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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.

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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

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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

clopidogrel
CLOPIDOGREL
  • LIMITS:
    • Slow onset of action
    • Large and unpredictable inter-individual variability

Bonello et al. Heart 2009

vasp studies pr could be used as a surrogate endpoint
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.

clopidogrel metabolism
Clopidogrel metabolism

Simon T. et al. N EJM 2008; Megat et al. NEJM 2008.

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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.

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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
method
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

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).

RESULTS

Biological impact of a 2nd clopidogrel LD in carriers of CYP 2C19 2* with HTPR.

dose adjustment in heterozygotes
Dose-adjustment in Heterozygotes
  • 123 Heterozygotes; 88 with HTPR
  • Dose adjustement was successful in 77/88 (88%)
dose adjustment in homozygotes
Dose-adjustment in Homozygotes
  • 11 homozygotes for the 2C19 2* alleles
  • 6 had HTPR and 5 / 6 reached a PR<50% after dose adjustement
final vasp in 2c19 2 carriers
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.
in hospital outcomes
In-hospital outcomes

2 MACE : 1 stroke and 1 SAT (Htz with FDA).

4 minor TIMI bleedings: Hmz WT.

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.

CONCLUSION
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.

Aknowledgements