Elsevier

American Heart Journal

Volume 158, Issue 6, December 2009, Pages 925-932
American Heart Journal

Clinical Investigation
Acute Ischemic Heart Disease
Association of platelet responsiveness with clopidogrel metabolism: Role of compliance in the assessment of “resistance”

https://doi.org/10.1016/j.ahj.2009.10.012Get rights and content

Background

Noncompliance is probably the major cause of clopidogrel “resistance.” However, noncompliance is difficult to prove without confirming that the drug has been administered. Therefore, detection of plasma clopidogrel and/or metabolite(s) as the reliable objective method to confirm compliance is important.

Methods

We sought to correlate the inhibition of platelet aggregation (IPA) with plasma levels of unchanged clopidogrel (UC), active thiol metabolite (ATM), and inactive carboxyl metabolite (ICM) in a large cohort of patients with coronary artery disease and ischemic stroke treated with clopidogrel. We conducted secondary post-hoc analyses of IPA and plasma UC, ATM, and ICM in a dataset consisting of presumably compliant patients with coronary disease (n = 422) and post-stroke (n = 209).

Results

Overall noncompliance rate was 22% (n = 138), while such risks were significantly higher in stroke survivors (n = 79, or 38%) when compared to patients with coronary disease (14%; n = 59; P = .001). Only ICM (19,154 ± 7,228 ng/ml) was suitable for detecting compliance, while UC (15.2 ± 9.4 ng/ml), and ATM (8.1 ± 3.7 ng/ml) in most cases are barely detectable, and diminish over time in the stored samples. The best correlation with IPA (r2 = 0.847) was observed for active metabolite, followed by unchanged clopidogrel (r2 = 0.602), and finally inactive metabolite (r2 = 0.529). The predictive value for noncompliance was also high for inactive metabolite (c-statistic = 0.911).

Conclusions

Therapy with clopidogrel is associated with double-digit underestimated risks for noncompliance, especially in stroke survivors, supporting the hypothesis that lack of IPA, and clopidogrel “resistance” are attributed to hidden noncompliance. Plasma ICM, but not UC, or ATM is a useful marker to monitor compliance to clopidogrel in registries and clinical trials.

Section snippets

Patients

This analysis represents a cohort of patients with CAD and ischemic stroke treated with clopidogrel. Patients were pooled from multiple databases yielded from 8 cardiology and 4 poststroke protocols, had their platelets tested pre and post clopidogrel therapy for the IPA determination, and were available for follow-up with regard to compliance assessment. The primary study protocols were approved by the various institutional review boards and performed at the different outpatient clinics and/or

Results

The demographics and clinical characteristics in the combined dataset in patients with CAD and after ischemic stroke are presented in Table I.

The age and gender were not distributed evenly between groups. Patients with CAD were younger and more often males. There was a high prevalence of African Americans in the poststroke group when compared with the predominantly white CAD cohort. The distribution of risk factors was also different, when patients with CAD exhibited more frequent family

Discussion

This study, composed of a large mixed population base of patients with CAD and postischemic stroke patients, demonstrates that (a) potential compliance violation with regard to clopidogrel therapy may be reliably detected by measuring plasma level of inactive carboxyl metabolite; (b) noncompliance in the outpatient setting may be associated with inadequate response after clopidogrel and reduced IPA; (c) noncompliance rates are double digit but especially high postischemic stroke; (d) among the

Disclosures

The primary studies were supported in part by the Sanofi-BMS Partnership, Boehringer Ingelheim, Novartis, AtheroGenics, and Johnson and Johnson. The secondary analysis was supported by the Sanofi-BMS Partnership. The sponsors had no role in study design, data collection, data analyses, interpretation of results, or manuscript writing.

Acknowledgements

We thank all the clinical coordinators and laboratory personnel for their outstanding effort.

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