurrent cerebral ischemic events were noted in only 6% of patients during a follow-up period averaging greater than 9 months, a figure that is similar to that for the risk of repeated events in the noncancer population.. Recognizing the limitations of this retrospective study, it appears nonetheless that conventional stroke origins account for the majority of cerebral ischemic events in the adult cancer population. Although hypercoagulability is present to a greater extent than in the nononcological population, recurrent strokes seem to occur no more frequently than in the nononcological population, and antiplatelet agents seem sufficient therapy for most patients.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Coagulation Disorders; Brain Ischemia; Cerebral Infarction; Cerebrovascular Disorders; Cohort Studies; Female; Follow-Up Studies; Heparin; Humans; Ischemic Attack, Transient; Male; Middle Aged; Neoplasms; Recurrence; Retrospective Studies; Thrombosis; Warfarin

We report 4 cases of Trousseau's syndrome, in which spontaneous recurrent or migratory venous thromboses, arterial emboli caused by nonbacterial thrombotic endocarditis, or both, develop in a patient with a recognized or occult malignant tumor. The clinical course of 3 of the patients emphasizes a key point: The occurrence for no known reason of thromboses preventable by anticoagulation therapy with heparin but not with warfarin sodium should alert a physician to focus diagnostic efforts on uncovering an underlying malignant lesion. Thromboses may occur months to years before the tumor is discovered, and a thorough negative initial examination does not obviate the need for a continuing search. Patients with Trousseau's syndrome have persistent low-grade intravascular coagulation, and therapy with heparin should be continued indefinitely. Stopping heparin therapy for even a day may permit a new thrombosis to develop. Immunostaining a biopsy specimen from 1 patient provided evidence that 2 properties of a neoplastic lesion are required for the syndrome to develop: The malignant cells express surface membrane tissue factor, and structural features of the tumor permit the malignant cells or vesicles it sheds to be exposed to circulating blood.

Topics: Adult; Embolism; Female; Heparin; Humans; Male; Middle Aged; Neoplasms; Recurrence; Syndrome; Thrombosis; Warfarin

Thirty-one patients with malignancy, anticoagulated for the treatment of venous thromboembolism (VTE) are reported. Complications of treatment included major bleeding (35%), redevelopment of VTE whilst on therapeutic levels of anticoagulants (13%) and recurrent VTE following cessation of anticoagulant (42%). Forty-two per cent of patients died within three months of initiating anticoagulant therapy. The cause of death was progressive malignancy, except in one patient who died of anticoagulant-related bleeding. The high incidence of bleeding is frequently associated with over-anticoagulation and indicates the need for improved monitoring. The frequent recurrence of VTE is associated with chronic disseminated intravascular coagulation, for which warfarin is ineffective and heparin is indicated.

Topics: Adult; Aged; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Monitoring, Physiologic; Neoplasms; Recurrence; Thromboembolism; Thrombophlebitis; Treatment Outcome; Warfarin

Topics: Humans; Lymphocyte Activation; Neoplasms; Reference Values; Rosette Formation; T-Lymphocytes; Warfarin

A modification of the assay for vitamin K-dependent carboxylase is described with which the enzyme could be detected in relatively low amounts of cells (n = 10(6)). Using this assay, we could demonstrate vitamin K-dependent carboxylase activity in hepatocytes, renal tubular cells, osteoblasts, endothelial cells and macrophages, but not in lymphocytes or platelets. The cultured tumor cells UMR-106, B16 and 5583 also contained vitamin K-dependent carboxylase activity. Vitamin K epoxide reductase activity was demonstrated only in cells where vitamin K-dependent carboxylase activity was present. The tumor cells possessed remarkably less K epoxide reductase activity than the normal cells. When cells were cultured in medium containing warfarin, the K epoxide reductase activity was found to be decreased and the amount of non-carboxylated precursor proteins had increased, suggesting an analogous vitamin K mechanism as in liver.

Topics: Animals; Carbon-Carbon Ligases; Cells, Cultured; Humans; Ligases; Mixed Function Oxygenases; Neoplasms; Tissue Distribution; Vitamin K Epoxide Reductases; Warfarin

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Topics: Blood Coagulation Tests; Cardiovascular Diseases; Fibrinogen; Fibrinopeptide A; Humans; Neoplasms; Platelet Count; Thrombin; Warfarin

Anticoagulants of the coumarin type have long been reported to inhibit metastasis growth in experimental animals; however, the mechanisms of such effects has not been clarified. Systemic anticoagulation per se does not appear to account completely for such metastasis growth depression. More recent information gathered on a cell procoagulant activity, which is vitamin K-dependent, could probably supply a fresh insight into this problem. Indeed, vitamin K deficiency induced either dietarily or pharmacologically by warfarin, does inhibit the activity of a cysteine protease with direct factor-X-activating properties. This protease is only present in warfarin-sensitive tumors. The correlation of this activity with cancer cell invasiveness is supported by experimental data in metastatic variants and, lately, also by the observation of markedly higher cancer procoagulant activity in extracts from metastases than from primary human melanomas.

