Abstract
Background
Hypertension and coronary artery disease (CAD) are predominant factors of heart failure (HF). The American College of Cardiology/American Heart Association and the Japanese Circulation Society/Japanese Heart Failure Society stages of HF emphasize the development and progression of disease, and advanced stages and progression are associated with reduced survival. In patients with new-onset or worsening HF, albuminuria is consistently associated with clinical and circulating biomarkers of congestion. Esaxerenone is an oral, non-steroidal, selective mineralocorticoid receptor antagonist. It has not been elucidated whether esaxerenone reduces the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients concomitant with HF and albuminuria.
Methods and Results
The ESPIAL trial (jRCTs 051210066) is a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study to evaluate whether esaxerenone reduces UACR in hypertensive patients concomitant with HF and albuminuria. This study enrolled hypertensive patients concomitant with HF and albuminuria. The patients were randomized to an esaxerenone group or an amlodipine group in a 1 : 1 ratio. The primary outcome was the ratio of UACR before treatment and 24 weeks after treatment.
Conclusions
The ESPIAL trial evaluates the effect of esaxerenone on reduction of UACR in hypertensive patients concomitant with HF and albuminuria.
Key Words: Albuminuria, Heart failure, Hypertension, Mineralocorticoid receptor antagonist, Urinary albumin to creatinine ratio
Hypertension and coronary artery disease (CAD) are predominant factors of heart failure (HF).1 The American College of Cardiology/American Heart Association and Japanese Circulation Society/Japanese Heart Failure Society stages of HF emphasize the development and progression of disease, and advanced stages and progression are associated with reduced survival. Therapeutic interventions at each stage aim to modify risk factors including hypertension (stage A), treat risk and structural heart disease to prevent HF (stage B), and reduce symptoms, morbidity, and mortality (stages C and D).2–6
In the RALES (Randomized Aldactone Evaluation Study) trial, spironolactone significantly reduced all-cause mortality and HF hospitalization compared with the placebo.7 In the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, spironolactone significantly reduced albuminuria compared with the placebo. Furthermore, albuminuria was independently associated with worse cardiovascular outcomes, and reducing albuminuria was independently associated with improved outcomes.8 In the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) study, eplerenone, as compared with a placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic HF and mild symptoms.9 In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) trial, in patients with chronic kidney disease (CKD) and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events.10 Also, in the FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trial, among patients with type 2 diabetes and stage 2–4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes.11
Urinary albumin-to-creatinine ratio (UACR) was one of the 2 biomarkers that was significantly associated with incident HF with preserved ejection function (HFpEF), and the other was natriuretic peptides, in the study including 4 longitudinal community-based cohorts: the Cardiovascular Health Study, the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Prevention of Renal and Vascular End-stage Disease study.12 Several studies have reported the usefulness of natriuretic peptides for evaluating HF,13–16 and we have reported that UACR could be a new useful biomarker to predict HF rehospitalization in patients with acute decompensated HF (ADHF), especially in combination with the levels of B-type natriuretic peptide (BNP).17 Hence, UACR is attracting attention as one of the important markers of cardiovascular events, especially incident and worsening HF.
Esaxerenone, a non-steroidal, selective mineralocorticoid receptor antagonist (MRA), was developed by Daiichi Sankyo Co., Ltd., Japan for the treatment of hypertension and diabetic nephropathies.18 In January 2019, based on positive results from a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval in Japan for the treatment of hypertension.19,20
As it has not yet been elucidated whether esaxerenone reduces UACR in hypertensive patients concomitant with HF and albuminuria, we studied whether esaxerenone reduces UACR in hypertensive patients concomitant with HF and albuminuria by conducting the ESPIAL (A prospective, randomized, exploratory study to evaluate the effect of ESaxerenone on reduction of urinary albumin to creatinine ratio in hyPertensive patients concomitant with heart faIlure and ALbuminuria) trial, a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study.
Methods
Study Design
To evaluate the effect of esaxerenone on the reduction of UACR in hypertensive patients concomitant with HF and albuminuria, we conducted the multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study known as ESPIAL (Japan Registry of Clinical Trials [jRCT] identifier jRCTs051210066).
