CardioExchange Archive

A key detail has now emerged about the problems encountered with vorapaxar, Merck’s thrombin receptor antagonist that suffered a large setback last week. TIMI investigators in the TRA-2P TIMI 50 trial have been informed by Eugene Braunwald that the reason vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial was because of an increase in intracranial hemorrhage in these patients. Merck issued a press release yesterday summarizing the TIMI chairman’s announcement.

Here is Braunwald’s statement:

“The DSMB has communicated to us that based on all of the data (safety and efficacy) available to them from both trials, they recommend that subjects with a history of stroke not receive vorapaxar. They have observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit.”

“In contrast, on the basis of their risk/benefit assessment in patients without a history of stroke, the DSMB recommended to us that it is important that the trial continue to completion in the more than 20,000 subjects who qualified for the trial with myocardial infarction or peripheral arterial disease who have not had a stroke. On the basis of their recommendation, we and Merck remain committed to completing this important scientific investigation with a potential for a reduction in death and ischemic events in these patients.”

Bob Harrington, chair of a second large vorapaxar trial, TRACER, said that both the TRACER investigators and Merck “remain blinded to the data” so they don’t know the specific details behind the DSMB’s recommendation. Here is Harrington’s statement:

“We have chosen not to receive the details of the TRACER interim analysis (in other words, we [the investigators and sponsor] remain blinded to the data). All patients in TRACER are coming off the study drug and the trial is being closed out. Consequently, we have no reason to be unblinded at this point. We sent our investigators the actual DSMB letter about closing out TRACER but this makes no reference to specific data on either safety or efficacy. This is therefore different than the 2P situation where the majority of the patients remain on study medication and so the sites required futher clarification.”

In TRACER, 13,000 hospitalized ACS patients were randomized to placebo or vorapaxar in addition to standard care. Last week Merck announced that TRACER had accumulated the predefined number of primary and major secondary endpoints, but not all patients had received the drug for the prespecified one-year followup. In TRA-2P TIMI 50, more than 25,000 patients with MI, ischemic stroke, or peripheral vascular disease were randomized to either vorapaxar or placebo in addition to standard care for the secondary prevention of MI and stroke. Last week Merck said that vorapaxar would be discontinued in patients who experienced a stroke prior to entry or during the trial. The study drug will be continued in more than 20,000 patients with previous MI or peripheral disease.