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

VALSARTAN in heart failure

VALSARTAN HEART FAILURE TRIAL

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