This study was performed according to the Declaration of Helsinki, and in compliance with the Clinical Trials Act in Japan. The certified review board (CRB) at Hyogo College of Medicine approved this trial (CRB5200003), and from 2023 the Kobe City Hospital Organization CRB (CRB5220001) succeeded operation of the CRB. The enrolment period was from August 17, 2021 to May 31, 2024. The trial is funded by investigator-initiated research grants from Daiichi Sankyo Co., Ltd., Japan.
Study Population
The eligibility criteria are summarized in Table 1. Briefly, this study enrolled hypertensive patients concomitant with HF and albuminuria, aged 20–90 years, who were prescribed with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Patients with albumin urea are defined as having a UACR >30 mg/g creatinine (Cre) at the time of screening.21 The definition of patients with HF is described in the Supplementary File.
Table 1.
Eligibility Criteria
| Inclusion criteria |
| Patients aged 20–90 years |
| Patients diagnosed with hypertension |
| Patients diagnosed with HF |
| Patients have UACR >30 mg/g Cre |
| Use of ACEI, ARB, or compounds containing these |
| Patients who are capable of providing written consent |
| Exclusion criteria |
| Use of MRA for >7 days in the past 3 months |
| Use of amlodipine at maximum dose |
| Patients with serum potassium level >5.0 mmol/L |
| Patients taking potassium supplementation |
| Patients with renal impairment with an eGFR <30 mL/min/1.73 m2 |
| Patients with hepatic dysfunction with AST or ALT 3-fold of the upper limit of normal |
| Patients initiated with SGLT2 inhibitor within a month before consent |
| Patients who are pregnant, possibly pregnant, or breastfeeding |
| Patients who have been enrolled in other clinical studies at the same time as this study |
| Patients who are judged by the investigator or subinvestigators to not be suitable for participation in the study |
ACEI, angiotensin-converting enzyme inhibitor; ALT, alanine aminotransferase; ARB, angiotensin receptor antagonist; AST, aspartate aminotransferase; BNP, B-type natriuretic peptide; Cre, creatinine; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-Brain Natriuretic Peptide; NYHA, New York Heart Association; SGLT, sodium glucose transporter; UACR, urine albumin-to-creatinine ratio.
All patients provide written informed consent to participate in this trial. Patients are screened for eligibility, and after eligibility is confirmed, eligible patients are registered in the trial. After the acquisition of baseline data, patients are randomized to the esaxerenone group or the amlodipine group in a 1 : 1 ratio.
Treatment Protocol
Esaxerenone is started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Amlodipine is started at 2.5 or 5 mg/day and could be gradually increased to 10 mg/day on the basis of BP and blood test results. Prohibited concomitant drugs are all MRAs, except esaxerenone, during the trial.
Study Procedures
The schema of the trial is summarized in Table 2 and the Figure. Data collected in this trial are described in the Supplementary File.
Table 2.
Study Schema
| Visit 1 | Visit 2 | Visit 3 | Visit 4 | Visit 5 | Visit 6 | Visit 7 | |
|---|---|---|---|---|---|---|---|
| Period | Screening | Baseline | 2 weeks after treatment |
4 weeks after treatment |
12 weeks after treatment |
24 weeks after treatment |
48 weeks after treatment or early discontinuation |
| Allowance | From informed consent to patient enrollment |
From patient enrollment to the start of treatment |
5–22 days after treatment |
23–36 days after treatment |
56–112 days after treatment |
140–196 days after treatment |
280–392 days after treatment |
| Informed consent | X | ||||||
| Patient characteristics | X | ||||||
| Height | X | ||||||
| Weight | X | X | X | ||||
| Vital signs | X | X | X | X | X | X | X |
| NYHA classification | X | X | X | X | X | X | X |
| Leg edema | X | X | X | X | X | X | |
| Cause of HF | X | ||||||
| Blood or urine test (on site) | X | X | X | X | X | X | X |
| Blood or urine test (central) | X | X | X | X | X | X | X |
| Echocardiography | X | X | X | ||||
| 12-lead ECG | X | X | X | ||||
| Pre-medication | X | ||||||
| Concomitant medication | X | X | X | ||||
| Adherence | X | X | X | X | X | ||
| Clinical endpoints | *
|
||||||
| Adverse events | *
|
||||||
*After the initiation of the study treatment until the end of the study. ECG, electrocardiogram. Other abbreviations as in Table 1.
Figure.
Study schema. After the acquisition of baseline data, enrolled patients are randomized to the esaxerenone group or the amlodipine group in a 1 : 1 ratio. Patients are observed up to 48 weeks.
