Shingo Matsumoto Mineralocorticoid Receptor

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. -, NO.
-, 2024
ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
Mineralocorticoid Receptor Antagonists

in Patients With Heart Failure and
Impaired Renal Function
Shingo Matsumoto, MD, PHD,a Alasdair D. Henderson, PHD,a Li Shen, MD, PHD,a Mingming Yang, MD, PHD,a
Karl Swedberg, MD, PHD,b Muthiah Vaduganathan, MD, MPH,c Dirk J. van Veldhuisen, MD, PHD,d
Scott D. Solomon, MD,c Bertram Pitt, MD,e Faiez Zannad, MD, PHD,f Pardeep S. Jhund, MBCHB, MSC, PHD,a
John J.V. McMurray, MDa
ABSTRACT
BACKGROUND Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy.
OBJECTIVES This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in
patients with HF with reduced ejection fraction experiencing significant kidney dysfunction.
METHODS We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and
EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association
between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate
(eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization.
RESULTS Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization
to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3
13.4 mL/min/1.73 m2 vs 70.5 21.8 mL/min/1.73 m2) and had a higher risk of the primary outcome than patients without
eGFR deterioration (HR: 2.49; 95% CI: 2.01-3.08; P < 0.001). However, the risk reduction in the primary outcome with
MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-
0.99) compared with those who did not (HR: 0.63; 95% CI: 0.56-0.71) (Pinteraction ¼ 0.87). In patients with a decrease in
eGFR to <30 mL/min/1.73 m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA
treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0 mmol/L).
CONCLUSIONS Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 are at very high risk, the
absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to
treatment discontinuation. (J Am Coll Cardiol 2024;-:-–-) © 2024 by the American College of Cardiology Foundation.
R enal impairment is common in heart failure

(HF) and kidney function often declines as
the severity of HF progresses over time.1-4
To complicate this picture, several treatments for
HF that improve outcomes can, paradoxically, lead
to a decrease in the estimated glomerular filtration
rate (eGFR). 5,6 Because of this, there is a growing
awareness that a modest initial decline in eGFR after
a
From the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom;
b
Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
c
Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; dDepartment of
Cardiology, Thorax Center, University Medical Center Groningen, Groningen, the Netherlands; eDepartment of Medicine, Uni-
versity of Michigan School of Medicine, Ann Arbor, Michigan, USA; and the fCentre d’Investigations Cliniques Plurithématique
1433, French Institute of Health and Medical Research U1116, French Clinical Research Infrastructure Network–Investigation
Network Initiative–Cardiovascular and Renal Clinical Trials, Centre Hospitalier Régional Universitaire de Nancy, Université de
Lorraine, Nancy, France.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received February 20, 2024; revised manuscript received March 22, 2024, accepted March 27, 2024.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.03.426

