Conference Coverage

TRILOGY: Prasugrel, Clopidogrel Look Similar in ACS Patients

Publish date: August 26, 2012
Author(s):
Mitchel L. Zoler, PhD

View on the News

Cost, Safety, and Efficacy Guide Drug Choice

The results from TRILOGY ACS clearly showed no overall advantage for treating acute coronary syndrome patients who are managed medically with prasugrel compared with clopidogrel for the study’s primary outcome. The efficacy results showed two very interesting advantages to prasugrel treatment: a statistically significant reduction in recurrent ischemic coronary events, and a statistically significant reduction in events starting a year after the onset of treatment. The recurrent-event analysis was prespecified, and is a very clinically relevant endpoint; the 1-year landmark analysis was done post hoc. Because the primary end point showed no significant benefit, both of these other outcomes must be considered just hypothesis generating.

The safety results for prasugrel were very reassuring. They indicated that barring patients with a history of stroke from the trial and using a reduced, 5 mg/day dosage for patients aged 75 or older and for patients who weighed less than 60 kg eliminated the excess risk for major bleeding events compared with clopidogrel, which were seen in the prior comparison of prasugrel and clopidogrel, the TRITON-TIMI 38 study.

In the United States clopidogrel is now available as a generic drug and is substantially cheaper than prasugrel. If cost were not an issue, then I might be inclined to use prasugrel over clopidogrel in the types of patients enrolled in TRILOGY ACS because of the signals of possible superior efficacy and no added safety risk. But cost is an issue and will remain so for several more years until prasugrel goes off patent. Until then, the possible advantages of prasugrel over clopidogrel do not tip the balance compared with prasugrel’s excess expense.

But the issue of which drug to choose in these patients doesn’t end there, because there is a third option, ticagrelor. A prespecified sub-analysis of the PLATO trial, which compared ticagrelor with clopidogrel in acute coronary syndrome patients, looked at the comparison between the two drugs specifically in patients with non–ST-segment elevation acute coronary syndrome who did not initially undergo invasive management. This is a population of patients very similar to those enrolled into TRILOGY ACS. The subanalysis showed that ticagrelor had a significant efficacy advantage over clopidogrel that was similar to what was seen in the entire PLATO trial, and that provides a compelling reason to consider ticagrelor over clopidogrel in these patients.

But the overall PLATO results as well as this subanalysis also showed a statistically significant excess risk for major bleeding events for ticagrelor, compared with clopidogrel. And ticagrelor, like prasugrel, is substantially more expensive than clopidogrel.

A further complication is that ticagrelor is a twice-daily drug, while clopidogrel and prasugrel are administered once daily.

If I were treating the TRILOGY ACS type of patients, cost were no object, the patients seemed likely to be compliant with their drug regimen, and their bleeding risk was relatively low, then I might want to go with ticagrelor to take advantage of its efficacy edge over clopidogrel. But if cost were a significant consideration, or I had doubts about regular patient compliance with a b.i.d. regimen, or the patient had a high risk for bleeding complications, then clopidogrel might seem like the most attractive option.

DEEPAK L. BHATT, M.D., is chief of cardiology at the VA Boston Healthcare System. Dr. Bhatt served as a coinvestigator and a member of the steering committee for TRILOGY ACS. He said that he has received grant support from several drug companies, but not from the companies that sponsored TRILOGY ACS. Dr. Bhatt made these comments in an interview.


 

AT THE ANNUAL CONGRESS OF THE EUROPEAN SOCIETY OF CARDIOLOGY

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.

Pages