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Results Published in the Online Edition of the New England Journal of Medicine and Presented at American College of Cardiology Scientific Session
Merck Continues Discussions with External Experts to Determine Next Steps
CHICAGO--(BUSINESS WIRE)--Researchers today presented and published results from the TRA-2P (Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) TIMI 50 study of vorapaxar, Merck's investigational anti-thrombotic medicine, in patients with a prior history of cardiovascular events or disease. In the study, the addition of vorapaxar to standard of care (e.g. aspirin, or thienopyridine or both) resulted in a significantly greater reduction in the risk of the composite of cardiovascular (CV) death, heart attack, stroke or urgent coronary revascularization. This is the first time that an anti-thrombotic medicine added to the standard of care, including aspirin, has been shown to provide an additional, significant reduction in cardiovascular events in the secondary prevention setting, defined as patients who previously experienced a heart attack, an ischemic stroke, or who had documented peripheral arterial disease, or PAD. There was also a significant increase in bleeding, including intracranial hemorrhage (ICH), among patients taking vorapaxar in addition to standard of care, although the risk of ICH was lower in patients without a history of stroke.
The results of TRA-2P in 26,449 patients were presented during a late-breaking clinical trials session at the American College of Cardiology 61st Annual Scientific Session (ACC.12) and published concurrently online in the New England Journal of Medicine. The study was led by the Thrombolysis In Myocardial Infarction (TIMI) Study Group of Brigham and Women's Hospital in Boston, Massachusetts.
In this three-year study, the addition of vorapaxar to standard of care in the full study population significantly reduced the risk of the protocol-specified primary composite endpoint of cardiovascular death, heart attack, stroke or urgent coronary revascularization by 12 percent compared to placebo plus standard of care (11.2 percent vs. 12.4 percent, p=0.001). The addition of vorapaxar also resulted in a significant 13 percent reduction in the protocol-specified key secondary composite endpoint of CV death, heart attack and stroke (9.3 percent vs. 10.5 percent, p<0.001). The addition of vorapaxar significantly increased moderate or severe bleeding, as measured by the GUSTO scale1, (4.2 percent vs. 2.5 percent, p<0.001). There was no statistically significant difference in the rate of fatal bleeding in the study between the group receiving vorapaxar and the group receiving standard of care alone (0.3 percent vs. 0.2 percent, p=0.19). Rates of intracranial hemorrhage (ICH) were significantly greater in the vorapaxar arm compared to placebo (1.0 percent vs. 0.5 percent, p<0.001), primarily driven by patients with a history of stroke. In patients without a history of stroke, the rates of ICH were numerically greater in the vorapaxar arm compared to placebo (0.6 percent vs. 0.4 percent p=0.049).
"Results from this trial demonstrated for the first time that inhibition of another platelet pathway in addition to standard antiplatelet therapy reduced the risk of recurrent cardiovascular events in long-term secondary prevention,” said David A. Morrow, M.D., MPH, senior investigator at the TIMI Study Group and Director, Levine Cardiac Intensive Care Unit, Brigham and Women's Hospital. "As is the case with other potent oral antiplatelet agents, the antithrombotic benefit of vorapaxar must be weighed against the increased risk of bleeding, and any potential clinical use of vorapaxar would have to be based on appropriate patient selection."
The presentation of the full results included patients with a prior history of stroke, who were part of the original study design but were discontinued from the trial following the recommendations of the Data Safety Monitoring Board in early 2011. Among patients without a history of stroke, the addition of vorapaxar reduced the risk of CV death, heart attack, stroke or urgent coronary revascularization by 14 percent compared to placebo plus standard of care (10.6 percent vs. 11.8 percent, p<0.001), and reduced the risk of CV death, heart attack or stroke by 16 percent (8.3 percent vs. 9.6 percent, p<0.001). Also, among patients without a history of stroke, there was a non-significant increase in GUSTO severe bleeding (1.4 percent vs. 1.1 percent, p=0.058) and a significant increase in GUSTO moderate bleeding (2.7 percent vs. 1.4 percent, p<0.001) in the vorapaxar group compared with the group receiving standard of care alone.
The benefits of vorapaxar were numerically greater in patients who qualified for the study due to a previous heart attack, which was 67 percent (n=17,779) of all patients in the study, the largest cohort. In these patients, vorapaxar reduced the relative risk of CV death, heart attack or stroke by 20 percent (8.1 percent vs. 9.7 percent at three years, p<0.001). Overall, in this subgroup vorapaxar significantly decreased the rate of heart attacks compared to standard of care alone by 17 percent (5.2 percent vs. 6.1 percent, p=0.001).
"Despite all of the advances made in cardiovascular medicine, significant residual risk for recurrence of cardiovascular events remains, and that is why Merck is committed to developing medicines like vorapaxar that are intended to provide incremental, additional reductions in residual risk," said Francis Plat, M.D., vice president, Clinical Research, Therapeutic Area Head Atherosclerosis and Cardiovascular Disease, Merck Research Laboratories. "The results from this study showed that the addition of vorapaxar to standard of care, including aspirin, provided an additional reduction in risk. We plan to continue our discussions with the investigators and other outside experts to help define the role of this investigational compound in secondary prevention."
TRA-2P included 26,449 stable patients at 1,032 sites in 32 countries who had previously experienced an ischemic stroke or heart attack no less than 2 weeks and no more than 12 months before randomization, or who had PAD. The goal of the study was to evaluate the efficacy and safety of vorapaxar compared with placebo in addition to standard of care in the secondary prevention setting. In TRA-2P, vorapaxar was administered at a 2.5 mg daily maintenance oral dose for more than one year. The median follow-up time in the trial was 30 months.
Additional Information on the Vorapaxar Development Program
Vorapaxar has now been evaluated in two major clinical outcomes studies: TRA-2P TIMI 50 (Clinicaltrials.gov identifier: NCT00526474)and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome), (Clinicaltrials.gov identifier: NCT00527943). TRACER was an acute care, hospital-based study of approximately 12,944 patients with non-ST-segment-elevation acute coronary syndrome. The study was led by the Duke Clinical Research Institute, and results were presented in 2011 at the American Heart Association Scientific Sessions and published in the January 5, 2012 issue of The New England Journal of Medicine (Vol. 366, No.1). The news release can be found at http://www.merck.com/newsroom/news-release-archive/research-and-development/2011_1113.html.
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(1)GUSTO (Global Use of Strategies to Open Occluded Arteries) scale is a criteria for classifying the severity of bleeding
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