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Mineralocorticoid receptor antagonists: spironolactone, eplerenone, and finerenone

Mineralocorticoid receptor antagonists in adults from aldosterone biology and drug selectivity through the outcome trials in heart failure, myocardial infarction, hypertension, and kidney disease, dosing by kidney function, and the prevention and management of hyperkalemia.

Aldosterone and the mineralocorticoid receptor

Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex by aldosterone synthase (CYP11B2), the final enzyme of the pathway. Three stimuli control its release: angiotensin II acting on the type 1 receptor, a rise in plasma potassium that depolarizes glomerulosa cells, and corticotropin. Potassium is a direct secretagogue, which is why aldosterone and potassium form a closed feedback loop: a potassium load raises aldosterone, and aldosterone promotes potassium excretion. In heart failure, cirrhosis, and nephrotic syndrome, reduced effective arterial filling activates renin and sustains aldosterone secretion; in primary aldosteronism, production is autonomous and renin is suppressed.

The mineralocorticoid receptor, encoded by NR3C2, is a ligand-activated transcription factor of the nuclear receptor superfamily. Its ligand-binding domain resembles those of the glucocorticoid, progesterone, and androgen receptors, a homology that explains the off-target effects of steroidal antagonists. Unbound receptor sits in the cytoplasm with heat-shock chaperones. Ligand binding releases the chaperones, and the receptor translocates to the nucleus, binds hormone response elements, and recruits coactivators that set the transcriptional program.

The receptor binds cortisol and aldosterone with similar affinity, and circulating cortisol exceeds aldosterone by two to three orders of magnitude. In aldosterone-selective epithelia, 11β-hydroxysteroid dehydrogenase type 2 converts cortisol to cortisone, which does not bind the receptor, and allows aldosterone to occupy it. Cardiomyocytes, macrophages, and many vascular cells express little of this enzyme, so their receptors are largely occupied by cortisol. Under oxidative stress and tissue injury, cortisol-bound receptors become activated. This is one reason MRAs benefit patients whose plasma aldosterone is normal. Licorice, which inhibits the enzyme, and inherited deficiency of the enzyme (apparent mineralocorticoid excess) produce hypertension and hypokalemia by letting cortisol act as a mineralocorticoid.

Epithelial actions. In principal cells of the connecting tubule and cortical collecting duct, receptor activation increases the expression and open probability of the epithelial sodium channel (ENaC) and the basolateral sodium-potassium ATPase. Sodium entry through ENaC generates a lumen-negative transepithelial potential that drives potassium secretion through apical renal outer medullary potassium (ROMK) channels and hydrogen ion secretion by intercalated cells. The net effects are sodium and water retention, kaliuresis, magnesium loss, and metabolic alkalosis. MRAs reverse each of these effects. They are weak natriuretics on their own, because the collecting duct reabsorbs only a few percent of filtered sodium, but they preserve potassium and magnesium during loop or thiazide therapy and potentiate distal natriuresis when aldosterone is high.

Non-epithelial actions. In the myocardium, vessel wall, and kidney interstitium, receptor activation promotes collagen synthesis, macrophage infiltration, oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, endothelial dysfunction with reduced nitric oxide availability, and myocyte hypertrophy. Aldosterone also reduces baroreceptor sensitivity, increases sympathetic activity, inhibits myocardial norepinephrine reuptake, and lowers the threshold for ventricular arrhythmias, partly through potassium and magnesium depletion. Rapid, nongenomic effects within minutes, mediated by membrane-associated signaling and transactivation of the epidermal growth factor receptor, add to vascular tone and inflammation.

Aldosterone escape. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) lower aldosterone acutely, but in many patients plasma aldosterone returns toward or above baseline within months. Potassium, corticotropin, non-ACE angiotensin II generation, and incomplete receptor blockade sustain secretion. Escape provided the physiologic rationale for adding receptor blockade to renin-angiotensin inhibition, the strategy tested in RALES.

Fibrosis, remodeling, and the evidence that receptor blockade changes them

Myocardial fibrosis links aldosterone to the clinical events that MRAs prevent. Interstitial collagen stiffens the ventricle, impairs relaxation, separates myocytes, and creates the slow conduction that sustains reentrant ventricular tachycardia. In a RALES substudy of 261 patients, baseline serum markers of collagen synthesis, the procollagen type III aminoterminal peptide (PIIINP) and the procollagen type I carboxyterminal peptide, were associated with worse outcomes. Spironolactone lowered these markers, and the survival benefit was confined largely to patients whose baseline PIIINP was above the median. These data support limitation of extracellular matrix turnover as one mechanism of benefit, independent of potassium preservation.

In heart failure with preserved ejection fraction (HFpEF), spironolactone reduced three measures over 12 months in Aldo-DHF (422 patients, LVEF 50% or more). They were the ratio of early mitral inflow velocity to early diastolic annular velocity (E/e′), left ventricular mass index, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). It did not improve peak oxygen consumption, symptoms, or quality of life. The structural effect of receptor blockade was measurable; its translation into function and outcomes was not demonstrated in that population.

Sudden death is the event most consistently reduced. RALES reduced death from progressive heart failure and sudden cardiac death. EPHESUS reduced sudden cardiac death after myocardial infarction, and EMPHASIS-HF reduced cardiovascular death. Proposed mechanisms include reduced fibrosis, prevention of hypokalemia and hypomagnesemia during diuretic therapy, improved heart rate variability, and reduced sympathetic activation.

Steroidal and nonsteroidal antagonists: chemistry and receptor selectivity

Spironolactone, introduced in 1959, is a 17-spirolactone steroid that competes with aldosterone in the ligand-binding pocket. Its steroid scaffold also binds the androgen receptor as an antagonist and the progesterone receptor as a partial agonist, the source of gynecomastia, breast tenderness, menstrual irregularity, and reduced libido. Eplerenone, approved in the United States in 2002, is a 9α,11α-epoxy derivative of spironolactone. The epoxy group reduces binding to androgen and progesterone receptors by two to three orders of magnitude, at the cost of a lower affinity for the mineralocorticoid receptor itself, so higher milligram doses are needed.

Finerenone belongs to a different chemical class. It is a dihydronaphthyridine, developed from a dihydropyridine screening series, with no steroid backbone. It binds the ligand-binding domain in a bulky, nonsteroidal mode that displaces helix 12 and prevents coactivator recruitment, so the receptor remains transcriptionally inactive even with some ligand occupancy. In preclinical models it distributes more evenly between heart and kidney than the steroidal agents, which concentrate in the kidney, and it produced greater reductions in cardiac and renal fibrosis and inflammatory markers than equinatriuretic doses of eplerenone. These are animal data; differences in clinical efficacy between agents have not been tested head to head.

