Loading...
Heparin, low-molecular-weight heparin (LMWH), and warfarin are the anticoagulants traditionally used for the prevention and treatment of venous thromboembolism (VTE). However, these agents require parenteral administration and frequent monitoring or have a narrow therapeutic index. Apixaban and rivaroxaban are new (and not yet FDA approved) anticoagulants that are given orally and do not require regular monitoring. Researchers tested these agents in separate industry-funded trials.
In the first trial — a multinational, double-blind study of VTE prophylaxis after hip replacement surgery — 5407 patients were randomized to receive oral apixaban (2.5 mg twice daily, initiated 12–24 hours after wound closure) or the LMWH enoxaparin (40 mg subcutaneously, 12 hours before surgery and then every 24 hours postoperatively) for 35 days. Major VTE, assessed using bilateral venography, occurred in 1.1% of apixaban recipients and 3.6% of enoxaparin recipients — a significant difference for both noninferiority and superiority. Apixaban had a similar advantage over enoxaparin for the primary composite endpoint of deep venous thrombosis (DVT), nonfatal pulmonary embolism, or death from any cause (1.4% vs. 3.9%). The two groups did not differ significantly in the composite incidence of major or clinically relevant nonmajor bleeding (roughly 5% in each group).
In the second trial — an open-label trial of therapy for acute, symptomatic proximal DVT — 3449 patients were randomized to receive either oral rivaroxaban (15 mg twice daily for 3 weeks and then 20 mg once daily) or subcutaneous enoxaparin followed by a coumarin. Treatment lasted for 3, 6, or 12 months. Recurrent VTE occurred in slightly fewer rivaroxaban than standard-therapy recipients (2.1% vs. 3.0%), and the bleeding rate was identical in the two groups (8.1%). Patients who completed 6 or 12 months of therapy were then randomized to receive rivaroxaban (20 mg once daily) or placebo for an additional 6 to 12 months. Recurrent VTE occurred in significantly fewer rivaroxaban recipients than placebo recipients (1.3% vs. 7.1%; P<0.001), but major bleeding occurred more often with rivaroxaban (4 episodes [0.7%], vs. none).
Lassen MR et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010 Dec 23; 363:2487.
Bauersachs R et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010 Dec 23; 363:2499.
Comment
Apixaban and rivaroxaban specifically target factor Xa, which occupies a central position in the coagulation cascade. Although the agents were safe and effective in these two clinical trials, the comparisons with the older anticoagulants are open to question. In the prophylaxis study, enoxaparin was given in lower doses (40 mg daily) than those used in North America (30 mg twice daily). In the treatment trial's extension phase, anticoagulants were stopped after 6 or 12 months in the placebo group, which might be premature for some patients (as suggested by the roughly 7% incidence of VTE). Rivaroxaban's noninferiority and superiority to longer-term coumarin are unclear.