Low CV Event Rate Prompts Closure of Prasugrel Trial



SAN FRANCISCO – Prasugrel can overcome a lack of platelet response to clopidogrel in patients undergoing elective, noncomplicated percutaneous coronary intervention. But the rate of cardiovascular events in this group of clopidogrel nonresponders is low no matter which agent they receive – so low, in fact, that it prompted early closure of a randomized trial comparing the two.

Dr. Dietmar Trenk

Trial results, reported at Transcatheter Cardiovascular Therapeutics 2011, showed that merely 1 of the 236 patients having 6 months of follow-up experienced a myocardial infarction and none died of cardiovascular causes, with no significant difference between those who continued on clopidogrel and those who switched to prasugrel. Rates of major bleeding were also low and similar.

"Given the low event rate in elective percutaneous coronary intervention [PCI] patients without periprocedural complications, it was not possible to assess the risk-benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility," lead investigator Dietmar Trenk, Ph.D., explained in a press conference. He presented results on behalf of the TRIGGER-PCI investigators.

Discussant Dr. Matthew J. Price, director of the Cardiac Catheterization Laboratory at the Scripps Clinic in La Jolla, Calif., agreed that the trial population had very low risk to begin with, and not just from a procedural perspective. For example, the patients on average had relatively large stented vessel diameters and received shorter stents.

"Also, this trial shows the challenges of performing a randomized clinical trial looking at individualized antiplatelet therapy, because about one-third of the patients who were identified as having high on-treatment platelet reactivity withdrew from the study because they did not want to participate," he commented. "So I think this shows that doing these trials, it’s very hard not to get selection bias for the lowest-risk patients, and that’s a challenge that we will have going forward in designing these randomized clinical trials."

"I do think it’s consistent [across trials] that in these low-risk patients, who have low-risk clinical scenarios and low [anatomical risk], the event rates are incredibly low, and although the hazard associated with on-treatment [platelet] reactivity may be substantial, ...the absolute event rates in these very low risk patients may mean that changing therapy may not provide net clinical benefit," Dr. Price maintained.

Patients were eligible for the trial, which was sponsored by Eli Lilly and Daiichi Sankyo Co., if they underwent successful PCI with implantation of drug-eluting stents, did not have any major complications, and did not receive any glycoprotein IIb/IIIa inhibitors, according to Dr. Trenk, who is a professor at the Herz-Zentrum Bad Krozingen (Germany).

All had received standard-of-care clopidogrel in the periprocedural period and were found to be clopidogrel nonresponders because they had a result of more than 208 platelet reactive units on the VerifyNow P2Y12 assay (Accumetrics) on the day after the procedure.

The patients were randomized in nearly equal numbers to either continue clopidogrel (Plavix; 75-mg daily maintenance dose) or switch to prasugrel (Effient; a one-time 60-mg loading dose and a 10-mg daily maintenance dose), with matching placebos.

When the trial was stopped, 423 patients had been enrolled and had data for clinical outcomes, Dr. Trenk reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

Analyses showed that the patients who switched to prasugrel indeed had lower platelet reactivity than did their counterparts who stayed on clopidogrel, both at 90 days (P less than .001) and at 176 days (P less than .001).

"Platelet reactivity in patients randomized to clopidogrel remained fairly constant, with a high rate of more than 70% of patients being hyporesponsive to the drug," Dr. Trenk pointed out. On the other hand, "prasugrel consistently decreased platelet reactivity, and only 5% of patients remained hyporesponsive at 3 months’ follow-up and at 6 months’ follow-up."

Despite this difference in platelet reactivity, the prasugrel and clopidogrel groups had similarly low 6-month rates of the primary composite efficacy end point of cardiovascular death and MI (0% and 0.5%), and secondary end points such as rehospitalization for cardiac ischemic events (0.9% and 1.9%), urgent target vessel revascularization (0.9% and 0.5%), and stroke (0% and 0.5%). There were no cases of definite or probably stent thrombosis.

Additionally, the prasugrel and clopidogrel groups had similarly low rates of the key safety end point of non–CABG-related TIMI (Thrombolysis in Myocardial Infarction) major bleeding (1.4% and 0.5%).

Dr. Trenk reported that he receives honoraria and advisory board fees from Daiichi-Sankyo, Eli Lilly, AstraZeneca, and Sanofi-Aventis. Dr. Price reported that he receives grant or research support from Bristol-Myers Squibb and Sanofi-Aventis, and that he is a consultant to, receives honoraria from, or is a speaker for Abiomed, AstraZeneca, Boston Scientific, Medtronic, Terumo Medical, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, Sanofi-Aventis, and W.L. Gore & Associates.

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