MUNICH – Prasugrel had no overall efficacy advantage over clopidogrel when treating patients with non–ST-elevation acute coronary syndrome in a prospective, randomized trial with more than 9,000 patients.
Results from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndrome (TRILOGY ACS) did provide reassuring, new safety data for prasugrel compared with clopidogrel in the enrolled patient population.
The study outcomes also supplied very suggestive evidence for certain efficacy advantages of prasugrel compared with clopidogrel in the study’s target patients. But prasugrel’s inability to beat clopidogrel for the study’s primary efficacy end point produced an inescapable argument against springing for the more expensive prasugrel rather than the cheaper clopidogrel in most non–ST-elevation ACS patients who initially undergo medical management rather than revascularization therapy.
"In the largest trial to date of ACS patients managed medically without revascularization, prasugrel was not statistically different from clopidogrel during 2.5 years of follow-up among patients less than 75 years of age," Dr. Matthew T. Roe said at the meeting. Concurrent with his presentation, the results appeared online (N.Engl.J.Med.2012;367:doi:10.1056/NEJMoa1205512).
Dr. Matthew T. Roe
Current European Society of Cardiology guidelines for managing patients with ACS without ST-segment elevation say that prasugrel is indicated for patients with known coronary anatomy who are proceeding to PCI (Eur. Heart J. 2011;32:2999-3054). "I believe these recommendations should not be changed," commented Dr. Raffaele De Caterina, professor and director of the division of cardiology at G. d’Annunzio University in Chieti, Italy. In contrast, the same guidelines say that another potent antiplatelet drug, ticagrelor, is recommended for all patients at moderate-to-high risk of ischemic events regardless of their initial treatment strategy. The ticagrelor recommendation was largely based on the results of a prespecified sub-analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial published last year (BMJ 2011;342:d3527), Dr. De Caterina said.
The new safety findings came from the TRILOGY ACS study design, which called for cutting the standard 10 mg daily dosage of prasugrel in half for patients aged 75 or older, and for patients who weighed less than 60 kg. The consequence was that the rates of severe or intracranial bleeds in patients in the prasugrel arm were not significantly different from patients in the clopidogrel arm, a marked contrast to the results from an earlier major trial that compared prasugrel and clopidogrel, the Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial (N. Engl. J. Med. 2007;357:2001-15).
"A reasonable solution for the problem of excess bleeding in the elderly appears to have been successfully arrived at by modifying the dose," commented Dr. Elliott M. Antman, director of the cardiac unit at Brigham and Women’s Hospital in Boston and lead investigator for the TRITON-TIMI 38 trial.
"The safety here was very comforting, because this trial had the longest follow-up of any antiplatelet treatment agent. The results point out clearly that one drug dose does not fit all," said Dr. E. Magnus Ohman, professor of medicine at Duke University in Durham, N.C., and co-lead investigator for the TRILOGY ACS trial along with Dr. Roe.
The trial’s main efficacy end point focused on the 7,243 enrolled patients who were younger than 75 years old. During a median follow-up of 17 months and as long as 30 months, patients treated with prasugrel had a 13.9% rate of the primary, combined end point of cardiovascular death, myocardial infarction, or stroke, compared with a 16% rate among patients randomized to clopidogrel. This difference did not reach statistical significance, reported Dr. Roe, a Duke cardiologist.
The trial included a prespecified, secondary analysis that focused on recurrent cardiovascular events (not just the incidence of initial events used for the primary analysis). Total recurrent events occurred in 459 patients treated with prasugrel and 530 patients treated with clopidogrel, a 15% relative hazard reduction in favor of prasugrel that reached statistical significance.
In addition, the rate of the primary efficacy end point in the two treatment arms was virtually identical during the first 12 months of follow-up. Subsequently the two arms showed a clear split, with the prasugrel-treated patients having a significant, 28% reduced rate of primary outcomes after the study’s first 12 months, a statistically significant difference in a post-hoc analysis.
The delayed benefit from prasugrel compared with clopidogrel in this trial contrasted with the TRITON-TIMI 38 results, which showed an immediate benefit from prasugrel in patients who underwent percutaneous coronary interventions. A likely explanation is that the highly thrombogenic stents that the TRITON-TIMI 38 patients received posed an acute thrombotic risk, while thrombotic events occurred more slowly in the medically managed patients enrolled in TRILOGY ASC, Dr. Antman suggested in an interview.