Skip to main content

Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes

Original Investigation

J Am Coll Cardiol, 78 (2) 142–152
Sections

Central Illustration

Abstract

Background

Patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) are at risk of atrial fibrillation or flutter (AFF) due to cardiac remodeling and kidney complications. Finerenone, a novel, selective, nonsteroidal mineralocorticoid receptor antagonist, inhibited cardiac remodeling in preclinical models.

Objectives

This work aims to examine the effect of finerenone on new-onset AFF and cardiorenal effects by history of AFF in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study.

Methods

Patients with CKD and T2D were randomized (1:1) to finerenone or placebo. Eligible patients had a urine albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g, an estimated glomerular filtration rate (eGFR) ≥25 to <75 ml/min/1.73 m2 and received optimized doses of renin–angiotensin system blockade. Effect on new-onset AFF was evaluated as a pre-specified outcome adjudicated by an independent cardiologist committee. The primary composite outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) and key secondary outcome (time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) were analyzed by history of AFF.

Results

Of 5,674 patients, 461 (8.1%) had a history of AFF. New-onset AFF occurred in 82 (3.2%) patients on finerenone and 117 (4.5%) patients on placebo (hazard ratio: 0.71; 95% confidence interval: 0.53–0.94; p = 0.016). The effect of finerenone on primary and key secondary kidney and cardiovascular outcomes was not significantly impacted by baseline AFF (interaction p value: 0.16 and 0.85, respectively).

Conclusions

In patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. The risk of kidney or cardiovascular events was reduced irrespective of history of AFF at baseline. ( EudraCT 2015-000990-11 [A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease]; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD]; NCT02540993)

Introduction

Atrial fibrillation is the most common sustained arrhythmia, with a rising prevalence that substantially increases the risk of stroke and heart failure (1,2). Chronic kidney disease (CKD) and type 2 diabetes (T2D) are associated with increased risk of atrial fibrillation, and also higher morbidity and mortality associated with atrial fibrillation compared with patients without diabetes (3–8). Both CKD and T2D have been shown to induce atrial structural or electrical remodeling that may, in turn, provide the substrate for the development of atrial fibrillation (3–6). Preclinical evidence suggests that aldosterone upregulation and mineralocorticoid receptor overactivation are associated with structural cardiac remodeling and may also be involved in the pathophysiology of atrial fibrillation (9–11). However, previous clinical data report inconsistent benefits of steroidal mineralocorticoid receptor antagonists (MRAs) in reducing the risk of atrial fibrillation, where MRA treatment reduced the incidence of new-onset atrial fibrillation or flutter (AFF) in patients with heart failure with reduced ejection fraction but not in patients with heart failure with preserved ejection fraction (12,13).

Finerenone, a novel, selective, nonsteroidal MRA, significantly reduced the risk of cardiovascular events in patients with CKD and T2D in the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) phase III trial (14,15). In preclinical models, finerenone reduced mineralocorticoid receptor–mediated myocardial remodeling, including prevention of left atrial dilatation and left atrial fibrosis (16). The aim of this secondary analysis of the FIDELIO-DKD trial was to describe the effect of finerenone on the incidence of new-onset AFF in patients with CKD and T2D. Furthermore, we aimed to assess the effect of finerenone on kidney and cardiovascular outcomes in patients with and without a history of AFF.

Methods

Study design and participants

The study design of FIDELIO-DKD, an international, multicenter, phase III, randomized, double-blind, placebo-controlled, parallel-group, event-driven trial has been described in detail previously (14,17). Eligible patients were aged ≥18 years with clinically diagnosed T2D, and either moderately elevated albuminuria (defined as urine albumin-to-creatinine ratio [UACR] ≥30 to <300 mg/g), an estimated glomerular filtration rate (eGFR) ≥25 to <60 ml/min/1.73 m2, and a history of diabetic retinopathy, or severely elevated albuminuria (defined as UACR ≥300 to ≤5,000 mg/g) and an eGFR ≥25 to <75 ml/min/1.73 m2. Patients were required to have been treated with a maximum tolerated dose of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker according to the manufacturer’s label for at least 4 weeks before the screening visit and to have a serum potassium level of ≤4.8 mEq/l at the run-in and screening visits. Patients with known nondiabetic kidney disease, chronic symptomatic heart failure with reduced ejection fraction (New York Heart Association class II–IV), a recent history of dialysis for acute kidney failure or a kidney transplant, or uncontrolled hypertension were excluded. The trial was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the relevant regulatory authorities and ethics committees at each trial site, and written informed consent was obtained from all participants. The study is registered with the European Union Clinical Trials Register ( EudraCT 2015-000990-11) and ClinicalTrials.gov ( NCT02540993).

