Cardiology PRN and American Heart Association Focus

Annual Meeting

Cardiology PRN and American Heart Association Focus Session—The “Me” Generation of Healthcare: Personalized Medicine in Cardiovascular Disease Activity No. 0217-0000-11-072-L01-P (Application-Based Activity) Monday, October 17 1:30 p.m.–3:30 p.m. Convention Center: Spirit of Pittsburgh Ballroom A Moderators: Sheryl L. Chow, Pharm.D., BCPS (AQ Cardiology) Assistant Professor, Western University of Health Sciences, Los Angeles, California and Robert L. Talbert, Pharm.D., FCCP, FAHA, BCPS SmithKline Professor of Pharmacy, Division of Pharmacotherapy, The University of Texas at Austin; Professor of Medicine, The University of Texas Health Science Center, San Antonio, Texas Agenda 1:30 p.m. What Is the Role of Warfarin Genotyping in Current and Future

Clinical Practice? Julie A. Johnson, Pharm.D., FCCP, FAHA, BCPS V. Ravi Chandran Professor of Pharmaceutical Sciences, Distinguished Professor of Pharmacy; Departments of Pharmacotherapy and Translational Research (primary) and Pharmaceutics; and Professor of Medicine, Department of Medicine, Division of Cardiovascular Medicine at the University of Florida Colleges of Pharmacy and Medicine; Director, University of Florida Center for Pharmacogenomics and Director of the University of Florida and Shands Personalized Medicine Program, Gainesville, Florida and L. Kristin Newby, M.D., MHS, FAHA Professor of Medicine and Cardiology, Duke University School of Medicine, Durham, North Carolina

2:30 p.m. Clopidogrel Pharmacogenomics: Will the FDA’s Black Box Change Practice? Eric Bates, M.D., FAHA Professor of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan and Craig R. Lee, Pharm.D., Ph.D. Assistant Professor of Pharmacy, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina

Annual Meeting

Faculty Conflict of Interest Disclosures Eric Bates: consultant/member of advisory board for AstraZeneca, Eli Lilly, sanofi-aventis, Merck, Takeda Julie A. Johnson: consultant/member of advisory board for Medco; clinical investigator for NIH; received grant funding from NIH. Craig R. Lee: no conflicts to disclose. L. Kristin Newby: received grant funding from Adolor Corporation; AstraZeneca, Biostie, Inc., Bristol Myers Squibb, Medicure, sanofi-aventis, Schering-Plough Corporation. Learning Objectives

1. Identify the potential role of warfarin genotyping in current clinical practice. 2. Describe the benefits and limitations of warfarin genotyping. 3. Identify the potential role of clopidogrel genotyping in current clinical practice. 4. Describe the benefits and limitations of clopidogrel genotyping.

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am

W f i h i hWarfarin pharmacogenetics hasa role in current and future

clinical practice

Julie A. Johnson, Pharm.D, BCPS, FCCP, FAHAUniversity of FloridaUniversity of Florida

Gainesville, FL

D lDisclosure

• Site PI and Steering Committee Vice Chair for NHLBI COAG Trial– Genotype-guided warfarin trial

• Leader – International Warfarin Leader International Warfarin Pharmacogenetics Consortium

• Advisory Board Medco• Advisory Board - Medco

Variability in drug responseVar ab l ty n drug responseWARFARIN

Liver function Genetics Disease phenotype

Body Size

Drug ResponseKidney function

Age

Body Size

Drug Response

Disease states

Age

Other drugs Foods

EnvironmentalFactors (e.g. smoking)g smoking)

Trends in Warfarin Use and Stroke RiskM di d t 1992 2002Medicare data: 1992-2002

© 2005-2009 University of Pennsylvania School of Medicine

Lakshminarayan et al. Stroke 2006;37:1969

Warfarin PharmacogeneticsWarfarin Pharmacogenetics

• 2 genes have proven consistently 2 genes have proven consistently predictive and useful in prediction algorithmsalgorithms– CYP2C9

• Alters metabolism of S-warfarinAlters metabolism of S warfarin– Pharmacokinetic factor

