Clopidogrel is often the antiplatelet agent of choice for patients with ACS or those receiving a stent because, as a generic, it is inexpensive and, as a drug that has been around for a long time, it has shown consistent efficacy in most patients. However, 20% to 30% of patients have a genetic variant, CYP2C19*2, that is associated with reduced activation of clopidogrel and the antiplatelet response to clopidogrel.
It has been hypothesized, based on observational data and knowledge of the mechanism of action of clopidogrel, that testing patients for the CYP2C19*2 variant and giving those without the variant clopidogrel and those with the variant a newer, more expensive antiplatelet agent such as prasugrel (Effient, Daiichi Sankyo/Eli Lilly) or ticagrelor (Brilinta, AstraZeneca) would lead to better outcomes. It also was hypothesized that testing for platelet function to guide the choice of antiplatelet agent and dosing would improve outcomes.
Paul A. Gurbel, MD, discussed results of
recent trials that studied personalized
Image: Scott Wendler, LifeBridge Health
However, recent randomized prospective trials yielded results that did not confirm the hypotheses. The GRAVITAS trial data, published in 2010, showed that outcomes were not affected when patients with high platelet reactivity who underwent PCI were switched to a higher dose of clopidogrel. Results from the ARCTIC trial, published in 2012, did not show that platelet function monitoring affected ischemic outcomes. Findings from ARCTIC-GENE, a substudy of the ARCTIC population, presented at the European Society of Cardiology Congress in 2013, did not show that genotyping for the CYP2C19*2 variant led to better outcomes for death, MI, stroke, stent thrombosis and urgent revascularization at 1 year after stent implantation.
“That is confounding the picture,” Robert Roberts, MD, FRCPC, MACC, FAHA, president and CEO of the University of Ottawa Heart Institute, professor of medicine at the University of Ottawa and director of the Ruddy Canadian Cardiovascular Genetics Centre in Ottawa, Ontario, Canada, told Cardiology Today.
The outlook for genetic profiling and platelet function testing for response to clopidogrel may come down to whether the cardiology community is willing to use testing based on observational and pharmacological data, or whether it insists on randomized, prospective trial results for proof of concept.
For the ARCTIC-GENE trial, Jean-Philippe Collet, MD, PhD, professor of cardiology at the Pitié-Salpêtrière Hospital in Paris, and colleagues analyzed DNA samples from 1,420 patients who were genotyped for CYP2C19 genes related to platelet reactivity. Patients were stratified by whether genotyping predicted them as slow or fast metabolizers of clopidogrel.
The rate of the primary composite endpoint (death, MI, stroke, stent thrombosis and urgent revascularization) at 1 year was 32.7% in slow metabolizers compared with 32.2% in rapid metabolizers (HR=0.99; 95% CI, 0.81-1.2). The rate of death or MI was 30.5% in slow metabolizers compared with 29.3% in rapid metabolizers (HR=0.97; 95% CI, 0.79-1.18). The rate of stent thrombosis or urgent revascularization was 4.4% in slow metabolizers compared with 5.7% of rapid metabolizers (HR=1.31; 95% CI, 0.79-2.2), according to data presented at ESC 2013.
There was no difference between the groups in bleeding outcomes. All types of bleeding were observed in 3.5% of slow metabolizers compared with 3.6% of rapid metabolizers (HR=1.05; 95% CI, 0.58-1.9), major bleeding occurred in 3.1% of slow metabolizers compared with 2.2% of rapid metabolizers (HR=0.74; 95% CI, 0.38-1.45) and minor bleeding occurred in 0.9% of slow metabolizers compared with 1.7% of rapid metabolizers (HR=1.98; 95% CI, 0.66-5.93).
Paul A. Gurbel, MD, director of the Sinai Center for Thrombosis Research at Sinai Hospital in Baltimore, professor of medicine at Johns Hopkins University School of Medicine, and adjunct professor of medicine at Duke University School of Medicine, cautioned against interpreting the ARCTIC-GENE findings as definitive proof that personalized antiplatelet therapy has no benefit.