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Congestive Heart FailureCongestive Heart Failure
Dr Bernard Silke, MD, DSc, FRCP,
Cardiovascular Physician,
St. James’ Hospital, Dublin 8.
Congestive Heart FailureCongestive Heart FailureChanging population trendsChanging population trends
No.(millions)
Rate per million
W. Europe 5.3 14000
E. Europe 1.3 13000
USSR 5.6 19000
N. America 5.2 18000
Japan 2.4 19000
Clinical ScenarioClinical Scenario
JB is 75 and is a retired publican. First presented 12 yr ago JB is 75 and is a retired publican. First presented 12 yr ago
with MI.with MI.
A strong family Hx of CVS disease. Father died at age 40 A strong family Hx of CVS disease. Father died at age 40
with Stroke. Mother had angina.with Stroke. Mother had angina.
Subsequent LVF 5 yr ago with hospitalization. Echo dilated / Subsequent LVF 5 yr ago with hospitalization. Echo dilated /
asymmetrical contraction / dysynergy.asymmetrical contraction / dysynergy.
Ejection Fraction 35%. Effort DyEjection Fraction 35%. Effort Dysspnoeapnoea
What are the therapeutic options?What are the therapeutic options?
Congestive Heart FailureCongestive Heart FailureIncidence and ageIncidence and age
Eur Heart J 1999: 20; 421-428.
0
4
8
12
16
Males
Females
55-64 65-74 75-84 85+Age group (yr)
Inci
den
ce p
er 1
000
pat
ien
t ye
ars
Congestive Heart FailureCongestive Heart FailureChanging population trendsChanging population trends
< 5% of population< 5% of population
CHF in 1.5% (25-75 yr)CHF in 1.5% (25-75 yr)
LV Systolic function LV Systolic function
abnormality in 1%abnormality in 1%
Clinical CHF - 1%Clinical CHF - 1%
Suspect CHF - 1%Suspect CHF - 1%
0
1
2
3
4
5
CH
F
LV
SD
Eit
he
r
Su
sp
ec
t
Congestive Heart FailureCongestive Heart FailureChanging population trendsChanging population trends
MI deaths peaked 1985 MI deaths peaked 1985
Rate 215 / 100,000Rate 215 / 100,000
Between 1985 - 1995 Between 1985 - 1995
mortality rates decrease mortality rates decrease
by 33% (215.3 - 144.2)by 33% (215.3 - 144.2)
Numbers of very elderly Numbers of very elderly
predicted to increase by predicted to increase by
30% and 57% over next 30% and 57% over next
two decadestwo decades
-50
-40
-30
-20
-10
0
10
60-64
70-74
80-85
Heart FailureHeart FailureDefinitionDefinition
Heart unable to meet peripheral blood flow Heart unable to meet peripheral blood flow
requirements without a rise in filling volumerequirements without a rise in filling volume
Contraction energy is reducedContraction energy is reduced
Stroke volume incompletely expelledStroke volume incompletely expelled
Chamber volume increasesChamber volume increases
Heart FailureHeart FailureNatural historyNatural history
0
100
Morbidity
0
100
MortalityNo symptoms
No deaths
Rest symptomsPump Failure
Time from onset
Heart FailureHeart FailureTherapeutic goalsTherapeutic goals
AI
A + V
V
D
Ventricular Filling Pressure
StrokeVolume
Normal
CHF
Heart FailureHeart FailureEjection FractionEjection Fraction
Ejection Fraction - % of Ejection Fraction - % of
EDV ejected each beatEDV ejected each beat
Normal 50 - 75%Normal 50 - 75%
Impaired function < 40%Impaired function < 40%
Symptomatic < 30%Symptomatic < 30%
If EDV 100 mlIf EDV 100 ml
Stroke volume 65 mlStroke volume 65 ml
CHF < 40 mlCHF < 40 ml
Heart FailureHeart FailureTherapeutic implicationsTherapeutic implications
Volume overload Volume overload
DiureticsDiuretics
Elevated impedance Elevated impedance
VasodilatorsVasodilators
Decreased contractility Decreased contractility
InotropesInotropes
Heart FailureHeart FailureClinical goalsClinical goals
Patient oedema freePatient oedema free
AmbulantAmbulant
Avoid hospitalisationAvoid hospitalisation
Optimise quality of lifeOptimise quality of life
Heart FailureHeart FailureClinical assessmentClinical assessment
Peripheral oedema – none to minimalPeripheral oedema – none to minimal
Paroxysmal nocturnal dyspnoea - infrequentParoxysmal nocturnal dyspnoea - infrequent
Posture at night - < 2 pillowsPosture at night - < 2 pillows
