by Payam Dehghani, MD, FRCP(C), FACC, FSCAI
SAN DIEGO — Efficacy is established in randomized clinical trials. Effectiveness, however, is established in registry and/or nonrandomized observational data. The PROMETHEUS and TRIAGE studies, both presented as late-breaking clinical trials at the Society for Cardiovascular Angiography and Interventions Scientific Sessions, were attempts to establish effectiveness of prasugrel (Effient, Daiichi Sankyo/Eli Lilly).
For the PROMETHEUS study, Usman Baber, MD, MS, and colleagues retrospectively characterized a cohort of nonrandomized ACS patients taking prasugrel and then compared their 90-day major adverse cardiac event rates vs. patients who were taking clopidogrel. The study was performed at eight U.S. academic medical centers. The researchers found the following: (1) only one in five patients were assigned prasugrel (total cohort = 19,914); (2) the prasugrel group was a much lower-risk group than the clopidogrel group, with less diabetes, chronic kidney disease and MI; and (3) the primary endpoint of adjusted MACE at 90 days from PCI was not statistically significant between the two treatment groups.
The TRIAGE study, presented at SCAI 2015 by Jaya Chandrasekhar, MBBS, was a prospective trial designed to compare outcomes in patients treated with prasugrel compared with clopidogrel at PCI following determination of platelet reactivity in conjunction with clinical risks. By extension, a more important question was whether higher-risk patients assigned prasugrel would have a lower primary endpoint of MACE at 1 year. The findings presented here were notable because: (1) recruitment was terminated at 318 patients due to slow enrollment (originally designed to enroll 1,000 patients; (2) by protocol, prasugrel was assigned to only 28% of the study population; and (3) MACE at 1 year was not statistically significantly different at 1 year in the two treatment groups.
Based on these study findings, what we should not derive is that prasugrel is less effective than clopidogrel in patients with ACS. Both studies highlight similar themes.
First, the PROMETHEUS study tells us that we may be scared to start patients on prasugrel in exactly the patients who require it the most. Could it be that the reported excess bleeding as consciously, and maybe subconsciously, concerned us to such a degree that we are “cherry picking” patients? Therefore, to justify its use, we come up with complex algorithmic approach, as in the TRIAGE study, as to who should be on prasugrel. Lack of recruitment of the right number of patients again highlights our attitudes about committing patients to prasugrel. As the late-breaking clinical trial session panelists Roxana Mehran, MD, and Matthew Price, MD, discussed, the bigger question we should ask is why have the novel antiplatelet agents not penetrated the U.S. market?
Second, it is difficult, despite complex propensity scoring systems, to derive meaningful conclusions regarding MACE rates when the two arms are so different (as in the PROMETHEUS study), or when they come up so short in meeting their sample size (as in the TRIAGE study).
However, a silver-lining finding from both of these studies is that bleeding was not increased with prasugrel, suggesting that our fear may not be warranted. This finding is particularly notable as there was a signal, although not statistically significant, that adjusted MACE rates were favoring prasugrel from both studies. Perhaps the TRIAGE study would have demonstrated superior effectiveness in the prasugrel group if the study investigators could have completed the study. I agree that we cannot make any conclusions from studies with negative primary endpoints or inadequate power. However, Dr. Baber, Dr. Chandrasekhar and the PROMETHEUS and TRIAGE study investigators should be congratulated for attempting to characterize and find the right niche for patients taking prasugrel, a medication proven to be efficacious and still looking to establish its effectiveness.
Payam Dehghani, MD, FRCP(C), FACC, FSCAI, is a SCAI 2015-2017 Emerging Leader Mentorship fellow; an interventional cardiologist within the Regina Qu’Appelle Health Region; director of the Adults with Structural Heart Disease Clinic; clinical co-director of the Prairie Vascular Research Network; and assistant professor at the University of Saskatchewan, Canada.
Disclosure: Dehghani reports no relevant financial disclosures.