Procedures and outcomes

Patients were randomly assigned (1:1) to receive once-daily oral treatment with finerenone (10 or 20 mg) or matching placebo. Randomization was stratified by region (North America, Europe, Asia, Latin America, other), albuminuria at screening (moderately increased, severely increased), and eGFR at screening (25 to <45, 45 to <60, ≥60 ml/min/1.73 m2). Electrocardiograms (ECGs; 12-lead) were performed at run-in, screening, and baseline visits and annually thereafter, as well as on an ad hoc basis if potassium levels were severely elevated or if there was another clinical need. New-onset of AFF was a pre-specified exploratory outcome defined as newly detectable AFF (verified through ECGs, electrophysiology study, exercise ECG, or echocardiogram) in patients without a prior medical history of AFF and with irregular ventricular rate and rhythm, and an absence of P-waves, or the presence of sawtooth flutter waves, particularly in leads II, III, and aVF; variable P-wave morphology that was re-entrant source dependent and a regular atrial rate of 250 to 350/min, with variation in conduction of impulses to the ventricles. For this analysis, outcomes were assessed in a time-to-event analysis based on the following outcomes: 1) number of patients with and time to new-onset AFF; 2) key subgroup analysis for time to new-onset AFF; 3) incidence of AFF by medical history and baseline ECG; 4) impact of finerenone versus placebo on the primary composite kidney outcome (time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes), key secondary composite cardiovascular outcome (time to first onset of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), secondary composite kidney outcome (time to first onset of kidney failure, a sustained decrease of ≥57% in eGFR from baseline [equivalent to a doubling of the serum creatinine level], or death from renal causes), all-cause mortality, all-cause hospitalization, and the change in UACR from baseline to month 4 in patients with a history of AFF at baseline compared with those without; and 5) time to new-onset AFF in the subgroups by change from baseline to month 4 in serum potassium. The history of AFF was determined by the investigator. Investigator-reported new-onset AFF events were prospectively adjudicated by cardiologists from an independent clinical event committee blinded to treatment assignment.

Statistical analysis

Efficacy analyses were performed in the full analysis set comprising all randomly assigned patients without critical Good Clinical Practice violations. Baseline characteristics of patients, grouped by history of AFF status, were reported in mean ± SD, medians, and interquartile ranges or percentages. Events were reported from randomization up to the end-of-study visit. Patients without an event were censored at the date of their last contact with complete information on all components of their respective outcomes. A log-rank test, stratified by region, eGFR, and albuminuria categories at screening was used to test the null hypothesis of equal hazards of the primary, secondary, and exploratory time-to-event efficacy outcomes in the finerenone and placebo groups. Treatment effects were expressed as hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) from a Cox proportional hazards model adjusted for stratification factors. The proportional hazards assumption for the stratified Cox model for time to new diagnosis of AFF was evaluated, including a time–treatment interaction term (time-log transformed). Additionally, medical history of AFF and its interaction with treatment was included in the model to test the independence of the treatment effect from medical history of AFF. Treatment effect on change in UACR from baseline to month 4 was assessed by analysis of covariance with factors treatment group, region, eGFR category at screening, type of albuminuria at screening, log-transformed baseline value as covariate nested within type of albuminuria, subgroup, and treatment group by subgroup interaction. A stratified Cox proportional hazards model, landmarked at the month 4 visit, was used to investigate the treatment effect on new-onset AFF in the subgroups by change from baseline to month 4 in serum potassium.

Results

Patients

A total of 5,734 patients were randomly assigned in the FIDELIO-DKD trial. After the prospective exclusion of 60 patients from all analyses, owing to violations of Good Clinical Practice, 5,674 patients were assessed in the full analysis set. Among the 5,674 patients, 461 (8.1%) had a history of AFF at baseline. Of these patients, 240 were treated with finerenone (equivalent to 8.5% of all patients in the finerenone group) and 221 were treated with matching placebo (equivalent to 7.8% of all patients in the placebo group). Patients with a history of AFF were more likely to be older, male, White, with a history of cardiovascular disease, higher body mass index, higher waist circumference, higher level of C-reactive protein, and lower median UACR than those without a history of AFF (Table 1). In contrast, blood pressure, eGFR, glycated hemoglobin, and duration of diabetes were similar in patients with and without a history of AFF. Patients with a history of AFF were more likely to be receiving concomitant beta-blockers, loop diuretics, potassium supplements, antithrombotic agents, and direct oral anticoagulants. In contrast, patients without a history of AFF were more likely to be treated with aspirin and other antiplatelet therapies.