Topics: Animals; Antineoplastic Agents; Blood Coagulation Factors; Cysteine Endopeptidases; Endopeptidases; Humans; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Protease Inhibitors; Vitamin K; Warfarin

Altered concentrations of serum proteins and nonesterified fatty acids (NEFAs) often accompany malignant diseases. Free fractions (fu) of apazone and warfarin were measured by equilibrium dialysis in serum samples obtained from 31 patients with cancer and 18 control subjects. Mean fu values of both drugs were significantly higher in the patient group. Multivariate analysis showed albumin, NEFA, and AAG for apazone and albumin, NEFA, and age for warfarin accounted for 60% and 63%, respectively, of interpatient variation in bound/free drug concentration ratios in the group of patients with cancer. The interactions of apazone and warfarin with AAG were further characterized; the more avid site had association constants of 4.5 X 10(5) and 2.3 X 10(5) L/mol, respectively. Finally, it is strongly suggested that when hypoalbuminemia is present and a drug binds to AAG with an affinity constant comparable to or higher than that to albumin, then fu will become dependent on the concentration of AAG.

Topics: Adult; Aged; Analysis of Variance; Apazone; Chromatography, Gas; Drug Interactions; Fatty Acids, Nonesterified; Female; Humans; Male; Middle Aged; Neoplasms; Orosomucoid; Protein Binding; Serum Albumin; Triazines; Warfarin

Little information exists on the population of cancer patients from which individual patients are selected for admission to a clinical trial. In fact, most reports of clinical trials of cancer chemotherapeutic agents begin by describing samples of treated patients but neglect to collect data and describe the population from which the samples were taken. In a multi-institutional VA Cooperative Study in which two different cancer treatments were compared, an attempt was made to screen all lung, colorectal, prostate, and head and neck patients seen at participating hospitals prior to randomization to a therapeutic regimen. Of a total of 2687 patients screened, 437 (16.3%) were randomized and 2250 (83.7%) were excluded for 2981 reasons. Protocol reasons were the basis for 68.6% of all exclusions, 21.3% were physician refusals, and 10.1% were patient refusals. The number of patients randomized did not correlate well with number of patients screened across participating centers. Patients admitted to the study tended to be younger and in better health than excluded patients. Overestimates of randomization rates projected initially from published information point to the need for improved screening data in the planning of future studies. Factors such as screening methods, physician acceptance of the experimental approach, number of competing protocols within each center, and cooperation among medical center departments and personnel all are important ingredients in any screening effort.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Neoplasms; Population Surveillance; Random Allocation; Research Design; Warfarin

Peripheral blood lymphocyte mitogen responsiveness was studied in 12 normal and 51 cancer patients. One group of patients was treated with warfarin, the second group with coumarin. There was a significant increase in lymphocyte response to phytohaemagglutinin (PHA) following both drugs. This increase indicates that both agents are capable of activating lymphocytes and thus stimulating some immunological functions.

Topics: Coumarins; Humans; Immunity; Neoplasms; Rosette Formation; T-Lymphocytes; Warfarin

We have reviewed our experience with the treatment of 250 patients with deep vein thrombosis diagnosed by contrast venography. The level of thrombosis was recorded according to the anatomic level to which it extended. A third of the patients had cancer, and the most common clinical findings were swelling and pain. The risk of the development of pulmonary embolism, based on the anatomic level of initial deep vein thrombosis, revealed the following: 12 of 115 patients (10 percent) with level I (calf) deep vein thrombosis developed pulmonary embolism, as did 2 of 27 patients (7 percent) with level II (popliteal) disease, 5 of 60 (8 percent) with level III (thigh) disease, 1 of 19 patients (5 percent) with level IV (groin) disease, and 2 of 26 patients (8 percent) with level V (iliac) disease. Based on our favorable experience with heparin we believe that heparin is the treatment of choice for deep vein thrombosis regardless of the anatomic level. The incidence of pulmonary embolism does not appear to be influenced significantly by the level of the deep vein thrombosis.

