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 HospitalParis, France

SummarySummarySummarySummary

Strong correlation between 2C19 genotype and Strong correlation between 2C19 genotype and platelet biological response to clopidogrelplatelet biological response to clopidogrel

2C19 *2 = independent correlate of biological 2C19 *2 = independent correlate of biological response to clopidogrel response to clopidogrel

Dose dependent gene effect Dose dependent gene effect

No known relation to clinical outcomeNo known relation to clinical outcome

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

EndpointsEndpointsEndpointsEndpoints Primary:Primary: CV death, myocardial infarction, UR CV death, myocardial infarction, UR

Objectif secondaire:Objectif secondaire: Definite stent thrombosis Definite stent thrombosis

HypothesisHypothesisHypothesisHypothesis

The loss of function driven by the 2C19*2 genetic variant The loss of function driven by the 2C19*2 genetic variant increases cardiovascular events in young post-MI patients increases cardiovascular events in young post-MI patients on a MD of clopidogrel on a MD of clopidogrel

ObjectivesObjectivesObjectivesObjectives to evaluate the impact of CYP2C19*2 polymorphism on

their long-term prognosis during clopidogrel exposure.

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

Inclusion criteriaInclusion criteria

Age >18 and <45

Established CAD : STEMI or Non STEMI

Exposition to clopidogrel for > one month

Genotyping for CYP2C19*2

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

Flow chartFlow chart

119 patients never exposed to clopidogrel

Clopidogrel as first line therapy of the qualifying event (ACS) (n=216)Clopidogrel as first line therapy of the qualifying event (ACS) (n=216)

Clopidogrel initiated later after the qualifying event (n=43)

Clopidogrel initiated later after the qualifying event (n=43)

213 patients still on clopidogrel at the last follow-up visitMedian [25th-75th] 1.26 [0.36-3.59] years

213 patients still on clopidogrel at the last follow-up visitMedian [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

378 patients aged <45 years enrolled between April 1996 and March 2008

259 patients on clopidogrel during follow-up32 MACE on clopidogrel therapy

259 patients on clopidogrel during follow-up32 MACE on clopidogrel therapy

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

MethodsMethods

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

Patients characteristics (1)Patients characteristics (1)

CharacteristicsCharacteristics OverallOverall CYP2C19*2CYP2C19*2 genotype 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 (%)Race (%)White europeanNorth african

78.016.6

79.016.7

76.614.6

66.733.3

Risk factors-no (%)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 (%)Clinical presentation (%)STEMI 78.8 79.3 78.1 77.8

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 (%)Number of vessel (%)Single DoubleTriple

63.223.03.8

61.425.113.4

68.020.311.9

66.70

33.3

Revascularization (%)Revascularization (%)PCIDrug-Eluting StentBypass

73.032.08.0

73.231.27.0

71.937.59.4

77.811.122.2

Polyvascular disease (%)Polyvascular disease (%) 13.4 7.5 9.4 11.1

HIV disease (%) 9.6 10.7 7.8 0

Drug therapy during follow up (%)Drug therapy during follow up (%)Clopidogrel initiation at first eventAspirinStatinsBeta-blockersACE-inhibitorsVitamin K antagonistProton pump inhibitors

83.497.395.091.174.53.1

31.9

83.997.394.193.573.72.1

30.4

82.896.996.985.979.76.237.5

77.810010077.8

55.61 0

22.2

Patients characteristics (2)Patients characteristics (2)

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

Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure

Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure

3030

2525

2020

1515

1010

55

000 1 2 3 4 5 6 7 8

Years from clopidogrel initiation

Num

ber o

f pati

ents

with

eve

nts

Median (25th-75th) time to event2.07 (0.72-3.31) years

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

OutcomeCYP2C19*2 allele

P valueNon 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

Clinical outcomesClinical outcomes

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

Stent thrombosis Stent thrombosis

OutcomeCYP2C19*2 allele

P valueNon 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

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

death/non fatal MI /urgent revascularization

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

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

ConclusionsConclusions

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