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2 Matsumoto et al JACC VOL. -, NO. -, 2024
MRA in Heart Failure With Renal Impairment -, 2024:-–-
ABBREVIATIONS starting these therapies may be acceptable. concern in patients treated with a sodium-glucose
AND ACRONYMS However, a decrease in eGFR to below cotransporter 2 inhibitor and also an angiotensin re-
30 mL/min/1.73 m 2 is generally regarded as ceptor neprilysin inhibitor. 15-17 A mineralocorticoid
ACE = angiotensin-converting
enzyme
concerning and is the commonly accepted receptor antagonist (MRA) is another life-saving
threshold below which these drugs should treatment for patients with heart failure with reduced
ARB = angiotensin II type 1
receptor blocker not be initiated and, by extension, it is often ejection fraction (HFrEF) that can cause a decline in
eGFR = estimated glomerular considered the eGFR level at which these eGFR. Several surveys have reported that MRAs are
filtration rate treatments should be stopped.7-10 An eGFR often withheld or discontinued because of renal
HF = heart failure below this threshold has been reported in dysfunction.18-22 We hypothesized that a decline in
HFrEF = heart failure and 5% to 15% of outpatient clinic attendees eGFR to <30 mL/min/1.73 m 2 would occur more often
reduced ejection fraction and 15% to 20% of patients hospitalized in patients treated with an MRA, compared with pla-
LVEF = left ventricular ejection with worsening HF. 11-14 Recently, however, cebo, but this decrease in eGFR would not compro-
fraction
it has been shown that even an eGFR mise the therapeutic benefits of MRA therapy or
MRA = mineralocorticoid of <30 mL/min/1.73 m 2 is not necessarily a result in an unacceptable safety profile. To test this
receptor antagonist
hypothesis, we created a pooled dataset from the
RALES (Randomized Aldactone Evaluation Study)
and EMPHASIS-HF (Eplerenone in Mild Patients Hos-
T A B L E 1 Baseline Characteristics
pitalization and Survival Study in Heart Failure) trials
No Decrease in eGFR Decrease in eGFR that demonstrated the benefit of spironolactone and
to <30 mL/min/1.73 m 2 to <30 mL/min/1.73 m 2
(n ¼ 4,060) (n ¼ 295) P Value
eplerenone, respectively, across the spectrum of
Age, y 67.0 9.6 70.7 8.8 <0.001
severity in HFrEF.7,23 We examined the occurrence
Age >70 y 1,507 (37.1) 159 (53.9) <0.001 of a decline in eGFR to <30 mL/min/1.73 m 2, subse-
Male 3,120 (76.8) 207 (70.2) 0.01 quent outcomes in patients related to this, and the ef-
Race 0.02 ficacy and safety of MRA therapy in patients
Asian 333 (8.2) 14 (4.7) developing an eGFR <30 mL/min/1.73 m2 .
Black 178 (4.4) 7 (2.4)
White 3,400 (83.7) 267 (90.5) METHODS
Others 149 (3.7) 7 (2.4)
Weight, kg 76.6 16.7 72.7 15.7 <0.001
STUDY DESIGN AND POPULATION. We pooled indi-
Heart rate, beats/min 75.0 13.8 77.5 13.7 <0.01
vidual participant data from patients enrolled in 2
Systolic blood pressure, mm Hg 123.5 17.9 121.9 20.8 0.15
Systolic blood pressure 512 (12.6) 41 (13.9) 0.53 large double-blind randomized placebo-controlled
>140 mm Hg trials, RALES and EMPHASIS-HF.7,23 The end of pa-
Diastolic blood pressure, mm Hg 74.8 10.7 72.9 11.6 <0.01 tient enrollment was 1996 in the RALES trial and 2010
Potassium, mmol/L 4.3 0.4 4.3 0.5 0.86
in the EMPHASIS-HF trial. Briefly, RALES compared
eGFR, mL/min/1.73 m2 70.5 21.8 47.3 13.4 <0.001
2
spironolactone and matching placebo in patients who
<60 mL/min/1.73 m 1,407 (34.7) 253 (85.8) <0.001
had a left ventricular ejection fraction (LVEF) #35%
<45 mL/min/1.73 m2 384 (9.5) 148 (50.2) <0.001
LVEF, % 25.9 5.5 25.2 6.5 0.05 and severe HF symptoms (NYHA functional class III or
<25% 1,246 (31.8) 109 (37.6) 0.04 IV), despite treatment with an angiotensin-
<20% 430 (11.0) 44 (15.2) 0.03 converting enzyme (ACE) inhibitor (if tolerated) and
Medical history a loop diuretic. Patients with a serum creatinine level
Diabetes mellitus 1,115 (27.5) 99 (33.6) 0.02 of >2.5 mg/dL or a serum potassium concentration of
Hypertension 2,081 (51.3) 113 (38.3) <0.001
>5.0 mmol/L were excluded from the trial. Patients
Ischemic heart failure 2,560 (63.1) 198 (67.1) 0.17
were initially assigned to either 25 mg of spi-
Myocardial infarction 1,718 (42.3) 120 (40.7) 0.58
Atrial fibrillation/flutter 961 (23.7) 59 (20.0) 0.15
ronolactone or matching placebo, taken once daily.
Chronic obstructive pulmonary 575 (14.2) 46 (15.6) 0.50 After 8 weeks, the dose could be increased to 50 mg
disease once daily if the patient showed signs or symptoms of
Treatments
progression of HF without evidence of hyperkalemia.
Diuretics 3,522 (87.1) 266 (90.2) 0.13
If hyperkalemia developed at any time, the dose of
ACE inhibitor or ARB 3,824 (94.6) 282 (95.6) 0.45
spironolactone could be decreased to 25 mg every
Beta-blocker 2,436 (60.2) 98 (33.2) <0.001
Digoxin 1,769 (43.7) 166 (56.3) <0.001 other day.
In the EMPHASIS-HF trial, 2,737 patients with a
Values are mean SD or n (%). LVEF #35% and mild HF symptoms (NYHA functional
ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin II type 1 receptor blocker; eGFR ¼ estimated
glomerular filtration rate; LVEF ¼ left ventricular ejection fraction. class II), treated with an ACE inhibitor or angiotensin
II type 1 receptor blocker (ARB) and a beta-blocker
JACC VOL. -, NO. -, 2024 Matsumoto et al 3
-, 2024:-–- MRA in Heart Failure With Renal Impairment
(unless contraindicated), were randomly assigned to

T A B L E 2 Associations Between a Decrease in eGFR to <30 mL/min/1.73 m 2 and
eplerenone (up to 50 mg daily) or matching placebo. Subsequent Outcomes
Patients with serum potassium levels exceeding
No Decrease in eGFR to Decrease in eGFR to
5.0 mmol/L or an eGFR <30 mL/min/1.73 m2 calcu- <30 mL/min/1.73 m2 <30 mL/min/1.73 m2
lated using the Modification of Diet in Renal Disease (n ¼ 4,060) (n ¼ 295) P Value
formula 24 were excluded from the trial. The CV death or hospitalization for HF
randomization was stratified according to renal No. of events 1,304 93

