Clopidogrel Pharmacogenetics: Whether and When to Test Versus Platelet Reactivity Monitoring

Antiplatelet therapy has a key role in preventing atherothrombotic events in patients with coronary artery disease; however, a delicate balance between thrombotic and bleeding events is critical to achieve optimal outcomes, which may depend on the level of platelet inhibition that is achieved in a given patient. Jessica L. Mega, MD, Brigham and Women's Hospital, Boston, Massachusetts, USA, assessed the use of routine genetic and platelet function testing in the setting of clopidogrel treatment.

Significant interindividual variability in the platelet inhibitory response from clopidogrel occurs in as many of 31% of patients who have an inadequate response [Gurbel PA et al. Circulation 2003]. Investigators for the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) reported that carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular (CV) events, including stent thrombosis, than noncarriers, and a meta-analysis that incorporated data from nine studies supported the clinical findings [Mega JL et al. N Engl J Med 2009; Mega JL et al. JAMA 2010]. Another study, however, found a consistent response to clopidogrel among patients with acute coronary syndromes or atrial fibrillation, regardless of CYP2C19 loss-of-function carrier status [Paré G et al. N Engl J Med 2010]. Nevertheless, the FDA added a boxed warning to the prescribing information for clopidogrel in March 2010, addressing the diminished effectiveness of clopidogrel in patients who are CYP2C19 carriers (ie, poor metabolizers).

To date, genetics and platelet function testing offer complementary information owing to the genotype, environment, and phenotype relationship, Dr. Mega noted. Several trials continue to explore whether or not altering treatment strategies that are based on the CYP2C19 genotype and high on-treatment reactivity are associated with improved outcomes with clopidogrel use. Currently, there are no established recommendations for the use of genetic or platelet function testing in routine clinical practice, despite the FDA's warning regarding increased risk in patients with loss-of-function CYP2C19 alleles.

Warfarin Pharmacogenetics: Whether and When to Test, and Impact on INR Monitoring

Munir Pirmohamed, MD, University of Liverpool, Liverpool, UK, summarized the current state of knowledge regarding the use of pharmacogenetics to determine warfarin dosing. While noting that pharmacogenetics testing is usually reserved for more difficult-to-treat patients, Prof. Pirmohamed said there is a narrow therapeutic window for warfarin with high risks for bleeding, depending on the number of clinical factors, including drug interactions, genetic factors, age, gender, and BMI. Polymorphisms of the CYP2C9 and VKORC1 genes account for approximately 40% of the variation in individual response to warfarin [Jonas DR, McLeod HL. Trends Pharmacol Sci 2009].

No clinical trial to date has definitively established the benefit of pharmacogenetics to determine warfarin dosing. One trial of genotype-guided versus standard warfarin dosing did not find a difference in the time within the therapeutic international normalized ratio (INR) between these dosing strategies. However, there were favorable trends toward lower INR values and fewer, smaller changes in dose with pharmacogenetic-guided dosing [Anderson JL et al. Circulation 2007]. The next step will be to determine if stroke risk, bleeding risk, and genotyping are good stratification tools for oral anticoagulant use, Prof. Pirmohamed said. Whether the use of pharmacogenetic testing for the determination of warfarin dosing becomes integrated into routine clinical practice in the setting of newer, more stable oral anticoagulant options remains to be seen.

Predicting Versus Monitoring for Statin Efficacy and Safety

Despite the increasing use of high-potency statins, the majority of CV events are not prevented, and adverse drug-related events continue to be associated with discontinuation of treatment. It has been suggested that genetic markers that are predictive of the benefit versus risk of statin therapy could have medical and economic value. Ronald M. Krauss, MD, Children's Hospital Oakland Research Institute, Oakland, California, USA, reviewed some of the conflicting evidence surrounding routine predictive genetic testing for statin efficacy and toxicity.

