Researchers today presented and published results from TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome), the first clinical outcomes trial of vorapaxar, the investigational Protease Activated Receptor 1 (PAR-1) thrombin receptor antagonist from Merck (NYSE:MRK) (known as MSD outside the U.S. and Canada). The results from TRACER were presented during the late-breaking clinical trials session at the American Heart Association (AHA) 2011 Scientific Sessions and published concurrently online in the New England Journal of Medicine.
Merck is developing vorapaxar for the prevention of thrombosis and the reduction of cardiovascular events, and it is being evaluated in two major clinical outcomes studies in different patient groups: TRACER was a study in patients with acute coronary syndrome (ACS), and TRA-2P is a secondary prevention study in patients who have experienced a previous heart attack or ischemic stoke or who have documented peripheral artery disease (PAD). TRACER is being led by the Duke Clinical Research Institute (DCRI) in Durham, N.C. and TRA-2P is being led by the Thrombolysis in Myocardial Infarction (TIMI) academic research group at the Brigham and Women's Hospital in Boston, Mass.
TRACER compared vorapaxar plus standard of care to placebo plus standard of care in 12,944 patients with ACS. At time of randomization, more than 85 percent of patients in both groups were taking both aspirin and a P2Y12 inhibitor (mostly clopidogrel). On the primary endpoint, the addition of vorapaxar to standard of care resulted in a non-significant 8 percent reduction in the first occurrence of any component of the composite of cardiovascular death, myocardial infarction (MI, or heart attack), stroke, recurrent ischemia with re-hospitalization and urgent coronary revascularization, with a p-value of p=0.072, which means that TRACER did not achieve its primary endpoint. On the key secondary endpoint, the addition of vorapaxar to standard of care reduced the composite of CV death, MI, or stroke, by 11 percent, with a p-value of p=0.018; this finding was driven by a 12 percent relative reduction (p=0.021) in heart attacks, primarily spontaneous heart attacks. However, due to the pre-specified data analysis plan, superiority for the key secondary endpoint cannot be declared because the primary endpoint was not achieved. Rates of bleeding were approximately 40 percent greater in the group that also received vorapaxar compared to the group that received only standard of care, and there was a three-fold increase in intracranial hemorrhage (1.07 percent versus 0.24 percent, p<0.001).
"Because most patients in TRACER had vorapaxar added to a regimen containing both a P2Y12 inhibitor and aspirin, we now better understand the effect of using these three mechanisms together to prevent clots in patients with ACS," said Peter S. Kim, Ph.D., executive vice president, Merck and president, Merck Research Laboratories. "Fewer patients in TRA-2P were taking both aspirin and a P2Y12 inhibitor, so the results from the second vorapaxar study should give us greater insight into the effect of blocking PAR-1 in different groups of patients, including many patients who were not taking the combination of a P2Y12 inhibitor and aspirin."
The TRA-2P study is in the final stage of being closed out and the external investigators and Merck plan to submit TRA-2P for presentation and publication in early 2012. Merck will determine its potential regulatory strategy and consider potential additional studies for vorapaxar when it can consider the TRACER data in ACS patients together with the TRA-2P data in heart attack, stroke and PAD patients, once those data are available in early 2012.
"The results of TRACER provide us with some insight into the potential role of PAR-1 inhibition in the fight against thrombosis, and are certainly worthy of further examination," said Kenneth W. Mahaffey, M.D., co-director for cardiovascular research at DCRI and senior author of the TRACER manuscript. "We look forward to conducting more analyses on these results, as well as seeing the results of TRA-2P when they become available."
Researchers also noted that results on the primary and key secondary efficacy endpoints were generally consistent across subgroups. However, among a subgroup of patients who were taking vorapaxar but not a P2Y12 inhibitor at randomization, the risk of bleeding was not increased, and the observed effect on efficacy tended to be more pronounced in these patients who received vorapaxar plus aspirin only. This analysis is exploratory, and will be reviewed again based on the data from TRA-2P. Additional studies may be considered to better understand the effects of vorapaxar in different patient populations.
"Despite all of the progress that has been made, cardiovascular disease remains the world's leading killer. Merck thanks the researchers and the thousands of study participants around the world for their contribution to advancing the scientific community's understanding of this critical area of cardiovascular medicine," said Dr. Kim.
Additional Information on the Vorapaxar Development Program
Vorapaxar is a novel, oral, PAR-1 antagonist that inhibits thrombin-induced platelet activation. The vorapaxar development program was designed to understand the potential role of blocking PAR-1 with vorapaxar in patients with ACS and in the chronic care setting. Key differences between the two studies are:
- Patient population: TRACER included 12,944 patients being admitted to the hospital with ACS. TRA-2P included 26,447 stable patients 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.
- Dosing: In TRACER, vorapaxar was administered starting with a 40 mg loading dose, followed by a 2.5 mg daily maintenance oral dose, for at least one year of follow-up. In TRA-2P, patients received 2.5 milligrams for more than one year.
- Control arm: In both studies, vorapaxar was added to standard of care. In TRACER, at the time of enrollment, of the 6,743 patients in the vorapaxar group, 88 percent were taking clopidogrel and 96 percent were taking aspirin, and 87 percent of the 5,639 patients in the placebo group were taking clopidogrel and 97 percent were taking aspirin. Fewer patients in the TRA-2P study received both aspirin and a P2Y12 inhibitor as standard of care than patients in TRACER.
- Status: TRACER has been completed and the data from TRACER have been shared. The TRA-2P study is in the final stage of being closed out and remains blinded; all final patient visits have been completed.
In January of this year, Merck and the external study investigators announced that the combined Data and Safety Monitoring Board (DSMB) for the two clinical trials had reviewed the available safety and efficacy data, and recommended that patients in the TRACER trial discontinue study drug and investigators close out the study. At that time, TRACER had accumulated the pre-defined number of primary and major secondary endpoints, although not all patients continued to receive study drug through the pre-specified one-year follow up. For the TRA-2P study, the DSMB recommended that the study drug be continued in patients who had experienced a previous heart attack or PAD (approximately 75 percent of the patients enrolled in the study), but immediately discontinued in patients who experienced a stroke prior to entry into the study or during the course of the study.
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