CHICAGO – Vorapaxar, a new type of platelet inhibitor drug, showed unequivocal efficacy for preventing new cardiovascular events in patients with a history of myocardial infarction, stroke, or peripheral artery disease already on a standard antiplatelet regimen in a pivotal study with 26,449 patients.
Treatment with vorapaxar also led to worrisome adverse effects of moderate or severe bleeding, as well as an excess of intracranial hemorrhage, in all treated patients, raising concerns about the drug’s safety.
But a series of prespecified analyses showed that the hazard from vorapaxar focused in patients with a history of stroke, while in patients with a history of myocardial infarction and no history of cerebrovascular disease, the risk for bleeding or intracranial hemorrhage was modest. In addition, the efficacy findings showed that it was the post-MI patients who gained the most from adding vorapaxar to their standard treatment with aspirin and a thienopyridine, usually clopidogrel.
The study’s analysis also identified another key modifier of bleeding risk, body weight of at least 60 kg (132 lbs.).
Among the 18,966 patients in the study who had no history of stroke and body weight of at least 60 kg (72% of the total study population), treatment with vorapaxar over a median of 2.5 years led to an absolute 1.9% reduction in the incidence of new MI, stroke, or cardiovascular death, while causing a 0.2% excess of intracranial hemorrhages and a 1% excess of other moderate or severe bleeding events, Dr. David A. Morrow reported at the meeting. This level of benefit and risk appeared primarily in the patients with a history of MI.
"Our data showed that these patients did very well with respect to risk and benefit," said Dr. Morrow, director of the cardiac unit at Brigham and Women’s Hospital in Boston. "This is a reasonable group to treat. The results are clear and exciting. We have been able to identify simple demographic and historic features that allow us to identify patients where the benefit from reducing clotting outweighs the smaller increase in bleeds. We think this is an important advance."
Mitchel L. Zoler/IMNG Medical Media
Dr. David A. Morrow
Concurrent with Dr. Morrow’s report, the results appears online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1200933]).
Experts who heard the results agreed that the potential benefit could be important to post-MI patients, but if vorapaxar was approved for this indication, it would require very careful prescribing.
"It’s exciting that we have found something that moves the needle, even a little bit, for secondary prevention. For selected patients, this is an important addition to treatment," commented Dr. Patrick T. O’Gara, professor of medicine at Harvard Medical School and director of clinical cardiology at Brigham and Women’s Hospital, both in Boston, who had no involvement in the study. But he cautioned that if vorapaxar were approved, its use would have to be carefully assessed for each patient’s bleeding risk, based not only on weight and history of cerebrovascular events, but also on patient frailty and other global assessments of appropriateness, he said in an interview.
Vorapaxar looks like a drug that should only be used "in very selected patients, and in selected medical centers" in which physicians will take the time and have the experience to adequately judge the risk-to-benefit ratio, commented Dr. David R. Holmes Jr., president of the ACC and a cardiologist and professor of medicine at the Mayo Clinic in Rochester, Minn.
The Food and Drug Administration would likely decide either that vorapaxar needs further testing in MI patients with no history of cerebrovascular disease or that it could receive conditional approval but with need for a follow-up trial or collection of data to validate it safety in routine practice, commented Dr. Elliott M. Antman, a cardiologist and professor of medicine at Harvard Medical School.
The TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events – Thrombolysis in Myocardial Infarction) study enrolled patients at 1,032 sites in 32 countries during September 2007–November 2009. Patients received either 2.5 mg oral vorapaxar daily or placebo. Other medications enrolled patients received included aspirin, in 98%, and a thienopyridine, in 78%. The study’s primary end point was the combined rate of cardiovascular death, myocardial infarction, or stroke. For the entire study population, addition of vorapaxar reduced this rate by 1.2 percentage points, a relative reduction of 13% that was statistically significant. For the entire study, vorapaxar increased the incidence of intracranial hemorrhage by 0.5 percentage points, a 94% risk increase that was statistically significant. The drug also increased moderate or severe bleeds by 1.7 percentage points, a relative hazard increase of 66% that was statistically significant.