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Authors: Stormi Gale, PharmD, Jeannie L. Poon, PharmD, and Kristin Watson, PharmD, BCPS-AQ Cardiology
The most recognized population for the use of mineralocorticoid receptor antagonists (MRAs) is patients with heart failure with a reduced ejection fraction (HFrEF). These agents (spironolactone and eplerenone) are recommended in the 2013 American College of Cardiology Foundation/American Heart Association heart failure (HF) guideline for patients with HFrEF with New York Heart Association (NYHA) Class II-IV symptoms. The recommendation for patients with NYHA Class II symptoms is reserved for those with an elevated brain natriuretic peptide (BNP) or previous cardiovascular (CV) hospitalization.1 The strength of these recommendations are based on the results of two randomized, controlled trials (RCTs): the Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), which evaluated the efficacy of spironolactone and eplerenone, respectively.
In RALES, patients with NYHA Class III or IV with left ventricular ejection fractions (LVEF) <35% who were receiving an angiotensin converting enzyme inhibitor (ACEi) and a diuretic were randomized to spironolactone or placebo. The trial was terminated early due to the benefits of therapy, as the use of spironolactone decreased the risk of death 45.9% vs. 34.4% (hazard ratio (HR), 0.70 [95% confidence interval (CI), 0.60-0.82], p<0.001) with a number needed to treat (NNT) of 9 over 24 months.2 The use of spironolactone was associated with a 35% reduction in HF hospitalization (p<0.001) as well as a significant improvement in NYHA functional class. Over ten years later, EMPHASIS-HF was published, which was not only important for determining a “class-effect” for MRAs in HFrEF, but established the utility of these agents for patients with less severe disease on superior guideline-directed medical therapy (GDMT). In RALES, only 10.5% of patients were on beta-blockers and many critics argued that the benefits of spironolactone were due to a lack of GDMT. EMPHASIS-HF evaluated the efficacy of eplerenone in HFrEF, and included patients with LVEF <35% and NYHA class II symptoms, 88% of which were on beta-blocker therapy. Despite better baseline medical therapy, the trial was also terminated early due to a decrease in the composite primary outcome of CV death and hospitalization for HF (HR 0.63 [95% CI, 0.54-0.74], p<0.001).3 The NNT to reduce the composite endpoint was 19 per year of follow-up.
The population in which MRAs are arguably the most underutilized may be those with HF with preserved ejection fraction (HFpEF). The limited use of MRAs in HFpEF is likely due to the results of the Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT) trial, which showed no difference in the composite primary outcome of CV death, aborted cardiac arrest, or hospitalization for HF in patients with LVEF ³45%. Other than a preserved LVEF, patients in this trial were included if they had a hospitalization within the previous 12 months or elevated BNP within 60 days; most patients were NYHA Class II or III. Approximately one-half of the patients were studied in the Americas, and the remaining half was studied in Russia and Georgia. Although no reduction in mortality was seen, there was a significant decrease in hospitalizations with spironolactone (HR 0.83, [95% CI, 0.69-0.99], p=0.04), with a NNT of 45 over a 3.3 year period.4 One point of discussion after the trial was published was the difference in outcomes between patients in the Americas versus those in Russia and Georgia. The population studied in the Americas had a much higher event rate of 27.3% in the spironolactone group, compared to a rate of only 9.3% in Russia and Georgia. This translated to a significant decrease in the treatment group in the Americas, whereas no difference was seen in Russia and Georgia. A possible reason for this is the differences in the standards and structure of healthcare systems in these countries. Patients in the Americas are much more likely to be hospitalized for less life-threatening ailments than those in Russia or Georgia; therefore, it would be difficult to detect a difference with such low rates of events from the latter population. It is thought-provoking to consider if these outcomes would have been different had the study only included the population in the Americas. There have since been trials confirming the improvement in symptoms with MRA therapy in HFpEF.
