The RE-SONATE trial compared 6 months of dabigatran etexilate (DE) 150 mg twice daily to placebo in patients at equipoise for needing additional oral anticoagulation following 6–18 months of anticoagulant therapy with a vitamin K antagonist. DE provided a 92% relative risk reduction for recurrent symptomatic VTE compared with placebo and a low risk of major bleeding. We present here the results of an extended observational follow-up period of 12 months following completion of study treatment, which was conducted to determine whether there was an increase in VTE recurrence following discontinuation of study treatment.
RE-SONATE is an international, randomized, double-blind, event-driven, superiority study for efficacy. Patients were ≥ 18 years of age with creatinine clearance ≥ 30 mL/min. The primary efficacy endpoint (assessed by an independent adjudication committee blinded to treatment allocation) was symptomatic recurrent VTE (including symptomatic deep vein thrombosis, non-fatal and fatal pulmonary embolism) and unexplained death. The primary safety endpoint was major bleeding. Events were counted within the intended treatment period plus 3 days. A protocol amendment extended the post-treatment follow-up period from 1 month to 12 months. The extended follow-up population, used for the analysis of efficacy for patients who continued into this period, was a subset of the full analysis set, including patients who signed the consent form for the relevant protocol amendment.
In the initial double-blind treatment period of up to 6 months from randomization, recurrent symptomatic VTE or unexplained death occurred in 3 (0.4%) of 681 patients treated with DE and 37 (5.6%) of 662 patients treated with placebo (hazard ratio [HR] 0.08; 95% CI 0.02, 0.25%; P < 0.0001). Two patients had major bleeds (0.39%) on treatment with DE versus none in the placebo group. No unexplained deaths occurred in the DE group compared with one in the placebo group (Schulman et al. J Thromb Haem 2011 Supp 2 11–10626).
In the extended follow-up analysis of 1323 patients, the cumulative incidences of recurrent symptomatic VTE and unexplained death at intermediate time points during the uncontrolled, post-treatment follow-up were (Table 1): at 40 days, 2.0% in the former DE group versus 5.7% in the former placebo group (p=0.0005); and at 6 months, 6.0% versus 10.2% (p=0.0060), respectively. These represent absolute risk differences of 3.7% and 4.3% after 40 days and 6 months of uncontrolled follow-up, respectively. At 1 year of follow-up (540 days after randomization), these events occurred in 7.8% in the former DE group compared with 11.6% in the former placebo group (p=0.0261), for a risk difference of 3.8% (95% CI 0.5%, 7.1%).
The reduced risk of recurrent VTE associated with extending treatment with DE during the double-blind treatment period is preserved during 1 year of follow-up after discontinuation of study drug. However, the high rate of recurrent VTE, even in the former DE treatment group (7–8%), suggests that a longer duration of anticoagulant therapy may be warranted.
Off Label Use: Dabigatran etexilate is an oral thrombin inhibitor under investigation for anticoagulant prophylaxis or treatment in venous and arterial thrombomebolism. Baanstra:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.