August 27th, 2012
The Return of Vorapaxar, This Time for Post-MI Patients
The once highly promising novel antiplatelet agent vorapaxar, widely thought to be dead on arrival after unacceptably high serious bleeding rates were found in two large clinical trials, has now returned to active duty. On Sunday the drug’s sponsor, Merck, announced that it would seek approval of the drug, with a narrower indication than originally planned, based on new data from a prespecified analysis of the TRA 2P-TIMI 50 trial presented at the ESC and published simultaneously in the Lancet.
Merck said it planned to file applications next year in the United States and Europe for an indication for the prevention of CV events in patients with a history of MI and no history or stroke or TIA.
The new hope for the drug is based on an analysis of the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events trial, which was originally presented in March at the ACC and published simultaneously in the New England Journal of Medicine. In the overall trial, which randomized 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease to either vorapaxar or placebo in addition to standard therapy, the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but a doubling of the rate of intracranial bleeding left many convinced the drug was not commercially viable.
The new analysis, presented at the ESC by Ben Scirica, focused on the subgroup of 17,779 TRA 2P patients — a group larger than usually found in the entire population of most clinical trials, it should be noted — with a history of myocardial infarction. After a median 2.5 years of follow-up, the rate of CV death, MI, or stroke was significantly lower in the vorapaxar group than in the placebo group, although vorapaxar was also associated with an increased risk for bleeding, but not intracranial bleeding:
- Primary endpoint: 8.1% versus 9.7% (HR, 0.80; 95% CI 0.72-0.89, P<0.0001)
- Moderate or severe bleeding: 3.4% versus 2.1% (HR, 1.61; 95% CI, 1.31-1.97, P<0.0001)
- Intracranial hemorrhage: 0.6% versus 0.4%; P=0.076
The authors acknowledged the limitations of subgroup analysis but proposed that vorapaxar might benefit a population with a history of MI but with no history of stroke or TIA, age below 75, and weight over 60 kg.
In an accompanying comment in the Lancet, Stefan James and Claes Held write that the “results support the addition of long-term antithrombotic treatment for patients who have had a myocardial infarction.” But, they ask, “will doctors, patients, health-care providers, and funding agencies accept use of an expensive drug to reduce the risk of myocardial infarction and possibly death in view of the increased risk of severe bleeding?”