Topics: Adolescent; Adult; Aged; Drug Therapy, Combination; Female; Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Risk; Thrombophlebitis; Warfarin

Fibrinopeptide A (FPA) levels have been followed sequentially in a three-year study of 50 patients with advanced carcinoma. Evidence for activation of blood coagulation was found in 26 of 43 subjects (60%) at the time of entry into the study. Serial FPA determinations revealed an upward trend which paralleled the progression of clinical disease. Persistent elevation of the FPA level suggested treatment failure and a poor prognosis. Anticoagulation with sodium warfarin significantly reduced the FPA level in subjects with cancer. Short-term anticoagulation with heparin decreased FPA levels in two patients with thromboembolic disease but failed to reduce FPA to the normal range in any of the three patients with cancer so tested. These data suggest that most patients with advanced cancer have evidence for activation of blood coagulation and suggest that serial FPA determinations may be useful in following tumor progression or response to therapy in patients with cancer.

Topics: Aged; Blood Coagulation; Fibrinogen; Fibrinopeptide A; Heparin; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Prognosis; Prothrombin Time; Warfarin

Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.

Topics: Animals; Blood Platelets; Cell Survival; Cyclooxygenase Inhibitors; Dogs; Enzyme Inhibitors; Fibrinogen; Fibrinolytic Agents; Kinetics; Mopidamol; Neoplasms; Phosphodiesterase Inhibitors; Platelet Count; Sulfinpyrazone; Warfarin

Topics: Humans; Neoplasms; Pulmonary Embolism; Warfarin

Topics: Humans; Neoplasms; Warfarin

Five cancer patients (three with lesions in the lung and one each with breast and head and neck cancer) with multiple metastases developed "migratory thrombophlebitis." These patients were not ambulatory. None of the patients showed a picture of "consumptive coagulopathy," although a "hypercoagulable state" was observed. Fibrinogen levels were normal or increased, FDP were slightly increased, and AT-III was decreased. Prior to heparin therapy, values for PT and PTT were within normal range. Sodium heparin, 30,000 to 36,000 units per day, was administered by continuous intravenous infusion. Despite prolongation of the PTT to twice the baseline levels, signs and symptoms of thrombophlebitis persisted for several days. When thrombophlebitis was controlled with heparin, Coumadin therapy was instituted, but thrombophlebitis recurred at the original site and at new sites, even though the prothrombin time was in the therapeutic range (2 to 2 1/2 times the normal value). The antithrombotic action of heparin depends on a normal quantity of plasma AT-III. Long-term use of heparin is feasible, but the optimal time for discontinuation of heparin treatment has not been established. Heparin is superior to oral anticoagulation therapy to control thrombophlebitis associated with advanced cancer.

Topics: Adult; Aged; Female; Fibrinolysis; Heparin; Humans; Male; Middle Aged; Mucus; Neoplasms; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Thrombophlebitis; Warfarin

The records of 32 cancer patients who were treated with heparin sodium and warfarin sodium for thromboembolic disease were reviewed. Standard techniques for anticoagulation were neither safe nor effective. Sixteen patients experienced 21 different hemorrhagic complications. Eight patients had major hemorrhages that led to cessation of therapy or death. Six of 32 patients had pulmonary embolisms while receiving anticoagulants. It is suggested that venous interruption may be a safer and more effective method of prophylaxis against pulmonary embolism in cancer patients.

Topics: Adolescent; Adult; Aged; Anticoagulants; Female; Gastrointestinal Hemorrhage; Hemorrhage; Heparin; Humans; Male; Middle Aged; Neoplasms; Pulmonary Embolism; Thromboembolism; Warfarin

Benzopyrones have been shown to affect several functions of macrophages. We examined the effects of two benzopyrones, coumarin and warfarin, on the capacity of mouse macrophages to inhibit microorganisms and tumour target cells. Mice were treated with daily i.v. doses of either drug. Then the mice were challenged with lethal doses of Toxoplasma gondii or peritoneal macrophages from these mice were challenged in vitro with T. gondii or tumour target cells Survival of coumarin or warfarin-treated mice challenged with T. gondii was similar to that of control mice. Multiplication of T gondii and growth of tumour target cells were similar in preparations of macrophages from coumarin-treated, warfarin-treated, or control mice and were inhibited in preparations of activated macrophages from Corynebacterium parvum-treated mice that served as positive controls. Under our experimental conditions, benzopyrones did not activate mouse macrophages.