Recently, the SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE Capacity (STRUCTURE) trial suggested an improvement in exercise capacity with spironolactone in this population.5 In a specialty saturated with large randomized trials and impactful outcomes, we often forget that mortality should not be the only criteria for therapies in CV disease. In patients with HFpEF, reducing symptoms and the risk of hospitalizations is currently the best strategy we have, and thus MRAs should be considered in this population. Furthermore, it is possible that long-term MRA therapy could reduce death in patients with HFpEF; it has been demonstrated that this population is at a decreased risk for sudden cardiac death (SCD) in studies of up to 5 years, thus this population may require a mean-follow up of much longer than 3.3 years before a difference in mortality can be observed.6-7
Although many benefits regarding the use of MRAs have been demonstrated in the literature, apprehension surrounding adverse effects often preclude their use. Prescribers are frequently hesitant to start spironolactone in patients with borderline “low” pressures due to concerns for hypotension. However, a Cochrane review in 2010 found similar BP-lowering effects in patients with primary essential hypertension with spironolactone versus placebo.8 As is discussed throughout this entry, there are many non-hypertensive patients who have indications for MRAs. This is especially prevalent in HFrEF, a population in which normotension is common due to reduced cardiac output (CO). That being said, in HFrEF, a decrease in systemic vascular resistance can actually increase CO, leaving overall mean arterial pressure unchanged. This does not necessarily translate to HFpEF patients, as filling is more dependent on preload and can be affected by a decrease in sodium and water retention. As such, MRAs should still be considered in normotensive patients with other indications for aldosterone antagonism, especially in HFrEF.
Although data exist for the use of MRAs in chronic HF management, few studies have evaluated the role of MRAs in acute decompensated heart failure (ADHF). Disappointingly, the Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA HF) trial demonstrated no improvements in N-terminal-proBNP, dyspnea, or urine output with spironolactone 100 mg in 360 HF patients with signs of pulmonary congestion and an elevated N-terminal-proBNP.9 There is currently no role for spironolactone for the treatment of ADHF.
MRAs are also recommended for patients who are post-myocardial infarction (MI) with reduced ejection fraction and diabetes mellitus or symptoms of HF.10 This is based on the results of the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) study, which randomized the patients to eplerenone or placebo. Use of eplerenone was associated with a reduction in all-cause death (HR 0.85, [95% CI, 0.75-0.96], p=0.008) and a composite of CV death and CV hospitalization (HR 0.87, [95% CI, 0.79-0.95], p=0.002).11 The data for MRAs is not as strong, however, for patients post-MI without HF. The recently published Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated With or Without Reperfusion to Improve Outcome and Survival at Six Months’ Follow-Up (ALBATROSS) study found no difference in outcomes with spironolactone therapy within 12-24 hours of MI versus standard treatment in post-MI in this population.12 However, there was a reduction in mortality in a subgroup of patients who presented with ST-elevation MI (STEMI) (HR 0.20, [95% CI, 0.06-0.69], p=0.0044) who received early MRA therapy. The Early Mineralocorticoid Receptor Antagonist Treatment to Reduce Myocardial Infarct Size (MINIMISE-STEMI) study evaluating the use of MRA therapy in STEMI patients with preserved EF post-MI has been completed, but results have not yet been published.13
In conclusion, the underutilization of MRAs remains despite benefits observed in the literature, particularly in HFpEF. Reduction in both symptoms and the risk of hospitalizations should not be taken lightly, especially when treatment options for HFpEF patients are already limited. Despite the mortality benefits seen in HFrEF and MI, adverse effects associated with this drug class may also contribute to its low use. Considerations on the effects of blood pressure, potassium, and renal function will be discussed in Part 2 of this series, as well as the role of MRAs in treating resistant hypertension.
Kristin Watson, PharmD, BCPS-AQ Cardiology
Stormi Gale, PharmD
Jeannie L. Poon, PharmD
- Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Eng J Med. 1999;341(10):709-17.
- Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Eng J Med. 2011;364(1):11-21.
- Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-92.
- Kosmala W, Rojek A, Przewlocka-Kosmala M, et al. Effect of aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;68:1823-34.
- Zile MR, Gaasch WH, Anand IS et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial. 2010;121:1393–1405.
- Adabag S, Smith LG, Anand IS et al.Sudden cardiac death in heart failure patients with preserved ejection fraction. Journal of Cardiac Failure. 2012;18(10):749-754.
- Batterlink J, Stabler S, Tejani A et al. Spironolactone for hypertension. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD008169.
- Butler J, Konstam MA, Felker M, et al. Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) Trial. Presented at: the 2016 American Heart Association Scientific Sessions. November 12-16, 2016; New Orleans, LA.
- Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:139-228.
- Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-1321.
- Beygui, G. Cayla, V. Roule, et al. Early aldosterone blockade in acute myocardial infarction: the ALBATROSS randomized clinical trial. J Am Coll Cardiol. 2016;67:1917–1927.
- Bullock H, Frohlich G, Mohdnazri S et al. Mineralocorticoid Receptor Antagonist Pretreatment to MINIMISE Reperfusion Injury After ST‐Elevation Myocardial Infarction (The MINIMISE STEMI Trial): Rationale and Study Design. Clin Cardiol. 2015;38(5):259–266.
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