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Addition of investigational platelet blocker to standard therapy reduced cardiovascular death, ischemic events
Adding vorapaxar, an investigational platelet blocker, to standard antiplatelet therapy significantly reduced the risk for cardiovascular death and ischemic events in patients with stable atherosclerosis, according to results of the TRA 2P–TIMI 50 trial.
At 3 years, risk for cardiovascular death, myocardial infarction or stroke was lower in patients with previous MI, stroke or peripheral arterial disease who were randomly assigned to vorapaxar (9.3%) compared with those assigned to placebo (10.5%; P<.001).
Cardiovascular death, MI, stroke or recurrent ischemia leading to hospitalization occurred in 11.2% of patients assigned to vorapaxar (Merck) vs. 12.4% assigned placebo (P=.001). This reduction in new cardiovascular events was greatest in patients with prior MI, among whom there was a 20% decline (P<.001).
However, vorapaxar was associated with an increased risk for moderate or severe bleeding at 3 years compared with placebo (4.2% vs. 2.5%), including intracranial hemorrhage (1% vs. 0.5%; P<.001 for both). Bleeding rates were lower in patients with no history of stroke (0.6% with vorapaxar vs. 0.4% with placebo; P=.049).
The data were presented at the American College of Cardiology’s 61st Scientific Sessions and published in The New England Journal of Medicine.
Vorapaxar is an investigational protease activated receptor 1 (PAR-1) thrombin receptor antagonist. The drug blocks thrombin from stimulating platelets to stick together and create clots.
“This is the first study to show definitively that blocking this pathway reduces the risk for suffering another cardiovascular event,” David A. Morrow, MD, MPH, senior investigator at the TIMI Study Group and director of the Samuel A. Levine Cardiac Unit at Brigham and Women’s Hospital, said in a press release.
The randomized, double blind, placebo-controlled, multinational Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events — Thrombolysis in Myocardial Infarction 50 (TRA 2P-TIMI 50) trial followed 26,449 patients for more than 2 years. All patients had received standard antiplatelet therapy for established atherosclerosis, including previous MI (n=17,779) or peripheral arterial disease (n=3,787). Patients were randomly assigned once-daily vorapaxar 2.5 mg (n=13,225) or placebo (n=13,244), both in addition to standard therapy.
“This is the birth of a brand new class of platelet blockers. [These data are] the first proof that we can improve antiplatelet treatment, on top of aspirin, in patients with previous myocardial infarction,” Morrow said at a press conference.
The researchers noted that vorapaxar may not be appropriate for patients with stroke or those at high risk for bleeding. Stroke patients enrolled in TRA 2P–TIMI 50 ended their participation early after being advised by the study’s data and safety monitoring board. Morrow said it will be important to “select patients in whom we think there is an appropriate balance of the potential benefit vs. the risk [with vorapaxar].”
“There have been tremendous advances in drug therapy over the past several decades, but it is remarkable that our antiplatelet therapy for this group of patients has not changed,” he said. “We have been left with just aspirin in this particular setting, until now.”
References:
- Morrow DA. N Engl J Med. 2012;doi:10.1056/NEJMoa1200933.
Disclosure:
- Dr. Morrow has received research grant support and consulting fees from Merck and other manufacturers of antiplatelet and anticoagulant therapies.
Perspective
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The FDA will likely look at the results of this study and the TRACER study together. If I were to guess, [vorapaxar] is probably not going to be ready for prime time and will not be prescribed in the near future. What we are learning is that dosage is critical. With some of these drugs, particularly when you start adding them on top of other drugs, sometimes patients have been lucky and others have not been so lucky. The other important point that came out of this trial, as well as in studies of prasugrel and so on, is that some patients are more likely to be harmed than they are likely to be helped. When I look at the differences in mortality and intracranial hemorrhage with vorapaxar, it is hard to get excited about this drug.