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Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease

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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  1. 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

  2. Trial Organization Supported by an Investigator-Initiated Grant from Bristol-Myers Squibb & Sanofi-Aventis. Research Supplies from Accumetrics and Nanosphere.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. CYP2C19*2 Heterozygotes Non-Responders (PRU≥230) P<0.001 Ptrend<0.001 P=0.002 Percent P=0.90 Clopidogrel Daily Dose (mg)

  11.  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.

  12. 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.

  13. Compliance and Events CYP2C19*2 Carriers There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events.

  14. 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.

  15. Published Online First November 16, 2011 Available at www.jama.com

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