Simon de Denus, pharmacist, MSc (Pharm), PhD Université de Montréal Beaulieu-Saucier Chair in Pharmacogenomics Assistant professor, Faculty of

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1 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 Researcher, Pharmacist, Montreal Heart Institute April 17th 2011

2 Genetic Variation Patient 1 Patient 2 Patient 3 What is a SNP? Single Nucleotide Polymorphism - can be rare or common in specific populations Patient 4 Patient 1 A C T G A C T G Patient2 A C T G C C T G Patient 3 A C T G A C T G Patient4 A C T G A C T G

3 Allele to Genotype 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 Genotype N Engl J Med 2010;362:

4 Why ypersonalized medicine? 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 Brunner M, et al. Am J Cardiol. 2007;99: Gandhi TK, et al. NEJM 2003;348: Lazarou J, et al. JAMA. 1998;279: Evans WE, McLeod HL. NEJM 2003;348: Jackevicius, C. A. et al. CMAJ 2009;181:E19-E28

5 Potential of Pharmacogenomics All patients with same diagnosis 1 Non-responders and toxic responders 2 Treat with alternative dose Responders and patients not predisposed to toxicity Treat with conventional drug or dose

6 Cardiovascular drugs with Pgx information in their labels Drug Atorvastatin Carvedilol Clopidogrel Isosorbide dinitrate and Hydralazine Propafenone Propranolol Quinidine Timolol Warfarin Biomarker LDL receptor CYP2D6 CYP2C19 NAT1; NAT2 CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP2C9, VKORC1 Accessed on April 7th 2011.

7 Pgx of clopidogrel and warfarin, ready for prime time? It all depends on the evidence!

8 Warfarin

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10 Warfarin Metabolism and Activation Pathway Candidate proteins in the pathway Warfarin CYP1A1 CYP1A2 CYP3A4 rin rin R-warfariwarfari R-warfarin Vitamin K Reductase S-w S-warfarin S-warfarin CYP2C9 Oxidized Vitamin K Calumenin Reduced Vitamin K CO 2 O 2 Hypofunctional F. II, VII, IX, X Protein C, C S, S Z γ-glutamyl glutamyl carboxylase Functional F. II, VII, IX, X Proteins C, S, Z Gage et al. 2005

11 Association of CYP2C9 and VKORC1 and warfarin dosing N = 369 P < CYP2C9 Rieder, MG, et al. N Engl J Med 2005;352:

12 Coumarin derivatives and excessive anticoagulation Voora L, et al. Thromb Haemost 2005; 93: Schwarz UI, et al. N Engl J Med 2008;358:

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14 Results: Unadjusted 6 mo. hospitalization rates >=1 hospitalization per 100 patients/6months 28% Historical control (n=2688) Intervention group (n=896) % All cause Bleed or thromboembolism p-value < Intention to treat (ITT) Epstein RS, et al. J Am Coll Cardiol 2010:

15 Circulation. 2007;116:

16 Clopidogrel

17 Clopidogrel pharmacokinetics

18 Mega JL, et al. N Engl J Med. 2009;360:

19 Balance of Efficacy and Safety Endpoint (%) CV Death / MI / Stroke Clopidogrel Prasugrel events HR 0.81 ( ) 0.90) P= NNT = TIMI Major NonCABG Bleeds Prasugrel Clopidogrel Days Wiviott SD, et al. N Engl J Med. 2007;357: events HR 1.32 ( ) 1.68) P=0.03 NNH = 167

20 Primary end point according to CYP2C19 genotype in patients receiving clopidogrel Mega JL, et al. N Engl J Med. 2009;360:

21 Risk of stent thrombosis according to CYP2C19 genotype in patients receiving clopidogrel Mega JL, et al. N Engl J Med. 2009;360:

22 Replication???

23 Replication!!!

24 Can we do anything about this? Use of high-dose clopidogrel? 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. Genotype-guided use vs unselected use of these new agents in all patients? Price AJ, et al. JAMA. 2011;305(11): CURRENT-OASIS 7 Investigators. N Engl J Med ;363: Mehta SR, et al. Lancet 2010; 376: Wallentin L, et al. Lancet 2010; 376: Mega JL, et al. Circulation 2009;119:

25 Pgx of clopidogrel and warfarin, ready for prime time? It all depends on the evidence! and your definition of evidence

26 «Evidence» - based medicine 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 t results from well-designed, well-conducted studies.

