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Results of the treatment trial of the studies of left ventricular dysfunction (SOLVD)
Results of the Treatment Trial of the Studies of Left Ventricular Dysfunction (SOW/D) Hubert Pouleur,
MD,
for the SOLVD Investigators
T
he primary objective of the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial was to determine if long-term mortality could be reduced by treatment with an angiotensin-converting enzyme (ACE) inhibitor, namely, enalapril, in patients with left ventricular dysfunction (resting ejection fraction I 35%) and a history of overt congestive heart failure (CHF) treated concomitantly with conventional therapy. The secondary aims were to assess the effect of treatment on hospitalization fdr CHF and on mortality by cause. METHODS The SOLVD study was double-blind, randomized, and placebo controlled. This was a multinational study with 23 centers, mainly in the United States, but also in Canada and Belgium. Patients with CHF (aged 21-80 years) were eligible for the study if they had an ejection fraction 135% and were not currently taking an ACE inhibitor as part of their conventional therapy. Exclusion criteria were acute ischemia, including myocardial infarction during the previous month, unstable angina, or any other disease that might substantially shorten survival or impede participation in a long-term study. The methods have been reported in detail e1sewhere.l All eligible patients participated in a prerandomization run-in. Patients received 2.5 mg enalapril twice daily for 2-7 days. Any patients exhibiting noncompliance or side effects were excluded at this stage. All patients were then given placebo for 14-17 days, and patients whose medical condition worsened or who were unable to comply with the regimen were identified and excluded from the study. At the end of this run-in phase, patients classified as having overt CHF were enrolled in the treatment trial and randomized to placebo or enalapril. The dose was increased, according to From the Department of Medicine, University of Louvain, Brussels, Belgium. Address for reprints: Hubert Pouleur, MD, Department of Medicine, University of Louvain, Brussels, Belgium.
renal function and tolerance, to a target dose of 10 mg twice daily. Baseline patient characteristics are shown in Table I. RESULTS This study demonstrated a clinically important and significant reduction in mortality and hospitalizations for CHF over a 4-year period in patients treated with an ACE inhibitor in addition to conventional therapy.’ At the end of the study, there were 510 deaths in the placebo group (39.7%) compared with 452 deaths (35.2%) in the enalapril group, a 16% reduction of risk in the intervention group (p = 0.0036). This benefit was mainly due to a 22% reduction in the risk of dying from progressive pump failure (p <0.0045). There was little apparent effect on sudden deaths or deaths from arrhythmia (Figure 1). Overall, the total number of hospitalizations and the number of patients hospitalized were reduced significantly (p < 0.001). Analysis of combined cardiac deaths and the number of hospitalizations for worsening heart failure showed a 26% risk reduction with enalapril. Most patients reported apparent side effects at some time during the study (87% with enalapril vs 82% with placebo). As shown in Table II, adverse effects related to hypotension (i.e., dizziness or fainting) occurred more frequently with enalapril (p
of Left Ventricular Dysfunction (SOLVD)
Age (yr) Qualifying EF Males lschemic etiology NYHA Class I Class II Class III Class IV CT ratio > 50%
61.0 24.9 79.8 72.1
60.7 24.8 80.9 70.2
10.5 56.6 30.7 1.9 55.6
11.4 56.8 30.1 1.5 57.6
CT: cardiothoracic; EF = ejectlon fraction; NYHA = New York Heart Assocation. Adapted with permission from N Engl J Med.’
A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
=
TABLE II Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial: Adverse Effects Repotted at Any Postrandomization Visit Adverse
Effect
Dizziness/fainting Coughing Angioneurotic edema Serum creatinine (> 2 mg/dL) Serum potassium (~5.5 mEq/liter)
o’f,
, , , , , , , , 0
6
12
18
24
36
42
Placebo (%)
57.2 35.0 3.4
50.4 30.2 3.8 7.7 2.5
10.7 6.4
p Value
NS = difference not significant. Adapted with permission from N Engl J Med.1
, , , , , , , 30
Enalapril (%)
48
Months
30
Ex 4! 9 s
1
20 -
Placebo
io-
0
,
0
,
,
6
,
,
,
12
,
18
,
,
24
,
,
,
30
,
36
,
,
,
42
,
48
Months
Fl6URE 1. MortalRy due to progressive heart fallure (upper panel) (p = 0.0046) and presumed to be due to an arrhythmia but not preceded by worsening congestive heart fallure (lower panel) (p = not significant). Reprinted withpermlsslonfromNEnglIMed~l
I
(p 2 mg/dL, and hyperkalemia > 5.5 mEq/liter was also noted in the enalapril group. There was no excess of angioedema. These events seldom required discontinuation of the study drug, but rather dosage adjustment of both the study drug and concomitant medications. The overall results of this trial appear to be consistent with the results of other studies of the benefit of ACE inhibitor therapy in CHF.2*3Indeed these studies suggest that ACE inhibitors are the vasodilators of choice in the management of this condition.4 The reductions in deaths and rates of hospitalization are probably related to the observed improvements in pump function5 although the exact mechanism underlying the beneficial action of this class of drugs remains to be determined.
