By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Valenti R, et al. Prasugrel in clopidogrel nonresponders undergoing percutaneous coronary intervention: The RECLOSE (REsponsiveness to CLOpidogrel and StEnt Thrombosis) 3 Study. JACC Cardiovasc Interv 2015 Sept 9. pii:S1936-8798(15)01138-3.
For years, clopidogrel has been the mainstay of dual antiplatelet therapy following coronary stent implantation. Clopidogrel is a prodrug, however, and its conversion to the active drug is highly variable across patient populations. We have known for some time that patients who respond poorly to clopidogrel have higher event rates post-myocardial infarction and post stent. Despite this observation, as well as the ready availability of tests to determine which patients have high residual platelet reactivity on clopidogrel, no trial to date has been able to demonstrate a positive effect of platelet function testing-guided therapy on clinical outcomes. The recent availability of more potent antiplatelet agents, including prasugrel and ticagrelor, has improved the ability to treat clopidogrel nonresponders effectively.
Enter the RECLOSE-3 trial. In this study, Valenti et al screened 1550 patients undergoing percutaneous coronary intervention (PCI) with light transmittance aggregometry, of whom 302 were deemed to be clopidogrel nonresponders. This subset was subsequently switched to prasugrel 10 mg, after which all but 26 patients had a markedly improved antiplatelet response. The primary endpoint was a composite of cardiac death, myocardial infarction, urgent coronary revascularization, and stroke at 2-year follow-up. Stent thrombosis and the individual components of the composite were followed as secondary endpoints. Outcomes for patients from RECLOSE-3 were compared with those from the earlier RECLOSE 2-ACS trial, which had a similar design but included only acute coronary syndrome patients, and switched clopidogrel nonrespondeers to either high-dose clopidogrel or to ticlopidine (which are less effective than prasugrel at overcoming clopidogrel resistance).
Two-year mortality was lower in the RECLOSE-3 patients who took prasugrel compared with the RECLOSE 2-ACS nonresponders (4% in the RECLOSE-3 study vs 9.7% in nonresponders of the RECLOSE 2-ACS study, P = 0.007). This difference held true even when examining only the subset of patients with acute coronary syndromes (all of the RECLOSE 2-ACS patients, but only 42% of the RECLOSE-3 patients). Rates of cardiac death and of definite/probable stent thrombosis were also significantly lower in the prasugrel-treated RECLOSE-3 population. While major bleeding events were not different, minor bleeding was unsurprisingly higher in RECLOSE-3 than in RECLOSE 2-ACS nonresponders (5.3% vs 1.2%; P = 0.009).
The authors concluded that platelet function testing-defined clopidogrel nonresponsiveness can be overcome by prasugrel treatment, and that this is a modifiable risk factor whose treatment can improve outcomes.
COMMENTARY
Researchers have long known that clopidogrel is plagued by a significant number of patients with high on-treatment platelet reactivity, and that these patients have higher cardiac event rates compared with patients having a more robust clopidogrel response. Why, then, have previous trials failed to show a positive effect of platelet testing on cardiac outcomes? For older trials, the answer lies in the lack of good options for overcoming clopidogrel resistance. The randomized GRAVITAS trial, like RECLOSE 2-ACS, used high-dose clopidogrel in the treatment arm, and failed to show a treatment effect, compared with standard-dose clopidogrel. We know from pharmacodynamic studies, however, that simply doubling the dose of clopidogrel does not effectively overcome resistance in true clopidogrel nonresponders. The only large randomized platelet function testing trial to use prasugrel in the intervention arm was the TRIGGER PCI study, which enrolled only low-risk elective PCI patients, and had an event rate in both arms that was simply too low to show a treatment effect.
RECLOSE-3 was not a randomized trial, but rather compared 2-year outcomes in prasugrel-treated patients with those from the earlier RECLOSE 2-ACS trial in which clopidogrel nonresponders were treated with less-effective therapy. The potential problems with this approach are obvious and are acknowledged by the authors. Nonetheless, the outcome difference appears both robust and plausible. Concluding that clopidogrel resistance can be effectively overcome by switching to the more-potent drug seems quite reasonable.
Should we, then, invest in platelet function testing for all of our PCI patients? This is one interpretation of the data, but I believe most would say no. We already know that unselected ACS patients have lower event rates when treated with the more potent antiplatelet agents (prasugrel and ticagrelor, studied in the TRITON and PLATO trials, respectively) as compared with clopidogrel. Why not simply recommend, like the European Society of Cardiology, that the more-potent agents be preferred over clopidogrel in ACS? Platelet testing could alternatively be invoked in order to identify those higher-risk patients who respond well to clopidogrel, and could therefore be maintained on the less-expensive drug. We already know from TRIGGER and other studies that lower-risk elective PCI patients do well on clopidogrel, even among the so-called clopidogrel nonresponders. So in the end, while RECLOSE-3 is an important milestone, it is unlikely to change practice substantially.
