Dabigatran Cuts Bleeding Risk in VTE Prophylaxis : Rate 29% lower than with warfarin.

NEW ORLEANS — Dabigatran etexilate had comparable efficacy and significantly lower or comparable bleeding rates to warfarin in patients with acute venous thromboembolism, according to data from the RE-COVER trial.

The direct thrombin inhibitor is among several emerging oral anticoagulants that might replace warfarin, which has accumulated a notorious safety record over its 60-year history in humans and requires frequent dose adjustments.

Dabigatran, which is approved as Pradaxa in 40 countries for the primary prevention of venous thromboembolism (VTE) in patients who have undergone total knee or hip replacement, is not approved for use in the United States.

Dabigatran met this phase III study's primary end point, demonstrating noninferiority to warfarin for prevention of recurrent or fatal VTE. After 6 months of treatment, 2.4% of 1,274 patients randomized to dabigatran and 2.1% of patients assigned to warfarin experienced recurrent VTE or related death (hazard ratio 1.10), Dr. Sam Schulman said during a plenary session at the annual meeting of the American Society of Hematology.

Major bleeding events occurred in 1.6% of dabigatran patients and in 1.9% of warfarin patients (hazard ratio 0.82). Dabigatran reduced the risk of any bleeding event at 6 months by 29% (P = .0002, HR 0.71). Fatal bleeding occurred in one patient in each arm; intracranial bleeding was reported in no patients on dabigatran and three patients on warfarin.

“Dabigatran etexilate provides a convenient, oral fixed-dose treatment for acute VTE that offers an alternative to warfarin in the treatment of VTE,” said Dr. Schulman, professor of medicine at McMaster University in Hamilton, Ont. and director of the clinical thromboembolism program at Hamilton General Hospital.

Liver function abnormalities, which caused the only previously available oral direct thrombin inhibitor, ximelagatran, to be withdrawn from European markets and to be denied FDA approval, were infrequent in both groups. A combination of elevated alanine aminotransferase level three times the upper limit of normal and bilirubin two times the upper limit of normal occurred in two dabigatran patients and four warfarin patients.

The number of MIs was similar with dabigatran and warfarin (four vs. two), he said. In the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial in patients with atrial fibrillation, dabigatran at the same 150 mg twice-daily dose was associated with lower rates of stroke, compared with warfarin, and a slight but significant increase of MI (N. Engl. J. Med. 2009;361:1139–51).

When this point was raised by reporters at a press briefing during the meeting, Dr. Schulman responded that the number of MIs with dabigatran was too small to support conclusions. He speculated that it may be an issue of dose dependence, based on data from the phase II RE-DEEM study of dabigatran in patients with acute coronary syndrome.

“As always, it is a question of finding the right dose,” he said. “Whether in general oral thrombin inhibitors increase the risk of MI, I don't think we can say that. I know there was a rumor of this with ximelagatran in orthopedic studies” based on “very vague data.”

Price was a key issue raised during both the press briefing and the discussion following the formal study presentation. Dr. Schulman told the audience that it was unclear what the price would be for the treatment of VTE, which has a different dosage than for VTE prevention in orthopedic patients. During the press briefing, he suggested that the price to treat VTE would be about double that for the orthopedic indication, which is about $7 per day for dabigatran versus $8 a day plus lab monitoring costs for low-molecular-weight heparin.

Press briefing moderator Dr. Bradford Schwartz, regional dean of the college of medicine at the University of Illinois at Urbana-Champaign, said oral dabigatran will “simplify the management of a feared disorder.”

Dr. Mary Cushman of the University of Vermont in Burlington, who introduced the formal study presentation, said anticoagulation is underutilized in the United States because of the difficulties in managing warfarin; for example, 50% of elderly patients eligible for treatment are not treated and remain at risk for stroke. Dabigatran meets some of the requirements for an “optimal new anticoagulant,” she added, in that it is an oral agent that does not require lab monitoring and has few drug and food interactions.

Patients in the double-blind multinational trial had symptomatic VTE for a maximum of 14 days and were given initial parenteral anticoagulation therapy and warfarin or placebo until they reached an international normalized ratio (INR) of 2.0 or more on 2 consecutive days; then they were randomized to dabigatran 150 mg b.i.d. or warfarin dose-adjusted to an INR of 2.0 and 3.0. Patients with a creatinine clearance rate less than 30 mL per minute, who were excluded from the study, should not be treated with dabigatran, Dr. Schulman advised.