Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

Rajiv Agarwal; Peter Kolkhof; George Bakris; Johann Bauersachs; Hermann Haller; Takashi Wada; Faiez Zannad


Eur Heart J. 2021;42(2):152-161. 

In This Article

Resurrection of Steroidal Mineralocorticoid Receptor Antagonists

Summary of Key Clinical Trials in Cardiac Diseases

Despite preclinical data on BP lowering and cardiorenal protection, it was not until 1999 that the first seminal trial with spironolactone in patients with HF with reduced ejection fraction (HFrEF) was published.[17] Results of the Randomized Aldactone Evaluation Study (RALES; N = 1663) showed that spironolactone (~25 mg/day) reduced the risk of death by 30% vs. placebo [hazard ratio (HR) = 0.70; 95% confidence interval (CI) 0.60–0.82; P < 0.001) in patients with HFrEF New York Heart Association (NYHA) Class III–IV [left ventricular ejection fraction (LVEF) <35%).[17] The effects were so robust that the trial was stopped prematurely for efficacy. Incidences of progressive HF and sudden death were reduced; HR for hospitalization for heart failure (HHF) was 0.65; and NYHA class improved. However, rates of breast pain and gynaecomastia increased (10% with spironolactone vs. 1% with placebo).[17]

The major limitation of aldosterone blockade with spironolactone was hyperkalaemia. In 2004, a pharmacoepidemiological study noted an increased incidence of hyperkalaemia after the RALES publication; this also correlated with an increase in prescription of spironolactone.[17] The increased incidence of hyperkalaemia was likely related to spironolactone use in patients who would have been excluded from RALES [i.e. those with low estimated glomerular filtration rate eGFR)], and to the use of higher spironolactone doses than that used in RALES.[18] A more judicious use of spironolactone and closer patient monitoring may reduce the occurrence of hyperkalaemia.[19,20]

Eplerenone was subsequently developed as a more selective version of spironolactone, with another seminal trial to test its effects among myocardial infarction (MI) patients with an LVEF ≤40% and symptomatic HF.[21] Results of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS; N = 6642) showed that eplerenone was associated with a 15% relative risk reduction in all-cause mortality compared with placebo and a 13% relative risk reduction in cardiovascular (CV) mortality or hospitalization due to CV causes compared with placebo.[21]

In 2011, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF; N = 2737) showed that compared with placebo, eplerenone substantially reduced the risk of death and both the risk of all-cause hospitalization and HHF among patients with LVEF ≤30% and a recent (≤6 months) admission for CV reasons and mild HF symptoms (NYHA Class II).[22] Eplerenone has also been studied in patients with acute coronary syndrome without HF in the Impact of Eplerenone on Cardiovascular Outcomes in Patients Post Myocardial Infarction (REMINDER; N = 1012) trial.[23] Treatment with eplerenone was found to be safe and well tolerated, but early MRA use did not demonstrate any clear benefit in patients admitted for MI when added to standard of care (SOC). Although the hyperkalaemia rate was higher with eplerenone vs. placebo, no sexual adverse events were reported, unlike those observed for spironolactone in RALES. Despite the demonstrated efficacy and safety of eplerenone, its use in routine clinical practice in patients with CKD is limited.[24] This may be due to the associated hyperkalaemia risk,[24,25] in addition to contraindications in the label for its use in patients with hypertension and concomitant T2D with microalbuminuria.[26]

Important drug disposition differences were recognized between spironolactone and eplerenone and translated into clinical benefits and harms. In a small head-to-head study of patients with mild-to-moderate hypertension, eplerenone was well tolerated with an adverse event incident rate similar to that of placebo;[27] increases in serum aldosterone, total/active plasma renin, and serum potassium were significantly smaller with eplerenone, which paralleled the relatively reduced BP-lowering efficacy of eplerenone (25–50% less potent) compared with spironolactone; no incidence of impotence, gynaecomastia, or dysmenorrhoea was reported with eplerenone.[27]