– VKORC1• Target of warfarin

– Pharmacodynamic factor

© 2005-2009 University of Pennsylvania School of Medicine

Weekly dose by CYP2C9 genotypey y g yp

International Warfarin Pharmacogenetics Consortium, NEJM 2009;360: 760

CYP2C9 explains 5-15% of warfarin dose variability

Time to First BleedTime to First BleedCYP2C9 variant carriers vs *1*1: HR 3.94

JAMA, April 3, 2002 – Vol 287, No. 13

VKORC1 genotype explains up to 30% of warfarin dose variabilitywarfarin dose variability


Coumadin labelFDA pharmacogenetics revisions to label:

August 2007and January 2010August 2007and January 2010

How do you incorporate clinical ND fAND genetic factors?

• www.warfarindosing.org– Algorithm developed by Brian Gage, g p y g

Washington University; CPT 2008;84:326

• International Warfarin Pharmacogenetics Consortium– 21 research groups, 9 countries, 4

continents, n=5700; NEJM 2009;360:760

Patient initiated on 5 mg/day with multiple high INRsg y p gStable therapeutic dose was 2.14 mg/d (15 mg/wk)

Warfarin dose prediction: Cli i l h i l i hClinical vs pharmacogenetics algorithms


Warfarin dosing precision by i s h svarious approaches

JACC 2011;57:612 (PMID: 21272753)

Clinical validity proven: Genetic guided dosing can improve Genetic-guided dosing can improve

warfarin dose prediction• What are the arguments against its use in clinical

practice?– No randomized controlled trials showing

differences in outcomes• Also don’t have that for anticoag clinics• Also don t have that for anticoag clinics• We do not ask for randomized controlled trials to show

that using renal function to adjust dosing of drugs is betterbetter

– why a different standard for genetics to guide dosing?• There is a prospective cohort study showing that patients

with CYP2C9 and VKORC1 genotype had 30% � in with CYP2C9 and VKORC1 genotype had 30% � in hospitalizations

Hospitalization rates in genotype p g ypgroup and historical controls

JACC 2010;55:2804 (PMID: 20381283

Arguments against use of warfarin pharmacogenetics

Mi i l id f i d ti t t bl INR • Minimal evidence for improved time to stable INR, fewer OOR INRs– Multiple large randomized trials ongoing; US, Europe, p g g g , p ,

Asia• Can manage patient well through close monitoring

of INR and dose adjustmentof INR and dose adjustment– Not helpful for the 80+% of warfarin patients not

managed in an anticoag clinic-type settingPBM d t ti t t bl d i b t 90 d • PBM data - time to stable dose is about 90 days

– Even in an excellent anticoag clinic, time to stable dose 95 days longer in CYP2C9 variant carriers (p=0.004). JAMA;2002:287:1690JAMA;2002:287:1690

Arguments against use of warfarin pharmacogenetics

H d h (h l )• Have to order the test (hassle)• Have to wait for the results (and INR data

i ht d l f t )might reduce value of genotype)– Data suggest value of CYP2C9 genotype (even

with INR) up to 10 days; perhaps 30 days with INR) up to 10 days; perhaps 30 days • Most insurance companies will not

reimburse for the genetic testing ($$)re mburse for the genet c test ng ($$)• Have to know what to do with the test

result when it comes back (education)( )• But….. What if none of these were issues?

Genomics, pharmacogenomics and h ( ) f lithe (near) future reality

• Human Genome Project finished ahead of 15 year Human Genome Project finished ahead of 15 year planned duration; cost $2.7B (2001) – delivered 1 composite genome

$• Today – personal genome costs $5,000 to $20,000, takes about 2 weeks

• In 2-3 years expected to cost < $1000 take < 1 In 2-3 years, expected to cost < $1000, take < 1 day– Discussions on replacing neonatal screening with whole

s igenome sequencing

• At some point, the entire genome (or lots of genetic data) will be available for nearly of genetic data) will be available for nearly all patients

Warfarin pharmacogenetic testing i th li i l tti in the clinical setting:

