European Heart Journal (2024) 00, 1–3 EDITORIAL

https://doi.org/10.1093/eurheartj/ehae040 Heart failure and cardiomyopathies

Mineralocorticoid receptor antagonists for the

prevention of atrial fibrillation in patients with

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and without heart failure: one more beneficial
effect?
1,2,3 4 1,2,3
Daniela Zurkan , Bertram Pitt , and Frank Edelmann *
1
Department of Cardiology, Deutsches Herzzentrum der Charité, Angiology and Intensive Care Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany;
2
Charité—Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, D-10117 Berlin, Germany; 3DZHK (German
Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany; and 4University of Michigan School of Medicine, Ann Arbor, MI, USA

This editorial refers to ‘Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis of clinical trials’, by
A. Oraii et al., https://doi.org/10.1093/eurheartj/ehad811.

Graphical Abstract

Landmark MRA trials

AREA IN-CHF TOPCAT IMPRESS-AF HOMAGE SPIRRIT-HfpEF

RALES ALDO-DHF MINIMIZE-STEMI ESAX-DN SPIRIT-HF

2000 2010 2020

EPHESUS ARTS PRIORITY FIGARO-DKD FINEARTS

EMPHASIS-HF ALBATROSS FIDELIO-DKD EARLIER

REMINDER CONFIRMATION-HF

Meta-analysis by Oraii et al.

MRA

CV and HF risk factors Atrial fibrillation Heart failure

Reduction of CV death and HFH Reduction of AF events, new and recurrent Reduction of CV death and HFH
(RR 0.84; 95% CI: 0.75–0.93) (RR 0.76; 95% CI: 0.67–0.87) (RR 0.81; 95% CI: 0.67–0.98)

Primary prevention Secondary prevention

Future research challenges

Handling hyperkalaemia Timing of treatment in primary Adequate risk and

Patients selection
in high-risk patients and secondary prevention benefit measures

