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Patients at risk of venous thromboembolism obtained similar protection from rivaroxaban (Xarelto) and enoxaparin (Lovenox, others) for standard-duration therapy but significantly better protection with rivaroxaban during extended treatment, a large randomized trial showed.

Treatment with either of the anticoagulants led to a 10-day VTE rate of 2.7%. When rivaroxaban prophylaxis continued for 35 days, patients had a statistically significant 23% reduction in relative risk as compared with the standard 10-day enoxaparin course followed by placebo.

But clinically relevant and severe bleeding occurred significantly more often with rivaroxaban at both 10 and 35 days, the investigators reported in the Feb. 7 issue of the New England Journal of Medicine.

"The results of the current study support those from earlier studies that showed the efficacy of extended thromboprophylaxis but also the increased risk of bleeding," Alexander T. Cohen, MD, of King's College London, and co-authors said of their findings.

A prespecified secondary outcome analysis of net clinical benefit or harm showed no benefit of rivaroxaban at 10 days or 35 days.

A variety of illnesses heighten the risk of VTE, including cancer, myocardial infarction, stroke, and acute exacerbations of several other conditions. Randomized controlled trials have shown that thromboprophylaxis for as long as 14 days can reduce the risk of VTE in hospitalized patients, but no studies have supported more extended prophylaxis on a routine basis.

The multicenter MAGELLAN study compared extended versus standard prophylaxis in a large, clinically diverse patient population. Hospitalized patients at increased risk of VTE were randomized to rivaroxaban or enoxaparin for 10 days of prophylaxis. Patients in the enoxaparin group switched to placebo, whereas the rivaroxaban group continued prophylaxis for 35 days without interruption.

The primary efficacy endpoint was the composite of asymptomatic proximal and symptomatic VTE. The trial was statistically powered to test the non-inferiority of rivaroxaban versus enoxaparin at 10 days and rivaroxaban superiority at 35 days. The primary safety outcome was the composite of major and clinically relevant nonmajor bleeding.

Patients underwent ultrasonography on day 10 and day 35 for detection of asymptomatic VTE.

The investigators randomized 8,101 hospitalized adults age 40 and older to enoxaparin and rivaroxaban. About 45% of the patients had a principal diagnosis of infectious disease, followed by heart failure (32%), respiratory insufficiency (28%), and ischemic stroke (17%). Almost a third of the patients had two or more conditions.

Risk factors for VTE included age ≥75 (38%), history of cancer (17%), chronic venous insufficiency (15%), obesity (15%), and severe varicosis (12%).

At day 10, 2,938 patients in the rivaroxaban group and 2,993 in the enoxaparin arm were evaluable for the primary endpoint, which did not differ between the groups.

After 35 days, the evaluable population comprised 2,967 patients in the rivaroxaban arm and 3,057 in the enoxaparin arm. Continuous rivaroxaban was associated with a VTE rate of 4.4% versus 5.7% for enoxaparin followed by placebo (RR 0.77, P=0.02).

During the first 10 days of randomized therapy, 2.8% of rivaroxaban patients had episodes of major or clinically relevant bleeding versus 1.2% of the enoxaparin group (P<0.001). By day 35 the rates had increased to 4.1% with rivaroxaban and 1.7% with enoxaparin (P<0.001). Seven fatal hemorrhages occurred in the rivaroxaban arm versus one in the enoxaparin group.

A secondary efficacy outcome was net clinical benefit or harm, derived from the primary endpoint plus fatal VTE, death from any cause, cardiovascular death, MI, and acute ischemic stroke. That analysis yielded a total event rate of 6.6% with rivaroxaban and 4.6% with enoxaparin at 10 days (P<0.001), and event rates of 9.4% and 7.8%, respectively, at 35 days (P=0.02).

From the American Heart Association:

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