In a study of patients with acute coronary syndromes, low doses of rivaroxaban were effective in reducing the primary end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban also reduced overall mortality, although there was more bleeding.
After an acute coronary syndrome, patients remain at risk for recurrent cardiovascular events despite optimal medical therapy, including long-term antiplatelet therapy with aspirin and an adenosine diphosphate-receptor blocker. This risk may be related in part to excess thrombin generation that persists beyond the acute presentation in such patients. As such, there has been interest in evaluating the role of oral anticoagulants after an acute coronary syndrome. Improved cardiovascular outcomes were reported for patients who were treated with the anticoagulant warfarin in addition to aspirin. However, widespread use of long-term warfarin in such patients has been limited by challenges associated with drug administration and the risk of bleeding. Likewise, treatment with the factor IIa inhibitor ximelegatran after a myocardial infarction showed cardiovascular benefits, but the drug was associated with hepatotoxicity.
• What side effects should be considered with the use of rivaroxaban?
In the study reported in this week’s Journal, rivaroxaban was associated with a significantly increased rate of TIMI major bleeding that was not related to CABG, as compared with placebo, as well as rates of TIMI minor bleeding, TIMI bleeding requiring medical attention, and intracranial hemorrhage. There was no significant difference in the rates of fatal bleeding associated with rivaroxaban as compared with placebo. The rates of adverse events that were not related to bleeding were similar in the rivaroxaban and placebo groups. Specifically, clinical and laboratory liver abnormalities were similar among patients treated with rivaroxaban or placebo, with alanine aminotransferase levels of more than three times the upper limit of the normal range and total bilirubin levels of more than two times the upper limit of the normal range occurring in 0.2% of patients in each study group. Syncope and hypersensitivity reactions have also been reported.
• Is there a role for the use of rivaroxaban in patients with a recent acute coronary syndrome?
In this study of patients with a recent acute coronary syndrome followed for a mean of 13 months, rivaroxaban was associated with a significant reduction in the primary efficacy end point of death from cardiovascular causes, myocardial infarction, or stroke, as compared with placebo, with rates of 8.9% and 10.7%, respectively (hazard ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008).
Morning Report Questions
Q: Which component of the coagulation cascade is directly inhibited by rivaroxaban?
A: Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade and results in the formation of thrombin, which catalyzes additional coagulation-related reactions and promotes platelet activation.
Q: How did the 2.5-mg dose of rivaroxaban compare to the 5.0-mg dose in terms of study outcome?
A: The 2.5-mg dose of rivaroxaban, as compared with placebo, was associated in a reduction in the rate of death from cardiovascular causes and the rates of death from any cause. The 5-mg dose of rivaroxaban, as compared with placebo, was not associated with a reduction in death from either cardiovascular causes or any cause and differed significantly from the 2.5 mg-dose of rivaroxaban. The authors indicate that this observation is explained in part by the numerical increase in fatal bleeding associated with the higher dose of rivaroxaban. However, other consequences of nonfatal bleeding may also have contributed to this finding.