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
SummarySummary
Strong correlation between 2C19 genotype andplatelet biological response to clopidogrelStrong correlation between 2C19 genotype andplatelet biological response to clopidogrel
2C19 *2 = independent correlate of biologicalresponse to clopidogrel2C19 *2 = independent correlate of biologicalresponse to clopidogrel
Dose dependent gene effectDose 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
EndpointsEndpoints
Primary: CV death, myocardial infarction, URPrimary: CV death, myocardial infarction, UR
Objectif secondaire: Definite stent thrombosisObjectif secondaire: Definite stent thrombosis
HypothesisHypothesis
HypothesisHypothesis
The loss of function driven by the 2C19*2 genetic variantincreases cardiovascular events in young post-MI patientson a MD of clopidogrelThe loss of function driven by the 2C19*2 genetic variantincreases cardiovascular events in young post-MI patientson a MD of clopidogrel
ObjectivesObjectives
ObjectivesObjectives
to evaluate the impact of CYP2C19*2 polymorphism ontheir long-term prognosis during clopidogrel exposure.
www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
Inclusion criteria
Inclusion 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 chart
Flow chart
119 patients never exposed to clopidogrel
Clopidogrel as first line therapy ofthe qualifying event (ACS) (n=216)
Clopidogrel as first line therapy ofthe qualifying event (ACS) (n=216)
Clopidogrel initiated later after thequalifying event (n=43)
Clopidogrel initiated later after thequalifying 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 betweenApril 1996 and March 2008
378 patients aged <45 years enrolled betweenApril 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.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
Methods
Methods
A precise determination of the duration of exposition toclopidogrel 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 independentcardiologists 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*2 genotypeCYP2C19*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 (%)Race (%)
White european
North african
78.0
16.6
79.0
16.7
76.6
14.6
66.7
33.3
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
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 (%)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 (%)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 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
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/urgentrevascularization during clopidogrel exposure
Cumulative occurrence of CV death/non fatal MI/urgentrevascularization during clopidogrel exposure
3030
2525
2020
1515
1010
55
00
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.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, nonfatal 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 outcomes
Clinical outcomes
www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
Stent thrombosis
Stent thrombosis
Outcome
CYP2C19*2 allele
P value
Non carriers(n=186)
Carriers (n=73)
Definite Stent Thrombosis
Event rate per 1000 person-years
1.14
6.79
Adjusted HR (95% CI) a
1.0
6.04 [1.75-20.80]
0.004
Ischemic endpoint not related toStent 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 /urgentrevascularization
death/non fatal MI /urgentrevascularization
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
0.20.1
0.0
www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
Landmark analysis from 6 months
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
0.20.1
0.0
www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
Conclusions
Conclusions
Strong relationship between CYP2C19*2 and recurrentthrombotic coronary events in clopidogrel-treated pts <45 yo
Genotyping for CYP2C19*2 could be considered for the optimalmanagement of such patients
Whether higher doses of clopidogrel or use of new drugs lessdependent of CYP2C19 can better protect carriers of the *2variant remains unknown.
www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0