Table 1 Patient Baseline Characteristics Stratified by History of AFF at Baseline

Without History of AFF (n = 5,213)With History of AFF (n = 461)
Age, y65.1 ± 9.170.3 ± 7.7
Male3,615 (69.3)368 (79.8)
Race
 White3,196 (61.3)396 (85.9)
 Black/African American256 (4.9)8 (1.7)
 Asian1,398 (26.8)42 (9.1)
Systolic blood pressure, mm Hg138.1 ± 14.4137.5 ± 14.2
Diastolic blood pressure, mm Hg75.8 ± 9.775.9 ± 9.5
BMI, kg/m231.0 ± 6.032.4 ± 5.9
Duration of diabetes, y16.5 ± 8.716.9 ± 9.3
HbA1c, %7.69 ± 1.357.46 ± 1.23
Serum potassium, mEq/l4.38 ± 0.464.26 ± 0.48
eGFR, mL/min/1.73 m244.4 ± 12.643.9 ± 12.0
eGFR, mL/min/1.73 m2
 <25121 (2.3)14 (3.0)
 25 to <452,730 (52.4)251 (54.4)
 45 to <601,754 (33.6)146 (31.7)
 ≥60606 (11.6)50 (10.8)
UACR, mg/g858 (447‒1,659)801 (416‒1,439)
UACR, mg/g
 <3022 (0.4)1 (0.2)
 30 to <300631 (12.1)54 (11.7)
 ≥3004,557 (87.4)406 (88.1)
Mean waist–hip ratio1.00 ± 0.121.01 ± 0.09
Waist circumference, cm106.3 ± 15.1112.3 ± 15.0
CRP, mg/l4.5 ± 9.05.5 ± 9.3
Heart rate, beats/min72.4 ± 11.370.3 ± 12.5
History of CVD
 Yes2,319 (44.5)286 (62.0)
 No2,894 (55.5)175 (38.0)
Current smoker760 (14.6)46 (10.0)
Medication use at baseline
 Angiotensin-converting enzyme inhibitors1,742 (33.4)200 (43.4)
 Angiotensin receptor blockers3,465 (66.5)260 (56.4)
 Beta-blockers2,610 (50.1)358 (77.7)
 Diuretics2,887 (55.4)327 (70.9)
  Loop diuretics1,407 (27.0)212 (46.0)
  Thiazide diuretics1,240 (23.8)115 (24.9)
 Statins3,864 (74.1)351 (76.1)
 Potassium supplements131 (2.5)39 (8.5)
 Potassium-lowering agents129 (2.5)7 (1.5)
 Glucose-lowering therapies5,079 (97.4)445 (96.5)
  Insulin and analogs3,369 (64.6)268 (58.1)
  Metformin2,295 (44.0)195 (42.3)
  Sulfonylureas1,222 (23.4)105 (22.8)
  DPP-4 inhibitors1,402 (26.9)120 (26.0)
  GLP-1RAs362 (6.9)32 (6.9)
  SGLT-2 inhibitors235 (4.5)24 (5.2)
 Antithrombotic medications
  Antithrombotic agents3,145 (60.3)425 (92.2)
  Aspirin2,652 (50.9)131 (28.4)
  Antiplatelet therapy3,051 (58.5)171 (37.1)
  DOACs30 (0.6)163 (35.4)

Values are mean ± SD, n (%), or median (interquartile range). Full analysis set.

Medical history of AFF was determined by the investigator.

AFF = atrial fibrillation or flutter; BMI = body mass index; CRP = C-reactive protein; CVD = cardiovascular disease; DOAC = direct oral anticoagulant; DPP-4 = dipeptidyl peptidase-4; eGFR = estimated glomerular filtration rate; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated hemoglobin; SGLT-2 = sodium-glucose co-transporter-2; UACR = urine albumin-to-creatinine ratio.

∗ Missing data for n ≤ 14 patients.

† Missing data for n ≤ 3 patients without a history of AFF.

Baseline ECG data were available for 5,668 (99.9%) patients. There were 251 patients with AFF detected at baseline ECG and 5,423 patients in whom AFF was not detected at baseline ECG. A comparison of baseline characteristics for patients with and without AFF detected at baseline ECG revealed a similar pattern to that observed between patients with and without a prior history of AFF (Supplemental Table 1).

Of the 461 patients with a history of AFF, 234 (50.8%) also had AFF on baseline ECG. In contrast, of the 5,213 patients without a history of AFF, there were 17 (0.3%) with AFF detected on baseline ECG (Table 2). The numbers of patients with a history of AFF and with AFF detected by baseline ECG were balanced by treatment groups (Supplemental Table 2).

Table 2 Relations Between History of AFF and Presence of AFF at the Time of Randomization as Determined by ECG (N = 5,674)

AFF by Baseline ECGHistory of AFF
YesNo
Yes234 (4.1)17 (0.3)
No227 (4.0)5,196 (91.6)

Values are n (%). Full analysis set.

ECG = electrocardiogram; other abbreviation as in Table 1.

Effect of finerenone on new-onset of AFF

The median follow-up was 2.6 years (interquartile range: 2.0 to 3.4 years) in the full analysis set. In the overall population, the prevalence of AFF was reported in 273 patients by investigators as an adverse or outcome event. The prevalence of AFF events in the overall population was lower with finerenone compared with placebo (120 [4.2%] patients vs 153 [5.4%] patients, respectively). Atrial flutter was infrequent in both groups (Table 3).