Dyspnoea – absent at rest, activity possibleDyspnoea – absent at rest, activity possible
Nocturia – common and not significantNocturia – common and not significant
Heart FailureHeart FailureTherapeutic groupsTherapeutic groups
DiureticsDiuretics
Thiazide group, LoopThiazide group, Loop diureticsdiuretics
Angiotensin converting enzyme inhibitorsAngiotensin converting enzyme inhibitors
Long-acting nitratesLong-acting nitrates
Captopril, Enalapril, Lisinopril, TrandoloprilCaptopril, Enalapril, Lisinopril, Trandolopril
InotropesInotropes
DigoxinDigoxin
Cortex
Medulla
ThiazidesInhibit active exchange of Cl-Na
in the cortical diluting segment of the ascending loop of Henle
K-sparingInhibit reabsorption of Na in the
distal convoluted and collecting tubule
Loop diuretics Inhibit exchange of Cl-Na-K in
the thick segment of the ascending loop of Henle
Loop of HenleCollecting tubule
DIURETICS
Heart Failure Heart Failure Diuretics : Sites of ActionDiuretics : Sites of Action
Glomerulus
ProximalTubule(CAI)
Na/K/Cl
AscendingLimb
(Loop)
Distal CT(Thiazides)
Na/Cl
AmilorideNa
Spironolactone
Na/K
CollectingDuct
Heart Failure Heart Failure Diuretics : Sites of ActionDiuretics : Sites of Action
Na/K/Cl
AscendingLimb
(Loop)
CollectingDuct
Tubular cellhypertrophy
Sodium loadto distal nephronincreased
Heart Failure Heart Failure Diuretics : ResistanceDiuretics : Resistance
Check complianceCheck compliance
Check NaCheck Na++ intake intake
Low salt dietLow salt diet
Avoid bread / processed foodsAvoid bread / processed foods
Daily fluid allowance 1LDaily fluid allowance 1L
Check not taking a NSAIDCheck not taking a NSAID
Increased dose of a loop diuretic?Increased dose of a loop diuretic?
Metolazone (pulse 2.5 mg) once / twice weekMetolazone (pulse 2.5 mg) once / twice week
Heart FailureHeart FailureACE InhibitorsACE Inhibitors
Prolong survival in early and established CHFProlong survival in early and established CHF
Improve Quality of LifeImprove Quality of Life
Relieve symptomatic congestionRelieve symptomatic congestion
Increase exercise toleranceIncrease exercise tolerance
Reduce hospitalisationReduce hospitalisation
Heart Failure Heart Failure Choice of ACE Inhibitor Choice of ACE Inhibitor
Captopril - first generationCaptopril - first generationShort duration of actionShort duration of action
Multiple dose administration (50 mg tds)Multiple dose administration (50 mg tds)
Enalapril, Lisinopril - second generationEnalapril, Lisinopril - second generationLonger duration of action (once daily)Longer duration of action (once daily)
Increased liklihood of hypotensionIncreased liklihood of hypotension
Perindopril, Trandolopril - third generationPerindopril, Trandolopril - third generationVascular selectiveVascular selective
Favourable side-effect profileFavourable side-effect profile
Lack of first-dose effectLack of first-dose effect
Placebo
Enalapril
12111098765
PROBABILITYOFDEATH
MONTHS
0.1
0.8
0
0.2
0.3
0.7
0.4
0.5
0.6p< 0.001
p< 0.002
CONSENSUSN Engl J Med 1987;316:1429
43210
Heart Failure Heart Failure Benefits of ACEIBenefits of ACEI
Heart Failure Heart Failure Benefits of ACEIBenefits of ACEI
50
40
30
20
10
0
Months0 6 12
p = 0.0036
%MORTALITY
2418 30 36 42 48
Enalapriln=1285
Placebon=1284
SOLVD (Treatment)N Engl J M 1991;325:293
n = 2589CHF - NYHA II-III- EF < 35
Heart Failure Heart Failure Contemporary management with ACEIContemporary management with ACEI
Considerable variations in ACE prescribingConsiderable variations in ACE prescribing
ACE Inhibitors used in 30 - 60% of CHF casesACE Inhibitors used in 30 - 60% of CHF cases
Elderly less likely to be treated (21 vs 69%)Elderly less likely to be treated (21 vs 69%)
Physician perceptions of contra-indicationPhysician perceptions of contra-indication
No documented contra-indications in 35%No documented contra-indications in 35%
Elderly high rate of morbid eventsElderly high rate of morbid events
Withhold ACE more complications (p < 0.01)Withhold ACE more complications (p < 0.01)
Am. Heart J. 1998:136;43.
