The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P<0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.
Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.
BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear.
METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.
RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).
CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).
BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin.
METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding.
RESULTS: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups.
CONCLUSIONS: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).
BACKGROUND: Anticoagulants such as warfarin and dabigatran can significantly reduce the risk of stroke in individuals with atrial fibrillation that may lead to increased risk of bleeding, especially in older people. Evidence for bleeding risks with anticoagulants within the context of doses, multimorbidity and impaired renal function in real world setting is lacking. Therefore we aimed to assess and compare real world bleeding risks with warfarin and dabigatran. Secondary analyses involved examining risk of fatal haemorrhages.
METHODS AND RESULTS: We formed two inception cohorts of propensity score (PS) matched older patients (≥ 65 years), who initiated dabigatran or warfarin between July 2011 and December 2012. A total of 4835 dabigatran users were matched to 4385 warfarin users in dose independent binary PS matching. A dose dependent PS matching resulted in 2383 warfarin, 2153 dabigatran 150 mg and 3395 dabigatran 110 mg users. In the first cohort, compared to warfarin, the hazard ratios (95% confidence intervals) for dabigatran were 0.45 (0.37-0.55) for any haemorrhage; 1.16 (0.87-1.56) for gastrointestinal haemorrhage; and 0.29 (0.09-0.86) for intracerebral haemorrhage. Similar associations were observed in the first 30 days of treatment. In dose dependent matched cohort, the risk of any haemorrhage was lower in individuals receiving dabigatran 110 mg (HR; 95% CI: 0.40 (0.31-0.52)) and 150 mg (HR; 95% CI: 0.29 (0.19-0.41)) compared to warfarin.
CONCLUSIONS: The risk of any haemorrhage and intracerebral haemorrhage was lower in dabigatran users compared to warfarin users. Importantly no increased risk of gastrointestinal haemorrhage was found in dabigatran users. The incidence rates for any haemorrhage were found to be higher in first 30 days of any anticoagulant treatment, but hazard ratios remained similar during the study period.
BACKGROUND: Choosing short-term (3-6 months) or indefinite anticoagulation after a first unprovoked venous thromboembolic event (VTE) is a common and difficult clinical decision. The long-term absolute risk of recurrent VTE after a first unprovoked VTE, in all patients and sub-groups, is not well established, hindering decision making.
METHODS: We conducted a multi-center multi-national prospective cohort study in first unprovoked VTE patients to establish the long-term risk of recurrent VTE after short-term anticoagulation in first unprovoked VTE patients (and sub-groups).We followed patients for symptomatic suspected VTE off of OAT. Suspected recurrent VTE was investigated with reference to baseline imaging and then independently and blindly adjudicated.
FINDINGS: We recruited 663 participants between October, 2001 and March 2006 with the last follow-up in April 2014. During a mean 5.0 years of follow-up, 165/663 suspected VTE (in 408 patients) were adjudicated as recurrent VTE resulting in an annualized risk of recurrent VTE of 5.0% (95% CI: 4.2-5.8%) with a cumulative risk of 29.6% at 8 years. Men had a 7.6% (95% CI: 6.3-9.2%) annual risk of recurrent VTE. High risk women (2 or more HERDOO2 points; see text) had an annual risk of recurrent VTE of 5.9% (95% CI: 4.2-8.1%). Low risk women (1 or 0 HERDOO2 points) had 1.1% (95% CI: 0.6-2.0%) annual risk of recurrent VTE with a cumulative risk of 8.7% at 8 years.
INTERPRETATION: Men and high risk women with unprovoked VTE should be considered for long-term anticoagulant therapy given a high risk of recurrent VTE after long-term follow-up. Women with a low HERDOO2 score may be able to safely discontinue anticoagulants.
FUNDING: This study was funded by the Canadian Institutes of Health Research (Grant # MOP 64319) and Heart and Stroke Foundation of Ontario (Grant # NA 6771). Registered at www.clinicaltrials.gov identifier: NCT00261014.
In elderly patients (≥ 75 years), evidence of dabigatran efficacy is lacking and increased vigilance is warranted. We aimed to assess dabigatran effectiveness and safety in elderly patients in real-world practice. We conducted a population-based study using administrative databases, in Quebec (1999-2013). Dabigatran users (110/150 mg) were compared with matched warfarin users with regard to stroke and bleeding events. Age was categorised into < 75 or ≥ 75 years. Propensity score adjusted models were used. The cohort consisted of 15,918 dabigatran users and 47,192 matched warfarin users, with 67.3% being elderly patients. The elderly predominantly used the lower dose (80.1%) while younger patients mainly used the higher dose (80.0%). In multivariable analyses adjusted for propensity score, the risk of stroke in elderly patients using dabigatran, was no different than the risk in warfarin users (HR 1.05, 95% CI: 0.93, 1.19) regardless of dabigatran dose. However, dabigatran was associated with lower rates of intracranial haemorrhage (HR 0.60, 95% CI: 0.47-0.76) and higher rates of gastrointestinal bleeding (HR 1.30 95% CI: 1.14-1.50) when compared to warfarin. Based on real-life experience, dabigatran can offer an alternative to warfarin in elderly patients, with fewer intracranial bleeding events. However, caution is warranted for gastrointestinal bleeding.
