Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis

J Thromb Haemost. 2010 May;8(5):923-33. doi: 10.1111/j.1538-7836.2010.03809.x. Epub 2010 Feb 12.


BSUMMARY BACKGROUND: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non-response, and data have shown considerable, unexplored heterogeneity.

Objectives: To evaluate the magnitude of cardiovascular risk associated with clopidogrel non-response and to explore heterogeneity.

Methods: This was a systematic review and meta-analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events.

Results: Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non-responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non-responders was 3.5 [95% confidence interval (CI) 2.4-5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I(2) = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3-3.8) after 2007, and global RR = 6.6 (95% CI 3.7-11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb-IIIa inhibitors [Cochran P = 0.003 and I(2) = 70%; RR = 3.8 (95% CI 2.9-5.1)] and was absent in the other studies [Cochran P = 0.88 and I(2) = 0; RR = 2.5 (95% CI 1.7-3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut-offs (> 65%) for clopidogrel non-response than in studies using lower cut-offs [RR = 5.8 (95% CI 3.2-10.3) and RR = 2.9 (95% CI 2.2-3.7), respectively, P = 0.03].

Conclusions: The risk of ischemic events associated with clopidogrel non-response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb-IIIa inhibitors and the use of different cut-offs to identify non-responders.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Cardiovascular Diseases / drug therapy*
  • Clopidogrel
  • Humans
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use


  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • Ticlopidine