1. www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Study sponsored and funded by Assistance Publique – Hôpitaux de Paris (AP-HP) Paris, France (CRC #97109) Institut de Cardiologie – Pitié-Salpêtrière Hospital Paris, France

2. Summary  Strong correlation between 2C19 genotype and platelet biological response to clopidogrel  2C19 *2 = independent correlate of biological response to clopidogrel  Dose dependent gene effect  No known relation to clinical outcome www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

3. Endpoints  Primary: CV death, myocardial infarction, UR  Objectif secondaire: Definite stent thrombosis HypothesisHypothesis  The loss of function driven by the 2C19*2 genetic variant increases cardiovascular events in young post-MI patients on a MD of clopidogrel ObjectivesObjectives  to evaluate the impact of CYP2C19*2 polymorphism on their long-term prognosis during clopidogrel exposure. www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

4. Inclusion criteria   Age >18 and <45   Established CAD : STEMI or Non STEMI   Exposition to clopidogrel for > one month   Genotyping for CYP2C19*2 www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

5. Flow chart 119 patients never exposed to clopidogrel Clopidogrel as first line therapy of the qualifying event (ACS) (n=216) Clopidogrel initiated later after the qualifying event (n=43) 213 patients still on clopidogrel at the last follow-up visit Median [25th-75th] 1.26 [0.36-3.59] years 213 patients still on clopidogrel at the last follow-up visit Median [25th-75th] 1.26 [0.36-3.59] years 46 patients discontinued clopidogrel 378 patients aged <45 years enrolled between April 1996 and March 2008 259 patients on clopidogrel during follow-up 32 MACE on clopidogrel therapy 259 patients on clopidogrel during follow-up 32 MACE on clopidogrel therapy www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

6. Methods   A precise determination of the duration of exposition to clopidogrel was calculated − − first date of prescription to end of treatment − − first date of prescription to end of follow-up   These time delays were used as adjustment variables   All clinical events were adjudicated by two independent cardiologists blinded to the genetic analysis. www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

7. Patients characteristics (1) CharacteristicsOverall CYP2C19*2 genotype N=259 *1/*1 N=186 *1/*2 N=64 *2/*2 N=9 Mean Age- yr (SD)40.1 (5.1)39.9 (5.0)40.7 (4.8)39.3 (7.5) Male gender (%)92.392.590.6100 Race (%) White european North african 78.0 16.6 79.0 16.7 76.6 14.6 66.7 33.3 Risk factors-no (%) Familial history of CAD38.037.739.144.4 Active cigarette smoking56.058.650.044.4 Dyslipidemia54.054.353.155.6 Arterial hypertension20.121.017.222.2 Diabetes mellitus10.49.714.10 Clinical presentation (%) STEMI 78.879.378.177.8 www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

8. Characteristics Overall CYP2C19*2 genotype N=259 *1/*1 N=186 *1/*2 N=64 *2/*2 N=9 Number of vessel (%) Single Double Triple 63.2 23.0 3.8 61.4 25.1 13.4 68.0 20.3 11.9 66.7 0 33.3 Revascularization (%) PCI Drug-Eluting Stent Bypass 73.0 32.0 8.0 73.2 31.2 7.0 71.9 37.5 9.4 77.8 11.1 22.2 Polyvascular disease (%) 13.4 7.59.411.1 HIV disease (%) 9.6 10.77.80 Drug therapy during follow up (%) Clopidogrel initiation at first event Aspirin Statins Beta-blockers ACE-inhibitors Vitamin K antagonist Proton pump inhibitors 83.4 97.3 95.0 91.1 74.5 3.1 31.9 83.9 97.3 94.1 93.5 73.7 2.1 30.4 82.8 96.9 85.9 79.7 6.2 37.5 77.8 100 77.8 55.61 0 22.2 Patients characteristics (2) www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

9. Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure 302520151050 0 1 2 3 4 5 6 7 8 Years from clopidogrel initiation Number of patients with events Median (25th-75th) time to event 2.07 (0.72-3.31) years www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

10. Outcome CYP2C19*2 allele P value Non carriers (n=186) Carriers (n=73) Primary endpoint (death, non fatal MI, urgent revascularization) Event rate per 100 patient-years2.8910.90 Adjusted HR (95% CI) a 1.05.38 [2.32-12.47]<0.0001 Cardiovascular death Event rate per 100 person-years0.261.45 Myocardial infarction Event rate per 100 patient-years1.587.27 Adjusted HR (95% CI) a 1.05.57 [1.94-16.01]0.001 Urgent revascularization Event rate per 100 patient-years1.052.18 Adjusted HR (95% CI) a 1.03.24 [0.69-15.09]0.13 Clinical outcomes www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

11. Stent thrombosis Outcome CYP2C19*2 allele P value Non carriers (n=186) Carriers (n=73) Definite Stent Thrombosis Event rate per 1000 person-years 1.146.79 Adjusted HR (95% CI) a 1.06.04 [1.75-20.80]0.004 Ischemic endpoint not related to Stent thrombosis Event rate per 100 patient-years 1.995.09 Adjusted HR (95% CI) a 1.03.31 [1.05-10.47]0.04 www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

12. death/non fatal MI /urgent revascularization HR=3.66; 95%CI (1.69-8.05) P=0.0005 CYP 2C19 *1/*1 *1/*2 or *2/*2 0 1 2 3 4 5 years 1.0 0.0 0.8 0.7 0.6 0.5 0.2 0.1 0.0 www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

13. Landmark analysis from 6 months HR=3.00; 95%CI (1.27-7.10) P=0.009 CYP 2C19 *1/*1 *1/*2 or *2/*2 0 1 2 3 4 5 years 1.0 0.0 0.8 0.7 0.6 0.5 0.2 0.1 0.0 www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

14. Conclusions   Strong relationship between CYP2C19*2 and recurrent thrombotic coronary events in clopidogrel-treated pts <45 yo   Genotyping for CYP2C19*2 could be considered for the optimal management of such patients   Whether higher doses of clopidogrel or use of new drugs less dependent of CYP2C19 can better protect carriers of the *2 variant remains unknown. www.thelancet.comwww.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0