Table 3 Prevalence of Components of AFF Events in the Overall Population

Finerenone (n = 2,833)Placebo (n = 2,841)Total (N = 5,674)
AFF120 (4.2)153 (5.4)273 (4.8)
Atrial fibrillation104 (3.7)137 (4.8)241 (4.2)
Atrial flutter16 (0.6)16 (0.6)32 (0.6)

Values are n (%). Full analysis set.

Abbreviation as in Table 1.

The incidence for adjudicated new-onset AFF in patients without a history of AFF was significantly lower with finerenone than with placebo (82 of 2,593 [3.2%] vs 117 of 2,620 [4.5%] patients, respectively; incidence per 100 patient-years: 1.20 and 1.72, respectively; HR: 0.71; 95% CI: 0.53–0.94; p = 0.0164). As shown by the Kaplan–Meier curve (Figure 1), a gradual separation in treatment effect was observed between finerenone and placebo, which was evident at 6 months, followed by a consistent divergence throughout the duration of the trial. There was no evidence of a violation of the proportional hazards assumption. The lower incidence of new-onset AFF with finerenone in patients without a history of AFF was generally consistent across subgroups for sex, age, body mass index, history of cardiovascular disease, baseline systolic blood pressure, baseline UACR, and baseline serum potassium (Figure 2), and there was no indication of heterogeneity in treatment effect on new-onset AFF landmarked at month 4 across different levels of serum potassium change from baseline to month 4 (p value for interaction: 0.65) (Supplemental Figure 1).

Figure 1
Figure 1

Time to New-Onset of AFF in Patients Without a History of AFF

Incidence of new-onset atrial fibrillation or flutter (AFF) was assessed in a time-to-event analysis. The Kaplan–Meier curve shows that the risk of new-onset AFF was lower with finerenone (blue line) in patients without a history of AFF compared with those in the placebo group (red dashed line). This effect was evident at 6 months, followed by a consistent divergence throughout the trial (full analysis set in patients without a history of AFF). CI = confidence interval; HR = hazard ratio; PY = patient-years.

Figure 2
Figure 2

New-Onset AFF in Prespecified Patient Subgroups

Incidence of new-onset AFF by prespecified subgroups was analyzed using a stratified Cox proportional hazards model. The forest plot shows the risk of new-onset AFF being consistently lower across these patient subgroups (full analysis set in patients without a history of AFF). BMI = body mass index; eGFR = estimated glomerular filtration rate; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated hemoglobin; SBP = systolic blood pressure; SGLT-2i = sodium-glucose co-transporter-2 inhibitor; UACR = urine albumin-to-creatinine ratio; other abbreviations as in Figure 1.

Effect of finerenone on the kidney and cardiovascular composite outcomes according to history of AFF

The overall incidence of the primary kidney outcome (composite of time to first onset of kidney failure, a sustained decrease of ≥40% in eGFR from baseline, or death from renal causes) was significantly lower with finerenone than with placebo (504 [17.8%] patients vs 600 [21.1%] patients, respectively; HR: 0.82; 95% CI: 0.73–0.93; p = 0.001). Patients with a medical history of AFF had a lower risk of the primary kidney outcome (placebo incidence per 100 patient-years: 6.75 in patients with a history of AFF compared with 9.28 in patients without a history of AFF). There was no significant difference in the effect of finerenone between patients with and without a history of AFF (HR: 1.13; 95% CI: 0.71–1.79 and HR: 0.81; 95% CI: 0.71–0.91, respectively; p value for interaction = 0.16) (Figure 3). Similarly, there were significantly fewer patients with events for the key secondary cardiovascular outcome (composite of time to first onset of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) with finerenone compared with placebo (367 [13.0%] patients vs 420 [14.8%] patients, respectively; HR: 0.86; 95% CI: 0.75–0.99; p = 0.034). An elevated risk of the key secondary cardiovascular outcome was observed in patients with a history of AFF (placebo incidence per 100 patient-years: 12.86 in patients with a history of AFF compared with 5.38 patients without a history of AFF). Nevertheless, the effect of finerenone was found to be consistent for patients with and without a history of AFF (HR: 0.88; 95% CI: 0.62–1.24 and HR: 0.85; 95% CI: 0.73–0.99, respectively; p value for interaction = 0.85) (Figure 3).

Figure 3
Figure 3

Outcomes According to History of AFF

Primary kidney outcome, key secondary cardiovascular outcome, secondary composite kidney outcome, all-cause mortality, all-cause hospitalization, and ratio of UACR at month 4 to baseline were analyzed using a stratified Cox proportional hazards model. The forest plot shows that incidence of all outcomes were consistently lower in patients treated with finerenone, irrespective of history of AFF, compared with patients in the placebo group (full analysis set). gmean = geometric mean; other abbreviations as in Figures 1 and 2.