Now

• Given issues of cost (and unlikely reimbursement), and turn-around time and lack of clear data on and turn around time, and lack of clear data on outcomes or time to stable INR– Reasonable to not use warfarin pharmacogenetic testing in

broad populationbroad population• Although 13M patients with Rx benefit through Medco have it

available to themMay still have value in patient with unusual INR between – May still have value in patient with unusual INR between days 4 and 10; may help clinicians move more quickly to the dose patient will actually require

Warfarin pharmacogenetics: Th fThe future

• If genetic data availableg– No delay – available immediately at time of

warfarin prescriptionC f l d d– Cost for genotyping already accrued

– Smart EMR will incorporate genetic information and other factors to recommend warfarin doseand other factors to recommend warfarin dose

• Can one ignore the genetic information in selecting a starting information in selecting a starting warfarin dose if it were available?– Available data documents ability to better – Available data documents ability to better

predict dose

Warfarin pharmacogenetics: The future

PREDICTION: Genetic information will be • PREDICTION: Genetic information will be routinely incorporated into the calculation of warfarin starting doseof warfarin starting dose

Questions?

Genotyping for Antiplatelet Therapyyp g p pyTwo Perspectives: Con

Eric R. Bates, M.D.

Professor of Internal MedicineProfessor of Internal Medicine

University of Michigan

Conflicts of Interest

No conflicts to disclose.

Top 10 Reasons Why Genotyping for Antiplatelet Therap for Antiplatelet Therapy

Is Not Needed

Patient Compliance Is Much More ImportantIs Much More Important

sis (%

)

Overall ST=1.3% (P=0.09, n=2229)

29.030

nt T

hrom

bos

20

denc

e Ste

n

2 5 3 3 3.66.2

8.710

Unstable angina (UA)

Thrombus Diabetes Unprotected left main

Bifurcation lesion

Renal failure

Prior brachytherapy

Premature antiplatelet

Inci 1.4 2.0 2.5 3.3 3.6

0

( ) y py pdiscontinuation

Iakovou I, et al. JAMA. 2005;293:2126-2130. #10

CYP3A4 Activity/Conversion to Acti e Metabolite is Important

100100

Active Metabolite is Important

8080

100100

on

(%

)o

n (

%)

4040

6060

agg

reg

atio

agg

reg

atio

2020

4040

r=r=--0.60.6PP=.003=.003P

late

let

aP

late

let

a

00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.000

Lau W et al. Circulation. 2004;109:166-171.

CYP3A4 ActivityCYP3A4 Activity--1414COCO22 exhaled/hour (%)exhaled/hour (%)

#9

Clopidogrel-Drug InteractionsM b I t tMay be Important

ClopidogrelBisulfate

Intestinal Absorption

Inactive Carboxylic AcidMetabolite

CYP3A4 CYP3A4/5 inducers: rifampin, St John’s wort, etc.15%

Esterases85%

CYP3A5CYP2C19CYP2C9

Hepatic P450Cytochromes

p , ,CYP3A4/5 inhibitors: erythromycin, atorvastatin, etc.2C19 inhibitors: omeprazole

Smoking (induction)CYP1A22C9 inhibitors: phenprocoumon

Active Thiol MetaboliteMultistep Conversion

Smoking (induction)CYP1A2CYP2B6, 2C19

Inhibition of Platelet Aggregation (Wide Response Variability)

P2Y12 Receptor

Gurbel PA et al. Thromb Res. 2007;120:311-321. Taubert, et al. Clin Pharmacol. 2006;80:486-501. von Beckerth, et al. Eur Heart J. 2007;28:1814-1819. #8

There Are Other Genes

Poor complianceIntestinal AbsorptionInadequate administration

Variable absorption

Genetic polymorphisms:

CYP2C19PMs, CYP2C9*3, ABCB1

Drug-drug interactions

Hepatic MetabolismCytochrome P450 pathway

Drug drug interactions

G ti l hi

Active Metabolite

P2Y Receptor Genetic polymorphisms :

P2Y12 receptor

Alternate platelet activation pathways

P2Y12 Receptor (irreversible inhibition)

GP IIb/IIIa receptor Alternate platelet activation pathways

Genetic polymorphisms

G b/ a eceptoexpression

O’Donoghue M. Circulation. 2006;114:e600-e606.Simon T et al. N Engl J Med. 2009;360:363-375.

