November 16, 2011 – Johnson & Johnson Pharmaceutical Research & Development announced that adding oral rivaroxaban to standard antiplatelet therapy significantly reduced the composite primary efficacy endpoint of cardiovascular-related deaths, heart attacks or strokes in patients with acute coronary syndrome (ACS) compared to those receiving standard therapy alone. Results from the pivotal Phase 3 ATLAS ACS 2 TIMI 51 trial presented at the American Heart Association Scientific Sessions and published in the New England Journal of Medicine also showed that rivaroxaban significantly increased rates of major bleeding, but did not create an excess risk of fatal bleeding over standard therapy alone.
"The clinical benefit of giving rivaroxaban in combination with standard antiplatelet therapy seen in ATLAS TIMI 51 is welcome, and could lead to significant improvement in the management of patients with acute coronary syndrome," said Eugene Braunwald, M.D., Distinguished Hersey Professor of Medicine at Harvard Medical School and founding chairman of the Thrombolysis In Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital.
ACS is a complication of coronary heart disease, which is the leading cause of death in the United States and one of the most prevalent non-communicable diseases in the world. ACS occurs when a blood clot blocks a coronary artery, reducing blood supply to the heart. This disruption of blood flow can directly cause a heart attack, or unstable angina, a condition signifying that a heart attack may soon occur. Each year, an estimated 1.2 million patients in the United States are discharged from the hospital with a primary or secondary diagnosis of ACS.
Results from the ATLAS ACS 2 TIMI 51 study showed that both 2.5 or 5 mg of rivaroxaban dosed twice daily (BID) in addition to standard therapy — low-dose aspirin with or without a thienopyridine such as clopidogrel — was superior to standard therapy alone in the primary efficacy endpoint of preventing secondary cardiovascular events (cardiovascular death, myocardial infarction or stroke) in patients with ACS [combined doses 8.9 percent vs. 10.7 percent (1) (P=0.008), Relative Risk Reduction (RRR) = 16 percent]. Additionally, rivaroxaban significantly reduced stent thrombosis compared with placebo [2.3 percent vs. 2.9 percent (P=0.02)].
Patients dosed with 2.5 mg BID of rivaroxaban showed a significant reduction in risk of the composite primary endpoint [9.1 percent vs. 10.7 percent (P=0.02)], driven by a significant 34 percent RRR in the rate of cardiovascular death [2.7 percent vs. 4.1 percent (P=0.002)]. There was also a significant reduction in deaths from any cause [2.9 percent vs. 4.5 percent (P=0.002)]. The 5 mg BID dose of rivaroxaban also significantly reduced the risk of the primary efficacy endpoint in the study [8.8 percent vs. 10.7 percent (P=0.03)].
The principal safety endpoint for the study was TIMI major bleeding events not associated with coronary artery bypass graft (CABG) surgery. In patients receiving rivaroxaban and standard therapy, rates were low overall, yet statistically significantly increased versus those treated with standard therapy plus a placebo [2.1 percent vs. 0.6 percent (P<0.001)]. Similarly, rivaroxaban exhibited higher rates of TIMI major bleeding events not associated with CABG surgery at both the 2.5 and 5 mg BID doses compared to placebo [1.8 percent vs. 0.6 percent (P<0.001) and 2.4 percent vs. 0.6 percent (P<0.001), respectively]. Importantly, these differences were not associated with an excess risk of fatal bleeding. Other treatment-emergent adverse events were generally balanced across treatment groups.
"For more than a decade, ACS patients have been effectively treated with a low-dose aspirin given in combination with a thienopyridine to help reduce their risk of a recurrent cardiovascular event. This study showed that by adding the oral Factor Xa inhibitor rivaroxaban to standard therapy, this risk is greatly reduced, resulting in a significant reduction in mortality," said C. Michael Gibson, M.D., senior investigator of the TIMI Study Group, Harvard Medical School, and the principal investigator in the ATLAS ACS studies of rivaroxaban. "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."
The U.S. Food and Drug Administration (FDA) had previously granted rivaroxaban "fast track" designation for this indication. Fast track designation allows the FDA to expedite review of drugs for serious or life-threatening conditions that demonstrate the potential to address unmet medical needs. Products in a fast track drug development program are eligible for priority review, but the FDA will only make their final determination upon review of the results.
The ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome) study was designed to test the efficacy of rivaroxaban compared to placebo in preventing cardiovascular death, heart attack or stroke in ACS patients. Patients were given standard antiplatelet therapy – low-dose aspirin with or without a thienopyridine such as clopidogrel – plus rivaroxaban dosed at 2.5 or 5 mg BID, or a placebo. Of the 15,526 patients randomized into the study, 93 percent received aspirin and thienopyridine in addition to rivaroxaban or placebo, and the balance were treated with aspirin and rivaroxaban or placebo.
The double blind, randomized, placebo-controlled study was coordinated by the TIMI Study Group and Brigham and Women's Hospital and Harvard Medical School and was funded and led by Johnson & Johnson Pharmaceutical Research & Development, L.L.C. and Bayer HealthCare.
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