Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

Abstract

BACKGROUNDAlthough 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. METHODSIn 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. RESULTSA 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. CONCLUSIONSAmong 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.) a bs tr ac t

Clinical outcomes of prolonged anticoagulation with rivaroxaban after unprovoked venous thromboembolism

“…However, with limited information on clinical factors in a claims database, we were not able to test this “reverse causation” hypothesis. Regarding major bleeding events, the non‐significant rate difference estimated from our 6‐month analysis was smaller than the rate difference reported in the EINSTEIN‐EXT trial but similar to that in the EINSTEIN‐CHOICE trial, although the level of events was higher (our study: 1.51% vs. 1.39% for the continued and discontinued cohorts, respectively; EINSTEIN‐EXT: 0.7% vs 0% in rivaroxaban and placebo cohorts, respectively; EINSTEIN‐CHOICE: 0.5% and 0.4% vs 0.3% for the 10 mg, 20 mg rivaroxaban, and aspirin cohorts, respectively) 14, 16. This may be due to a lower risk of bleeding in the population of clinical trials given their restrictive eligibility criteria.…”

“…The relative risk reduction of recurrent VTE event at 12 months was 65% lower for those who continued treatment vs discontinued in our study. The corresponding risk reduction was 82% in EINSTEIN‐EXT (rivaroxaban vs. placebo), and about 70% in EINSTEIN‐CHOICE (rivaroxaban vs. aspirin) 14, 16, 25…”

“…Findings from a pair of phase III clinical trials have shown that extended treatment with rivaroxaban for an additional 6–12 months is safe and effective to decrease VTE recurrence risk in patients with VTE who have previously completed 6 or 12 months of anticoagulant therapy 14, 16. The double‐blind placebo‐controlled EINSTEIN‐Extension trial (EINSTEIN‐EXT) reported a VTE recurrence rate of 1.3% in patients receiving extended treatment with once‐daily 20 mg rivaroxaban vs 7.1% in patients receiving placebo, representing a statistically significant 82% relative risk reduction ( P  <   .001) 17.…”

“…A marginal increase in the rate of major bleeding that did not reach statistical significance was observed in the rivaroxaban cohort (0.7% vs 0% for placebo; P  =   .11). More recently, data from the double‐blind EINSTEIN‐CHOICE trial reported VTE recurrence rates of 1.5% and 1.2% in patients receiving up to 12 months of extended treatment with once‐daily 20 mg or 10 mg rivaroxaban respectively vs 4.4% for patients receiving once‐daily 100 mg aspirin, representing statistically significant 66% and 74% relative risk reductions ( P  <   .001 for both) 16. Observed rates of major bleeding were comparable at 0.5% and 0.4% in the 20 mg and 10 mg rivaroxaban cohorts vs 0.3% in the aspirin cohort.…”

“…For the main analyses, the minimum duration of treatment was set at 3 months per ACCP guideline recommendations,12 and a sensitivity analysis was adopting an alternative minimum duration of treatment of 6 months as used in the EINSTEIN‐EXT and EINSTEIN‐CHOICE trials 14, 16…”