Carrying one or two reduced-function CYP2C19 alleles is associated with an increased risk of major adverse cardiovascular events in people undergoing percutaneous coronary intervention and treated with clopidogrel
- 1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 2Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Correspondence to Alan R Shuldiner
Division of Endocrinology, Diabetes and Nutrition, 660 West Redwood Street, Room 494, Baltimore, MD 21201, USA;
The antiplatelet effect of clopidogrel varies among users as measured by ex vivo platelet function studies and clinical outcomes. Studies have identified common reduced-function variants in the cytochrome P450 enzyme gene, CYP2C19, that are associated with clopidogrel responsiveness. The fully functional form of the gene, designated CYP2C19*1, metabolises clopidogrel from its native prodrug state to its active antiplatelet metabolite more efficiently than CYP2C19*2, found commonly in Caucasians, African Americans and Asians, and CYP2C9*3, common only in Asians. Individuals carrying one of these reduced-function alleles are intermediate metabolisers, whereas those carrying two reduced-function alleles are poor metabolisers. In patients on clopidogrel, these variants have been associated with poorer clinical outcomes in many studies, although not all have shown an effect, particularly in patients with one reduced-function allele.
Relevant studies for this meta-analysis were gathered with a combination of computer database searches and expert consultation. Of the 31 possible studies, 9 met the inclusion criteria of patients predominantly invasively managed with percutaneous coronary intervention (PCI) and with clinical end points reported. Participants were classified in an additive fashion as carriers of 0, 1, or 2 reduced-function alleles including CYP2C19*2, *3 or more rare *4, *5 and *8. End points included cardiovascular death, myocardial infarction, ischaemic stroke and a composite of these. The HRs and 95% CIs for each study were combined using a random-effects model with weighting based on inverse variance. A time-to-event analysis was also performed, categorised by 0–30 days and 31 days to end of follow-up. Heterogeneity across studies was described with the Cochran Q statistic and I2.
The nine included studies supplied composite outcome data on 9685 patients with average age 64.2 years. Of which, 74.4% were male, 95.8% were White and 91.3% underwent PCI. At least one reduced-function allele was present in 2544 (26.3%) and 2 in 218 (2.2%). Median follow-up time ranged from 30 to 445 days, depending on study. The composite end point occurred in 863 (8.9%) patients. For carriers of one or two copies of a reduced-function allele, the summary HR was 1.57 (95% CI 1.13 to 2.16). A gene-dose effect was observed. The HR was 1.55 (95% CI 1.11 to 2.17) in patients with one reduced-function allele and 1.76 (95% CI 1.24 to 2.50) in those with two reduced-function alleles. Data on stent thrombosis were available for 5894 patients of which 84 had such an event. The summary HRs for 1 or 2, only 1 and only 2 reduced-function alleles were 2.81 (1.81 to 4.37), 2.67 (1.69 to 4.22) and 3.97 (1.75 to 9.02), respectively. Time-to-event analysis found the increased risk of the composite end point and stent thrombosis in reduced-function carriers was similar in the first 30 days, as it was in the period from 31 days to the end of follow-up. Heterogeneity was detected only in the composite endpoint comparison of carriers of 1 reduced-function allele. Excluding two studies, both of which tended to have a lower proportion of patients who underwent PCI, resolved the heterogeneity but did not significantly change the HR.
This meta-analysis strengthens evidence of the pharmacogenetic basis of variable clopidogrel response for patients undergoing PCI. As trials employing primarily a conservative treatment strategy such as PLATlet inhibition and patient Outcomes (PLATO)1 and Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE)2 were excluded, the contribution of CYP2C19 variants to clopidogrel resistance cannot be generalised to patients on clopidogrel therapy for indications other than PCI. Although all meta-analyses are subject to publication bias of positive findings, it can be argued that publishing negative studies to debunk uncertain findings is of similar impact to positive results and likely to be in print in this case.
Of note, this analysis did not directly address the concurrent use of proton pump inhibitors, as some inhibit CYP2C19 activity, and conflicting data exist regarding contribution to clopidogrel non-response. Also not included were the gain-function allele CYP2C19*17 and variants in other genes with some evidence of contribution to clopidogrel response including ABCB1 and PON1.
Given the high frequency of reduced-function CYP2C19 alleles across ancestries and the non-trivial increase in cardiovascular event risk in those carrying one or two copies of these reduced-function alleles, incorporating genotype into clinical decision making could have an important impact on outcomes. In March 2010, the Food and Drug Administration mandated a boxed warning on the label of clopidogrel which stated, “Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.” This meta-analysis would suggest that these recommendations also apply to intermediate metabolisers, at least in the setting of PCI. In addition, demonstration in this meta-analysis of an impact of CYP2C19 genotype in the early post-PCI period supports genetic testing with a rapid turnaround time or pre-emptively in patients with a high likelihood of receiving a future PCI.
Although the boxed warning makes no specific recommendations for alternative treatment, other antiplatelet agents such as prasugrel or ticagrelor (approved for use in the European Union) are compelling alternative treatments in that they do not require activation by CYP2C19. Clinical judgement for each patient will be necessary to weigh the potential benefits of these alternative therapies with increased risk of bleeding (prasugrel), less convenient twice-daily dosing of reversible P2Y12 antagonists (ticagrelor) and the cost differential as clopidogrel nears the end of its patent and will be available in generic form. Another possible option is increased daily dose of clopidogrel for carriers of reduced-function alleles; however, the current literature is mixed with regard to efficacy of this alternative.
As noted in the recently published American College of Cardiology Foundation/American Heart Association Clopidogrel clinical alert consensus statement,3 there is a need for randomised trials of genotype-guided therapies to inform alternative therapeutic strategies for carriers of CYP2C19 reduced-function alleles. In the absence of these trials, well-executed meta-analyses such as this study are integral to evaluating the evidence and advancing inertia in implementing evidence-based practice.
Competing interests ARS receives grant support from the National Institutes of Health to study the pharmacogenomics of antiplatelet agents. ARS is also a consultant for Bristol-Myers Squibb/Sanofi-aventis. AHR and JTD have no competing interests.