The use of mineralocorticoid receptor antagonists for patients with heart failure with a reduced ejection fraction: A time for reassessment

This article refers to ‘Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: data from Swedish Heart Failure Registry’ by F. Guidetti et al., published in this issue on pages 2164–2173.

The steroidal mineralocorticoid receptor antagonists (sMRAs), spironolactone and eplerenone, have been shown to reduce heart failure (HF) hospitalizations (HFH), and cardiovascular (CV) and total mortality in patients with HF and a reduced ejection fraction (HFrEF).^{1, 2} Based on the pivotal randomized trials, MRAs are recommended as a class I indication in both European and US guidelines^{3, 4} and are part of the ‘four-pillar’ strategy currently recommended for treating patients with HFrEF. However, despite the evidence from randomized trials, their use remains suboptimal, especially in patients with moderate and severe kidney disease. For example, in the US Get With The Guidelines-HF registry, the use of MRAs was 35% in patients with an estimated glomerular filtration rate (eGFR) of 45–60 ml/min/1.73 m² body surface area, 26% when eGFR is 30–45 and only 14% in those with eGFR <30.⁵ Thus, those patients at highest risk of HFH and death were paradoxically deprived from effective therapy. In part the suboptimal use of MRAs in patients with HF can be attributed to the observational study by Juurlink et al.⁶ from Canada published shortly after publication of the RALES trial¹ suggesting that the use of the MRA spironolactone in patients with HF was associated with a relatively high incidence of hyperkalaemia (HK), renal dysfunction and was poorly tolerated. Many clinicians failed to recognize that the patients in the study by Juurlink et al.⁶ were receiving far higher doses of spironolactone than used in RALES (12.5–50 mg/day), had a degree of renal dysfunction which was excluded from the RALES trial¹ and often were not monitored for serum potassium or renal function. The suboptimal initiation of steroidal MRAs and the perception that they are poorly tolerated in patients with HF and kidney disease has unfortunate consequences since there is evidence that patients with HFrEF who meet guideline criteria for the initiation of an MRA are at increased cardiovascular risk if they do not receive them or persist on them.

In this issue of the Journal, Guidetti et al.⁷ from the Karolinska Institute examined the Swedish HF registry from 2012 to 2020 to determine the characteristics of patients with HFrEF (ejection fraction <40%) independently associated with MRA use and outcomes. They found, as expected, that MRA use was less common in those with renal disease. Of 33 942 patients, 51% received an MRA of whom 32% had an eGFR <30, 45% 30–45, 54% 45–59% and 54% ≥60 ml/min/1.73 m². However, reassuringly, in multivariate analysis they found that MRA use was safe and not associated with a higher risk of renal events (composite of dialysis/renal death/hospitalization for renal failure or HK), all-cause death, as well as all-cause hospitalizations across the eGFR spectrum, including those with severe kidney disease. They also noted that only 11% of patients on a MRA discontinued them at 1 year, which was consistent across the spectrum of renal disease. Consistently with the findings of previous studies, Guidetti et al. also found that younger age, hypertension, and obesity were associated with a higher use of an MRA. Based on these findings, they suggest that MRAs should not be withheld due to impaired renal function if close laboratory surveillance is possible.

Furthermore, Guidetti et al. found that the use of diuretics predicted treatment with an MRA and postulated that the greater use of MRAs in patients on a diuretic could in large part be explained by the fact that diuretics reduce serum potassium levels and thereby reduce the risk of HK. While the use of a diuretic in conjunction with an MRA reduces the risk of HK, as does the concomitant use of a sodium–glucose cotransporter 2 inhibitor (SGLT2i)⁸ or sacubitril/valsartan,⁹ it should also be pointed out that the use of a diuretic is associated with an unwanted increase in serum of aldosterone,¹⁰ which adverse effects may be best mitigated by concomitant MRA therapy. Furthermore, even though the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocking agent may transiently suppress aldosterone levels, there is evidence that over several months aldosterone levels return to baseline value or above in a large percentage of patients (aldosterone escape or breakthrough),¹¹ an untoward effect also best mitigated by concomitant MRA therapy.

