Novel Antiplatelet Agent Reduces CV Events But Increases Bleeding

Vorapaxar, the novel antiplatelet agent from Merck, appears to effectively reduce cardiovascular death and ischemic events in patients with MI, ischemic stroke, or peripheral vascular disease, but its potential utility is clouded by bleeding complications, including intracranial hemorrhage. Results from the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial were presented in Chicago on Saturday at the American College of Cardiology and published simultaneously in the New England Journal of Medicine.

Results of TRA 2P-TIMI 50 were broadly consistent with the TRACER trial (published last November in the New England Journal of Medicine), which tested the same drug in patients with acute coronary syndromes. In that trial also, vorapaxar effectively reduced negative outcomes but at the cost of an increase in serious bleeding complications. Earlier optimism over the drug had been greatly reduced in January 2011 when the combined data and safety monitoring board (DSMB) of the two trials stopped the TRACER trial and curtailed the TRA 2P-TIMI 50 trial.

TRA 2P-TIMI 50 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. Because of an increased risk of intracranial hemorrhage in patients with a history of stroke, at 2 years the DSMB stopped treatment with vorapaxar in patients with a history of stroke.

At 3 years the rate of CV death, MI, or stroke was significantly reduced by vorapaxar, but there were also more bleeding events associated with the drug:

CV death, MI, or stroke: 9.3% in the vorapaxar group versus 10.5% in the placebo group (HR 0.87, CI 0.80-0.94, p<0.001)

  • CV death: 2.7% versus 3.0% (HR 0.89, p=0.15)
  • MI: 5.2% versus 6.1% (HR 0.83, p=0.001)
  • Stroke: 2.8% in both groups

Moderate or severe bleeding: 4.2% versus 2.5% (HR 1.66, p<0.001)

  • Intracranial bleeding: 1% versus 0.5% (HR 1.94, p<0.001)

The TIMI investigators reported that in the subgroup of patients with a qualifying diagnosis of MI vorapaxar caused a 20% reduction in the primary endpoint. In light of the heightened risk for stroke patients, the investigators also performed a separate analysis of patients without a history of stroke and found “a significant benefit” in this group.

In an ACC press release, lead investigator David Morrow said: “In the lab, we have seen very compelling science showing the importance of thrombin’s action on platelets causing blood clots in arteries. This is the first study to show definitively that blocking this pathway reduces the risk of suffering another cardiovascular event.”

Click here to download a PDF of the ACC press release for TRA 2P-TIMI 50. Readers should note that the press release does not mention the bleeding complications until the second page of the press release.  In sharp contrast, the press release from Merck discloses the bleeding complications in the first paragraph.


  1. One of the panelists suggested he wouldn’t take this drug along for his medicine chest if he thought he’d be stranded alone on an island.

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