Take-aways

• The role of platelet reactivity and genotype testing in the prevention of atherothrombotic cardiovascular events remains unproven.
• While routine testing is not recommended, there is evidence (and guidelines support) for genetic and platelet function testing in selected patients, mainly those at increased risk of future events.

With the discovery of the double helix, the human genome era began in earnest in 1953; the second wave of this revolution has been cresting for some time now. Given the lack of a uniform response to therapies and interventions, physicians have been promised a golden age when they don't have to wait for symptoms but instead base treatment decisions on genetic predispositions of individual patients.

In 2011, the ACC's CardioSurve panel explored the perceptions of personalized medicine and its future. The survey asked cardiologists to first choose from options that they felt defined "personalized medicine." Nearly three out of four (72%) cited genetic testing as a key defining attribute while approximately half (53%) chose molecular diagnostics. Additional considerations for age (56%), gender (56%), race (52%), and comorbidity (49%) were other aspects of personalized medicine selected.

However, few cardiologists felt that personalized medicine is impacting the treatment of their patients. The primary reason for the short-term skepticism: a lack of patient outcome data to support the implementation of personalized medicine technologies. Additionally, they cited reimbursement concerns for these tests (68%), a shortage of physician education on the topic (66%), and a lack of guidance from professional societies/associations (55%) on personalized medicine.

Better Know a Patient
Certainly recent advances in genetics and proteonomics have great potential to help tailor treatment to individual patients in remarkable ways. A focus of intense research is on "clopidogrel nonresponders," who despite treatment with conventional-dose clopidogrel, still demonstrate high on-treatment platelet reactivity (HTPR), which has been associated with in-stent thrombosis and recurrent cardiovascular events. This decreased response to clopidogrel is thought to affect roughly one-third of patients.

Several genetic polymorphisms have been linked to reduced hepatic metabolism of clopidogrel (the most prevalent of which is CYP2C19), leading to a lower concentration of the active metabolite. This pathophysiological explanation lends itself to clinical applications, because targeting those patients with a positive genetic screen or HTPR after DES to receive a more effective antiplatelet agent may prove an effective strategy.

Recently, Vamsi Krishna, MD, George A. Diamond, MD, and Sanjay Kaul, MD, reviewed the evidence linking platelet function and genetic testing to adverse cardiovascular outcomes and evaluated the data supporting platelet function and genetic test-guided tailored treatment approaches.¹ (At ACC.14, Dr. Kaul also discussed some of these same issues.)

In brief, they concluded:

• There is a lack of consensus regarding the definition of resistance to antiplatelet therapy. Terms that have been applied in the literature include nonresponsiveness, hyporesponsiveness, semiresponsiveness, low responsiveness, and suboptimal responsiveness.
• Platelet function testing plays a role in determining responsiveness to antiplatelet therapy, but the available tests are not standardized and use different methodologies and cutoff values to define platelet responsiveness. Furthermore, correlations between assays are modest, and concordance in defining suboptimal response poor.
• The growing body of evidence linking HTPR while on clopidogrel therapy to risk of adverse events after percutaneous coronary intervention (PCI) has led to investigations aimed at evaluating whether tailoring antiplatelet therapy according to results of platelet function tests will lead to improved clinical outcomes. As happens all too often, however, the results from large randomized multicenter prospective trials have failed to confirm the promising results seen in early, smaller studies.
• There also is mixed evidence that modifying therapy in response to genetic testing might improve platelet aggregation in response to clopidogrel.
• On the basis of the totality of evidence, Dr. Kaul and his colleagues conclude that the value of routine platelet function testing and genotyping in all patients remains unproven; therefore, they cannot be recommended at this time. Neither genotyping nor platelet function testing, they said, is a strong discriminator of subsequent clinical outcomes, highlighting the complexity of platelet biology and function, the multifactorial nature of cardiovascular risk, and the challenges underlying risk stratification and treatment decisions.

A Second Opinion
Two members of the Working Group on High On-Treatment Platelet Reactivity responded to the paper by Dr. Kaul and colleagues. Paul Gurbel, MD, and Udaya S. Tantry, PhD, had co-authored the working group's white paper in JACC entitled Consensus and Future Directions on the Definition of High On-Treatment Platelet Reactivity to Adenosine Diphosphate,² cited by Dr. Kaul and company.

In the white paper, they reviewed the published literature and acknowledged a lack of consensus on the optimal method to quantify HTPR, the optimal cutoff value associated with clinical risk, and sparse data to support changing therapy based on platelet function measurements. The authors also noted that the absolute level of platelet reactivity during treatment is a better measure of thrombotic risk than responsiveness to clopidogrel. The working group members offered guidance on future studies that are needed to show clinical benefit from changing therapy in response to a finding of high on-treatment platelet reactivity.

In their response, Drs. Gurbel and Tantry noted: "Kaul et al. argue against routine platelet function testing and genotyping; we agree with them, and we stated, 'the evidence is strong enough now to recommend genotyping and phenotyping in the high-risk PCI patient.'"

Indeed, the conclusion of the working group's paper stated specifically: "Currently, platelet function testing may be considered in determining an antiplatelet strategy in patients with a history of stent thrombosis and in patients prior to undergoing high-risk PCI. However, until the results of large-scale trials of personalized antiplatelet therapy are available, the routine use of platelet function measurements in the care of patients with cardiovascular disease cannot be recommended."

Also in response to the "controversies" paper by Drs. Gurbel and Tantry, Kaul et al. wrote that prognostic indicators (platelet reactivity and genotype) should be interpreted in the context of the clinical presentation, not as stand-alone tests. "As with clinical risk factors, they are meant to help physicians assess risk—not to diagnose which patients will have events. Discounting the utility of prognostic indicators on the basis of poor diagnostic performance results from inappropriate interpretation of the information provided."

The current ACC/AHA guidelines for the management of unstable angina/non–ST-segment elevation myocardial infarction reflects the growing consensus that genetic and platelet function testing are useful in selected patients, mainly those at increased risk of future events.³ (Currently, platelet function testing carries a Class IIb recommendation, Level of Evidence: B.)

References

1. Krishna V, Diamond GA, Kaul S. Circulation. 2012;125:1288-1303.
2. Bonello L, Tantry US, Marcucci R, et al. J Am Coll Cardiol. 2010;56:919-33.
3. Anderson JL, Adams CD, Antman EM, et al. J Am Coll Cardiol. 2013;61:e179-e347.

To listen to an interview with Sanjay Kaul, MD, about the case against personalized medicine, scan the code. This interview was conducted by Allan S. Jaffe, MD.

Keywords: Myocardial Infarction, Platelet Aggregation Inhibitors, Platelet Function Tests, Referral and Consultation, Comorbidity, Risk Factors, Ticlopidine, Genetic Testing, Purinergic P2Y Receptor Antagonists, Precision Medicine, Stents, Percutaneous Coronary Intervention, Consensus, Polymorphism, Genetic, Platelet Aggregation, Thrombosis, Genetic Predisposition to Disease, Genome, Human, Genotype

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