Half-maximal inhibitory concentrations in the cell-based transactivation assays reported during finerenone development (Kolkhof and Bärfacker, 2017). Lower values indicate higher potency. Absolute values differ between assays, but the pattern is consistent: spironolactone is potent and unselective, eplerenone is selective and less potent, and finerenone is both potent and selective.

The receptor pharmacology has three clinical consequences. Gynecomastia and other sex-steroid effects are a spironolactone problem, and switching to eplerenone or finerenone removes them. Hyperkalemia is a class effect that follows from blockade of the mineralocorticoid receptor in the collecting duct, so no agent is free of it. Third, the outcome evidence is agent-specific. Spironolactone and eplerenone have mortality data in HFrEF and after infarction, and finerenone has outcome data in diabetic kidney disease and in heart failure with LVEF of 40% or more. The agents are not interchangeable across these indications.

Pharmacokinetics of spironolactone, eplerenone, and finerenone

Spironolactone is a prodrug with a parent half-life of about 1.4 hours. It is converted to sulfur-containing metabolites, chiefly 7α-thiomethylspironolactone, and to canrenone, which carry most of the antimineralocorticoid activity and have half-lives of about 14 to 17 hours. Peak concentrations occur at about 2.6 hours for the parent drug and 4.3 hours for canrenone. Food increases bioavailability by about 95%, so the drug is taken consistently with respect to meals. Because of the long-lived metabolites, the full effect develops over several days and persists for days after the last dose, which matters when hyperkalemia develops. Spironolactone and its metabolites are more than 90% protein bound and are eliminated mainly in urine and secondarily in bile. Clearance is reduced in cirrhosis.

An oral suspension (25 mg/5 mL) produces serum concentrations 15% to 37% higher than the same dose of tablets and is not therapeutically equivalent to them. Its heart failure doses differ from tablet doses, and for doses above 100 mg a tablet formulation is used. RALES was conducted with tablets.

Eplerenone has an absolute bioavailability of 69% that food does not change, a peak at 1.5 to 2 hours, and a half-life of about 3 to 6 hours. It is metabolized by cytochrome P450 3A4 (CYP3A4) to inactive metabolites, is about 50% protein bound (mainly to alpha-1-acid glycoprotein), and reaches steady state within 2 days. Its dependence on CYP3A4 makes strong inhibitors a contraindication and moderate inhibitors a reason to cap the dose at 25 mg daily. The short half-life means that once-daily dosing gives incomplete 24-hour receptor coverage; in primary aldosteronism, eplerenone is usually given twice daily.

Finerenone has an absolute bioavailability of 44%, a half-life of about 2 to 3 hours, a volume of distribution of about 53 L, and 92% protein binding. It is metabolized by CYP3A4 (about 90%) and CYP2C8 (about 10%) to inactive metabolites, which are excreted about 80% in urine and 20% in feces. Exposure rises 38% in moderate hepatic impairment (Child-Pugh B), and use is avoided in severe impairment. The tablets may be crushed and taken with or without food.

Pharmacokinetic properties and US labeling of the three agents in clinical use, from the Aldactone, Inspra, and Kerendia prescribing information. CKD, chronic kidney disease; HFrEF, heart failure with reduced ejection fraction; NYHA, New York Heart Association.

Outcome trials of mineralocorticoid receptor antagonists

The table gathers the randomized trials that define current use. Their populations are narrow, and the exclusion criteria, usually potassium above 5.0 mEq/L and creatinine above 2.5 mg/dL or eGFR below 25 to 30 mL/min/1.73 m², are as much part of the evidence as the results.

Randomized trials that define the indications for mineralocorticoid receptor antagonists. HR, hazard ratio; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

MRAs in heart failure with reduced ejection fraction

RALES. The Randomized Aldactone Evaluation Study enrolled patients with LVEF of 35% or less and NYHA class III or IV symptoms (class IV within the previous 6 months). Background therapy was an ACE inhibitor if tolerated, a loop diuretic, and usually digoxin. Only about one in ten received a beta blocker. The dose of spironolactone was 25 mg daily, which could be raised to 50 mg for worsening heart failure or lowered to 25 mg every other day for hyperkalemia. Spironolactone reduced all-cause mortality from 46% to 35% (relative risk 0.70), and the trial was stopped early after a mean of 24 months. Death from progressive heart failure and sudden death both fell, hospitalization for worsening heart failure was 35% lower, and NYHA class improved. Serious hyperkalemia occurred in 2% of the spironolactone group and 1% of the placebo group, and gynecomastia or breast pain in 10% of men versus 1%.

EMPHASIS-HF. RALES left open whether the benefit extended to milder symptoms and to patients on beta blockers. EMPHASIS-HF enrolled patients aged 55 or older with NYHA class II symptoms and LVEF of 30% or less (or 30% to 35% with QRS duration above 130 ms), nearly all on renin-angiotensin inhibitors and beta blockers. Eplerenone was started at 25 mg daily and increased to 50 mg daily after 4 weeks when potassium allowed. At eGFR 30 to 49 mL/min/1.73 m², it was started at 25 mg every other day and increased to 25 mg daily. The trial was stopped early at a median of 21 months. The primary composite of cardiovascular death or heart failure hospitalization fell from 25.9% to 18.3% (hazard ratio [HR] 0.63), all-cause death from 15.5% to 12.5% (HR 0.76), and heart failure hospitalization from 18.4% to 12.0%. Hyperkalemia was reported in 8.0% versus 3.7%, without excess renal failure. New-onset atrial fibrillation or flutter was less frequent with eplerenone (2.7% versus 4.5%; HR 0.58) in a prespecified secondary analysis.

Guideline position. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guideline recommends spironolactone or eplerenone to reduce morbidity and mortality in patients with HFrEF and NYHA class II to IV symptoms (Class 1, Level A). Treatment requires eGFR above 30 mL/min/1.73 m² and potassium below 5.0 mEq/L. Potassium, renal function, and diuretic dosing are monitored at initiation and closely thereafter. When potassium cannot be maintained below 5.5 mEq/L, the MRA is discontinued (Class 3: Harm). The guideline attaches a high economic value statement to MRA therapy. The 2024 ACC Expert Consensus Decision Pathway places the MRA among the four foundational classes. It is started early and in parallel with an angiotensin receptor-neprilysin inhibitor (ARNI) or ACE inhibitor or ARB, an evidence-based beta blocker, and a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Sequencing, titration, and device decisions are covered in the HFrEF hub.

Which steroidal agent. No trial has compared spironolactone and eplerenone for outcomes. Spironolactone is the usual first choice in the United States because of cost and the RALES mortality data. Eplerenone is used when gynecomastia or other sex-steroid effects occur and after myocardial infarction, where its label and trial evidence lie. Trial target doses are spironolactone 25 to 50 mg and eplerenone 50 mg daily. A milligram-for-milligram conversion between the two has not been validated; a switch for gynecomastia starts eplerenone at 25 mg daily and titrates by potassium.

Finerenone is not a substitute in HFrEF. No outcome trial of finerenone has been completed in HFrEF, and FINEARTS-HF excluded LVEF below 40%. Finerenone does not replace spironolactone or eplerenone in standard HFrEF therapy, and it is not combined with them. A trial testing finerenone in HFrEF patients who cannot tolerate a steroidal MRA is under way.

Improved ejection fraction. Patients whose LVEF rises above 40% on therapy (heart failure with improved ejection fraction) continue the full regimen, including the MRA. Withdrawal of guideline-directed medical therapy in recovered dilated cardiomyopathy was followed by relapse in a substantial proportion of patients in the TRED-HF trial, which withdrew all classes together; the effect of stopping the MRA alone has not been isolated.

Mortality and hospitalization effect sizes across MRA trials

The relative benefit of MRAs is similar across trials, but the absolute benefit follows baseline risk and the endpoint. Mortality reduction is established only for the steroidal agents in reduced ejection fraction and after infarction with left ventricular dysfunction. In preserved and mildly reduced ejection fraction and in diabetic kidney disease, the benefit is concentrated in heart failure hospitalization or worsening heart failure events.

Absolute and relative effects, and numbers needed to treat calculated from the absolute differences reported in each trial over its follow-up. They are not comparable across trials with different durations and endpoints.

The first-30-day analysis of EPHESUS showed that eplerenone reduced all-cause mortality by 31% within 30 days of randomization, which supports starting the drug before discharge after infarction when criteria are met. In HFrEF, the benefit of each foundational class appears within weeks.

After myocardial infarction with left ventricular dysfunction

EPHESUS randomized patients 3 to 14 days after acute myocardial infarction with LVEF of 40% or less and either clinical heart failure or diabetes. Most received ACE inhibitors or ARBs, beta blockers, aspirin, and statins. Patients with creatinine above 2.5 mg/dL or potassium above 5.0 mEq/L were excluded. Eplerenone 25 mg titrated to 50 mg daily reduced all-cause death (14.4% versus 16.7%; HR 0.85), cardiovascular death (12.3% versus 14.6%; HR 0.83), and the co-primary outcome of cardiovascular death or cardiovascular hospitalization (HR 0.87). Sudden cardiac death fell by 21%. Serious hyperkalemia (6.0 mEq/L or more) occurred in 5.5% versus 3.9%. In the prescribing information, patients older than 75 years and patients with diabetes without clinical heart failure did not appear to benefit in subgroup analyses.

The 2025 ACC/AHA/ACEP/NAEMSP/SCAI acute coronary syndromes guideline recommends a mineralocorticoid receptor antagonist for patients with acute coronary syndrome (ACS), LVEF of 40% or less, and heart failure symptoms or diabetes (Class 1, Level B-R). The aim is to reduce all-cause death and major adverse cardiovascular events, and advanced CKD, hyperkalemia, or another contraindication excludes use. The 2025 guideline replaced the 2013 American College of Cardiology Foundation/AHA (ACCF/AHA) STEMI guideline. The 2013 guideline gave the same population a Class 1 recommendation (Level B) and described EPHESUS eligibility as creatinine of 2.5 mg/dL or less in men or 2.0 mg/dL or less in women and potassium of 5.0 mEq/L or less. Eplerenone carries the US indication for this population. Spironolactone is used when eplerenone is unavailable, by extrapolation from RALES.

Routine MRA after infarction without the EPHESUS phenotype. Three trials tested broader use. REMINDER randomized patients with STEMI and no heart failure to eplerenone started within 24 hours. The primary composite fell, but the difference was driven by natriuretic peptide elevation, not by clinical events. ALBATROSS gave intravenous potassium canrenoate followed by oral spironolactone early after myocardial infarction and found no reduction in its composite of death, resuscitated arrest, ventricular arrhythmia, implantable cardioverter-defibrillator indication, or heart failure. CLEAR, a factorial trial in 7,062 patients after percutaneous coronary intervention for STEMI or large non-ST-elevation infarction, compared spironolactone 25 mg with placebo over a median of 3 years. The first co-primary outcome, cardiovascular death or new or worsening heart failure counted as total events, did not differ (183 versus 220 events; HR 0.91; 95% confidence interval [CI] 0.69 to 1.21), nor did the second, a composite of infarction, stroke, new or worsening heart failure, or cardiovascular death (7.9% versus 8.3%; HR 0.96). Hyperkalemia was more common with spironolactone. The indication after infarction therefore remains the EPHESUS phenotype: reduced ejection fraction with heart failure or diabetes. Acute coronary syndrome management is covered in the STEMI hub.

MRAs in mildly reduced and preserved ejection fraction

TOPCAT. In 3,445 patients with symptomatic heart failure and LVEF of 45% or more, spironolactone 15 to 45 mg daily did not significantly reduce the composite of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization (18.6% versus 20.4%; HR 0.89; 95% CI 0.77 to 1.04). Heart failure hospitalization alone was reduced (12.0% versus 14.2%; HR 0.83). Hyperkalemia was doubled (18.7% versus 9.1%), and creatinine doubling was more frequent. The results differed sharply by region. Patients enrolled in Russia and Georgia had a placebo event rate of 2.3 per 100 patient-years, compared with 12.6 in the Americas, and showed no treatment effect (HR 1.10). In the Americas, spironolactone was associated with fewer primary events (HR 0.82; 95% CI 0.69 to 0.98) and produced the expected rises in potassium and creatinine and fall in blood pressure. Canrenone was frequently undetectable in stored samples from Russian participants who reported taking the drug, evidence that many did not. The Americas analysis is post hoc and hypothesis-generating, but it underlies the guideline view that spironolactone may benefit selected patients.

