TRACER: Vorapaxar failed to reduce death, MI, stroke risks

AHA Scientific Sessions 2011

ORLANDO, Fla. — When added to standard care in patients with non-ST-segment elevation acute coronary syndrome, the first-in-class PAR-1 agonist, vorapaxar, did not reduce cardiovascular death, myocardial infarction or stroke. Conversely, the drug was associated with a significantly increased risk for bleeding, compared with placebo.

“Whether PAR-1 blockade improves outcomes with different medication strategies, or in other patient populations with coronary disease awaits further study,” Robert A. Harrington, MD, director at the Duke Clinical Research Institute, said during a press conference.

Previous studies demonstrated the association between vorapaxar (Merck) and reduced risk for MI in patients with acute coronary syndromes (ACS) or underwent percutaneous coronary intervention, with minimal bleeding risk. Based on this, Harrington, and the TRACER trial group studied whether adding the drug to standard therapy reduced the risk for ischemic events.

The prospective, randomized, double blind, placebo-controlled trial included 12,944 patients with ACS without ST-segment elevation who had ischemic symptoms within 24 hours of hospitalization. The median age was 64 years and more than 60% of patients had diabetes. Almost all patients were receiving an antiplatelet agent (aspirin or thienopyridine) and had positive troponin or creatine kinase-MB.

Patients were randomly assigned to placebo or vorapaxar at 40 mg (loading dose) followed by 2.5 mg daily (maintenance dose). The primary endpoint was the composite of CV death, MI, stroke, hospitalization for ischemia and urgent revascularization. The secondary and safety endpoints were CV death, MI and stroke; and moderate to severe GUSTO bleeding and clinically significant TIMI bleeding. Median follow-up was 502 days.

The primary endpoint occurred in 18.5% of patients assigned to vorapaxar vs. 19.9% assigned to placebo (HR=0.92; 95% CI, 0.85-1.01). Rates were similar between groups for the secondary endpoint: 14.7% for voraxapar vs. 16.4% for placebo (HR=0.89; 95% CI, 0.81-0.98).

In addition, the rate of bleeding was significantly higher in the treatment arm vs. placebo. Moderate to severe GUSTO bleeding rates were 7.2% for vorapaxar vs. 5.2% for placebo (HR=1.35; 95 %CI, 1.16-1.58); the rate of intracranial hemorrhage was 1.1% for treatment vs. 0.2% for placebo (HR=3.39; 95% CI, 1.78-6.45).

“We were surprised and disappointed that TRACER failed to meet its primary endpoint,” Harrington said in a press release. “The lower incidence of CV death, heart attack or stroke with voraxapar, while not significant, is promising and we look forward to seeing the data from the next trial (TRA 2P TIMI 50) to better understand if or how to proceed with further development of voraxapar.” – by Stacey L. Fisher

For more information:

• Harrington RA. LBCT01. Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16, 2011; Orlando, Fla.
• Tricoci P. N Engl J Med. 2011;doi:10.1056/NEJMoa1109719.

Disclosure: The TRACER trial was funded by Merck. Dr. Harrington reports significant research grants and is a consultant/advisory board member for Merck.

My interpretation is that the placebo study population had a clinically important event rate that was not just the result just of an underpowered study— it had events. More than half [of events] were in first 4 months. Interestingly, bleeding continues over time and 80% of intracranial hemorrhage bleeds are beyond 4 months. If you consider the primary endpoint, I would argue that the addition of softer components to the primary endpoint is just added noise. The risk vs. benefit was not worthwhile in the tested dose and study population, as designed here. The potential remains to reduce thrombotic events, but I would argue that TRACER has missed the ‘sweet spot’ between efficacy and safety.

– Keith A.A. Fox, MB, ChB, FRCP

Edinburgh Centre for Cardiovascular Science, Edinburgh, Scotland

Disclosure: Dr. Fox reports modest research grants from Bayer and Lilly; modest honoraria from AstraZeneca, Bayer, Boehringer Igelheim, Johnson & Johnson and Lilly; and is a consult/advisory board member for Bayer and Johnson & Johnson.

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