How personalized medicine can attack the #1 killer in the US

This article, by Transgenomic's Tom Callis, explores how genetic testing can predict a patient's genetic predisposition to cardiovascular drug response and adverse events to help clinicians determine necessary dose adjustments or safer alternative therapies.

Heart disease remains the leading cause of death in the United States, claiming nearly 600,000 lives every year.1 There's a plethora of cardiovascular (CV) medications on the market to address patients at risk for CV disease due to acute coronary syndrome, prior myocardial infarction, stroke, atrial fibrillation, and peripheral artery disease. Such CV agents include antiplatelets, anticoagulants, statins, beta-blockers, and antiarrhythmics. Unfortunately, a significant drawback to these medicines is that they are standardized to treat the majority of patients, not individualized to take into account genetic predisposition to CV drug response and adverse events.2-4

Pharmacogenomic variants can influence the absorption and metabolism of CV drugs. Up to 50% of patients may have one or more genetic variants that have been demonstrated to influence the efficacy and safety of many common CV medications.2-4 Knowledge of a patient's genetic variants can help a physician determine optimal drug selection as well as dosing decisions.

Enter the age of personalized medicine

With access to new genetic tests, physicians can now incorporate the principles of personalized medicine to treat CV patients in order to achieve optimal outcomes. Let's examine how genetic testing can help physicians make more informed CV treatment decisions. Clopidogrel (Plavix®) is a standard-of-care antiplatelet agent, but limitations exist 5 Important genetic variants in CYP2C19 and ABCB1 result in impaired clopidogrel absorption and activation, which can lead to an increase in ischemic events.3 In fact, about half of us carry a genotype associated with an increase in major adverse CV events on standard doses of clopidogrel.3 Armed with such knowledge, physicians can identify patients who may require customized therapeutic approaches when being prescribed clopidogrel, including careful monitoring or alternative therapeutic choices.

Genotype-guided prescribing also influences the efficacy and safety of anticoagulants. Warfarin (Coumadin®) is a highly effective agent, and remains a commonly used drug in spite of the significant morbidity and mortality associated with its use.6 Approximately 2 million Americans start warfarin therapy every year.7 It is the second-leading drug-related reason for emergency department visits, and the most often cited reason for drug-related mortality.7 The Medco-Mayo Warfarin Effectiveness Study concluded that warfarin genotyping significantly reduces hospitalization rates.7

Now let's look at statins. Typical statins such as atorvastatin (Lipitor®), simvastatin (Zocor®), and lovastatin (Mevacor®) are primarily metabolized by the CYP3A family of enzymes.8 However, 25% to 30% of patients carry a CYP3A4 and CYP3A5 genetic variation that influences statin metabolism, which can potentially affect lipid-lowering response and increase side effects such as myopathy.8 The payoff: once a clinician identifies patients with these variants, options open and alternative statins such as rosuvastatin (Crestor®), pravastatin (Pravachol®), and fluvastatin (Lescol®), which have a different metabolic pathway than atorvastatin, simvastatin, and lovastatin, may be found to be beneficial alternate therapeutic choices.9-11

The same logic applies to beta-blockers and antiarrhythmics, which are predominantly metabolized by CYP2D6.2,4 Approximately 20% of patients carry genetic variation associated with reduced CYP2D6 metabolism, and that can lead to increased drug plasma concentrations of the commonly used medication metoprolol (Lopressor®)2,4,12 Therefore, understanding a patient's genotype can help inform treatment decisions.

