Thromboembolic disease is common in patients with cancer and increases risk of mortality. Recent studies showed that the oral factor Xa inhibitor rivaroxaban (Xarelto) was as effective and safe as standard anticoagulant therapy in treating deep-vein thrombosis, with superior efficacy of rivaroxaban observed in a continued-treatment cohort.1 Rivaroxaban may thus represent a simple, fixed-dose alternative to standard anticoagulant therapy that can be used without need for laboratory monitoring in treatment of deep-vein thrombosis. A more recent investigation (EINSTEIN-PE study) has assessed the effects of rivaroxaban in the treatment of acute symptomatic pulmonary embolism, finding that the agent had efficacy noninferior to standard therapy in initial and continued treatment while offering a potential improvement in risk-benefit profile.2
Study Design
In this open-label, noninferiority trial,2 4,832 patients with acute symptomatic pulmonary embolism with or without deep-vein thrombosis were randomly assigned to receive rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily; n=2,420) or standard therapy consisting of enoxaparin followed by dose-adjusted vitamin K antagonist treatment (n = 2,413) for 3, 6, or 12 months.
The primary efficacy outcome was symptomatic recurrent venous thromboembolism, defined as a composite of fatal or nonfatal pulmonary embolism or deep-vein thrombosis. The primary safety outcome was major bleeding or clinically relevant nonmajor bleeding (the latter defined as bleeding requiring medical intervention, unscheduled physician contact, interruption of study treatment, or impairment of activities of daily life).
The rivaroxaban and standard therapy groups were similar with regard to mean age (58 years), gender (54% and 52% male), proportion with concurrent deep-vein thrombosis (25%), and proportion hospitalized (89%). Causes of pulmonary embolism in the two groups were unprovoked (65% and 64%), recent surgery/trauma (17% in both), immobilization (16% in both), estrogen therapy (9% in both), and active cancer (5% in both). Before randomization, almost all patients received low-molecular-weight heparin pending confirmation of a pulmonary embolism diagnosis. This therapy was limited to 1 day in almost 60% of patients, and less than 2% received more than 2 days of treatment.
The intended duration of study treatment was 3 months in approximately 5% of patents in both groups, 6 months in 57%, and 12 months in 37%. The mean study duration was 263 days in the rivaroxaban group and 268 days in the standard therapy group. Treatment was discontinued early in 11% of rivaroxaban patients and 12% of standard therapy patients, with the most common reasons being adverse events and withdrawal of consent. Proportions of patients lost to follow-up were similar in the two groups (0.3% and 0.4%). During study treatment, international normalized ratio (INR) was in the therapeutic range 62.7% of the time and exceeded 3.0 15.5% of the time in the standard therapy group.
Intent-to-treat Analysis
On intent-to-treat analysis, symptomatic recurrent venous thromboembolism occurred in 2.1% of rivaroxaban patients, compared with 1.8% of standard therapy patients (HR = 1.12, 95% CI = 0.75-1.68), with the difference meeting the prespecified criterion for noninferiority of rivaroxaban (P = .003). Similar numbers of patients in the rivaroxaban and standard therapy groups had fatal pulmonary embolism (2 vs 1), death in which pulmonary embolism could not be ruled out (8 vs 5), nonfatal pulmonary embolism (22 vs 19), recurrent deep-vein thrombosis plus pulmonary embolism (0 vs 2), and recurrent deep-vein thrombosis (18 vs 17).
There was no difference between the rivaroxaban group and the standard therapy group with regard to risk for the composite safety endpoint of major bleeding or clinically relevant nonmajor bleeding during treatment (10.3% vs 11.4%; HR = 0.90, 95% CI = 0.76-1.07). A significantly smaller proportion of rivaroxaban patients experienced a major bleeding event (1.1% vs 2.2%; HR = 0.49, 95% CI = 0.31-0.79, P = .003). Fatal major bleeding events occurred in two rivaroxaban patients and three standard therapy patients. Clinically relevant nonmajor bleeding occurred in 9.5% of rivaroxaban patients and 9.8% of standard therapy patients.
A measure of net clinical benefit combined the number of patients with recurrent venous thromboembolism and the number of patients with major bleeding experienced during treatment or during the study period after treatment had stopped. The rate of this composite outcome was nonsignificantly lower in the rivaroxaban group (3.4% vs 4.0%, HR = 0.85, 95% CI = 0.63-1.14).
Key Data
The two treatments were similar with regard to adverse events. Any adverse event occurred in 80% of rivaroxaban patients and 79% of standard therapy patients, with serious adverse events occurring in approximately 20% in each group, events resulting in discontinuation of study drug occurring in 5% and 4%, and events leading to hospitalization occurring in 20% and 18%. Acute coronary events during treatment occurred in 0.6% and 0.9% of patients, respectively, with the rate during the 30-day poststudy treatment period being 0.1% in both groups.
Overall, death occurred in 2.4% of rivaroxaban patients and 2.1% of standard therapy patients. Causes of death in the two groups included pulmonary embolism or pulmonary embolism not ruled out in 11 and 7 patients and bleeding in 5 and 4 patients, respectively; fatal bleeding episodes occurred in 3 rivaroxaban patients and 1 standard therapy patient when they were no longer taking study medication. Other causes of death included cancer (20 and 23 patients), myocardial infarction (2 and 1 patient), ischemic stroke (2 and 1 patient), other cardiac disorder/respiratory failure (4 and 4 patients), and infectious disease/septicemia (10 and 6 patients).
The notion that rivaroxaban can be administered at the same dose in all patients without laboratory monitoring has raised concern. However, as stated by the investigators, subgroup analyses showed that rates of recurrent venous thromboembolism and bleeding were similar in the two study groups regardless of age, sex, presence or absence of obesity, level of renal function, or extent of pulmonary embolism. ■
References
1. The EINSTEIN Investigators: Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499-2510, 2010.
2. The EINSTEIN-PE Investigators: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287-1297, 2012.
