Braunwald: Vorapaxar Problem Based on Intracranial Bleeding in Patients with History of Stroke

Updated with additional information from TRACER chair Bob Harrington.

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 (see below).

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.

It is unclear at this point whether intracranial hemorrhage in stroke patients is also the cause of the discontinuation of the study drug and early close out of the TRACER trial. CardioBrief has requested clarification of this question from Merck and the study leadership at the Duke Clinical Research Institute.

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. Lasts 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.

Update: Bob Harrington, chair of TRACER, told CardioBrief 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 to CardioBrief:

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.

Here is the Merck press release:

Merck Says Additional Information Provided to Investigators in Clinical Study of Vorapaxar

WHITEHOUSE STATION, N.J., Jan. 19, 2011 – Merck (known outside the United States and Canada as MSD) reported today that investigators in the TRA-2P study of vorapaxar have been provided with additional information about the recommendations of the Data and Safety Monitoring Board (DSMB) regarding the TRA-2P study. The additional information was sent yesterday in a communication to investigators from the Operations Committee of the TRA-2P study of vorapaxar. Vorapaxar is one of Merck’s investigational cardiovascular medicines.

This communication follows announcements issued on Thursday, January 13 by the academic centers leading TRA-2P and TRACER, the two large clinical studies of vorapaxar, and by Merck (http://www.merck.com/newsroom/news-release-archive/research-and-development/2011_0113.html). Those communications reported on changes being made to these clinical studies following recommendations from the joint DSMB overseeing the studies. In the new communication, Dr. Eugene Braunwald, Chairman of the TRA-2P study, reported to investigators that:

“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.”

Commenting on the new communication, Dr. Braunwald said, “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.”

The two major clinical endpoint trials to evaluate vorapaxar for the prevention of cardiac events are: TRA-2P (also known as TIMI 50), a study in patients with prior heart attack, stroke and peripheral artery disease, and TRACER, a study in patients with acute coronary syndrome.

Vorapaxar is a selective PAR-1 (Protease Activated Receptor 1) Thrombin Receptor Antagonist designed to diminish thrombosis (clot formation).

TRA-2P, or TIMI 50, is a chronic care, secondary prevention study of approximately 26,500 patients who have experienced a heart attack, an ischemic stroke, or have documented peripheral vascular disease. In TRA-2P, vorapaxar is administered at a 2.5 mg daily dose. The study completed enrollment in November 2009. (Clinicaltrials.gov identifier: NCT00526474; A Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients with Atherosclerosis.)

TRACER is an acute care (hospital-based) study of approximately 13,000 patients with non-ST-segment-elevation acute coronary syndrome. In TRACER, vorapaxar was administered starting with a 40 mg loading dose, followed by a 2.5 mg daily dose. The study completed enrollment in June 2010. (Clinicaltrials.gov identifier: NCT00527943; A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of SCH 530348 in Addition to Standard of Care in Subjects With Acute Coronary Syndrome: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome.)

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  1. […] trial with vorapaxar, was terminated early last year due to similar safety concerns. As reported here last year, at the same time TRACER was stopped the TRA-2P trial was modified. TRA-2P investigator […]

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