Feher G et al. Clin Genetics. 2009;75:1-18.#7

There are Other Platelet ReceptorsOther Platelet Receptors

Platelet Platelet

Thrombin

FibrinogenPAR-4

PAR-1

`ADPADP

GPIIb/IIIa

P2Y1

P2Y12

GPIIb/IIIa

EpinephrineEpinephrine

IIb/IIIaTBX ATBX A22 TBXA2-R

SerotoninSerotonin 5HT A

EPI-R

CollagenCollagen Anionicphospholipid

GP Ia

GP VI

SerotoninSerotonin 5HT2A

phospholipidsurfaces

#6

There Are Important Cli i l F tClinical Factors

#5

Not Much Contribution of CYP2C19*2 T V i ti ICYP2C19*2 To Variation In

Clopidogrel Responsivenessp g p

Genome wide Association StudiesGenome-wide Association Studies

Amish PAPI Study: 12%Amish PAPI Study: 12%

EXCELSIOR Study: 11.5%

Shuldiner AR, et al. JAMA. 2009;302:849-57.Hochholzer W, et al. J Am Coll Cardiol. 2010;55:2427-34.

#4

Loss-of-Function Carrier Status Not Important inCarrier Status Not Important in

(Some) Clinical Trials

No heterogeneity for the first primary (P=0.84), second primary (P=0 87) or safety (P=0 74) endpointsecond primary (P=0.87) or safety (P=0.74) endpoint

Pare G, et al. N Engl J Med. 2010;363:1704-14. #3

Phenotype Is More ImportantOn Treatment Platelet ReactivityOn-Treatment Platelet Reactivity

Pl t l tW k

Impedance Aggregometry PFA-100 ® analysis

PlateletWorks

gg g y(MULTIPLATE)

Born aggregometry

VerifyNow

#2

There Are Better P2Y12 InhibitorsClinical Outcomes: Carriers vs Non-carriers

of a Reduced-function CYP2C19 Allele

More Ischemic Less Ischemic Events Events

Prasugrel 0.89 P=0.27

0.046

Clopidogrel 1.53 P=0.01

3.5 3.0 2.5 2.0 1.5 1.0 0.5

Odds Ratio

Mega JL et al. Circulation. 2009;119:2553-2560.Mega JL et al. N Engl J Med. 2009;360:354-362.

#1

Top 10 Reasons Why Genotyping for Antiplatelet Therap for Antiplatelet Therapy

Is Not Needed

10. Compliance is key! 5. Clinical factors p y

9. Metabolic pathways 4. Limited contribution

8. Drug Interactions

7. Other Genes

3. No RCT proof

2. Phenotype Rules!

6. Other Receptors

yp

1. Better drugs

Clopidogrel Pharmacogenomics:Clopidogrel Pharmacogenomics: Will the FDA’s Black Box Change Practice?

Pro Argument –Clopidogrel-CYP2C19 Black Box Warning:

The Elephant in the Room

Craig R. Lee, Pharm.D., Ph.D.UNC Eshelman School of Pharmacy

UNC Institute for Pharmacogenomics & Individualized Therapyg py

ACCP Annual MeetingPittsburgh PAPittsburgh, PA

October 17, 2011

Personalized MedicineIs this really a new concept?

Definition

• Integrating evidence generated at the population level (e.g., registries, RCT’s) into clinical decisions for individual patientsindividual patients.– Diagnostics, pharmacotherapy

The “Omics” Definition

Can we integrate “omics” into what we already do?

The Omics Definition

• Integrating “omics” technology into clinical decisions– Genomics, biomarkers (e.g., transcriptomics, proteomics,

metabolomics)

Substantial Inter-Individual Variability in Cl id l’ A ti Pl t l t Eff t E i tClopidogrel’s Anti-Platelet Effect Exists

“Resid al” platelet acti it (RPA) associated• “Residual” platelet activity (RPA) associated with higher risk of death, MI and stent thrombosisthrombosis.

