RE-SONATE

Twice-daily oral direct thrombin inhibitor dabigatran etexilate in the long-term prevention of recurrent symptomatic VTE (2011)

Condition

Secondary prevention of VTE after 6–16 months successful treatment for acute symptomatic DVT or PE

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Objective

To evaluate if dabigatran is effective and safe compared to placebo in the extended treatment after symptomatic proximal DVT or PE

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Trial design

Randomized, double-blind phase III study
Active treatment: dabigatran 150 mg p.o. twice daily for 6 months (n=681)
Control treatment: placebo tablets twice daily for 6 months (n=662)

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Endpoints

Primary efficacy endpoint: recurrent symptomatic VTE (DVT, fatal/nonfatal PE) and related deaths at the end of the planned treatment period
Primary safety endpoint: major bleeding and clinically relevant non-major bleeding
Secondary endpoints: clinically relevant bleeding events, deaths and cardiovascular events

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Trial participants

1343 patients with confirmed symptomatic PE or proximal DVT of the leg(s) who have been treated for 6–18 months with therapeutic dosages (INR 2–3) of an oral vitamin K antagonist

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Results

Efficacy outcome: Recurrent VTE occurred in 3 (0.4%) of 681 patients treated with dabigatran and 37 (5.6%) of 662 patients treated with placebo (hazard ratio 0.08; p<0.001). The rates of symptomatic DVT in the dabigatran and placebo group were 0.3% and 3.3%, respectively. One patient (0,1%) assigned to dabigatran compared with 14 (2,1%) patients in the placebo arm had a symptomatic non-fatal PE
Safety outcome: Clinically relevant bleeding was observed in 36 patients (5.3%) in the dabigatran group and in 12 patients (1.8%) on placebo (hazard ratio 2.9; p=0.001). The rates of major bleeding were 0.3% on Dabigatran and 0% on placebo (p=1.0). Any bleeding occurred in 10.5% of the patients receiving dabigatran compared to 5.9% of the patients in the placebo arm (p<0.003). Cardiovascular events occurred in 3 patients (0.4%) assigned to dabigatran and in 2 patients (0.4%) on placebo. There was no difference in acute coronary syndrome events between groups

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Summary

Efficacy outcome: Extended treatment with the direct thrombin inhibitor dabigatran signigficantly reduced the rate of recurrent VTE
Safety outcome: On treatment with dabigatran, the frequency of any bleeding events was about two times greater than with placebo; the rate of major bleeding was low

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Reference

(1) Schulman S, Baanstra D, Eriksson H, Goldhaber S, Kakkar A, Kearon C, Mismetti P, Schellong S, Schnee J and the RE-SONATE Study Group Thrombosis Service. Dabigatran vs. placebo for extended maintenance therapy of venous thromboembolism. ISTH 2011; July 25. Journal of Thrombosis and Haemostasis 2011;9 (Suppl 2):22; Abstract O-MO-037
(2) Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-718

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Corresponding author

Sam Schulman, M.D., Ph.D., Thrombosis Service, HHS-General Hospital, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada, e-mail: schulms@mcmaster.ca

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