Event rate per 100 person-years 19.7 (18.6-20.8) 40.6 (33.1-49.7)
function at baseline: patients with an eGFR of be-
(95% CI)
tween 30 and 50 mL/min/1.73 m 2 received 25 mg/d of HR (95% CI) Reference 2.49 (2.01-3.08) <0.001
eplerenone (or placebo) and patients with an eGFR Adjusted HR (95% CI)a Reference 1.49 (1.19-1.87) 0.001
>50 mL/min/1.73 m 2 received 50 mg/d of eplerenone Hospitalization for HF
(or placebo). No. of events 875 45
Both trials had ethical approval and all patients Event rate per 100 person-years 13.2 (12.4-14.1) 19.6 (14.7-26.3)
(95% CI)
gave written informed consent.
HR (95% CI) Reference 1.86 (1.37-2.51) <0.001
Adjusted HR (95% CI)a Reference 1.08 (0.79-1.48) 0.63
eGFR ASSESSMENT. In the RALES trial, longitudinal
CV death
creatinine values were measured after randomization
No. of events 758 93
at each follow-up visit (at 4 weeks, 8 weeks, 12 weeks,
6 months, 9 months, 12 months, 18 months, and every (95% CI)
6 months up to the end of the trial). We calculated HR (95% CI) Reference 2.96 (2.38-3.68) <0.001
eGFR levels at each visit using the Modification of Adjusted HR (95% CI)a Reference 1.83 (1.45-2.33) <0.001
All-cause death
Diet in Renal Disease formula, including race, as this
23 No. of events 913 112
was used in the EMPHASIS-HF trial. The following
1.154
equation was used: eGFR ¼ 175 (creatinine) (95% CI)
(age) 0.203 (0.742 if female) (1.178 if Black). In the HR (95% CI) Reference 2.92 (2.40-3.56) <0.001
EMPHASIS-HF trial, creatinine level was measured at Adjusted HR (95% CI)a Reference 1.74 (1.40-2.16) <0.001
5 months, 13 months, 21 months, 29 months,

Time-to-first-event analyses were performed using time-updated Cox proportional hazards models. A clinical
37 months, 42 months, 48 months, and every event before eGFR deterioration in patients experiencing a subsequent decrease in eGFR to <30 mL/min/1.73 m2
6 months up to the end of the trial.7 was counted as an event in those who did not deteriorate. Events that occurred on the day of eGFR
deterioration <30 mL/min/1.73 m2 were not included. aAdjusted for age, sex, baseline eGFR, and randomized
treatment, using a shared frailty model (trial).
CLINICAL ENDPOINTS. In the present study, time to
CV ¼ cardiovascular; eGFR ¼ estimated glomerular filtration rate; HF ¼ heart failure.
the first occurrence of the composite of cardiovascu-
lar death or hospitalization for HF was used as the
primary outcome. We also examined each of the we thought that many physicians would likely stop
components of the primary outcome and all-cause MRA treatment at the time of the first decrease in
death. Study drug discontinuation and adverse eGFR to <30 mL/min/1.73 m 2, the primary analysis
events including hyperkalemia, worsening kidney only accounted for the first detected decline in
function, and hypotension were also examined. eGFR (even though some of these patients had a
STATISTICAL ANALYSIS. A small number of partici- subsequent increase in eGFR). Clinical outcomes
pants (37 of 4,400 patients) had an estimated eGFR and safety endpoints according to eGFR decrease
of <30 mL/min/1.73 m 2 at baseline and were excluded are reported as the number of events and rates per
from this study. We used eGFR <30 mL/min/1.73 m 2 100 person-years. Time-to-first-event data were
as a time-updated binary variable in this study. evaluated with Cox proportional hazards models to
Patient characteristics were analyzed according to calculate HRs with 95% CIs. In the analyses of the
those who did and did not have eGFR decrease to associations between eGFR decrease and subse-
<30 mL/min/1.73 m 2 at any point after randomization. quent outcomes, the HRs were adjusted for vari-
For continuous variables, the difference between ables thought to be likely confounders of the
eGFR groups was assessed using Student’s t-test. relationship between decline in eGFR and HF out-
Categorical variables were compared using a chi- comes. We selected a parsimonious model given the
square test. expected small number of events in the eGFR
We incorporated eGFR decline as a time-updated decline group (ie, randomized treatment, age, sex,
variable by dividing follow-up time into before or and baseline eGFR value) using a shared frailty
after eGFR decline to <30 mL/min/1.73 m 2 to assess model (trial).
the association between eGFR decrease and the The safety and efficacy of MRA therapy compared
development of subsequent clinical events. Because with placebo according to eGFR decrease were
T A B L E 3 Effects of MRA Treatments According to Whether eGFR Decreased to <30 mL/min/1.73 m 2 or Not
No Decrease in eGFR Decrease in eGFR

to <30 mL/min/1.73 m2 (n ¼ 4,060) to <30 mL/min/1.73 m2 (n ¼ 295)
Placebo MRA Placebo MRA P Value for

(n ¼ 2,084) (n ¼ 1,976) (n ¼ 109) (n ¼ 186) Interaction
CV death or hospitalization for HF

