December 27th, 2011

Clopidogrel Testing Comes Under Fire

The phenomenon of clopidogrel resistance has been much discussed, but no consensus has emerged about the best, or any, response to the problem. Now a review published in JAMA finds no clinically relevant relationship between the CYP2C19 genotype  and cardiovascular events.

Michael Holmes and colleagues performed a meta-analysis of 32 studies involving CYP 2C19 genotyping and more than 42,000 patients. In the observational studies of patients receiving clopidogrel, the investigators found an association between CYP 2C19 alleles and outcomes. However, they also found evidence of small-study bias, and when only larger studies were included the association was much diminished. In randomized trials, the clopidogrel genotype had no effect on outcome.

In an accompanying editorial, Steven Nissen writes that attempts to integrate clopidogrel testing in clinical practice, including a boxed warning about clopidogrel resistance from the FDA, have been premature:

No matter how promising, pharmacogenetic approaches to treatment must withstand the same scrutiny required of all therapeutic advances — careful evaluation through well-designed randomized clinical trials.

In the absence of a large randomized controlled trial demonstrating the benefits of the clopidogrel pharmacogenomics, writes Nissen, “physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution.”

[EDITOR’S NOTE: We’ve closed comments on this post to focus the discussion over at this related piece by David Hillis and Rick Lange. Please join the discussion there!]

2 Responses to “Clopidogrel Testing Comes Under Fire”

  1. Joel Wolkowicz, MDCM says:

    Wouldn’t it have nice if the FDA had the same concept?

    Competing interests pertaining specifically to this post, comment, or both:

  2. What genotype defines a poor metabolizer? Diploidy protects humans against the deleterious effects of heterozygous mutations, particularly in classical enzyme systems, in which a single functional copy is typically more than sufficient to adequately catalyze a biochemical reaction. So, to some extent, the study design comparing those with one or more loss-of-function CYP2C19 alleles was a straw man. My main concern, as a geneticist, would have been those with 2 loss-of-function alleles, which is a rare genetic category (for which even the meta-analysis was underpowered). However, the results of the Holmes et al JAMA meta-analysis reinforced my concern as follows:

    “By comparison, the RR of CVD events among carriers of 2 loss-of-function alleles was 3.75 (95% CI, 2.40-5.86; I2=8%; 95% CI, 0%-73%) for fixed effects and 3.76 (95% CI, 2.34-6.06) for random-effects modeling in studies with fewer than 100 cases and 1.52 (95% CI, 1.04-2.21; I2=51%; 95% CI, 0%-86%) for fixed effects and 1.45 (95% CI, 0.82-
    2.56) for random-effects modeling in studies with 100 or more cases.”

    In their meta-analysis, Holmes et al. clearly demonstrated that the clinical utility of CYP2C19 genotyping has not been established. However, the authors did not comment at all in their Discussion on patients with 2 loss-of-function alleles. This topic requires further research, and the take-home message for cardiologists should not be that CYP2C19 genotype “doesn’t matter.” It’s important research in progress — too soon for strong opinions, far too soon for an FDA black box warning that encourages clinicians to order genetic tests that even a geneticist won’t be able to interpret.

    Competing interests pertaining specifically to this post, comment, or both: