Dabigatran Can Replace Warfarin in Venous Thromboembolism: RECOVER Results

Zosia Chustecka

December 07, 2009

December 7, 2009 (New Orleans, Louisiana) — The new anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) could replace the older product, warfarin, say researchers presenting new data from a large clinical trial in patients with acute venous thromboembolism (the RECOVER study). The results show that dabigatran is as effective and as safe as, if not safer than, the older agent, but it also offers the advantage of a fixed dose and no need for blood monitoring, as opposed to the regular monitoring and dose adjustment needed with warfarin.

Dr. Sam Schulman

"In other words, patients can achieve the same results in a more convenient manner," said lead researcher Sam Schulman, MD, professor of medicine, thrombosis service, McMaster Clinic and Hamilton General Hospital, in Ontario. These findings will change the standard of care for venous thromboembolism, he predicted.

The results were presented here at the American Society of Hematology (ASH) 51st Annual Meeting and published online December 6 in the New England Journal of Medicine. Introducing the presentation at a plenary session, Mary Cushman, MD, MSc, from the University of Vermont in Burlington, said this was a "landmark trial."

Experts at the meeting were enthusiastic about the results. Joel Anne Chasis, MD, associate professor of hematology/oncology at the University of California in San Francisco, and a staff scientist at the Lawrence Berkeley National Laboratory in Berkeley, highlighted this presentation as one of the hot topics of the meeting. She told Medscape Oncology that the results suggest that dabigatran could replace warfarin, and the lack of a need for monitoring would "be welcome news for both patients and their physicians."

Dr. Bradford Schwartz (Courtesy of ASH)

Bradford Schwartz, MD, professor of medicine and dentistry and dean of the University of Illinois College of Medicine at Urbana-Champaign, who moderated an ASH press briefing at which the RECOVER results were highlighted, noted that dabigatran is also free of the interactions with diet and other drugs that make taking warfarin so difficult for patients. Any foods that contain vitamin K (such as salads and vegetables) can increase coagulability, whereas interactions with many different drugs, particularly antibiotics, can put the patient at increased risk of bleeding, he explained. "Over the course of a year, the number of these incidents that throw warfarin out of whack is quite large," 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 and adherence to treatment will be greatly improved.

Noting that there are several other new oral anticoagulants on the horizon, including the investigational agent rivaroxaban, which was also featured at the press briefing, Dr. Schwartz said that "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, and bad, such as in pulmonary embolism," he added.

Dr. Schwartz said that as more of these new anticoagulants become available, physicians will need to decide which drug to use in which patients, and he urged them to take into consideration the clinical trial data for each drug in each individual indication. "These are different drugs with different characteristics," but they are "beautiful new drugs," he said, coming after 60 to 70 years of using "rat poison."

"Warfarin has a very narrow therapeutic index, with a small difference between the dose that is therapeutic and the dose that is toxic," he said, adding that "there is no more dangerous drug on the market."

Third Major Indication

The use of dabigatran for venous thromboembolism, which was explored in the RECOVER study, represents a third major indication for the drug. A second similar trial, known as RECOVER-2, is underway, and Dr. Schulman told Medscape Oncology that both trials are likely to be needed for approval of this indication.

Venous thromboembolism, which covers both deep vein thrombosis and pulmonary embolism, is now considered to be a single disease entity and is a huge clinical problem, said Harry Buller, MD, PhD, professor of medicine at the Academic Medical Center in Amsterdam, the Netherlands, speaking at the press briefing. It affects about 2 or 3 people in every 1000, and "each year, more people die from pulmonary embolism than die from AIDS, breast cancer, prostate cancer, and traffic accidents combined," he said.

The initial indication for dabigatran, and the only one that is currently approved — but not in the United States — is for prophylaxis in orthopedic surgery patients. Dabigatran was approved for this use in Europe and Canada in 2008, on the basis of 2 large trials (the RE-MODEL study in patients undergoing total knee replacement and the RE-NOVATE study of total hip replacements), which showed that dabigatran was comparable to enoxaparin 40 mg once daily in preventing venous thromboembolism. However, 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 United States, Dr. Schulman explained. A new North American trial in hip replacement patients (RE-NOVATE 2) is now underway, and is using the enoxaparin 40 mg dose, he said.

The second potential indication for dabigatran is in atrial fibrillation, and highly positive results in this population were recently reported in the RE-LY study. A long-term safety follow-up study of these patients is currently underway (RELY-ABLE). The company has said that it plans to file for registration for this indication in 2010.

All of these studies have been funded by the manufacturer, Boehringer Ingelheim.

Details of RECOVER Study

The RECOVER study was conducted in 2539 patients with acute symptomatic venous thromboembolism who were randomized to 6 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 to 3. All patients received initial treatment for 6 days with a parenteral anticoagulant (either intravenous heparin or a subcutaneous low-molecular-weight heparin derivative), to allow the dose of warfarin to be adjusted to achieve an INR of 2 to 3.

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Dr. Sam Schulman

The final analysis was conducted on 1274 patients who received dabigatran and 1265 who received warfarin.

The primary end point was recurrent venous thromboembolism or fatal pulmonary embolism, which was confirmed in 2.4% of patients receiving dabigatran and 2.1% of patients receiving warfarin. There was 1 death in each treatment group. The hazard ratio was 1.1 (95% confidence interval [CI], 0.65 - 1.84), and this shows noninferiority, Dr. Schulman reported.

Major bleeding was seen in 1.6% of patients receiving dabigatran and in 1.9% of patients receiving 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 receiving dabigatran and in 8.8% patients receiving warfarin. The hazard ratio was 0.63 (95% CI, 0.47 - 0.84; P = .002).

The difference was also significant for any bleeding event, which was seen in 16.1% of patients receiving dabigatran and in 21.9% receiving warfarin. The hazard ratio for this was 0.71 (95% CI, 0.59 - 0.85; P < .001), which represents a 29% risk reduction, and this was highly significant, Dr. Schulman noted.

It is these significant differences in bleeding events that led Dr. Schulman and the 2 commenters, Dr. Chasis and Dr. Schwartz, to suggest that dabigatran might be safer than warfarin.

Dr. Schulman noted that there was no signal in the RECOVER study for either myocardial infarction (which was seen in the RE-LY study in patients with atrial fibrillation) or for increases in liver enzymes (a problem that led to the withdrawal of an earlier oral anticoagulant, ximelagatran). The only adverse effect that was reported in slightly more patients receiving 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," Dr. Schulman and colleagues write in their 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."

The RECOVER study was funded by Boehringer Ingelheim, the manufacturer of dabigatran. Dr. Schulman reports receiving funding from GlaxoSmithKline, Bayer, Boehringer Ingelheim, and Sanofi-Aventis. Several of his coauthors also report financial relationships, as detailed in the paper. Dr. Buller reports receiving funding from Bayer. Dr. Chasis and Dr. Schwartz have disclosed no relevant financial relationships.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 1. Presented December 6, 2009.

N Engl J Med. Published online December 6, 2009.

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