The beneficial effects of spironolactone in chronic heart failure (HF) have been demonstrated in patients with New York Heart Association (NYHA) class III to IV HF. This study examined the effect of spironolactone on left ventricular (LV) function and functional capacity of patients with mild to moderate HF (NYHA class I to II). One hundred sixty-eight patients with NYHA class I to II HF and LV ejection fraction ≤40% were randomized to spironolactone or placebo and assessed by echocardiography, gated single-photon emission computed tomography, technetium-99m sestamibi single-photon emission computed tomographic radionuclide ventriculography, and cardiopulmonary exercise testing at baseline and after 6 months of treatment. In the spironolactone group LV ejection fraction increased from 35.2 ± 0.7% to 39.1 ± 3.5% (p <0.001), with a decrease in LV end-diastolic and end-systolic volumes and myocardial mass and an improvement in LV diastolic filling pattern. Cardiopulmonary exercise testing parameters did not change. In conclusion, administration of spironolactone to patients with NYHA class I to II HF has beneficial effects on LV remodeling and diastolic function.
Long-term administration of spironolactone is associated with lower mortality and rehospitalization rates in patients with heart failure (HF). These studies were, however, performed in patients with New York Heart Association (NYHA) functional class III to IV in the Randomized Aldactone Evaluation Study (RALES) or with recent myocardial infarction, left ventricular (LV) systolic dysfunction, and HF, shown by pulmonary rales, third heart sound, and/or pulmonary congestion at chest x-ray, or diabetes mellitus in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Only few studies have been performed in patients with mild-moderate HF and in asymptomatic LV dysfunction. The present study was designed to evaluate the effects of 6-month administration of spironolactone in addition to standard HF therapy on LV systolic and diastolic functions and the functional capacity of patients with low-to-moderate grade HF (NYHA class I to II).
Methods
To be included into the study patients fulfilled the following criteria: clinical evidence of HF, defined according to European Cardiology Society guidelines, by a history of HF symptoms and/or signs plus evidence of LV systolic dysfunction, defined by an LV ejection fraction (EF) ≤40% measured within 1 month before enrollment, NYHA class I to II severity of symptoms at time of enrollment, and optimal medical treatment, including renin-aldosterone-angiotensin inhibitors and β blockers, maintained at stable doses for ≥6 months. Exclusion criteria were acute coronary syndrome or revascularization procedures in the 3 months before enrollment, planned cardiac surgery for the next 3 months, chronic renal insufficiency with serum creatinine >2.5 mg/dl, hyperkalemia (>5.5 mEq/L), neoplasia, or illnesses limiting life expectancy to <1 year.
Patients were randomized, in a single-blinded 1:1 manner, to spironolactone or placebo, administered as a single dose per day. The initial dosage of spironolactone drugs was 25 mg/day with uptitration every 2 weeks to 50 or 100 mg/day if tolerated. Potassium and renal function were tested every week during uptitration and then every 2 to 4 weeks as clinically indicated. If serum potassium remained >5.5 mEq/L or if creatinine was ≥3 mg/dl, the study medication was discontinued and the patient was managed with conventional treatment only.
All patients were assessed at baseline and after 6 months by Doppler echocardiography, technetium-99m sestamibi gated single-photon emission computed tomographic radionuclide ventriculography, cardiopulmonary exercise testing, and blood tests for serum urea nitrogen, creatinine, electrolytes, renin, and aldosterone activity. Investigators performing the examinations were unaware of ongoing drug regimen. A VIVID 7 echocardiograph (General Electric Medical Systems, Horten, Norway) was used. LV end-diastolic and end-systolic diameters, interventricular septal and posterior wall thicknesses, and systolic excursion of the tricuspid ring plane were measured in M-mode. The sphericity index was calculated as the ratio of LV diastolic long axis to LV diastolic short axis. Myocardial mass was calculated using the Devereaux equation: ([interventricular septal thickness + LV end-diastolic diameter + posterior wall thickness] 3 − LV end-diastolic diameter 3 ) × 1.05 g/cm 3 and was expressed in grams. LV volumes and EF were calculated by 2- and 4-chamber apical views using the Simpson formula. The Doppler method was used to calculate pulmonary arterial pressure, transmitral early and late flow velocities (E- and A-wave components), deceleration time, isovolumetric relaxation time, pulmonary venous flow velocities (systolic, diastolic, and retrograde atrial wave components), and myocardial performance index. Relaxation abnormalities were classified according to according to the European Study Group on Diastolic Heart Failure. Gated single-photon emission computed tomographic technetium-99m sestamibi radionuclide ventriculography was used for assessment of LVEF and volumes because of its greater reproducibility compared to echocardiography. The method is based on tomographic acquisition synchronized with the cardiac cycle. Each single RR interval is subdivided into 8 to 16 intervals (from early-diastolic to end-systolic phases) by automatic border recognition methods with 3-dimensional reconstruction of the epicardium, endocardium profile, and relative movements during the cardiac cycle. We used a Millennium VG (General Electric Medical Systems) double-head high-resolution gamma camera. We used a Marquette Hellige cycloergometer and Medical Graphics cardiopulmonary exercise testing equipment (St. Paul, Minnesota). We measured peak oxygen consumption (V o 2 ) as the average of the V o 2 measured during the last 30 seconds of exercise. Peak V o 2 was also measured as percent theoretical maximum values based on age, gender, and body surface. Results were expressed as the mean ± SD. Changes in calculated parameters within each group were analyzed using Student’s t test for paired samples. Differences between the 2 groups were compared by analysis of variance. A p value <0.05 was considered statistically significant.
