Devang M. Desai, MD, FACC, FSCAI

When discussing pharmacogenetics in cardiology practice, it is almost obligatory to bring up clopidogrel. Clopidogrel is an antiplatelet used for acute coronary syndrome, percutaneous coronary intervention (PCI) with stenting, and secondary stroke prevention in patients with aspirin allergy, among other indications. It is a prodrug that must be metabolized through the cytochrome P450 system to form its active molecule. Consequently, differences in hepatic metabolism are responsible for considerable variability in clopidogrel response among patients. Indeed, my colleagues and I have managed dozens of cases in which pharmacogenetics played a central role in the efficacy of clopidogrel.

Clopidogrel is commonly prescribed to patients after PCI to prevent clots from forming in and around their new drug-eluting stent. This is how we used the antiplatelet in a 56-year-old man after PCI for coronary artery disease. Three weeks after stent placement, the man returned to our center because he was experiencing cardiac chest pain. He insisted he had been taking clopidogrel exactly as prescribed, along with all his other medications. Angiography showed he had developed thrombosis (blood clots) in the stent, and pharmacogenetics testing revealed 

The clopidogrel molecule has very little platelet-inhibiting ability. Cytochrome P450 enzymes, mainly CYP2C19, are responsible for “activating” the prodrug clopidogrel into 1 or more active metabolites. Because our patient was a CYP2C19 poor metabolizer, the medicine he was dutifully taking remained in its native state without exerting an antiplatelet effect. Based on the pharmacogenetic testing results, the man was switched to ticagrelor and had no further thrombosis at the stent.

Is It Time to Start Conducting Routine Pharmacogenetic Testing Before Clopidogrel Use?

In 2010, an expert panel convened by the American College of Cardiology Foundation and the American Heart Association reported on the potential for altered CYP2C19 metabolism to lead to adverse clinical outcomes. The panel’s recommendations led to the FDA’s decision to issue a black box warning on clopidogrel regarding CYP2C19 metabolism. Clinicians are supposed to be aware of the ramifications of altered metabolism, yet neither the expert panel nor the FDA recommended routine CYP2C19 polymorphism testing prior to clopidogrel use. Unfortunately, this puts providers in reactive posture: without pharmacogenetics data on patients, we must assume that all patients can metabolize the drug, as most patients will. The obvious weakness in this approach is when a patient, like the one described, fails to benefit from the drug. Only then does polymorphism testing confirm what we already suspected after the patient experiences an adverse effect (AE).

For some clopidogrel indications, pharmacogenetic testing is not needed because the risk of treatment failure is low. However, stent thrombosis is associated with long-term morbidity and possible fatal outcomes. Moreover, approximately 1 in 5 patients undergoing PCI with stenting does not respond to clopidogrel, which may be due to genetic polymorphisms in hepatic metabolism—at least in part. With these realities in mind, routine (or more common) pharmacogenetic testing becomes a reasonable consideration.

Some institutions have started enacting local screening protocols, despite these recommendations. For example, in June 2012, the University of Florida Health Personalized Medicine Program launched CYP2C19 testing for patients undergoing cardiac catheterization. Although testing was initially paid for by grant support, CYP2C19 testing remains on the post-PCI order set today as the standard-of-care for patients undergoing PCI. A pharmacist reviews all genotyping results and contacts the treating physician for patients with the poor or intermediate metabolizer phenotype to recommend alternative antiplatelet therapy in the absence of any contraindications. Moreover, an alert appears in the electronic health record to help guide future decision making. We anxiously await outcomes data from this program.

Genotype Informs Dose Selection: Warfarin

Warfarin has become legend for its drug interactions and its intra- and interpatient variability. Pharmacogenetic testing can be used to predict some of this variability. Specifically, pharmacists involved in cardiology medication therapy management (MTM) can recommend a safe and effective initial warfarin dosage by knowing a person’s CYP2C9 and VKORC1 genotypes. As a cytochrome P450 enzyme, CYP2C9 affects plasma levels and clearance of warfarin. VKORC1, on the other hand, controls the oxidation state of vitamin K. Genotypic variations in VKORC1 explain differences in warfarin sensitivity. Indeed, the Clinical Pharmacogenetics Implementation Consortium has developed an algorithm to support medication decisions based on CYP2C9/VKORC1 genotyping results. Consequently, genotype-guided warfarin dosing has become the standard-of-care at several institutions. These efforts have been spearheaded by pharmacy services as part of MTM.

Although statins are an effective means of treating dyslipidemia with few AEs, myopathies continue to limit their use in some patients. Statin-induced myopathy ranges from mild muscle ache to serious rhabdomyolysis. To date, it has been difficult to predict who might develop myopathy. A standard starting dose is usually prescribed and changed if AEs occur. If the consequence is myalgia, this is a reasonable approach. If the AE is rhabdomyolysis, however, the result could be fatal. In general, myopathies are more common and more serious when a patient takes a high dosage and/or another medication that interferes with statin metabolism. Researchers and providers now know that dose-dependent toxicities and “idiosyncratic” drug reactions can often be traced to an underlying genetic polymorphism related to metabolism or mechanism of action. Indeed, this appears to be at play in statin-induced myopathy.

Pharmacogenetics is beginning to influence statin therapy decisions. For instance, certain polymorphisms of the 

 gene make patients who carry them more susceptible to statin-induced myopathy, particularly from simvastatin (for reasons that are not entirely clear). The association has enough clinical relevance that Vanderbilt University has incorporated 

 genotyping into routine clinical practice. Therefore, patients with a certain 

 polymorphism are either given a very low dose of a statin drug (likely not simvastatin) or an alternate lipid-lowering regimen. As outcomes data become available, other organizations may follow this model.

Clopidogrel, warfarin, and statins (particularly simvastatin) are examples of how pharmacogenetics can influence cardiology practice today. However, several other drugs and drug classes may soon join their ranks. Nascent research is showing that uncommon genetic polymorphisms can significantly change outcomes with the use of aspirin, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and digoxin. Although testing in patients with unusual reactions to these medication classes may not yet be ready for routine use by clinicians and pharmacists, anecdotal reports are increasingly common. Pharmacists are seeing them as frequently as cardiologists are, if not more often.

Consider the experience of pharmacist Olivia Santoso Bentley, who was discussing pharmacogenetic testing results with a woman during MTM. Dr. Bentley informed the woman she was a poor metabolizer of metoprolol and at risk for severe beta-blockade. The woman had an immediate and profound emotional reaction to this information, explaining that just 2 weeks prior, her mother had had a heart attack and was discharged on metoprolol. Within 2 days of discharge, she was back in the hospital because “her heart almost stopped,” which no doubt meant severe bradycardia. It was then obvious that her mother shared this polymorphism, but the information came too late to prevent her AE. Fortunately, the mother survived this ordeal.

Although it is too soon to make firm testing and treatment recommendations for most cardiovascular drugs using pharmacogenetics, it is not difficult to track the arc of history in this field. The use of pharmacogenetic testing in cardiology is rapidly expanding and constantly refining. Basic and clinical research should be accelerated by growing and widespread interest in the field, and, more specifically, by federal programs, such as the Precision Medicine Initiative. It is an exciting time.

Dr Olivia Santoso Bentley provided the pharmacist’s perspective for this article. She is a leader of the Pharmacogenetic Center of Excellence and is a clinical pharmacist consultant to the 

Devang M. Desai, MD, FACC, FSCAI, is director of interventional cardiology and an interventional cardiologist at Saint Mary’s Regional Medical Center, Reno, Nevada.

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Articles

When discussing pharmacogenetics in cardiology practice, it is almost obligatory to bring up clopidogrel.