Further investigations showed that the risk of fatal or nonfatal stroke was elevated after a new-onset of AFF. The results from a stratified Cox proportional hazards model for stroke with a new-onset AFF index event, modeled as a time-dependent covariate, indicated an approximately 7-fold increased risk of stroke after new-onset of AFF (HR: 7.13; 95% CI: 4.01–12.70). Occurrence of the secondary composite kidney outcome (time to first onset of kidney failure, a sustained decrease of ≥57% in eGFR from baseline [equivalent to a doubling of the serum creatinine level], or death from renal causes) was also lower in the overall population with finerenone compared with placebo (HR: 0.76; 95% CI: 0.65–0.90) and was not modified by history of AFF (HR: 0.71; 95% CI: 0.34–1.48 for patients with AFF and HR: 0.76; 95% CI: 0.65–0.91 for patients without AFF; p value for interaction = 0.85) (Figure 3). Additionally, the reduction in UACR as a ratio to baseline at month 4 (ratio of least-squares mean: 0.69; 95% CI: 0.66–0.72 in the overall population) was consistent irrespective of history of AFF (ratio of least-squares mean, 0.69; 95% CI: 0.67–0.72 for patients without a history of AFF and ratio of least-squares mean: 0.64; 95% CI: 0.55–0.73 for patients with a history of AFF; p value for interaction = 0.22). The effects of finerenone on all-cause mortality and all-cause hospitalization were consistent in patients with and without a history of AFF (Figure 3).

Concomitant treatment for new-onset AFF was provided for 60 patients in the finerenone group and 83 in the placebo group. Treatment with cardiac therapy, as defined by the Anatomical Therapeutic Chemical classification system, in these patients was balanced for finerenone and placebo (22 of 82 [26.8%] and 35 of 117 [29.9%], respectively), and a higher proportion of patients in the finerenone group were treated with antithrombotic agents (47 of 82 [57.3%] for finerenone and 57 of 117 [48.7%] for placebo) (Supplemental Table 3).

Discussion

This pre-specified exploratory analysis of the FIDELIO-DKD trial indicates that finerenone lowers the incidence of new-onset AFF in patients with CKD and T2D. The lower incidence of new-onset AFF with finerenone compared with placebo was notable at month 6 and continued throughout the trial, suggesting a sustained effect. A similar observation was reported in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial, in which the incidence of new-onset AFF was decreased by treatment with the steroidal MRA eplerenone in a different population of patients with symptomatic heart failure with reduced ejection fraction, who were excluded from the FIDELIO-DKD trial (12). In contrast, a post hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial showed that spironolactone did not reduce the risk of either new-onset atrial fibrillation or atrial fibrillation recurrence in patients with symptomatic heart failure with preserved ejection fraction (13). Differences between these and the present findings may be partly because of the different patient populations studied. Whether finerenone will also lead to a reduction in new-onset AFF in patients with heart failure with preserved ejection fraction is currently being studied in the ongoing FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure) trial (18).

A potential mechanism explaining the benefit of finerenone on new-onset AFF is the attenuation of adverse atrial remodeling associated with CKD or T2D by the inhibition of aldosterone activity (9,10,16). CKD was associated with atrial structural remodeling that led to atrial fibrillation in a murine model (5). T2D may further predispose patients to atrial fibrillation through atrial electrical and structural remodeling triggered by increased reactive oxygen species or advanced glycation end-products (6). Patients with atrial fibrillation have been found to have increased atrial mineralocorticoid receptor expression compared with those with normal sinus rhythm, and preclinical studies have shown that inhibition of mineralocorticoid receptor prevented fibrotic remodeling of the atrial myocardium via interfering with the small guanosine-5’-triphosphatase Rac1 (10,11). Transgenic mice with cardiac-specific overexpression of Rac1 develop an age-dependent phenotype with atrial dilatation, fibrosis, and atrial fibrillation (19). In cardiac fibroblasts, finerenone completely prevented aldosterone/mineralocorticoid receptor-induced expression of the key profibrotic mediator connective tissue growth factor and the collagen crosslinking enzyme lysyl oxidase, as well as microRNA-21, which enhances myocardial remodeling and fibrosis (16). Furthermore, finerenone attenuated left atrial and left ventricular dilatation and significantly reduced mineralocorticoid receptor overactivation–mediated protein expression of transforming growth factor–beta and collagen 3 alpha 1, as well as fibrosis in transgenic mice with cardiac-specific overexpression of Rac1 (16). Taken together, these preclinical data suggest that the mineralocorticoid receptor plays a key role in the development of cardiac fibrosis and remodeling and that finerenone has demonstrated inhibitory activity against these processes.