No. of events 782 522 35 58
Event rate per 100 person-years (95% CI) 24.5 (22.8-26.3) 15.2 (14.0-16.6) 55.9 (40.1-77.8) 34.8 (26.9-45.0)
HR (95% CI) 0.63 (0.56-0.71) 0.65 (0.43-0.99) 0.87
Hospitalization for HF
No. of events 530 345 18 27
HR (95% CI) 0.62 (0.54-0.71) 0.60 (0.33-1.08) 0.92
CV death
No. of events 450 308 40 53
HR (95% CI) 0.68 (0.59-0.79) 0.65 (0.43-0.98) 0.84
All-cause death
No. of events 537 376 50 62
HR (95% CI) 0.70 (0.61-0.79) 0.61 (0.42-0.88) 0.51
Time-to-first-event analyses were performed using time-updated Cox proportional hazards models. A clinical event before eGFR deterioration in patients experiencing a
subsequent decrease in eGFR to <30 mL/min/1.73 m2 was counted as an event in those who did not deteriorate. Events that occurred on the day of eGFR
deterioration <30 mL/min/1.73 m2 were not included.
MRA ¼ mineralocorticoid receptor antagonist; other abbreviations as in Table 2.
analyzed using time-updated Cox proportional haz- RESULTS

ards models including an interaction between treat-
ment and eGFR decrease. Incidence rate difference Overall, 4,355 patients were included in this post
was also examined according to eGFR decline. Sur- hoc analysis of the RALES and EMPHASIS-HF trials,
vival curves for the outcomes of interest were also of whom 2,193 were randomized to placebo and
plotted using flexible parametric survival function 2,162 to an MRA. A total of 295 (6.8%) of 4,355 par-
according to treatment assignment in patients who ticipants experienced a deterioration in eGFR
experienced eGFR decline and in those who did not. to <30 mL/min/1.73 m 2 at least once after randomiza-
A sensitivity analysis was conducted to examine tion, 186 of (8.6%) of 2,162 patients in the MRA group
the association between eGFR decrease and subse- compared with 109 (5.0%) of 2,193 patients in the
quent outcomes in each trial separately. Further- placebo group (OR: 1.80; 95% CI: 1.41-2.30; P < 0.001).
more, the effects of MRA treatment on outcomes were Among these patients, 53.6% (n ¼ 158 of 295) experi-
also examined in patients who did and did not have enced eGFR deterioration within 6 months of
permanent study drug discontinuation during follow- randomization (and around one-half beyond
up. We also analyzed patients including those who 6 months). Overall, the median time to eGFR
had a lower eGFR than 30 mL/min/1.73 m 2 at baseline. deterioration <30 mL/min/1.73 m2 was 168 days (Q1-
In addition, outcomes and the effect of MRA Q3: 59-406 days) (Supplemental Figure 1). Of the
therapy were analyzed using an eGFR decline 295 patients who experienced an initial decline in
to <30 mL/min/1.73 m 2 as a time-updated covariate at eGFR to <30 mL/min/1.73 m2 , 142 (47.8%) of 295
several time points in patients who experienced a experienced a subsequent improvement in eGFR to
change in the eGFR status over time (eGFR decrease $30 mL/min/1.73 m 2 over a median duration of
2
to <30 mL/min/1.73 m or not). We tested the pro- 111 days (Q1-Q3: 56-215 days). The median duration of
portional hazards assumption using Schoenfeld re- follow-up overall was 23 months.
siduals and examined log-log survival plots, which
showed that the proportional hazards assumption BASELINE CHARACTERISTICS IN PATIENTS WITH AN
was not violated in the present analyses. Values of eGFR DETERIORATION TO <30 mL/min/1.73 m2.
P < 0.05 were considered statistically significant. All Patients who experienced eGFR deterioration
analyses were performed using STATA version 17.0 to <30 mL/min/1.73 m2 were older, were more often
(StataCorp). female, and had lower body weight than those
F I G U R E 1 Outcomes According to eGFR Decrease to <30 mL/min/1.73 m2 and Treatment
CV Death or Hospitalization for HF Hospitalization for HF

100 100
Incidence Probability (%)

90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 1 2 3 0 1 2 3
Years At-Risk by Exposure Category Years At-Risk by Exposure Category
CV Death All-Cause Death

