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 American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society for Thoracic Surgeons (final endorsement list TBD) David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved. 1

WRITING COMMITTEE MEMBERS David R. Holmes, Jr, MD, FACC, FSCAI, Chair Gregory J. Dehmer, MD, FACC, FAHA, FSCAI, FACP Dana Leifer, MD, FAHA Sanjay Kaul, MBBS, FACC, FAHA Patrick T. O'Gara, MD, FACC, FAHA C. Michael Stein, MD David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Clopidogrel 1. An antiplatelet drug used in patients with cardiovascular disease to reduce risk for heart attack, stroke, unstable angina, and cardiovascular death. The liver’s cytochrome P450 (CYP) system converts it to its active metabolite. Several genotypes of the liver enzyme exist in humans: CYP2C19* 2,*3, *4, *5, *6, *7, and *8. 2. There are subgroups of patients (2-14% of the population) who are poor metabolizers of clopidogrel because of genetic differences (genetic polymorphisms) in this enzyme. Racial background is also a factor. As a result, these patients do not get the drug’s full benefit and have a higher risk for cardiac, cerebrovascular, and peripheral arterial events. David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Boxed Warning On March 12, 2010 the FDA approved a boxed warning for clopidogrel to Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body. Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function. Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug FDA Drug Safety Communication, March 2010 © 2010, American Heart Association. All rights reserved

Pharmacogenetics of Clopidogrel CYP2C19 polymorphisms exist in 3 major forms. CYP2C19*1 – normal function Loss-of-function alleles are CYP2C19*2 and CYP2C1*3, accounting for 85-99% of the nonfunctioning alleles for Asians and whites Other forms exist that could play a role in reduced clinical response. The number of reduced function alleles is also important. David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Ethnic Differences Approximately 50% of Chinese, 34% of African Americans, 25% of Caucasians and 19% of Mexican Americans carry at least 1 copy of the reduced function CYP2C19*2 allele. David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Issues The FDA did not offer a recommendation to do routine CYP2C19 genetic testing. Rather, they provided the information and left the decision to the clinician. The boxed warning addressed ‘poor’ metabolizers only (2 loss-of-function alleles); intermediate metabolizers (1 loss-of-function allele) may have reduced antiplatelet levels with clopidogrel, also. Information on this area is incomplete and changing; some data are not finalized. Prospective trials are needed. For currently available genetic tests: cross validation is limited; results are not available in the acute setting; point-of-care assays are not currently available; cost is about $500 and is not usually reimbursed. David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Recommendations for Practice Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined. Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. Continued on Next Slide David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Recommendations for Practice Continued The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. There are several possible therapeutic options for patients who experience an adverse event while taking clopidogrel in the absence of any concern about medication compliance. Alternative dosing strategies or newer antiplatelet drugs could improve platelet inhibition and might be considered. David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved

Conclusions Because of a lack of evidence-based data, specific recommendations and strategies for routine genetic testing and identification of optimal care strategies cannot be offered at this time. “The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. There is no information that routine testing improves outcome in large subgroups of patients. In addition, the clinical course of the majority of patients treated with clopidogrel without either genetic testing or functional testing is excellent. …Careful clinical judgment is required to assess the importance of the variability in response to clopidogrel for an individual patient and its associated risk to the patient.” David Holmes, et al, ACCF/AHA Clinical Alert , 2010 © 2010, American Heart Association. All rights reserved