ORLANDO – A new era in the management of patients with a recent episode of acute coronary syndrome arrived with the report that adding a low dose of the oral anticoagulant drug rivaroxaban to standard medical therapy with aspirin and clopidogrel produced a striking mortality-rate improvement over as much as 2 years of follow-up at a price of only a modest increase in major bleeds.
"Very low-dose anticoagulation with rivaroxaban, 2.5 mg b.i.d., in addition to antiplatelet therapies, represents an effective strategy to reduce cardiovascular events in patients with a recent ACS" [acute coronary syndrome] event, Dr. C. Michael Gibson said at the meeting. "Rivaroxaban reduced the risk of cardiovascular death, myocardial infarction, or stroke in patients across the spectrum of ACS, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina."
Rates of major bleeding and intracranial hemorrhage were higher with rivaroxaban; however, there was no excess of fatal intracranial hemorrhage or fatal bleeding with rivaroxaban compared with placebo, particularly the twice-daily 2.5 mg dosage.
"There was increased major bleeding and intracranial hemorrhage, but this kind of mortality benefit bleeding seems to trump the nonfatal bleeds," he said. In addition, among patients who developed intracranial hemorrhages or ischemic strokes, "Rankin scores after strokes were significantly better in the rivaroxaban-treated patients. They had better functional status," compared with placebo-treated patients who had a stroke, said Dr. Gibson, chief of clinical research in the division of cardiology at Beth Israel Deaconess Medical Center in Boston.
The efficacy result showed that among the 93% of patients enrolled in the trial who were maintained on concurrent treatment with aspirin plus clopidogrel, the lower rivaroxaban dosage resulted in the prevention of one death for every 56 patients treated for 2 years.
Concurrent with Dr. Gibson’s report at the meeting the results from the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 trial (ATLAS ACS-2 TIMI 51) appeared online (N. Engl. J. Med. 2011;365:doi:10.1056.NEJMoa1112277).
Although rivaroxaban received Food and Drug Administration approval earlier this year for the indications of preventing stroke in patients with atrial fibrillation, and for preventing venous thromboembolism in patients following hip or knee replacement surgery, a 10-mg pill is the smallest formulation now sold in the United States, which would make it difficult for physicians to prescribe a 2.5-mg twice-daily dosage until the ACS indication goes through FDA review, Dr. Gibson cautioned.
Cardiologists who heard these findings hailed the 2.5-mg twice daily dosage of rivaroxaban as an important addition to standard management of most patients with a recent ACS if they could also be put on the aspirin and clopidogrel background used in the study. They also highlighted the importance of the phase III study’s design, which showed that a 5-mg twice daily dosage did not produce as clear a benefit and also led to substantially more major bleeds, intracranial hemorrhages, and fatal bleeds.
The lower tested dose of rivaroxaban "is a new standard of antithrombotic drug in ACS," commented Dr. Paul W. Armstrong, professor of medicine at the University of Alberta in Edmonton, Canada.
"The 2.5 mg b.i.d. dosage looked spectacular. A trial showing a reduction of all-cause mortality is pretty incredible," said Dr. Deepak L. Bhatt, chief of cardiology at the VA Boston Healthcare System and a co-investigator on the study.
Moreover, the results showed that "adding a little sprinkle of an anticoagulant reduced mortality, while adding more drug, 5 mg b.i.d., still reduced ischemic events but increased bleeds." In contrast, results in the recently completed APPRAISE-2 study, which used a similar design to test another oral anticoagulant, apixaban in ACS patients, administered a more potent, 5 mg b.i.d. dosage of apixaban and failed to show benefit and generated an even higher rate of bleeds (N. Engl. J. Med. 2011;365:699-708). If ATLAS "had just tested the 5 mg b.i.d. dosage, we would have been left with the issue of whether a lower dose would have worked," he said in an interview.
Continued separation of the combined-event and mortality curves between the 2.5 mg b.i.d. rivaroxaban patients and the placebo controls over time throughout the 2 years of follow-up provided another major observation that guide therapy. This finding "is a sign to continue treatment indefinitely," Dr. Bhatt said. "The platelet activation during an ACS event decreases substantially after 30 days, and after 6 months, but thrombin seems to linger, so there may be a role for prolonged anticoagulant treatment that surpasses the role for prolonged antiplatelet treatment."