Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease
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Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease. JL Mega, W Hochholzer, AL Frelinger III, MJ Kluk, S Isserman, WJ Rogers, DJ Angiolillo, DJ Kereiakes, CT Ruff, DD Berg, J Cyr, BM Scirica, L Grip, RA Mesa,

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Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease

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Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Increasing ClopidogrelBased on CYP2C19 Genotypein Patients with Cardiovascular Disease

JL Mega, W Hochholzer, AL Frelinger III, MJ Kluk,

S Isserman, WJ Rogers, DJ Angiolillo, DJ Kereiakes,

CT Ruff, DD Berg, J Cyr, BM Scirica, L Grip, RA Mesa,

JF Mattimore, JA Longtine, AD Michelson, MS Sabatine


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Trial Organization

Supported by an Investigator-Initiated Grant from Bristol-Myers Squibb & Sanofi-Aventis.

Research Supplies from Accumetrics and Nanosphere.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

PI: GineteRC: GundersonDuluth, MN

PI: HamroffRC: Fuerst-Carter

Cortland Manor, NY

PI: Peterson

RC: Pape

Spokane, WA

PI: GipsRC: Davis

Haddon Heights, NJ

PI: FerrierRC: HockettRapid City, SD

PI: StaniloaeRC: Pinassi

New York, NY

PI: AlbiriniRC: Campbell

Zanesville, OH

PI: BhagwatRC: Winterrowd

Hammond, IN

PI: DenningRC: Cuenot

Canton, OH

Dr. BlonderRC: Gneiting

Colorado Springs, CO

PI: Cole

RC: Fisher

Baltimore, MD

PI: Kereiakes

RC: White

Cincinnati, OH

PI: Haskel

RC: Powell

Baltimore, MD

PI: Korban

RC: Manns

Jackson, TN

PI: Isserman

RC: Moore

Hickory, NC

PI: Goldberg

RC: BarrettLa Mesa, CA

PI: JonesRC: Stover

Birmingham, AL

PI: Wefald

RC: Moore

Smithfield, NC

PI: ReddyRC: Qureshi

Atlanta, GA

PI: Bertolet

RC: McDuffie

Tupelo, MS

PI: AycockRC: Tatum

Pensacola, FL

PI: RogersRC: Thorington

Birmingham, AL

PI: SotolongoRC: Jones

Jacksonville Beach, FL

PI: Kleiman

RC: Hernandez

Houston, TX

PI: PeartRC: Stephens

Tucson, AZ

PI: Angiolillo

RC: McElveen

Jacksonville, FL

PI: Chandna

RC: Holly

Victoria, TX

PI: DotyRC: Parsons

Pensacola, FL

PI: Iteld

RC: Stevenson

Slidell, LA

PI: Fastabend

RC: Bruney

Lake Charles, LA

PI: Katopodis RC: Knap

Tallahassee, FL

PI: VicariRC: St. Cyr

Melbourne, FL


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Variable Response to Clopidogrel

24 Hours After 300mg Clopidogrel

N=96, Elective PCI

20

Patients (%)

10

≤ -30

(-20,-10)

(0,10)

(20,30)

(40,50)

>60

(-30,-20)

(-10,0)

(10,20)

(30,40)

(50,60)

 Platelet Aggregation Before and After Clopidogrel (%)

Gurbel PA et al. Circulation 2003;107:2908-13.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Clopidogrel → Active Metabolite

O

CH3

O

C

N

S

Cl

Clopidogrel 75 mg

Clopidogrel (pro-drug)

Clopidogrel Metabolite

(Log AUC0-t)

hCE1

85% Inactive Metabolites

CYPs:2C19

1A22B6

O

CH3

O

C

CYPs:2C19

3A2B62C9

N

O

S

0

(non-carriers/

wild-type)

1

(heterozygotes)

2

(homozygotes)

Cl

CYP2C19

Reduced-

Function

Alleles

26%

2%

OCH3

O

28%

Carriers

N

HOOC

Cl

* HS

Active Metabolite

Mega JL, Close SL, Wiviott SDet al. N Eng J Med. 2009;360:354-62.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Hypotheses

  • Increasing the daily maintenance dose of clopidogrel in patients who carry a CYP2C19*2 allele will reduce platelet reactivity.

  • Among carriers of CYP2C19*2,a highermaintenance dose of clopidogrel will reduce platelet reactivity to the levels achieved in non-carrierstreated with the standard 75 mg daily dose of clopidogrel.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Study Design

Investigator-Initiated Study

IND #: 107635

335 Patients Enrolled

Stable CAD Pts on Clopidogrel 75 mg daily

(>4 Weeks and <6 Months Post-MI or PCI)

2 Not Genotyped

333 Blinded Genotyping

247 CYP2C19*2 Non-Carriers

86 CYP2C19*2 Carriers

(80 Heterozygotes; 6 Homozygotes)

Randomized to various blinded sequences of daily doses of clopidogrel

Randomized to various blinded sequences of daily doses of clopidogrel

225 mg

75 mg

150 mg

300 mg

75 mg

75 mg

150 mg

150 mg

Each dose given for ~14 days followed by platelet function testing(VASP and VerifyNow P2Y12 assays) and assessment for events


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

75 mg Clopidogrel Daily

VerifyNow PRU

VASP PRI

Non-

Carriers

Non-

Carriers

CYP2C19*2

Heterozygotes

CYP2C19*2

Heterozygotes

CYP2C19*2

Homozygotes

CYP2C19*2

Homozygotes

<0.001

<0.001

<0.001

%

PRU

<0.001

Squares represent the means and vertical lines the 95% confidence intervals.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

CYP2C19*2 Heterozygotes

VerifyNow PRU

VASP PRI

Ptrend<0.001

Ptrend<0.001

PRU

%

Clopidogrel Daily Dose (mg)

Squares represent the means and vertical lines the 95% confidence intervals.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

CYP2C19*2 Heterozygotes

Non-Responders (PRU≥230)

P<0.001

Ptrend<0.001

P=0.002

Percent

P=0.90

Clopidogrel Daily Dose (mg)


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

 Clopidogrel in CYP2C19*2 Heterozygotes

vs. 75 mg in Non-Carriers

Non-

Carriers

CYP2C19*2

Heterozygotes

PRUdiff +61

P<0.001

PRUdiff +24

P=0.02

PRUdiff -10

P=0.31

PRU

PRUdiff -37

P<0.001

Clopidogrel Daily Dose (mg)

Squares represent the means and vertical lines the 95% confidence intervals. Differences are reported as least squares differences.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Platelet Reactivity with  Clopidogrel

Non-

Carriers

CYP2C19*2

Heterozygotes

CYP2C19*2

Homozygotes

PRU

Clopidogrel Daily Dose (mg)

Squares represent the means and vertical lines the 95% confidence intervals.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Compliance and Events

CYP2C19*2 Carriers

There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Conclusion

Among patients with stable CV disease:

  • CYP2C19*2 heterozygotes: tripling the maintenance dose of clopidogrel to 225 mg daily achieved levels of platelet reactivity similar to the standard 75 mg dose in non-carriers.

  • CYP2C19*2 homozygotes: even 300 mg of clopidogrel daily, is unlikely to result in optimal degrees of platelet inhibition.


Increasing clopidogrel based on cyp2c19 genotype in patients with cardiovascular disease

Published Online First

November 16, 2011

Available at

www.jama.com


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