Genotype-Guided vs Conventional Oral P2Y₁₂ Inhibitors in Acute Coronary Syndrome

Background Genotype-guided P2Y₁₂ inhibitor selection may improve outcomes in acute coronary syndrome (ACS) or percutaneous coronary interventions (PCI) patients. Objectives This study sought to assess the impact of guided therapy escalation or de-escalation vs conventional therapy. Methods Randomized controlled trials comparing guided therapy using CYP2C19 genetic testing vs conventional therapy among patients with ACS undergoing PCI were searched and individual participant-level data obtained. The primary safety endpoint was time-to-first type 2, 3, or 5 Bleeding Academic Research Consortium (BARC) bleeding at 12 months. The primary efficacy endpoint was time-to-first major adverse cardiovascular event (MACE) at 12 months. Results A total of 6,734 participants from 2 randomized controlled trials were available for analysis. After 1 year, there were no differences in the primary safety or efficacy endpoints with overall guided therapy vs conventional therapy. However, guided therapy reduced myocardial infarction (0.68; 95% CI: 0.48-0.97) and net adverse cardiovascular events (NACE) (0.85; 95% CI: 0.73-1.00) compared with conventional therapy. Guided therapy de-escalation reduced the primary safety endpoint (0.77; 95% CI: 0.62-0.97) and NACE (0.77; 95% CI: 0.62-0.94) with no significant difference in MACE, compared with conventional therapy. The primary safety and efficacy endpoints were similar between patients undergoing guided therapy escalation and conventional therapy groups. Time-dependent covariate analyses showed that overall guided therapy and de-escalation strategies reduced bleeding and NACE before 90 days, compared with conventional therapy. Conclusions These findings support evaluating genotype-guided therapy by separately analyzing de-escalation and escalation. In ACS patients undergoing PCI, genotype-guided de-escalation reduces bleeding and NACE without increasing MACE, with the greatest benefit in the first 3 months post-PCI.