Clopidogrel resistance
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Synonyms: Clopidogrel non-responders, clopidogrel hyporesponders, clopidogrel non-responsiveness, clopidogrel hyporesponsiveness
Overview
Administration of the same dose of a drug to all patients has the advantages of simplicity and ease of use. However, data regarding the variability in platelet inhibition across patients highlights the potential importance of tailoring the antiplatelet or dose of an antiplatelet to the pharmacogenomic response of the patient. Patients who do not achieve adequate inhibition in response to a dose of clopidogrel are variably termed “Clopidogrel non-responders” or “Clopidogrel hyporesponders”. This chapter reviews the underlying etiology and clinical relevance of clopidogrel non-responsiveness.
Definitions of Clopidogrel Non Responsiveness
There are multiple definitions of clopidogrel non-responsiveness:
It should also be noted that the degree of non-responsiveness will also vary depending upon the timing following clopidogrel administration that responsiveness is tested. For instance, Gurbel et al have shown that using the same assay and the same definition, at 2 hours following clopidogrel administration, the rate of non-responsiveness was 60%; by one day the number was 33%, and by one month the number was 15%. Thus, non-responsiveness may vary depending upon the degree of activation of the platelets themselves. As the platelets become less activated following an acute coronary syndrome episode, the rate of non-responsiveness may be lower. This variability in platelet activation and variability in non-responsiveness raises important questions regarding the potential differences in the optimal acute dose and the optimal chronic dose of clopidogrel and other thienopyridines.
Association of Clopidogrel Non-Responsiveness with Adverse Clinical Outcomes
There are a large number of studies associating clopidogrel non-responsiveness with adverse outcomes:
Is there a Threshold Effect to Efficacy or are Clinical Outcomes Improved with Higher and Higher Doses (a Continuous Relationship to Clinical Outcomes)
One unresolved question is whether there is a “threshold effect” whereby clinical outcomes are not further improved above a certain level of platelet inhibition, or alternatively whether clinical outcomes are further improved with higher and higher doses in which case there is a “continuous variable” relationship between platelet inhibition and clinical outcomes. Data supporting a potential threshold effect comes from Gurbel et al. When data regarding the relationship between stent thrombosis and clinical outcomes was plotted as a cumulative distribution function rather than a bell curve, it was noted that stent thrombosis was infrequent above % inhibition.
The Genetic Basis for Clopidogrel Hyporesponsiveness
The cyp 2c19 allele has been postulated to be related to the ability to metabolize clopidogrel. Simon et al have demonstrated that those patients who carry either one or two alleles that reduce the ability to metabolize clopidogrel are at higher risk of adverse clinical outcomes compared to those patients in who tow alleles that code for normal clopidogrel metabolism.
Inhibition of Metabolism by Co-Ingestion of Other Drugs
Statins
Statins have been found to interfere with the generation of clopidogrel’s active metabolite. One statin that does not interfere with clopidogrel metabolism is pravastatin. Non-randomized data from clinical trials have not confirmed a higher risk of adverse outcomes among patients co-ingesting statins in addition to clopidogrel versus those treated with clopidogrel alone.
Omeprazole and Proton Pump Inhibitors
Clinical Utility of Point of Care Testing Versus Genetic Testing
In so far as point of care testing results are more readily available, these may be a more suitable choice for use in clinical practice as compared to genetic testing. Furthermore, there may be mechanisms other than variability in metabolism that account for differences in response to clopidogrel which are assessed by point of care tests and not by genetic testing.
Gold Standrad Tests of Clopidogrel Responsiveness
Light transmittance aggregometry (LTA): This is a laboratory based study (not a bedside test) that evaluates the aggregation or clumping of platelets based upon the turbidity (how much light is transmitted through) a test tube. This test is capable of evaluating platelet aggregation in response to not only thienopyridines, but also aspirin and glycoprotein IIbIIIa inhibitors. [1]
Point of Care Devices
References
- ↑ Wang T et al. Eur Heart J. 2006;27:647-654.