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Clopidogrel-treated patients who are genetically predisposed to poorly metabolize the antiplatelet drug are at no greater risk of cardiovascular events than those with a normal genotype, according to a large meta-analysis published in the December 28, 2011, issue of the Journal of the American Medical Association. The findings appear to cast doubt on the wisdom of the US Food and Drug Administration’s (FDA) decision in 2010 to add a ‘black box’ warning to clopidogrel, highlighting a genetic risk and recommending genetic testing.

Investigators led by Michael V. Holmes, MBBS, MSc, of University College London (London, United Kingdom), identified 32 studies involving 42,016 patients that focused on associations of clopidogrel therapy with platelet and/or clinical response to CYP2C19 genotype. The CYP2C19-coded enzyme helps convert the prodrug clopidogrel to its active form.

Twenty-one studies included patients with ACS and 8 included those with stable CHD, while the remaining 3 did not report CHD status. Six studies were randomized trials looking at treatment effect based on CYP2C19 status and the remaining 26 looked at the effects of genotype on platelet reactivity and outcomes only in patients treated with clopidogrel.

Allelic Variants Increase Platelet Reactivity

Among patients receiving 75 mg of clopidogrel daily, those with a loss-of-function allele (*2 through *8) had about half the mean concentration of active metabolite as the overall population. Moreover, in 4 of the randomized treatment-only studies (n = 4,341), there was a per-allele effect of the *2 variant on platelet aggregation.

As for the impact of CYP2C19 genotype on clinical outcomes, a pooled analysis of 22 studies using the treatment-only approach supplemented by data from the clopidogrel-treatment arm of 4 randomized trials (26,251 patients and 2,465 events) showed that patients with any loss-of-function allele had a higher risk of CV events than those with wild-type or gain-of-function alleles (RR 1.18; 95% CI 1.09-1.28).

Size Matters

However, according to the authors, when the studies were stratified by number of events, there was a trend toward no effect in larger studies, consistent with small-study bias. In fact, in the 4 largest studies reporting at least 200 events, the point estimate was attenuated (RR 0.97; 95% CI 0.86-1.09). Among patients with loss-of-function alleles, that translated to an excess event rate of 8 for those with stable CHD and 12 for those with ACS.

Eleven studies involving 10,291 patients provided data that enabled comparison of clinical outcomes in loss-of-function heterozygotes vs. homozygotes. In studies with 100 or more events, the relative risk of loss-of-function heterozygotes was 0.94 (95% CI 0.80-1.10), while that of loss-of-function homozygotes was 1.52 (95% CI 1.04-2.21).

Although stent thrombosis showed the strongest association with CYP2C19 loss-of-function alleles (RR 1.75; 95% CI 1.50-2.03), again a trend toward loss of effect was observed in larger studies (P = 0.08). Assuming an event rate of 18 per 1,000 individuals in the control group, the increased risk translated to 14 excess cases of stent thrombosis.

Not surprisingly, patients who carried a loss-of-function allele had a reduced risk of any bleeding (RR 0.84; 95 % CI 0.75-0.94). Moreover, in meta-regression analyses, CHD status (stable disease vs. ACS), blinding to genotype, and concomitant use of proton pump inhibitors or aspirin did not affect the association of CYP2C19 genotype with CV events (P > 0.09 for all).

No Increased Clinical Risk

The authors conclude that the meta-analysis “does not demonstrate a clinically important association of genotype with cardiovascular outcomes with the possible exception of stent thrombosis.”

Dr. Holmes and colleagues also point out that the potential usefulness of CYP2C19 genotyping is mitigated by the fact that any attempt to individualize clopidogrel dose to optimize treatment response in terms of ischemic events will be offset by increased risk of bleeding. In fact, further analysis showed that an absolute risk reduction of 12 CV events per 1,000 among ACS patients (compared with the expected rate) was paralleled by an absolute risk increase of 8 bleeding events. Thus, the net potential benefit of adjusting drug dosage may be lower than anticipated, they explain.

The investigators acknowledge a number of study limitations:

• Because they used aggregate data, the power to detect differences among subgroups was diminished
• The components of the composite CV endpoints differed across the studies, which may have influenced the summary relative risk
• The inclusion of studies enrolling both stable CHD and ACS patients might have diluted any association with CYP2C19 genotype if the magnitude of the effect was greater in ACS patients

Taming ‘Irrational Exuberance’

In an accompanying editorial, Steven E. Nissen, MD, of the Cleveland Clinic Foundation (Cleveland, OH), portrays the study results as a salutary counterweight to the “irrational exuberance” for genotyping prompted by the FDA’s black box warning on clopidogrel stating that CYP2C19 slow metabolizers were more susceptible to cardiovascular events.

According to Dr. Nissen, overreaction to the FDA initiative was stoked by unrealistic expectations for personalized medicine. Other factors encouraging genetic testing included the positive results of many early studies, which were based on nonclinical surrogate endpoints such as the association between CYP2C19 loss-of-function alleles and clopidogrel active metabolites or platelet reactivity, or both.

Although recent studies and systematic reviews on the issue have been inconsistent, none have been as “thorough and rigorous” as the current report, Dr. Nissen asserts. “A large randomized controlled trial is needed to adequately test the clopidogrel pharmacogenomics hypothesis,” he writes. “In the absence of such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution.”

But in a December 27, 2011, post on his blog, Eric J. Topol, MD, of the Scripps Translational Science Institute (La Jolla, CA), and colleagues counter that the prospect of such a trial is “a fantasy,” since it would require thousands of patients and there is no entity that would support it. “The era of individualized medicine needs to transcend megatrials of populations, which are not only unsustainable but also crowd out the benefits that can be exceptionally important and validated for the individual patient,” they write.

‘Remarkably Misleading’

More importantly, Dr. Topol and colleagues call the current study “remarkably misleading.” Its conclusion, they say, “is directly contradicted by the data presented, showing a significant and highly consistent excess of stent thrombosis in patients with a loss-of-function CYP2C19 allele.”

A “critical flaw” in the current analysis, they assert, is that “no data for a genotype-by-treatment (medical vs. stenting) interaction [were] provided. The analysis includes a large number of patients from trials that had nothing to do with coronary stenting . . . and assess outcomes where the benefit of clopidogrel itself is dubious (eg, [TVR]).” Instead of acknowledging the extensive data that document the risk of stent thrombosis in poor clopidogrel metabolizers, the authors “homogenized the data, resulting in an erroneous and sweeping conclusion.”

 

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Sources:
1. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: A systematic review and meta-analysis. JAMA. 20111;306:2704-2714.

2. Nissen SE. Pharmacogenomics and clopidogrel: Irrational exhuberance? JAMA. 2011;306:2727-2728.

3. Topol, E. An important miscue in clopidogrel pharmacogenomics. Topoblog. http://blogs.theheart.org/topolog/2011/12/27/miscue-in-clopidogrel-pharmacogenomics/. Published December 27, 2011. Accessed January 4, 2012.

 

 

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