New Orleans, LA - New randomized trial results from the RECOVER trial suggest that the new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) could replace warfarin for the treatment of patients with acute venous thromboembolism (VTE) .
The new findings, presented Sunday at the American Society of Hematology (ASH) 2009 Meeting and published online in the New England Journal of Medicine, come hard on the heels of the RE-LY results, reported by heart wire , showing dabigatran to be superior to warfarin in preventing strokes and peripheral embolic events in patients with atrial fibrillation (AF)
In the new RECOVER study, results show that dabigatran is as effective and as safe as, if not safer than, the older agent, but, as was much discussed with RE-LY, offers the advantage of a fixed dose and no need for blood monitoring, vs the regular monitoring and dose adjustment needed with warfarin.
"In other words, patients can achieve the same results in a more convenient manner," said lead researcher Dr Sam Schulman (Hamilton General Hospital, ON). These findings will change the standard of care for venous thromboembolism, he predicted.
Introducing the presentation at a plenary session, Dr Mary Cushman (University of Vermont, Burlington) said this was a "landmark trial."
Experts at the meeting were enthusiastic about the results. Dr Joel Anne Chasis (University of California, San Francisco) said that the results suggest that dabigatran could replace warfarin and that the lack of a need for monitoring would "be welcome news for both patients and their physicians."
Dr Bradford Schwartz (University of Illinois College of Medicine, Urbana-Champaign) highlighted the lack of dietary interactions with dabigatran: with warfarin, any foods that contain vitamin K can increase coagulability and interactions with many drugs, particularly antibiotics, can put the patient at increased risk of bleeding, he explained.
"An oral agent that frees patients from these concerns about diet and drug interactions and that behaves in a predictable manner is a very positive development," he said. These factors will simplify the use of anticoagulants, and he predicted that patient compliance will be greatly improved.
Noting that there are several other new oral anticoagulants on the horizon, including rivaroxaban ((Xarelto, Johnson & Johnson), which was also featured in the press briefing, Schwartz commented: "We are so enthusiastic about these new agents that don't need monitoring that we are assuming that the future is going to be both bright and complication free.
"But we must remember to be appropriately cautious, so that our optimism doesn't cause us to become careless, because the bottom line is that these drugs inhibit both good clotting, such as wound healing, as well as bad, as in pulmonary embolism," he added.Details of RECOVER study
The RECOVER study was conducted in 2539 patients with acute symptomatic venous thromboembolism, who were randomized to six months of treatment with either dabigatran 150 mg twice daily or warfarin once daily, given in doses adjusted to an international normalized ratio (INR) of 2-3. All patients received initial treatment for six days with a parenteral anticoagulant (either heparin intravenously or a low-molecular-weight-heparin derivative administered subcutaneously) for six days, to allow the dose of warfarin to be adjusted to achieve an INR of 2-3.
The final analysis included 1274 patients on dabigatran and 1265 on warfarin.
The primary end point was recurrent VTE or fatal pulmonary embolism, which was confirmed in 2.4% of patients on dabigatran and 2.1% of patients on warfarin. There was one death in each treatment arm. The hazard ratio was 1.1 (95% CI 0.65-1.84), and this shows noninferiority, Schulman reported.
Major bleeding was seen in 1.6% of patients on dabigatran vs 1.9% of patients on warfarin, which is not significantly different, he said.
However, when major bleeding was combined with clinically relevant nonmajor bleeding events there was a significant difference, with such events being confirmed in 5.6% of patients on dabigatran vs 8.8% patients on warfarin. The hazard ratio was 0.63 (95%CI 0.47-0.84; p=0.002).
The difference was also significant for any bleeding event, which was seen in 16.1% of patients on dabigatran vs 21.9 % on warfarin. The hazard ratio for this was 0.71 (95% CI 0.59-0.85; p<0.001), which represents a 29% risk reduction, and this was highly significant, Schulman commented.
MI was seen in four patients in the dabigatran group and two in the warfarin groups, a difference that was not significant (p=0.69). These numbers are very low, and Schulman emphasized that there is no signal for MI from the RECOVER study. There was such a concern in the RE-LY study, but that was a different patient population, with atrial fibrillation and likely other cardiovascular comorbidities, he added. There was also no signal for increases in liver enzymes (a problem that led to the withdrawal of an earlier oral anticoagulant, ximelagatran). The only side effect that was reported in slightly more patients on dabigatran than warfarin was dyspepsia, he added.
"Our trial provides data to support dabigatran as a fixed-dose oral treatment for deep vein thrombosis and pulmonary embolism," Schulman and colleagues write in the published paper. "For patients and healthcare providers, dabigatran is a far more convenient drug than warfarin, because it has no known interactions with foods and minimal interactions with other drugs and therefore does not require routine blood-coagulation testing."Indications sought
A second VT trial, known as RECOVER-2, is under way; Schulman commented that both RECOVER and RECOVER-2 are likely to be needed for approval of this indication. Also ongoing is a long-term safety follow-up study of the RE-LY cohort, dubbed RELY-ABLE. The company has said that it plans to file for registration for the AF indication during 2010.
The drug is actually already approved in Europe and Canada for prophylactic use in orthopedic-surgery patients. Those approvals were based on the large RE-MODEL study in patients undergoing total knee replacement and the RE-NOVATE study in total hip replacements, which showed that dabigatran was comparable to enoxaparin 40 mg once daily in preventing venous thromboembolism.
Of note, a similar study conducted in North America in knee replacement (RE-MOBILIZE) used a higher dose of enoxaparin (30 mg twice daily) and showed dabigatran to be inferior, so the company did not file in the US, Schulman commented. A new North American trial in hip-replacement patients (RE-NOVATE 2) is now under way and is using the enoxaparin 40-mg once-daily dose, he said.
| RECOVER and the other stud ies mentioned here were funded by Boehringer Ingelheim. Schulman reports receiving funding from GlaxoSmithKline, Bayer, Boehringer Ingelheim, and Sanofi-Aventis; disclosures for the coauthors are listed in the paper. Chasis and Schwartz report no conflicts of interest.
Heartwire from Medscape © 2009
Cite this: RECOVER: Dabigatran beats warfarin in VTE - Medscape - Dec 07, 2009.