December 30th, 2011
CYP2C19 Genotyping: Down For The Count?
Richard A. Lange, MD, MBA and L. David Hillis, MD
The controversy over the use of genetic testing to guide antiplatelet therapy reminds us of a WWF (Worldwide Wrestling Federation) tag team match.
What we agree upon (the match rules):
Clopidogrel is a prodrug activated by several enzymes, including CYP2C19, and common genetic variations alter CYP2C19 activity.
Here’s where the wrestling match begins:
Are the CYP2C19 genetic variants associated with reduced enzyme function clinically important?
Should we be genotyping patients to identify those with reduced clopidogrel responsiveness?
The heavyweights weigh in…
The FDA: “Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.”
The ACC and AHA: “The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.”
Now for the fun…
Authors of the most recent meta-analysis involving 42,016 patients in 32 studies conclude: “This study identified no clinically significant interaction of CYP2C19 genotype with the association of clopidogrel therapy and cardiovascular events.”
Steven Nissen (in an accompanying editorial) asserts: “It now appears that the FDA warning reflected a case of “irrational exuberance…”
Topol and friends enter the ring, calling the meta-analysis misleading: “A critical flaw of the analysis by Holmes and colleagues was the lack of testing for heterogeneity among patients who underwent stenting as compared with those treated medically….The analysis includes a large number of patients from trials that had nothing to do with coronary stenting (eg, atrial fibrillation or STEMI patients treated with thrombolytics) and assess outcomes where the benefit of clopidogrel itself is dubious (eg, target vessel revascularization).”
Lange on the “slow-mo” replay: Stratified by number of events per study, the meta-analysis by Holmes et al. showed that the association between CYP2C19 genetic variants linked to reduced enzyme function and risk for stent thrombosis was as follows:
|
Number of events per study |
Studies (No.) |
Relative Risk of Stent Thrombosis |
Confidence Intervals |
| < 100 events |
12 |
2.01 |
(1.60-2.53) |
| 100-199 events |
2 |
1.54 |
(1.26-1.88) |
| All studies |
14 |
1.75 |
(1.50-2.03) |
How do we score the fight? It’s a draw!! The CYP2C19 genetic variants associated with reduced enzyme function are clinically important in patients who receive a drug-eluting stent (i.e., associated with increased risk for stent thrombosis), but we shouldn’t be genotyping patients until we have an effective (and safe) alternative therapy.
Do you feel comfortable jumping in the ring?
Should we genotype patients who undergo stenting?
Why or why not?
3 Responses to “CYP2C19 Genotyping: Down For The Count?”
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The CYP2C19 story appears to be similar to many situations where genetic testing may be available, but the actual adverse outcome of interest (stent thrombosis) is a culmination of numerous variables (age, BMI, inflammation, medication non-compliance, etc). Some of these may be measurable, but most others are beyond the scope of laboratory testing. I think that choosing an anti-platelet agent based on a genetic test in the absence of definitive data, despite several large studies, and not paying heed to the individual patient, may deliver, ironically, the exact opposite of the promise of ‘personalized medicine’.
Here is how I score Round 1:
Evidence-based medicine: 1
Genetic “determinism”: 0
Are the CYP2C19 genetic variants associated with reduced enzyme function clinically important?
The key point here is “clinically important”. Although CYP2C19*2 genotype is statistically significantly associated with the risk of stent thrombosis, stronger associations (HR exceeding at least 10 or ideally 100) are required for clinical utility in individual patients. Furthermore, information regarding important measures such as discrimination, calibration, and reclassification that are needed for a more refined assessment of the prognostic utility of genetic testing are currently lacking.
Should we be genotyping patients to identify those with reduced clopidogrel responsiveness?
When viewed through the cold lens of evidence-based medicine, there remains insufficient justification for ROUTINE use of genetic testing in clinical practice at the present time. However, it might be justified in high-risk patients where, in the judgment of the physician, the consequences of stent thrombosis could be catastrophic. In case of a positive test, I would first consider avoiding stenting. If that is not possible, I would then consider alternative therapies such as prasugrel or ticagrelor after a full discussion of their benefit-risk balance with the patient.
Competing interests pertaining specifically to this post, comment, or both:
I was a member of the Writing Committee for the ACC/AHA Clopidogrel Clinical Alert in response to the FDA boxed warning.
What genotype defines a poor metabolizer? Diploidy protects humans against the deleterious effects of heterozygous mutations, particularly in classical enzyme systems, in which a single functional copy is typically more than sufficient to adequately catalyze a biochemical reaction. So, to some extent, the study design comparing those with one or more loss-of-function CYP2C19 alleles was a straw man. My main concern, as a geneticist, would have been those with 2 loss-of-function alleles, which is a rare genetic category (for which even the meta-analysis was underpowered). However, the results of the Holmes et al JAMA meta-analysis reinforced my concern as follows:
“By comparison, the RR of CVD events among carriers of 2 loss-of-function alleles was 3.75 (95% CI, 2.40-5.86; I2=8%; 95% CI, 0%-73%) for fixed effects and 3.76 (95% CI, 2.34-6.06) for random-effects modeling in studies with fewer than 100 cases and 1.52 (95% CI, 1.04-2.21; I2=51%; 95% CI, 0%-86%) for fixed effects and 1.45 (95% CI, 0.82-
2.56) for random-effects modeling in studies with 100 or more cases.”
In their meta-analysis, Holmes et al. clearly demonstrated that the clinical utility of CYP2C19 genotyping has not been established. However, the authors did not comment at all in their Discussion on patients with 2 loss-of-function alleles. This topic requires further research, and the take-home message for cardiologists should not be that CYP2C19 genotype “doesn’t matter.” It’s important research in progress — too soon for strong opinions, far too soon for an FDA black box warning that encourages clinicians to order genetic tests that even a geneticist won’t be able to interpret.