CardioExchange Archive

The results of TRILOGY-ACS were released today simultaneously at the ESC and in the New England Journal of Medicine. In this study, 7243 under the age of 75 with unstable angina or NSTEMI were randomized to 30 months of aspirin plus clopidogrel or aspirin plus prasugrel.

The primary endpoint studied was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The authors found no significant difference in between each group, with the primary endpoint occurring in 13.9% of patients on prasugrel and 16% of the patients on clopidogrel. There was no significant difference in major bleeding events. Click here to see our news story and here to read Harlan Krumolz’s summary and comment in Journal Watch Cardiology.

At CardioExchange, we are fortunate to be joined by lead author Matthew Roe MD MHS to discuss aspects of this study.

RYAN: The primary endpoint in TRILOGY-ACS was reduced by an absolute risk reduction (ARR) of 2.1%. This is a similar ARR as to what was observed in TRITON-TIMI 38, but that study showed a significant improvement in their primary endpoint (same as in TRILOGY-ACS). Can you describe the differences in TRILOGY-ACS such that the results failed to show a difference in between the strategies- even as the absolute difference was 2.1%.  Is this due to the difference in power between the two studies?

ROE: Thank you for this question.  You are correct.  We estimated a higher event rate in TRILOGY ACS compared with what was observed in the TRITON trial given the higher-risk features of the TRILOGY population and the longer duration of follow-up in our study.  Importantly, among patients <75 years of age (the primary analysis cohort), we accumulated far more events for the primary endpoint than we had calculated would be necessary for the trial to be adequately powered (761 vs. 688 events).  Thus, TRILOGY was not an under-powered study.  Additionally, the sample size for the primary cohort in TRILOGY (7,243 patients) is roughly half the size of the overall TRITON population.  So, even though we observed the same ARR for the primary endpoint in TRILOGY compared with TRITON, we did not show a significant reduction in the primary endpoint due to the smaller sample size in TRILOGY.

RYAN: How should we interpret this study overall? And should it change practice? You note that there prasugrel starts to have a more pronounced benefit later in the study (beyond 30 months). What do you think this means and do you think that prasugrel should be studied for longer in order to realize it’s full therapeutic benefit?

ROE: The implications of this study for clinical practice will require further deliberation and consideration. TRILOGY ACS is a unique study that evaluated a previously under-studied population, studied the longest duration of dual anti-platelet therapy post-ACS, and is the first study to test individualized dosing of anti-platelet therapy. We believe that patients with ACS who are medically managed without revascularization are fundamentally different than patients who undergo in-hospital revascularization and we showed that they respond differently to intensified anti-platelet therapy compared with the TRITON results. Since patients in TRILOGY were unlikely to undergo post-randomization revascularization procedures, they typically remained medically managed for the duration of the study. As a result, these patients may have delayed benefit from intensified anti-platelet therapy that is not related to the reduction of revascularization-related events, although it is important to recognize that we did not design the study to evaluate this specific question. However, the favorably long-term safety profile of prasugrel compare with clopidogrel suggests that there are no safety concerns in terms of evaluating longer-term treatment in the post-ACS setting.

RYAN: Given the cost difference, are there any groups of patients in whom prasugrel is definitely preferable? In looking at the hazard ratio (Figure 2), there are many pre-specified comparisons, but it appears that prasugrel therapy is very beneficial in smokers with UA/NSTEMI. Based on TRILOGY-ACS, should we be considering prasugrel for this population and what is your opinion for this observation?

ROE: Given that we did not demonstrate a significant reduction in the primary endpoint with prasugrel vs. clopidogrel, sub-group analyses should only be considered to be hypothesis-generating and not definitive.  Nonetheless, we plan further analyses of many of the presented sub-groups, including current/recent smokers, and we will be presenting results of an embedded platelet function sub-study from TRILOGY-ACS at the AHA 2012 Sessions in November, 2012 and these data will be helpful for evaluating the impact of prasugrel within certain sub-groups.