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Extended use of dabigatran no better than warfarin for high-risk pts after VTE; no net benefit vs placebo for avg-risk pts

Clinical Question:
Does extended anticoagulation with dabigatran or warfarin following venous thromboembolism provide a net benefit?

Bottom Line:
These authors do their best to spin the results in favor of using dabigatran for extended anticoagulation. Yet there was no benefit to dabigatran over warfarin in patients felt to be at high risk for recurrent venous thromboembolism (VTE): There were a similar number of deaths and a similar number of the combination of critical bleeds and recurrent episodes of VTE. And, remember, aspirin can reduce VTE without increasing bleeds, as we learned in the WARFASA study (N Engl J Med 2012;366:1959-67). In an average-risk group, extended anticoagulation with dabigatran caused more bleeds than placebo, with a benefit of fewer episodes of recurrent VTE. (LOE = 1b)

Reference:
Schulman S, Kearon C, Kakkar AK, et al, for the RE-MEDY Trial Investigators; RE-SONATE Trial. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-718.  [PMID:23425163]

Study Design:
Randomized controlled trial (double-blinded)

Funding:
Industry

Allocation:
Concealed

Setting:
Outpatient (any)

Synopsis:
This articles reports the results of 2 similar randomized controlled trials, one comparing dabigatran with warfarin (active control study, N = 2856), the other comparing dabigatran with placebo (placebo control study, N = 1343). Both studies recruited patients with a symptomatic pulmonary embolism (~25%), symptomatic proximal deep vein thrombosis (~65%), or both (~10%). Patients in the active control group were felt to be at increased risk for recurrent VTE by the recruiting physician, and all patients had undergone at least 3 months of previous anticoagulation. Groups in the 2 studies were balanced at the beginning of the study, allocation and masking was appropriate, and analysis was by intention to treat. The average age of participants was approximately 55 years, with a range of 18 to 93 years, and approximately 40% were women. The duration of the active control group study was extended from up to 18 months to up to 36 months, because after 18 months there was a lower-than-expected event rate, and the researchers hadn't seen a difference in outcomes. The placebo control group study had a 6-month treatment phase, and was extended by 12 months to monitor outcomes after the intervention ended. Let's review the results for the active control study first. There were slightly more recurrent or fatal VTE events in the dabigatran group than in the warfarin group (26 vs 18), slightly fewer bleeds into a critical organ or deaths (8 vs 14), and a similar number of deaths (17 vs 19). The bottom line is that the combination of recurrent VTE, fatal VTE, fatal bleed, or bleed into a critical organ was nearly identical between groups (34 vs 32). None of these differences were statistically significant. In the placebo-controlled study, there were fewer recurrent or fatal episodes of VTE in the dabigatran group (0.4% vs 5.6%; P < .001; number needed to treat = 19), but also more major or clinically relevant bleeds (5.3% vs 1.8%; P = .001; number needed to treat to harm = 29). If you combine those outcomes ("all bad things"), you get 39 in the dabigatran group and 43 in the warfarin group, a nonsignificant difference. The authors do not report "all deaths" in the placebo-controlled study, burying the number of fatal VTE episodes in the composite outcome and reporting unexplained deaths separately. A review of the supplementary materials did not reveal the all-cause mortality.

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