Effects of CYP2C19 Genotype on Outcomes of Clopidogrel Treatment
I have to question the conclusions drawn in this study. The number of patients found to have variant alleles does not compute. Of the 5059 patients genotyped, only 25.5% had a variant allele including those patients the authors categorized as unknown. This is the lowest percentage in any large clopidogrel CYP2C19 study to date as outlined in the table below. Some of these studies also excluded patients of Asian and African descent with a higher number of variations so that doesn’t explain the discrepancy. This naturally leads one to question why the tested population had a lower percentage of patients with variants. Patients in the Active A and Cure trials were originally enrolled four to ten years ago. It is likely the results of this study are skewed because a number of patients from the original studies with CYP2C19 variations were given clopidogrel, and failed to respond. Numerous studies and a meta-analysis have confirmed that reduced CYP2C19 function is linked to excess mortality, so many non-responders were eliminated from the patient population. If anything, this study confirms that patients with variant alleles are at increased risk, otherwise where did they go?
|Title||% with variant||MACE in CYP2C19 variants||MACE in CYP2C19 wt|
|Effects of CYP2C19 Genotype on Outcomes of Clopidogrel Treatment||25.55%||10.40%||11.10%|
|Genetic Determinants of Response to Clopidogrel and Cardiovascular Events||28.76%||21.5 % PMs||13.30%|
|Cytochrome P-450 Polymorphisms
and Response to Clopidogrel
|Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents||30.74%||3.30%||2.10%|
|Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy||29.52%||20.90%||10%|
His response was as follows:
Thank you for your interest in our manuscript. We believe our allele frequencies to be in line with other reports given the expected random fluctuation in frequency estimates. For example, the very large PLATO genetics study (Lancet 2010) reported a frequency of ~26% for loss-of-function carriers. Estimates are likely to fluctuate in smaller studies because of the play of chance. CURE and ACTIVE are double-blind randomized prospective studies and our analysis was performed on a intent-to-treat basis. We therefore feel unlikely that selective censoring of loss-of-function carriers explain these results.
My thoughts on his response:
Actaully, the Plato study reported a frequency of 26.96% for loss-of-function carriers- lower than any other large-scale study to date, but still much higher than 25.55%.
Are there any biostatiticians or other experts reading this or someone that can tell me what reasonable ranges are? In a purely Caucasion population, I would expect a range from 27-29%, higher if other ethnicities were included in the study. I am not saying I am right- I am just wondering if any experts out there can tell me what a reasonable variance would be.