Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants...

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Cardiovascular pharmacogenomics: ready for prime time? Simon de Denus, pharmacist, MSc (Pharm), PhD Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics Assistant professor, Faculty of Pharmacy, Université de Montréal Co-director of the heart failure research group, Montreal Heart Institute March 12, 2012

Transcript of Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants...

Page 1: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Cardiovascular pharmacogenomics:

ready for prime time?

Simon de Denus, pharmacist, MSc (Pharm), PhD

Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics

Assistant professor, Faculty of Pharmacy, Université de Montréal

Co-director of the heart failure research group,

Montreal Heart Institute

March 12, 2012

Page 2: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• I have received grants or been an co-

investigator of grants from AstraZeneca,

Pfizer, Hoffman-Laroche, Novartis et

Johnson et Johnson

Disclosures

Page 3: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Plan of the presentation

• Overview of pharmacogenomics

• Warfarin and clopidogrel pharmacogenomics,

ready for prime time?

• Conclusion

Page 4: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• An allele represents one of two or

more versions of a genetic sequence at

a particular location in the genome.

• The term genotype refers to the two

alleles inherited for a particular gene.

Allele to Genotype

N Engl J Med 2010;362:2001-11.

Page 5: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Why personalized medicine?

Brunner M, et al. Am J Cardiol. 2007;99:1549-54. Gandhi TK, et al. NEJM 2003;348:1556-64. Lazarou J, et al. JAMA.

1998;279:1200-05. Evans WE, McLeod HL. NEJM 2003;348:538-49. Jackevicius, C. A. et al. CMAJ 2009;181:E19-E28

• Variable response to CV drugs

• Adverse drug reactions in the US:

– 4th to 6th cause of death

– 2 million hospitalisations/year

– Up to $160 billion/year

• The annual cost of CV medications in

Canada surpassed $5 billion in 2006

Page 6: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Potential of Pharmacogenomics

All patients with same diagnosis

1

2

Responders and patients not predisposed to toxicity

Non-responders and toxic

responders

Treat with alternative

or agent dose

Treat with conventional

drug or dose

Page 7: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Drug Biomarker

Atorvastatin LDL receptor Carvedilol CYP2D6 Clopidogrel CYP2C19

Isosorbide dinitrate and Hydralazine NAT1; NAT2 Prasugrel CYP2C19 Pravastatin ApoE2 Propafenone CYP2D6 Propranolol CYP2D6 Quinidine CYP2D6 Timolol CYP2D6 Ticagelor CYP2C19

Warfarin CYP2C9, VKORC1

Cardiovascular drugs with Pgx

information in their labels

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Accessed on February 13th 2012.

Page 8: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Pgx of clopidogrel and warfarin,

ready for prime time?

• It all depends on the evidence!

Page 9: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Warfarin

Page 10: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• Many clinical studies have associated

CYP2C9 and VKORC1 with:

– Warfarin dosing requirements

– The risk for overanticoagulation and bleeding

• Nevertheless, data from randomized

studies demonstrating the clinical utility of

genotype-guided warfarin prescribing is

limited.

Association of CYP2C9 and

VKORC1 and warfarin

Schwarz UI, et al. N Engl J Med 2008;358:999-1008. Voora L, et al. Thromb Haemost 2005; 93: 700-5.

Rieder, MG, et al. N Engl J Med 2005;352:2285-93. Andersen JL. Circulation. 2007;116:2563-2570.

Page 11: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest
Page 12: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Clopidogrel

Page 13: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Clopidogrel pharmacokinetics

http://www.pharmgkb.org/do/serve?objId=PA154424674&objCls=Pathway

Page 14: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Clopidogrel pharmacogenomics

• Patient undergoing PCI treated with clopidogrel

who are carrying a reduced-function CYP2C19

allele (e.g. *2 or *3) have a higher risk of

cardiovascular events, including stent thombosis.

• A meta-analysis by Mega indicated that carriers

of two reduced-function allele may have a near

four-flod increase in the risk of sent thrombosis.

Mega JL, et al. N Engl J Med. 2009;360:354-62. Simon T, et al. N Engl J Med. 2009:22; 360:363-75. Sibbing

D, et al. Eur Heart J. 2009 Apr;30(8):916-22. Mega JL, et al. JAMA. 2010;304:1821-1830

Page 15: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Can we do anything about this?

• Use of high-dose clopidogrel?

– In stable CAD patients (n = 333), clopidogrel 225-300

mg/day produced similar levels of platelet reactivity in

CYP2C19*2 heterozygotes than 75 mg in non carriers.

• But not in homozygotes!

– No Pgx data available from CURRENT-OASIS 7

– Limited data from GRAVITAS study.

• No improvement in reduced function CYP2C19 alleles

• Alternatives?

– The effects of prasugrel and ticagrelor are independent of

CYP2C19.

• Genotype-guided use vs unselected use of these new agents ?

Price AJ, et al. JAMA. 2011;305(11):1097-1105. CURRENT-OASIS 7 Investigators. N Engl J Med. 2010 ;363:930-42. Mehta

SR, et al. Lancet 2010; 376: 1233–43. Wallentin L, et al. Lancet 2010; 376: 1320–28. Mega JL, et al. Circulation

2009;119:2553-60. Mega JL, et al. JAMA 2011;306:2221-8.

