This is a February 18, 2014 follow-up from the individual whom I responded to in a January 30 post entitled Clopidogrel Efficacy. I had collaborated with Prof. Bernadette Rodak of Indiana University on the original email to the questioner. Here is the comment (with identification removed):
“I would like to thank you and Prof. Rodak for your response to my question regarding clopidogrel genotyping vs VerifyNow testing. I appreciate the response and am wondering if you could further explain the advantages and drawbacks of the VerifyNow test as I would like to know when a physician may order genotyping vs platelet aggregation testing. Although I have a decent understanding of 2C19 genotyping for Plavix, I was not aware of the study you mentioned from the American Heart Association meeting suggesting genotype guided dosing actually increased the rate risk of thrombotic events including death. How is that? Although I have not seen the results, it seems counter-intuitive that genotype information would put patients at a higher risk. Isn’t that like saying knowing too much about a patient’s physical makeup is bad for their health?
Would you mind providing the name of the two studies you mentioned and I will try to find copies? Thank you very much. PS, I am not one to often correct people, but you mentioned in your email that Effient is administered in its active form, when, in fact, Effient is also a prodrug.”
Thank you for your question and the update on Effient (prasugrel), which is indeed administered as a prodrug. Upon absorption, Effient is rapidly converted to its active metabolite through hydrolysis independent of the CYP2C19 pathway, thus it is not affected by the polymorphisms that slow the conversion of clopidogrel.
The ARCTIC study, conducted in France, contrasted the efficacy and safety for patients whose anti-platelet therapy was monitored using the Accumetrics VerifyNow assay system versus those who were not monitored, and found no difference in outcomes. In fact, for those patients whose therapy was modified in response to the VerifyNow test, there was a trend (that did not rise to the level of statistical significance) implying a slightly worse outcome for those receiving the intervention and subsequent therapeutic modification. The authors did not perform molecular assays and do not attempt to pinpoint a specific source for this trend, though it probably had to do with treatment changes. This trend was not seen in the TRILOGY study, which was conducted worldwide. The outcomes of these studies generated an eloquent blog from Dr. Seth Bilazarian, entitled “Frustrated in Los Angeles.”
Dr. Bilazarian outlines the issues that surround clopidogrel monitoring with reference to patient needs, and nearly everyone associated with the two clinical trial outcomes concludes that monitoring serves no useful purpose, however for those who still prefer to monitor, particularly in special cricumstances, the Accumetrics VerifyNow would be used first, and the molecular assay would be reserved for confirmation of VerifyNow results. I hope this is helpful.
the topic of clopidogrel efficacy has been an
the topic of clopidogrel efficacy has been an interesting topic for quite some time now. Because clopidogrel is metabolized by a very polymorphic pathway (cytochrome P450) hepatic pathway, there has been a suggestion that genotyping may be able to identify the patients who will suffer poor outcomes associated with percutaneous coronary interventions in the form of stent thrombosis. I would refer the readers to the PEGASUS-PCI study by Siller-Matula where genotyping was able to identify only 27% of the patients who expressed the clopidogrel poor responder phenotype. In comparing various platelet function assays (verify-now was not included) it demonstrated that phenotype was more predictive of stent thrombosis than genotyping. I would caution that when reviewing the literature on platelet function testing, there is a bias to assume that all testing platforms are equal when in fact the clinical community has yet to recognize that some platforms may perform better than others. Each test is measuring platelet function from a slightly different perspective. For example, the verify-now is detecting free floating platelet aggregates, whereas the Multiplate is measuring platelet aggregation on a surface (electrode)to which the platelet aggregates must attach. In closing, I would concur with your suggestion that a platelet function test be performed as a screen and if a poor responder is identified, a genetic test be performed to exclude a potential cause for the poor response.