ACCF AHA Clopidogrel Clinical Alert.pptx

7/27/2019 ACCF AHA Clopidogrel Clinical Alert.pptx

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David Holmes, et al, ACCF/AHA Clinical Alert , 2010 2010, American Heart Association. All rights reserved .

ACCF/AHA Clopidogrel Clinical Alert:Approaches to the FDA Boxed

Warning A Repor t of the Am erican Col lege of Cardio logy Foundat ion

Task Force on Cl in ical Exper t Consensus Document s and the Am erican Hear t Associa t ion

Endorsed by the American Academy of Family Physic ians ,Socie ty for Cardiovascular Angiog raphy

and In tervent ions , and the Socie ty for Tho rac ic Surgeons (final endorsement l i s t TBD)


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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, MDDavid Holmes, et al, ACCF/AHA Clinical Alert , 2010 2010, American Heart Association. All rights reserved


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Clopidogrel

1. An antiplatelet drug used in patients with cardiovascular disease to reduce risk for heart attack, stroke, unstable angina,and cardiovascular death. The livers cytochrome P450 (CYP)system converts it to its active metabolite. Several genotypesof 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 p o o r metabolizers of clopidogrel because of geneticdifferences (genetic polymorphisms) in this enzyme. Racialbackground is also a factor. As a result, these patients do notget the drugs 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


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Boxed WarningOn 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 effectivelyconvert Plavix to its active form in the body.

Inform healthcare professionals that tests are available toidentify 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
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htmhttp://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htmhttp://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htmhttp://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm


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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 Asiansand whites

Other forms exist that could play a role in reduced clinicalresponse.

The n u m b e r of reduced function alleles is also important.



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Ethnic Differences

Approximately

50% of Chinese, 34% of African Americans, 25% of Caucasians and 19% of Mexican Americanscarry at least 1 copy of the reduced function CYP2C19*2

allele.



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Issues The FDA did not offer a recommendation to do routine

CYP2C19 genetic testing. Rather, they provided theinformation 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 withclopidogrel, also.

Information on this area is incomplete and changing; somedata 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-careassays are not currently available; cost is about $500 and is notusually reimbursed.



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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 CYPenzymes alter clopidogrel metabolism, which in turn can affectits inhibition of platelet function.

The specific impact of the individual genetic polymorphisms onclinical 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 ongoingstudies.

Cont inued o n Next Sl ide



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Recommendations for PracticeContinued

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

There are several possible therapeutic options for patients who experience an adverse event while takingclopidogrel in the absence of any concern aboutmedication compliance.

Alternative dosing strategies or newer antiplatelet drugscould improve platelet inhibition and might beconsidered.



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ConclusionsBecause of a lack of evidence-based data, specific

recommendations and strategies for routine genetic testing andidentification of optimal care strategies cannot be offered at

this time.

The evidence base is insufficient to recommend either routinegenet ic or p la tele t funct io n tes t ing a t the present t im e. There i s no in fo rmat ion tha t rou t ine te s ting im proves ou tco me in l a rge subg roups o f p a ti en t s . In add i t ion , the c l in ica l course o f the m ajor i ty of pat ients t rea ted wi th c lopid og rel wi th ou t ei ther genetic testing or functional testing is excellent. Careful c l in ical judgm ent i s r equ i red to assess the impo r tance o f the var iabi l i ty in respon se to c lopido grel for an ind ividu al pa t ient and its associated risk to the patient.


ACCF AHA Clopidogrel Clinical Alert.pptx

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