CYP2C19 Loss-of-Function Gene ups Risk of Events Post-PCI New Meta-Analysis

October 27, 2010

October 26, 2010 (Boston, Massachusetts) — A new meta-analysis has shown that patients with either one or two loss-of-function CYP2C19 alleles undergoing PCI on normal doses of clopidogrel have an increased risk of cardiovascular events compared with noncarriers [1].

The meta-analysis, published in the October 27, 2010 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Jessica Mega (Brigham and Women’s Hospital, Boston, MA).

Mega commented to heartwire that the FDA has highlighted the increased risk of cardiac events in patients with two CYP2C19 reduced-function alleles but has remained silent on the risk in those with just one. "We found that both individuals carrying two copies and those carrying just one copy of a CYP2C19 reduced-function allele were at a significantly increased risk of death, MI, stroke, and particularly stent thrombosis. Therefore, when we consider the impact of genetics on the response to clopidogrel, we cannot only consider the 2% to 4% of the population with two reduced-function CYP2C19 alleles, we must also consider the additional 26% with one reduced-function allele," she said.

Dr Eric Topol (Scripps Clinic, La Jolla, CA), a leading light in this field, called the results of the meta-analysis "a big deal."

In the paper, the researchers explain that the CYP2C19 enzyme plays a key role in clopidogrel metabolism, and carriers of reduced-function variants in the CYP2C19 gene have lower active clopidogrel metabolite levels and diminished platelet inhibition. About 26% of the white population carries one loss-of-function variant of this gene, and about 2% carry two such alleles. But these percentages are slightly greater in blacks and substantially greater in Chinese.

For the current meta-analysis, Mega et al found nine genetic studies in which patients scheduled to undergo PCI were treated with clopidogrel as per the current guideline recommendations and in which clinical outcomes were ascertained. The studies involved a total of 9685 patients (91.3% of whom underwent PCI and 54.5% of whom had an ACS). Of these, 863 experienced the composite end point of cardiovascular death, MI, or stroke; 84 patients had stent thrombosis. Overall, 71.5% were noncarriers of the CYP2C19 loss-of-function variant, 26.3% had one reduced-function allele, and 2.2% had two reduced-function alleles.

Results showed a significantly increased risk of the composite end point and of stent thrombosis in both carriers of either one or two reduced-function CYP2C19 alleles, as compared with noncarriers.

Hazard Ratio of Composite End Point and of Stent Thrombosis in Carriers of Reduced-Function CYP2C19 Alleles Compared With Noncarriers

Composite end point (CV death/MI/stroke) HR (95% CI) p
1 loss-of-function allele 1.55 (1.11–2.17) 0.01
2 loss-of-function alleles 1.76 (1.24–2.50) 0.002
Stent thrombosis    
1 loss-of-function allele 2.67 (1.69–4.22) <0.0001
2 loss-of-function alleles 3.97 (1.75–9.02) 0.001

The researchers conclude: "The findings of this collaborative meta-analysis demonstrate that common genetic variants in the CYP2C19 gene are associated with almost one in three patients not receiving ideal protection from ischemic events when treated with standard doses of clopidogrel for PCI. Given how widely clopidogrel is used to treat patients with cardiovascular disease, determination of the optimal antiplatelet treatment doses or regimens for individual patients is needed to tailor therapy appropriately."

They note that there are some early data suggesting that increasing the dose of clopidogrel in carriers of a CYP2C19 reduced-function allele may enhance the degree of platelet inhibition, but these studies have been small, and larger studies are needed. They add: "Understanding the ability to treat patients effectively with clopidogrel across CYP2C19 genotypes will be particularly important from a healthcare cost perspective, as the drug is already off patent in some countries and anticipated to go off patent in the US and elsewhere in the near future."

Do These Results Support Routine Genetic Testing?

In an accompanying editorial [2], Drs Valentin Fuster and Joseph Sweeny (Mount Sinai Medical Center, New York) say this meta-analysis confirms that the prevalence of reduced-function alleles might not be as insignificant as previously thought. But they claim it is still uncertain whether these new findings actually support the use of CYP2C19 genetic testing. They point out that the positive predictive value of CYP2C19 reduced-function genetic testing is low (between 12% and 20%) in ACS patients undergoing PCI, so a large proportion of carriers with the loss-of-function genes will not develop a future cardiovascular event, and multiple mechanisms beyond the CYP2C19*2 allelic variant will influence platelet reactivity.

They add that the information obtained by CYP2C19 genetic testing may be particularly useful in patients at risk of poor outcomes, either because they have already had an adverse event (eg, stent thrombosis) or other at-risk characteristics such as diabetes, chronic renal failure, or angiographic high-risk features.

Everything is lining up. . . . This is a syzygy of modern medicine.

Noting that three ongoing studies are currently under way to find the best genome-guided strategy for these higher-risk patients, they conclude: "In the meantime, clopidogrel and CYP2C19 genetic testing appear to be only a limited piece of the overall therapeutic puzzle of clopidogrel therapy and personalized medicine."

But Topol told heartwire that Fuster and Sweeny "completely sidestepped" the question of how to provide best care for patients now. "This study pooling nine separate cohorts and almost 10 000 PCI patients tells the story exceptionally well. Even carriers of one CYP2C19 loss-of-function allele have a 55% increased risk of major events and a 270% risk of stent thrombosis. That is a big deal," he said.

Topol added: "The total evidence base now shows a definite increased risk of stent thrombosis and other cardiac events in carriers of CYP2C19 loss-of-function alleles. We also know that poor platelet suppression is associated with poor outcomes. Everything is lining up. We have a life-or-death result, a choice of alternative therapies, and another intermediate measurement (platelet-function tests) to help guide decisions. This is a syzygy of modern medicine. To ignore this impressive knowledge base on CYP2C19 will leave some patients unnecessarily at risk of stent thrombosis."


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