SOLVDSOLVD(Studies of Left Ventricular Dysfunction)(Studies of Left Ventricular Dysfunction)
• Enalapril vs placebo in 6,794 patientsEnalapril vs placebo in 6,794 patients• Ejection fraction Ejection fraction << 35% 35%• End points include:End points include:
– Delaying the progression of heart failureDelaying the progression of heart failure
– Improving signs and symptomsImproving signs and symptoms
– Reducing mortalityReducing mortality
• Treatment arm - 2,568 symptomatic class II-III patients most Treatment arm - 2,568 symptomatic class II-III patients most on digitalis and diureticson digitalis and diuretics
• Prevention arm - 4,226 asymptomatic class I-II patients, Prevention arm - 4,226 asymptomatic class I-II patients, most on no concomitant therapymost on no concomitant therapy
N Engl J Med 1991:325:293-302N Engl J Med 1991:325:293-302
SOLVD Treatment TrialSOLVD Treatment TrialAll Cause MortalityAll Cause Mortality
0
10
20
30
40
50
0 6 12 18 24 30 36 42 48
Months
Mo
rtal
ity%
PlaceboEnalapril
N Engl J Med 1991;325:293-302N Engl J Med 1991;325:293-302
16% Risk Reduction16% Risk Reductionp = 0.0036p = 0.0036
Benefits of Enalapril Benefits of Enalapril
• Patients: Symptomatic HF patients with LVD (EF Patients: Symptomatic HF patients with LVD (EF << 35%) 35%) • Increased SurvivalIncreased Survival
– 32% at 3 months32% at 3 months
– 28% at 6 months28% at 6 months
– 21% at 12 months21% at 12 months
– 18% at 24 months18% at 24 months
– 12% at 36 months12% at 36 months
– 12% at 48 months12% at 48 months
• 11% reduction of overall mortality at end of study (P=0.0036)11% reduction of overall mortality at end of study (P=0.0036)
The SOLVD Investigators, N Engl J Med. 1991;325:293The SOLVD Investigators, N Engl J Med. 1991;325:293
SOLVD Treatment TrialSOLVD Treatment TrialMortality or Hospitalization for CHFMortality or Hospitalization for CHF
0
10
20
30
40
50
60
70
0 6 12 18 24 30 36 42 48
Months
Eve
nts
%
PlaceboEnalapril
N Engl J Med 1991;325:293-302N Engl J Med 1991;325:293-302
26% Risk Reduction26% Risk Reductionp<0.0001p<0.0001
SOLVD Treatment-Enalapril SOLVD Treatment-Enalapril Symptomatic HF Patients with LVD (EF Symptomatic HF Patients with LVD (EF << 35%) 35%)
(NYHA Class II-III)(NYHA Class II-III)
0
200
400
600
800
1000
Placebo + Conv TX
Enalapril + Conv TX
Number of Hospitalizations Due to Heart failureNumber of Hospitalizations Due to Heart failureThe SOLVD Investigators, N Engl J Med, 1991The SOLVD Investigators, N Engl J Med, 1991
971971 683683
30% Reduction30% Reductionp<0.001p<0.001
SOLVD Treatment-Enalapril SOLVD Treatment-Enalapril Symptomatic HF Patients with LVD (EF Symptomatic HF Patients with LVD (EF << 35%) 35%)
(NYHA Class II-III)(NYHA Class II-III)
0
50
100
150
200
250
Placebo + Conv TX
Enalapril + Conv TX
Number of Readmissions for Heart failureNumber of Readmissions for Heart failureThe SOLVD Investigators, N Engl J Med, 1991The SOLVD Investigators, N Engl J Med, 1991
234234 157157
33% Reduction33% Reductionp<0.001p<0.001
SOLVD Treatment TrialSOLVD Treatment Trial
• Implications:Implications:– Treating Treating 1,0001,000 patients for 3 years patients for 3 years
• Prevents about Prevents about 5050 deaths deaths
• Prevents about Prevents about 350350 hospitalizations hospitalizations
Benefits of EnalaprilBenefits of Enalapril• Patients: Symptomatic HF patients with LVD (EF Patients: Symptomatic HF patients with LVD (EF < < 35%) 35%)