It is noteworthy that patients with eGFR as low as 30 ml/min/1.73 m², could be enrolled in the EMPHASIS-HF trial where over 30% of patients had GFR <60 ml/min/1.73 m². Subgroup analysis based on baseline eGFR revealed no heterogeneity of benefit of eplerenone. In an individual patient data meta-analysis of the 12 700 enrolled in four sMRA randomized trials, investigator-reported HK and worsening renal function were more frequent (two- to three-fold) among MRA users, and HK was more frequent as eGFR decreased; however, importantly, sMRAs reduced HFH and mortality, with statistically significant hazard ratios ranging from 0.62 to 0.79 across a wide range of eGFR, down to 30 ml/min/1.73 m².¹² It was only in the small subgroup of 331 (2.6%) patients with eGFR ≤30 ml/min/1.73 m² that the benefit was no longer significant.

Non-steroidal MRAs (nsMRAs), such as finerenone, appear to be better tolerated than the sMRAs in regard to HK and have been shown to be safe and effective in reducing cardiovascular and renal outcomes in patients with renal disease and diabetes.^{13, 14} Finerenone is undergoing several trials in HF, notably in HF with preserved ejection fraction (NCT04435626), in patients with acute HF (NCT06008197), with hospitalized HF receiving SGLT2is (NCT06024746), and in patients intolerant or not eligible for treatment with sMRAs (NCT06033950), where patients are enrolled with eGFR down to 30 or 25 ml/min/1.73 m². The results of these trials will examine whether finerenone may be safe and effective in HF patients with chronic kidney disease (CKD). It is hypothesized that the nsMRAs may be superior to sMRAs, regarding a reduction in inflammation since the binding characteristics of the steroidal and non-steroidal MRAs are different resulting in activation of some common gene pathways but also some different gene pathways. Direct comparative studies of a steroidal and non-steroidal MRA may be needed to establish superiority and cost-effectiveness of nsMRAs over sMRAs given that sMRAs are generic in many parts of the world. In view of the suboptimal use of sMRAs in patients with HFrEF, especially in patients with concomitant renal disease, the findings by Guidetti et al.⁷ that the sMRAs are relatively well tolerated in patients with HFrEF, even in patients with severe renal disease, suggest that given their proven efficacy and relative low cost they should be initiated in patients with HFrEF across the spectrum of renal disease, down to an eGFR of 30 ml/min/1.73 m², with careful monitoring of serum potassium and renal function.

There is evidence that mineralocorticoid receptor expression is increased in patients with CKD and the elderly.^{15, 16} In patients with renal disease, an increase in serum aldosterone levels has been associated with an increase in progression to end-stage renal disease.¹⁵ If aldosterone levels are not reduced and/or the mineralocorticoid receptor remains unprotected, there is a risk of further inflammation, oxidative stress, myocardial and vascular fibrosis, and cell death. Beyond common CKD, patients with end-stage kidney disease were excluded from all MRA outcome trials in HF and CKD. Whether sMRAs or nsMRAs may help improving the excessively poor cardiovascular outcome in end-stage kidney disease is being investigated in the recently completed ALCHEMIST trial (NCT01848639).

Conflict of interest: B.P. has received consulting fees from Lexicon, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and PhaseBio; has received consulting fees from and/or owns stock options in Vifor, KBP Biosciences, Cereno Scientific, Tricida, scPharmaceuticals, SQ Innovation, G-3 Pharmaceuticals, ProtonIntel, and Brainstorm Medical; and holds U.S. Patent No. 9931412 on site-specific delivery of eplerenone to the myocardium and U.S. Patent No. 63/045783 (pending) on histone-modulating agents for the protection and treatment of organ damage. F.Z. reports personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer, BMS, CVRx, Cardior, Cambrian, Cereno pharmaceutical, Cellprothera, CEVA, Merck, Northsea, Novartis, NovoNordisk, Otsuka, Owkin, Salubris, Servier, having stock options at G3Pharmaceutical and equities at Cereno pharmaceutical, Cardiorenal, Eshmoun Clinical research and being the founder of Cardiovascular Clinical Trialists (CVCT).