To the Editor: The systematic review by Drs McGettigan and Henry1 provides a timely summary of the observational studies investigating the cardiovascular risk associated with nonsteroidal anti-inflammatory drugs. Nonetheless, as pointed out in the accompanying editorial by Dr Graham,2 data on the cardiovascular risk of celecoxib remain in conflict. Our case-control study,3 which was published too recently to be included in the meta-analysis, found a significantly increased risk of acute myocardial infarction associated with rofecoxib and celecoxib, as well as the newer etoricoxib. These findings are at odds with the conclusion of McGettigan and Henry that celecoxib in commonly used doses may not increase cardiovascular risk.
There is important heterogeneity in the observational studies that may have contributed to the variations in findings with respect to the risk with celecoxib. While differences in patterns of drug utilization and duration, population comorbidity, and reference groups could have played a role, we believe that genetic variations may have had a significant influence on this heterogeneity. Four of the 5 observational studies reporting the highest point estimates for celecoxib (3 from Table 3 in McGettigan and Henry and our study) are from Europe, with relative risks of 1.21 to 2.57. However, the 5 studies reporting the lowest point estimates in Table 3 were all performed within the United States or Canada, with relative risks of 0.43 to 0.96.
Celecoxib is mainly metabolized by cytochrome CYP2C9,4 which shows large genetic variability. The proportion of carriers of mutant CYP2C9 alleles varies substantially among different populations.5 The low-function CYP2C9*3 allele occurs with a frequency of up to 2.0% in black individuals from the United States, whereas in white individuals from the US, allele frequencies of up to 15.3% have been reported.5 Homozygosity for CYP2C9*3 may cause as much as a 9-fold higher celecoxib exposure (measured by the area under the plasma concentration–time curve) and a 3- to 6-fold higher peak concentration compared with the wild type genotype.6 Given that the cardiovascular risk of celecoxib seems to be dose dependent,2 poor metabolizers of CYP2C9 treated with common doses of celecoxib might have an inherently increased risk of cardiovascular events. A pooled re-analysis of the available clinical trial data of celecoxib that includes genotyping results of CYP2C9 may provide important insight into this question.
Financial Disclosures: Dr Suissa reports that he received grants for being an external consultant for Merck in preparation of the FDA COX-2 Advisory Committee Meeting. Drs Andersohn and Garbe report no disclosures.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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