Conventional mineralocorticoid receptor antagonists (MRAs) have limited usefulness in patients with hypertension (HT) and concomitant heart failure (HF) because of adverse effects, including hyperkalemia and impaired renal function [1, 2]. Esaxerenone (ESAX) is a novel nonsteroidal MRA that may overcome the limitations of conventional MRAs [3]. However, the efficacy and safety of ESAX remain unclear in patients with HT and concomitant HF for whom current guidelines recommend treatment with MRAs.

From April 2019 to February 2020, we identified 48 patients with HT concomitant with HF in the outpatient clinic who satisfied two criteria (1) office systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg; (2) home SBP ≥ 135 mmHg and/or DBP ≥ 85 mmHg) despite treatment with more than two antihypertensive agents, including angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), beta blockers, calcium channel blockers, diuretics (thiazide diuretics and/or loop diuretics), and MRAs. HF was defined as New York Heart Association (NYHA) class II or III and plasma B-type natriuretic peptide (BNP) > 40 pg/mL or NT-Pro-BNP > 125 pg/mL [4]. BP measurement and its target values were based on the current Japanese guidelines [1, 4]. Of the patients, 39 were treated with ESAX and included in the present study. ESAX was initially administered at 2.5 or 1.25 mg (if eGFR was below 60 mL/min/1.73 m2) and titrated to 5.0 mg to achieve the target home BP. All patients were followed through clinic visits at least every 2 weeks, without any changes in concomitant antihypertensive agents during the study period. The mean home SBP and DBP for each 2-week interval were also calculated. We evaluated ESAX efficacy and safety at 24 weeks of retrospective administration. The primary efficacy outcome measure was the change in home SBP/DBP; the secondary outcome measure was the change in plasma BNP level from at least 4 weeks before ESAX administration until week 24. The safety outcome measure was the incidence of treatment-related adverse events (TRAEs), defined as treatment-related abnormal laboratory findings or symptoms that caused discontinuation of ESAX. All patients provided written informed consent, and the present study was approved by the Ethics Committee on Human Investigation at each institution and conducted in accordance with the Declaration of Helsinki (64th The World Medical Association General Assembly, Fortaleza, Brazil, 2013).

Elderly patients over 75 years old comprised 41% (n = 16) of the study population, and the prevalence of reduced ejection fraction (HFrEF, left ventricular ejection fraction <40% measured by echocardiography) and rate of history of hospitalization for acute decompensated HF was 18% and 46%, respectively. Basal heart diseases included ischemic heart disease (41%), cardiomyopathy (26%), and valvular heart disease (15%) (Table 1). No patients with severe respiratory disease and/or physical dysfunction were included in this study. The baseline home SBP/DBP was 146 [142–150]/85 [74–89] mmHg, with a median number of 3 [2, 3] antihypertensive agents. The absolute change in home SBP/DBP during the study period was −18 [−22 to −8]/−7 [−11 to −1] mmHg (p < 0.001, compared with baseline). Home SBP/DBP was 128 [124–134]/77 [73–80] mmHg at week 24 (Fig. 1A). Plasma BNP levels were significantly decreased at 24 weeks (−73.9 [−196.6 to −36.4] pg/mL, p < 0.01, compared with baseline), though a significant improvement in NYHA grade was not observed (Fig. 1B). TRAEs were observed in 12.8% of the patients, which consisted of drug eruption (n = 1), symptomatic fainting (n = 2), and impaired renal function (eGFR decline >30% of baseline, n = 2). A serum K+ > 5.5 mEq/L was not observed in any patient during the study period.

Table 1 Baseline patient’s characteristics
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Fig. 1
figure 1

Changes in home SBP/DBP and plasma BNP during the study period. A Serial change in home BP. *p < 0.001 vs. baseline; SBP systolic blood pressure, DBP diastolic blood pressure. B Serial change in BNP level. †p < 0.01 vs. baseline

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The results suggest the antihypertensive and antiheart failure efficacy and good tolerability of additional ESAX in patients with HT and concomitant HF. The present study further notes several important aspects of ESAX in clinical practice. First, the present study reports the efficacy of home BP; this measure is more associated with the incidence of cerebrovascular events and mortality than office BP, which was used in a previous ESAX study [3, 5]. Second, 41% (n = 16) of the study population was elderly (>75 years old), in contrast to a previous study that only included 2% elderly patients [3, 5]. The finding of sufficient antihypertensive effects of ESAX in the present cohort suggests the feasibility of additional ESAX treatment for elderly patients with HT. Third, ESAX may contribute to a significant reduction in plasma BNP levels. Although it is still unclear whether the effect is independent of the reduction in BP, the present finding might be partly attributed to the high potency and selectivity of mineralocorticoid receptor blockade by ESAX. The safety of additional ESAX is also remarkable. The incidence of hyperkalemia and impaired renal function after conventional MRAs has been reported to be ~5–25% and 15%, respectively. In particular, the rate is reportedly increased in high-risk patients, such as elderly patients and those with chronic kidney disease, diabetes mellitus, and concomitant drug use, such as ACEis and ARBs [6, 7]. Ferreira et al. conducted a meta-analysis of large clinical trials of MRAs for patients with HF, and the authors reported that the incidence of impaired renal function (defined as an eGFR decline >30%) was 39.3% in patients >75 years old over a median of 2.2 years of MRA treatment [8]. In contrast, the incidence of hyperkalemia and impaired renal function causing ESAX discontinuation for 24 weeks was 0 and 5.1% in the present study, respectively. Although long-term safety should be investigated in further studies, the present findings suggest the safety of additional ESAX prescriptions for patients with concomitant HF.

Several limitations of this study need to be mentioned. This is a single-arm, nonrandomized, retrospective, observational study with a small sample size. The definition of HF was based on the NYHA class and BNP values, which might lead to overdiagnosis. Administration of ESAX was decided by a local physician without any strict criteria regarding the clinical judgment.

In conclusion, the present study demonstrates the antihypertensive effect, antiheart failure effect, and tolerability of ESAX in patients with HT and concomitant HF. Further prospective studies in larger cohorts are necessary to confirm the efficacy of ESAX for improving HF.