Atrial fibrillation is a major and growing public health problem, with heart failure reported in 20% to 30% of patients (2). It is also associated with a 5-fold increase in the risk of stroke and up to 3.5-fold increase in the risk of death (2). The increasing burden of atrial fibrillation is, at least in part, related to the increase in age-associated predisposing conditions such as CKD and T2D (20). This would appear to be the case when comparisons were drawn between the FIDELIO-DKD and the TOPCAT trials, where a higher incidence of new-onset AFF was observed in the placebo arm of the FIDELIO-DKD trial (1.72 per 100 patient-years) compared with the placebo arm of the TOPCAT trial (1.33 per 100 patient-years) (13). Indeed, CKD increased the incidence of atrial fibrillation in the large population-based Atherosclerosis Risk In Communities study conducted in the United States (3). T2D also increases the risk of atrial fibrillation, despite good control of glycemia and albuminuria, and this is further exacerbated by the coexistence of impaired kidney function (4). Therefore, therapies that have kidney-protective and cardioprotective properties may be effective in reducing the burden of AFF in patients with T2D; this was demonstrated here with finerenone and reported by others with glucose-lowering sodium glucose co–transporter-2 inhibitors (21–23). In addition to a reduction in the risk of new-onset AFF, the previously reported kidney-protective and cardioprotective effects of finerenone in these patients with CKD and T2D were shown here to be consistent in patients with or without a history of AFF (14,15).

The process of atrial electrical, structural, and functional remodeling, collectively called atrial disease or atrial myopathy, that provides the substrate for the development of atrial fibrillation seems to be triggered by different cardiac and extracardiac morbidities, including heart failure with reduced ejection fraction, T2D, and CKD (24,25). This may partly explain the reduction in incidence of atrial fibrillation that was observed in the FIDELIO-DKD trial. Data from the ongoing FINEARTS-HF trial may clarify the different outcomes in new-onset AFF observed between finerenone in this study and that reported with spironolactone in the TOPCAT trial. In this regard, atrial disease has been proposed as the intersect of the pathogenetic processes leading to atrial fibrillation, heart failure with preserved ejection fraction, and perhaps thromboembolism, all of which coexist frequently (26). As a result, targeting atrial derangement at an early stage of development with drugs such as finerenone may result in the prevention of downstream conditions and the improvement of overall outcomes in high-risk patients (27). The present and previous findings are a positive step in this direction, but further prospective clinical research is required to test the hypothesis.

Study limitations

This is a secondary analysis of a randomized controlled trial with a low number of new-onset AFF events and, therefore, its findings should be interpreted with caution. One limitation is the possibility that clinically silent or asymptomatic cases of new-onset AFF may have been missed, given that: 1) the history of AFF was determined by investigators only at the start of the trial; and 2) 12-lead ECGs were only performed annually after the start of the trial unless there was a clinical need.

Conclusions

Among patients with CKD and T2D, finerenone reduced the risk of new-onset AFF. In addition, finerenone reduced the risk of kidney or cardiovascular events, with no significant differences between patients with and without a history of AFF at baseline (Central Illustration).

Central Illustration
Central Illustration

New-Onset AFF and Cardiorenal Outcomes by AFF History in FIDELIO-DKD

In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) trial, finerenone significantly lowered the incidence of new-onset atrial fibrillation or flutter (AFF) in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Finerenone also reduced the risk of kidney and cardiovascular outcomes irrespective of history of AFF at baseline. The observed effects of finerenone to lower new-onset AFF in this analysis may be via the reduction of mineralocorticoid receptor-mediated cardiac remodeling. CI = confidence interval; CV = cardiovascular; NS = not significant.

Perspectives

COMPETENCY IN PATIENT CARE: Treatment with the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone was associated with a lower incidence of newly detected atrial fibrillation in patients with CKD and T2D.

TRANSLATIONAL OUTLOOK: Future research should assess the long-term clinical outcomes of treatment with finerenone in patients with CKD and T2D, including its impact on stroke and other cardiovascular events and survival.

