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No association found between CYP2C19 genotype, CV events
Holmes MV. JAMA. 2011;306:2704-2714.
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Results of a systemic review and meta-analysis of 32 studies demonstrated an association between CYP2C19 genotype and sensitivity to clopidogrel, but no significant association between genotype and CV events.
The FDA recently recommended that physicians consider CYP2C19 genotyping before prescribing clopidogrel, but these findings appear to support the position of the American Heart Association and American College of Cardiologists. Those organizations argue that the evidence is insufficient to support genotype testing.
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The studies reviewed included 42,016 patients who reported 3,545 CVD events, 579 stent thromboses and 1,413 bleeding events. Six studies were randomized trials and the remaining 26 reported those exposed to clopidogrel.
In treatment-only analysis, those with at least one CYP2C19 allele associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk for bleeding (RR=0.84; 95% CI, 0.75-0.94) and an absolute risk reduction of five to eight events per 1,000 population. Those patients were also at higher risk for CVD events (RR=1.18; 95% CI, 1.09-1.28) with an absolute risk increased of eight to 12 events per 1,000 population.
Researchers found evidence of small study bias and determined that the point estimate was attenuated (RR=0.97; 95% CI, 0.86-1.09) when analyses were restricted to studies with a minimum of 200 events.
In the effect modification studies, CYP2C19 genotype was not associated with improved incidence of major bleeding (RR=1.99; 95% CI, 1.31-3.02) compared with placebo, nor improved incidence of major CV disease events (0.78; 95% CI, 0.69-0.89).
In an accompanying editorial, Steven E. Nissen, MD, chairman of the department of CV medicine at the Cleveland Clinic Foundation and Cardiology Today Editorial Board member, wrote that the FDA was guilty of “irrational exuberance” and developed unrealistic expectations for the effectiveness of genotyping for clopidogrel. Clopidogrel must be studied in a large, randomized controlled trial to properly assess the drug’s pharmacogenomic potential.
“In the absence of such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution,” Nissen wrote. “It is still likely that pharmacogenomics has a bright future in cardiovascular medicine, but the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies. Overzealous adoption based on limited biochemical data does not serve the public interest.”
Disclosure: Several researchers report financial involvement with companies. Dr. Nissen reports no relevant financial disclosures.
Part of the hesitancy regarding the AHA/ACC statement is that there are not randomized controlled clinical trial data showing that guiding therapy based on genotype leads to different outcomes. This is true, although such trials are currently planned or underway. However, there are many examples in clinical practice in which we use information to guide therapy without randomized controlled trial data. Adjusting doses based on renal function is an example that is well accepted for many drugs across the clinical spectrum, but we don't require randomized clinical trial data to accept that such an approach is reasonable and logical. Some believe the genetic data fall in this realm, ie, it is pharmacologically logical and the information can be helpful. Others believe you must await randomized controlled trial data.
The other part of the controversy is that if one looks across the board at the clopidogrel-CYP2C19 data, it is a bit confusing. Some studies suggest substantial risk based on genotype, others do not. However, when one focuses on the participants in the trial and why they are being treated with clopidogrel, the picture that emerges is that the risk for the CYP2C19 loss of function genotype parallels the potential benefit from clopidogrel. In other words, those where the population benefit is relatively small appear to have less risk association with a loss of function genotype than those who accrue very large benefit from clopidogrel (namely, those who are post-PCI). The data, even in the JAMA meta-analysis, support that post-PCI patients are at increased risk with carriage of CYP2C19 loss of function alleles. This is particularly true for risk for stent thrombosis, where various meta-analyses have placed the risk between a 75% to 350% increased risk.
These data add to the interpretation that the patients with lower potential benefit from clopidogrel do not accrue as much risk with the genotype. It is important to point out, however, that the JAMA meta-analysis included a clinical trial in patients with atrial fibrillation (an indication where the drug is rarely, if ever, used) and included a clinical trial where clopidogrel was not better than placebo. Inclusion of these low benefit and no benefit populations, as it relates to clopidogrel efficacy, cannot help but reduce the ability to observe an effect of genotype.
People are probably most interested in seeing the results of the randomized controlled trials that test the impact of guiding therapy with genotype.
– Julie A. Johnson, PharmD
Distinguished
Professor of Pharmacy and Medicine
Director, Center for
Pharmacogenomics
University of Florida College of Pharmacy, Gainesville
Disclosure: Dr. Johnson reports no relevant financial disclosures.
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