FINEARTS-HF. The trial enrolled 6,001 patients with heart failure, LVEF of 40% or more, elevated natriuretic peptides, and structural heart disease. Finerenone, titrated to 20 or 40 mg daily by eGFR, reduced the primary composite of total worsening heart failure events and cardiovascular death over a median of 32 months (rate ratio 0.84; 95% CI 0.74 to 0.95). Total worsening heart failure events fell (rate ratio 0.82), and cardiovascular death did not differ significantly (8.1% versus 8.7%; HR 0.93). The benefit was consistent across the LVEF range studied and in patients enrolled during or soon after a heart failure hospitalization. Hyperkalemia was more frequent (9.7% versus 4.2%), as was investigator-reported hypotension (7.6% versus 4.7%), and hypokalemia was less frequent. The US Food and Drug Administration (FDA) approved finerenone in 2025 to reduce the risk of cardiovascular death, heart failure hospitalization, and urgent heart failure visits in adults with heart failure and LVEF of 40% or more.

SPIRIT-HF (conference presentation, not published in a journal). In 730 older adults with HFpEF or heart failure with mildly reduced ejection fraction (HFmrEF), the composite of heart failure hospitalization or cardiovascular death did not differ significantly (12.7 events per 100 patient-years with spironolactone and 10.8 with placebo; American College of Cardiology press release).

Guideline positions. The 2022 AHA/ACC/HFSA guideline, written before FINEARTS-HF, rates MRAs as possibly useful to reduce hospitalization in selected patients with HFpEF, particularly at the lower end of the ejection fraction spectrum (Class 2b, B-R). It gives the same class to MRAs in HFmrEF (Class 2b, B-NR). The 2026 ACC Expert Consensus Decision Pathway for HFpEF recommends an MRA in addition to an SGLT2 inhibitor unless contraindicated and favors finerenone because it has direct outcome evidence. Spironolactone is a reasonable alternative when cost or tolerability precludes finerenone, and eplerenone is an alternative for spironolactone gynecomastia. Diagnosis, phenotypes, and the full HFpEF regimen are covered in the HFpEF hub.

Spironolactone as the fourth drug in resistant hypertension

Resistant hypertension is blood pressure above goal on three classes at maximally tolerated doses, including a diuretic. In most patients it is a volume-expanded state in which aldosterone activity is inappropriately high for the sodium intake, whether or not primary aldosteronism is present. That physiology explains why an MRA is the most effective fourth drug. The definition, exclusion of pseudoresistance, and secondary-cause evaluation are covered in the hypertension hub.

PATHWAY-2 randomized 335 patients with resistant hypertension, already taking an ACE inhibitor or ARB, a calcium channel blocker, and a diuretic, to 12-week cycles of spironolactone 25 to 50 mg, bisoprolol, doxazosin, and placebo in a double-blind crossover design. Spironolactone lowered home systolic pressure by 8.7 mm Hg more than placebo and by more than either active comparator, and it was the most effective drug in most patients. The response was inversely related to plasma renin: the lower the renin, the larger the fall in pressure, consistent with occult sodium retention. A substudy found amiloride, which blocks ENaC directly, about as effective as spironolactone. PATHWAY-2 excluded patients with eGFR below 45 mL/min/1.73 m², the population in which hyperkalemia limits treatment.

The 2025 AHA/ACC high blood pressure guideline recommends adding an MRA when resistant hypertension persists on an ACE inhibitor or ARB, a calcium channel blocker, and a thiazide-like diuretic, with eGFR of 45 mL/min/1.73 m² or more (Class 1). The 2018 AHA scientific statement on resistant hypertension specifies spironolactone when eGFR is 45 or more and potassium is below about 4.5 mEq/L. Spironolactone is started at 12.5 to 25 mg and titrated to 50 mg. Eplerenone, at 50 mg once or twice daily, is the alternative when antiandrogenic effects limit spironolactone, though its blood pressure effect per milligram is smaller and its short half-life favors twice-daily dosing. When an MRA is not tolerated, amiloride, a beta blocker, an alpha blocker, a central sympatholytic, a dual endothelin receptor antagonist, or a direct vasodilator is considered reasonable (Class 2a).

Advanced kidney disease narrows the margin. AMBER enrolled 295 patients with resistant hypertension and eGFR 25 to 45 mL/min/1.73 m² who started open-label spironolactone and were randomized to patiromer 8.4 g daily or placebo. At 12 weeks, 86% of the patiromer group and 66% of the placebo group remained on spironolactone, mostly because hyperkalemia stopped it less often. The trial established that a potassium binder can enable spironolactone in this group; it did not test cardiovascular or kidney outcomes. Finerenone has not been tested for resistant hypertension, and its blood pressure effect in the kidney trials was modest, a few millimeters of mercury.

A good response to spironolactone does not diagnose primary aldosteronism, and aldosterone and renin are measured before the drug is started whenever possible, because an MRA raises renin and can mask the diagnosis for weeks.

MRA therapy in primary aldosteronism

Primary aldosteronism, renin-independent aldosterone production from a unilateral adenoma or bilateral adrenal hyperplasia, accounts for about 5% to 10% of hypertension and about one in five patients with resistant hypertension. Screening, confirmation, and lateralization are covered in the primary aldosteronism section of the hypertension hub. MRAs enter the pathway at two points.

Before screening. MRAs raise renin and can produce a false-negative aldosterone-to-renin ratio. The 2025 AHA/ACC guideline continues most antihypertensive drugs during screening and withdraws only MRAs, for at least 4 weeks when that is safe. When an MRA cannot be stopped, a still-suppressed renin despite MRA therapy continues to support the diagnosis.

Medical treatment. Unilateral disease is treated by laparoscopic adrenalectomy when the patient is a candidate. Bilateral disease, and unilateral disease when surgery is declined or not possible, is treated with an MRA. The 2025 Endocrine Society guideline recommends MRA therapy for patients who are not treated surgically. Spironolactone is the most widely used agent, and eplerenone, usually given twice daily, is used when antiandrogenic effects limit spironolactone. The label dose of spironolactone for preoperative preparation is 100 to 400 mg daily; for long-term treatment, the lowest effective dose is used. Doses are titrated to normalize potassium and blood pressure and to raise renin out of the suppressed range. In medically treated cohorts, the excess of cardiovascular events, atrial fibrillation, and death over essential hypertension was confined to patients whose renin remained suppressed. Amiloride is the alternative when no MRA is tolerated.

Glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type 1) is treated with low-dose glucocorticoid, and Liddle syndrome, a gain-of-function ENaC variant with low aldosterone, does not respond to spironolactone and responds to amiloride or triamterene.