27 Cardiovascular drugs with Pgx information in their labels Drug Atorvastatin Carvedilol Clopidogrel Isosorbide dinitrate and Hydralazine Propafenone Propranolol Quinidine Timolol Warfarin Biomarker LDL receptor CYP2D6 CYP2C19 NAT1; NAT2 CYP2D6 CYP2D6 CYP2D6 CYP2D6 CYP2C9, VKORC1 Accessed on April 7th 2011.

28 Can RCTs of Pgx markers be performed? Yes! Mallal S, et al. N Engl J Med. 2008;358:

29 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 blocker in a patient with severe renal dysfunction (atenolol vs metoprolol)

30 Are they always necessary? Clopidogrel RCTs not necessary when alternatives exist for a specific indication (prasugrel or ticagrelor in non-st elevation ACS undergoing a PCI) How ethical are such RCTs? Becomes a question of the cost-effectiveness of the Pgx testst 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? 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non ST-Elevation Myocardial Infarction Circulation online before print

31 Are they always necessary? Different paradigms: An alternative e for personalizing ing 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

32 Cardiovascular pharmacogenomics: ready for prime time? For most CV drugs, no. Warfarin Extensive data RCTs are required to determine whether genotype- guided therapy is superior to INR-guided Clopidogrel l Testing for CYP2C19 should be considered for specific indications where alternatives are available Cost-effectiveness? Availability of point-of-care tests?

33 Ashley EA, et al. Lancet. 2010;375: The future

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35 «Prediction is very difficult, especially about the future.» Niels Bohr, Danish physicist.

36 Summary Many Pgx associations reported in CV diseases Few replicated associations with clinical outcomes (clopidogrel and warfarin) The definition of «Evidence-based practice» in Pgx remains an issue of discussion Personalized evaluation of the evidence

37 Is this clinically relevant?

38 TRITON TIMI 38 Genex treatment interaction Mega ML, et al. Circulation 2009;119:

39 TRITON-TIMI 38 - Pgx of clopidogrel Mega ML, et al. N Engl J Med. 2009;360:

40 Other biomarkers in CV diseases B-type natriuretic peptide (BNP) and NT- probnp Established diagnostic and prognostic markers of heart failure Commonly used to enrich clinical Others: Left ventricular ejection fraction, QRS duration Cannot distinguish «responders» from «non responders», only low vs high-risk Still no convincing data regarding BNP-guided therapy.

41 SNP (pronounce snip!), is A) One of the 3 Rice Krispies characters (SNP, Crackle et Pop!) B) A rap band from the 90 s C) The abbreviation of Single Nucleotide Polymorphisms

42 Association Studies Uses: Unrelated individuals Case and Controls Reconstruct ancestral haplotypes Cardon and Bell, Nature Reviews: Genetics, 2001

43 Maladies mendéliennes vs maladies complexes Maladies mendéliennes (ex: Fibrose kystique) Gène 1 Maladies complexes (ex: hypertension) Gène 5 Gène 1 Gène 2 Gène 4 Gène 3 L expression de la maladie est sous le contrôle d un gène à forte pénétrance Environneme nt Plusieurs facteurs génétiques et environnementaux conférant un faible risque sont impliqués.

44 GWAS of clopidogrel PD

45 Is this clinically relevant?

46 Too much hype??? JAMA. 2010;304:

47 Plan of the presentation Genetics 101 Do we need personalized medicine? Selected examples: Warfarin Clopidogrel Ready for prime time? Summary and conclusions

48 Oh, I forgot,. here s mygenome

49 Variant alleles frequencies differ significantly between populations Yasuda, et al. Clin Pharmacol Ther ;84:

50 The Treatment of CV diseases; "A One Size Fits All Approach " The efficacy and safety of drugs are established in populations. In practice, we treat individuals.

51 Pharmacogenomics is complex (genetics) de Denus S, et al. Pharmacogenomics. In : Clinical approach to cardiac death syndromes. R Brugada, ed. Spinger; 2010: