MRAs are an important part of medical therapy in patients with CHF.
These agents are not widely used in patients with CHF and CKD because of the higher risk of adverse events in this population.Table 2 summa-rizes randomized and registry data with MRAs on cardiovascular out-comes among patients with CKD. As further discussed below, the majority of the evidence for our population of interest comes from sub-group analyses–often also post-hoc–which may limit the confidence one has in the estimates of effects (Sun, Ioannidis, Agoritsas, Alba, &
Guyatt, 2014).
2.1. Randomized control trials (RCTs) - MRA and heart failure with reduced ejection fraction (HFrEF)
Thefirst trial that assessed the efficacy and safety of spironolactone in patients with HFrEF was the RALES trial. Spironolactone was used at the dose of 25 mg with an adjustment to 12.5 mg/day if serum
potassium (K+) > 5.5 mmol/l or to 50 mg at 1 month if K+ stayed below 5 mmol/l. All patients were on standard therapy for CHF at that time [Angiotensin-converting-enzyme inhibitors (ACEI), diuretic and digoxin], whereas the majority of them were not on beta-blockers (only 10% in the placebo and 11% in the spironolactone group). The trial was stopped after a mean follow-up of 24 months due to a signifi -cant 30% decrease in all-cause mortality and 35% reduction in CHF hos-pitalizations for patients randomized in the spironolactone group (Pitt et al., 1999). In the subgroup of patients with estimated glomerularfi l-tration rate (eGFR) <60 ml/min/1.73m2, spironolactone was superior to placebo for all-cause mortality and the composite outcome of all-cause mortality or CHF hospitalization with an absolute risk reduction of 10%
in all-cause mortality (Vardeny et al., 2012). Worsening renal function (WRF), defined as a reduction of >30% in eGFR from baseline, was more frequently observed in patients treated with spironolactone com-pared with placebo (17% vs. 7%). The risk of hyperkalemia was higher in CKD and most common in patients with WRF [odds ratio 3.6, 95% Con-fidence Interval (CI) 1.5–8.6]. WRF and hyperkalemia were associated with a higher probability of treatment discontinuation.
EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) was a randomized, double-blind trial, enrolling 2737 patients with New York Heart Association (NYHA) II CHF and a left ventricular ejection fraction (LVEF)≤35%, eGFR >30 ml/min/1.73 m2and K+< 5.0 mmol/l to receive eplerenone (25–50 mg/day) or placebo, in addition to recommended therapy (Zannad et al., 2011). The trial was stopped after a mean follow-up of 21 months due to a 37% reduction in the primary outcome of CV death or hospitalization for CHF for the eplerenone group compared with pla-cebo [Hazard Ratio (HR) 0.63; 95% CI 0.54–0.74;p< 0.001]. In a post hoc analysis in patients with an eGFR of 30–60 ml/min/1.73m2, eplerenone was equally effective to reduce the primary composite end point as compared with placebo (HR 0.62, 95% CI 0.49–0.79, p < 0.001) (Eschalier et al., 2013). In a second post hoc analysis in patients with CKD from the same trial, the efficacy of eplerenone was similar across the different eGFR strata (Ferreira et al., 2019). Although, the incidence of hyperkalemia was higher in eplerenone treated patients with CKD compared with placebo, there was a lower incidence of serious hyperkalemia, defined as K+> 6 mmol/l, with eplerenone (1.9%) com-pared with placebo (3.3%,p= 0.01). In addition, in patients with CKD, drop in eGFR from baseline during the follow-up was similar in both groups (2.0 ml/min/1.73m2with eplerenone versus 4.2 with placebo).
However, more patients with CKD discontinued eplerenone due to hyperkalemia compared with patients without CKD (Eschalier et al., 2013).
ARTS (MinerAlocorticoid Receptor Antagonist Tolerability Study) was a phase 2b multicentre, randomized, double-blind clinical trial eval-uating the safety and tolerability offinerenone in high-risk patients with NYHA II-III HFrEF and LVEF≤40%, CKD and/or type 2 diabetes mellitus already on standard treatment (Pitt et al., 2012). Part B of this trial was conducted in patients with moderate CKD (eGFR 30–60 mL/
min/1.73 m2), randomized 393 patients, and had an open-label active comparator (spironolactone 25-50 mg/day) in addition to the placebo group. Mean increases in serum K+levels and drop in eGFR from base-line were higher with spironolactone compared with all four doses of finerenone. Only the cumulative dose of 10 mg offinerenone daily was associated with higher incidence of hyperkalemia compared with placebo (Pitt et al., 2013). However, spironolactone seemed more effec-tive in reducing systemic blood pressure thanfinerenone, with no clear explanation.