Finerenone in chronic kidney disease with diabetes

FIDELIO-DKD enrolled 5,734 adults with type 2 diabetes and chronic kidney disease (CKD) on maximally tolerated ACE inhibitor or ARB. Eligibility required either a urine albumin-to-creatinine ratio (UACR) of 30 to less than 300 mg/g with eGFR 25 to less than 60 mL/min/1.73 m² and diabetic retinopathy, or UACR 300 to 5,000 mg/g with eGFR 25 to less than 75. Potassium had to be 4.8 mEq/L or less. Over a median of 2.6 years, finerenone reduced the primary kidney composite of kidney failure, a sustained decrease in eGFR of 40% or more, or renal death (17.8% versus 21.1%; HR 0.82; 95% CI 0.73 to 0.93) and the key secondary cardiovascular composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization (13.0% versus 14.8%; HR 0.86). Hyperkalemia leading to discontinuation occurred in 2.3% versus 0.9%.

FIGARO-DKD enrolled 7,437 patients with less advanced kidney disease: UACR 30 to less than 300 mg/g with eGFR 25 to 90, or UACR 300 to 5,000 mg/g with eGFR of 60 or more. Over a median of 3.4 years, finerenone reduced the primary cardiovascular composite (12.4% versus 14.2%; HR 0.87; 95% CI 0.76 to 0.98), driven mainly by heart failure hospitalization (3.2% versus 4.4%; HR 0.71). Discontinuation for hyperkalemia occurred in 1.2% versus 0.4%.

FIDELITY, the prespecified pooled analysis of 13,026 patients followed for a median of 3.0 years, found reductions in the cardiovascular composite (12.7% versus 14.4%; HR 0.86) and in a kidney composite of kidney failure, a sustained eGFR decrease of 57% or more, or renal death (5.5% versus 7.1%; HR 0.77). Heart failure hospitalization accounted for much of the cardiovascular benefit (HR 0.78), with no clear effect on stroke. Permanent discontinuation for hyperkalemia was 1.7% versus 0.6%, and the mean potassium rise was about 0.2 to 0.3 mEq/L. About 40% of the pooled population had eGFR above 60 and qualified by albuminuria alone, which places finerenone early in diabetic kidney disease, not only in advanced stages.

Guideline recommendations. The Kidney Disease: Improving Global Outcomes (KDIGO) 2024 guideline suggests a nonsteroidal MRA with proven kidney or cardiovascular benefit (Recommendation 3.8.1, grade 2A). The suggestion applies to adults with type 2 diabetes, eGFR above 25 mL/min/1.73 m², normal serum potassium, and albuminuria of 30 mg/g or more despite a maximally tolerated renin-angiotensin inhibitor. Its practice points state that the drug is most appropriate when albuminuria persists despite other standard care and that it may be added to a renin-angiotensin inhibitor and an SGLT2 inhibitor. Candidates have consistently normal potassium and are monitored regularly. A steroidal MRA may be used for heart failure, hyperaldosteronism, or refractory hypertension but may cause hyperkalemia or a reversible fall in the glomerular filtration rate (GFR), particularly at low GFR. The American Diabetes Association Standards of Care recommend finerenone in type 2 diabetes with CKD and albuminuria on maximally tolerated ACE inhibitor or ARB to improve cardiovascular outcomes and reduce CKD progression.

Combination with SGLT2 inhibition. CONFIDENCE randomized about 800 adults with type 2 diabetes, CKD, and albuminuria on a renin-angiotensin inhibitor to finerenone, empagliflozin, or both, started together. At 180 days, UACR fell by 52% with the combination, a reduction 29% greater than with finerenone alone and 32% greater than with empagliflozin alone. Hyperkalemia was less frequent with the combination than with finerenone alone, and early eGFR declines were mostly reversible. The trial used albuminuria as its endpoint; outcome trials of combined therapy are not yet available.

Type 1 diabetes and nondiabetic kidney disease. FINE-ONE randomized 242 adults with type 1 diabetes and CKD and found a 25% greater reduction in UACR with finerenone than with placebo over 6 months. On that basis the US label includes reduction of UACR in CKD associated with type 1 diabetes. In FIND-CKD, which randomized 1,584 adults with nondiabetic CKD and albuminuria, finerenone slowed the mean annual eGFR decline over 32 months (−3.3 versus −4.0 mL/min/1.73 m² per year). Finerenone does not carry a US indication for nondiabetic CKD.

Finerenone for CKD starts at 20 mg daily when eGFR is 60 or more and 10 mg daily when eGFR is 25 to less than 60, with a target of 20 mg. The dose rules appear in the dosing table and the calculator below. The relation of finerenone to glucagon-like peptide-1 (GLP-1) receptor agonists in diabetic kidney disease is covered in the GLP-1 receptor agonist hub.

Dialysis, cirrhosis, edema, and other uses

Dialysis. Spironolactone was tested in maintenance dialysis because left ventricular hypertrophy, fibrosis, and sudden death dominate mortality there. ACHIEVE randomized 2,538 patients in 143 dialysis programs in 12 countries to spironolactone 25 mg or placebo after a run-in that confirmed tolerance. It was stopped for futility after a median of 1.8 years. The composite of cardiovascular death or heart failure hospitalization occurred at 10.46 versus 11.33 events per 100 patient-years (HR 0.92; 95% CI 0.78 to 1.09), and severe hyperkalemia was more frequent (6.6% versus 4.5%; HR 1.44). Spironolactone is not used in dialysis for cardiovascular protection.

Cirrhosis with ascites. Secondary hyperaldosteronism drives sodium retention in cirrhosis, and spironolactone is the backbone of diuretic therapy for ascites. The 2021 American Association for the Study of Liver Diseases guidance combines spironolactone with furosemide in a ratio of about 100 mg to 40 mg, titrated together up to 400 mg and 160 mg daily. The label specifies initiation in hospital in cirrhosis, because rapid fluid and electrolyte shifts can precipitate hepatic encephalopathy, and notes reduced clearance of spironolactone and its metabolites.

Nephrotic syndrome and refractory edema. Spironolactone is labeled for nephrotic edema when treatment of the underlying disease, sodium and fluid restriction, and other diuretics are inadequate. As a distal agent it adds to loop diuretics in sequential nephron blockade and limits the hypokalemia and hypomagnesemia of loop and thiazide therapy.

Hypokalemia and arrhythmia prevention. MRAs preserve potassium and magnesium during diuretic therapy, an effect that contributes to the reduction of sudden death in HFrEF. Apart from the EMPHASIS-HF secondary analysis, trials of MRAs specifically for atrial fibrillation prevention are small, and no MRA carries a rhythm indication.

Obstructive sleep apnea. Aldosterone-driven fluid shifts to the neck at night may worsen upper airway obstruction. Small trials in resistant hypertension with sleep apnea report reductions in apnea severity with spironolactone; outcome data are lacking.

Noncardiac uses. Spironolactone is used for its antiandrogenic effects in acne, hirsutism, female-pattern hair loss, and gender-affirming hormone therapy. The same potassium and kidney considerations apply when patients also take renin-angiotensin inhibitors.

Initiation thresholds for potassium and eGFR

The thresholds that govern initiation come from trial exclusion criteria and are written into the guidelines and labels. They differ by agent and indication.

Initiation thresholds by agent and indication. The eplerenone hypertension contraindications reflect the higher hyperkalemia risk in patients without a mortality indication.

A patient with HFrEF and potassium of 5.1 mEq/L does not start an MRA until the cause is addressed. Potassium supplements, salt substitutes, nonsteroidal anti-inflammatory drugs (NSAIDs), and trimethoprim are removed, the diuretic dose is reviewed, and a potassium binder is an option when hyperkalemia is the only barrier. The eGFR used for eligibility is a recent steady-state value, because a value obtained during decongestion or acute illness misclassifies eligibility in either direction.

Dosing by indication and kidney function

Dosing from the 2022 AHA/ACC/HFSA guideline, the 2025 AHA/ACC hypertension guideline, and the Aldactone, Inspra, and Kerendia prescribing information. Potassium values are in mEq/L. Spironolactone and eplerenone are not started at eGFR of 30 or less; finerenone is not started below 25.

Potassium and eGFR dose-action calculator

The eplerenone and finerenone actions reproduce the potassium tables of the prescribing information. The spironolactone actions follow the 2022 guideline thresholds (start below 5.0 mEq/L, discontinue when potassium cannot be kept below 5.5 mEq/L) and the 2022 guideline starting and target doses by eGFR, halved at eGFR 31 to 49 mL/min/1.73 m². A single value is confirmed before a hold when hemolysis or a delayed sample is possible. Potassium and creatinine are measured after each start or dose change, then periodically. Interacting drugs, acute illness, and dietary potassium are not accounted for.

Hyperkalemia: mechanism, risk factors, and population consequences

Hyperkalemia is the mechanism-based toxicity of every MRA. Blocking the receptor in principal cells reduces ENaC activity, collapses the lumen-negative potential that drives potassium secretion through ROMK, and reduces basolateral sodium-potassium ATPase activity. Potassium secretion falls most when distal sodium delivery and tubular flow are already low, as in CKD, volume depletion, and low-output heart failure, and when renin-angiotensin inhibition has already lowered aldosterone. The rise in potassium is therefore modest in a patient with normal kidney function and a free diet, and steep in an older patient with diabetes, CKD, and an intercurrent illness.

The population cost of ignoring these conditions was measured after RALES. In Ontario adults aged 66 or older recently hospitalized for heart failure and taking ACE inhibitors, spironolactone prescriptions rose from 34 to 149 per 1,000 patients between 1994 and 2001. Hospitalizations for hyperkalemia rose from 2.4 to 11.0 per 1,000 patients, and associated in-hospital deaths rose from 0.3 to 2.0 per 1,000. This corresponded to an estimated 560 additional admissions and 73 additional deaths in 2001, without a fall in heart failure admissions or deaths that would have offset them. RALES had excluded patients with creatinine above 2.5 mg/dL or potassium above 5.0 mEq/L and measured potassium by protocol. Those exclusions and that monitoring are part of the trial result.

Risk factors for hyperkalemia during MRA therapy. Several are commonly present together in older patients with heart failure, diabetes, and CKD.

Trial rates understate rates in practice, because trial patients were selected and had frequent protocol-mandated potassium measurements and dose rules. Serious hyperkalemia occurred in 2% versus 1% in RALES, and potassium of 6.0 mEq/L or more in 5.5% versus 3.9% in EPHESUS. Reported hyperkalemia occurred in 8.0% versus 3.7% in EMPHASIS-HF, 18.7% versus 9.1% in TOPCAT, and 9.7% versus 4.2% in FINEARTS-HF. In the pooled finerenone kidney trials, adverse-event hyperkalemia occurred in 14.0% versus 6.9%, with permanent discontinuation in 1.7% versus 0.6%. Hyperkalemia leading to hospitalization or death remained uncommon in every trial, a result of monitoring as much as of the drugs.

Discontinuing an MRA after a single mildly elevated value removes a therapy that reduces mortality in HFrEF. In a Swedish target-trial emulation of 7,366 MRA users who developed hyperkalemia, stopping the MRA lowered the risk of recurrent hyperkalemia (HR 0.75). It was also associated with a higher risk of death, heart failure admission, myocardial infarction, or stroke (HR 1.10; 95% CI 1.06 to 1.14). The result is observational and open to residual confounding. Mild elevations (5.0 to 5.4 mEq/L) are managed by removing contributors and holding titration, and moderate elevations by a hold or dose reduction with planned reintroduction.

Monitoring schedule and potassium action thresholds

Potassium and creatinine are measured before the first dose. The 2022 AHA/ACC/HFSA guideline specifies measurement at about 1 week and 4 weeks after starting or increasing an MRA, then every 6 months, with more frequent testing during clinical instability and after changes in interacting drugs. The 2013 ACCF/AHA heart failure guideline, which preceded it, specified measurement within 2 to 3 days and again at 7 days, monthly for the first 3 months, and every 3 months thereafter, a closer schedule used for higher-risk patients. The eplerenone label calls for measurement within the first week and at 1 month after a start or dose change, and within 3 to 7 days of starting a moderate CYP3A4 inhibitor, ACE inhibitor, ARB, or NSAID. The finerenone label specifies 4 weeks after a start or dose change. KDIGO's finerenone algorithm measures potassium at 1 month and then every 4 months.

Potassium action thresholds from the 2022 AHA/ACC/HFSA guideline and the Inspra and Kerendia prescribing information. KDIGO considers the finerenone trial thresholds conservative and states that continuing an MRA at potassium of 5.5 to 6.0 mEq/L may be appropriate in selected patients.

