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10 rencontres biomédicale LIR Faiez Zannad
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10 rencontres biomédicale LIR Faiez Zannad

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2ND INTERNATIONAL RESEARCH MEETING

2ND INTERNATIONAL RESEARCH MEETING
4 JUNE 2010- HÔTEL DE MARIGNY PARIS

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  • In another study, Brilla and Weber compared low-dose and high-dose spironolactone treatment with no treatment in rats receiving continuous aldosterone infusion. The control rats had hypertension, left ventricular hypertrophy, and myocardial fibrosis. Treatment with 20 mg/kg/day of spironolactone prevented the fibrosis. Treatment with 200 mg/kg/day of spironolactone prevented all the aldosterone-mediated effects. Because the low dose of spironolactone prevented fibrosis, but not hypertension or LVH, aldosterone receptor blockade (rather than the hemodynamic effect) was the crucial factor in preventing ventricular remodeling.

10 rencontres biomédicale LIR Faiez Zannad 10 rencontres biomédicale LIR Faiez Zannad Presentation Transcript

  • Biotargets, drug discovery and therapeutic innovation. How French clinical networks can accelerate the discovery of new treatments in the field of cardiovascular and metabolic diseases? Faiez Zannad, MD, PhD, Nancy
  • 54 modules de CIC dans 23 des 29 CHU Bichat Henri Mondor (94 Créteil) Pitié- Salpêtrière Necker Enfants Malades HEGP Robert Debré Saint-Louis Saint- Antoine HEGP Les 15-20 Cochin Pasteur IGR/Curie (Villejuif/Paris) Ile de la Réunion Lille Rennes Nantes Tours Nancy Strasbourg Lyon Montpellier Marseille Bordeaux Toulouse Grenoble Rouen Saint-Etienne Dijon Brest Clermont-Ferrand Besançon Garches Poitiers Limoges Cayenne Pointe-à-Pitre Fort-de-France The network of Clinical Investigation Centers CARDIOVASCULAR CIC-P (27) CIC-EC (9) CIC-IT (8) CIC-BT (10)
  • The network of Clinical Investigation Centers DIABETES and METABOLIC DISORDERS Lille Rennes Tours Nancy Strasbourg Montpellier Marseille Bordeaux Toulouse Rouen Bichat Saint- Antoine Robert Debré Saint-Pierre Ile de la Réunion Lille Rennes Tours Nancy Strasbourg Montpellier Marseille Bordeaux Toulouse Rouen Bichat Saint- Antoine Robert Debré Saint-Pierre Ile de la Réunion U545 U476 U608 U561 U695 U620 U522 U690 U626 U498 U499 U308 U317 U383 U530 U680 EMI9906 EMI9920 EMI586 U921 UMR5232 UMR6061 IRD EA4188 ESPRI25 UR545
  • Academic resources within a basic research and sophisticated technological environment and with immediate access to patients in University Hospitals Biobanks Databases COHORTS Clinical trials Patient organisations Disease Management programs
  • International funding bodies and consortia, with specific schemes of partnering with Industry
  • European Drug Development Hub Under the Aegis of a Foundation One solution to coordinate multicenter (multiple countries) trials EDDH, an Academic Research Organisation
    • Advisory Board
    • Faiez Zannad
    • Alain Leizorovicz
    • Gilles Montalescot
    • Gabriel Steg
  • Academic Research Organization Network of private practice Physicians - research practicioners GPs Cardiologists National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs Network of private practice Physicians - research practicioners GPs Cardiologists Network of private practice Physicians - research practicioners GPs Cardiologists Psychiatrists National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home National network of technicians and Technical research nurses National network of technicians and Technical research nurses  Experienced  Working in hospitals , Physician’s office , patient’s home • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs • INSERM label • standardized procedures • professional clinical researchers Coordination of 16 cardiovascular CICs EDDH