Personalized medicine can now be incorporated into cardiovascular therapy. A new genetic test, CardioPredict™ Pharmacogenomic Optimization Panel, enables physicians to tailor cardiovascular treatment to a patient's genotype. Since a person's genetic makeup doesn't change over time, the CardioPredict™ genetic test needs to be performed only once in a patient's lifetime. Cardiovascular drug responsiveness is predicted in this single test that analyzes 48 genetic markers, in 10 genes: ABCB1, CYP2C19, CYP2C9, VKORC1, CYP2D6, CYP3A4, CYP3A5, Factor V, Factor II, and MTHFR. Test results enable physicians to determine individual genetic predisposition to CV drug response and adverse events and then tailor treatment to those individual patient characteristics. A report summarizes the results of the test providing a detailed pharmacogenetic profile along with clinical implications. Recommendations in the report point out alternative therapies (without genetic limitations), dose adjustments, and monitoring decisions, which a physician can use to create a customized therapeutic approach.

Genetic testing is currently underutilized

Nearly one-fourth of patients receive one or more drugs with pharmacogenomic information in their labels.13 Family history and concomitant CV conditions provide physicians with some insight into prescribing, but genotyping brings that insight to the next level. Personalized genomic medicine is currently practiced in large part by medical geneticists, genetic counselors, and pathologists, but there's no reason why every cardiologist (or every PCP in the country for that matter) should not be utilizing the invaluable clinical guidance gleaned from genetic testing.

References

1. Centers for Disease Control and Prevention. Heart disease. CDC Web site. Updated August 28, 2013. http://www.cdc.gov/heartdisease/facts.htm.

2. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther. 2011;89(5):662-673.

3. Mega JL, Close SL, Wiviott SD, et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010;376(9749):1312-1319.

4. Voora D, Ginsburg GS. Clinical application of cardiovascular pharmacogenetics. JACC. 2012;60(1):9-20.

5. Plavix [prescribing information]. Bridgewater, NJ: Bristol-Myers Squib; September 2013.

6. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;83(3):460-470.

7. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates: results from the MM-WES (Medco-Mayo Warfarin Effectiveness Study). JACC. 2010;55(25):2804-2812.

8. Kitzmiller JP, Sullivan DM, Phelps MA, Wang D, Sadee W. CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control. Drug Metab Drug Interact. 2013;28(1):59-63.

9. Crestor [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; August 2013.

10. Pravachol [prescribing information]. Princeton, NJ: Bristol-Myers Squib; October 2012.

11. Lescol [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2012.

12. Bijl MJ, Visser LE, van Schaik RH, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther. 2009;85(1):45-50.

13. Frueh FW, Amur S, Mummaneni P, et al. Pharmacogenomic biomarker information in drug labels approved by the United States Food and Drug Administration: prevalence of related drug use. Pharmacotherapy. 2008;28(8):992-998.

About the author:

Tom E. Callis, PhD, is Director of Clinical Genetics at Transgenomic, Inc., a global biotechnology company and leader in cardiac genetic testing. Dr. Callis is responsible for providing scientific support and training to internal and external customers on several pharmacogenetic and mutation detection tests, including CardioPredict™ Pharmacogenomic Optimization Panel, in the area of CV medicine. He also provides clinical and scientific presentations to health care audiences, contributes to scientific publication writing, develops test report language and marketing materials based on customer feedback and emerging scientific information, reviews technical content of patents and patent applications, and assesses scientific merits of competitors' products.

Dr. Callis earned a Doctor of Philosophy in Cellular and Developmental Biology from the University of North Carolina and a Bachelor of Science in Biology with Honors from the University of Central Florida. He has been awarded the American Heart Association Pre-doctoral Fellowship, the University of North Carolina Integrative Vascular Biology Pre-doctoral Fellowship, and the American Cancer Society Research Fellowship.

Transgenomic can be reached by contacting Eliza Schleifstein at Argot Partners: eliza@argotpartners.com or (973) 361-1546.

Transgenomic, Inc. (www.transgenomic.com) is a global biotechnology company advancing personalized medicine in cardiology, oncology, and inherited diseases. The Company has three complementary business units: Patient Testing, Biomarker Identification, and Genetic Assays and Platforms, which provide specialized diagnostic tests, contract research services for drug development, and equipment, reagents and other consumables for clinical and research applications in molecular testing and cytogenetics.