Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis
C Combescure1, P Fontana, N Mallouk
1Division of Clinical Epidemiology, Geneva University Hospital, Geneva, Switzerland.
Insights
Patients with clopidogrel non-response face a significantly higher risk of recurrent ischemic events. This cardiovascular risk is heterogeneous, influenced by factors like glycoprotein IIb/IIIa inhibitor use and differing non-response definitions.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Research
Background:
- Previous studies indicate a significant cardiovascular event risk in patients exhibiting clopidogrel biological non-response.
- Considerable heterogeneity exists within the data on clopidogrel non-response, warranting further investigation.
Purpose of the Study:
- To quantify the cardiovascular risk associated with clopidogrel non-response.
- To explore the heterogeneity observed in clopidogrel non-response studies.
Main Methods:
- Systematic review and meta-analysis of prospective studies.
- Inclusion of patients treated with clopidogrel for symptomatic atherothrombosis.
- Evaluation of clopidogrel response using light transmission aggregometry with ADP and prospective monitoring for ischemic events.
Main Results:
- Fifteen studies comprising 3960 patients were analyzed, with 25% identified as clopidogrel non-responders.
- Clopidogrel non-responders exhibited a global relative risk (RR) of 3.5 for recurrent ischemic events (95% CI 2.4-5.2).
- Significant heterogeneity was noted (Cochran P = 0.01, I(2) = 52%), with lower RRs in recent studies and studies not using glycoprotein IIb/IIIa inhibitors, and higher RRs with higher ADP aggregation cut-offs.
Conclusions:
- The cardiovascular risk associated with clopidogrel non-response is now more precisely defined.
- Heterogeneity in risk is linked to the use of glycoprotein IIb/IIIa inhibitors and varying cut-off values for defining clopidogrel non-response.
Unlabelled:
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.
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