1. H ypertension INHIBITEURS DE L’ANGIOTENSINE II - valsartan écompensation cardiaque D Dr O. Gurné Univ. Cathol. Louvain

3. H ypertension:Epidémiologie Touche 8 à 18% de la population adulte mondiale Facteur de risque important de coronaropathie Première cause d’accident vasculaire cérébral Risque directement proportionnel à l’élévation de la pression artérielle Large population de patients traités de façon inadéquate patients conscients 2/3 patients traités 1/2 patients contrôlés Population des patients hypertendus population de patients hypertendus World Health Organisation 1996 The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI 1997) 1/4

4. V ALSARTAN in heart failure VALSARTAN HEART FAILURE TRIAL

5. ANNUAL COST OF HF ESTIMATED TO BE $22.5 BILLION (USA) A American Heart Association, 2000 Heart and Stroke Statistical Update n economic burden Hospital/Nursing home Healthcare providers Indirect Costs Home health/Other medical durables Drugs 15.5 2.2 1.5 2.2 Costs in billions of dollars 1.1

6. A Source: Vital Statistics of the United States, National Center for Health Statistics growing burden DEATHS FROM HF 1979-1997 (USA)

7. U Davies et al. BMJ 2000;320:428-431 sual treatment today To improve symptoms Diuretics Digoxin ACE inhibitors Spironolactone  blockers (long term) To improve survival ACE inhibitors  blockers Spironolactone (Oral nitrates plus hydralazine) AIMS OF HEART FAILURE MANAGEMENT

8. A Biollaz et al. J Cardiovasc Pharmacol 1982;4:966 NG II levels increase over time despite ACEI HOSPITAL 0 4 8 12 16 20 24 PLACEBO 4H24H123456 MONTHS 80 100 120 140 160 180 BLOOD PRESSURE mm Hg PLASMA ANG II pg/mL

9. B lockade of RAS ANGIOTENSIN I ANGIOTENSINOGEN (LIVER) AT 1 AT 2 ANGIOTENSIN II ACE INHIBITOR VALSARTAN AT 1 RECEPTOR BLOCKER RENIN INHIBITOR BRADYKININ PEPTIDES CHYMASE LOCAL ANG II SYNTHESIS IS INDEPENDENT OF ACE

10. D IOVANE ® + IEC Amélioration des paramètres hormonaux Baruch L. et al. Augmented Short and Long-Term Hemodynamic and Hormonal Effects on Angiotensin Receptor Blocker Added to Angiotensin Converting Enzyme Inhibitor Therapy in Patients With Heart Failure. Circulation 1999 ; 99 : 2658-2664 Patients insuffisants cardiaques -120 -100 -80 -60 -40 -20 0 20 40 Etude randomisée, 4 semaines, n=83 IEC = lisinopril 10 ou 20 mg/j * ** *p = 0,001 versus placebo **p < 0,001= versus placebo Changement (pg/ml) Taux aldostérone Taux adrénaline IEC+placebo IEC+Diovane 2x80 mg/j IEC+Diovane 2x160 mg/j

11. V alsartan Heart Failure Trial Long-term cardiac morbidity & mortality trial Chronic stable heart failure patients Valsartan added to usual heart failure therapy (aceis; diuretics; digoxin;  blockers) 5010 patients 300 centers in 16 countries

12. V Cohn et al. J Card Fail 1999;5:155-160 al-HeFT design HF patients >18 yr; ef <40%; NYHA II-IV 906 deaths (events recorded) Valsartan 40 mg bid titrated to 160 mg bid Placebo Randomized to Receiving usual therapy including ACEI, diuretics, digoxin,  blockers (stratified randomization)

13. P rimary efficacy endpoints All cause mortality (time to death) Combined all cause mortality and morbidity (time to event) –All cause mortality –Sudden death with resuscitation –Hospitalization for HF –Need for therapeutic doses of iv inotropic or vasodilating agent for at least 4 hrs

