Responsiveness to Plavix (clopidogrel) and genetics

Responsiveness to clopidogrel, sold under the brand name Plavix, is an issue for some patients who undergo anti-platelet treatment to prevent heart attack and stroke. Particularly susceptible are patients who receive the drug to prevent clotting and embolism after coronary stenting. Approximately 30 to 40 percent of people have a genetic mutation that makes them unresponsive to clopidogrel treatment. In 2009, Scripps Health began offering, for the first time in the U.S. healthcare arena, a genetic test for patients undergoing coronary stenting to determine upfront whether they will be non-responsive to anti-platelet treatment with clopidogrel. In subsequent years other companies and institutions followed suit, with a clinical point-of-care test that only takes 60 minutes for a result being common enough by 2011 to be the focus of retrospective research.

Clopidogrel is metabolized by the cytochrome P450 (CYP) enzyme family. This metabolism is necessary for activation of the molecule and its anti-platelet effects. Patients with genetic variants of CYP2C19 (known as CYP2C19*2, CYP2C19*3, and so forth) have reduced enzyme activity and, accordingly, reduced activation of the drug. Scripps patients undergoing coronary stenting are tested by Quest Diagnostics for CYP2C19 variants that may affect clopidogrel responsiveness, allowing physicians to choose other anti-platelet drugs (such as prasugrel or ticagrelor) or to adjust dosage to the best benefit of the patient. Patients in other parts of the U.S. have other genetic testing companies their healthcare institutions may consult – such as Boston Heart Diagnostics – or the convenience of the point-of-care system like Nanosphere Verigene, which tests for 11 variants of CYP2C19 within 3 hours.

Some feel that this testing was debuted too soon. Research is still indicating other potential genes involved in the treatment response, including controversial findings regarding PON-1, which encodes the paraoxonase-1 enzyme. The December 2010 findings that PON-1 is the enzyme responsible for bioactivation of clopidogrel have been refuted by more than one study, and CYP2C19 involvement supported. Experts consulted by Heartwire in October 2009 upon Scripps’ announcement felt that platelet function tests were necessary companions to genetic testing at this stage of the research on clopidogrel responsiveness.

In March 2010, the U.S. Food and Drug Administration (FDA) required a warning on Plavix to warn patients that a portion of them may be poor metabolizers of the drug. The warning also reminds health care providers that CYP2C19 genetic tests are available to aid in treatment planning. More than 2 million prescriptions were written for the drug each month in 2010 according to the Wall Street Journal, leading to a great number of genetic tests. Some experts feel that, at best, the testing will aid in researching more appropriate dosing of the drug among those with genetic variants.

According to Heartwire in June 2010, the American Heart Association and American College of Cardiology did not recommend genetic testing as a determinant of therapy. They issued statements that urged care givers to follow current prescribing guidelines. The chair of the joint committee that issued the statement reiterated that the alternative drugs lacked the track record of clopidogrel – but others urged platelet function tests in conjunction with genetic testing to ensure successful treatment planning that benefits the patient. By 2013, the Clinical Pharmacogenetics Implementation Consortium issued guidelines on how genetic test results and alternative therapies can be combined to best serve the patients being treated.

The new approach to genotype-based treatment recognizes how far medicine has come in personalized care. Patients who require anti-platelet treatment to prevent heart attack or stroke can have all the options made available to them with a simple blood test.