Increasing Clopidogrel Based on CYP2C19 Genotype in Patients with Cardiovascular Disease

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1 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, JF Mattimore, JA Longtine, AD Michelson, MS Sabatine

2 Trial Organization TIMI Study Group Brigham and Women s Hospital Harvard Medical School Clinical Events Adjudicator Independent Data Monitor UT Southwestern Platelet Function Laboratory Children s Hospital Genotyping Laboratory Brigham and Women s Hospital Independent Biostatistics Harvard Clinical Research Institute M Sabatine, MD, MPH (Chairman) J Mega, MD, MPH (PI) W Hochholzer, MD & C Ruff, MD, MPH (Co-Inv) L Grip, BA (Project Director) R Mesa, BS & J Mattimore, BA (Research Monitors) J Cyr, PA & D Berg, MD (Medical Monitors) C Contant, PhD (Director of Biostats) S Mohanavelu, MS & K Crowley, MS (Stats) B Scirica, MD, MPH J de Lemos, MD A Michelson, MD A Frelinger, PhD J Longtine, MD, PhD M Kluk, MD, PhD M Pencina, PhD L Lei & G Doros, PhD Supported by an Investigator-Initiated Grant from Bristol-Myers Squibb & Sanofi-Aventis. Research Supplies from Accumetrics and Nanosphere.

3 PI: Ginete RC: Gunderson Duluth, MN PI: Hamroff RC: Fuerst-Carter Cortland Manor, NY PI: Peterson RC: Pape Spokane, WA PI: Goldberg RC: Barrett La Mesa, CA PI: Peart RC: Stephens Tucson, AZ PI: Ferrier RC: Hockett Rapid City, SD Dr. Blonder RC: Gneiting Colorado Springs, CO PI: Chandna RC: Holly Victoria, TX PI: Katopodis RC: Hernandez Huston, TX PI: Fastabend RC: Bruney Lake Charles, LA PI: Bertolet RC: McDuffie Tupelo, MS PI: Bhagwat RC: Winterrowd Hammond, IN PI: Korban RC: Manns Jackson, TN PI: Iteld RC: Stevenson Slidell, LA PI: Albirini RC: Campbell Zanesville, OH PI: Kereiakes RC: White Cincinnati, OH PI: Rogers RC: Thorington Birmingham, AL PI: Jones RC: Stover Birmingham, AL PI: Doty RC: Parsons Pensacola, FL PI: Gips RC: Davis Haddon Heights, NJ PI: Denning RC: Cuenot Canton, OH PI: Haskel RC: Powell Baltimore, MD PI: Aycock RC: Tatum Pensacola, FL PI: Katopodis RC: Knap Tallahassee, FL PI: Reddy RC: Qureshi Atlanta, GA PI: Vicari RC: St. Cyr Melbourne, FL PI: Staniloae RC: Pinassi New York, NY PI: Isserman RC: Moore Hickory, NC PI: Wefald RC: Moore Smithfield, NC PI: Sotolongo RC: Jones Jacksonville Beach, FL PI: Angiolillo RC: McElveen Jacksonville, FL PI: Cole RC: Fisher Baltimore, MD

4 Patients (%) Variable Response to Clopidogrel Hours After 300 Clopidogrel N=96, Elective PCI (-20,-10) (-30,-20) (-10,0) (0,10) (10,20) (20,30) (40,50) (30,40) (50,60) >60 Platelet Aggregation Before and After Clopidogrel (%) Gurbel PA et al. Circulation 2003;107:

5 Clopidogrel Metabolite (Log AUC 0-t ) Clopidogrel Active Metabolite S O C N Cl O CH 3 Clopidogrel 75 Clopidogrel (pro-drug) hce1 85% Inactive Metabolites CYPs: 2C19 1A2 2B6 O C O CH 3 N O S Cl O HOOC N * HS Cl Active Metabolite OCH 3 CYPs: 2C19 3A 2B6 2C9 CYP2C19 Reduced- Function Alleles 0 (non-carriers/ wild-type) 1 (heterozygotes) 26% 28% Carriers 2 (homozygotes) 2% Mega JL, Close SL, Wiviott SD et al. N Eng J Med. 2009;360:

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 higher maintenance dose of clopidogrel will reduce platelet reactivity to the levels achieved in non-carriers treated with the standard 75 daily dose of clopidogrel.

7 Study Design Investigator-Initiated Study IND #: Patients Enrolled Stable CAD Pts on Clopidogrel 75 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 Each dose given for ~14 days followed by platelet function testing (VASP and VerifyNow P2Y 12 assays) and assessment for events

8 % 75 Clopidogrel Daily PRU VASP PRI VerifyNow PRU 95 Non- Carriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes Non- Carriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes 90 < < <0.001 < Squares represent the means and vertical lines the 95% confidence intervals. 100

9 % CYP2C19*2 Heterozygotes PRU VASP PRI VerifyNow PRU P trend < P trend < Clopidogrel Daily Dose () Squares represent the means and vertical lines the 95% confidence intervals.

10 Percent CYP2C19*2 Heterozygotes Non-Responders (PRU 230) P< % 50% 52% P=0.002 P trend < % 30% 26% P= % 10% 10% 10% 0% Clopidogrel Daily Dose ()

11 PRU 250 Non- Carriers Clopidogrel in CYP2C19*2 Heterozygotes vs. 75 in Non-Carriers PRU diff +61 P<0.001 CYP2C19*2 Heterozygotes PRU diff +24 P= PRU diff -10 P= PRU diff -37 P< Clopidogrel Daily Dose () Squares represent the means and vertical lines the 95% confidence intervals. Differences are reported as least squares differences.

12 PRU Platelet Reactivity with Clopidogrel Non- Carriers CYP2C19*2 Heterozygotes CYP2C19*2 Homozygotes Squares represent the means and vertical lines the 95% confidence intervals. Clopidogrel Daily Dose ()

13 Compliance and Events CYP2C19*2 Carriers Clopidogrel Doses () Compliance (%) 97.3% 98.1% 98.6% 98.3% Adverse Events (n) Serious Adverse Events (n) TIMI Bleeding Requiring Medical Attention (n) Cardiac Ischemic Events (n) 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 daily achieved levels of platelet reactivity similar to the standard 75 dose in non-carriers. CYP2C19*2 homozygotes: even 300 of clopidogrel daily, is unlikely to result in optimal degrees of platelet inhibition.

15 Published Online First November 16, 2011 Available at