Funding Support and Author Disclosures

The FIDELIO-DKD trial was conducted and funded by Bayer AG, Berlin, Germany. Analyses were conducted by the sponsor, and all authors had access to and participated in the interpretation of the data. Dr. Filippatos has received lectures fees and/or that he is a committee member of trials and registries sponsored by Bayer, Novartis, Vifor Pharma, Medtronic, Servier, Amgen, and Boehringer Ingelheim; is a senior consulting editor for JACC: Heart Failure; and has received research support from the European Union. Dr. Bakris has received research funding, paid to the University of Chicago Medicine, from Bayer, during the conduct of the study; has received research funding, paid to the University of Chicago Medicine, from Novo Nordisk and Vascular Dynamics; has acted as a consultant and received personal fees from for Merck, Relypsa, and Alnylam Pharmaceuticals; is an editor of American Journal of Nephrology, Nephrology, and Hypertension, and section editor of UpToDate; and is an associate editor of Diabetes Care and Hypertension Research. Dr. Pitt has received consultant fees for Bayer, AstraZeneca, Sanofi/Lexicon, scPharmaceuticals, SQ Innovation, G3 Pharmaceuticals, Sarfez Pharmaceutical, Inc., PhaseBio, Vifor Pharma/Relypsa, Cereno Scientific, Ardelyx, KBP Biosciences, Boehringer Ingelheim, Brainstorm Medical, and Tricida; has stock options for Ardelyx, KBP Biosciences, SQ Innovation, Sarfez Pharmaceutical, scPharmaceuticals, Cereno Scientific, G3 Pharmaceuticals, Vifor Pharma/Relypsa, Brainstorm Medical, and Tricida; and also holds a patent for site-specific delivery of eplerenone to the myocardium (US patent #9931412) and a provisional patent for histone-acetylation-modulating agents for the treatment and prevention of organ injury (provisional patent US 63/045,784). Dr. Agarwal has received personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals during the conduct of the study; has received personal fees and nonfinancial support from Akebia Therapeutics, Janssen, Relypsa, Vifor Pharma, Boehringer Ingelheim, Sanofi, Eli Lilly and Company, AstraZeneca, and Fresenius; has received personal fees from Ironwood Pharmaceuticals, Merck & Co., Lexicon, and Reata Pharmaceuticals; has received nonfinancial support from Otsuka America Pharmaceutical, OPKO Health, and E. R. Squibb & Sons; is a member of data safety monitoring committees for Amgen, AstraZeneca, and Celgene; is a member of steering committees of randomized trials for Akebia Therapeutics, Bayer, Janssen, and Relypsa Inc.; is a member of adjudication committees for AbbVie, Bayer, Boehringer Ingelheim, and Janssen; has served as associate editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation and has been an author for UpToDate; and has received research grants from the U.S. Veterans Administration and the National Institutes of Health. Dr. Rossing has received personal fees from Bayer, during the conduct of the study; has received research support and personal fees from AstraZeneca and Novo Nordisk; and has received personal fees from Eli Lilly and Company, Boehringer Ingelheim, Astellas Pharma, Gilead, Mundipharma, Sanofi, and Vifor Pharma. All fees are given to Steno Diabetes Center Copenhagen. Dr. Butler serves as a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, V-Wave, and Vifor Pharma. Dr. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/ Executive Committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research & Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as co-founder and non-executive director of Us2.ai. Dr. Kolkhof is a full-time employee of Bayer AG, Division Pharmaceuticals, Germany; and is the co-inventor of finerenone and holds U.S. and European patents relating to finerenone (US8436180B2 and EP2132206B1). Dr. Roberts is a full-time employee of Bayer PLC, GD Medical, Great Britain. Drs. Tasto and Joseph are full-time employees of Bayer AG, Division Pharmaceuticals, Germany. Dr. Anker has received research support from Abbott Vascular and Vifor Pharma; and has received personal fees from Abbott Vascular, Boehringer Ingelheim, Bayer, BRAHMS, Novartis, Servier, Vifor Pharma, Impulse Dynamics, and Cardiac Dimensions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

AFF

atrial fibrillation or flutter

CI

confidence interval

CKD

chronic kidney disease

ECG

electrocardiogram

eGFR

estimated glomerular filtration rate

HR

hazard ratio

MRA

mineralocorticoid receptor antagonist

T2D

type 2 diabetes

UACR

urine albumin-to-creatinine ratio

  • 1. Xu J., Luc J.G., Phan K. "Atrial fibrillation: review of current treatment strategies". J Thorac Dis 2016;8:E886-E900.

    CrossrefMedlineGoogle Scholar
  • 2. Hindricks G., Potpara T., Dagres N., et al. "2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)". Eur Heart J 2021;42:373-498.

    CrossrefMedlineGoogle Scholar
  • 3. Alonso A., Lopez F.L., Matsushita K., et al. "Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study". Circulation 2011;123:2946-2953.

    CrossrefMedlineGoogle Scholar
  • 4. Seyed Ahmadi S., Svensson A.M., Pivodic A., Rosengren A., Lind M. "Risk of atrial fibrillation in persons with type 2 diabetes and the excess risk in relation to glycaemic control and renal function: a Swedish cohort study". Cardiovasc Diabetol 2020;19:9.

    CrossrefMedlineGoogle Scholar
  • 5. Qiu H., Ji C., Liu W., et al. "Chronic kidney disease increases atrial fibrillation inducibility: involvement of inflammation, atrial fibrosis, and connexins". Front Physiol 2018;9:1726.

    CrossrefMedlineGoogle Scholar
  • 6. Bohne L.J., Johnson D., Rose R.A., Wilton S.B., Gillis A.M. "The association between diabetes mellitus and atrial fibrillation: clinical and mechanistic insights". Front Physiol 2019;10:135.

    CrossrefMedlineGoogle Scholar
  • 7. Echouffo-Tcheugui J.B., Shrader P., Thomas L., et al. "Care patterns and outcomes in atrial fibrillation patients with and without diabetes: ORBIT-AF registry". J Am Coll Cardiol 2017;70:1325-1335.

    View ArticleGoogle Scholar
  • 8. Stroke Risk in Atrial Fibrillation Working Group. "Independent predictors of stroke in patients with atrial fibrillation: a systematic review". Neurology 2007;69:546-554.

