Topol vs Gurbel: experts split on routine genotyping for DAPT

Routine genotyping to guide dual-antiplatelet therapy (DAPT) seems like a great idea. After all, argue Damani and Topol in a Viewpoint in JACC, the arguments are overwhelming, and the consequences of not rushing to adopt the new technique are dire.

They write that loss-of-function and gain-of-function variants of CYP2c19 are extremely common, and are “the root cause of adverse cardiovascular events during clopidogrel treatment.” Further, even though prasugrel and ticagrelor appear to be superior to clopidogrel, the benefit was likely caused by patients who were taking clopidogrel “who harbored resistance alleles.”

They continue: “Many experts will continue to call for results from randomized prospective trials before individualizing antiplatelet therapy on the basis of CYP2C19 carrier status, despite the overwhelming evidence presented here. This doggedness represents a false premise for a number of reasons and denies current patients state-of-the-art care. …we cannot afford to wait years for results from these trials that to date have yet to be initiated. In the interim, we should implement all potential interventions to help prevent the catastrophic outcomes of stent thrombosis and death in the tens of thousands of patients currently at risk.”

In response to one alternative, platelet function tests, they write that “the predictive capacities of these tests were modest compared with genotyping.” Genotyping, they conclude, “represents the prototype of individualized medicine for the future.”

On the other hand…

In an accompanying commentary, Paul Gurbel and colleagues reject the claim for “overwhelming evidence” to support routine genotyping. Pointing out something already mentioned by Damani and Topol, they note that “there has not been a single, adequately powered prospective trial with clinical end points performed to support” routine genotyping. In fact, they write, no study has yet demonstrated a connection between genotype and adverse clinical outcomes.

Further, even if genotyping is valid, it is possible that only patients who are homozygous for certain alleles may be at increased risk. In addition, there may well be several or even many gene variants that are still unknown and therefore can not now be tested. Outside of genetics, Gurbel and colleagues note a wide number of factors that can influence clopidogrel response, including outside factors, such as PPIs, lipophilic statins, calcium-channel blockers, caffeine, St. John’s wort, smoking, and warfarin, and internal factors, like diabetes and BMI.

Gurbel et al conclude that “the safety and efficacy of altering therapy in response to genotypic or phenotypic testing are entirely unknown.” They largely agree with the suggestion by Damani and Topol that the combination of genotyping and platelet function tests may ultimately be the best solution, but “ultimately, prospective randomized clinical trials will be needed to test specific personalized antiplatelet algorithms to provide the evidence base necessary for widespread adoption into clinical practice.”

Comments

  1. Dr.Dubrawsky says

    Is phenotyping and genotyping good for the individual and the masses in health care?Maybe(Yet to be prove).
    Is it practical?I doubt.Is it expesive?Absolutly yes.
    On the other side we have the Environment factor.This
    factor change by the second.It involves the Innate Immunology first(The first line of body’s defense).
    Playing with Genomics is nice,but the body doe not have all the time to spare,especially when its own survival depends on it.Time is Life!

  2. addendum says

    Paul A. Gurbel, MD, FACC

    Disclosure: Consulting Fees/Honoraria: Schering-Plough, AstraZeneca, Bayer, Portola, Eli Lilly, Daiichi Sankyo, sanofi-aventis, Significant; Research Grants: Schering-Plough, AstraZeneca, Bayer, Portola, Eli Lilly, Daiichi Sankyo, sanofi-aventis, Significant.

    Disclosure: Dr. Eric J. Topol has disclosed the following relevant financial relationships:
    Served as an advisor or consultant to: sanofi-aventis; HUYA Bioscience International; Daiichi Sankyo, Inc.

  3. As the authors stated, the evidence threshold supporting individualized clopidogrel therapy has been clearly surpassed, as numerous published reports have linked both the CYP2C19 genotype and on-treatment platelet reactivity to clinical outcomes. However, there is still some uncertainty about how best to utilize these testing strategies. Which is more important, the genotype or the phenotype?
    Measurements of platelet reactivity offer a direct measure of the phenotype; that is, the antiplatelet effect of the drug, offering an understanding of the individual patient’s response to antiplatelet therapy. There is heterogeneity in the response to clopidogrel, and platelet function testing provides a direct measure of the combined effect of factors that influence the individual response to clopidogrel. There are several factors that can influence this heterogeneity, including concomitant medications, clinical risk factors, non-compliance, and genetic factors. The effect of many of these factors, including genetic factors, has been characterized by measurements of platelet function, which is a direct measure of the sum of all factors that could influence a patient’s response to clopidogrel. Shuldiner et al (JAMA 2009) found that 12% of the variability in clopidogrel response can be attributed to the CYP2C19 genotype. Studies utilizing platelet function testing have also demonstrated that there are patients that carry the reduced-function CYP2C19*2 allele that respond well to clopidogrel, and there are patients with the wild type CYP2C19 allele that exhibit a poor response to clopidogrel. This indicates that the CYP2C19 genotype is not the sole predictor of the phenotype, which in turn emphasizes that the phenotype cannot be ignored in these patients. In patients whose phenotype indicates that they are not responding adequately to clopidogrel, an understanding of the genotype may be particularly useful.

    In addition, only platelet function testing can measure the actual antiplatelet effect of any change in therapy that may be undertaken. In contrast to genotyping tests, platelet function tests offer fast turnaround time, with results available in minutes, and their cost is only a fraction of that for genotyping.

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