Heart Failure Heart Failure Survival benefits & dosage (mg / day)Survival benefits & dosage (mg / day)
EnalaprilEnalapril
CaptoprilCaptopril
RamiprilRamipril
LisinoprilLisinopril
TrandolaprilTrandolapril
QuinaprilQuinapril
2020
150150
10 10
10 / 20 10 / 20
4 4
4040
Am. Heart J. 1998:136;43.
Heart Failure Heart Failure Contemporary issues & ACEIContemporary issues & ACEI
Pharmacodynamic response to ACEI elderlyPharmacodynamic response to ACEI elderly
Valid concerns hypotension / renal dysfunctionValid concerns hypotension / renal dysfunction
Reluctance to adequately dose titrateReluctance to adequately dose titrate
Many patients left on initiation dosageMany patients left on initiation dosage
Elderly patients will tolerate ACEI and achieve Elderly patients will tolerate ACEI and achieve
target doses if titrated graduallytarget doses if titrated gradually
Suboptimal RSuboptimal Rxx important due to high morbidity important due to high morbidity
Am. Heart J. 1998:136;43.
Heart Failure Heart Failure Contemporary management with ACEIContemporary management with ACEI
SPICE registry SPICE registry
Eight countriesEight countries
Hospital casesHospital cases
Consecutive 9581Consecutive 9581
Current practice Current practice
USA and EuropeUSA and Europe
Treated
Intolerant
High risk
Unknown
Recent82%
9%
4%2%
3%
Heart FailureHeart FailureACEI ADR profileACEI ADR profile
SPICE registry of 8485 casesSPICE registry of 8485 cases
Cough (308 - 4%)Cough (308 - 4%)
Renal sufficiency (188 - 2%)Renal sufficiency (188 - 2%)
Symptomatic hypotension (147 - 2%)Symptomatic hypotension (147 - 2%)
Hyperkalaemia (35)Hyperkalaemia (35)
Rash / pruritus (25)Rash / pruritus (25)
Angioedema / analyphaxis (19)Angioedema / analyphaxis (19)
Na+
K+
K+
Na+
Na+ Ca++
Ca++
Na-K ATPase Na-Ca Exchange
Myofilaments
DIGOXIN
CONTRACTILITY
Heart Failure Heart Failure Drug Therapy : DigoxinDrug Therapy : Digoxin
Positive InotropicPositive Inotropic
S-A and A-V Nodal actionsS-A and A-V Nodal actions
Enhanced AutomaticityEnhanced Automaticity
%WORSENING
OF CHFp = 0.001DIGOXIN: 0.125 - 0.5 mg /d
(0.7 - 2.0 ng/ml)EF < 35%Class I-III (digoxin+diuretic+ACEI)Also significantly decreased exercisetime and LVEF.