100 100
90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 1 2 3 0 1 2 3
Years At-Risk by Exposure Category Years At-Risk by Exposure Category
eGFR Deterioration and Placebo eGFR Deterioration and MRA
No Deterioration and Placebo No Deterioration and MRA
The curves were estimated by time-to-first-event analyses using Cox proportional hazards models with estimated glomerular filtration rate (eGFR) deterioration as a
time-updated exposure. Therefore, the x-axis shows the number of years at risk in each exposure category (not years since randomization). In patients experiencing an
eGFR decline to <30 mL/min/1.73 m2, day 0 is the date of eGFR deterioration <30 mL/min/1.73 m2. CV ¼ cardiovascular; HF ¼ heart failure; MRA ¼ mineralocorticoid
receptor antagonist.
without such a deterioration (Table 1). Diabetes Supplemental Table 1 shows the baseline charac-
mellitus was more common in patients experiencing teristics of patients allocated to an MRA or placebo
eGFR deterioration, but a history of hypertension in patients experiencing a decrease in eGFR to
was less common than in those who did not <30 mL/min/1.73 m2. These characteristics were well
develop eGFR deterioration. Baseline eGFR and balanced between the treatment groups, except for
LVEF were lower in patients experiencing eGFR ischemic etiology.
deterioration, compared with those who did not,
whereas systolic blood pressure and potassium OUTCOMES ACCORDING TO eGFR DETERIORATION
levels were similar between the 2 groups. The use TO <30 mL/min/1.73 m 2 . The number of patients
of diuretics and an ACE inhibitor or ARB was similar who survived at each subsequent time point is shown
between the 2 groups. in Supplemental Table 2. Table 2 and Supplemental
C E NT R AL IL L U STR AT IO N Estimated Glomerular Filtration Rate Decline to <30 mL/min/1.73 m 2 and Effects of
Mineralocorticoid Receptor Antagonist Therapy
Matsumoto S, et al. J Am Coll Cardiol. 2024;-(-):-–-.
The benefit-risk balance of mineralocorticoid receptor antagonist (MRA) therapy in patients with heart failure with reduced ejection fraction (HFrEF) is maintained,
irrespective of decrease in estimated glomerular filtration rate (eGFR) to <30 mL/min/1.73 m2. Patients with eGFR decline to <30 mL/min/1.73 m2 had worse heart
failure (HF) outcomes; therefore, the absolute risk reduction in these patients was large. CV ¼ cardiovascular; EMPHASIS-HF ¼ Eplerenone in Mild Patients Hospi-
talization and Survival Study in Heart Failure; LVEF ¼ left ventricular ejection fraction; RALES ¼ Randomized Aldactone Evaluation Study.
Figure 2 show the associations between eGFR dete- to <30 mL/min/1.73 m 2 as a time-varying covariate at
2
rioration to <30 mL/min/1.73 m and subsequent several time points showed similar results
outcomes. The primary outcome (composite of car- (Supplemental Table 3).
diovascular death or hospitalization for HF) was more The association between eGFR deterioration and
frequent in following eGFR deterioration to <30 mL/ the primary outcome was similar between the RALES
min/1.73 m2 compared with those who did not dete- and EMPHASIS-HF trials (Supplemental Table 4).
riorate, and the same was true for all other outcomes
of interest (Table 2, Supplemental Figure 2). These EFFECTS OF MRA TREATMENTS ACCORDING TO
trends were also seen after adjustment for other eGFR DETERIORATION TO <30 mL/min/1.73 m 2 . For
prognostic variables, except for HF hospitalization all outcomes examined, the benefits of MRA therapy
(Table 2). A sensitivity analysis using eGFR decline were consistent between patients with and without
T A B L E 4 Safety Outcomes Among Patients With eGFR Decrease to <30 mL/min/1.73 m 2 or not, According to Treatment
No Decrease in eGFR Decrease in eGFR

to <30 mL/min/1.73 m 2 (n ¼ 4,060) to <30 mL/min/1.73 m2 (n ¼ 295)
Placebo MRA Placebo MRA P Value for

(n ¼ 2,084) (n ¼ 1,976) (n ¼ 109) (n ¼ 186) Interaction
Study drug discontinuationa

No. of events 409 374 25 53
HR (95% CI) 0.91 (0.79-1.05) 1.11 (0.69-1.79) 0.42
Hyperkalemia (potassium >5.5 mmol/L)
No. of events 127 254 3 26
HR (95% CI) 2.08 (1.68-2.58) 5.56 (1.68-18.37) 0.07
Severe hyperkalemia (potassium >6.0 mmol/L)
No. of events 31 56 1 8
HR (95% CI) 1.81 (1.17-2.81) 4.31 (0.54-34.43) 0.38
Creatinine $2.5 mg/dL
HR (95% CI) 1.61 (1.09-2.38) 1.06 (0.54-2.10) 0.30
Creatinine $3.0 mg/dL
HR (95% CI) 1.47 (0.76-2.83) 0.86 (0.36-2.06) 0.34
Hypotension
HR (95% CI) 1.29 (0.96-1.74) 0.10 (0.01-0.83) <0.01
Time-to-first-event analyses were performed using time-updated Cox proportional hazards models. A clinical event before eGFR deterioration in patients experiencing
a subsequent decrease in eGFR to <30 mL/min/1.73 m2 was counted as an event in those who did not deteriorate. Events that occurred on the day of eGFR deterioration
<30 mL/min/1.73 m2 were not included. aPermanent discontinuation for reasons other than death.
eGFR ¼ estimated glomerular filtration rate.
eGFR deterioration to <30 mL/min/1.73 m2 several time points showed consistent results (ie, ef-
(Table 3, Figure 1). The overall HR for MRA fects of MRA treatment were not modified by whether
treatment, compared with placebo, for the primary eGFR decreased to <30 mL/min/1.73 m 2 or not)
outcome was 0.66 (95% CI: 0.59-0.73); in patients (Supplemental Table 7).
who did not experience eGFR deterioration DISCONTINUATION OF RANDOMIZED THERAPY.
to <30 mL/min/1.73 m 2, it was 0.63 (95% CI: Discontinuation of randomized treatment was more
0.56-0.71); and in patients experiencing eGFR common in patients after eGFR deterioration
deterioration, it was 0.65 (95% CI: 0.43-0.99) compared with those who did not have eGFR deteri-
(P interaction ¼ 0.87) (Table 3, Central Illustration). oration: 78 (26.4%) of 295 for patients with an eGFR
By contrast, the absolute risk reduction, as opposed decline to <30 mL/min/1.73 m 2 and 783 (19.3%) of
to relative risk reduction, with MRA therapy was 4,060 for patients without such an eGFR decline
greater in patients experiencing an eGFR decline, (Table 4). This trend was also seen irrespective of
with a difference in incidence rate (per 100 person- assignment to placebo or MRA (eg, among patients
years) of 21.1 (95% CI: 0.5-41.6) compared with 9.3 assigned to placebo), 25 (22.9%) of 109 of those
(95% CI: 7.1-11.4) in those without an eGFR decrease experiencing an eGFR decline to <30 mL/min/1.73 m 2
2
to <30 mL/min/1.73 m . This finding was consistent in stopped treatment compared with 409 (19.6%) of
the RALES and EMPHASIS-HF trials (Supplemental 2,084 of patients not experiencing this eGFR decline
Table 5). These results were consistent in the anal- (Table 4, Figure 2). The rate of discontinuation of MRA
ysis including patients who had an eGFR lower than therapy was not greater than placebo therapy in
30 mL/min/1.73 m2 at baseline (Supplemental either eGFR change category (Table 4).
Table 6). A sensitivity analysis using eGFR decline Event rates were higher among patients who
to <30 mL/min/1.73 m2 as a time-varying covariate at stopped randomized treatment than in those who
decrease (P interaction ¼ 0.38); the rate of severe