An unexpected high value is repeated before treatment is stopped when hemolysis, a delayed sample, or fist clenching during phlebotomy is possible. Magnesium is measured with potassium in patients on loop diuretics, because MRAs and loop diuretics have opposite effects on magnesium and hypokalemia and hypomagnesemia also carry arrhythmic risk.

Potassium binders to enable MRA therapy

Patiromer, a calcium-exchanging polymer acting mainly in the colon, and sodium zirconium cyclosilicate, a crystalline compound that exchanges sodium and hydrogen for potassium throughout the gut, lower serum potassium within hours to days and maintain it with daily dosing. Their role in cardiology is to allow renin-angiotensin inhibitors and MRAs to be started, continued, or reintroduced in patients whose potassium would otherwise prevent it.

DIAMOND randomized 878 patients with HFrEF and current or prior hyperkalemia related to renin-angiotensin inhibitors, after a run-in in which patiromer allowed titration to target doses including spironolactone or eplerenone 50 mg. Compared with placebo, continued patiromer produced a small but significant difference in potassium (−0.10 mEq/L), fewer episodes of potassium above 5.5 mEq/L (HR 0.63), and fewer MRA dose reductions. The trial was not powered for clinical outcomes. AMBER showed the same enabling effect for spironolactone in resistant hypertension with eGFR 25 to 45.

The 2022 AHA/ACC/HFSA guideline gives patiromer or sodium zirconium cyclosilicate a Class 2b recommendation in patients with heart failure who develop hyperkalemia (5.5 mEq/L or more) while taking renin-angiotensin-aldosterone inhibitors. The effectiveness of these binders in improving outcomes by allowing continuation of therapy is uncertain. Patiromer is started at 8.4 g daily and taken at least 3 hours apart from other oral drugs. Sodium zirconium cyclosilicate contains about 400 mg of sodium per 5 g and causes dose-related edema, a consideration in a congested patient. Neither binder has been shown to improve hard outcomes as a strategy, and neither replaces removal of potassium sources and interacting drugs.

Worsening kidney function, intercurrent illness, and dietary potassium

MRAs lower eGFR modestly and reversibly through reduced plasma volume and intraglomerular pressure. In FIDELIO-DKD the initial eGFR dip was followed by a slower long-term decline, and in heart failure trials early creatinine rises were not associated with loss of benefit. A rise in creatinine of up to about 30% after starting an MRA is expected and does not by itself prompt discontinuation. A larger rise prompts evaluation for volume depletion from excessive diuresis, NSAID use, urinary obstruction, and renal artery stenosis. The finerenone label withholds up-titration when eGFR has fallen by more than 30% from the previous measurement, and acute kidney injury prompts a hold until kidney function recovers.

Most severe hyperkalemia during MRA therapy occurs during an intercurrent illness: gastroenteritis, poor oral intake, sepsis, or decompensation with low output. Sick-day guidance, in which the MRA, renin-angiotensin inhibitor, SGLT2 inhibitor, and diuretic are paused during dehydrating illness and restarted when eating and drinking normally resume, is widely taught in heart failure and kidney clinics. It rests on physiology and practice consensus, not trials, and it carries the risk that drugs are not restarted; the restart date is written into the plan.

Patients taking MRAs avoid potassium-based salt substitutes and over-the-counter potassium supplements, and they avoid NSAIDs. Dietary potassium from fruits and vegetables is not restricted routinely in patients with normal potassium, because potassium-rich diets lower blood pressure; restriction is individualized in advanced CKD and recurrent hyperkalemia.

Gynecomastia and other endocrine effects

Spironolactone binds the androgen receptor as an antagonist, binds the progesterone receptor as a partial agonist, and at higher doses inhibits testicular androgen synthesis. In men the result is gynecomastia, breast tenderness, reduced libido, and erectile dysfunction. In RALES, gynecomastia or breast pain occurred in 10% of men on a mean dose of 26 mg, versus 1% with placebo; the prescribing information reports about 9%. Risk rises with dose and duration, onset ranges from 1 to 2 months to more than a year, and the change is usually reversible after the drug is stopped. In women, spironolactone causes breast tenderness and menstrual irregularity, including intermenstrual bleeding and amenorrhea. These effects are the main reasons for discontinuation in long-term use.

Eplerenone was not associated with an excess of gynecomastia over placebo in its heart failure trials. In hypertension studies, the label reports gynecomastia with eplerenone but not placebo, at low frequency and rising with duration. Finerenone, which does not bind androgen or progesterone receptors, has no sex-steroid adverse effects. The standard response to spironolactone gynecomastia in a patient with HFrEF is a switch to eplerenone, which preserves the outcome benefit; stopping MRA therapy is not.

The spironolactone label also lists hyponatremia, particularly with concomitant thiazides, hypomagnesemia, hypochloremic alkalosis, hyperglycemia, and asymptomatic hyperuricemia, with gout rarely precipitated. Finerenone caused hyponatremia in 1.3% versus 0.7% and hypotension in 4.6% versus 3.0% in the pooled kidney trials. Spironolactone and its metabolites raise prostate-specific antigen with abiraterone and interfere with some digoxin immunoassays.

Drug interactions of spironolactone, eplerenone, and finerenone

Clinically relevant interactions from the Aldactone, Inspra, and Kerendia prescribing information. Interactions common to cardiovascular drugs are covered in the drug interactions hub. PSA, prostate-specific antigen.

Combination with renin-angiotensin inhibitors, ARNI, and SGLT2 inhibitors

Renin-angiotensin inhibitors. Every MRA outcome trial in heart failure and kidney disease was conducted on a background of ACE inhibitor or ARB, and the combination is the standard of care, not a hazard to be avoided. What is avoided is the triple combination of an ACE inhibitor, an ARB, and an MRA, which adds hyperkalemia and renal dysfunction without proven benefit.

Sacubitril/valsartan. In a secondary analysis of PARADIGM-HF in 4,671 patients taking an MRA at baseline, severe hyperkalemia (above 6.0 mEq/L) was less frequent with sacubitril/valsartan than with enalapril (2.2 versus 3.1 per 100 patient-years). Natriuretic peptide augmentation may enhance distal potassium excretion. An ARNI therefore makes MRA therapy easier to maintain.

SGLT2 inhibitors. SGLT2 inhibitors increase distal sodium delivery and flow and reduce hyperkalemia risk. In EMPEROR-Reduced, empagliflozin reduced the risk that patients taking an MRA would discontinue it (HR 0.78) and reduced severe hyperkalemia, and its benefit was the same with or without an MRA. Similar findings came from DAPA-HF and from the HFpEF trials. In CONFIDENCE, combined finerenone and empagliflozin produced less hyperkalemia than finerenone alone. The two classes are complementary in heart failure and diabetic kidney disease, and starting an SGLT2 inhibitor early lowers the barrier to MRA therapy.

