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 1st 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. ### Competing Interest Statement Cattaneo M., Rocchetti M. and Minardi A. have no disclosures to declare. Birocchi S. has received honoraria from Boehringer Ingelheim; Podda GM has received consulting fees from Bayer, Sanofi, Novartis, Boehringer Ingelheim; Squizzato A. has received honoraria from Daiichi Sankyo, Bayer, Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, Werfen, Alexion, Roche, Viatris. ### Funding Statement No funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors