Pharmacogenetics-Guided De-Escalation of Dual Antiplatelet Therapy Based on CYP2C19 Testing in Patients After Acute Coronary Syndrome: Clinical Outcomes and Cost–Consequence Analysis

Background/Objectives: De-escalation of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) reduces bleeding risk; however, in carriers of loss-of-function CYP2C19 alleles, it may carry a risk of insufficient platelet inhibition. This study compared the safety and efficacy of CYP2C19 genotype-guided DAPT de-escalation with standard clinical practice in patients after ACS and PCI, and evaluated the cost implications of this approach. Methods: We conducted a prospective, randomized, open-label, parallel group trial (n = 75 genotype-guided group; n = 75 control group) with 12 months of follow-up. In the genotype-guided group, the de-escalation decision was based on the CYP2C19 genotype; in the control group, it followed standard practice at the treating physician’s discretion. The primary safety endpoint was the cumulative incidence of clinically relevant bleeding (BARC ≥2); the secondary efficacy endpoint was a composite of ischemic events. The economic evaluation was performed as a cost–consequence analysis (CCA), reporting drug and testing costs alongside the clinical outcomes described above, including a break-even threshold and one-way sensitivity analysis. Results: In the intention-to-treat population (n = 150), the 12-month cumulative incidence of BARC ≥ 2 bleeding was 10.7% in the genotype-guided group versus 12.0% in the control group (HR 0.88; 95% CI 0.34–2.28; p = 0.79). The cumulative incidence of the ischemic composite was 13.3% versus 14.7% (HR 0.91; 95% CI 0.38–2.13; p = 0.82), and neither difference was statistically significant. A per-protocol sensitivity analysis excluding eight patients who required non-protocol anticoagulant therapy yielded similar results for bleeding (9.7% vs. 11.4%; HR 0.84) and a numerically larger, though still non-significant, effect for the ischemic composite (11.1% vs. 15.7%; HR 0.69). Use of the genotype-guided strategy was associated with savings in drug and pharmacogenetic testing costs of RUB 1,036,340.21 for the cohort (RUB 15,278.16 per patient), a saving that remained positive across the full range of observed drug prices; the drug-and-testing-cost break-even price for testing was RUB 19,748.16 per patient. Conclusions: No statistically significant differences in bleeding or ischemic events were detected between genotype-guided de-escalation of DAPT based on CYP2C19 testing and standard practice in this trial, and the genotype-guided strategy was associated with a reduction in drug and testing costs. Confirmation of the clinical benefit of this approach requires further studies in larger cohorts.