THE AMERICAN
REFERENCES 1. The SOLVD Investigators. Effect of enalapril on survival in patients with
DISCUSSION
136C
Until now, most regulatory authorities have only recommended the addition of an ACE inhibitor to CHF therapy when the patient could not be stabilized with conventional therapy. However, the SOLVD treatment trial data indicate that ACE inhibitors should be introduced earlier, preferably at the time of diagnosis of CHF. Indeed, for the CHF population defined in the SOLVD trial, there is compelling evidence that delaying this treatment is keeping these patients under increased cardiovascular risk. This is also true for the patients who appear to be in a stable clinical condition (class I or II) with conventional therapy. The SOLVD investigators have calculated that treating 1,000 patients with an ACE inhibitor in conjunction with conventional therapy for 3 years could prevent 50 premature deaths and 350 hospitalizations. Therefore, in terms of cost and quality of life, the benefit of the early use of ACE inhibitors in the management of heart failure appears to be substantial.
JOURNAL
OF CARDIOLOGY
VOLUME
70
reduced left ventricular ejection fractions and congestive heart failure. N En& .I Med 1991;325:293-302. 2. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian EnaiapriI Survival Study (CONSENSUS). N Engl JMed 1987;316:1429-1435. 3. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Fletcher RD, Doherty J. Hughes V, Carson P, Cintron G, Shabehai R, Haabenson C. A comparison of enalapril with hydralazine-isosorbide dmitrate in the treatment of chronic congestive heart failure. NEngZ J&fed 1991;325:303-310. ABraunwald E. ACE inhibitors-a cornerstone of the treatment of heart failure. N Erg1 J Med W!X;325:351-353. 5.Ader R, Chatterjee K, Ports T, Brundage B, Hiramatau B, ParmIey W. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulatin 1980;61:931-937.
OCTOBER
8, 1992
MD,
for the SOLVD Investigators
T
he primary objective of the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial was to determine if long-term mortality could be reduced by treatment with an angiotensin-converting enzyme (ACE) inhibitor, namely, enalapril, in patients with left ventricular dysfunction (resting ejection fraction I 35%) and a history of overt congestive heart failure (CHF) treated concomitantly with conventional therapy. The secondary aims were to assess the effect of treatment on hospitalization fdr CHF and on mortality by cause. METHODS The SOLVD study was double-blind, randomized, and placebo controlled. This was a multinational study with 23 centers, mainly in the United States, but also in Canada and Belgium. Patients with CHF (aged 21-80 years) were eligible for the study if they had an ejection fraction 135% and were not currently taking an ACE inhibitor as part of their conventional therapy. Exclusion criteria were acute ischemia, including myocardial infarction during the previous month, unstable angina, or any other disease that might substantially shorten survival or impede participation in a long-term study. The methods have been reported in detail e1sewhere.l All eligible patients participated in a prerandomization run-in. Patients received 2.5 mg enalapril twice daily for 2-7 days. Any patients exhibiting noncompliance or side effects were excluded at this stage. All patients were then given placebo for 14-17 days, and patients whose medical condition worsened or who were unable to comply with the regimen were identified and excluded from the study. At the end of this run-in phase, patients classified as having overt CHF were enrolled in the treatment trial and randomized to placebo or enalapril. The dose was increased, according to From the Department of Medicine, University of Louvain, Brussels, Belgium. Address for reprints: Hubert Pouleur, MD, Department of Medicine, University of Louvain, Brussels, Belgium.