DIGOXIN EFFECT ON CHF PROGRESSION
RADIANCEN Engl J Med 1993;329:1
Placebo n=93DIGOXIN Withdrawal
DIGOXIN n=85
30
10
0
20
10080200 40 60Days
Heart Failure Heart Failure The DIG StudyThe DIG Study
CHF patients (6800) studied 1991 - 1995CHF patients (6800) studied 1991 - 1995
Sinus rhythm; E.F. < 45%Sinus rhythm; E.F. < 45%
NYHA Class III 33%; Class II < 50%NYHA Class III 33%; Class II < 50%
Background ACEI and/or diuretic (78%)Background ACEI and/or diuretic (78%)
Digoxin (median 250 ug / day) vs. placeboDigoxin (median 250 ug / day) vs. placebo
Endpoints: mortality and hospitalisationEndpoints: mortality and hospitalisation
N. Engl. J. Med. 1997: 336; 525
50
40
30
20
10
0
Placebon=3403
DIGOXINn=3397
480 12 24 36
OVERALL MORTALITY
%
DIG StudyN. Engl. J. Med. 1997: 336; 525 Months
p = 0.8
Heart Failure Heart Failure The DIG StudyThe DIG Study
Mortality similar (34.8% vs. 35.1%)Mortality similar (34.8% vs. 35.1%)
Hospitalisations reduced 22% (16 - 28)Hospitalisations reduced 22% (16 - 28)
Benefits greatest in those at highest riskBenefits greatest in those at highest riskLower E.F. ( < 25% )Lower E.F. ( < 25% )
Enlarged heartsEnlarged hearts
NYHA Class III & IVNYHA Class III & IV
Digoxin toxicityDigoxin toxicityVentricular fibrillation / tachycardiaVentricular fibrillation / tachycardia
Supraventricular dysrhythmiaSupraventricular dysrhythmia
Second or 3rd degree heart blockSecond or 3rd degree heart block
N. Engl. J. Med. 1997: 336; 525
Heart Failure Heart Failure The DIG StudyThe DIG Study
No substantial change in mortality /morbidityNo substantial change in mortality /morbidity
No ethical mandate for its useNo ethical mandate for its use
May be prescribed for symptomatic reliefMay be prescribed for symptomatic relief
Other drug categories have proven benefitOther drug categories have proven benefit
ACEI and ß-blockers drugs ACEI and ß-blockers drugs
N. Engl. J. Med. 1997: 336; 575
Heart Failure Heart Failure Digoxin TherapeuticsDigoxin Therapeutics
Atrial fibrillation with uncontrolled responseAtrial fibrillation with uncontrolled response
Reduce apex rate to 100 or less.Reduce apex rate to 100 or less.
Loading 15 ug / kg in three doses over 24 hrLoading 15 ug / kg in three doses over 24 hr
Maintenance dose 250 to 500 ug / dayMaintenance dose 250 to 500 ug / day
Therapeutic concentration 0.8 - 2.0 ng / mlTherapeutic concentration 0.8 - 2.0 ng / ml
Heart Failure Heart Failure ß ß - - blocking Therapyblocking Therapy
Reduce heart rate & myocardial contractilityReduce heart rate & myocardial contractility
Concern about risk of cardiac depressionConcern about risk of cardiac depression
In CHF ß - adrenoceptors are downregulatedIn CHF ß - adrenoceptors are downregulated
Cardiac efficiency impaired by compensationCardiac efficiency impaired by compensation
Upregulation during ß - blocking treatmentUpregulation during ß - blocking treatment
CIBIS I in 641 CHF - 20% mortality reductionCIBIS I in 641 CHF - 20% mortality reduction
Carvedilol(n=696)
Placebo(n=398)
Survival
Days0 50 100 150 200 250 300 350 400
1.0
0.9
0.8
0.7
0.6
0.5
Risk reduction=65%p<0.001
Packer et al (1996)Packer et al (1996)
CIBIS-II Investigators (1999)CIBIS-II Investigators (1999)
0 200 400 600 800
1.0
0.8
0.6
0
Bisoprolol
Placebo
Time after inclusion (days)
p<0.0001
Survival
Risk reduction=34%
The MERIT-HF Study Group (1999)The MERIT-HF Study Group (1999)
Months of follow-up
Mortality (%)
0 3 6 9 12 15 18 21
20
15
10
5
0
Placebo
Metoprolol CR/XL
p=0.0062
Risk reduction=34%
US Carvedilol Programme
blockers in blockers in heart failure –heart failure –
all-cause mortalityall-cause mortality
CIBIS-II MERIT-HF
Heart Failure Heart Failure ß ß - - blocking Therapyblocking Therapy
Over 13 000 patients evaluated in placebo-Over 13 000 patients evaluated in placebo-
controlled clinical trialscontrolled clinical trials
Consistent improvement in cardiac function, Consistent improvement in cardiac function,