F I G U R E 2 Study Drug Discontinuation According to eGFR Decrease and MRA Therapy
hyperkalemia in patients experiencing an eGFR
deterioration was 3.9 per 100 person-years (95% CI:
Study Drug Discontinuation 2.0-7.8 per 100 person-years) in these individuals
100 compared with 1.5 per 100 person-years (95% CI: 1.2-
2.0 per 100 person-years) in those who did not have
90
80 an eGFR decline to <30 mL/min/1.73 m 2. Regarding
other safety outcomes, by definition, increases in
70
creatinine above the predefined safety thresholds (2.5
60
and 3.0 mg/dL) were much more common in patients
50
experiencing an eGFR decline to <30 mL/min/1.73 m 2,
40
irrespective of assignment to placebo or MRA, but not
30
significantly more common with MRA therapy,
20
compared with placebo treatment, within either eGFR
10
change category (Table 4).
0
0 1 2 3 DISCUSSION
Years At-Risk by Exposure Category
In this post hoc analysis of the RALES and EMPHASIS-
eGFR Deterioration and Placebo
HF trials, a higher proportion of patients (n ¼ 186 of
eGFR Deterioration and MRA
2,162 [8.6%]) assigned to an MRA experienced a
No Deterioration and Placebo
decline in eGFR to <30 mL/min/1.73 m 2 compared
No Deterioration and MRA
with patients assigned to placebo (n ¼ 109 of 2,193
[5.0%]), as expected. However, the relative efficacy
The curves were estimated by time-to-first-event analyses using Cox proportional haz- of MRA therapy was maintained in these
ards models with eGFR deterioration as a time-updated exposure. Therefore, the x-axis
patients, and the safety profile was similar to that
shows the number of years at risk in each exposure category (not years since randomi-
zation). In patients experiencing an eGFR decline to <30 mL/min/1.73 m2, day 0 is the observed in patients not experiencing a decline in
date of eGFR deterioration <30 mL/min/1.73 m2. Abbreviations as in Figure 1. eGFR to <30 mL/min/1.73 m2 . Importantly,
because patients experiencing a decrease in eGFR to
<30 mL/min/1.73 m 2 were at such high risk, the ab-
solute rate reduction in these patients was large (21
continued treatment, irrespective of assignment to
fewer patients experienced the primary outcome per
placebo or MRA (Supplemental Table 8a and 8b).
100 person-years of treatment compared with 9 fewer
However, the benefits of MRA therapy were consis-
in patients not experiencing a decline in eGFR
tent in patients who stopped or continued random-
to <30 mL/min/1.73 m 2).
ized treatment (Supplemental Tables 8a and 8b).
While not as substantial as the decrease reported
SAFETY OF MRA THERAPY ACCORDING TO eGFR with renin-angiotensin-system inhibitors (ACE in-
DETERIORATION TO <30 mL/min/1.73 m 2 . The hibitors and ARBs), a decline in eGFR typically in the
occurrence of hyperkalemia (potassium level range of 2 to 7 mL/min/1.73 m 2 is sometimes observed
>5.5 mmol/L) was more common in patients assigned after starting an MRA in patients with HF.25-27 The
to an MRA compared with placebo (overall popula- mechanism underlying this initial drop in eGFR with
tion, HR: 2.22; 95% CI: 1.80-2.72) and was substan- an MRA is still not well understood, although acute
tially more common among those who experienced intrarenal hemodynamic changes may be implicated,
eGFR deterioration to <30 mL/min/1.73 m 2 (HR: 5.56; as with renin-angiotensin system inhibitors.27 In an
95% CI: 1.68-18.37) compared with those who did not individual patient, it is difficult to know whether an
have this decline in eGFR (HR: 2.08; 95% CI: 1.68- observed decrease in eGFR is causally linked to the
2.58) (P interaction ¼ 0.07). initiation of a specific treatment or due to other fac-
Overall, the risk of severe hyperkalemia (potassium tors, including progression of HF. A decline in eGFR
levels >6.0 mmol/L) was higher (2.9 per 100 person- due to the former may be reversible, and a decrease in
years) in patients experiencing eGFR decrease eGFR need not automatically lead to treatment
to <30 mL/min/1.73 m 2 compared with those who did discontinuation. This is illustrated by the data from
not have this decline in eGFR (1.2 per 100 person- the 2 trials analyzed here. While more patients with
years). The occurrence of severe hyperkalemia ac- an eGFR decline to <30 mL/min/1.73 m 2 stopped
cording to MRA use was not modified by eGFR randomized treatment than patients with no decrease
in eGFR (26.4% [n ¼ 78 of 295] vs 19.3% [n ¼ 783 of changes in eGFR following in those with and without
4,060]), the rate of treatment discontinuation did not an eGFR decline to <30 mL/min/1.73 m 2 were not
differ significantly between patients assigned to an addressed in this study. Although patients were ran-
