Background: The renin–angiotensin–aldosterone system (RAAS) is activated in patients with systolic heart failure. While this activation initially helps increase blood volume and maintains blood pressure, chronic activation promotes cardiac fibrosis and remodeling. In patients with systolic heart failure, inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEi) significantly reduced mortality and morbidity, as seen in the CONSENSUS and SOLVD trials.
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Preliminary data suggested that adding the aldosterone-receptor blocker spironolactone to ACEi, reduced the levels of atrial natriuretic peptide and did not lead to serious hyperkalemia.
The Randomized Aldactone Evaluation Study (RALES) sought to test the hypothesis that spironolactone would significantly reduce the risk of all-cause death in patients with severe systolic heart failure.
Patients: Eligible patients had left ventricular ejection fraction of 35% or less, had NYHA class IV heart failure within the 6 months before enrollment and NYHA class III or IV at the time of enrollment, and were treated with ACEi (if tolerated) and a loop diuretic.
Patients were excluded if they had primary operable valvular disease (other than mitral or tricuspid regurgitation), congenital heart disease, unstable angina, primary liver failure, active cancer or any life-threatening condition, other than heart failure, prior heart transplant or awaiting heart transplant, serum creatinine >2.5 mg/dL, or serum potassium > 5.0 mmol/L.
Baseline characteristics: Patients were recruited from 195 centers in 15 countries. The trial randomized 1,663 patients – 822 randomized to receive spironolactone and 841 to receive placebo.
The average age of patients was 65 years and 73% were men. The average left ventricular ejection fraction was 25%. Cardiomyopathy was ischemic in 55% of the patients and non-ischemic in the rest. The NYHA class was III in 71% of the patients and IV in 29%.
Data on baseline comorbid conditions were not provided.
At the time of enrollment, 100% were taking loop diuretics, 94% were taking ACEi, 73% were taking digitalis, and 10% were taking beta-blockers. The mean daily dose of ACEi were as following: 63mg for captopril, 15mg for enalapril, and 14mg for lisinopril.
Note: Max daily dose is 450mg for captopril, 40mg for enalapril, and 40mg for lisinopril.
Procedures: The trial was double-blinded. Patients were assigned in a 1:1 ratio to receive spironolactone 25mg PO daily or placebo.
The dose could be increased to 50mg daily after 8 weeks of treatment, If the patient had worsening heart failure and had no evidence of hyperkalemia. In the event of hyperkalemia, the dose could be lowered to 25 mg every other day. Laboratory testing including potassium were performed every 4 weeks for the first 12 weeks, then every 3 months for up to 1 year and every 6 months thereafter until the end of the study.
Endpoints: The primary outcome was all-cause death. Secondary end points included death from cardiac causes, hospitalization for cardiac causes and change in the NYHA class.
Analysis was performed based on the intention-to-treat principle. The planned sample size was not mentioned in the methods. However, the results mention that recruitment was complete. The sample size calculation assumed 38% mortality rate in the placebo group and that spironolactone would reduce mortality by 17% (relative risk reduction). The power of the study was set at 90% with a two-sided alpha of 5%.
Results: Recruitment was complete in Dec, 1996 with follow up planned through Dec, 1999. However, the study was stopped early on Aug, 1998 after interim analysis showed significant reduction in mortality with spironolactone. The mean follow up time was 24 months. After 24 months of follow up, the mean daily dose of spironolactone was 26 mg.
Spironolactone reduced all-cause death (35% vs 46%, RR: 0.70, 95% CI: 0.60 - 0.82; p< 0.001). Death from cardiac causes was also reduced with spironolactone (27% vs 37%, RR: 0.69, 95% CI: 0.58 - 0.82; p<0.001). Patients who were assigned to spironolactone had less hospitalizations for cardiac causes 260 patients vs 336 patients, RR: 0.70, 95% CI: 0.59 - 0.82; p<0.001).
In the placebo group, NYHA class improved in 33% of the patients, worsened in 48% and did not change in 18%. In the spironolactone group, NYHA class improved in 41% of the patients, worsened in 38% and did not change in 21%. The difference between placebo and spironolactone was significant (p<0.001 by the Wilcoxon test).
The median potassium levels increased by 0.3 mmol/L in the spironolactone group and did not change in the placebo group. Serious hyperkalemia occurred in 2% of patients in the spironolactone group and 1% in the placebo group. Gynecomastia occurred in 9% of the men in the spironolactone group and 1% of the men in the placebo group.
There were no significant subgroup interactions for the primary outcome.
Conclusion: In patients with severe systolic heart failure, spironolactone reduced all-cause death with a number need to treat of approximately 9 patients over 2 years of follow up. This benefit was consistent among all subgroups. This is a large treatment benefit that is infrequently seen in trials of cardiovascular medicine. It further supports the role of RAAS inhibition in patients with systolic heart failure. A key strength of the trial is that low-dose spironolactone was sufficient to demonstrate benefit, without requiring high doses.
The risk of hyperkalemia in the trial was low. However, one should appreciate that the dose of ACEi used was low and that concomitant use of high-dose ACEi and spironolactone will likely increase this risk, therefore, frequent monitoring of such patients is required.
The trial did not report the number of patients screened to enrolled, which limits its external validity. Nonetheless, based on the the large treatment benefit observed, we recommend spironolactone for patients with systolic heart failure who do not meet the exclusion criteria particularly regarding creatinine (>2.5 mg/dL) and potassium (>5.0 mmol/L) levels.
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