Results
One hundred fifty-eight patients were enrolled into the study and randomized to spironolactone or placebo. Mean dose of spironolactone was 51.7 ± 17.5 mg/day. During follow-up 5% of patients interrupted therapy because of side effects (2 patients for hyperkaliemia and worsening renal function and 2 patients for gynecomasty with mastodynia). Follow-up at 6 months was complete for all patients.
Baseline characteristics of the 158 patients who completed the study are listed in Table 1 . No differences were found between the 2 study groups with respect to all baseline characteristics.
| Variable | Placebo | Spironolactone | p Value |
|---|---|---|---|
| (n = 79) | (n = 79) | ||
| Age (years) | 58 ± 13 | 61 ± 13 | 0.38 |
| Gender, men | 65 (82%) | 67 (84%) | 0.39 |
| Cause of heart failure | |||
| Idiopathic cardiomyopathy | 45 (56%) | 43 (54%) | 0.34 |
| Coronary artery disease | 34 (44%) | 36 (45%) | 0.39 |
| Diabetes mellitus | 19 (24%) | 13 (16%) | 0.21 |
| History of hypertension | 19 (24%) | 22 (27%) | 0.12 |
| Left ventricular ejection fraction (%) | 35.4 ± 10 | 35.2 ± 0.7 | 0.18 |
| Peak oxygen consumption (ml/kg/min) | 16.9 ± 6.1 | 17.1 ± 5 | 0.72 |
| Concomitant treatment | |||
| Loop diuretics | 71 (90%) | 70 (88%) | 0.29 |
| Angiotensin-converting enzyme inhibitors | 70 (88%) | 69 (87%) | 0.34 |
| Angiotensin receptor blockers | 8 (10%) | 7 (9%) | 0.26 |
| β Blockers | 71 (90%) | 70 (88%) | 0.29 |
| Nitrates | 7 (9%) | 6 (8%) | 0.44 |
| Amiodarone | 12 (15%) | 11 (14%) | 0.42 |
| Implantable cardioverter–defibrillator | 40 (50%) | 38 (48%) | 0.24 |
After 6 months of treatment, LVEF increased and LV end-diastolic and end-systolic volumes decreased significantly with spironolactone compared to placebo ( Table 2 ). LV mass, assessed by echocardiography, decreased significantly in the spironolactone compared to the placebo group (from 269 ± 74 to 243 ± 67 g vs 250 ± 43 to 247 ± 38 g on placebo, p <0.05).