Clopidogrel Pharmacogenomics – PK/PD

Clopidogrel (pro-drug)

CYP2C19*1 (wild-type)

Active metabolite

CYP2C19*2• “Null” allele (no metabolic activity)• Accounts for ~75-85% of CYP2C19 ‘poor

metabolizers’ across populations• Caucasian: 15% ; African-Am: 17% ; Asian:

Platelet Function

Caucasian: 15% ; African Am: 17% ; Asian: 30%

• CYP2C19*3 also has “null” function, but less commoncommon

Clopidogrel Pharmacogenomics

Clopidogrelp g

CYP2C19*2

Active metabolite

Pharmacokinetic (lower active metabolite exposure)

Platelet Function

Pharmacodynamic(less inhibition of aggregation)

CYP2C19 genotype predicts clinical outcomeValidated in multiple populations (ACS, PCI)Validated in multiple populations (ACS, PCI)

CV Death / MI / Stroke Stent Thrombosis

CYP2C19 LOF Carrier vs. Wild-type

TRITON-TIMI 38:

CYP2C19 LOF Carrier vs. Wild-type

TRITON-TIMI 38:12.1% vs. 8.0%

HR 1.53 (1.07-2.19)

Mega et al. NEJM. 2009;360:354-62.

2.6% vs. 0.8%HR 3.09 (1.19-8.00)

Mega et al. NEJM. 2009;360:354-62.

Meta-analysis:

HR 1 57 (1 13-2 16) P=0 006

Meta-analysis:

HR 2 81 (1 81-4 37) P<0 001HR 1.57 (1.13-2.16), P=0.006

Mega et al. JAMA. 2010;304:1821-30

HR 2.81 (1.81-4.37), P<0.001

Mega et al. JAMA. 2010;304:1821-30

FDA Labeling Changes(June 2009)

• CYP2C19 variant alleles

→ impaired metabolism to active metabolite (PK)→ less inhibition of platelet activation (PD)

hi h i k f d th / MI / t t th b i ( t )→ higher risk of death / MI / stent thrombosis (outcome)

PRECAUTIONC U O

“… patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of

l id l d di i i h d ti l t l t dclopidogrel and diminished anti-platelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with g y p

normal CYP2C19 function”

Black Box Warning (M h 2010)(March 2010)

Plavix® prescribing information : 3/12/2010

JACC. 2010; 56(4): 321-41

“Information regarding the predictive value of pharmacogenomic testing is very limited at this time”

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

“Genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism (“poor metabolizers”) may be considered before starting clopidogrel therapy in patients believed to be atbefore starting clopidogrel therapy in patients believed to be at

moderate or high risk for poor outcomes.”

“If such testing identifies a potential poor metabolizer, otherIf such testing identifies a potential poor metabolizer, other therapies, particularly prasugrel for coronary patients, should be

considered.”

Clinical Pharmacogenetics Implementation Consortium Guidelines

ACS/PCI PopulationACS/PCI Population

Initiate antiplatelet therapy with standard dosing of clopidogrel

CYP2C19 testing if genotype unknown

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

EM(*1/*1)

IM(*1/*2)

PM(*2/*2)

Standard dosing of clopidogrel

Prasugrel or other alternative therapy

Scott et al. CP&T. 2011;90:328-32.

p g py

Clopidogrel PharmacogenomicsWhat alternatives are available?What alternatives are available?

• Therapeutic switchP l ACS– Prasugrel (FDA approved July 2009) – ACS

– Ticagrelor (FDA approved July 2011) – ACS – Ticlopidine (FDA approved 1991) – stroke, PCITiclopidine (FDA approved 1991) stroke, PCI

• Increase clopidogrel dose– 600-900 mg loading doseg g– 150 mg/day maintenance dose

• Add an adjunctive therapyj py– Cilostazol

• Alter PCI strategygy– Use BMS instead of DES (lower stent thrombosis risk)

If a patient presented for PCI, and they were known to carry a CYP2C19*2 variant allele,known to carry a CYP2C19 2 variant allele,

what course of action would you take?

Documents

Cardiology PRN and American Heart Association Focus