Level 1: Likely reliable evidence

Anticoagulation treatment for individuals with venous thromboembolism (VTE) is generally recommended for at least three months,1,2 but there is a high risk of recurrence. Extended treatment decreases the risk of recurrence, but can increase the risk of major bleeding.3 Therefore, the decision concerning how long to continue anticoagulation can be complicated, especially in patients with unprovoked VTE.

Two new trials, AMPLIFY-EXT and RE-SONATE, evaluated the safety and efficacy of extended anticoagulation treatment with either apixaban4 or dabigatran.5

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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 therapy. 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 with 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 six to 18 months of anticoagulation therapy were randomized to dabigatran 150 mg orally twice daily vs. placebo for six 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) comparing dabigatran with warfarin was reported in the same article. The rates of recurrent or fatal VTE were similar for the two active drugs, but dabigatran was associated with a 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 rivaroxaban6 (N Engl J Med. 2010;363:2499-2510; available at www.nejm.org/doi/full/10.1056/NEJMoa1007903, accessed July 15, 2013) and aspirin7 (N Engl J Med. 2012;366:1959-1967; available at www.nejm.org/doi/full/10.1056/NEJMoa1114238, accessed July 15, 2013). In the absence of head-to-head trials comparing the different possible treatments, the decision as to whether to give additional treatment and the decision as to which agent to use must be individualized, based on risks for bleeding and risks for recurrence of VTE.


  1. Torbacki A et al. Eur Heart J. 2008;29:2276-2315.
  2. Kearon C et al. Chest. 2012;141[2 Suppl]:e419S-e494S.
  3. Hutten BA et al. Cochrane Database Syst Rev. 2006;1:CD001367.
  4. Agnelli G et al. N Engl J Med. 2013; 368:699-708.
  5. Schulman S et al. N Engl J Med. 2013. 21; 368: 709-718.
  6. The Einstein Investigators. N Engl J Med. 2010; 363:2499-2510.
  7. Becattini C et al. N Engl J Med. 2012; 366:1959-1967.