Dabigatran proved to be an effective extended treatment for venous thromboembolism, with a lower risk of bleeding than warfarin but a higher risk than placebo in two randomized, double-blind studies. Still, it flirted with the upper limit of the predefined noninferiority margin in one study. The results were published in the Feb. 21 issue of the New England Journal of Medicine.
Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, has been shown to be noninferior to warfarin with a lower rate of clinically relevant nonmajor bleeding at six months of treatment (N Engl J Med 2009;361:2342-2352). Sam Schulman, MD, PhD, of the Thrombosis and Atherosclerosis Research Institute in Hamilton, Ontario, and colleagues wanted to examine the efficacy and safety of dabigatran as a long-term prophylaxis after venous thromboembolism.
They used two studies: In the RE-MEDY trial, dabigatran was compared with warfarin to determine if dabigatran was noninferior to warfarin in preventing recurrent venous thromboembolism. In RE-SONATE, dabigatran was compared with placebo to assess if it was superior to placebo.
Both trials enrolled patients who had completed at least three months of treatment for venous thromboembolism. The major difference between the two trials was that patients in RE-MEDY (the active-control trial, 2,866 patients recruited between 2006 and 2010) were assessed as being at an increased risk of recurrent venous thromboembolism. Patients in the active-control trial received either a fixed dose of 150 mg dabigatran twice daily and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. In RE-SONATE (the placebo-controlled study, 1,353 patients enrolled between 2007 and 2010) patients received either a fixed dose of 150 mg dabigatran twice daily or a placebo.
Patients were evaluated at 15 and 30 days after being randomized and then monthly until day 180. After day 180, the active study group patients were assessed every 90 days until they completed treatment (a range of six to 36 months). Patients in both groups had one additional visit 30 days after the end of treatment. Follow-up in the placebo-control group was extended to 12 months after completion of treatment to evaluate the long-term risk of recurrence.
In the active-control study:
- Recurrent venous thromboembolism occurred in 1.8 percent of patients in the dabigatran group and 1.3 percent in the warfarin group;
- Major bleeding occurred in 0.9 percent in the dabigatran group vs. 1.8 percent in the warfarin group;
- Major or clinically relevant bleeding occurred in 5.6 percent in the dabigatran group vs. 10.2 percent in the warfarin group; and
- Acute coronary syndromes occurred in 0.9 percent in the dabigatran group vs. 0.2 percent in the warfarin group.
In the placebo-control study:
- Recurrent venous thromboembolism occurred in 0.4 percent of the dabigatran group vs. 5.6 percent in the placebo group;
- Major bleeding occurred in 0.3 percent in the dabigatran vs. none of the placebo group patients;
- Major or clinically relevant bleeding occurred in 5.3 percent in the dabigatran group vs. 1.8 percent in the placebo group; and
- Acute coronary syndromes occurred in one patient in each group.
Dabigatran compared with warfarin met the predefined noninferiority criteria for the prevention of venous thromboembolism. It also had a lower rate of recurrent thromboembolism compared with placebo but a higher rate of major or clinically relevant bleeding.
“In the active-control study, there was a numerical increase in recurrent or fatal venous thromboembolic events during treatment with dabigatran (26 events/1.8 percent) vs. 18 events with warfarin (1.3 percent),” Schulman et al observed. “The upper limit of the 95 percent confidence interval for the hazard ratio (2.64) was close to the predefined noninferiority margin (2.85), and the confidence interval gives boundaries for the event rate with dabigatran as low as 1 percent and as high as 3.4 percent.”
Their findings placed dabigatran’s annual risk at 0.8 percent to 2.6 percent, a range that is comparable to estimates in other trials assessing extended treatment of warfarin or experimental drugs, they noted. “The prespecified noninferiority margin for the hazard ratio of 2.85 is large, since it allows an increase in risk by a factor of nearly three to be accepted as noninferior,” they wrote, citing this as a study limitation.
They highlighted that dabigatran had a higher rate of acute coronary events