New Antiplatelet Agent Vorapaxar Shows Promise, But At the Expense of Bleeding

CHICAGO, IL—When added to aspirin therapy, vorapaxar, the first of a new class of investigational antithrombotic agents, reduces the risk of cardiovascular death, myocardial infarction (MI), or stroke in patients with atherosclerosis, according to results presented March 24, 2012, at the annual American College of Cardiology/i2 Scientific Session. However, the drug also increased the risk of moderate or severe bleeding, including intracranial hemorrhage.

The study was simultaneously published online in the New England Journal of Medicine.

David A. Morrow, MD, MPH, of Brigham & Women’s Hospital (Boston, MA) presented data from the large, multinational TRA 2P-TIMI 50 trial, in which 26,449 patients with stable atherosclerosis were assigned in a 1:1 ratio to receive either vorapaxar (2.5 mg daily) or placebo plus standard care, including aspirin, at one of 1,032 sites in 32 different countries. 

Vorpaxar inhibits PAR-1, the predominant receptor for thrombin on the surface of human platelets.

At 3 years, the composite of death from cardiovascular causes, MI, or stroke (primary endpoint), was reduced in the vorapaxar group compared to placebo plus standard care. The vorapaxar group also had a significant reduction in the composite endpoints of CV death, MI, stroke and urgent revascularization, and CV death or MI. However, compared with placebo, patients who received vorapaxar had significantly more GUSTO-defined moderate or severe bleeding (table 1). 

Table 1. Outcomes at 3 Years

Among patients with no history of stroke, the primary endpoint occurred in 8.3% of patients in the vorapaxar group compared with 9.6% of those in the placebo group (P < 0.001). There was no significant heterogeneity for the benefit of vorapaxar on the rate of cardiovascular death, MI, or stroke across any of the major subgroups examined, including those defined according to the use or nonuse of a thienopyridine.

The rate of fatal bleeding was similar in the group receiving vorapaxar and the placebo group (0.3% vs. 0.2%, P = 0.19). However, intracranial hemorrhage was higher with vorapaxar than placebo (1.0% vs. 0.5%; P < 0.001). Dr. Morrow acknowledged that the increase in intracranial hemorrhage seen in the trial was “unacceptable.”

In January 2011, the data and safety monitoring board recommended the discontinuation of vorapaxar in patients with a history of stroke on the basis of an excess of intracranial hemorrhage.

Emphasis on Number Needed to Treat

But Dr. Morrow pointed out that there were differences in the absolute rates of bleeding that may be important for clinical consideration. In particular, patients with prior stroke had an absolute risk difference of 1.5% for intracranial hemorrhage compared with 0.2% in patients with no history of stroke (P = 0.049). Similarly, when GUSTO moderate or severe bleeding was examined across major subgroups, there was a higher risk in patients over age 75, or who had  body weight less than 60 kg, previous stroke, peripheral artery disease or previous MI.

“PAR-1 antagonism is an effective approach to reducing recurrent atherosclerosis,” Dr. Morrow said. “We have also shown definitively for the first time that adding it to standard antiplatelet therapy that includes aspirin administered for long-term secondary prevention reduces recurrent atherosclerosis in patients with prior myocardial infarction.”

But Roberto Bolli, MD, of the University of Louisville (Louisville, KY), said in order to know if the treatment would be worth the risk, it is important to determine the number needed to treat and the number needed for harm in specific subsets of patients to narrow down who may best benefit from vorapaxar.

“If you look at the entire [study] population, the number needed to treat for reduction of the composite endpoint is 83 and the number needed to treat for reduction of TIMI major bleed is 143, suggesting that overall it would be hard to justify this treatment,” Dr. Bolli said.

Source:

Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the Secondary Prevention of Atherothrombotic Events. N Engl J Med. 2012;Epub ahead of print.

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