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Clopidogrel vs aspirin in patients with established cardiovascular disease: Systematic review and meta-analysis

Key Takeaway

This systematic review and meta-analysis of 05 RCTs* compared clopidogrel monotherapy with aspirin monotherapy in patients with established CVD.
Clopidogrel monotherapy vs aspirin monotherapy was associated with:

  • 17% relative risk reduction for nonfatal MI (P = 0.02).
  • Marginally decreased risk for MACE (P = 0.05).
  • Similar risks for ACM, ischemic stroke, and major bleeding events.

Clopidogrel monotherapy provides better or at least similar benefits in patients with established CVD vs aspirin monotherapy.

Overall, study findings might contribute toward future clinical practice recommendations for the choice of antiplatelet drugs in patients with established CVD.

Why this Matters

Aspirin is recommended for secondary prevention of CVD, while clopidogrel is only used in cases of aspirin resistance.

  • The RCTs comparing aspirin and clopidogrel have reported heterogeneous results.

This systematic review compared clopidogrel monotherapy vs aspirin monotherapy to provide the best currently available evidence in patients with established CVD.

Study Design

This systematic review and meta-analysis (CRD42021283866) was performed by applying
PICO strategy to define search question.

Studies Included

  • Peer-reviewed RCTs

  • Articles published in English

  • Articles comparing aspirin with clopidogrel monotherapies

Studies Excluded

  • Studies in non-English language

  • Observational studies

  • Studies on aspirin + dipyridamole combinations

  • Meta-analyses

  • Systematic reviews

  • Editorials

  • Letters to the editor

  • Case series or case reports

Intervention and Comparator Arm

Intervention Arm: Clopidogrel monotherapy.

Comparator Arm: Aspirin monotherapy.

Endpoints Assessed

  • Primary Outcome: ACM.
  • Secondary Outcomes: IS, nonfatal MI, MACE and major bleeding events.

Key Results

Overall, 05 RCTs (26,855 adult patients) were eligible for the analysis.

Baseline Characteristics
  Clopidogrel Arm Aspirin Arm
Mean Age 62.7 years
Mean Follow-up 19.9 months
Number of Patients 13,426 13,429
Females (n) 3,473 3,470


Outcome Studies reported (Total number of patients) Patients in clopidogrel arm Patients in aspirin arm OR (95% CI) P-value I2

Primary Outcome

ACM 5 (26,855) 717 708 1.01 (0.91–1.13) 0.83 0.00%

Secondary Outcomes

IS 4 (26,671) 546 0.87 (0.71–1.06) 0.87 (0.71–1.06) 0.16 11.13%
Nonfatal MI* 5 (26,855) 305 367 0.83 (0.71–0.97) 0.02 0.00%
MACE 5 (26,855) 1,330 1,267 0.84 (0.71–1.00) 0.05 36.49%
Major bleeding events 4 (26,667) 181 223 0.77 (0.56–1.06) 0.11 34.77%
*RRR: 16.9%; ARR: 0.5%; NNT: 217 for a mean period of 20 months

Cumulative study results compared with individual studies

  • Results were consistent for mortality, stroke and major bleeding events
  • No difference found for nonfatal MI
  • Results from individual studies varied considerably for nonfatal MI for MACE

For information on sensitivity analysis, please click on the hyperlink.

Key Limitations

  • The included studies had great heterogeneity.

  • Aspirin dose varied between studies, which might have confounded study results.

  • All included studies were conducted in different countries, so populations studied may differ in terms of treatment response

For additional details, please refer the source publication Tasoudis PT, et al.
* Studies included in the analysis: Cadet, Watch, ASCET, Caprie and Host-Exam
 In Terms of efficacy and safety
 Defined differently between the studies.


ACM; all-cause-mortality; ARR, absolute risk reduction; CI, confidence interval; CVD, cardiovascular disease; I2, heterogeneity; IS, ischemic stroke; MACE, major adverse cardiovascular events; MI, myocardial infraction; NNT, number needed to treat; OR, odds ratio; PICO, patient intervention control outcome; RCT, randomized controlled trial; RRR, relative risk reduction.


  1. Tasoudis PT, Kyriakoulis IG, Sagris D, Diener HC, and Ntaios G. Clopidogrel monotherapy versus aspirin monotherapy in patients with established cardiovascular disease: Systematic review and meta-analysis. Thromb Haemost. 2022;122(11):1879-1887. doi: 10.1055/a-1853-2952. PMID: 35577054.