CYTP4502C19TheLancet.pp Clopidogrel

1. www.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

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 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 www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

7. Patients characteristics (1) www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Characteristics Overall 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 (%) 92.3 92.5 90.6 100 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 CAD 38.0 37.7 39.1 44.4 Active cigarette smoking 56.0 58.6 50.0 44.4 Dyslipidemia 54.0 54.3 53.1 55.6 Arterial hypertension 20.1 21.0 17.2 22.2 Diabetes mellitus 10.4 9.7 14.1 0 Clinical presentation (%) STEMI 78.8 79.3 78.1 77.8

8. Patients characteristics (2) www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 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 7.5 9.4 11.1 HIV disease (%) 9.6 10.7 7.8 0 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 96.9 85.9 79.7 6.2 37.5 77.8 100 100 77.8 55.61 0 22.2

9. Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 30 25 20 15 10 5 0 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

10. Clinical outcomes www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 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-years 2.89 10.90 Adjusted HR (95% CI) a 1.0 5.38 [2.32-12.47] <0.0001 Cardiovascular death Event rate per 100 person-years 0.26 1.45 Myocardial infarction Event rate per 100 patient-years 1.58 7.27 Adjusted HR (95% CI) a 1.0 5.57 [1.94-16.01] 0.001 Urgent revascularization Event rate per 100 patient-years 1.05 2.18 Adjusted HR (95% CI) a 1.0 3.24 [0.69-15.09] 0.13

11. Stent thrombosis www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Outcome CYP2C19*2 allele P value Non carriers (n=186) Carriers (n=73) Definite Stent Thrombosis Event rate per 1000 person-years 1.14 6.79 Adjusted HR (95% CI) a 1.0 6.04 [1.75-20.80] 0.004 Ischemic endpoint not related to Stent thrombosis Event rate per 100 patient-years 1.99 5.09 Adjusted HR (95% CI) a 1.0 3.31 [1.05-10.47] 0.04

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.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

13. Landmark analysis from 6 months www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 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