Laurent Bonello, MD Unité de cardiologie interventionnelle Pôle de cardiologie

1. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19 2* loss-of function polymorphism. Laurent Bonello, MD Unité de cardiologie interventionnelle Pôle de cardiologie Hôpital universitaire nord de Marseille FRANCE

2. Potential conflicts of interest Speaker’s name: BONELLO Laurent  I have the following potential conflicts of interest to report:  Research contracts  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s) xI do not have any potential conflict of interest

3. CLOPIDOGREL • LIMITS: • Slow onset of action • Large and unpredictable inter-individual variability Bonello et al. Heart 2009

4. Relationship between Post-Treatment PR and post-PCI outcome. Bonello et al. JACC 2010 In press.

5. VASP studies: PR could be used as a surrogate endpoint PR monitoring enables optimal PR inhibition to be reached which translates into a reduction in thrombotic events post-PCI without increased bleeding. Bonello et al. AJC 2009.

6. Clopidogrel metabolism Simon T. et al. N EJM 2008; Megat et al. NEJM 2008.

7. 2C19 2* loss-of function polymorphism is associated with a worse outcome post-PCI in clopidogrel-treated patients CV Death / MI / Stroke 12-15 months Megat et al. NEJM 2008.

8. Investigate the biological impact of tailored clopidogrel LD according to PR monitoring in carriers of the CYP 2C19 2* loss-of function polymorphism undergoing PCI. AIM

9. METHOD prospective multicenter study dose adjustment is performed by using up-to three additional LD of clopidogrel until a VASP <50% was obtained. HTPR: VASP ≥50% .Primary end-point: PR <50% in « HTPR » patients .Secondary: In-hospital bleeding and MACE

10. 134 patients (35.3%) carried at least one loss of function 2C19 2* alleles 11 homozygotes (2.7%) and 123 heterozygotes (32.6%). VASP index was significantly higher than that of WT homozygotes (61.7 ±18.4 vs 49.2 ±24.2%; p<0.001). 104/134 (77.6%) were considered to have HTPR. After a 2nd LD, the VASP index was significantly decreased in these patients (69.7 ±10.1 vs 50.6 ±17.6 %; p <0.0001). RESULTS Biological impact of a 2nd clopidogrel LD in carriers of CYP 2C19 2* with HTPR.

11. Dose-adjustment in Heterozygotes • 123 Heterozygotes; 88 with HTPR • Dose adjustement was successful in 77/88 (88%)

12. Dose-adjustment in Homozygotes • 11 homozygotes for the 2C19 2* alleles • 6 had HTPR and 5 / 6 reached a PR<50% after dose adjustement

13. Final VASP in 2C19 2* carriers • Among 2C19 2* carriers, factors associated with failed dose adjustment in multivariate analysis: • BMI OR : 20.9 (95% CI: 3.9-11.8; p<0.00.1) • gender OR : 6.8 (HR 1.2- 40.4; p=0.03). • Finally, dose-adjustment was efficient in 88% of 2C19 2* carriers with HTPR to reach a <50% using up-to three additional 600 mg LD of clopidogrel.

14. In-hospital outcomes 2 MACE : 1 stroke and 1 SAT (Htz with FDA). 4 minor TIMI bleedings: Hmz WT.

15. Increased and tailored loading dose of clopidogrel overcome HTPR in carriers of the loss-of function 2C19 2* polymorphism. Since studies have demonstrated the clinical benefit of dose-adjustement in patients with HTPR undergoing PCI, this therapeutic strategy may improve the prognosis of carriers of this loss-of function polymorphism. CONCLUSION

16. Armero Sébastien, Ait Mokhtar Omar, Aldebert Philippe, Bartho Marie-Noelle, Franck Paganelli Mancini Julien, Saut Noémie, Bonello Nathalie Barragan Paul Arques Stéphane Giacomoni Marie-Paule, Dignat-George Françoise, Camoin-Jau Laurence Marie-Christine Alessi, Karine Berthaux. Aknowledgements