October 11, 2010
Genomics and effectiveness of Plavix or Effient
I received the following question via email:
I got my genomics testing. But it bugs me how little the DTC genomics company tells you about how to use the information or whether it matters. For example, the DTC genomics company says I am CYP2C19*1/*17. And they say that my response to Plavix should be ‘typical’. What would the alternatives be, besides ‘typical’? Would people with those other genotypes have to stop using Plavix, or use a different dose, or what?
The experience you describe is frustrating and all-too-common. It mostly likely happens because the DTC genomics companies don’t have the staff to create and publish detailed decision-support interpretations for all of the SNPs for which there is enough published info to do it. In some instances, the recent U.S. FDA actions (to require regulatory filings and clearance/approval) may deter the DTC genomics companies from creating and publishing them, because it would cost too much. The result is that, in the short run, you can “do-it-yourself” (DIY).
Clopidogrel (Plavix™) and prasugrel (Effient™) decrease the morbidity and mortality associated with several cardiovascular diseases. But these drugs are not active until they are metabolized to an active compound by the cytochrome P450 (CYP) enzymes in your liver. Differences in activation cause inter-individual variability in response to these drugs. Drug interactions with and genetic variation in CYP2C19 and CYP3A4/5 enzymes have been implicated in decreased activation. In addition, polymorphisms in the genes encoding P-glycoprotein (a drug transporter) and platelet purinergic receptor P2Y12 (the active site for these GpIIbIIIa inhibitor medicines) have been studied for their role in clot prevention and bleeding.
All three of the big DTC genomics companies’ advice on Plavix pharmacogenomics neglect to include the effect of the 3435C>T SNP in the ABCB1 transporter gene. The homozygous ‘AA’ version at rs1045642 affects more than 20% of Caucasians and Asians and about 2% of people of African descent. That’s a far more common cause for ineffectiveness of oral GPIIbIIIa inhibitor medications like Plavix or Effient than the polymorphisms in the CYP2C19 liver enzyme. So any reasonably comprehensive predictive model for Plavix dose-response really needs to include ABCB1 3435C>T genotype.
U.S. FDA has required drug manufacturers to amend their labels to advise that CYP2C19 genotyping can help to personalize the dosing of these medications and to anticipate which patients the drug will be ineffective for. But the routine genotyping for CYP2C19 or ABCB1 polymorphisms in order to predict GpIIbIIIa responsiveness has so far not been mandated, because logistics and cost issues would arise were the testing advocated on a large-scale population basis. But in your case, you’ve already paid for the test out of your own pocket.
To respond to your question, I retrieved the recent medical research literature on ABCB1 and CYP2C19, extracted information from those articles to create a simple logistic regression statistical model, and put that equation into an Excel spreadsheet that you can download and play with to see how it works (link below).
CYP2C19*1 is the “normal” version of the enzyme. Many of the other versions of the enzyme have decreased activity and if you are homozygous for one of them (or if you are heterozygous for 2 of them) very little of the Plavix™ will get converted into the active form. People with those versions have blood platelets that will stay about as sticky and clot-prone as they ever were, and they won’t get the intended benefit from taking the drug. The dose may need to be increased, or another drug may need to be added or substituted in order to get the blood-thinning, clot-preventing benefit.
But CYP2C19*17 is a version that has higher-than-normal enzyme activity, and so more Plavix™ gets converted to its active form. Your haplotype is *1/*17. You have only one copy of the *17 allele. But people who are *17/*17 may be so much more efficient at converting Plavix™ to the active form that they would have increased risk of bleeding on a normal Plavix™ dose, or if they take Plavix™ with aspirin or some other blood thinner.
You have an ‘AA’ genotype at the ABCB1 3435C>T SNP, and that will cause you to have a response like an ‘intermediate metabolizer’. Instead of having a ‘typical’ response like your DTC genomics company suggested, it is likely that you will have limited benefit from the Plavix™, unless the dose is adjusted or aspirin or another medication is added. You can print this blog post and the spreadsheet and articles and take them to your next doctor visit to discuss with your doctor.
[NOTE: The text presented on this page is not a substitute for professional medical advice. It is for your information only.]
de Caterina R, et al. Mortality predictors and effects of antithrombotic therapies in atrial fibrillation: insights from ACTIVE-W. Eur Heart J. 2010;31:2133-40.
Mega J, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Aug 27. [Epub ahead of print]
Momary K, et al. Genetic causes of clopidogrel nonresponsiveness: which ones really count? Pharmacotherapy. 2010;30:265-74.
Tiroch K, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. 2010;160:506-12.
Wallentin L, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Aug 27. [Epub ahead of print]