NEW ORLEANS – The investigational oral anticoagulant rivaroxaban was as effective as injection enoxaparin in preventing venous thromboembolism at 10 days and superior at 35 days among critically ill hospitalized patients in the phase III MAGELLAN study.
Overall bleeding rates were low, at about 1%, but were significantly higher in patients receiving rivaroxaban across the entire study period, lead author Dr. Alexander T. Cohen said April 5 at the annual meeting of the American College of Cardiology.
"MAGELLAN confirms that there is a continued risk of VTE [venous thromboembolism] beyond the initial period of hospitalization, and I believe this is an important finding because the benchmark data said we should get a figure of 4%, and we got a figure of 5.7% at day 45," he said.
The study randomly assigned 8,101 patients hospitalized for an acute medical illness including heart failure, acute infectious disease, and acute respiratory insufficiency to oral rivaroxaban 10 mg daily for 35 days or subcutaneous enoxaparin 40 mg daily for 10 days plus placebo.
At day 10, the primary composite efficacy end point, defined as the cumulative incidence of asymptomatic proximal deep venous thromboembolism (DVT) detected by ultrasonography, symptomatic DVT, symptomatic nonfatal pulmonary embolism (PE), and VTE-related death, occurred in 2.7% of patients in both arms, reaching the prespecified noninferiority benchmark for day 10.
At 35 days, significantly fewer rivaroxaban patients experienced the primary efficacy end point, at 4.4% vs. 5.7% of patients in the enoxaparin arm, reaching the superiority end point for day 35. The absolute risk reduction was 1.3% and the relative risk reduction was 23%, said Dr. Cohen, who is with King’s College in London.
Clinically relevant bleeding occurred significantly more often in the rivaroxaban group than in the enoxaparin group from day 1 to 10 (2.8% vs. 1.2%), from day 1 to 35 (4.1% vs. 1.7%), and from day 11 to 35 (1.4% vs. 0.5%).
Among major bleeding events, a drop in hemoglobin of 2 g/dL or more was observed in 31 rivaroxaban patients and 10 enoxaparin patients, 2 or more units of blood were transfused in 34 and 8 patients, respectively, and critical site bleeds occurred in 9 and 4 patients, respectively.
Notably, seven rivaroxaban patients died of fatal bleeds, compared with only one enoxaparin patient. Overall, about 5% of patients in the trial died of all causes.
The net clinical benefit was 9.4% for rivaroxaban and 7.8% for enoxaparin. Based on the prespecified net clinical benefit analysis, Dr. Cohen acknowledged that a consistently positive benefit-risk balance was not seen among the cohort, but that they plan to conduct subgroup analyses to determine factors related to bleeding and to identify patients who might derive greater benefit from thromboprophylaxis with rivaroxaban.
He stressed that the study used a highly sensitive analysis of bleeding, such as a drop in hemoglobin of just 2 g/dL, and that even nosebleeds and bruising were counted in the risk-benefit analysis. When asked whether removal of these lesser bleeding events would result in a positive clinical benefit for rivaroxaban, Dr. Cohen said he was hesitant to speculate outside the trial’s prespecified outcome measures. When pressed further, he replied, "If we looked at a traditional risk-benefit analysis of major bleeds, then the picture swings back the other way. ... It would start to look more favorable toward rivaroxaban, but I have to stick to the study protocol."
When asked whether he had a theory as to why fatal bleeds occurred, Dr. Cohen pointed out that while there were 7 bleeding deaths with rivaroxaban and only 1 with enoxaparin, there were 30 PE-related deaths with enoxaparin and 19 with rivaroxaban.
"So we saved 11 lives from blood clots, if you want to [make that sort of analysis], and lost 6 lives through bleeding," he said.
In a separate interview, Dr. A. Michael Lincoff, director of the Cleveland Clinic Coordinating Center for Clinical Research, said numerous studies have shown that the risk of DVT persists beyond the acute hospitalization period and that the ability to give rivaroxaban after patients are discharged is valuable.
"It’s a much more practical drug to send patients home on," he said in an interview. "Yes, you can train patients to inject themselves with enoxaparin, but it’s not well accepted in many cases."
Dr. Cohen reported financial ties with more than a dozen pharmaceutical companies, including Bayer (maker of rivaroxaban). Dr. Lincoff had no relevant disclosures.