MRA and those randomized to placebo, in either eGFR domized to placebo or MRA therapy, biases have
change category. Therefore, the very large benefits of occurred postrandomization as MRA treatment
MRA therapy in this particularly high-risk group of affected both eGFR and event-free survival.
patients may justify the continuation of therapy,
CONCLUSIONS
provided that the eGFR reaches an acceptable plateau
and the potassium level does not increase to a
Patients treated with an MRA are more likely than
dangerous degree.
patients given placebo to experience a decline in
The risk of severe hyperkalemia (potassium levels
eGFR to <30 mL/min/1.73 m 2. However, the relative
>6.0 mmol/L) was higher in patients with an eGFR
efficacy of MRA therapy is maintained in these
decrease to <30 mL/min/1.73 m 2 compared with those
patients, and the safety profile is similar to
who did not have this decline in eGFR (2.9 per 100
that observed in patients not experiencing a
person-years vs 1.2 per 100 person-years), and in the
decline in eGFR to <30 mL/min/1.73 m 2. Because
eGFR <30 mL/min/1.73 m 2 group, the relative risk in
patients experiencing a decrease in eGFR to
patients assigned to an MRA was 4-fold higher than
<30 mL/min/1.73 m2 are at very high risk, the absolute
among those assigned to placebo. Although the ab-
risk reduction in these patients is large, and a decline
solute risk of severe hyperkalemia was low in the
in eGFR to <30 mL/min/1.73 m 2 should not automat-
MRA group (excess of 3 patients per 100 person-years
ically lead to treatment discontinuation unless
of follow-up compared with placebo), and much
there is some other reason to stop therapy such as
smaller than the benefit of therapy (21 fewer patients
hyperkalemia.
experienced the primary outcome per 100 person-
years of treatment), continued use of MRA treat- FUNDING SUPPORT AND AUTHOR DISCLOSURES
ment mandates careful monitoring of potassium
levels if the eGFR decreases to <30 mL/min/1.73 m 2. Drs Jhund and McMurray were supported by a British Heart Foun-
dation Centre of Research Excellence Grant (RE/18/6/34217) and the
As expected, patients experiencing a decrease in
Vera Melrose Heart Failure Research Fund. The EMPHASIS-HF trial
eGFR to <30 mL/min/1.73 m 2 were older, had more was sponsored by Pfizer. Dr Matsumoto has received research grants
impaired kidney and cardiac function, and were more and personal fees from Abbott, Bayer Pharma, Boehringer Ingelheim,
Daiichi-Sankyo, Medtronic, Novartis, Ono Pharma, Orbus Neich,
likely to have a diagnosis of diabetes. Although only
Otsuka Pharma, and the Uehara Memorial Foundation. Dr Yang has
6.8% (n ¼ 295 of 4,355) of patients had an eGFR received a grant from AstraZeneca to attend a medical congress. Dr
decline to <30 mL/min/1.73 m 2, this small proportion Swedberg has received honoraria from AstraZeneca, Boehringer
must be interpreted in light of the kidney function Ingelheim, and Novartis. Dr Vaduganathan has received research
grant support, served on advisory boards, or had speaker engage-
entry criteria in the 2 trials. Patients with an
ments with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter
eGFR <30 mL/min/1.73 m 2 were excluded from the Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon
EMPHASIS-HF trial (the mean baseline eGFR was Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos,
71 mL/min/1.73 m 2 and 33% [n ¼ 912 of 2,737] of pa- Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has served
on clinical trial committees for studies sponsored by AstraZeneca,
tients had an eGFR <60 mL/min/1.73 m 2). Patients
Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr
with a serum creatinine level >2.5 mg/dL were Solomon has received research grant support from Actelion, Alnylam,
excluded from the RALES trial (the mean baseline Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cel-
eGFR was 65 mL/min/1.73 m 2 and 48% [n ¼ 792 of ladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly,
Mesoblast, MyoKardia, the National Institutes of Health/National
1,663] of patients had an eGFR <60 mL/min/1.73 m2 ).
Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nor-
Consequently, a larger proportion of unselected disk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; and has
patients might be at risk of developing an served as consulted for Abbott, Action, Akros, Alnylam, Amgen,
eGFR <30 mL/min/1.73 m 2 than observed in the Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers
Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo,
RALES and EMPHASIS-HF trials. These findings also
GlaxoSmithKline, Lilly, Merck, MyoKardia, Novartis, Roche, Ther-
