"Spironolactone for Severe Heart Failure".The New England Journal of Medicine. 1999. 341(10):709-717.PubMed•Full text•PDF

Contents

1Clinical Question
2Bottom Line
3Major Points
4Guidelines
5Design
6Population
6.1Inclusion Criteria
6.2Exclusion Criteria
6.3Baseline Characteristics
7Interventions
8Outcomes
8.1Primary Outcome
8.2Secondary Outcomes
9Criticisms
10Funding
11Further Reading

Clinical Question

In patients with severe heart failure and a left ventricular ejection fraction of 35% or less being treated with an ACE inhibitor, does the addition of spironolactone reduce mortality and morbidity?

Bottom Line

In patients with severe heart failure and a left ventricular ejection fraction of no more than 35%, addition of spironolactone to standard therapy including an ACE inhibitor significantly reduces mortality and hospitalization for cardiac reasons, improves symptoms, and is well-tolerated.

Major Points

Aldosterone has a key role in the progression of heart failure, and standard therapy with an ACE inhibitor may not adequately suppress aldosterone production. Previous research indicated that low doses of spironolactone, an aldosterone-receptor antagonist, in conjunction with standard heart failure treatment, might be effective and safe without leading to serious hyperkalemia.

Guidelines

At the time of this study's publication, guidelines did not reflect the study's findings and would presumably be updated to accommodate the new evidence on spironolactone's effect on heart failure management.

Design

- Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
- N=1,663 patients with recent severe heart failure
- Spironolactone (n=822)
- Placebo (n=841)
- Mean follow-up: 24 months
- Analysis: Intention-to-treat

Population

Inclusion Criteria
- NYHA class IV heart failure within six months before enrollment
- NYHA class III or IV at the time of enrollment
- Diagnosis of heart failure at least six weeks before enrollment
- Treatment with an ACE inhibitor and loop diuretic
- Left ventricular ejection fraction of no more than 35%

Exclusion Criteria
- Primary operable valvular heart disease, congenital heart disease
- Unstable angina, primary hepatic failure, active cancer
- Waitlisted or undergone heart transplantation
- Serum creatinine >2.5 mg/dL, serum potassium >5.0 mmol/L

Baseline Characteristics
- Balanced characteristics between placebo and treatment groups

Interventions

- Patients were randomized to receive 25 mg of spironolactone daily or matching placebo.

Outcomes

Primary Outcome
- All-cause mortality: 35% reduction in the spironolactone group compared to placebo (relative risk 0.70; P<0.001).

Secondary Outcomes
- Cardiac mortality and hospitalization for cardiac reasons were significantly reduced in the spironolactone group.
- Improvement in symptoms based on NYHA functional class (P<0.001).

Criticisms

- The long-term safety and efficacy of spironolactone in a broader range of heart failure patients or in those at lower risk were not assessed in this study.

Funding

- Supported by a grant from Searle (manufacturer of spironolactone).

Further Reading

- The preliminary data from this study were presented at the AHA meeting in Dallas, November 8–11, 1998.