- Published online December 23, 2008 DOI: /S (08) Study sponsored and funded by Assistance Publique – Hôpitaux de Paris (AP-HP) Paris, France (CRC #97109) Institut de Cardiologie – Pitié-Salpêtrière Hospital Paris, France

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 - Published online December 23, 2008 DOI: /S (08)

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. - Published online December 23, 2008 DOI: /S (08)

Inclusion criteria   Age >18 and <45   Established CAD : STEMI or Non STEMI   Exposition to clopidogrel for > one month   Genotyping for CYP2C19*2 - Published online December 23, 2008 DOI: /S (08)

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 [ ] years 213 patients still on clopidogrel at the last follow-up visit Median [25th-75th] 1.26 [ ] years 46 patients discontinued clopidogrel 378 patients aged <45 years enrolled between April 1996 and March patients on clopidogrel during follow-up 32 MACE on clopidogrel therapy 259 patients on clopidogrel during follow-up 32 MACE on clopidogrel therapy - Published online December 23, 2008 DOI: /S (08)

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. - Published online December 23, 2008 DOI: /S (08)

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 (%) Race (%) White european North african Risk factors-no (%) Familial history of CAD Active cigarette smoking Dyslipidemia Arterial hypertension Diabetes mellitus Clinical presentation (%) STEMI Published online December 23, 2008 DOI: /S (08)

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 Revascularization (%) PCI Drug-Eluting Stent Bypass Polyvascular disease (%) HIV disease (%) Drug therapy during follow up (%) Clopidogrel initiation at first event Aspirin Statins Beta-blockers ACE-inhibitors Vitamin K antagonist Proton pump inhibitors Patients characteristics (2) - Published online December 23, 2008 DOI: /S (08)

Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure Years from clopidogrel initiation Number of patients with events Median (25th-75th) time to event 2.07 ( ) years - Published online December 23, 2008 DOI: /S (08)

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 Adjusted HR (95% CI) a [ ]< Cardiovascular death Event rate per 100 person-years Myocardial infarction Event rate per 100 patient-years Adjusted HR (95% CI) a [ ]0.001 Urgent revascularization Event rate per 100 patient-years Adjusted HR (95% CI) a [ ]0.13 Clinical outcomes - Published online December 23, 2008 DOI: /S (08)

Stent thrombosis Outcome CYP2C19*2 allele P value Non carriers (n=186) Carriers (n=73) Definite Stent Thrombosis Event rate per 1000 person-years Adjusted HR (95% CI) a [ ]0.004 Ischemic endpoint not related to Stent thrombosis Event rate per 100 patient-years Adjusted HR (95% CI) a [ ] Published online December 23, 2008 DOI: /S (08)

death/non fatal MI /urgent revascularization HR=3.66; 95%CI ( ) P= CYP 2C19 *1/*1 *1/*2 or *2/* years Published online December 23, 2008 DOI: /S (08)

Landmark analysis from 6 months HR=3.00; 95%CI ( ) P=0.009 CYP 2C19 *1/*1 *1/*2 or *2/* years Published online December 23, 2008 DOI: /S (08)

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. - Published online December 23, 2008 DOI: /S (08)