In 2014, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT; N = 3445) trial demonstrated that spironolactone (15–45 mg/day) did not reduce the risk for the primary outcome (a composite of CV death, aborted cardiac arrest, or HHF), in patients with symptomatic HF with preserved ejection fraction (LVEF ≥45%) vs. placebo (HR = 0.89; 95% CI 0.77–1.04; P = 0.14).[28] In a post hoc subgroup analysis of the trial, spironolactone was associated with a significant reduction in the primary outcome for patients in the Americas but not in Eastern Europe.[29] Spironolactone treatment was associated with increased serum creatinine levels and a doubling of the rate of hyperkalaemia (potassium ≥5.5 mmol/L).[28]

In 2016, the Aldosterone Blockade Early After Acute Myocardial Infarction (ALBATROSS; N = 1603) trial was published.[30] Patients with acute MI were randomized to receive an MRA regimen with a single intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) for 6 months plus SOC or SOC alone. The primary outcome (a composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6 months) occurred in 11.8% and 12.2% of patients in the treatment and control groups, respectively (HR = 0.97; 95% CI 0.73–1.28), demonstrating no benefit of early MRA use when added to SOC in patients admitted for MI. Hyperkalaemia (potassium ≥5.5 mmol/L) occurred in 3% and 0.2% of patients in the treatment and SOC groups, respectively (P < 0.0001).

Summary of Key Clinical Trials in Chronic Kidney Disease

Despite growing evidence for MRA use in HF, data from clinical trials of MRAs were sparse in patients with kidney failure. To address this, a proof-of-concept study assessed whether steroidal MRAs could protect the heart of patients with CKD Stages II and III receiving an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) (N = 112).[31] Spironolactone treatment resulted in reduced left ventricular mass and improved arterial stiffness after 40 weeks that was BP independent.[31]

In 2014, a Cochrane Database Systematic Review extended these observations to 27 studies (N = 1549) but covered fewer patients than those in RALES alone.[17,32] Hard endpoints such as end-stage kidney disease (ESKD) or major adverse CV effects were not noted in these trials. Spironolactone decreased proteinuria and BP; however, aldosterone antagonist treatment had imprecise effects at the end of treatment on glomerular filtration rate (GFR) (nine studies, N = 528; mean difference −2.55 mL/min/1.73 m2, 95% CI −5.67 to 0.51). Steroidal MRAs doubled the risk of hyperkalaemia (11 studies, N = 632) with a risk ratio (RR) of 2.00 (95% CI 1.25–3.20), and a number needed to treat for an additional harmful outcome (NNTH) of 7.2 (95% CI 3.4 to ∞). Spironolactone increased the risk of gynaecomastia compared with ACEis or ARB or both (four studies, N = 281): RR = 5.14, 95% CI 1.14–23.23; NNTH = 14.1, 95% CI 8.7–37.3.[32] An updated 2019 systematic review evaluated the role of MRAs alone or on top of ACEi/ARB (31 studies, N = 2767) and noted that MRA addition was associated with a change in eGFR of −2.38 mL/min/1.73 m2 (95% CI −3.51 to −1.25).[33]

A 2016 meta-analysis limited observations to patients on dialysis (nine trials, N = 829). MRAs reduced CV mortality in patients receiving dialysis by 66% but increased hyperkalaemia risk threefold vs. controls.[34] Following this meta-analysis, the multicentre feasibility study, Safety and CV efficacy of spironolactone in dialysis-dependent ESRD (SPin-D), did not demonstrate CV benefit for spironolactone; rate of hyperkalaemia (potassium >6.5 mmol/L) was similar between placebo and spironolactone 25 mg but increased with spironolactone 50 mg.[35]

Steroidal MRAs have a relative or absolute contraindication in late-stage CKD. Efforts to find a signal for the efficacy and safety of spironolactone (25 mg) are ongoing in two Phase III placebo-controlled trials in patients receiving dialysis. The Aldosterone bloCkade for Health Improvement EValuation in End-stage renal disease (ACHIEVE) trial will assess CV death or HHF events as the primary outcome in patients with T2D.[36] The ALdosterone antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST) will assess time to first incident of non-fatal MI, acute coronary syndrome, HHF, non-fatal stroke, or CV death as the primary outcome in patients with or without T2D.[36]