Aldosterone antagonists for the treatment of systolic heart failure

By Dr. Mustafa Toma (biography and disclosure) and Dr. Neda Amiri (biography and disclosure)

What I did before

Heart failure (HF) is a common condition, affecting 1% of all Canadians (1) and is associated with 4.9% of hospitalizations in Canada.(2) This results in a large burden on the health care system, with an average length of hospital stay that is nearly twice that for all other causes (12 days compared with 6.8).  Furthermore, patients with heart failure have an in-hospital mortality rate of 13.3% – triple the average rate of all other causes (4.4%).(2)

Large clinical trials have demonstrated mortality benefit for certain classes of medications in HF with reduced ejection fraction (EF).  Select beta-blockers (Carvedilol, Bisoprolol and Metoprolol SR) as well as angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are among these agents.(3)

Prior to 2011, I used the aldosterone antagonist, spironolactone, only in patients with NYHA class III or IV (Table 1) and EF < 30% based on the results of the RALES trial.(4)

Table 1. New York Heart Association (NYHA) Classifications

What changed my practice

In January 2011, the EMPHASIS-HF (5) study was published in the New England Journal of Medicine (NEJM). The study’s aim was to determine the effects of the selective aldosterone antagonist, eplerenone, added to evidence based therapy, on the clinical outcomes of patients with systolic heart failure and mild (NYHA II) symptoms.

The study was a multicentre, international, double-blind, randomized, placebo-controlled clinical trial.  Study subjects included were patients with NYHA class II symptoms who were over 55 years old and had EF < 30% (or EF < 35% and QRS duration > 130 msec). According to the study’s inclusion criteria, these patients were already treated with ACEi, ARB (or both) as well as beta blockers at recommended/tolerated doses. Exclusion criteria included NYHA class III or IV symptoms, serum potassium greater than 5 mmol/L, and eGFR < 30 ml/min/1.73 m².

Eplerenone was initiated at the dose of 25 mg PO daily and increased to 50 mg PO daily after 4 weeks. Patients were followed up every 4 months with instructions to decrease the dose of the study drug for potassium levels 5.5-6 or stop the medication for potassium > 6.0.

The study enrolled 2737 patients and was stopped before the goal of 3100 patients recruited was achieved after an interim analysis of data revealed an overwhelming benefit in favor of using eplerenone.

Baseline characteristics were similar in both placebo and eplerenone groups with 33% of participants having a GFR of < 60 ml/min/1.73 m². Medications use at randomization included diuretics (85%), ACEi/ARB or both (94%) and beta-blocker (87%).

Results of the study showed that the primary outcome (death from cardiovascular causes or hospitalization for heart failure) occurred in 18.3% in the eplerenone group and 25.9% in the placebo group (hazard ratio (HR) 0.63; 95% CI, 0.54-0.74; p<0.001). The secondary outcome (death from any cause or hospitalization for heart failure) was met in 19.8% of patients in eplerenone group compared with 27.4% in the placebo group (HR 0.65; 95% CI, 0.55-0.76; p<0.001). In total, 12.5% of patients in the eplerenone and 15.5% of patients in the placebo group died (HR 0.76; 95% CI, 0.62-0.93; p=0.008). The numbers needed to treat to prevent one primary outcome or death per year of follow-up were19 and 51, respectively.

At the end of trial, the mean change in serum creatinine level from baseline was 8±32.7 μmol/L in the eplerenone group compared with 3.5±35.4 μmol/L in the placebo group, while potassium levels were increased from baseline by 0.16±0.56 mmol/L in the eplerenone group compared with 0.05±0.53 mmol/L (p<0.001). More patients in the eplerenone group had high potassium levels (K+>5.5, 11.8% in eplerenone group vs 7.2% in the placebo arm; K+ >6: 2.5% in eplerenone group vs. 1.9% in the placebo group, p=0.29). There were no statistically significant differences between the two groups for hypokalemia, renal failure, hypotension or gynecomastia.

What I do now

There is high mortality and morbidity associated with heart failure. Previously, aldosterone antagonists were used in patients with moderate to severe heart failure symptoms and low EF or those with reduced ejection fraction after a myocardial infarction based on RALES and EPHESUS trials, respectively (4,6).

 Based on the results of the EMPHASIS-HF study, I now use spironolactone or eplerenone in patients with EF <30-35% and NYHA class II symptoms.  Although eplerenone was studied in the EMPHASIS trial, it is thought that the clinical benefit derived is based on a class effect (7). Thus we recommend eplerenone as a first line agent in NYHA class II patients, however we believe that spironolactone can also be used if cost is a limiting factor.  Patients who develop disabling side effects from spironolactone, (gynecomastia, breast tenderness or sexual dysfunction) should use eplerenone given its specific mineralocorticoid blockade (8).

Retrospective trials have shown that while the use of aldosterone antagonists increased in the years following the publication of the RALES trial, the rates of hospitalizations for hyperkalemia also significantly increased (9). Therefore, I monitor the patients’ creatinine and potassium levels closely after initiation of an aldosterone antagonist and with each uptitration to monitor for hyperkalemia and kidney injury. Furthermore, the use of both an ACEi and ARB in combination with an aldosterone antagonist should be avoided.

Conclusion: Spironolactone or eplerenone should be added to BB and ACEi/ARB in NYHA class II HF patients with EF < 30-35% in the absence of significant renal impairment or hyperkalemia.

References (Note: Article requests might require a login ID with CPSBC or UBC):

1. Chow C-M et al. Can J Cardiol 2005;21(14):1265-71 (View article)
2. Dai S, Walsh P, Wielgosz A, et al. Comorbidities and mortality associated with hospitalized heart failure in Canada. Can J Cardiol. 2012;28(1):74-9 (View article with CPSBC or UBC)
3. Am Fam Physician. ACC and AHA Update on Chronic Heart Failure Guidelines. 2010;81(5):654-665 (View article)
4. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Eng J Med 1999;341:709-17 (View article)
5. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-2 (View article)
6. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Eng J Med 2003;348:1309-21 (View article)
7. Armstrong PW. Editorial. New Eng J Med. 2011;364(1):79-80Chatterjee S, Moeller C, Shah N, et al. Eplerenone is not superior to older and less expensive aldosterone antagonists. Am J Med. 2012;125(8):817-25 (View article with CPSBC or UBC)
8. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.  N Engl J Med. 2004;351(6):543-51 (View article)

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Aldosterone antagonists for the treatment of systolic heart failure

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