support the investigation of the newer MRAs that acos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions,
may have a lower risk of hyperkalemia and, therefore, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProthera, Moderna,
American Regent, and Sarepta. Dr Pitt has served as a consultant for
potentially a more favorable benefit-risk balance.28-30
Bayer, AstraZeneca, Boehringer Ingelheim, Merck, Lexicon, and G3
STUDY LIMITATIONS. As well as the limitation Pharmaceuticals; owns stock options in KBP BioSciences, Vifor, Sar-
fez, scPharmaceuticals, SQInnovation, ProtonIntel, Cereno Scientific,
mentioned previously, we cannot exclude residual
and Brainstorm Medical; holds U.S. patent US9931422 (site specific
bias potentially influencing the results of this study. delivery of eplerenone to the myocardium); and is an inventor of U.S.
This was not a prespecified analysis. Temporal patent pending US63/045,783 (histone acetylation modulating agents
for the protection and treatment of organ damage). Dr Zannad has Clinical Trial Partners Ltd. All other authors have reported that they
received personal fees from Boehringer Ingelheim (during the have no relationships relevant to the contents of this paper to
conduct of the study), Janssen, Novartis, Boston Scientific, Amgen, disclose.
CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical,
Applied Therapeutics, Merck, Bayer, and CellProthera; and has
ADDRESS FOR CORRESPONDENCE: Dr John J.V.
received other fees from CVCT and Cardiorenal, outside the submit-
ted work. Dr Jhund has received speaker fees from AstraZeneca, McMurray, British Heart Foundation Cardiovascular
Novartis, Alkem Metabolics, ProAdWise Communications, Sun Phar- Research Centre, University of Glasgow, 126 Univer-
maceuticals, and Intas Pharmaceuticals; has received advisory board
sity Place, Glasgow G12 8TA, United Kingdom. E-mail:
fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has
[email protected].
received research funding from AstraZeneca, Boehringer Ingelheim,
and Analog Devices Inc; his employer (University of Glasgow) has
been remunerated for clinical trial work from AstraZeneca, Bayer AG,
Novartis, and Novo Nordisk; and he is a director of Global Clinical PERSPECTIVES
Trial Partners. Dr McMurray has received payments through Glasgow
University from work on clinical trials, consulting, and other activ-
ities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, COMPETENCY IN PATIENT CARE AND
KBP Biosciences, and Novartis; has received personal consultancy PROCEDURAL SKILLS: Patients with HFrEF who
fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis
develop impaired kidney function (eGFR <30 mL/
Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River 2
Renal Corporation; has received personal lecture fees from Abbott,
min/1.73 m2) may benefit from continuation of MRA
Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, medication.
Boehringer Ingelheim, Canadian Medical and Surgical Knowledge,
Emcure Pharmaceuticals Ltd, Eris Lifesciences, the European TRANSLATIONAL OUTLOOK: A prospective eval-
Accreditation Council of Continuing Medical Education, Hikma
uation of the benefit-to-risk balance of MRAs is
Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chem-
icals & Pharma Pharmaceuticals Ltd, Lupin Pharmaceuticals, needed in patients with HFrEF and advanced renal
Medscape/Heart.org, ProAdWise Communications, Radcliffe Cardiol- impairment.
ogy, Sun Pharmaceuticals, The Corpus, Translation Research Group,
and the Translational Medicine Academy; and is a director of Global
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Shingo Matsumoto Mineralocorticoid Receptor

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. -, NO.

Mineralocorticoid Receptor Antagonists

R enal impairment is common in heart failure

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2024.03.426

(unless contraindicated), were randomly assigned to

randomization was stratiﬁed according to renal No. of events 1,304 93

5 months, 13 months, 21 months, 29 months,

No Decrease in eGFR Decrease in eGFR

Placebo MRA Placebo MRA P Value for

CV death or hospitalization for HF

analyzed using time-updated Cox proportional haz- RESULTS

F I G U R E 1 Outcomes According to eGFR Decrease to <30 mL/min/1.73 m2 and Treatment

CV Death or Hospitalization for HF Hospitalization for HF

Incidence Probability (%)

CV Death All-Cause Death

Incidence Probability (%)

Matsumoto S, et al. J Am Coll Cardiol. 2024;-(-):-–-.

No Decrease in eGFR Decrease in eGFR

Placebo MRA Placebo MRA P Value for

Study drug discontinuationa

decrease (P interaction ¼ 0.38); the rate of severe

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