Saturday, July 3, 2010

ACCF/AHA Black Box warning on Clopidogrel (Plavix)

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
Date Posted: June 28, 2010
Authors: Holmes DR, Dehmer G, Kaul S, et al.
Citation: J Am Coll Cardiol 2010;Jun 28:[Epub ahead of print].


The following are 10 points to remember about this American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Expert Consensus Document.

1. On March 12, 2010, the Food and Drug Administration (FDA) approved a new label for clopidogrel with a “boxed warning” about the diminished effectiveness of the drug in patients with impaired ability to convert the drug into its active form.

2. Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions than patients with normal CYP2C19 function.

3. The clopidogrel boxed warning leaves the issue of whether to perform CYP2C19 testing up to the individual physician. It serves to make clinicians aware of the imperfect, but significant knowledge that we have about genetic variations in response to clopidogrel, and to emphasize that clinicians should use this knowledge to make decisions about how to treat individual patients.

4. Although genetic variability plays an important role in adenosine diphosphate (ADP)-stimulated platelet aggregation in response to clopidogrel, known genetic and nongenetic factors explain only a portion of the majority of variation.

5. The number of reduced function alleles is important: individuals with one variant allele (intermediate metabolizers) had 26-31% lower exposure to the active metabolite of clopidogrel, and those with two genetic polymorphisms (poor metabolizers) had 46-55% lower exposure compared with those with no CYP2C19 polymorphisms. Other genetic variations (ABCB1, P2Y12 receptor, and the CYP3A4 and CYP3A5 enzymes) may also affect the pharmacokinetics, pharmacodynamics, and clinical efficacy of clopidogrel.

6. Platelet function assays can measure the effect of ADP or P2Y12 activation on platelet aggregation, receptor expression, or the level of intracellular molecules (e.g., vasodilator-stimulated phosphoprotein phosphorylation), thereby directly or indirectly measuring the platelet inhibitory effect of clopidogrel.

7. Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. 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.

8. The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.

9. Higher loading doses (LDs) (600 mg vs. 300 mg), double-dose loading (600 mg twice over 2 hours), and higher maintenance doses (MDs) of clopidogrel (150 mg daily) have been found to improve platelet inhibition and might be considered alternatives for high-risk patients who respond poorly to standard loading and MDs of clopidogrel, although there is uncertainty of the long-term safety and efficacy of this approach. New antiplatelet drugs such as prasugrel and ticagrelor, if FDA approved, are additional alternatives.

10. The risk-benefit ratio, in terms of safety and efficacy of each of these alternative strategies, remains to be determined by adequately powered clinical trials.


Debabrata Mukherjee, M.D., F.A.C.C.

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