Study Endpoints
The primary outcome is the ratio of UACR before treatment and 24 weeks after treatment. Secondary endpoints are summarized in Table 3.
Table 3.
Primary and Secondary Outcomes
| Primary outcome |
| Ratio of UACR before treatment and 24 weeks after treatment |
| Secondary outcomes |
| Ratio of UACR before treatment and 48 weeks after treatment |
| Changes in the ratio of UACR over time from before treatment to after treatment (until 48 weeks after treatment) |
| Changes in UACR over time after treatment (until 48 weeks after treatment) |
| Patient proportion of normo-, micro- or macro-albuminuria classification (until 48 weeks after treatment) |
| Patient proportion of improved, unchanged or worsening albuminuria classification (24 weeks after treatment) |
| Changes in office blood pressure (24 weeks and 48 weeks after treatment) |
| Changes in eGFR over time after treatment (24 weeks and 48 weeks after treatment) |
| Changes in the ratio of eGFR over time before treatment and after treatment (24 weeks and 48 weeks after treatment) |
| Changes in urinary β2-microglobulin (24 weeks and 48 weeks after treatment) |
| Changes in urinary NGAL (24 weeks after treatment) |
| Changes in serum cystatin C (24 weeks after treatment) |
| Changes in serum NT-proBNP concentration (24 weeks and 48 weeks after treatment) |
| Changes in plasma aldosterone concentration (24 weeks after treatment) |
| Changes in plasma renin activity (24 weeks after treatment) |
| Changes in plasma arginine vasopressin (24 weeks after treatment) |
| Time to the occurrence of the composite endpoints (cardiac death or re-hospitalization due to HF) |
| Time to the occurrence of the composite endpoints (cardiac death or re-hospitalization due to cardiovascular disease) |
| Time to the occurrence of cardiac death |
| Time to the occurrence of re-hospitalization due to any cause |
| Time to the occurrence of re-hospitalization due to cardiovascular disease |
| Time to the occurrence of re-hospitalization due to HF |
| Time to the occurrence of the composite endpoints (non-fatal MI or non-fatal stroke and all-cause death) |
| Time to the occurrence of non-fatal MI |
| Time to the occurrence of non-fatal stroke |
| Time to the occurrence of all cause death |
| Time to the occurrence of sudden death |
| Changes in NYHA cardiac function class (24 weeks and 48 weeks after treatment) |
| Changes in LV ejection fraction measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in LV end diastolic diameter measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in LV mass index measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in left atrium diameter measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in left atrium volume measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in e′ measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in E/e′ measured by echocardiography (24 weeks and 48 weeks after treatment) |
| Changes in TRPG measured by echocardiography (24 weeks and 48 weeks after treatment) |
LV, left ventricular; MI, myocardial infarction; NGAL, neutrophil gelatinase-associated lipocalin; TRPG, tricuspid regurgitation pressure gradient; UACR, urinary albumin to creatinine ratio. Other abbreviations as in Table 1.
Statistical Analysis and Sample Size Calculation
In the analysis of patient characteristics, continuous variables will be summarized by mean (SD) or median (IQR). Categorical variables will be summarized by frequency distribution.
Efficacy analysis will be performed in the full analysis set, which consists of randomized subjects who received at least a portion of the assigned treatment protocol. In the analysis of the primary endpoint, log-transformed UACR at 24 weeks will be analyzed using the 2-way analysis of variance model with the treatment group (esaxerenone, amlodipine) and UACR at baseline (≥100 mg/g Cre; <100 mg/g Cre) as factors. The least squares means for each treatment group will be calculated. The difference in the least squares means between the treatment groups and its confidence interval will be calculated. These estimates will be exponentially transformed. The contrast test for the difference in the least squares means between the treatment groups will be performed. Missing values in the primary endpoints will be imputed by the last observation carried forward. A mixed model for repeated measures may be performed as a supplementary analysis for handling missing values. The analyses of the secondary endpoints are described in the Supplementary File. In all statistical tests, P values <0.05 (2-sided significance level) will be considered statistically significant. Safety data will be summarized using descriptive statistics.