ARTS-HF (MinerAlocorticoid Receptor antagonist Tolerability Study - Heart Failure) trial was a multicentre, randomized, double-blind, phase 2b dose-finding study comparingfinerenone (one of thefive doses of 2.5, 5, 7.5, 10, or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg/
day respectively, on day 30) and eplerenone (25 mg every other day, in-creased to 25 mg once daily on day 30, and to 50 mg once daily on day 60) for 90 days (Pitt et al., 2015). The study was designed to assess the
safety and potential efficacy offinerenone in patients with worsening HFrEF (LVEF≤40%) complicated by CKD and/or type 2 diabetes (eGFR
>30 mL/min/1.73m2in patients with diabetes and 30–60 mL/min/
1.73m2in patients without diabetes). The incidence of the exploratory composite endpoint (death from any cause, CV hospitalization or emer-gency presentation for worsening CHF) at day 90 was lower in all finerenone groups (with the exception of the 2.5–5 mg group), com-pared with eplerenone (Filippatos et al., 2016). Hyperkalemia“at any time post baseline”defined as K+> 5.5 mmol/l was similar in both treatment groups, occurring in 4.7% of cases in the eplerenone arm and 4.2% of cases in thefinerenone arms, while serious hyperkalemia (K+> 6 mmol/l) was rare (detected in 1 and 4 cases in the eplerenone andfinerenone arms, respectively). WRF≥25%,≥30% and≥40% was de-tected in 12.5%, 7.2% and 1.8% of patients treated withfinerenone,
compared with 13.3%, 9.1% and 2.1% of patients in the eplerenone arm, respectively.
2.2. RCTs - MRA and heart failure with preserved ejection fraction (HFpEF)
The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial was thefirst study to randomize patients with HFpEF to spironolactone or placebo (Pitt et al., 2014). Al-though there was no statistically significant difference in the primary outcome of time to CV death, aborted cardiac arrest or hospitalization for CHF, a fourfold difference in the primary outcome incidence rate was identified between Russia-Georgia and the Americas, whereas spironolactone was superior to placebo for the primary outcome in Fig. 1.Possible mechanism of mineralocorticoid receptor (MR) activation and it specific role in the pathogenesis in cardiovascular disease (CVD) chronic kidney disease (CKD) , its detrimental effects on target organs and potential beneficial effects of MRAs on acute or chronic kidney graft protection. MR is activated by an aldosterone independent mechanism as Rac1 with a ligand-dependent and -independent MR activation mechanism. Glucocorticoid (GCT); Renin–angiotensin system (RAS); Adrenocorticotropic hormone (ACTH); Acute Kidney Injury (AKI); CardioVascular (CV); T-Cell Lymphocytes (TCL); Acute Heart Failure (AHF); Acute Coronary Syndrome (ACS); Macrophage markers (M1 and M2);
Phosphorylation (Phospho); calcineurin inhibitor-induced nephrotoxicity (CIN); Natriuretic peptide precursor type A (ANP); endothelial sodium channel (ENaC); Na+/H+ exchanger (NHE); vascular smooth muscle cells (VSMC). [This picture is created starting by following studies:Belden et al., 2017;Nishiyama, 2019;Barrera-Chimal et al., 2019;Capelli et al., 2020;Girerd and Jaisser, 2018]
C. Cosimato, T. Agoritsas and T.A. Mavrakanas Pharmacology & Therapeutics 219 (2021) 107701
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the subgroup of patients recruited in the Americas (HR 0.82; 95% CI 0.69–0.98) (Pfeffer et al., 2015;Pitt et al., 2014).
A recent post hoc analysis stratified patients recruited in the Americas into three subgroups based on renal function at baseline:
eGFR <45, 45 to 59, and≥60 mL/min/1.73m2(Beldhuis et al., 2019).
The effect of spironolactone on the primary outcome was consistent across the three CKD subgroups (with no statistical subgroup effect, p-value for interaction = 0.13). Spironolactone was associated with a Table 1
Pharmacological features of MRA of each generation.
Steroidal structure Non-Steroidal structure
1st Generation 2nd Generation 3rd–4th Generation⁎
Spironolactone SC-9420
Canrenone C-9376 Eplerenone CGP-30083 Finerenone BAY
94–8862
Esaxerenone CS-3150
Half-life (h) 1.4 16.5 3–6 2.2–2.8 18.6 (±2.4) to 34(±9)
SHR
IC50-MR (nM) 36 ≥1000 713 18 9.4
IC50-GR (nM) 764 ≥1000 3060 >10,000 >10,000
IC50-AR (nM) 133 NR >100,000 >10,000 >10,000
IC50-PR (nM) 1200 NR >100,000 >10,000 >10,000
Affinity target
MR High Moderate Moderate (40-fold <SPL) High (similar to SPL) Very High (4-fold >SPL and
76-fold>EPL)
Other SHR Moderate Moderate (lesser
affinity to AR than SPL)
>100-fold less affinity for GR, AR and PR >500-fold less affinity for GR, AR and PR
At least 1000 folds higher selectivity for MR over other SHR.
