Pretreatment with P2Y12 inhibitors in patients with nonST-segment elevation acute coronary syndrome: A meta-analysis

In this meta-analysis, clopidogrel pretreatment was associated with significantly lower risk of mortality, major adverse cardiovascular events (MACE), myocardial infarction (MI), death, and revascularization without increase in risk of major bleeding in nonST-segment elevation acute coronary syndrome (NSTE-ACS) patients. However, prasugrel or ticagrelor pretreatment lacked ischemic protection and caused major bleeding events.

Key Takeaway

  • This meta-analysis comparing pretreatment with P2Y12 inhibitors with no pretreatment in patients with NSTE-ACS from nine studies demonstrated that:
    • P2Y12 inhibitor pretreatment was associated with lower death from any cause without increasing the risk of major bleeding with no distinction in MI, revascularization and MACE
    • Clopidogrel pretreatment subgroup was significantly associated with lower incidence of mortality, MACE, MI, and revascularization without increasing major bleeding
    • Prasugrel or ticagrelor pretreatment subgroup was associated with no significant difference in mortality, MACE, MI or revascularization, whereas major bleeding events were significantly increased
    • Lower mortality and ischemic protection were observed in non- randomized controlled trials (RCTs) vs RCTs

Why This Matters

  • P2Y12 receptor inhibitor loading (300 mg clopidogrel) before percutaneous coronary intervention (PCI) is found to reduce MACE but slightly increase bleeding events
    • However, large-scale RCTs of clopidogrel pretreatment are lacking
  • Current RCTs for prasugrel and ticagrelor do not recommend pretreatment, as they do not reduce ischemic events but increase the risk of major bleeding.
  • In the era of prasugrel and ticagrelor, the optimal timing of P2Y12 receptor inhibitor administration remains controversial.
  • This meta-analysis compared pretreatment with P2Y12 inhibitors with no pretreatment in patients with NSTE-ACS.

Study Design

  • This meta-analysis included trials meeting following criteria: Studies with >50% of patients with NSTE-ACS; studies comparing pretreatment with P2Y12 inhibitor with no pretreatment; observational or randomized studies; studies with data on loading dose and timing of P2Y12 inhibitors were available; data reporting any data of interest, including at least any cause mortality, major bleeding
  • Excluded trials: Ongoing and no control group studies and duplicate reports
  • Primary efficacy and safety endpoint: Death from any cause and major bleeding
  • Secondary endpoint: MACEs, MI and revascularization

Key Results

Characteristics of the included studies

  • This meta-analysis included nine studies (2 RCTs, 2 post hoc analyses of RCTs and 5 non-RCTs).
  • Pretreatment with prasugrel or ticagrelor was included in 2 studies, pretreatment with 3 P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) in one study, and pretreatment with clopidogrel in 6 studies.
  • Of the 94,506 NSTE-ACS patients enrolled, 80,272 patients were pretreated with P2Y12 inhibitor.
  • In total 51,922 patients (55.6%) were treated with clopidogrel, and 41,389 (44.4%) patients were treated with prasugrel or ticagrelor.

Impact on primary outcomes

  • Pretreatment before coronary angiography (CAG) in NSTE-ACS patients was associated with
    • Significant lower incidence of mortality (odds ratio [OR] = 0.62, 95% confidence interval, [CI]: 0.53–0.72, P <0.00001)
    • No significant difference in the incidence of major bleeding (OR = 1.02, 95% CI: 0.80–1.30, P = 0.89)

Impact on MACE, MI, and revascularization

  • No difference was noticed between the pretreatment group and no pretreatment group
    • MACE: OR = 0.83, 95% CI: 0.68–1.01, P = 0.07
    • MI: OR = 0.74, 95% CI: 0.54–1.00, P = 0.05
    • Revascularization: OR = 0.82, 95% CI: 0.67–1.00, P = 0.05

Subgroup analyses: Prasugrel or ticagrelor vs clopidogrel

  • Prasugrel or ticagrelor pretreatment was associated with:
    • No striking differences in mortality (OR = 0.70, 95% CI: 0.31–1.59, P = 0.40), MACE, MI, and revascularization
    • Significantly increased major bleeding events (OR = 1.67, 95% CI: 1.10–2.54, P = 0.02)
  • Clopidogrel pretreatment was associated with lower incidence of mortality (OR = 0.61, 95% CI: 0.52–0.72, P <0.0001), MACE, MI, and revascularization without increasing major bleeding.

Sensitivity analysis and reporting bias

  • Results remained unchanged post excluding study with largest number of patients.
  • No obvious heterogeneity in research results of different era* was observed.


  • Most included studies were non RCTs with inherent biases and confusions
  • Obvious heterogeneity in MI and MACE was observed
  • Pretreatment definition as well as the time from P2Y12 inhibitor load to PCI differed in various studies.
  • The analysis of the potency of P2Y12 was limited due to a lack of data

*The relevant research results before (before 2011) and after the change (after 2011) For additional details, please refer to the source publication, Yan L et al.

    Yan L, Zhou Y, Yu Z, Xuan M, Xu B, Peng F. P2Y12 inhibitor pretreatment in patients with nonST-segment elevation acute coronary syndrome: A meta-analysis. Medicine(Baltimore). 2022;101(27): e29824. doi: 10.1097/MD.0000000000029824. PMID: 35801776.