AHA: Prasugrel Reduces Ischemic Events but Increases Bleeding in Acute Coronary Syndrome

ORLANDO, Nov. 4 -- Prasugrel, a super-potent investigational antiplatelet agent, significantly reduced myocardial infarction, urgent target vessel revascularization, and stent thrombosis compared with clopidogrel (Plavix), researchers reported here today.The primary efficacy endpoint -- cardiovascular death, MI, or stroke -- was reached by 12.1% of the clopidogrel patients and 9.9% of the prasugrel patients (HR for prasugrel versus clopidogrel, 0.81; 95% CI 0.73-0.90 P0.001), said Elliott M. Antman, M.D., who reported results of the 13,608-patient TRITON-TIMI 38 trial at the American Heart Association meeting here.
Action Points
Explain to patients that this report describes a trial of an investigational antiplatelet drug that is not FDA approved.
Note that prasugrel decreased ischemic events but was also associated with an increased risk of major bleeding especially in patients with a history of stroke or TIA or in patients older than 75 who weigh less than 60 kg.
But the downside of increased antiplatelet activity was an increase in major bleeding events -- in 2.4% of prasugrel patients versus 1.8% of those in the clopidogrel arm. The results, reported at a late-breaking clinical trials plenary session, were simultaneously published online by the New England Journal of Medicine.
Dr. Antman said, however, that most of the bleeding was driven by two groups -- patients with a history of stroke or transient ischemic attacks and elderly, frail patients (older than 75 weighing less than 60 kg) -- who comprised 20% of the total population.
"For the remaining 80% of the patients, which I would say represented eight of 10 patients undergoing stenting, the drug works very well," Dr. Antman said in an interview.
Moreover, among one high-risk group -- diabetics -- "there was no excess bleeding and a 30% reduction in MIs compared with clopidogrel."
Overall, compared with clopidogrel, prasugrel was associated with a 19% reduction in cardiovascular death, MI, or stroke, a 52% reduction in stent thrombosis, a 34% reduction in urgent target vessel revascularization, and a 24% reduction in MI, Dr. Antman said.
The data also suggested that using radial access -- the preferred percutaneous approach in Europe -- versus femoral access, which is preferred in the U.S., was associated with a lower bleeding rate. The trial was conducted at 707 sites in 30 countries including a number of centers in Europe that used only radial access.
The trial randomized 6,813 patients with moderate- to high-risk acute coronary syndromes with percutaneous coronary intervention to prasugrel (60 mg loading dose and 10 mg daily maintenance) and 6,795 patients to clopidogrel (300 mg loading dose and 75 mg daily maintenance). Irrespective of treatment, the antiplatelet regimen was continued for six to 15 months.
Most of the patients (10,074) had unstable angina or non-ST elevation MI, while 3,534 had ST-elevation MI. Ninety-nine percent of patients had percutaneous interventions at the time of randomization, 94% of them with at least one coronary stent and 47% with a drug-eluting stent.
Prasugrel, Dr. Antman said, has the advantage of speedy metabolism through the liver. So while it takes six hours for 600 mg of clopidogrel -- a dose twice as high as the dose used in the TRITON study -- to achieve maximum inhibition of platelet aggregation, it takes just 30 minutes for a 60 mg loading dose of prasugrel to achieve that same level of inhibition.
Among the findings:
There were 138 fewer events in the prasugrel arm than in the clopidogrel arm (HR 0.81, 95% CI 0.73-0.90, P=0.0004), number needed to treat to avoid event: 46, and among diabetics the number needed to treat was 37.
There were 74 fewer stent thromboses reported in prasugrel patients (HR: 0.48, P=0.0001, number needed to treat =77).
For every 1,000 patients treated there were six more major bleeding events -- including fatal events -- in the prasugrel arm and 23 fewer MIs.
There was no significant difference in all-cause mortality (3.2% in the clopidogrel arm versus 3.0% in the prasugrel arm P=0.64).
But the excess bleeding was a red flag for many. Deepak L. Bhatt, M.D., of the Cleveland Clinic, wrote in an accompanying NEJM editorial that "for each death from cardiovascular causes prevented by the use of prasugrel as compared with clopidogrel, approximately one additional episode of fatal bleeding was caused by prasugrel."
Dr. Antman repeatedly stated that bleeding was always a risk with antiplatelet therapy so "when we attempt to increase the inhibition of platelet aggregation activity, it is not surprising that the bleeding risk increased as well."
Moreover, he said, he was convinced that ongoing pharmacokinetic studies of prasugrel would identify a lower effective dose that may prove safer in high-risk groups, such as the frail elderly. "For right now, based on the evidence from this trial, at the dose tested I would not recommend the drug in frail elderly patients or in patients with a history of TIA or stroke," Dr. Antman said.
Raymond Gibbons, M.D., of the Mayo Clinic, a former president of the AHA, said the study proved an "important scientific principle that increasing inhibition of platelet aggregation activity can reduce events," but he agreed that if approved, patient selection criteria should be spelled out on the drug label.
Bleeding, said Gordon F. Tomaselli, M.D., of Johns Hopkins, may signal the need for additional studies of the drug. Asked whether post-marketing studies would answer this safety issue, Dr. Tomaselli said that he always preferred pre-approval trials.
A surprising assessment was offered by Steven Nissen, M.D., chairman of cardiovascular medicine at the Cleveland Clinic, who said, "I think this drug is approvable." Dr. Nissen is well known for his opposition to approval of drugs before all safety questions have been answered.
"The reduction in MI is very, very significant," Dr. Nissen said. He suggested additional trials to determine whether lowering the dose could attenuate the bleeding risk.
And two well known interventional cardiologists were split on their assessment of the drug. Ron Waksman, M.D., of the Washington Hospital Center, said he did not think the drug was approvable, but even if approved it would fail to win acceptance by interventionalists "because of the bleeding. We don't like bleeding."
By contrast Gregg Stone, M.D., of Columbia University and the Cardiovascular Research Foundation, said he thought the drug was approvable. "Patient selection will be an issue, that's clear," he said. But he added that he liked the fast-action of prasugrel and he would "use it if approved."
The TRITON study was supported by Lilly, which is developing prasugrel. Dr. Antman reported financial support from Lilly and Sanofi-Aventis. Dr. Waksman reported financial support from Radiance, Guidant, Cordis, Mirvant, and Nuccetron. Dr. Gibbons reported financial support from KAI Pharmaceuticals, TargeGen, Hawaii Biotech, Radiant Medical, and King Pharmaceuticals. Dr. Tomaselli reported financial support from Sanofi-Aventis. Dr. Stone support from The Medicines Company, Boston Scientific, and Pfizer. Dr. Nissen said he receives no financial support from pharmaceutical companies.
Additional source: New England Journal of MedicineSource reference: Wiviott, SD "Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndroms."N Engl J Med 2007; 357: 2001-2015.