GLP-1 receptor agonists. In diabetic kidney disease and HFpEF with obesity, finerenone is increasingly combined with semaglutide or tirzepatide. Post hoc analyses of the finerenone kidney trials found effects consistent with or without baseline GLP-1 receptor agonist use. No outcome trial has tested the combination directly.

Beta blockers. Beta blockers reduce cellular potassium uptake slightly and do not require changes in MRA dosing.

Pregnancy, lactation, older adults, and liver disease

Pregnancy. MRAs are avoided in pregnancy. Spironolactone causes feminization of male fetuses in animals through antiandrogenic effects, and its label advises avoidance or counseling about risk to a male fetus. Human data for eplerenone are insufficient, and finerenone has no human pregnancy data and produced developmental toxicity in animals at about twice human exposure. Women of reproductive potential with heart failure are counseled about contraception, and MRAs are stopped when pregnancy is planned or confirmed.

Lactation. Spironolactone is considered compatible with breastfeeding: the parent drug has not been detected in milk, and the metabolite canrenone appears at low, clinically inconsequential concentrations. After delivery in peripartum cardiomyopathy, spironolactone is part of the lactation-compatible regimen. Breastfeeding is not recommended during finerenone treatment and for 1 day after the last dose, and eplerenone lacks human data.

Older adults. Older patients derive the same relative benefit in HFrEF but have the highest hyperkalemia risk, because creatinine overestimates GFR in low muscle mass and interacting drugs are common. Lower starting doses, eGFR-based dosing, and more frequent potassium measurement apply.

Liver disease. Spironolactone is started in hospital in cirrhosis with ascites because of the risk of encephalopathy from rapid fluid and electrolyte shifts. Finerenone is avoided in severe hepatic impairment and monitored more closely in moderate impairment.

Advanced CKD and dialysis. Steroidal MRAs are not started at eGFR of 30 or less for heart failure, and finerenone is not started at an eGFR below 25. The dialysis trial evidence is under Dialysis, cirrhosis, edema, and other uses.

Underuse and dose gaps in practice

MRAs are among the least used of the foundational HFrEF therapies. In the CHAMP-HF registry of US outpatients with HFrEF, 67% of eligible patients were not prescribed an MRA. Among those who were, 77% received the target dose, a higher proportion than for any other class, because the effective dose range is narrow and low. About 1% of eligible patients received target doses of all of a renin-angiotensin inhibitor, a beta blocker, and an MRA. The usual barriers are concern about hyperkalemia and kidney function, monitoring burden, and clinical inertia after discharge. Structured titration clinics, pharmacist-led protocols, in-hospital initiation, and early SGLT2 inhibitor and ARNI use, which lower hyperkalemia risk, raise MRA use. Initiation before discharge, when eGFR and potassium allow, avoids the inertia that follows a hospitalization.

The same gap exists for finerenone in diabetic kidney disease, where albuminuria testing is the first barrier: patients who are never tested are never identified as candidates.

Emerging agents and ongoing trials

Esaxerenone, a nonsteroidal MRA, is approved in Japan for hypertension. Balcinrenone, a mineralocorticoid receptor modulator, is being tested in combination with dapagliflozin in heart failure and CKD. Aldosterone synthase inhibitors such as baxdrostat and lorundrostat lower aldosterone production without blocking its receptor. They reduced blood pressure in uncontrolled and resistant hypertension, with hyperkalemia as the main safety signal, but they do not yet have cardiovascular outcome data. Finerenone trials under way enroll patients hospitalized with heart failure and LVEF of 40% or more, test simultaneous initiation of finerenone and empagliflozin after a heart failure hospitalization, and enroll patients with HFrEF intolerant of steroidal MRAs. SPIRRIT-HFpEF is an ongoing pragmatic registry-based trial in Sweden and the United States. It randomizes patients with HFpEF or HFmrEF to spironolactone added to usual care or usual care alone, with about 2,400 patients planned (NCT02901184).

European Society of Cardiology recommendations and dose rules for MRAs

The 2021 European Society of Cardiology (ESC) heart failure guideline recommends an MRA for all patients with symptomatic HFrEF to reduce heart failure hospitalization and death (Class I). Its 2023 focused update recommends finerenone in CKD with type 2 diabetes to reduce heart failure hospitalization (Class I). ESC practical guidance halves the MRA dose when potassium rises above 5.5 mEq/L, creatinine rises to 2.5 mg/dL, or eGFR falls below 30 mL/min/1.73 m². It stops the MRA when potassium exceeds 6.0 mEq/L or eGFR falls below 20 mL/min/1.73 m². The acceptance of a creatinine rise of up to 50% in that guidance applies to renin-angiotensin inhibitors.

Sources of error in MRA prescribing

• Starting an MRA with potassium of 5.0 mEq/L or more, or at eGFR of 30 or less for spironolactone or eplerenone: both fall outside the trial populations and the 2022 guideline criteria.
• Continuing potassium supplements or a potassium-based salt substitute after an MRA is started.
• No potassium measurement at 1 week and 4 weeks after a start or dose increase: the RALES experience in Ontario showed the population cost.
• Stopping the MRA permanently after a single value of 5.1 to 5.4 mEq/L, when holding titration and removing contributors would allow it to continue.
• Stopping all MRA therapy for spironolactone gynecomastia, when switching to eplerenone preserves the outcome benefit.
• Substituting finerenone for spironolactone or eplerenone in HFrEF, or combining finerenone with a steroidal MRA.
• Prescribing eplerenone with clarithromycin, ketoconazole, or ritonavir, or exceeding 25 mg daily with verapamil, diltiazem, or erythromycin.
• Adding routine spironolactone after myocardial infarction without reduced ejection fraction plus heart failure or diabetes: CLEAR showed no benefit.
• Prescribing an MRA for cardiovascular protection in maintenance dialysis.
• Starting spironolactone for resistant hypertension before measuring aldosterone and renin, which masks primary aldosteronism for weeks.
• Combining an ACE inhibitor, an ARB, and an MRA.
• Continuing an MRA through vomiting, diarrhea, or poor intake without a sick-day plan and a restart date.
• Interpreting a digoxin level in a patient on spironolactone without knowing whether the assay cross-reacts.
• Continuing an MRA after conception, or omitting contraception counseling in women of reproductive potential.

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