• Decreased hospitalizationsDecreased hospitalizations
– 48% at 3 months48% at 3 months
– 51% at 6 months51% at 6 months
– 46% at 12 months46% at 12 months
– 23% at 24 months23% at 24 months
– 28% at 36 months28% at 36 months
• 30% reduction of overall hospitalization at end of study 30% reduction of overall hospitalization at end of study (P<0.0001)(P<0.0001)
• Convenient once - or twice - daily dosingConvenient once - or twice - daily dosing
The SOLVD Investigators, N Engl J Med. 1991;325:293The SOLVD Investigators, N Engl J Med. 1991;325:293
SOLVD Treatment Trial SOLVD Treatment Trial ConclusionsConclusions
• Hospitalizations:Hospitalizations:– Risk reduced by 20% (p<0.001)Risk reduced by 20% (p<0.001)
– Significant reduction in CHF Significant reduction in CHF hospitalization by 1/3 (p<0.0001)hospitalization by 1/3 (p<0.0001)
– Sustained benefit over 4 yearsSustained benefit over 4 years
N Engl J Med 1991;325:293-302N Engl J Med 1991;325:293-302
SOLVD Prevention TrialSOLVD Prevention TrialAll Cause MortalityAll Cause Mortality
0
5
10
15
20
25
0 6 12 18 24 30 36 42 48
Months
Mor
talit
y fr
om A
ll C
ause
s (%
)
PlaceboEnalapril
Risk Reduction 8%Risk Reduction 8%
P=0.30P=0.30
N Engl J Med 1992;327:685-91N Engl J Med 1992;327:685-91
SOLVD Prevention TrialSOLVD Prevention TrialDeath or Development of CHFDeath or Development of CHF
05
101520253035404550
0 6 12 18 24 30 36 42 48Months of Follow-up
% E
ven
ts
PlaceboEnalapril
Risk Reduction 29%Risk Reduction 29%
p<0.001p<0.001
N Engl J Med 1992;327:685-91N Engl J Med 1992;327:685-91
SOLVD Prevention TrialSOLVD Prevention TrialFirst Hospitalization for CHFFirst Hospitalization for CHF
0
2
46
8
10
1214
16
18
0 6 12 18 24 30 36 42 48
Months of Follow-up
% E
ven
ts
PlaceboEnalapril
Risk Reduction 36%Risk Reduction 36%
p<0.001p<0.001
N Engl J Med 1992;327:685-91N Engl J Med 1992;327:685-91
SOLVD Prevention TrialSOLVD Prevention Trial
13.2
8.3
27.8
22.3
0
5
10
15
20
25
30
35
Median length of time to first CHFhospitalization
Median length of time to develop CHF
months
placeboenalapril
N Engl J Med 1992;327:685-91N Engl J Med 1992;327:685-91
SOLVD Prevention- Enalapril SOLVD Prevention- Enalapril Asymptomatic HF Patients w/ LVD (EF Asymptomatic HF Patients w/ LVD (EF << 35%) 35%)
(NYHA Class I-II)(NYHA Class I-II)
0
50
100
150
200
250
300
Placebo (n=2,177)
Enalapril (n=2,111)
32% Fewer First32% Fewer FirstHospitalizationsHospitalizations
p<0.001p<0.001
Number of First Hospitalizations for Heart FailureNumber of First Hospitalizations for Heart Failure
The SOLVD Investigators, N Engl J Med, 1992.The SOLVD Investigators, N Engl J Med, 1992.
273273 184184
SOLVD Prevention TrialSOLVD Prevention TrialMorbidity and Combined OutcomesMorbidity and Combined Outcomes
Endpoint Placebo%
Enalapril%
RR P value
Development of CHF 30.2 20.7 37% <0.001
Development of CHF andanti-CHF Rx
22.5 13.9 43% <0.001
First Hospitalization for CHF 12.9 8.7 36% <0.001
Multiple Hospitalization forCHF
4.8 2.7 44% <0.001
Death or Development ofCHF
38.6 29.8 29% <0.001
Death or Hospitalization forCHF
24.5 20.6 20% <0.001
Enalapril - DosingEnalapril - Dosing
Initial dose: enalapril 2.5 mg bid
Targeted dose: enalapril 20 mg
Mean daily dose: CONSENSUSSOLVD-TV-HeFT II
18.4 mg16.6 mg15 mg
In the SOLVD Treatment Trial dosage rangedfrom 2.5 mg to 10 mg twice daily
Careful dose titration is important to minimize riskof hypotension in heart failure patients