  • An Industry- Academic collaboration with the aim to Assist Investigators to enroll more patients in clinical trials
    • How French clinical networks can accelerate discovery in the field of cardiovascular and metabolic diseases?
      • A new class of medication
      • A new potential biomarker
    SUCCESS STORIES
  • Biomarker Substudy Confirms mechanism of action Circulation 2000 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0 6 12 18 24 30 36 Placebo Spironolactone % Survival 30% reduction in risk P < 0.001 N Engl J Med. 1999;341:709-717 . RALES: Trial based Evidence Circulation.1991;83:1849-1865. Fibrosis No fibrosis Aldosterone blockade prevents myocardial fibrosis
  • 70 75 80 85 90 95 100 1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 Days Cumulative survival rate (%) Quartile 1 (lowest) Quartile 2 Quartile 3 Quartile 4 (highest) Log-rank p=0.005 Circulation 2006 ACS French Registry; Aldosterone levels at admission are associated with poor outcome. N Engl J Med. 2003 New Trial in Post MI, New drug (Eplerenone) acquired by Pfizer EPHESUS
  • Twin trials ALBATROSS (academic) and REMINDER (Industry)
    • Primary end points: Death or (MRI) LVEF < 30% within 30 days
    • Secondary end points: All-cause mortality
    • CV mortality
            • Length of Stay
    Randomize < 48 hours From onset of symptoms STEMI, Anterior, LVEF  40%, HF signs/symptoms, CK-MB>x or Troponin>y orBNP> z, Standard Therapy* Eplerenone 25 mg QD up to week 4 Placebo
  • New drugs : Aldosterone inhibitors +++++ 0 ++++ +++ 0 Fourth Non renal ++ + ++ +++ ++++ Third Non steroidal ++ + + ++ +++ Second Eplerenone ++ + + ++ + First Spiro Anti-inflammatory Priamry Aldo Vasculra/renal effect potency Selectivity (sex side effects) Genration
  • Aldosterone inhibitors: Potential indications
    • Primary hyperaldosteronism
    • Glucocorticoid remediable aldosteronism (GRA)
    • Low renin/high aldosterone hypertension
    • Resistant hypertension
    • Congestive heart failure
    • Liver cirrhosis
    • Metabolic syndrome
    • High normal blood pressure
  • LCI699 (Aldo synthase inhibitor) in Patients With Primary aldosteronism : proof of concept study in the CIC CV network
    • Design
      • 4 week, Single-blind, Forced-titration
    • Patients:
      • Hypertensive patients with primary aldosteronism
    • Objectives:
      • to Assess the Hemodynamic and Hormonal Effects, Safety and Tolerability
  • Pharmacological postconditioning ( Inhibition of mitochondrial permeability transition) INSERM Unité 886, Lyon Am J Physiol Heart Circ Physiol. 2007
  • From Bench to Bedside Pharmacological postconditioning Cyclosporine A Hôpital Arnaud de Villeneuve, Montpellier, Hospices Civils de Lyon, Service de Cardiologie, Mulhouse NEJM, 2008 PHRC CYCLADE, Post Surgical conditioning
  • Pro-M22: a new biomarker in acute heart failure A Mebazaa, JL Samuel, A Cohen Solal et al U 942 Inserm Validation plasma of dyspneic patients BNP (ELISA) Pro-M22 (MS) Sensitivity 0 1 0 1 1 – Specificity AUC BNP: 0.86; AUC Pro-M22: 0.88 GREAT Network (15 countries) Discovery: Proteomics, human failing heart P1 P2 S2 S1 Pronota, Inserm, AP-HP, Paris 7
  • Innovative biomarkers of post MI remodelling Exp MI U644 (Rouen) « OMICS » U744 (Lille)   CIC Network
  • Derivation to Validation: CV CIC Network
  • The Stanislas Cohort Feasibility Visit 1 Visit 2 Visit 3 1993 1995 2000 2004 1006 families, 4295 subjects enrolled in the program 600 demographics and laboratory dataset values Preventive Medicine Center and Clinical Investigation Center, Nancy 117 original publications « Open access » to international scientific community Visit 4 2010
  • One common ancestor born in the XVIth century Aortic stenosis genetics Probst et al, Circulation 2006 Genetic Epidemiology and Biobanks
  • SYNERGISM