A pharmacodynamic analysis of genotype-guided P2Y12-inhibitor monotherapy or dual antiplatelet therapy after PCI in patients with chronic coronary syndrome – the POPular STRATEGY study

Background Genotype-guided P2Y12-inhibitor de-escalation instead of routine prasugrel or ticagrelor based dual antiplatelet therapy (DAPT) reduces bleeding without compromising the ischemic risk in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Early aspirin withdrawal after uneventful ticagrelor-based DAPT is another option to mitigate bleeding risk. Whether genotype-guided P2Y12-inhibitor monotherapy is safe and effective in patients undergoing PCI is unknown. We performed a pharmacodynamic study in patients undergoing elective PCI. Objective To evaluate the pharmacodynamic response of genotype-guided P2Y12 inhibitor monotherapy in patients undergoing elective PCI. Methods Patients were randomized 1:1 to genotype-guided P2Y12-inhibitor monotherapy (n=44) or standard DAPT with clopidogrel and aspirin (n=44). In the monotherapy group, carriers of a loss of function (LoF) allele received prasugrel or ticagrelor, while non-carriers received clopidogrel. Allocated treatment started the day after PCI. Baseline platelet function was measured in venous blood directly after PCI and at 30 days post-randomization. The primary endpoint was PRU levels measured with the VerifyNow system at 30 days. PRU levels at 30 days were assessed with an analysis of covariance (ANCOVA), using PRU levels at baseline as covariate. Results There were no differences in baseline characteristics between groups. In the monotherapy group, 14 patients were carriers of a LoF allele, of which 10 were discharged on prasugrel and 4 on ticagrelor. Standard DAPT with clopidogrel was prescribed in 43 patients in the control group. The adjusted mean PRU at 30 days was 94.2 (95%: CI 81.4–107.0) in the standard DAPT group and 68.7 (95% CI: 56.2–81.2) in the monotherapy group. The model-adjusted mean difference was -25.5 (95% CI: -43.0 to -8.0; p=0.0058), which was statistically significant. High platelet reactivity, defined as PRU≥208, was observed in 3 patients in the standard DAPT group and 1 patient in the monotherapy group at baseline. There was no HPR at 30 days as there was no PRU ≥208 measured. Stent thrombosis occurred once in both groups and there were two major bleeding events in the standard DAPT group. Conclusion Patients undergoing elective PCI treated with genotype-guided P2Y12-inhibitor monotherapy have significantly lower P2Y12-inhibitor induced platelet reactivity compared to those treated with standard DAPT with clopidogrel. A clinical study to demonstrate the efficacy and safety of genotype-guided P2Y12 monotherapy compared to clopidogrel-based DAPT after elective PCI is needed.