Extended Anticoagulation with Apixaban or Dabigatran Reduces Recurrent VTE and Mortality without Increasing Major Bleeding

EBM Focus - Volume 8, Issue 11

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Reference: N Engl J Med 2013 Feb 21;368(8):699, N Engl J Med 2013 Feb 21;368(8):709 (level 1 [likely reliable] evidence)

Anticoagulation treatment for patients with venous thromboembolisms (VTEs) is generally recommended for at least 3 months (Eur Heart J 2008 Sep;29(18):2276, Chest 2012 Feb;141(2 Suppl):e419S) but there is a high risk of recurrence. Extended treatment decreases the risk of recurrence but can increase the risk of major bleeding (Cochrane Database Syst Rev 2006 Jan 25;(1):CD001367), so the decision concerning how long to continue anticoagulation can be complicated, especially in patients with unprovoked VTE. Two new trials evaluated the safety and efficacy of extended anticoagulation treatment with either apixaban (AMPLIFY-EXT trial) or dabigatran (RE-SONATE trial).

In the AMPLIFY-EXT trial, 2,486 patients with VTE who had already completed 6-12 months of anticoagulation therapy were randomized to apixaban (2.5 mg vs. 5 mg) orally twice daily vs. placebo for an additional 12 months. Previous treatments included warfarin, apixaban, or enoxaparin. All patients were recurrence-free during previous treatment and were eligible for either continuation or cessation of anticoagulation.

Symptomatic or fatal VTE occurred in 1.7% in each apixaban group (2.5 mg and 5 mg doses) and in 8.8% in the placebo group (p < 0.001, NNT 14 for each apixaban dose). There were no significant differences in the rates of major bleeding among groups (0.1-0.2% with apixaban vs. 0.5% with placebo). The higher apixaban dose was associated with an increase in clinically-relevant nonmajor bleeding compared to placebo (4.2% vs. 2.3%, p < 0.05, NNH 52). The difference between the rates of clinically relevant bleeding between the lower dose and placebo (0.7%) was not significant.

In the RE-SONATE trial, 1,353 patients with VTE who had completed 6-18 months of anticoagulation were randomized to dabigatran 150 mg orally twice daily vs. placebo for 6 months. Recurrent or fatal VTE occurred in 0.4% with dabigatran vs. 5.6% with placebo (p < 0.001, NNT 20). Clinically relevant bleeding occurred in 5.3% vs. 1.8% (p = 0.001, NNH 28), but there was no significant difference in the rates of major bleeding. An additional noninferiority trial (RE-MEDY trial) comparing dabigatran to warfarin was reported in the same article. The rates of recurrent or fatal VTE were similar for the 2 active drugs, but dabigatran was associated with reduced risk of clinically-relevant bleeding (5.6% vs. 10.2%, p < 0.001, NNT 22), and with a nonsignificant reduction in major bleeding (0.9% vs. 1.8%, p = 0.06).

Other options for long-term prophylaxis against VTE recurrence include rivaroxaban (N Engl J Med 2010 Dec 23;363(26):2499) and aspirin (N Engl J Med 2012 May 24;366(21):1959). In the absence of head-to-head trials comparing the different possible treatments, the decisions of whether to give additional treatment and which agent to select must be individualized, based on risks for bleeding and risks for recurrence of VTE.

For more information, see the Anticoagulant therapy for venous thromboembolism topic in DynaMed.