Comparative discontinuation and non-bleeding side effects of Clopidogrel, Prasugrel and Ticagrelor in patients with acute coronary syndromes; a Network Meta-analysis of Randomized Controlled Trials

Abstract Background P2Y12 receptor inhibitors are highly effective treatment options following ACS. However, premature discontinuation compromises their effectiveness. Although extensive literature exists, the clinical assessment of their adherence remains controversial, requiring definitive investigation. Purpose To evaluate treatment discontinuation and non-bleeding adverse effects associatedwith platelet P2Y12 receptor inhibitors in individuals post-ACS through network meta-analysis. Methods Data Sources: MEDLINE, Embase, Cochrane, and clinicaltrials.gov to May 2021 and later updated to October 2022. Study Selection and Outcomes: Reviewers identified RCTs that enrolled patients post-ACS taking Clopidogrel, Ticagrelor, and Prasugrel. Exclusions included non-ACS indications, anticoagulation therapy, observational studies, and crossover designs. The primary outcomesincludedoverall treatment discontinuation, treatment discontinuation attributed to side effects, and dyspnea. Secondary outcomes included bradycardia and atrial fibrillation. Data Extraction and Synthesis:This network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, employing frequentist random-effects models. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework was utilized to assess the certainty of evidence. Results With 139,343 participants in 32 RCTs, the overall treatment discontinuation rate across all studies was 16.57% out of a total of 137,897 participants. Ticagrelor was associated with increased risk for overall treatment discontinuation compared to Clopidogrel (RR, 1.34; 95% CI, 1.19 to 1.49; P<0.0001), Prasugrel (RR, 1.23; 95% CI, 1.07 to 1.41; P=0.0031) and placebo (RR, 1,40; 95% CI, 1.19 to 1.65; P<0.0001). In compatibility to overall treatment discontinuation, Ticagrelor was associated with increased risk for treatment discontinuation due to side effects compared to Clopidogrel (RR, 1.80; 95% CI, 1.36 to 2.38; P<0.0001), Prasugrel (RR, 1.49; 95% CI, 1.06 to 2.10; P=0.0216) and placebo (RR, 1.85; 95% CI, 1.21 to 2.83; P=0.0044). Ticagrelor, Prasugrel and Clopidogrel were associated with an increased risk for dyspnea in comparison to placebo (RR, 2.86; 95% CI, 2.57 to 3.17; P<0.0001; RR, 1.61; 95% CI, 1.35 to 1.91; P<0.0001; RR, 1.60; 95% CI, 1.41 to 1.82; P<0.0001) respectively. Ticagrelor was associated with increased risk for dyspnea compared to Clopidogrel (RR, 1.78; 95% CI, 1.65 to 1.92; P<0.0001) and prasugrel (RR, 1.78; 95% CI, 1.55 to 2.05; P<0.0001). Conclusions The findings of this study suggest that Ticagrelor presents the highest risk for premature discontinuation compared to Clopidogrel and Prasugrel. Additionally, P2Y12 receptor inhibitors, in general, are notably associated with dyspnea, with Ticagrelor showing the highest risk. These results provide health professionals with valuable information for making treatment decisions in patients post-ACS.NMA netgraphsNMA of Overall treatment discontinuation