Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
Overall Study Question
The objectives of this trial were to determine the benefit on morbidity and mortality of adding low dose (25-50mg/day) spironolactone to patients with severe heart failure already receiving ACE inhibitors, diuretics and digoxin.
Are the Results of the Study Valid?
Was assignment of patients randomized?
Yes, patients meeting the inclusion criteria were randomly assigned to receive 25 mg of oral spironolactone (842 patients) or placebo (841 patients) once daily. After 8 weeks the spironolactone dose could be increased to 50 mg if the patient showed signs or symptoms of progressive heart failure.The results of this trial can be applied to a wide range of patients who are at high risk for cardiovascular events.
Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Unable to determine. Two hundred patients in the placebo group and 214 patients in the spironolactone discontinued treatment reportedly due to lack of response, side effects, or for administrative reasons. Whether all patients were followed up at the conclusion of the study was not reported, although patients who discontinued treatment were followed with regular telephone calls to determine their vital status.
Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Were the groups similar at the start of the trial?
Yes. The baseline characteristics between the spironolactone and placebo groups were similar.
Aside from the experimental intervention, were the groups treated equally?
Overall, are the results of the study valid?
What Were the Results?
How large was the treatment effect?
The trial was stopped early after a mean of 24 months follow up. Spironolactone reduced hospitalizations due to cardiac causes from 40% to 32%, death from cardiac causes from 37% to 28%, and death from any cause from 46% to 35% (NNT for 48 months were 13,11 and 9, respectively). In the spironolactone group, patient condition (change in heart failure class) improved for 41% of patients, was unchanged for 21%, and worsened in the remaining 38% of patients. In the placebo group, 33% of patients improved, 18% were unchanged and 48% worsened.
How precise was the estimate of the treatment effect?
Unknown. Confidence intervals for the absolute differences were not provided.
Are the Results of the Study Valid?
Can the results be applied to my patient care?
Yes. For patients with Class III or IV heart failure the addition of spironolactone reduces the incidence of 3 clinically important outcomes (i.e. hospitalizations due to cardiac causes, death from cardiac causes, and death from any cause) by a clinically important amount (8-10% absolute difference). In addition, there was a clinically important change in heart failure class for about 10% of patients over the placebo group.
Were all clinically important outcomes considered?
Yes. Other than quality of life issues, it appears that all the clinically important outcomes were considered.
Are the likely treatment benefits worth the potential harms and costs?
Yes. There were no differences in overall adverse effects between the groups; however, 3% more patients withdrew as a result of adverse events in the spironolactone group. There was a difference in the incidence of gynecomastia (9% spironolactone versus 1% on placebo). There was no difference in the incidence of serious hyperkalemia between the groups. Since spironolactone is available as a generic drug, the cost should not be much of an issue.
This study demonstrates that the use of spironolactone can provide a clinically important benefit to patients with Class III and IV heart failure who are already receiving standard therapy (i.e. loop diuretics, ACE inhibitors and digoxin). Given the low incidence of side effects and the low cost of spironolactone, all patients with Class III or IV heart failure should be given a trial of spironolactone. Whether patients with less severe heart failure would benefit is unknown.