www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Study sponsored and funded by A...
Summary <ul><li>Strong correlation between 2C19 genotype and platelet biological response to clopidogrel </li></ul><ul><li...
Endpoints <ul><li>Primary:  CV death, myocardial infarction, UR </li></ul><ul><li>Objectif secondaire:  Definite stent thr...
Inclusion criteria <ul><li>Age >18 and <45  </li></ul><ul><li>Established CAD :  STEMI or Non STEMI </li></ul><ul><li>Expo...
Flow chart 119 patients never exposed to clopidogrel Clopidogrel as first line therapy of the qualifying event (ACS) (n=21...
Methods <ul><li>A precise determination of the duration of exposition to clopidogrel was calculated  </li></ul><ul><ul><li...
Patients characteristics (1) www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Ch...
Patients characteristics (2) www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Ch...
Cumulative occurrence of CV death/non fatal MI/urgent revascularization during clopidogrel exposure   www.thelancet.com  -...
Clinical outcomes www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Outcome CYP2C...
Stent thrombosis  www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0 Outcome CYP2C...
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...
Landmark analysis from 6 months www.thelancet.com  -  Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0...
Conclusions <ul><li>Strong relationship between  CYP2C19*2  and recurrent thrombotic coronary events in clopidogrel-treate...
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Cytp4502 C19 The Lancet

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Clopidogrel

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Cytp4502 C19 The Lancet

  1. 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
  2. 2. Summary <ul><li>Strong correlation between 2C19 genotype and platelet biological response to clopidogrel </li></ul><ul><li>2C19 *2 = independent correlate of biological response to clopidogrel </li></ul><ul><li>Dose dependent gene effect </li></ul><ul><li>No known relation to clinical outcome </li></ul>www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
  3. 3. Endpoints <ul><li>Primary: CV death, myocardial infarction, UR </li></ul><ul><li>Objectif secondaire: Definite stent thrombosis </li></ul>Hypothesis <ul><li>The loss of function driven by the 2C19*2 genetic variant increases cardiovascular events in young post-MI patients on a MD of clopidogrel </li></ul>Objectives <ul><li>to evaluate the impact of CYP2C19*2 polymorphism on their long-term prognosis during clopidogrel exposure. </li></ul>www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
  4. 4. Inclusion criteria <ul><li>Age >18 and <45 </li></ul><ul><li>Established CAD : STEMI or Non STEMI </li></ul><ul><li>Exposition to clopidogrel for > one month </li></ul><ul><li>Genotyping for CYP2C19*2 </li></ul>www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
  5. 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
  6. 6. Methods <ul><li>A precise determination of the duration of exposition to clopidogrel was calculated </li></ul><ul><ul><li>first date of prescription to end of treatment </li></ul></ul><ul><ul><li>first date of prescription to end of follow-up </li></ul></ul><ul><li>These time delays were used as adjustment variables </li></ul><ul><li>All clinical events were adjudicated by two independent cardiologists blinded to the genetic analysis. </li></ul>www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0
  7. 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. 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. 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. 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. 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. 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. 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
  14. 14. Conclusions <ul><li>Strong relationship between CYP2C19*2 and recurrent thrombotic coronary events in clopidogrel-treated pts <45 yo </li></ul><ul><li>Genotyping for CYP2C19*2 could be considered for the optimal management of such patients </li></ul><ul><li>Whether higher doses of clopidogrel or use of new drugs less dependent of CYP2C19 can better protect carriers of the *2 variant remains unknown. </li></ul>www.thelancet.com - Published online December 23, 2008 DOI:10.1016/S0140-6736(08)61845-0

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