Rivaroxaban Noninferior to Standard Therapy, Reduces Major Bleeding in Patients with Pulmonary Embolism

Chicago—Patients with pulmonary embolism (PE) who took a fixed-dose regimen of rivaroxaban had a similar risk of recurrence and statistically significant fewer major bleeding events compared with those who were administered standard therapy, according to a randomized, phase 3 trial. The US Food and Drug Administration (FDA) has approved rivaroxaban to prevent deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery. Rivaroxaban, an oral factor Xa inhibitor, is also FDA approved for stroke prevention in patients with nonvalvular atrial fibrillation. Harry Roger Buller, MD, PhD, the study’s lead author, discussed the EINSTEIN-PE trial at the ACC meeting at a late-breaking clinical trial session. Results were simultaneously published online in the New England Journal of Medicine [10.1056/NEJMoa1113572]. In December 2010, the journal published the EINSTEIN-DVT study, a sister trial to EINSTEIN-PE, which found the drug was safe and effective in patients with DVT. In DVT, blood clots develop in the deep veins of the legs. PE is defined as a blockage in ≥1 lung arteries and is a complication of DVT. PE and DVT are both categories of venous thromboembolism (VTE), or blood clots occurring in the veins. “If we look at [the trials] together, they’re very consistent,” said Dr. Buller, professor of vascular medicine at the Academic Medical Center in Amsterdam, the Netherlands. “I think they reassure us that for patients with venous thromboembolism, we can now offer both physicians and patients an attractive alternative for a single drug [regimen].” Dr. Buller said VTE is the third most common cardiovascular disease in the world behind myocardial infarction and stroke. Each year in the United States, more patients die from PE than a combination of traffic accidents, breast cancer, prostate cancer, and AIDS, according to Dr. Buller. Between March 2007 and March 2011, the study enrolled 4832 patients at 263 sites in 38 countries. They were randomized in a 1:1 ratio to receive rivaroxaban (n=2419) or the standard therapy of enoxaparin and a vitamin K antagonist (n=2413). All patients had PE and 25% in both groups had DVT. Patients in the rivaroxaban group received 15 mg of the drug twice daily for the first 3 weeks and then 20 mg once daily for the remainder of the study. The standard therapy group received 1.0 mg per kilogram of body weight of injectable enoxaparin plus warfarin or acenocoumarol started within 48 hours of randomization. They took enoxaparin for ≥5 days and discontinued when the international normalized ratio was 2.0 for ≥2 consecutive days. Symptomatic recurrent VTE, the primary efficacy end point, occurred in 2.1% of the rivaroxaban group and 1.8% of the standard therapy group (hazard ratio [HR], 1.12; 95% confidence interval [CI], 0.75-1.68). There was also no significant difference in major or clinically relevant nonmajor bleeding, the primary safety end point, which occurred in 10.3% of patients in the rivaroxaban group compared with 11.4% of the standard therapy patients (HR, 0.90; 95% CI, 0.76-1.07; P=.23). In the rivaroxaban group, 1.1% of patients had major bleeding compared with 2.2% of patients in the standard therapy group (HR, 0.49; 95% CI, 0.31-0.79; P=.003). Patrick T. O’Gara, MD, FACC, cochair of the ACC meeting, said he would like more information about the drug’s cost as well as nonbleeding adverse events. However, the results are “a very important development in patient care,” according to Dr. O’Gara. “I don’t think you should underestimate the potential value of being able to manage patients like this with oral medications,” said Dr. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital in Boston, Massachusetts. “I could envision a future where length of stay would drop by more than 50% for patients admitted with this particular disease and no adverse risk factors at time of presentation.”