| Parameter | Placebo | Spironolactone | p Value ANOVA ⁎ | ||||
|---|---|---|---|---|---|---|---|
| (n = 79) | (n = 79) | ||||||
| Baseline | End of Study | p Value | Baseline | End of Study | p Value | ||
| Gated single photon emission computed tomography | |||||||
| Left ventricular ejection fraction (%) | 35.4 ± 10 | 34.6 ± 10 | 0.5 | 35.2 ± 0.7 | 39.1 ± 3.5 | 0.01 | <0.001 |
| Left ventricular end-diastolic volume (ml) | 192 ± 50 | 185 ± 48 | 0.61 | 195.8 ± 31.1 | 169 ± 12.7 | 0.003 | <0.001 |
| Left ventricular end-systolic volume (ml) | 120 ± 37 | 118 ± 33 | 0.51 | 130.9 ± 21.4 | 106.1 ± 13.9 | 0.002 | <0.001 |
| Echocardiography | |||||||
| Left ventricular ejection fraction (%) | 35.2 ± 4.1 | 34.9 ± 8.1 | 0.59 | 34.6 ± 9.8 | 38.4 ± 6.3 | <0.001 | 0.003 |
| Left ventricular end-diastolic volume (ml) | 190 ± 49 | 182 ± 38 | 0.34 | 173.2 ± 28.9 | 155.9 ± 4.2 | <0.001 | <0.001 |
| Left ventricular end-systolic volume (ml) | 119 ± 31 | 127 ± 28 | 0.39 | 114.5 ± 5.6 | 96.9 ± 9 | <0.001 | 0.002 |
| Left ventricular end-diastolic diameter (cm) | 6.6 ± 0.5 | 6.7 ± 0.5 | 0.3 | 6.5 ± 0.9 | 6.3 ± 0.7 | 0.04 | 0.002 |
| Left ventricular end-systolic diameter (cm) | 5 ± 0.9 | 5.0 ± 0.6 | 0.8 | 4.8 ± 0.5 | 4.8 ± 0.9 | 0.2 | 0.03 |
| Interventricular septum wall thickness (cm) | 0.77 ± 0.05 | 0.76 ± 0.06 | 0.17 | 0.81 ± 0.17 | 0.78 ± 0.15 | 0.04 | 0.07 |
| Posterior wall thickness (cm) | 0.73 ± 0.07 | 0.7 ± 0.07 | 0.43 | 0.78 ± 0.75 | 0.75 ± 0.12 | 0.03 | 0.03 |
| Sphericity index | 1.7 ± 0.5 | 1.6 ± 0.8 | 0.14 | 1.5 ± 0.1 | 2.3 ± 1.3 | <0.001 | 0.34 |
| Left ventricular mass (g) | 250 ± 43 | 247 ± 38 | 0.32 | 269 ± 74 | 243 ± 67 | <0.001 | 0.08 |
| Left ventricular mass index (g/m 2 ) | 135 ± 43 | 133 ± 18 | 0.43 | 145 ± 38 | 131 ± 33 | <0.001 | 0.12 |
| Myocardial performance index | 0.5 ± 0.2 | 0.5 ± 0.2 | 0.2 | 0.58 ± 0.4 | 0.46 ± 0.2 | <0.001 | <0.001 |
| Early wave of Doppler transmitral flow (cm/s) | 48 ± 24 | 35 ± 11 | 0.09 | 57 ± 54 | 37 ± 1.4 | <0.001 | 0.46 |
| Late wave of Doppler transmitral flow (cm/s) | 59 ± 33 | 63 ± 37 | 0.7 | 58 ± 39 | 64 ± 14 | 0.07 | 0.53 |
| Deceleration time (cm/s) | 249 ± 45 | 274 ± 56 | 0.59 | 236 ± 106 | 273 ± 70 | 0.001 | 0.42 |
| Isovolumetric relaxation time (ms) | 110 ± 25 | 114 ± 31 | 0.61 | 103 ± 28 | 112 ± 3 | <0.001 | 0.06 |
| Mitral regurgitation | 1.6 ± 0.3 | 1.4 ± 0.2 | 0.78 | 1.6 ± 0.7 | 1.4 ± 0.7 | 0.1 | 0.55 |
| Left atrial area (cm 2 ) | 19.6 ± 5.7 | 19 ± 6.8 | 0.93 | 20.8 ± 7 | 20.2 ± 8.4 | 0.2 | 0.31 |
| Left atrial volume (ml) | 59 ± 31 | 58 ± 29 | 0.73 | 64 ± 40 | 58 ± 35 | 0.18 | 0.07 |
| Tricuspid regurgitation | 1.5 ± 0.2 | 1.3 ± 0.4 | 0.45 | 1.1 ± 0.6 | 1.2 ± 0.5 | 0.36 | 0.22 |
| Tricuspid anular plane systolic excursion | 21.8 ± 5 | 21.4 ± 0.2 | 0.8 | 21.2 ± 4.2 | 21.4 ± 0.7 | 0.76 | 0.67 |
| Systolic flow wave of pulmonary venous flow (cm/s) | 40 ± 22 | 35.5 ± 14 | 0.41 | 31 ± 7 | 35 ± 27 | 0.23 | 0.32 |
| Diastolic flow wave of pulmonary venous flow (cm/s) | 44 ± 11 | 43 ± 11 | 0.95 | 45 ± 16 | 39 ± 0.7 | 0.03 | 0.41 |
| Reverse atrial flow wave of pulmonary venous flow (cm/s) | 32 ± 23 | 31 ± 22 | 0.71 | 31 ± 2 | 29 ± 2 | 0.22 | 0.34 |
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