The required sample size was calculated as 49 patients per treatment group (for a total of 98 patients) to achieve a power of 80% based on the 2-sample t-test at a 2-sided significance level of 5% for the group difference in the log-transformed values of UACR, assuming the group difference in the average of the log-transformed UACR to be −0.43078, and the standard deviation of the log-transformed UACR to be 0.75. These assumed values were derived from previous studies.22–24 The average value was derived as log(0.65/1.00)=−0.43078, where the ratio of UACR before treatment and 24 weeks after esaxerenon treatment was 0.65, and 1 after the standard of care treatments. Assuming that the UACR values follow a log-normal distribution, the standard deviation of the change from baseline in the log-transformed UACR was estimated to be 0.75.
Discussion
The ESPIAL trial is a multicenter, randomized, open-label, active-controlled, parallel-group, exploratory, investigator-initiated clinical study to evaluate whether esaxerenone reduces UACR in hypertensive patients concomitant with HF and albuminuria. In patients with new-onset or worsening HF, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.25 The presence and magnitude of albuminuria confers a strong prognostic association in forecasting the risk of incident HF as well as its progression, irrespective of the estimated glomerular filtration rate.26 Furthermore, although CKD and cardiorenal syndrome have been reported to be associated with cardiovascular disease,27–29 albuminuria is a major risk factor for cardiovascular and renal disease, which starts from levels not yet considered in the definition of CKD.30 Thus, UACR is attracting attention as one of the important markers of cardiovascular events, especially incident HF, as well as its progression.
The non-steroidal MRAs have a different mode of binding to the mineralocorticoid receptor than does the steroidal MRAs, interfering with a different panel of transcription coactivator partners, and they also have a different distribution between the kidney and heart.31 Furthermore, several studies demonstrated the efficacy and safety of finerenone in cardiovascular and renal endpoints.10,11 Esaxerenone is also among the non-steroidal, selective MRA, and its half maximal (50%) inhibitory concentration (IC50) is superior to that of spironolactone and eplerenone. After a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval for the treatment of hypertension in Japan,18,19 and esaxerenone has been reported to ameliorate proteinuria in hypertensive patients.32 Therefore, the ESPIAL trial is designed to evaluate whether esaxerenone reduces the UACR in hypertensive patients concomitant with HF and albuminuria.
The number of enrolled patients is calculated for the primary endpoint of this trial, which is the ratio of UACR before treatment and 24 weeks after treatment. This study is an open-label study, and not a blinded study. However, blood and urine examinations are performed at a central laboratory center, which does not know the result of the randomization. The ESPIAL trial evaluates whether esaxerenone reduces UACR in hypertensive patients concomitant with HF and albuminuria.
Disclosures
Y.S. has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca K.K., and Actelion Pharmaceuticals, and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb, Co, Biosense Webster, Inc., Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan, and Biotronik that include speaking and lecture fees. Y. Okumura has received research funding from Medtronic Japan, MicroPort CRM Japan, and Bayer Healthcare, has accepted remuneration from AstraZeneca, and Johnson & Johnson, and belongs to the endowed departments of Boston Scientific Japan, Abbott Medical Japan, Japan Lifeline, Medtronic Japan, and BIOTRONIK Japan. M.A. has received grants or contracts from Daiichi Sankyo, Otsuka, and Boehringer Ingelheim, and personal fees from AstraZeneca, Tanabe Mitsubishi, Daiichi Sankyo, Novartis, Bayer, Boehringer Ingelheim, Nippon Shinyaku, Viatris, Janssen, Astellas, Eli Lilly, and Otsuka. M. Ishihara has received grants from Abbott, Otsuka, MID, OrbusNeich Medical, Terumo, Nipro, Bayer, Fukuda Denshi, Boston Scientific, Medtronic, and Nippon Boehringer Ingelheim, research funding from Amgen, endowed departments by commercial entities from Abbott, Medtronic Japan, and Nippon Boehringer Ingelheim, and personal fees from Bayer, Daiichi Sankyo, Nippon Boehringer Ingelheim, Otsuka, Novartis, Kowa, Amgen, and AstraZeneca. The other authors have nothing to disclose. Y.U. is a member of Circulation Reports’ Editorial Team.
IRB Information
The present study was approved by the CRB at Hyogo Medical University (CRB5200003; reference no. C0023) until 2023, and Kobe City Hospital Organization Certified Review Board (CRB5220001; reference no. tk2397) since 2023.
Supplementary Files
Supplementary File.
Funding Statement
Funding: This trial was supported by Daiichi Sankyo Co., Ltd., Japan.
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Supplementary Materials
Supplementary File.