Tissue distribution (Kindney/Heart)
Kidney > Heart (at least 6-fold)
Kidney > Heart (~ 3-fold) Kidney = Heart
Action Partial agonist Inverse agonist
Main adverse hyperkalemia, drugs interaction mediates by CYP3A enzymes
Hyperkalemia (at lower percentage) No other major side effects but not yet widely commercially available
AR = androgen receptor, EPL = Eplerenone; GR = glucocorticoid receptor, IC50= half maximal inhibitory concentration, MR = mineralocorticoid receptor, NR = not reported, PR = progesterone receptor, SHR = Steroid hormone receptor, SPR = Spironolactone.
References:Amazit et al., 2015;Arai et al., 2015;Armanini, Sabbadin, Donà, Clari, & Bordin, 2014;Ito et al., 2020;Kolkhof & Bärfacker, 2017;Kolkhof & Borden, 2012;Sueta, Yamamoto, &
Tsujita, 2020;Yamada, Mendell, Takakusa, Shimizu, & Ando, 2019;Yang & Young, 2016.
⁎ New drugs ongoing development have not been reported due to the absence of available data.
Table 2
Clinical outcomes with MRAs in patients with CHF and CKD.
Study Treatment groups eGFR Patients with
EMPHASIS-HF EPL 25–50 qd vs.
placebo ARTS (Part B) FNR 2.5–5-10qd
SPL 25–50 qd vs.
placebo
30–60 392 (100%)
NR NR NR 1.5% (FNR), 7.9% (SPL), 0%
(placebo)p= 1.00 vs. placebo p = 0.02 vs. SPL
5.3% (FNR), 12.7% (SPL), 1.5%
(placebo)p= 0.32 vs. placebo p= 0.05 vs. SPL
ARTS-HF† FNR 2.5–20 qd EPL 25–50 qd
ATHENA-HF SPL 100 vs. usual care (SPL 25 or
−4.1 vs.−4.7 mL/min/1.73m2at 96 h (p= 0.77)
≤2% at day 30 for both groups
Results are presented for the subgroup of patients with CKD. The absolute number of patients with CKD and the percentage of the total number of study participants (in parentheses) are depicted. Doses are shown in mg. Estimated glomerularfiltration values are shown in as mL/min/1.73m2. For worsening renal function, results are presented as mean ± standard deviation.
CHF, congestive heart fauilure; CI, Confidence Interval; CKD, Chronic kidney disease; eGFR: estimated glomerularfiltration rate; EPL, Eplerenone; FNR, Finerenone; HR, hazard ratio; MRAs, Mineralocorticoid Receptor Antagonists; NR, not reported; qd, once daily; SPL, Spironolactone; WRF, worsening renal function.
¶ Composite outcome of all-cause mortality or CHF admission.
⁎ For patients with eGRF 30–49 mL/min/1.73 m2.
† Results are reported only for thefinerenone 10 and 20 mg doses.
‡ Composite outcome of drug discontinuation due to persistent hyperkalemia (>5.5 mmol/l), persistent creatinine levels >3.0 mg/dl, anaphylactic reaction, drug intolerance, or gynecomastia.
higher incidence of hyperkalemia (K+> 5.5 mmol/l) and WRF (defined as doubling of serum creatinine from baseline) leading to permanent drug discontinuation (HR 3.80; 95% CI 2.24–6.45 and HR 2.12; 95% CI 1.41–3.19 for the eGFR groups of 45–60 and 30–45 mL/min/1.73m2 re-spectively). Based on these data, for every 100 patients treated with spironolactone, the authors would expect to prevent 9 occurrences of the primary composite outcome but provoke 27 drug discontinuations for adverse events among patients with an eGFR<45 ml/min/1.73m2 and 8 drug discontinuations in those with an eGFR >60 ml/min/
1.73m2. The authors suggested that spironolactone use in patients with HFpEF and eGFR <45 ml/min/1.73m2should only be considered when close laboratory monitoring is possible.
2.3. RCTs - MRA and acute CHF
ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial was a prospective, multicen-ter, double-blind clinical trial (Butler et al., 2017). The authors tested the hypothesis that addition of high-dose spironolactone (100 mg), compared with placebo or spironolactone≤25 mg (standard of care), would result in greater symptomatic relief in patients presenting with acutely decompensated CHF. The study enrolled patients with eGFR
≥30 mL/min/1.73m2. High-dose spironolactone was well tolerated but did not improve the primary outcome (change in NT-proBNP levels from baseline to 96 h), the secondary efficacy outcomes (clinical con-gestion score, dyspnea assessment, net urine output, net weight change, diuretic dosage at discharge, in-hospital worsening CHF, and a compos-ite of all-cause mortality, all-cause readmission, or outpatient worsen-ing CHF a day-30) or the secondary safety outcomes (hyperkalemia and changes in renal function during the 96-h treatment period).
