Guided antiplatelet therapy with P2Y12 antagonists in patients undergoing percutaneous coronary intervention: 3 systematic reviews with meta-analyses of randomized controlled trials with homogeneous design

Background Conflicting results were reported by randomized controlled trials (RCTs) exploring guided therapy (GT) with anti-P2Y12 drugs in patients undergoing percutaneous coronary intervention (PCI). Meta-analyses of RCTs failed to clearly identify what GT strategy, if any, is effective, because they lumped together RCTs with heterogeneous designs, comparing either genotype-GT or platelet function test (PFT)-GT with unguided standard therapy. Some meta-analysis also included RCTs that did not actually explore GT, but tested the effects of switching patients with high on-treatment platelet reactivity (HTPR) to alternative therapies (HTPR-Therapy), rather than comparing GT with unguided standard therapy. We performed 3 distinct systematic reviews with meta-analyses, each exploring only RCTs with homogeneous design. Methods MEDLINE, Embase and Central databases were searched for RCTs testing genotype-GT, PFT-GT or HTPR-Therapy in PCI-treated patients, through October 1 st 2022. Two reviewers extracted the data. Risk ratios (RR) (95% confidence intervals) were calculated. Primary outcomes were major bleedings (MB) and major adverse cardiovascular events (MACE). Results In 7 genotype-GT RCTs, RR were: MB, 1.06 (0.73–1.54; p=0.76); MACE, 0.64 (0.45–0.91; p=0.01), but significant risk reduction was observed only in RCTs performed in China (0.30, 0.16-0.54; p<0.0001) and not elsewhere (0.74, 0.46-1.18; p=0.21). In 6 PFT-GT RCTs, RR were: MB, 0.91 (0.64-1.28, p=0.58); MACE, 0.82 (0.5 –1.19; p=0.30): 0.62 (0.42-0.93; p=0.02) in China, 1.08 (0.82-1.41; p=0.53) elsewhere. In 8 HTPR-Therapy RCTs, RR were: MB, 0.71 (0.41-1.23; p=0.22); MACE, 0.57 (0.44–0.75; p<0.0001): 0.56 (0.43-0.74, p<0.0001) in China, 0.58 (0.27-1.23, p=0.16) elsewhere. Conclusion No GT strategy affected MB. Genotype-GT but not PFT-GT reduced MACE; subgroup analysis revealed that genotype-GT and PFT-GT reduced MACE in China, but not elsewhere. PFT-GT (which analyzed both patients with and without HTPR) performed poorly compared to HTPR-Therapy (which analyzed HTPR patients only), likely due to inaccurate identification of HTPR patients by PFTs. PROSPERO registration: CRD42022362739.