Clinical outcomes of clopidogrel vs ticagrelor in acute coronary syndrome: Results of a comprehensive meta-analysis

This meta-analysis of 28 studies suggests that ticagrelor was not superior to clopidogrel in major adverse cardiovascular events (MACE) and was associated with higher risk of bleeding compared to clopidogrel in patients with acute coronary syndrome (ACS).

Key Takeaway

  • This meta-analysis comparing clinical outcomes of clopidogrel vs ticagrelor in patients with ACS suggested that:
    • Ticagrelor was not superior to clopidogrel in MACE and but increased bleeding risk
    • In patients who underwent percutaneous coronary intervention (PCI), ticagrelor was more effective vs clopidogrel, as it significantly reduced the incidence of MACE. However, risk of bleeding was more with former
  • Clinicians should consider the reduced bleeding risk of P2Y12 inhibitor monotherapy after a short-duration dual antiplatelet therapy, based on the individual's ischemia and bleeding risks.

Why This Matters

  • Several meta-analyses reporting clinical applications of ticagrelor and clopidogrel reported inconsistent results.
  • Previous meta-analyses either mixed all studies together and ignored the heterogeneity between clinical trials and observational studies or did not perform further subgroup analyses based on other studies (or population) characteristics.
  • This meta-analysis was conducted to address the above conflicting conclusions.

Study Design

  • This meta-analysis was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline.
  • Inclusion: Clinical trials and observational studies comparing ticagrelor vs. clopidogrel in adult patients with ACS who underwent PCI or intended for PCI and reported one or more of the following outcomes during any follow-up period: MACE, all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke, stent thrombosis (ST), and (major or minor) bleeding
  • Exclusion: Studies with incomplete data, or observational studies with unadjusted endpoints, studies from the same sample source and studies not in English
  • Primary efficacy endpoint: MACEs; secondary endpoints (stroke, ST, MI, CV death, and all-cause death); and safety endpoints (bleeding, major or minor bleeding)
  • Two subgroup analyses, namely, propensity score-matched/adjusted analyses (PA group) and multivariate-adjusted analyses (MA group) were performed.

Key Results

  • This meta-analysis included 28 studies with 2,70,937 patients (88,490 and 1,82,447 in the ticagrelor and clopidogrel groups, respectively).
  • There were 10 clinical trials and 18 observational studies.
    • Patients who underwent PCI (19 studies) or intended for PCI (9 studies) 
  • Primary endpoint:
    • Clinical trials: no significant difference in MACE between ticagrelor and clopidogrel groups (odds ratio [OR] 0.81, 95% confidence interval [CI]: 0.60–1.08, P = 0.15)
    • Observational studies: MACEs were similar in both the MA group (OR 0.97, 95% CI: 0.82–1.15, P = 0.76) and the PA group (OR 0.86, 95% CI: 0.75–1.00, P = 0.05)
  • Secondary endpoints: Compared with clopidogrel group, the ticagrelor group demonstrated reduction in:
    • ST (OR 0.72, 95% CI: 0.58–0.90, P = 0.00) in clinical trials
    • All-cause death (OR 0.83, 95% CI: 0.70–0.98, P = 0.03) and CV death (OR 0.66, 95% CI: 0.44–0.99, P = 0.04) in the PA group
    • CV death (OR 0.59, 95% CI: 0.45–0.79, P <0.001) in the MA group
  • Safety:
    • Clinical trials: Ticagrelor was associated with significantly higher risks of bleeding (OR 1.46, 95% CI: 1.17–1.83, P = 0.00) and minor bleeding (OR 1.71, 95% CI: 1.33–2.21, P = 0.00) compared to clopidogrel
    • PA group of observational studies: Risks of bleeding (OR 1.39, 95% CI: 1.06–1.83, P = 0.02) and minor bleeding (OR 1.61, 95% CI: 1.37–1.89, P = 0.00) was more with ticagrelor than clopidogrel
    • MA group of observational studies: Only minor bleeding risk (OR 1.21, 95% CI: 1.14–1.72, P = 0.007) increased significantly with ticagrelor
  • Subgroup analysis: Patients who underwent PCI (OR 0.38, 95% CI: 0.23–0.63, P = 0.00) benefited more from ticagrelor vs those intended for PCI (OR 1.03, 95% CI 0.76–1.38, P = 0.87) regarding MACE. However, with ticagrelor, risk of bleeding was high in both group of patients


  • Number of randomized controlled trials and sample sizes in several of these trials were relatively small
  • Duration of follow-up after PCI varied from in-hospital to one year or longer
  • Trials with heterogeneous populations that varied in study design, disease subtype, treatment strategy, and endpoint definition were pooled
  • Possible adverse drug reactions, loss of tolerability, and discontinuation of treatment were not considered

    Sun M, Cui W, Li L. Comparison of clinical outcomes between ticagrelor and clopidogrel in acute coronary syndrome: A comprehensive meta-analysis. Front Cardiovasc Med. 2022;8:818215. doi:10.3389/fcvm.2021.818215. PMID: 35155618.