Landmark achievements, current evidence and future challenges in the research of mineralocorticoid receptor antagonist use at different stages of
cardiovascular disease.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +49 30 450653731, Fax: +49 30 4507553731, Email: frank.edelmann@dhzc-charite.de
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
2 Editorial
Since mineralocorticoids were discovered as key endocrine regulators
of water and electrolyte homeostasis and blood pressure control, fur-
ther research has revealed their role in fibrotic myocardial and vascular
remodelling. Mineralocorticoid receptor antagonists (MRAs) have been
investigated in various clinical trials, initially focusing on the treatment of
heart failure with reduced left ventricular ejection fraction (HFrEF),
while heart failure with preserved ejection fraction (HFpEF) has been
receiving more and more attention in the past decades. Demonstrating
a reduction of all-cause mortality in highly symptomatic HFrEF patients
treated with spironolactone, the RALES trial set a landmark for heart
failure therapy.1 This fuelled further investigation and analyses of animal
models, human cardiac tissue and data from several randomized con-
trolled trials (RCTs), which suggested that aldosterone and the min-
eralocorticoid receptor (MR) might also play a role in atrial fibrosis
and subsequent development of atrial fibrillation (AF).2,3 However, pre-
viously published studies and meta-analyses yielded conflicting results
regarding the therapeutic potential of MRAs to prevent new-onset
AF and/or reduce the burden of AF episodes.4,5
In this issue of the European Heart Journal, Oraii et al. use a multistep
approach to investigate the interaction of MRA treatment, heart failure
(HF), and AF in an up-to-date meta-analysis of RCTs.6 Well-placed at
the intersection of two highly prevalent and relevant cardiovascular dis-
eases, this meta-analysis accentuates the link between primary and sec-
ondary prevention and contributes to bridging existing knowledge gaps.
All RCTs comparing MRA treatment vs. placebo or usual care in pa-
tients with cardiovascular (CV) risk factors or established CV disease
up until March 2023 were included in the analysis. Observational stud-
ies, and trials comparing multiple MRA dosages were excluded.
In the first step, the treatment effect of MRAs on different outcomes
was analysed in patients with and without HF or left ventricular (LV)
dysfunction. Of note, symptomatic HF and asymptomatic LV dysfunc-
tion were pooled into one patient group. Additional subgroups accord-
ing to AF status were then introduced in the previous subsets if data
availability allowed. CV outcomes of interest comprised CV death,
HF hospitalization (HFH; and a composite thereof), sudden cardiac
death, stroke, and myocardial infarction. Overall outcomes included all-
cause hospitalization and all-cause mortality. The authors conducted
thorough subgroup analyses in patients with and without HF and AF
to test for treatment interaction. However, limited information on
subgroup-specific outcomes in several trials inadvertently led to de-
creasing precision and quality of evidence for certain patient subsets.
Patient numbers and their baseline characteristics therefore vary across
different outcomes and patient groups. CV death, HFH, and their com-
posite were significantly reduced by MRA treatment in patients with
and without HF (or LV dysfunction), with an overall combined risk ratio
(RR) of .82 [95% confidence interval (CI) .74–.90] for the composite of
CV death or HFH. An absolute risk reduction of 1.2% and .6% could be
observed in patients with and without HF/LV dysfunction, respectively.
While the subtype of HF—HfrEF or HFpEF—showed no treatment
interaction for CV death or HFH separately, HFrEF patients showed
a greater benefit from MRAs than HFpEF patients for the composite of
CV death or HFH (RR .72, 95% CI .63–.83 vs. RR .91, 95% CI .80–1.05,
interaction P-value .02). Where data were available, pre-existing AF did
not affect the positive treatment effect. Similar results could be found
for all-cause hospitalization, sudden cardiac death, and all-cause mortality.
No significant benefit of MRAs could be found on myocardial infarction or
stroke. Although the analysed RCTs included five different MRA agents,
spironolactone, eplerenone, and finerenone were by far the most fre-
quently used substances. Information on trial drug discontinuation and
concomitant medication was not provided.
In the second step of the analysis, Oraii et al. assessed the effect of
MRA treatment on AF events, including new-onset and recurrent AF.
They found an overall relative risk reduction of .76 (95% CI .67–.87)
and absolute risk reduction of 1.2% for MRA vs. placebo or usual
care in patients with CV risk factors or established CV disease. Based
on the risk of bias due to potential differences in AF assessment be-
tween trials, the authors considered these findings to be moderate-
quality evidence. Subgroup and sensitivity analyses did not suggest