Topics: Animals; Cell Division; Coumarins; Female; Macrophages; Mice; Neoplasms; Propionibacterium acnes; Toxoplasma; Toxoplasmosis, Animal; Warfarin

Topics: Fibrinolysis; Humans; Neoplasms; Research; Warfarin

Two groups of patients were observed for evidence of acute radiation hepatitis during "high dose" radiation to the liver. The first group of 18 patients with metastatic liver disease received an average of 4,050 rad to the whole liver. Half received anticoagulation with warfarin. One patient on anticoagulation developed evidence of acute radiation hepatitis while 2 patients did so without anticoagulation. Eleven patients with Hodgkin's disease received 4,000 rad to the left lobe of the liver during extended field radiation. Four of these 11 patients were anticoagulated to therapeutic range. Only one of the fully anticoagulated patients showed changes on liver scan consistent with radiation hepatitis whereas three did so without anticoagulation. No serious sequelae from anticoagulation occurred in either group. These preliminary data suggest that anticoagulation may be safely administered with high dose hepatic radiation and that further trials with anticoagulation are warranted.

Topics: Adult; Aged; Female; Hepatitis; Hodgkin Disease; Humans; Male; Middle Aged; Neoplasms; Radiation Injuries; Radiation Tolerance; Radiotherapy Dosage; Radiotherapy, High-Energy; Remission, Spontaneous; Warfarin

Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.

Topics: Adult; Aged; Blood Cell Count; Blood Coagulation Factors; Blood Platelets; Brain Neoplasms; Breast Neoplasms; Chronic Disease; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasms; Prostatic Neoplasms; Prothrombin Time; Pulmonary Embolism; Solitary Pulmonary Nodule; Thrombophlebitis; Warfarin

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Amphetamine; Androgens; Anticonvulsants; Antithyroid Agents; Carcinogens; Cerebral Palsy; Diethylstilbestrol; Estrogens; Female; Fetus; Folic Acid Antagonists; Gestational Age; Humans; Lead; Maternal-Fetal Exchange; Methylmercury Compounds; Neoplasms; Polychlorinated Biphenyls; Pregnancy; Progesterone; Streptomycin; Tetracycline; Thalidomide; Tooth; Transposition of Great Vessels; Warfarin

Topics: Animals; Carbon Radioisotopes; Carcinoma, Bronchogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cell Division; Culture Techniques; Drug Synergism; Fluorouracil; Glioblastoma; HeLa Cells; Humans; L Cells; Liver; Liver Neoplasms; Mice; Mice, Inbred Strains; Microsomes, Liver; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Neuroglia; Pancreatic Neoplasms; RNA, Ribosomal; Warfarin

Topics: Abdominal Muscles; Aged; Cysts; Diagnosis, Differential; Female; Hematoma; Hemorrhage; Heparin; Hernia; Humans; Intestinal Diseases; Male; Middle Aged; Neoplasms; Radiography; Rest; Warfarin

Topics: Animals; Anticoagulants; Fibrin; Fibrinolytic Agents; Humans; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Warfarin

Topics: Animals; Anticoagulants; Cell Biology; Cell Movement; Humans; Leukocytes; Lymphocytes; Macrophages; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Neoplastic Cells, Circulating; Prothrombin Time; Rabbits; Thrombosis; Warfarin

Topics: Anticoagulants; Blood Coagulation; Coagulants; Fibrinogen; gamma-Globulins; Heparin; Iodine Isotopes; Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms; Neoplasms, Experimental; Pharmacology; Physiology; Rats; Research; Sodium; Warfarin

Topics: Anticoagulants; Fibrinogen; Fibrinolysis; Heparin; Iodine; Iodine Isotopes; Lymphoma; Lymphoma, Non-Hodgkin; Metabolism; Neoplasms; Neoplasms, Experimental; Pharmacology; Radiometry; Rats; Research; Warfarin

Topics: Acenocoumarol; Aged; Anticoagulants; Cerebrovascular Disorders; Coronary Disease; Dicumarol; Drug Therapy; Ethyl Biscoumacetate; Geriatrics; Humans; Incidence; Middle Aged; Mortality; Neoplasm Metastasis; Neoplasms; Pathology; Phenindione; Thromboembolism; Warfarin

Topics: Blood Coagulation; Coagulants; Fibrinogen; Heparin; Iodine Isotopes; Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms; Neoplasms, Experimental; Pharmacology; Rats; Research; Warfarin

Topics: Coumarins; Hemorrhage; Humans; Neoplasms; Warfarin