Several studies have reported that carriers of a common polymorphism that encodes an arginine (Arg)-to-tryptophan substitution at position 719 on the KIF6 gene are at greater risk for primary and secondary CV events [Li Y et al. Am J Cardiol 2010]. However, whether statins provide an enhanced benefit for carriers (vs noncarriers) of this polymorphism is unclear. Iakoubova and colleagues reported that therapy with either pravastatin or atorvastatin significantly reduced the incidence of coronary events in Trp719Arg carriers but did not show similar benefit in noncarriers [Iakoubova OA et al. Eur J Cardiovasc Prev Rehabil 2010]. Further complicating the question of the value of genetic testing for KIF6 as a predictor of benefit versus risk is a recent report from Assimes and colleagues that showed no association between the KIF6 Trp719Arg polymorphism and the risk of coronary artery disease [Assimes TL et al. J Am Col Cardiol 2010].

The evidence appears to be stronger for the relationship between the SLCO1B1 genotype and statin-induced myopathy [SEARCH Collaborative Group et al. N Engl J Med 2008] and other adverse events [Voora et al. J Amer Coll Cardiol 2009]. More than 60% of the myopathy cases in SEARCH could be attributed to the C variant polymorphism of SLCO1B1, while in the study by Voora and colleagues, the SLCO1B1*5 genotype and female gender were associated mild statin-induced side effects, including a composite of discontinuation for any side effect, myalgia, or CK >3x upper limit of normal. Thus, SLCO1B1 genotyping could prove to be useful in identifying patients in whom the risks of statin therapy outweigh the benefits in clinical practice.

Dr. Krauss concluded that the clinical trials that support routine, predictive genetic testing for statin efficacy or toxicity are inconclusive and that more comprehensive genomic approaches and testing in various clinical populations and racial/ethnic groups are needed.

What is the Food and Drug Administration (FDA) Doing With Pharmacogenetic Data?

ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons.

• “The FDA…neither mandates…nor recommends genetic testing, thereby allowing for flexibility in clinical decisions.”

• “…the moderate position [reflects] an attempt to weigh the evidence and to give the prescriber more information.”

• “It…does not imply that there are solid evidence-based reasons for such actions. Rather, it serves to make clinicians aware of the imperfect, but significant, knowledge that we have.”

• “Guideline adherence remains the cornerstone of care.”

[Holmes DR et al. J Am Col Cardiol 2010]

Genetic variations are important determinants of a patient's response to a drug, said Issam Zineh, PharmD, MPH, FDA, Silver Spring, Maryland, USA. Thus, the use of pharmacogenetic data plays a role in the FDA's decision-making process. Dr. Zineh suggested that pharmacogenetic principles can guide drug development and regulatory decision-making. In addition, the Office of Clinical Pharmacology Genomics Group's regulatory science staff has been charged to assist in the crossdisciplinary review of investigational new drugs, new drug applications, license applications for biologics, and postapproval pharmacogenetic issues, thus providing additional structural support within the FDA for these important tasks. The FDA considers many factors when evaluating an emerging pharmacogenomic drug safety concern, including but not limited to reliability of the data, magnitude of the risk, seriousness of the event, biological plausibility, how broadly the drug is used, potential to prevent or mitigate the risk, effect on clinical practice, and disproportionate impact on particular populations.

Pharmacogenetics: Clinical Care and Cost Implications —2010 and 2020 Predictions

Dan M. Roden, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, USA, discussed the cost-effectiveness of using pharmacogenetics for drug monitoring. In one study, the authors cautioned against widespread adoption of pharmacogenetic monitoring, suggesting that genotyping before warfarin initiation would be cost-effective for patients with atrial fibrillation only if it reduces out-of-range INR values by more than 5 to 9 percentage points compared with usual care [Patrick AR et al. Circ Cardiovasc Qual Outcomes 2009].

Paraphrasing a statement by Francis Collins in September 2009, Dr. Roden said, “The economics would be different; however, if everyone's DNA sequence was already in their medical records.” To achieve this level of personalized medicine, Dr. Roden recommended several first steps including selecting a group of patients who are at high risk for receiving a drug that has an actionable pharmacogenetic interaction, genotyping them on a platform that assays genotypes, storing the genotypes, developing informatics tools to provide point-of-care advice, and tracking outcomes.

Advancing the concept of pharmacogenetics-based drug therapy is not without challenges, such as assessing outcomes, ethical concerns, and educating health care providers and patients. Dr. Roden noted, however, that 71% of respondents to a survey that was conducted at Vanderbilt agreed or strongly agreed with the statement, “I would choose to go to a doctor that used my genetic information to pick the best treatment for me over one who did not.”