    CrossrefMedlineGoogle Scholar
  • 9. Reil J.C., Hohl M., Selejan S., et al. "Aldosterone promotes atrial fibrillation". Eur Heart J 2012;33:2098-2108.

    CrossrefMedlineGoogle Scholar
  • 10. Lavall D., Selzer C., Schuster P., et al. "The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation". J Biol Chem 2014;289:6656-6668.

    CrossrefMedlineGoogle Scholar
  • 11. Tsai C.T., Chiang F.T., Tseng C.D., et al. "Increased expression of mineralocorticoid receptor in human atrial fibrillation and a cellular model of atrial fibrillation". J Am Coll Cardiol 2010;55:758-770.

    View ArticleGoogle Scholar
  • 12. Swedberg K., Zannad F., McMurray J.J., 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;59:1598-1603.

    View ArticleGoogle Scholar
  • 13. Neefs J., van den Berg N.W.E., Krul S.P.J., Boekholdt S.M., de Groot J.R. "Effect of spironolactone on atrial fibrillation in patients with heart failure with preserved ejection fraction: post-hoc analysis of the randomized, placebo-controlled TOPCAT trial". Am J Cardiovasc Drugs 2020;20:73-80.

    CrossrefMedlineGoogle Scholar
  • 14. Bakris G.L., Agarwal R., Anker S.D., et al. "Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes". N Engl J Med 2020;383:2219-2229.

    CrossrefMedlineGoogle Scholar
  • 15. Filippatos G., Anker S.D., Agarwal R., et al. "Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes". Circulation 2021;143:540-552.

    CrossrefMedlineGoogle Scholar
  • 16. Lavall D., Jacobs N., Mahfoud F., Kolkhof P., Bohm M., Laufs U. "The non-steroidal mineralocorticoid receptor antagonist finerenone prevents cardiac fibrotic remodeling". Biochem Pharmacol 2019;168:173-183.

    CrossrefMedlineGoogle Scholar
  • 17. Bakris G.L., Agarwal R., Anker S.D., et al. "Design and baseline characteristics of the finerenone in reducing kidney failure and disease progression in diabetic kidney disease trial". Am J Nephrol 2019;50:333-344.

    CrossrefMedlineGoogle Scholar
  • 18. Bayer. "Study to evaluate the efficacy (effect on disease) and safety of finerenone on morbidity (events indicating disease worsening) and mortality (death rate) in participants with heart failure and left ventricular ejection fraction (proportion of blood expelled per heart stroke) greater or equal to 40% (FINEARTS-HF)". 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT04435626. Accessed April 20, 2021.

    Google Scholar
  • 19. Lavall D., Schuster P., Jacobs N., Kazakov A., Bohm M., Laufs U. "Rac1 GTPase regulates 11beta hydroxysteroid dehydrogenase type 2 and fibrotic remodeling". J Biol Chem 2017;292:7542-7553.

    CrossrefMedlineGoogle Scholar
  • 20. Lane D.A., Skjøth F., Lip G.Y.H., Larsen T.B., Kotecha D. "Temporal trends in incidence, prevalence, and mortality of atrial fibrillation in primary care". J Am Heart Assoc 2017;6:e005155.

    CrossrefMedlineGoogle Scholar
  • 21. Li W.J., Chen X.Q., Xu L.L., Li Y.Q., Luo B.H. "SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: a systematic review with meta-analysis of 16 randomized controlled trials". Cardiovasc Diabetol 2020;19:130.

    CrossrefMedlineGoogle Scholar
  • 22. Ling A.W., Chan C.C., Chen S.W., et al. "The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors". Cardiovasc Diabetol 2020;19:188.

    CrossrefMedlineGoogle Scholar
  • 23. Zelniker T.A., Bonaca M.P., Furtado R.H.M., et al. "Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights from the DECLARE-TIMI 58 trial". Circulation 2020;141:1227-1234.

    CrossrefMedlineGoogle Scholar
  • 24. Shen M.J., Arora R., Jalife J. "Atrial myopathy". J Am Coll Cardiol Basic Trans Sci 2019;4:640-654.

    View ArticleGoogle Scholar
  • 25. Farmakis D., Chrysohoou C., Giamouzis G., et al. "The management of atrial fibrillation in heart failure: an expert panel consensus". Heart Fail Rev 2020.

    CrossrefGoogle Scholar
  • 26. Reddy Y.N.V., Borlaug B.A. "Left atrial myopathy in heart failure with preserved ejection fraction". Eur J Heart Fail 2020;22:486-488.

    CrossrefMedlineGoogle Scholar
  • 27. Patel R.B., Shah S.J. "Therapeutic targeting of left atrial myopathy in atrial fibrillation and heart failure with preserved ejection fraction". JAMA Cardiol 2020;5:497-499.

    CrossrefMedlineGoogle Scholar

Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

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.