Lab testing to help predict response to clopidogrel, brand name Plavix, has at times resembled a sign post with arrows pointing in opposite directions. In March 2010, the U.S. Food and Drug Administration (FDA) required its strictest warning — a black box — to be included in the labeling for clopidogrel, one of the most widely prescribed drugs in the world. The warning indicated that physicians may consider alternative treatments for patients identified as poor metabolizers, as identified by Cytochrome P450 2C19, or CYP2C19, gene testing. Then, about three months later, the American Heart Association (AHA) and American College of Cardiology (ACC) recommended predictive gene testing for “high-risk” patients — but without clearly defining these patients.
Despite these various pieces of information, it is possible to chart a direction toward personalized clopidogrel therapy, based on lab testing that is thoughtfully integrated with patient management.
Clopidogrel is a blood thinner indicated for the reduction of atherothrombotic events for patients with a history of recent myocardial infarction, stroke or established peripheral arterial disease. It is also indicated for patients who are to be managed with percutaneous coronary intervention (PCI), which may include coronary stent procedures. About one million stent procedures occur each year in the U.S., and it is likely the majority involve clopidogrel therapy.
An enormous body of peer-reviewed literature demonstrates that loss of function of the CYP2C19 gene reduces response to clopidogrel. For some patients, the only indication of poor response to clopidogrel may be an atherothrombotic event, such as an ischemic heart attack or stroke. Genetic testing to identify these variants may aid the physician in identifying which patients may have incomplete response to therapy before it is initiated. Testing may also be indicated for patients who had a recent cardiac event while on clopidogrel.
The type of CYP2C19 variants determine whether a patient is categorized as an extensive, intermediate, or poor responder. Patients who are poor or intermediate responders may be at increased risk for adverse cardiovascular events. Therapeutic alternatives for these patients can include increasing clopidogrel dosage or switching to another drug, such as prasugrel; however, it is up to the treating physician to make this decision for each individual patient.
Some of the controversy of clopidogrel response testing has centered on which of the CYP2C19 variants should comprise a clinical test panel. Any loss-of-function allele will have the same effect in increasing the likelihood of incomplete response to clopidogrel.
Many labs in the U.S. test for several alleles, often ranging from *2-*10. Another allele, *17, implicated in ultra-metabolism of clopidogrel, is found in up to 40% of Caucasians, Africans, and Asians. Patients with one or two alleles of *17 may be at heightened risk for internal bleeding and may be indicated for clopidogrel therapy at levels well below the standard dose.
While the FDA, in effect, endorsed the potential value of CYPC219 genetic testing in the black-box warning to clopidogrel, the ACC and AHA have been more cautious. Their joint clinical alert issued last summer did not support routine genetic testing, citing a lack of research on correlations between CYPC219 polymorphisms and therapeutic response, among other factors.
Nonetheless, the alert upheld the clinician’s discretion as the cornerstone of treatment decision making. It also asserted that testing prior to therapy may be indicated for “patients believed to be at moderate or high risk for poor outcomes,” which may include those undergoing elective high-risk PCI.
Another source of confusion is the use of genetic CYP2C19 tests and platelet-function or aggregation tests to guide clopidogrel therapy. On the surface, the two testing modalities appear competitive; in fact, they may provide complementary insights that aid treatment decisions.
Genetic CYP2C19 tests are performed once to provide definitive results based on the patient’s genotype. By comparison, platelet-function tests are employed periodically to evaluate the rate and degree to which platelets aggregate in response to clopidogrel. They must be performed no fewer than four hours after a patient has initiated clopidogrel therapy, which leaves open a window of time during which a patient’s response is difficult to assess. The literature very strongly demonstrates the value of genotyping to identify at-risk patients before a stent procedure.
Other limitations of platelet-function testing are its propensity to produce variable results, inability to shed light into factors unrelated to clopidogrel that may cause an abnormal result, and lack of widespread availability.
Nonetheless, platelet-function testing can enhance the prognostic value of genetic tests. A genetic test may show, for instance, that a patient has one reduced-function allele, such as *2, and the *17 ultra-metabolizer allele. The effect of the two variants on therapy could, in theory, cancel each other out, and platelet-function testing may be indicated.
Any confusion surrounding personalized clopidogrel therapy is shared in common with personalized medicine as a whole. At its root is the challenge of transcending knowledge of associations between genetic, proteomic and metabolic factors, and therapy response in order to demonstrate cause and effect. While the full story has yet to be written, personalized medicine’s final chapter is likely to assert the value of genetic lab testing in aiding the selection of therapies for cardiovascular and other diseases.
Jay G. Wohlgemuth, MD, is vice president, science and innovation, for Quest Diagnostics.
The company’s pharmacogenomic tests include its AccuType CP genetic clopidogrel-response test.