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