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.
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 lossof-function alleles); intermediate metabolizers (1 loss-offunction 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