Rivaroxaban After Acute Coronary Syndrome
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.
This article originally appeared in the March 2012 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan Weiss, MD. Dr. Crawford is Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, and Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford reports no financial relationships relevant to this field of study, and Dr. Weiss is a scientific advisory board member for Bionovo.
Source: Mega JL, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
After acute coronary syndromes (ACS), patients remain at risk for recurrent cardiovascular events. Antiplatelet agents are the mainstay of secondary preventive strategies aimed at reducing the rate of recurrent events. The recent development of more reliable oral antithrombin agents than warfarin has sparked interest in inhibiting not only platelet aggregation but also thrombin generation in patients who have experienced ACS. Rivaroxaban is an orally active inhibitor of activated factor X. After demonstrating non-inferiority to warfarin, it received FDA approval in 2011 for deep venous thrombosis stroke prophylaxis following knee and hip surgery, and for stroke prophylaxis in patients with atrial fibrillation (AF). Lower doses showed promise in early clinical trials of patients who had suffered ACS. This large Phase 3 trial, the ATLAS ACS 2–TIMI 51 study, studied two low-dose regimens of rivaroxaban in patients with ACS.
A total of 15,526 patients who presented with ACS were enrolled at 766 sites in 44 countries at a mean of 4.3 days after presentation. Inclusion criteria included patients > 18 years of age who presented with unstable angina, non-ST elevation myocardial infarction (MI), or ST elevation MI. Those aged < 55 years also had to have either diabetes or a prior ischemic event to be enrolled. Exclusion criteria included thrombocytopenia, anemia, creatinine clearance < 30 mL/min, gastrointestinal bleeding within 12 months, prior intracranial hemorrhage, and, for those taking dual antiplatelet therapy (DAPT), a prior stroke or transient ischemic attack. Patients were randomized to receive placebo or one of two doses of rivaroxaban: 2.5 mg twice daily or 5 mg twice daily for up to 31 months. All patients were to receive low-dose aspirin and a thienopyridine according to local guidelines. The primary efficacy endpoint was a composite of death from cardiovascular causes, MI, or stroke.
Baseline clinical and demographic data were similar in all groups and there was a large proportion of diabetics (31%). Aspirin was used in 99% and a thienopyridine in 93%. Rivaroxaban significantly reduced the combined primary efficacy endpoint of death from cardiovascular causes, MI, or stroke, as compared with placebo, with rates of 9.1% in the 2.5 mg group, 8.8% in the 5 mg group, and 10.7% in the placebo group (hazard ratio [HR] for rivaroxaban vs placebo, 0.84; P = 0.008). Interestingly, the 2.5 mg dose reduced total mortality (2.9% vs 4.5%; P = 0.002), but the 5 mg dose did not.
There was a significant dose-related increase in bleeding with rivaroxaban compared to placebo. Major non-CABG related bleeding was four-fold higher with rivaroxaban (2.1% vs 0.6%; HR 3.96; P < 0.001), as were minor bleeding (1.3% vs 0.5%; P = 0.003) and intracranial hemorrhage (0.6% vs 0.2%; P = 0.009), but there was no difference in fatal bleeding. The rates of bleeding were generally higher in the 5 mg group than the 2.5 mg group. There was no difference in other adverse events between the rivaroxaban and placebo groups. The authors conclude that in patients with a recent ACS, rivaroxaban reduced the risk of the composite endpoint of death from cardiovascular causes, MI, or stroke. Rivaroxaban also increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding.
Commentary
The addition of low-dose rivaroxaban to dual antiplatelet therapy in patients suffering an ACS reduced ischemic events but also resulted in increased bleeding. It is important to note that the doses of rivaroxaban used in this study were much lower than in atrial fibrillation (AF). The lowest dose (2.5 mg twice daily) appeared to be the most effective and safe in this trial, and this is substantially lower than the 20 mg dose that is indicated for stroke prophylaxis in AF. This is a large, well-designed study and the conclusions are strengthened by the consistency of benefit seen across most subgroups and in all geographic regions.
One important subgroup, patients with prior TIA or stroke, did not benefit from rivaroxaban. Prior stoke or TIA is also a contraindication to the use of the more potent antiplatelet agent prasugrel. One must exercise caution when prescribing anticoagulants and antiplatelet agents in this patient group.
Rivaroxaban is one of several newer anti-coagulants that demonstrate benefit in patients who have had an ACS. Factor Xa inhibitors and direct thrombin inhibitors appear to reduce recurrent ischemic events after ACS, but all appear to increase bleeding side effects. It is likely that in the coming years we will see several new anticoagulants approved for secondary prevention. The delicate balance between reducing thrombotic events and bleeding side effects will continue, and treatment regimens will become more complicated.
After acute coronary syndromes (ACS), patients remain at risk for recurrent cardiovascular events.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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