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any treatment interaction by HF/LV dysfunction status.
The meta-analysis by Oraii et al. discusses important questions of CV
and preventive practice, which still bear considerable clinical equipoise.
These questions encompass the rather large field of both primary and
secondary prevention of AF, HF, and their interaction in patients at
varying risk levels. Simultaneously addressing these matters can be con-
sidered a commendably comprehensive, rather than disentangling ap-
proach towards intertwined myocardial pathologies that have been
shown to be substantially affected by MR-mediated fibrosis.3,7 While
the CIs broaden with increasing subgroup complexity and decreasing
number of trials reporting outcomes of interest, the results of the ana-
lysis support established hypotheses and recent evidence that attribute
a more prominent role to MRAs in preventing and treating HF, irre-
spective of prevalent AF.8–10 Reflecting the prevailing uncertainty
with respect to MRA therapy of HFpEF, the treatment interaction ana-
lysis of HF subtypes yields conflicting results. Ongoing trials such as
SPIRIT-HF, SPIRRIT-HFpEF, or FINEARTS-HF aim to close this know-
ledge gap.
Albeit up to 41 RCTs were included in the analysis, the greatest
weight within the subanalyses still lies either with the well-known land-
mark trials which led to the implementation of MRAs in standard HF
therapy—RALES, EMPHASIS-HF, EPHESUS, for the HF subgroup—
or with recent large trials of the non-steroidal MRA finerenone in
patients with diabetic kidney disease—FIDELIO-DKD and FIGARO-
DKD, for the non-HF subgroup. Across a heterogeneous patient popu-
lation comprising HF stages from A to C, as defined by the AHA/ACC/
HFSA, MRAs seem to significantly reduce new-onset or recurrent AF
events. Nevertheless, the absolute risk reduction of 1.2% implies a num-
ber needed to treat of 83 for preventing one AF event, while the def-
inition, duration, and symptomatic burden of the latter remain vague or
unknown. Whether impaired study drug adherence could have influ-
enced the results of certain trials (and to what extent) also remains elu-
sive and might require further in-depth, patient-level meta-analyses.
Furthermore, unclear definitions and patient heterogeneity introduce
uncertainty with regards to the clinical relevance of these results and
impose challenges on the design and definition of adequate endpoints
in future cardiovascular trials. This comprehensive summary of re-
search over the past decades strongly supports the hypothesis of a
broad treatment effect of MRAs, thereby emphasizing several crucial
open questions. Which patients will benefit most from MRA treat-
ment? When is the best moment to initiate treatment on the individual
level? What are appropriate measures for researchers and practitioners
to assess disease risk and treatment benefit?
While several trials have failed to demonstrate an effect of MRAs on
quality of life, mechanistic trials such as ALDO-DHF showed an im-
provement in cardiac structure and function under MRA therapy.11
Biomarker analyses of the RALES and ALDO-DHF trials indicated
that patients with a high level of cardiac fibrosis, reflected by elevated
serum procollagen peptides, suffer from higher adverse outcome rates,
and benefit most from spironolactone treatment—shown to decrease
the markers of collagen turnover.7,12 Small studies have investigated
serum biomarkers of fibrosis in patients with AF and found a correlation
Editorial
with left atrial size.13 Whether there is an association of fibrosis markers
with hospitalizations or mortality in AF patients remains unknown.
Recent and ongoing trials provide a promising outlook on imple-
menting MRA therapy in patients at high risk of HF who often do
not tolerate MRAs due to hyperkalaemia, especially patients with
type 2 diabetes and/or chronic kidney disease (CKD). Post-hoc ana-
lyses of recent sodium–glucose co-transporter 2 inhibitor (SGLT2i)
trials showed a reduced rate of hyperkalaemia in high-risk patients
taking an MRA.14 Randomized trials investigating a combination ther-
apy or even a polypill approach of SGLT2i and MRAs in patients at high
risk or with prevalent HF (CONFIRMATION-HF) are currently being
initiated. While an SGLT2i may enhance MRA treatment adherence,
prevent HF events, and slow down CKD progression, the SGLT1/2
inhibitor sotagliflozin also showed a stroke rate reduction of 30% in
patients with diabetes and CKD.15 This observation is of particular im-
portance for AF patients, who might benefit in two ways from a com-
bined MRA/SGLT1/2i approach—with a reduction of AF events on
the one hand and a decrease of stroke risk without additional bleeding
risk on the other hand.
Overall, this meta-analysis by Oraii et al. further opens the door to-
wards studying and targeting mutual pathophysiological mechanisms of
AF and HF, potentially even prior to disease onset.
Thus, the cardiovascular research community will have to take on the