Journal»Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
AIMS: Randomized trials showed non-inferior or superior results of the non-vitamin-K-antagonist oral anticoagulants (NOACs) compared with warfarin. The aim of this study was to assess the effectiveness and safety of dabigatran (direct thrombin inhibitor) vs. acenocoumarol (vitamin K antagonist) in patients with atrial fibrillation (AF) in daily clinical practice.
METHODS AND RESULTS: In this observational study, we evaluated all consecutive patients who started anticoagulation because of AF in our outpatient clinic from 2010 to 2013. Data were collected from electronic patient charts. Primary outcomes were stroke or systemic embolism and major bleeding. Propensity score matching was applied to address the non-randomized design. In total, 920 consecutive AF patients were enrolled (442 dabigatran, 478 acenocoumarol), of which 2 × 383 were available for analysis after propensity score matching. Mean follow-up duration was 1.5 ± 0.56 year. The mean calculated stroke risk according to the CHA2DS2-VASc score was 3.5%/year in dabigatran vs. 3.7%/year acenocoumarol-treated patients. The actual incidence rate of stroke or systemic embolism was 0.8%/year [95% confidence interval (CI): 0.2-2.1] vs. 1.0%/year (95% CI: 0.4-2.1), respectively. Multivariable analysis confirmed this lower but non-significant risk in dabigatran vs. acenocoumarol after adjustment for the CHA2DS2-VASc score [hazard ratio (HR)dabigatran = 0.72, 95% CI: 0.20-2.63, P = 0.61]. According to the HAS-BLED score, the mean calculated bleeding risk was 1.7%/year in both groups. Actual incidence rate of major bleeding was 2.1%/year (95% CI: 1.0-3.8) in the dabigatran vs. 4.3%/year (95% CI: 2.9-6.2) in acenocoumarol. This over 50% reduction remained significant after adjustment for the HAS-BLED score (HRdabigatran = 0.45, 95% CI: 0.22-0.93, P = 0.031).
CONCLUSION: In 'real-world' patients with AF, dabigatran appears to be as effective, but significantly safer than acenocoumarol.
Essentials Long-term recurrence risk of venous thromboembolism (VTE) is uncertain. We performed a prospective cohort study of 839 patients with first unprovoked VTE. VTE recurrence risk is high, particularly in men with proximal thrombosis or pulmonary embolism. Sex and VTE site determine the recurrence risk and should be considered for patient counseling.
SUMMARY: Background The long-term recurrence risk (ltRR) of venous thromboembolism (VTE) is uncertain. Objective To assess the ltRR of patients with first unprovoked VTE. Patients/methods Patients were classified into three categories: distal deep vein thrombosis (DVT), proximal DVT or pulmonary embolism (PE), that is, PE associated with DVT or isolated PE. Patients with major thrombophilia or antithrombotic therapy were excluded. The endpoint was recurrent symptomatic VTE. Results A total of 839 patients were followed for a median of 7.7 years. VTE recurred in 263 patients (31%). After 10 and 20 years, the cumulative ltRR was 32% (95% confidence interval [CI], 29-36) and 44% (95% CI, 38-49) with 3.9 (95% CI, 3.3-4.6) and 3.3 (95% CI, 2.7-4.0) events per 100 patient-years, respectively. The adjusted hazard ratio was 2.1 (95% CI, 1.4-3.2) and 2.1 (95% CI, 1.4-3.2) for patients with proximal DVT or PE compared with patients with distal DVT and was 2.1 (95% CI, 1.6-2.9) for men compared with women. At 10 years, 4.7 (95% CI, 3.8-5.8) events per 100 patient-years occurred in men with proximal DVT or PE, 2.4 (95% CI, 1.2-4.4) in men with distal DVT, 1.9 (95% CI, 1.2-2.8) in women with proximal DVT or PE and 0.9 (95% CI, 0.2-1.9) in women with distal DVT. Conclusion The ltRR of patients with first unprovoked VTE is high and dependent upon sex and VTE site.
BACKGROUND: There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months.
METHODS: The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done.
FINDINGS: In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis.
INTERPRETATION: Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism.
FUNDING: Daiichi Sankyo.
The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P<0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.
