We hypothesized that the benefits of clopidogrel as compared with placebo would be decreased in persons who carry a loss-of-function CYP2C19 allele and increased in carriers of the gain-of-function *17 allele.
What did this team study?
we examined the efficacy and safety of clopidogrel as compared with placebo according to genotype status among patients in two randomized trials: the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which patients with acute coronary syndromes were enrolled, and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A, in which patients with atrial fibrillation were enrolled.
Ok, so they took 2 different populations and bundled them into the same article....
The 2 studies?
CURE -randomized, double-blind, placebo-controlled trial comparing clopidogrel (at a dose of 75 mg per day) with placebo — both in combination with aspirin — among 12,562 patients with acute coronary syndromes without ST-segment elevation.
ACTIVE A - was a randomized, double-blind trial comparing clopidogrel, at a dose of 75 mg per day, with placebo — both in combination with aspirin — for reducing the risk of stroke among patients with atrial fibrillation and at least one additional risk factor for stroke who were not eligible for warfarin therapy.
What did they find? No difference between Poor Metabolizer and Wild Type in secondary and primary outcomes.
So are we wrong with our studies showing 2C19 genotype matters in outcomes?
1st the authors note why.
1. One possible explanation for the divergence between our findings and those of previous studies involving patients with acute coronary syndromes is the difference in the rates of PCI with stenting. Only 18.0% of patients in the CURE population included in our study underwent PCI, and only 14.5% underwent PCI with placement of a stent, as compared with more than 70% in previous studies
2. We cannot definitely exclude the possibility of an interaction in the subgroup of patients who receive stents, particularly those who receive drug-eluting stents, which were not in use at the time of the CURE trial.
3. the ACTIVE A genetic data set contained fewer participants and outcome events than did the CURE data set and therefore had less statistical power.
The ACTIVE A trial to assess the hypothesis was powered at 45% to detect a difference, thus it is a worthless study and should not be included in this analysis.
While I agree that a placebo group may be useful. It is not needed to assess a difference between people using Plavix with normal Plavix metabolism and Poor metabolism. In fact it may even confuse the situation as it introduces further confounding factors not genotyped or phenotyped out.
The authors disagree First, the inclusion of a randomized placebo group in our analyses reduces various sources of confounding, such as potential pleiotropic genetic effects or population stratification.
Well, did they test or assess for pleiotropic genetic effects? No.
Further, by introducing a study COMPLETELY underpowered to observe and eval the hypothesis into this article, it ONLY creates a false image of scientific validity.
The authors disagree Third, we observed consistent benefits of clopidogrel, irrespective of CYP2C19 genotype, in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations.
Again to quote the article
Among patients with atrial fibrillation in ACTIVE A, our study had much lower power (45%) to detect a similar interaction.
So why did they include the POORLY POWERED study?
"in two different patient populations, which validates our findings and suggests that they could be generalizable to other populations." While I laud the effort to have Randomized and Observational versus retrospective efforts. I think we have to be very careful in our study design to make sure
1. We are properly powered to observe differences. 2. That we assess pleoitropic effects, rather than claim to control for them mysteriously.
The Sherpa Says: Why include the second study? It is improperly powered, further the CURE study did not include Drug Eluting Stents! Why? Plavix goes generic in 2011. They did this to save the market......Expect more screwy studies published in NEJM etc. As PGx gains traction, contrarians and Pharm will always fight it.....