symptoms and clinical statussymptoms and clinical status
Decrease in all-cause mortality by 30–35% Decrease in all-cause mortality by 30–35%
((pp<0.0001)<0.0001)
Decrease in combined risk of death and Decrease in combined risk of death and
hospitalisation by 25–30% (hospitalisation by 25–30% (pp<0.0001)<0.0001)
BackgroundBackground
Angiotensin II type 1 (AT1) receptor blockers (ARBs) provide a pharmacologically distinct mechanism of inhibiting the renin-angiotensin-aldosterone system
ARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor
CHARM Added
CHARMPreserved
CHARM ProgrammeCHARM Programme
3 component trials comparing candesartan to placebo in patients with symptomatic heart failure
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
n=3025
LVEF >40%ACE inhibitor
treated/not treated
Primary outcome for Overall Programme: All-cause death
Primary outcome for each trial: CV death or CHF hospitalisation
Study designStudy designDose-titration and visit scheduleDose-titration and visit schedule
32 mgCandesartan/matching placeboonce daily16 mg
8 mg 32 mg4 mg 16 mg8 mg
Time 0 w 2 w 4 w 6 w 6 mEvery 4 monthsuntil study end31 March 2003
Visit 1 2 3 4 5
Mean age (years) 67 64 67 66
Women (%) 32 21 40 32
NYHA class (%)II 48 24 60 45III 49 73 38 52IV 3 3 2 3
Mean LVEF 30 28 54 39
Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27
Baseline characteristics Baseline characteristics Alternative Added Preserved Overall
n=2028 n=2548 n=3023 n=7599
CHARM ProgrammeCHARM Programme
n=3025
LVEF >40% ACE inhibitor
treated/not treated
CHARM Added
CHARMPreserved
3 component trials comparingcandesartan to placebo
CHARMAlternative
n=2028
LVEF 40%ACE inhibitor
intolerant
n=2548
LVEF 40%ACE inhibitor
treated
Primary outcome:CV death or CHF hosp
CHARM-Alternative: Primary outcome CHARM-Alternative: Primary outcome CV CV deathdeath or CHF hospitalisation or CHF hospitalisation
%
Number at risk
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
0 1 2 3 years0
10
20
30
40
50
Placebo
Candesartan
HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001
3.5
406 (40.0%)
334 (33.0%)
CHARM-Alternative CHARM-Alternative Investigator reported CHF hospitalisationsInvestigator reported CHF hospitalisations
0
5
10
15
20
25
30
35
0
100
200
300
400
500
600
700
PlaceboCandesartanProportion of
patients (%)
Patients hospitalised Hospitalisations
p<0.0001 p=0.0001
Number of episodes
CHARM-Alternative CHARM-Alternative Permanent study drug discontinuationsPermanent study drug discontinuations
0
5
10
15
20
25Percent of patients
PlaceboCandesartan
19.3
0.92.7
0.3 0.4
21.5
3.76.1
1.90.2
p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69
Hypo-tension
Increased creatinine
Increasedpotassium
CoughAE/lab. abnorm.
0 0.1
p=0.50
Angio-edema
CHARM-AlternativeCHARM-AlternativeConclusionsConclusions
Despite prior intolerance to another inhibitor of the Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan renin-angiotensin-aldosterone system, candesartan
was well toleratedwas well tolerated
In patients with symptomatic chronic heart failure In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, and ACE-inhibitor intolerance, candesartan candesartan reduces cardiovascular mortality and morbidity reduces cardiovascular mortality and morbidity
Cardioprotective Effects of Valsartan Cardioprotective Effects of Valsartan as Seen in the Valsartan-Heart Failure as Seen in the Valsartan-Heart Failure
Trial (Val-HeFT)Trial (Val-HeFT)
Jay N. Cohn, MDJay N. Cohn, MD
Professor of MedicineProfessor of Medicine
University of Minnesota Medical SchoolUniversity of Minnesota Medical School
Minneapolis, Minnesota, USA Minneapolis, Minnesota, USA
49
Study OverviewStudy Overview
5010 patients 18 years; EF <40%; NYHA II-IV; LVIDd >2.9 cm/m2
ACE inhibitors (92.7%), diuretics (85.8%),digoxin (67.3%), -blockers (35.6%)
Valsartan40 mg bid titrated to
160 mg bid
Randomized to
Receiving background therapy
Placebo
Cohn JN et al. Eur J Heart Fail. 2000;2:439-446.