14. B aseline characteristics VALSARTAN N=2511 PLACEBO N=2499 MEAN AGE, YRS. (SD) 62.4 (11.1) 62.7 (11.1) SEX, % MALE 79.9 80.0 RACE % WHITE BLACK OTHER 89.8 7.3 2.9 90.9 6.5 2.6 ETIOLOGY % CHD IDIOPATHIC HYPERTENSION OTHER 57.6 31.1 6.1 5.2 56.8 31.2 7.3 4.7 NYHA CLASS % II III IV 62.1 36.1 1.7 61.4 36.3 2.2

15. B aseline characteristics EJECTION FRACTION, % (SD) 26.6 (7.3) 26.9 (7.0) LVIDD, cm/m 2 (SD) 3.7 ( 0.5) SYSTOLIC BP, mmHg (SD) 124 (18.4) 124 (18.6) DIASTOLIC BP, mmHg (SD) 75 (10.5) 76 (10.7) BACKGROUND THERAPY DIURETIC, % DIGOXIN, %  BLOCKER, % ACE INHIBITOR, % 85.8 67.1 34.4 92.6 85.2 67.6 35.3 92.8 VALSARTAN N=2511 PLACEBO N=2499

16. A ll cause mortality 1.0 0.9 0.8 0.7 VALSARTAN PLACEBO TIME SINCE RANDOMIZATION (MONTHS) P = 0.8 SURVIVAL PROBABILITY 0 369122118152427

17. C ombined all cause mortality and morbidity 1.0 0.9 0.8 0.6 13.3% RISK REDUCTION P= 0.009 0 EVENT-FREE PROBABILITY VALSARTAN PLACEBO 369122118152427 TIME SINCE RANDOMIZATION (MONTHS) 0.7

18. H F-hospitalization 1.0 0.9 0.8 0.7 27.5% RISK REDUCTION P =0.00001 VALSARTAN PLACEBO EVENT-FREE PROBABILITY 369122118152427 TIME SINCE RANDOMIZATION (MONTHS) 0

19. N YHA class and signs/symptoms at endpoint

20. S econdary variables Change from baseline QUALITY OF LIFE (MLWHF * SCORE) † EF (%) † 0 1 2 3 4 5 PLACEBO VALSARTAN p= 0.001 WORSE BETTER p = 0.005 N=1557N=1544 N=2509N=2499 † ENDPOINT ANALYSIS 0 1 2 3 * MINNESOTA LIVING WITH HEART FAILURE

21. C ombined morbidity/mortality in subgroups 0.30.40.50.60.70.80.911.11.21.31.4 % Patients All Patients 100 ³ 65 47 < 65 53 Male80 Female20 EF < 2750 EF ³ 27 50 ACEI (Yes)93 ACEI (No)7 BB (Yes)35 BB (No)65 IHD (Yes)57 IHD (No)43 FAVORS VALSARTANFAVORS PLACEBO

22. C ombined all cause mortality and morbidity Sub-group without ACEI background therapy 1.0 0.8 0.6 0.4 44.5% RISK REDUCTION P = 0.0002 EVENT-FREE PROBABILITY TIME SINCE RANDOMIZATION (MONTHS) 369122118152427 0 VALSARTAN (N = 185) PLACEBO (N = 181)

23. S Cohn et al.,Late breaking clinical trials,15 november 2000,a.H.A.,New orleans ummary of results Valsartan exerted a neutral effect on mortality but Significantly reduced the combined endpoint of mortality And morbidity by 13.3% in patients with heart failure - Significantly reduced hf hospitalizations by 27.5% - Significantly improved nyha functional class, ejection Fraction and signs and symptoms - Significantly improved quality of life Subgroup analysis confirms the benefit of valsartan in patients on no neurohormonal inhibitors or on aceis or  blockers the data raise the possibility that the combination of aceis,  blockers and valsartan may exert an unfavorable effect. This observation requires further analysis and study