Clopidogrel variability - GIFT data puts the brakes on PON1 as a major factor modifying the response to clopidogrel.

A presentation of the GIFT sub-study of GRAVITAS, delivered today at ACC in New Orelans has put a dampner on the PON-1 story building around clopidogrel responsiveness.

Clopidogrel is the most widely used antiplatelet agents and is indicated for use in ACS patients as well as the prevention of ischemic events in patients who have suffered a recent myocardial infarction, recent stroke, or with established peripheral arterial disease.

It is well known to the cardiovascular community that the response to clopidogrel is highly variable however the reason for this variability is not clear. Both genetic and baseline factors have been suggested to represent the underlying cause.

For example body weight and diabetes are known to alter the response to clopidogrel. On the other hand, polymorphisms in the gene encoding an enzyme known as CYP2C19 have also gained much attention over the past year or so in the context of clopidogrel variability.

CYP2C19 is a hepatic enzyme that is responsible for the metabolism of many therapeutic agents; one target agent is clopidogrel.

CYP2C19 is responsible for the conversion of clopidogrel to its active metabolite. Polymorphisms in the CYP2C19 gene, and especially the *2 allele result in much reduced clopidogrel activation. Carriers of two *2 alleles (poor metabolizers) show particularly poor activation. Similarly, certain other therapeutic agents that interact with the CYP2C19 enzyme, such as the proton pump inhibitor omeprazole, have also been reported to reduce clopidogrel activation.

Reduced clopidogrel activation has been related to lower antiplatelet activity and increased risk of ischemic events after percutaneous intervention - the procedure by which stents are placed in the coronary vasculature in patients after a myocardial infarction or those at risk of having one.

The fear that the *2 allele of CYP2C19 may limit the activity of clopiodgrel and increase the risk of stent thrombosis as well as other ischemic events in stented patients has recently lead the FDA to impose a box warning on the Plavix (clopidogrel) label. The warning is that "Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with PLAVIX at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function".

Despite the box warning, CYP2C19 genotype and other known factors account for just a very small part of clopidogrel's variability - in fact less than 20%. One of the big questions is what accounts for the rest? Earlier this year Dutch researchers reported in Nature Medicine that paraoxonase-1 (PON-1) is a major determinant of clopidogrel efficacy - in fact variability in the gene encoding this enzyme (another enzyme responsible for the activation of clopidogrel) was suggested to account for nearly all the variability in clopidogrel response.

The finding, stunning as may have been, has been greeted with emotions ranging from doubt to excitement. The finding was discussed on multiple occasions at this year's ACC meeting in New Orleans, the first big cardiology meeting following the PON-1 announcement.

Dr Matthew Price has however just put a damper on the PON-1 story.

GRAVITAS was a study looking at the ability to compensate for the poor response to clopidogrel in some patients by personalizing the dose of clopidogrel used. This study in itself was negative. Data presented last year at AHA reported that increasing the dose of clopidogrel in poor responders had no effect on clinical outcomes. GIFT was a genetic sub-study of GRAVITAS. Data presented from GIFT this morning reports that PON-1 has absolutely no effect on the response to clopidogrel.

So what next? The contradictory nature of the two reports is intriguing and also perplexing. Replication of the Dutch data could have lead to much improved use of clopidogrel. Explanation of the difference is eagerly awaited. One suggestion that we would like to put forward involves geographical differences in the studies. GRAVITAS was a North American study - the study looking at PON-1 recruited largely European individuals. Whether this difference is important remains to be seen.