Impact of clopidogrel metabolizer status on platelet aggregation and association with outcomes in AF patients undergoing PCI

Background Functionally altered platelet reactivity on clopidogrel associates with ischemic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). Purpose This study aimed to evaluate the association of CYP2C19 polymorphism and platelet reactivity with ischemic and bleeding risk in patients with atrial fibrillation (AF) undergoing PCI treated with oral anticoagulation (OAC) and clopidogrel. Methods Patients with AF and an indication for OAC were included in this two-center prospective cohort study up to 3 days after PCI. Carriers of ≥1 loss of function (LOF) allele CYP2C19*2 were classified as poor/intermediate metabolizers (PM/IM) and carriers of ≥1 gain of function allele (GOF) as rapid metabolizers (RM). Normal metabolizers (NM) were defined as absence of LOF and GOF alleles. Platelet reactivity was assessed by thromboelastography (TEG) and/or multiplate electrode aggregometry (MEA). High platelet reactivity on clopidogrel (HPR) was defined as the highest measured quartile (>58.1mm [TEG]; >17.5U [MEA]) and low platelet reactivity (LPR) as the lowest quartile (<39.9mm [TEG]; <6.7U [MEA]). Primary outcome was defined as death, myocardial infarction, or stroke (MACE) at 6 months ±2 weeks. Bleedings were defined according to ISTH. Results 283 patients were included in the study. Median age was 78 (interquartile range, IQR 72-82) years old and 204 (72%) were males. All patients received treatment with clopidogrel and OAC. 73 (26%) were PM/IM, 108 (38%) were NM and 102 (36%) RM. The primary ischemic outcome occurred in 22 (8%) and the secondary outcome in 38 (13%) patients. PM did not significantly associate with the primary ischemic outcome (PM: 6 [8.2%] vs. NM+RM: 16 [7.6%], p=0.869). Any bleeding rates were lower for patients with PM status (major, NMCR, or minor bleeding: PM 21 [29%] vs. NM+RM 83 [40%]; OR 0.618 [95% CI 0.347-1.101]; p=0.102). Presence of PM status increased the risk for HPR on clopidogrel (OR 1.929 [95% CI 1.088-3.420], p=0.025). This difference was mostly attributed to the subgroup where platelet aggregation was assessed by TEG. Median of MAADP was 56.9mm for patients with PM/IM status vs. 49.7mm for the rest of the patients (p=0.008), (Figure 1). LPR status associated with significantly increased risk for major bleedings at 6 months (13% vs. 5% no LPR; OR 2.646 [95% CI 1.075-6.509], p=0.034). HPR indicated a trend towards association with the ischemic outcome (12% vs 6% no HPR; OR 2.005 [95% CI 0.820-4.902], p=0.127, Figure 2). Conclusion This pilot study of patients with OAC for AF and clopidogrel after PCI did not detect an increased ischemic risk for carriers of ≥1 LOF allele CYP2C19*2 whereas LOF-carrier status might protect from bleeding. HPR might indicate a higher ischemic risk whereas LPR associated significantly with major bleedings. HPR is more pronounced in patients with PM/IM status.