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Patients with stable cardiovascular disease receiving clopidogrel have similar ischemic risk regardless of which variants of the drug-metabolizing CYP2C19 gene they carry, according to a substudy of the CHARISMA trial. The findings, published online March 26, 2012, ahead of print in the European Heart Journal, were originally presented at the 2009 Transcatheter Cardiovascular Therapeutics scientific symposium in San Francisco, CA.

In the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, 15,603 stable patients with clinically evident cardiovascular disease or multiple risk factors were randomized to daily aspirin plus clopidogrel or placebo. Overall, dual antiplatelet therapy was no more effective than aspirin alone in reducing ischemic events. While there was no excess fatal or intracranial bleeding in the clopidogrel arm, transfusions and milder forms of bleeding were increased.

For the genetic substudy, investigators led by Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), looked at the relationship between the CYP2C19 genotype and outcomes among 4,819 CHARISMA patients who had been tested for the CYP2C19 wild type (wt) and major polymorphisms associated with loss of function (*2 and *3) and gain of function (*17).

The main analysis included only the 4,537 patients of European ancestry. Metabolizer phenotypes in the clopidogrel arm were distributed as follows:

• Poor (*2/*2 or *2/*3): 2.3%
• Intermediate (wt/*2 or wt/*3): 20.2%
• Extensive (wt/wt): 39.1%
• Ultra (wt/*17 or *17/*17): 31.6%
• Unknown (*2/*17 or *3/*17): 6.9%

No Influence of Genotype on Primary Endpoints

In the clopidogrel-treated arm (n = 2,266), age- and sex-adjusted Kaplan-Meier estimates found no difference between loss-of-function carriers and noncarriers for the primary efficacy endpoint of first MI, stroke, or cardiovascular death (P = 0.17). Results were still equivalent when hospitalization for unstable angina, TIA, or revascularization were added to the primary endpoint (P = 0.593).

Nor did such carrier status affect the primary safety endpoint of moderate or severe GUSTO bleeding (P = 0.59). However, loss-of-function carriers had less overall GUSTO bleeding than noncarriers (36.1% vs. 42.5%; HR 0.80, 95% CI 0.69-0.93; P = 0.003). An interaction emerged between loss-of-function carrier status and clopidogrel treatment resulting in less bleeding (P = 0.023).

On the other side, gain-of-function carrier status had no effect on any of the efficacy or safety endpoints.

Poor metabolizers—those with *2/*2 or *2/*3 genotypes—had a higher rate of the primary efficacy endpoint than all of the other phenotypes (HR 2.27; 95% CI 1.06-4.85; P = 0.035), although only 7 events occurred. Moreover, there was no interaction between the clopidogrel vs. placebo effect on the primary efficacy endpoint and metabolizer phenotype (P = 0.21).

“The overall CHARISMA trial did not find a benefit of dual antiplatelet therapy in a very stable patient population and, similarly, there was no benefit as a function of genotype in the present analysis,” the authors conclude.

No Simple Link Between Clopidogrel Metabolism, Outcome

Loss-of-function carriers would be expected to have lower levels of active metabolite when taking clopidogrel and gain-of-function carriers higher levels, but “there is not necessarily a linear correlation between active drug levels and measured antiplatelet response, nor between measured antiplatelet response and antithrombotic efficacy or bleeding propensity,” the investigators observe.

In part, that may be due to the fact that CYP2C19 is not the only pathway involved in clopidogrel activation so polymorphisms in other genes may affect the drug’s action. But just as important, clinical factors such as whether a patient has activated platelets due to ACS, a newly implanted stent, diabetes, or obesity may influence the response to antiplatelet therapy. Moreover, the pharmacodynamic effect of clopidogrel is subject to drug-drug interactions, such as that with proton pump inhibitors—a factor that was not analyzed in the study.

Dr. Bhatt and colleagues acknowledge that “it is difficult to fully reconcile the relative protection from bleeding complications with the lack of increase in ischemic outcomes among the patients with loss-of-function CYP2C19 alleles.”

The current findings, however, are limited by the fact that CHARISMA was underpowered for primary endpoint events. Moreover, the trial enrolled stable patients across a broad spectrum of thrombotic risk, and thus the results may not apply to recently stented patients or those exhibiting ACS, the researchers note.

Results Consistent Regardless of How Data Are ‘Sliced’

“We couldn’t find an influence of genotype on clopidogrel no matter how we sliced the data,” Dr. Bhatt told TCTMD in a telephone interview. “Even in [a subset of] patients with a history of PCI, we didn’t find an interaction.”

In fact, he related, the researchers had hoped that so-called extensive or ultra-metabolizers might show some benefit from clopidogrel that was not seen in the overall CHARISMA population—but their analyses proved otherwise.

The only exception to the rule of no CYP2C19 effect was the reduction in all forms of bleeding in loss-of-function carriers. Nevertheless, Dr. Bhatt downplayed the importance of the finding, stressing that there was no impact on major bleeding. “Even though [the reduction in all bleeding] is statistically significant, and biologically plausible, in absolute terms the difference wasn’t that large—about 6%—and clinically is not that important,” he said.

Effect of Genotype Complex

Dr. Bhatt suggested that the findings should direct attention to the complex influence of genetics. “Even if there is some adverse impact of the CYP2C19 genotype on efficacy in other populations, what we observed about bleeding is a bit of a counterbalancing effect,” he observed. “Yes, if you carry a loss-of-function allele, maybe you have less efficacy, but if you also have less bleeding, in aggregate is that good or bad? It’s difficult to say.”

He added that 3 large randomized trials of clopidogrel vs. placebo, CURE, ACTIVE, and CHARISMA, have all found that “genotype does not really matter in a way that is clinically relevant.” (Notably, the patient demographics of those trials differ from those of earlier reports that had suggested an effect on ischemic outcomes, the paper points out.) In the absence of outcomes data showing that genotyping can improve therapeutic choices, any effort to institute such testing in practice distracts physicians “from what they should be doing”—evaluating individual patients’ relative ischemic and bleeding risks, Dr. Bhatt asserted.

“From a clinician’s perspective, the bottom line is there is no imperative in this dataset to go ahead and routinely genotype,” he concluded.

Related Stories:

• Certain Genotypes Hinder Antiplatelet Effect of Clopidogrel
• Study Suggests Genetic Basis for Patients’ Response to Clopidogrel
• CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance

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