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Study: Xarelto Cuts Heart Attack Mortality
ORLANDO -- Adding the oral anticoagulant rivaroxaban (Xarelto) to standard therapy after a myocardial infarction or unstable angina significantly reduced the risk of death, researchers reported here.
Patients randomized to 2.5 mg twice daily for 13 to 31 months were 34% less likely to die from cardiovascular disease than patients in the placebo group (HR 0.66, 95% CI 0.51 to 0.86) and 32% less likely to die from any cause (HR 0.68, 95% CI 0.53-0.87, P =0.002 for both), Jessica L. Mega, MD, MPH, of Brigham and Women's Hospital in Boston and colleagues, reported in a paper published online today by the New England Journal of Medicine.
The findings were also reported at a late-breaking clinical trials session at the American Heart Association meeting.
The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome (ATLAS-ACS 2 TIMI 51) randomized 15,526 patients to rivaroxaban 2.5 mg or 5 mg twice daily or matching placebo.
The 5 mg dose did not reduce the risk of death, but the rivaroxaban group as a whole had a 16% reduced risk of death (HR 0.84, 95% CI 0.74 to 0.96 P=0.008).
"In analysis of the components of the primary efficacy endpoint, rivaroxaban versus placebo had a hazard ratio of 0.80 (P=0.04) for death from cardiovascular causes (included hemorrhage-related deaths), 0.85 (P=0.47) for myocardial infarction, and 1.24 (P=0.25) for stroke (including ischemic hemorrhagic, and stroke of uncertain causes)," they wrote.
As might be expected, there were more bleeding incidents in the rivaroxaban group -- the rates of major bleeding not related to bypass surgery were 2.1% versus 0.6% (P<0.001) and the rate of intracranial bleeding was 0.6% versus 0.2% (P=0.009). But there was not a significant increase in fatal bleeding events, 0.3% versus 0.2% (P=0.66).
Rivaroxaban is a direct factor Xa inhibitor thus this safety finding takes on even greater significance given the history of this class of anticoagulants in this population.
A year ago, a phase III trial of apixaban was halted due to bleeding events, and in September Astellas Pharma discontinued development of darexaban maleate, following a report at the European Society of Cardiology that the drug caused excess bleeding in ACS patients.
The ATLAS-ACS researchers noted the differences in findings between their study and the earlier apixaban study, and they offered an explanation: ATLAS-ACS was specifically designed to exclude patients that proved problematic in the apixaban ACS study, those "who had a history of ischemic stroke or transient ischemic attack who were to be treated with aspirin and a thienopyridine, a group that has not appeared to benefit from greater decrees of antithrombotic therapy."
In a statement released by the trial's sponsor, Johnson & Johnson Pharmaceutical Research & Development, Eugene Braunwald, MD, of Harvard Medical School in Boston, said the addition of rivaroxaban to standard antiplatelet therapy "could lead to significant improvement in the management of patients with acute coronary syndrome." Braunwald is the founding chair of the Thrombolysis In Myocardial Infarction (TIMI) Study Group at Brigham and Women's Hospital.
Another researcher, C. Michael Gibson, MD, principal investigator of the ATLAS-ACS 2 TIMI 51 trial, and a senior TIMI investigator, was even more ebullient.
"If the data from ATLAS ACS 2 TIMI 51 were extrapolated into clinical practice, we could potentially see one life saved for every 56 patients treated with this combination of therapies over a two year period," Gibson said a statement released by Johnson & Johnson.
In an editorial published with the NEJM paper, Matthew T. Roe, MD, and E. Magnus Ohman, MB, from Duke Clinical Research Institute in Durham, N.C., pointed out that the bleeding rates appeared to be dose dependent as they occurred more often at the higher dose. Moreover, bleeding events were more common after 180 days on treatment and there were numerically higher rates of bleeding in "lighter-weight and elderly patients, as well as in those with reduced renal function and those enrolled in North America."
Since many ACS patients are elderly, that observation warrants additional study, Roe and Ohman noted.
And the findings in North America also require careful interpretation because only 5%-6% of the patients were enrolled in North America -- the highest enrollment was at centers in Eastern Europe, where about 40% of patients were enrolled, followed by centers in Asia (21%) and Western Europe (15%).
A similar regional difference was observed in the pivotal PLATO trial of the antiplatelet ticagrelor (Brilinta). That study, was lead by Lars Wallentin, MD, PhD,and colleagues from the Uppsala Clinical Research Centre in Sweden headed also had a number of TIMI investigators on its steering committee, compared ticagrelor with clopidogrel in 18,624 ACS patients and it reported overwhelmingly positive results for the study drug -- 9.8% reached the composite endpoint of death, stroke, or MI versus 11.7% of clopidogrel patients, a relative reduction of 16% (P<0.001).
But most of the PLATO patients came from Europe, the Middle East, or Africa. Only 11% of the patients were recruited in North America. In that cohort, ticagrelor-treated patients were 27% more likely to suffer one of the endpoint events, although the difference fell short of statistical significance (HR 1.27, 95% CI 0.92 to 1.75).
Nonetheless, that nonstatistical difference caught the eye of FDA reviewers and the drug's approval was held up for 12 months.
In ATLAS-ACS the average age of patients was 62 and roughly 75% were white males. About half of them had an ST-elevation MI, 25% had non-ST-elevation MI, and 25% had unstable angina. Sixty percent underwent revascularization with either coronary artery bypass graft or stenting.
Background medications included aspirin (99%), thienopyridine (93%), beta-blockers (66%), ACE inhibitor or ARB (40%) statin (84%), and calcium channel blocker (15%).