Patients’ Baseline Patients’ Baseline CharacteristicsCharacteristics
Valsartan(n = 2511)
Placebo(n = 2499)
Mean age (y) 62.4 63.0
Gender, male (%) 79.9 80.0
Race (%)White 89.8 90.9
NYHA Class (%)II 62.1 61.4III 36.1 36.3IV 1.7 2.2
Ejection fraction (%) 26.6 26.9
Background therapy (%)Diuretic 85.8 85.2Digoxin 67.1 67.6-Blocker 34.5 35.3ACE inhibitor 92.6 92.8
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Primary and Secondary Efficacy Primary and Secondary Efficacy Endpoints*Endpoints*
Combined all-cause mortality and Combined all-cause mortality and
morbidity (time to event) morbidity (time to event)
Hospitalization for heart failure Hospitalization for heart failure
Sudden death with resuscitationSudden death with resuscitation
Need for intravenous inotropes/vasodilators Need for intravenous inotropes/vasodilators
for worsening HFfor worsening HF
All-cause mortality (time to event)All-cause mortality (time to event)
Hospitalization for heart failureHospitalization for heart failure
Signs and symptoms of heart failureSigns and symptoms of heart failure
NYHA functional class (change from NYHA functional class (change from
baseline)baseline)
Echocardiographic indices of left Echocardiographic indices of left
ventricular function (LVEF and LVIDd ventricular function (LVEF and LVIDd
—— change from baseline) change from baseline)
Quality of life score (Minnesota Living Quality of life score (Minnesota Living
With Heart Failure score)With Heart Failure score)
*For the trial to be positive, one of the primary endpoints had to reach statistical significance (P < 0.02532).
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Mortality and Morbidity AnalysesMortality and Morbidity Analyses
Primary Endpoint AnalysesPrimary Endpoint Analyses
Combined all- cause mortality and morbidity
Events
Valsartan(n = 2511)
Placebo(n = 2499) P Value
723(28.8%)
495(19.7%)
0.009*
0.80
801 (32.1%)
484 (19.4%)
13.2%
–
RR
0.87 (0.77-0.97)
1.02 (0.88-1.18)
Reduction
All-cause mortality
*Log-rank test.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Effect of Valsartan on Morbidity Effect of Valsartan on Morbidity Endpoint*Endpoint*
Months
3 6 9 12 15 18 21 24 270
65
70
75
80
85
90
95
100
Probability of Event-Free
Survival
0
*All-cause mortality, sudden death with resuscitation, hospitalization for worsening heart failure, or therapy with IV inotropes or vasodilators.
Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
30
ValsartanPlacebo
P = 0.00913.2% Risk Reduction
All-Cause Mortality: All-Cause Mortality: Kaplan-Meier Analysis (Val-HeFT)* Kaplan-Meier Analysis (Val-HeFT)*
*P value (log-rank): 0.801; hazard ratio (Cox model): 1.017.Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
Patients at RiskMonths 0 6 12 18 24 30Valsartan 2511 2389 2279 1779 1201 439Placebo 2499 2370 2260 1784 1196 440
ValsartanPlacebo
Time Since Randomization (mo)
Proportion Survived
0 3 6 9 12 15 18 21 24 27 30
1.0
0.9
0.8
0.7
0.6
0.5
Favors PlaceboFavors Valsartann
Mortality by ACE Inhibitor/Beta Blocker Mortality by ACE Inhibitor/Beta Blocker SubgroupsSubgroups
ACEI - 366ACEI + 4644BB - 3260BB + 1750
ACEI - BB - 226ACEI - BB + 140ACEI + BB - 3034ACEI + BB + 1610
0.4 0.6 1.0 1.2 1.8 2.00.2 0.8 1.4 1.6
Data on file, Novartis Pharma AG.Cohn JN et al. N Engl J Med. 2001;345:1667-1675.
HF = heart failure.*First hospitalization.Cohn JN et al. Circulation. 2000;102:2672b.
3 6 9 12 15 18 21 24 270
65
70
75
80
85
90
95
100
Months
Event-Free Probability
P < 0.00001
27.5% Risk Reduction
0
ValsartanPlacebo
HF-Related Hospitalizations*HF-Related Hospitalizations*
30