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)
x I do not have any potential conflict of interest 2

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.
Author
Test
End-point n
Follow-up
Cut-off
Barragan
VASP index ST 46
1 mo.
50%
Bonello
MACE
144
6 mo.
Frere
MACE+ stroke
195
53%
Blindt 99
48%
Price
VerifyNow P2Y12
CVD + ST
380
235 U
Gurbel
LTA 5 µmol ADP
CVE
297
24 mo.
46%
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 months
Megat et al. NEJM 2008.

8. AIM
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.

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

10. RESULTS
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).
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: ; p<0.00.1)
gender OR : 6.8 (HR ; 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).WT
(n=277)
Htz
(n=123)
Hmz
(n=11) p
Thrombotic events
Death ns
Stent thrombosis
1(FDA)
ACS
Stroke 1
Urgent revasc.
All MACE
Bleedings
Major-TIMI bleeding
Minor-TIMI bleeding 4
2 MACE : 1 stroke and 1 SAT (Htz with FDA).
4 minor TIMI bleedings: Hmz WT.

15. CONCLUSION
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.

16. Aknowledgements
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.