New Anticoagulants Show Promise in Treatment of Clotting

Abstract

Two oral anticoagulants, apixaban and dabigatran, were found to be effective for the extended treatment of venous thromboembolism (VTE) in three industry-sponsored randomized clinical trials. However, the researchers said that more data are needed in patients over 75 years old. Both medications also reduced the risk of bleeding complications, the investigators said. The results were published online in the New England Journal of Medicine. In the first trial, two doses of apixaban were compared with placebo in 2,486 patients with VTE who had finished standard anticoagulation therapy, Dr. Giancarlo Agnelli of the University of Perugia (Italy) and his colleagues reported. The study subjects were enrolled at 328 medical centers in 28 countries. They were randomly assigned to receive a 2.5-mg dose (840 subjects), a 5-mg dose (813 subjects), or a matching placebo (829 subjects) twice daily for 1 year. The primary efficacy outcome was a composite of symptomatic recurrent VTE or death from any cause. This occurred in 3.8% of the maintenance-dose group and 4.2% of the treatment-dose group, both significantly lower rates than in the placebo group (11.6%). The primary safety outcome measure was major bleeding, which occurred in 0.2% of the maintenance-dose group and 0.1% of the treatment-dose group, compared with 0.5% of the placebo group. Clinically relevant but nonmajor bleeding occurred in 3.0% of subjects taking 2.5 mg of apixaban and 4.2% of those taking 5 mg of apixaban, which were significantly higher than the 2.3% rate in subjects taking placebo. “It should be noted, however, that only 15% of the patients in this study were older than 75 years of age, and few had a body weight below 60 kg or moderate or severe renal impairment,” the researchers said. In a separate report on two trials, Dr. Sam Schulman and his associates examined the direct thrombin inhibitor dabigatran as a long-term anticoagulation treatment. In one trial, 2,866 VTE patients who had completed at least 3 months of anticoagulation therapy and were considered to be at increased risk for recurrence were randomly assigned to receive either fixed-dose dabigatran twice daily (1,430 subjects) or warfarin (1,426 subjects) for up to 36 months. They were followed at 265 medical centers in 33 countries, said Dr. Schulman of McMaster University Thrombosis and Atherosclerosis Research Institute, Hamilton, Ont., and his colleagues. The other trial involved 1,343 VTE patients who had completed at least 3 months of anticoagulation therapy but were not considered to be at increased risk of recurrence. These subjects were randomly assigned to receive either fixed-dose dabigatran (681 patients) or a matching placebo (662 patients) and were followed at 147 medical centers in 21 countries. In the first trial, recurrent symptomatic VTE or VTE-related death occurred in 1.8% of the dabigatran group and 1.3% of the warfarin group, thus meeting the criteria for noninferiority to warfarin in preventing recurrent or fatal VTE. In the second trial, this outcome occurred in 0.4% of the dabigatran group, compared with 5.6% of the placebo group, so the drug was significantly more effective than placebo at preventing recurrent or fatal VTE. Dr. Jean M. Conners of the hematology division at Brigham and Women's Hospital, Boston, in a comment accompanying the reports, said, “The crux of using the new oral anticoagulants in clinical practice … lies in the selection of appropriate patients. Patients in these studies were younger (average age, 56 years), with fewer coexisting diseases and a lower bleeding risk than patients typically seen in practice.” Better risk-stratification strategies are needed to identify patients who stand to benefit most from extended anticoagulation, she said. Dr. Agnelli's study was funded by Bristol-Myers Squibb (BMS) and Pfizer. Dr. Schulman's trials were funded by Boehringer Ingelheim.