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
Trial Organization M Sabatine, MD, MPH (Chairman) TIMI Study Group J Mega, MD, MPH (PI) Brigham and Women’s Hospital W Hochholzer, MD & C Ruff, MD, MPH (Co-Inv) Harvard Medical School 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 Clinical Events Adjudicator J de Lemos, MD Independent Data Monitor UT Southwestern A Michelson, MD Platelet Function Laboratory A Frelinger, PhD Children’s Hospital J Longtine, MD, PhD Genotyping Laboratory M Kluk, MD, PhD Brigham and Women’s Hospital M Pencina, PhD Independent Biostatistics L Lei & G Doros, PhD Harvard Clinical Research Institute Supported by an Investigator-Initiated Grant from Bristol-Myers Squibb & Sanofi-Aventis. Research Supplies from Accumetrics and Nanosphere.
PI: Ginete RC: Gunderson PI: Hamroff Duluth, MN RC: Fuerst-Carter Cortland Manor, NY PI: Peterson PI: Gips RC: Pape RC: Davis PI: Ferrier Spokane, WA Haddon Heights, NJ RC: Hockett Rapid City, SD PI: Staniloae PI: Albirini RC: Pinassi RC: Campbell New York, NY Zanesville, OH PI: Denning PI: Bhagwat RC: Cuenot RC: Winterrowd Canton, OH Hammond, IN Dr. Blonder PI: Cole RC: Gneiting RC: Fisher Colorado Springs, CO PI: Kereiakes Baltimore, MD RC: White PI: Haskel Cincinnati, OH RC: Powell PI: Korban PI: Isserman PI: Goldberg Baltimore, MD RC: Manns RC: Moore RC: Barrett Jackson, TN Hickory, NC La Mesa, CA PI: Jones RC: Stover PI: Wefald PI: Reddy Birmingham, AL RC: Moore PI: Bertolet RC: Qureshi Smithfield, NC RC: McDuffie Atlanta, GA Tupelo, MS PI: Aycock PI: Rogers RC: Tatum PI: Sotolongo RC: Thorington Pensacola, FL RC: Jones PI: Katopodis Birmingham, AL Jacksonville Beach, FL RC: Hernandez PI: Peart Huston, TX RC: Stephens PI: Angiolillo Tucson, AZ RC: McElveen PI: Chandna PI: Doty Jacksonville, FL RC: Holly RC: Parsons Victoria, TX Pensacola, FL PI: Iteld PI: Fastabend PI: Katopodis PI: Vicari RC: Stevenson RC: Bruney RC: Knap RC: St. Cyr Slidell, LA Lake Charles, LA Tallahassee, FL Melbourne, FL
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.
Clopidogrel → Active Metabolite O CH 3 O C Clopidogrel 75 mg N Clopidogrel Metabolite S Cl Clopidogrel (pro-drug) (Log AUC 0-t ) hCE1 85% CYPs: Inactive 2C19 Metabolites 1A2 2B6 O O CH 3 C N CYPs: O S 2C19 Cl 0 1 2 CYP2C19 3A (non-carriers/ (heterozygotes ) (homozygotes) Reduced- 2B6 wild-type) 26% 2% 2C9 Function OCH O Alleles 3 N HOOC 28% Cl * HS Carriers Active Metabolite Mega JL, Close SL, Wiviott SD et al. N Eng J Med. 2009;360:354-62.
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 mg daily dose of clopidogrel.
Study Design Investigator-Initiated Study 335 Patients Enrolled IND #: 107635 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 Randomized to various blinded sequences of daily doses of clopidogrel of daily doses of clopidogrel 225 75 150 300 75 75 150 150 mg mg mg mg mg mg mg mg Each dose given for ~14 days followed by platelet function testing (VASP and VerifyNow P2Y 12 assays ) and assessment for events
75 mg Clopidogrel Daily VASP PRI VerifyNow PRU Non- Non- CYP2C19*2 CYP2C19*2 CYP2C19*2 CYP2C19*2 Carriers Carriers Heterozygotes Homozygotes Heterozygotes Homozygotes 95 400 <0.001 90 87 <0.001 85 350 329 80 300 75 <0.001 PRU % <0.001 250 70 70 226 65 200 60 164 58 150 55 50 100 Squares represent the means and vertical lines the 95% confidence intervals.
CYP2C19*2 Heterozygotes VASP PRI VerifyNow PRU 250 75 70 70 P trend <0.001 P trend <0.001 226 65 200 61 188 PRU 60 % 55 53 153 150 50 49 128 45 40 100 75 150 225 300 75 150 225 300 Clopidogrel Daily Dose (mg) Squares represent the means and vertical lines the 95% confidence intervals.
CYP2C19*2 Heterozygotes Non- Responders (PRU≥230) P<0.001 P trend <0.001 60% 52% P=0.002 50% Percent 40% P=0.90 26% 30% 20% 10% 10% 10% 0% 75 150 225 300 Clopidogrel Daily Dose (mg)
Clopidogrel in CYP2C19*2 Heterozygotes vs. 75 mg in Non-Carriers Non- CYP2C19*2 PRU diff +61 Carriers Heterozygotes P<0.001 250 226 225 PRU diff +24 P=0.02 200 188 PRU diff -10 PRU P=0.31 175 164 PRU diff -37 153 P<0.001 150 128 125 100 75 75 150 225 300 Clopidogrel Daily Dose (mg) Squares represent the means and vertical lines the 95% confidence intervals. Differences are reported as least squares differences.
Platelet Reactivity with Clopidogrel Non- CYP2C19*2 CYP2C19*2 Carriers Heterozygotes Homozygotes 400 350 300 250 PRU 200 150 100 50 75 75 150 225 300 75 150 225 300 Clopidogrel Daily Dose (mg) Squares represent the means and vertical lines the 95% confidence intervals.
Compliance and Events CYP2C19*2 Carriers Clopidogrel Doses (mg) 75 150 225 300 Compliance (%) 97.3% 98.1% 98.6% 98.3% Adverse Events (n) 12 10 2 6 Serious Adverse Events (n) 2 0 0 1 TIMI Bleeding Requiring 1 0 1 1 Medical Attention (n) Cardiac Ischemic Events (n) 1 0 0 0 There were no deaths, cerebrovascular events, or TIMI major or minor bleeding events.
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.
Published Online First November 16, 2011 Available at www.jama.com
Recommend
More recommend