crucial task of defining (para-) clinical characteristics to select appropri-
ate study populations and to treat patients who will benefit from MRA
therapy, be it on the level of primary or secondary prevention of either
AF or HF—or both.
Declarations
Disclosure of Interest
D.Z. has nothing to declare. B.P. reports being consultant for Bayer,
AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lexicon,
Sea Star Medical, CEVAAnimale, ANA Cardio, Corteria therapeutics,
SC Pharmaceuticals*∧, SQinnovations*, G3 Pharmaceuticals*, Vifor
(Relypsa), KBP Biosciences*,Sarfez*, Cereno Scientific*∧, Proton in-
tel∧, Brainstorm medical* (*stock options, ∧stock). US Patent
9931412 site specific delivery ofeplerenone to the myocardium US pa-
tent pending 63/045783 Histone Modulating agents for the prevention
and treatment of Organ injury Datasafety Monitoring Board: Millennial
pharmaceutics (Lorundrostat). F.E. was funded by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation)—
SFB-1470-Z02. He is study PI of the SPIRIT-HF trial, funded by the
German Center for Cardiovascular Research, and of the ALDO-DHF
trial, completed in 2013.
3
References
1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spirono-
lactone on morbidity and mortality in patients with severe heart failure. Randomized
aldactone evaluation study investigators. N Engl J Med 1999;341:709–17. https://doi.
org/10.1056/NEJM199909023411001
2. Tsai CT, Chiang FT, Tseng CD, Hwang J-J, Kuo K-T, Wu C-K, et al. Increased expression
of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial
fibrillation. J Am Coll Cardiol 2010;55:758–70. https://doi.org/10.1016/j.jacc.2009.09.045
3. Lavall D, Selzer C, Schuster P, Lenski M, Adam O, Schäfers H-J, et al. The mineralocor-
Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehae040/7601591 by guest on 07 February 2024
ticoid receptor promotes fibrotic remodeling in atrial fibrillation. J Biol Chem 2014;289:
6656–68. https://doi.org/10.1074/jbc.M113.519256
4. Swedberg K, Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Shi H, et al. Eplerenone
and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF
(Eplerenone in Mild Patients Hospitalization And SurvIval Study in heart failure) study.
J Am Coll Cardiol 2012;59:1598–603. https://doi.org/10.1016/j.jacc.2011.11.063
5. Liu T, Korantzopoulos P, Shao Q, Zhang Z, Letsas KP, Li G. Mineralocorticoid receptor
antagonists and atrial fibrillation: a meta-analysis. Europace 2016;18:672–8. https://doi.
org/10.1093/europace/euv366
6. Oraii A, Healey JS, Kowalik K, Pandey AK, Benz AP, Wong JA, et al. Mineralocorticoid
receptor antagonists and atrial fibrillation: a meta-analysis of clinical trials. Eur Heart J
2024;45:ehad811. https://doi.org/10.1093/eurheartj/ehad811
7. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix
turnover may contribute to survival benefit of spironolactone therapy in patients with
congestive heart failure: insights from the Randomized ALdactone Evaluation Study
(RALES). Circulation 2000;102:2700–6. https://doi.org/10.1161/01.cir.102.22.2700
8. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular
events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021;385:
2252–63. https://doi.org/10.1056/NEJMoa2110956
9. Filippatos G, Anker SD, Agarwal R, Ruilope LM, Rossing P, Bakris GL, et al. Finerenone
reduces risk of incident heart failure in patients with chronic kidney disease and type 2
diabetes: analyses from the FIGARO-DKD trial. Circulation 2022;145:437–47. https://
doi.org/10.1161/CIRCULATIONAHA.121.057983
10. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 fo-
cused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and
chronic heart failure. Eur Heart J 2023;44:3627–39. https://doi.org/10.1093/eurheartj/
ehad195
11. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W,
et al. Effect of spironolactone on diastolic function and exercise capacity in patients
with heart failure with preserved ejection fraction: the aldo-DHF randomized con-
trolled trial. JAMA 2013;309:781–91. https://doi.org/10.1001/jama.2013.905
12. Ravassa S, Trippel T, Bach D, Bachran D, González A, López B, et al. Biomarker-based
phenotyping of myocardial fibrosis identifies patients with heart failure with preserved
ejection fraction resistant to the beneficial effects of spironolactone: results from the
aldo-DHF trial. Eur J Heart Fail 2018;20:1290–9. https://doi.org/10.1002/ejhf.1194
13. Löfsjögård J, Persson H, Díez J, López B, González A, Edner M, et al. Atrial fibrillation and
biomarkers of myocardial fibrosis in heart failure. Scand Cardiovasc J 2014;48:299–303.
https://doi.org/10.3109/14017431.2014.940063
14. Banerjee M, Maisnam I, Pal R, Mukhopadhyay S. Mineralocorticoid receptor antagonists
with sodium–glucose co-transporter-2 inhibitors in heart failure: a meta-analysis. Eur
Heart J 2023;44:3686–96. https://doi.org/10.1093/eurheartj/ehad522
15. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in
patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129–39.
https://doi.org/10.1056/NEJMoa2030186