renal function and tolerance, to a target dose of 10 mg twice daily. Baseline patient characteristics are shown in Table I. RESULTS This study demonstrated a clinically important and significant reduction in mortality and hospitalizations for CHF over a 4-year period in patients treated with an ACE inhibitor in addition to conventional therapy.’ At the end of the study, there were 510 deaths in the placebo group (39.7%) compared with 452 deaths (35.2%) in the enalapril group, a 16% reduction of risk in the intervention group (p = 0.0036). This benefit was mainly due to a 22% reduction in the risk of dying from progressive pump failure (p <0.0045). There was little apparent effect on sudden deaths or deaths from arrhythmia (Figure 1). Overall, the total number of hospitalizations and the number of patients hospitalized were reduced significantly (p < 0.001). Analysis of combined cardiac deaths and the number of hospitalizations for worsening heart failure showed a 26% risk reduction with enalapril. Most patients reported apparent side effects at some time during the study (87% with enalapril vs 82% with placebo). As shown in Table II, adverse effects related to hypotension (i.e., dizziness or fainting) occurred more frequently with enalapril (p
of Left Ventricular Dysfunction (SOLVD)
Age (yr) Qualifying EF Males lschemic etiology NYHA Class I Class II Class III Class IV CT ratio > 50%
61.0 24.9 79.8 72.1
60.7 24.8 80.9 70.2
10.5 56.6 30.7 1.9 55.6
11.4 56.8 30.1 1.5 57.6
CT: cardiothoracic; EF = ejectlon fraction; NYHA = New York Heart Assocation. Adapted with permission from N Engl J Med.’
A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
=
TABLE II Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial: Adverse Effects Repotted at Any Postrandomization Visit Adverse
Effect
Dizziness/fainting Coughing Angioneurotic edema Serum creatinine (> 2 mg/dL) Serum potassium (~5.5 mEq/liter)
o’f,
, , , , , , , , 0
6
12
18
24
36
42
Placebo (%)
57.2 35.0 3.4
50.4 30.2 3.8 7.7 2.5
10.7 6.4
p Value
NS = difference not significant. Adapted with permission from N Engl J Med.1
, , , , , , , 30
Enalapril (%)
48
Months
30
Ex 4! 9 s
1
20 -
Placebo
io-
0
,
0
,
,
6
,
,
,
12
,
18
,
,
24
,
,
,
30
,
36
,
,
,
42
,
48
Months
Fl6URE 1. MortalRy due to progressive heart fallure (upper panel) (p = 0.0046) and presumed to be due to an arrhythmia but not preceded by worsening congestive heart fallure (lower panel) (p = not significant). Reprinted withpermlsslonfromNEnglIMed~l
I
(p
THE AMERICAN
REFERENCES 1. The SOLVD Investigators. Effect of enalapril on survival in patients with
DISCUSSION
136C
Until now, most regulatory authorities have only recommended the addition of an ACE inhibitor to CHF therapy when the patient could not be stabilized with conventional therapy. However, the SOLVD treatment trial data indicate that ACE inhibitors should be introduced earlier, preferably at the time of diagnosis of CHF. Indeed, for the CHF population defined in the SOLVD trial, there is compelling evidence that delaying this treatment is keeping these patients under increased cardiovascular risk. This is also true for the patients who appear to be in a stable clinical condition (class I or II) with conventional therapy. The SOLVD investigators have calculated that treating 1,000 patients with an ACE inhibitor in conjunction with conventional therapy for 3 years could prevent 50 premature deaths and 350 hospitalizations. Therefore, in terms of cost and quality of life, the benefit of the early use of ACE inhibitors in the management of heart failure appears to be substantial.
JOURNAL
OF CARDIOLOGY
VOLUME
70
reduced left ventricular ejection fractions and congestive heart failure. N En& .I Med 1991;325:293-302. 2. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian EnaiapriI Survival Study (CONSENSUS). N Engl JMed 1987;316:1429-1435. 3. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Fletcher RD, Doherty J. Hughes V, Carson P, Cintron G, Shabehai R, Haabenson C. A comparison of enalapril with hydralazine-isosorbide dmitrate in the treatment of chronic congestive heart failure. NEngZ J&fed 1991;325:303-310. ABraunwald E. ACE inhibitors-a cornerstone of the treatment of heart failure. N Erg1 J Med W!X;325:351-353. 5.Ader R, Chatterjee K, Ports T, Brundage B, Hiramatau B, ParmIey W. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulatin 1980;61:931-937.
OCTOBER
8, 1992