In the ATHENA-HF trial, 50% of patients had CKD and approximately 20% of them had an eGFR in the 30–45 mL/min/1.73m2range (Greene et al., 2019). There was no significant difference in the primary or sec-ondary end points between the spironolactone and standard of care arms across eGFR subgroups (P-value for interaction was not significant for all outcomes tested). No relevant changes in serum potassium or creatinine levels were detected from baseline to 96 h/discharge in the high-dose spironolactone and the standard of care groups across all eGFR strata (P-value for interaction was not significant). The authors concluded that use of spironolactone was safe in the hospital in patients with moderate CKD, even at high doses.
2.4. Registry data
In this section, we present registry data on outcomes with MRAs in patients with CKD. We report only propensity-matched cohorts or stud-ies attempting to account for baseline differences between the MRA users and non-users.
The Alabama Heart Failure Project included 1140 patients with HFrEF (LVEF <45%) and moderate-advanced CKD (eGFR <45 mL/min/
1.73m2). A total of 207 patients treated with spironolactone were com-pared with 933 patients who were not treated with an MRA using pro-pensity score - adjusted hazard ratios (aHR) (Inampudi et al., 2014).
Patients on spironolactone had a higher one-year risk of all-cause read-mission (HR 1.36; 95% CI 1.13–1.63,p= 0.001). This risk was highest among the 106 patients with stage 5 CKD (eGFR <15 ml/min/1.73m2) (HR 4.75; 95% CI 1.84–12.28, P-value for interaction = 0.003).
The Korean Heart Failure Registry studied the relationship between spironolactone use and all-cause mortality in 1035 patients with acute systolic heart failure and severe renal dysfunction (defined as GFR < 45 ml/min/1.73m2). A subgroup of 105 patients with acutely de-compensated CHF on spironolactone were propensity score-matched with 105 patient who did not receive an MRA (Oh et al., 2015). There was no statistically significant difference in all-cause mortality (HR 0.63; 95% CI 0.35–1.13,p= 0.12) or rehospitalization rates (40% vs.
36%,p= 0.72) between the two groups, after adjusting for other heart
failure risk factors. Overall, the clinical benefit of spironolactone was preserved in CKD stage 3b patients but not in CKD stage 4 or 5.
In the Norwegian Heart Failure Registry, the effect of spironolactone on all-cause mortality was studied using 170 propensity score-matched pairs of patients with CHF and CKD (defined as eGFR <60 mL/min/
1.73m2). A lower incidence of all-cause mortality at two years was ob-served in the spironolactone group compared with no treatment (HR 0.59, 95% CI 0.37 to 0.92,p= 0.02). A decrease in eGFR was seen in spironolactone-treated patients (from 46 to 41 mL/min/1.73m2; p< 0.001) but not in the control group (Stubnova, Os, Grundtvig, Atar,
& Waldum-Grevbo, 2017).
In a retrospective cohort study including all patients followed at the McGill University heart failure clinic, the authors compared 314 patients on spironolactone (121 with CKD) or eplerenone with 1116 patients who did not receive an MRA (408 with CKD), using propensity score-adjusted Cox proportional hazards models (Mavrakanas, Giannetti, Sapir-Pichhadze, & Alam, 2020). All patients were receiving an ACEI or an Angiotensin II receptor blocker (ARB). The MRA had to be discontinued in 30% of patients with CKD and 35% of patients without CKD (p= 0.39). In this cohort, there was no difference between the two groups in the incidence of a composite outcome of death from any cause, myocardial infarction, or hospital admission for decompen-sated CHF. The effect of MRAs on this outcome was not affected by CKD status (P-value for interaction = 0.27). The safety renal outcome, defined as hyperkalemia >6 mmol/l or any doubling of serum creatinine in patients not yet on dialysis, occurred more frequently in MRA users without CKD than MRA users with CKD (P-value for interaction = 0.02). The authors concluded that MRAs could be safely prescribed in patients with CHF and CKD who were already treated with an ACEI or an ARB.
2.5. Ongoing trials
SPIRO-CKD (Spironolactone in Chronic Kidney Disease) trial (NCT02502981) is an ongoing multicentre, prospective, randomized, open-label, blinded end point clinical trial that will compare the effect of spironolactone to chlorthalidone on left ventricular mass (LVM) (Hayer et al., 2017). The trial plans to enrol patients without history of CHF or diabetes mellitus and a preserved LVEF (≥50%). Recruitment of 154 patients had been completed by December 2016 but the results of this trial have not yet been reported.
3. MRAs for the prevention of worsening nephropathy in patients