Clopidogrel Pharmacogenomics

Jan 13, 2009 19:55 EST


3 new studies, 2 in the New England J of Medicine and one in Lancet on Dec 22 and 23 2008 have shed considerable light of the risk of a common variant of a cytochrome intimately involved withe metabolism of clopidogrel to its active metabolite----what are the implications???



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Your comments
Clopidogrel Pharmacogenomics
# 1 of 7
January 15, 2009 07:48 (EST)
JGB

I'm a 61 y/o retired physician (radiologist) who had CABG x4 about 11 years ago. I have done well (no MI or stroke). I was found to have PlA2 variant so I have been taking clopidigrel. Is there any association of that finding with CYP 2C19? Does ASA help balance the CYP 2C19 allele variant effect? (I take 81mg ASA daily to blunt flushing from Niaspan).

 Also, if one is taking clopidogrel and experienceing the usual easy bruising and prolonged bleeding, does that exclude the cytochrome variant issue?

I think this is a very important topic from a patient's perspective. It seems that ever since clopidogrel arrived on the scene complicated issues have arisen.

# 2 of 7
January 20, 2009 06:15 (EST)
Ron Stalica
I know some Dr's put a post MI patient on Clopidigrel for a year along with other meds. My ? is should patients stay on Clopidigrel permenantly?
# 3 of 7
January 23, 2009 03:59 (EST)
Rob Hillman

In addition to genetic variation, there are several  other factors that can affect clopidogrel's pharmacokinetics and pharmacodynamics (i.e., inhibition of the platelet P2Y12 receptor), including: 1) physical variables (such as weight, BMI),  2) drug-drug interactions, 3) disease associated variables (e.g., acute coronary syndrome), and 4) patient compliance. There are now several publications, the most recent one in Circulation (Dec 31, 2008 online) that demonstrate that suboptimal inhibition of platelet function can result in serious consequences; including stent thrombosis and death in patients who have received drug eluting stents and are taking daily aspirin and 75 mg of Plavix.   

By assessing the functional response of clopidogrel (ultilizing a measurement of platelet aggregation), one would obtain an integrated effect of all the factors cited above, as well as any other currently unrecognized variable that could potenitally impact platelet inhibition.

While measurement of platelet function has traditionally been both technically difficult and time consuming to perform, there is now at least one  FDA-cleared assay that has been validated against standard aggregometry as well as correlated with clinical outcome,  that is rapid, accurate, and easy to perform at the bedside and measures the effect of clopidogrel on platelet function.  

 If indeed platelet inhibition is impaired, further testing (including genetic testing), could be done to determine the specific cause and treat the patient appropriately.  
# 4 of 7
January 23, 2009 04:22 (EST)
Sergio Pinski, MD

Another corollary from the clopidrogel studies is that pro-drugs (ie, drugs that dependent on biotransformation to become active) are in general undesirable. With pro-drugs, you're adding another layer of uncertainty in the relation between administered dose and final pharmacodynamic effect.

 
# 5 of 7
January 26, 2009 09:33 (EST)
Andrés Marino
I believe that more clinical trials are needed at this moment. The great problem is that a coordination does not exist worldwide, and every group does a different trial. Efforts should be coordinated to value the response of these patients with slow metabolism to Clopidogrel's higher doses.
# 6 of 7
January 30, 2009 11:44 (EST)
Killu Sanborn

Very interesting, with huge implications for business as well as the emerging practice of pharmacogenomics-based decisionmaking in prevention and treatment decisions.  - Couple questions: when is FDA expected to make decisions about labeling of Plavix to recommend or require CYP2C19 genotyping, with or without any other tests for aggregation (roughly - 3 months? 6 months? more? any guess would be interesting)?

 If doctors were to start ordering the genotyping to be done, who would be the likely first movers to offer genotyping and other assay services? Are there clear front-runners that are obvious providers of such tests at present, or not? Would pharma companies provide genotyping services if required, or would it be left to Dx companies?

How will information likely be disseminated to docs pre-FDA label decisions? It seems that Prasugrel's label restrictions re excessive bleeding have wounded potential competition. Are similar studies being carried out for Prasugrel's potential pharmacogenomic effects in varied genetic backgrounds?

I am amazed that I have completely missed this news, and that there are not more responses to this post/video. Thank you for putting it out there - this is one of the most interesting news I have heard in a while (of course, I am not a cardiologist but more of a recovering VC and entrepreneur with a soft spot for pharmacogenomics and population genomics technologies).

# 7 of 7
March 6, 2009 04:55 (EST)
Kristine Ashcraft
Great post. Genelex already has cardiologists that are ordering 2C19 testing for clopidogrel. We include access to GeneMedRx cytochrome interaction software with each test to provide physicians with a decision support tool to apply the results.

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Who's talking
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Eric J Topol MD
Director, Scripps Translational Science Institute
The Gary and Mary West Chair of Innovative Medicine
Chief Academic Officer, Scripps Health
La Jolla, CA