Page 16: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Pgx of clopidogrel and warfarin,

ready for prime time?

• It all depends on the evidence!

• … and your definition of “evidence”

Page 17: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

« Evidence » - based pharmacogenomics

• Marked differences in the evaluation of the

“evidence”

– American Heart Association, American College of Chest

Physician

• RCTs are at the center of the evaluation process.

– Evaluation of Genomic Applications in Practice and

Prevention (EGAPP)

• One (Level 2) or two (level 1) RCTs are required to provide

convincing evidence of clinical utility

– Clinical Pharmacogenetics Implementation Consortium

of the NIH’s Pharmacogenomics Research Network:

• Level 1 evidence: the evidence includes consistent results from

well-designed, well-conducted studies.

Page 18: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

CYP2C19 and AHA/ACC

• “Genotyping for CYP2C19 for a loss of function

variant in patients wih UA/NSTEMI (or after ACS

with PCI) on lopidogrel herapy might be

considered if results of testing mau alter

management (IIB recommendation; LOI:C)”

2011 ACCF/AHA Focused Update of the Guidelines

Page 19: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

The Clinical Pharmacogenetics Implementation Consortium of

the NIH Pharmacogenomics Research Network - Clopidogrel

ACS/PCI patient population

Initiate antiplatelet therapy with

standard dosing of clopidogrel

CYP2C19 testing if

genotype is unknown

Strength of the

recommandation

UM

(*1/*17, *17/*17)

EM

(*1/*1) IM

(*1/*2) PM

(*2/*2)

Standard dosing of clopidogrel

Prasugrel or other

alternative therapy*

* If not contraindicated

Strong Strong Moderate

Adapted from Scott SA, et al. Clin Pharmacol Ther. 2011;90:328-32.

Page 20: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• « For patients initiating VKA therapy,

we recommend against the routine use

of pharmacogenetic testing for guiding

doses of VKA (Grade 1B).”

Warfarin pharmacogenomics and ACCP

Guyatt GH et al. Chest 2012 141:2 suppl 7S-47S.

Page 21: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• « The recommendations for dosing based

on genotype contained herein are rated as

level A, or strong, (...) However, (...) the

impact on clinical outcomes is unknown. »

The Clinical Pharmacogenetics Implementation Consortium

of the NIH Pharmacogenomics Research Network - Warfarin

Johnson JA, et al. Clin Pharmacol Ther. 2011;90:625-9.

Page 22: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

If you knew one of your patients undergoing PCI

with stenting was a CYP2C9*2/*2, would you…

A. … prescribe clopidogrel?

B. … prescribe clopidogrel and monitor using a

platelet function test?

C. … prescribe prasugrel?

D. … prescribe ticagrelor?

E. … feel a bit nostalgic about the good ‘ol

times and prescribe ticlopidine?

Page 23: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

If you had access to CYP2C9 and VKORC1 genotype

when you initiate warfarin in a patient, would you…

A. … prescribe warfarin as per your usual practice

B. … prescribe warfain dosing based on a clinical and

genetic algorithm

C. … prescribe dabigatran

D. I’m hungry, finish already, lunch is about to be served!

Page 24: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Can RCTs of Pgx markers be performed?

• Yes!

– Example: HLA-B*5701 screening for

hypersensitivity to abacavir.

Mallal S, et al. N Engl J Med. 2008;358:568-79.

Page 25: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Are they always necessary?

• No, not always.

• We use « markers » to personalize our selection

of drugs, in the absence of RCTs:

– Choice of an antibiotic in a patient treated with digoxin

or warfarin (clarithromycin vs cefuroxime)

– Choice of a beta-blocker in a patient with severe renal

dysfunction (atenolol vs metoprolol)

Page 26: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• Clopidogrel

– RCTs not necessary when alternatives exist for a

specific indication (prasugrel or ticagrelor in non-ST

elevation ACS undergoing a PCI)

– Becomes a question of the cost-effectiveness of the Pgx

tests

• Would not be an issue if the information was readily available

– Do we have RCTs of all drugs for which we adjust dosage based

on renal function?

Are they always necessary?

Page 27: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

Are they always necessary?

• Different paradigms:

– An alternative for personalizing the therapy is

available

• Monitoring of warfarin using the INR

– The Pgx test leads to withholding treatment (or

providing a less effective treatment):

• Beta-blockers appear ineffective in heart failure

patients who are ADRB1 Gly389 carriers

Page 28: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest

• For most CV drugs, no.

• Warfarin

– Extensive data

– RCTs are required to determine whether genotype-

guided therapy is superior to INR-guided

• Clopidogrel

– Testing for CYP2C19 should be considered following

PCI as alternatives are available

• Cost-effectiveness?

– Not readily available (or low cost) as creatinine clearance or

concomitant meds.

• Availability of point-of-care tests?

Cardiovascular pharmacogenomics:

ready for prime time?

Page 29: Cardiovascular pharmacogenomics: ready for prime time?...March 12, 2012 • I have received grants or been an co-investigator of grants from AstraZeneca, ... American College of Chest