Vorapaxar reduced cardiovascular events but increased bleeding in large trial

Adding Vorapaxar to standard treatment for patients with a medical history of cardiovascular events or disease was found to reduce cardiovascular events, but also increased bleeding significantly, including intracranial hemorrhage. The researchers added that ICH (intracranial hemorrhage) risk was lower for those with no history of stroke. The trial, called the TRA-2P (Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) TIMI 50 study, focused on the safety and efficacy of Vorapaxar, an experimental anti-thrombotic medication. The experimental drug was being tested for acute coronary syndrome chest pain caused by coronary artery disease. The human study showed that adding Vorapaxar to thienopyridine, aspirin, or both (standard care) considerably reduced the risk of composite cardiovascular death, stroke, heart attack, or urgent coronary revascularization. Merck & Co., Inc., the pharmaceutical company that owns Vorapaxar and organized the trial, wrote in its website: "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." Researchers from the Thrombolysis In Myocardial Infarction (TIMI) Study Group of Brigham and Women's Hospital in Boston, Massachusetts, presented the trial results at the ACC.12 (the American College of Cardiology 61st Annual Scientific Session). The New England Journal of Medicine (NEJM) published the TRA-2P results this week. The study, involving 26,449 patients and lasting three years, showed that, when Vorapaxar was added to standard care: There was a significant reduction in cardiovascular death, stroke, heart attack, or urgent coronary revascularization, when compared to therapy with a placebo There was a considerable increase in moderate-to-severe bleeding The impact of Vorapaxar on the fatal bleeding rate was not "statistically significant' Intracranial hemorrhage bleeding rates were significantly higher, compared to those on placebo, particularly among patients with a history of stroke 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, said: "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. 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." Francis Plat, M.D., vice president, Clinical Research, Therapeutic Area Head Atherosclerosis and Cardiovascular Disease, Merck Research Laboratories, said: "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. 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." Will Merck now seek approval of Vorapaxar? Unless the higher incidence of bleeding can be resolved, most experts today have said that it is doubtful now that Merck will seek approval for its experimental drug. In an interview with Reuters, Merck officials refused to reveal what their intentions are. One option would be to carry out another trial on people with just a history of heart-attack (not stroke). However, this would cost a great deal of money. In an Abstract in the New England Journal of Medicine, the authors concluded: "Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage.