h ypertension inhibiteurs de l’angiotensine ii - valsartan écompensation cardiaque d dr o. gurné...
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Hypertension
INHIBITEURS DE L’ANGIOTENSINE II - valsartan
écompensation cardiaqueD
Dr O. Gurné
Univ. Cathol. Louvain
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 conscients2/3
patients traités
1/2
patients contrôlés
Population des patients hypertenduspopulation de patients hypertendus
World Health Organisation 1996The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI 1997)
1/4
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
Healthcareproviders
Indirect CostsHome health/Othermedical durables
Drugs
15.5
2.2 1.5 2.2
Costs in billions of dollars
1.1
A
Source: Vital Statistics of the United States, National Center for Health Statistics
growing burden
0
10000
20000
30000
40000
50000
1979 1985 1991 1997
HF
dea
ths
DEATHS FROM HF 1979-1997 (USA)
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
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 4H 24H 1 2 3 4 5 6 MONTHS
80
100
120
140
160
180
BLOODPRESSURE
mm Hg
PLASMAANG IIpg/mL
B lockade of RAS
ANGIOTENSIN I
ANGIOTENSINOGEN(LIVER)
AT1 AT2
ANGIOTENSIN II
ACE INHIBITOR
VALSARTANAT1 RECEPTOR
BLOCKER
RENIN INHIBITOR
BRADYKININ
PEPTIDES
CHYMASE
LOCAL ANG II SYNTHESIS IS INDEPENDENT OF ACE
DIOVANE® + 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
Cha
ngem
ent (
pg/m
l)
Taux aldostérone
Taux adrénaline
IEC+placeboIEC+Diovane 2x80 mg/jIEC+Diovane 2x160 mg/j
Valsartan 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
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)
Valsartan40 mg bid titrated to
160 mg bidPlacebo
Randomized to
Receiving usual therapy including ACEI, diuretics, digoxin, blockers (stratified randomization)
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
B aseline characteristics
VALSARTANN=2511
PLACEBON=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
B aseline characteristics
EJECTION FRACTION, % (SD) 26.6 (7.3) 26.9 (7.0)
LVIDD, cm/m2 (SD) 3.7 ( 0.5) 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
VALSARTANN=2511
PLACEBON=2499
A ll cause mortality
1.0
0.9
0.8
0.7
VALSARTAN PLACEBO
TIME SINCE RANDOMIZATION (MONTHS)
P = 0.8
SU
RV
IVA
L P
RO
BA
BIL
ITY
0 3 6 9 12 211815 24 27
Combined all cause mortality and morbidity
1.0
0.9
0.8
0.6
13.3%RISK REDUCTION
P= 0.009
0
EV
EN
T-F
RE
E P
RO
BA
BIL
ITY
VALSARTAN PLACEBO
3 6 9 12 211815 24 27TIME SINCE RANDOMIZATION (MONTHS)
0.7
HF-hospitalization
1.0
0.9
0.8
0.7
27.5%RISK
REDUCTIONP =0.00001
VALSARTAN PLACEBOEV
EN
T-F
RE
E P
RO
BA
BIL
ITY
3 6 9 12 211815 24 27TIME SINCE RANDOMIZATION (MONTHS)
0
NYHA class and signs/symptoms at endpoint
SIGN /SYMPTOM
TREATMENT
% PATIENTS
P - VALUE BENEFIT
FAVORING
IMPROVE WORSE
NYHA CLASS VAL PL
22.9 20.5
10.0 12.8
<0.001 VAL
DYSPNEA (EFFORT)
VAL PL
34.0 31.4
18.7 21.1
<0.001 VAL
FATIGUE VAL PL
31.5 29.2
21.5 25.1
<0.01 VAL
EDEMA VAL PL
11.7 9.6
10.1 12.2
<0.05 VAL
RALES VAL PL
7.0 6.4
6.1 8.2
<0.01 VAL
S econdary variablesChange from baseline
QUALITY OF LIFE(MLWHF* SCORE)†
EF (%)†
012345
PLACEBO VALSARTAN
p= 0.001WORSE
BETTER
p = 0.005
N=1557 N=1544 N=2509 N=2499
† ENDPOINT ANALYSIS
0
1
2
3
* MINNESOTA LIVING WITH HEART FAILURE
C ombined morbidity/mortality in subgroups
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4
% PatientsAll Patients 100
³ 6547< 6553
Male 80Female 20EF < 27 50EF ³ 27 50ACEI (Yes) 93ACEI (No) 7BB (Yes) 35BB (No) 65IHD (Yes) 57IHD (No) 43
FAVORS VALSARTAN FAVORS PLACEBO
C ombined all cause mortality and morbiditySub-group without ACEI background therapy
1.0
0.8
0.6
0.4
44.5%
RISK REDUCTION
P = 0.0002
EV
EN
T-F
RE
E P
RO
BA
BIL
ITY
TIME SINCE RANDOMIZATION (MONTHS)3 6 9 12 211815 24 270
VALSARTAN (N = 185) PLACEBO (N = 181)
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