Antihypertensive Effects of Esaxerenone in Older Patients with Primary Aldosteronism

Design Retrospective cohort study. Patients. The data was obtained from a total of 87 PA patients treated with esaxerenone. The treatment group comprised 33 patients who received esaxerenone as first-line therapy and 54 patients that switched from another MRA to esaxerenone. Measurements. Blood pressure (BP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), serum potassium level, estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and brain natriuretic peptide (BNP) were assessed before and after treatment with esaxerenone. Patients with overall reductions in their systolic or diastolic BP by 10 mmHg, or more, were considered responders. Unpaired t-tests of the biochemical and personal parameters between responders and nonresponders were run to find the most influencing characteristic for treatment success. Results BP overall decreased after treatment with esaxerenone (systolic BP: P=0.025, diastolic BP: P=0.096). Serum potassium levels increased, while eGFR decreased (P=0.047 and 0.043, respectively). No patients needed a dose reduction or treatment discontinuation of esaxerenone based on the serum potassium and eGFR criteria. UACR and BNP decreased insignificantly. The responders were significantly older than the nonresponders of the esaxerenone treatment (P=0.0035). Conclusions Esaxerenone was effective in older patients with primary aldosteronism.


Introduction
Primary aldosteronism (PA) accounts for 4-10% of hypertensive patients and is the most common cause of secondary hypertension [1,2]. PA is caused by an autonomous aldosterone production from adrenal aldosteroneproducing adenomas (APAs) or by bilateral adrenal hyperplasia defned as idiopathic hyperaldosteronism [3]. Patients with PA are more likely to have arrhythmias such as atrial fbrillation, cardiovascular disease, and stroke than patients with essential hypertension (EHT) matched for age and blood pressure [4,5]. In a meta-analysis, PA patients had a signifcantly higher risk for developing stroke than those with essential hypertension, coronary artery disease, atrial fbrillation, and heart failure. PA is also associated with signifcantly higher risks of diabetes, metabolic syndrome, and left ventricular hypertrophy [5]. It is, therefore, important to accurately diagnose and treat patients with PA.
Te pathogenesis of PA has not been fully elucidated yet, however many histological and genetical fndings have been reported [6]. Multiple aldosterone-producing micronodules (APMs) (formerly known as aldosterone-producing cell clusters) appear to be a common histologic feature of bilateral PA [7]. Moreover, age-dependent accumulation of APMs in autopsy specimen of adrenal glands was reported, suggesting an age-dependent PA pathophysiology [8][9][10]. Also, aldosterone-producing driver-mutations are often found in APMs in normal adrenals, supporting that APMs acquiring somatic mutations induce an age-dependent aldosterone production [8,[10][11][12]. Tus, diagnosis and treatment of age-dependent aldosteronism has become more important.
Te common treatment of PA is an adrenalectomy for patients with an APA, which reduces all-cause mortality better than mineralocorticoid receptor antagonist (MRA) treatment alone [13]. Additionally, an adrenalectomy for patients with APA reduced the risks of incident stroke, regression of left ventricular hypertrophy, and risk of atrial fbrillation [14][15][16]. However, MRAs are recommended for patients with bilateral PA and patients with PA unable or unwilling to undergo surgery and have shown to improve their hypertension. Furthermore, MRAs improve cardiac function and prognosis in patients with heart failure accompanied by reduced left ventricular ejection fraction [17][18][19].
Esaxerenone is an oral nonsteroidal MRA with higher MR-binding specifcity than other MRA agents [20]. It has antihypertensive efects in patients with essential hypertension and PA and reduces microalbuminuria in patients with diabetic nephropathy [21][22][23]. Moreover, it is efective and well-tolerated in hypertensive patients with moderate kidney dysfunction [24]. However, the personal characteristics, such as age and sex, of patients that beneft most from esaxerenone treatment for PA have not been studied. Terefore, we investigated those characteristics of patients with PA under esaxerenone treatment to identify the patient type for whom this treatment is likely to be most efective.

Study Participants.
Tis retrospective study enrolled 87 consecutive patients (mean age, 56.0 ± 11.9; females, n � 44) who had been diagnosed with PA and treated with esaxerenone at our institution, Chiba University Hospital, Japan, between May 2019 and July 2020. We obtained data before and on the next consultation day after treatment with esaxerenone (consultations mainly took place approximately 2 months after introduction, ranging from 1-3 months). Te patients were diagnosed with PA based on the following criteria: (1) plasma aldosterone concentrations (PAC) of >120 pg/mL, determined via radioimmunoassay, (2) aldosterone-to-renin ratio (ARR) of >200, and (3) at least one positive confrmatory result for any of the following tests: captopril test (ARR >200 at 60 or 90 min after loading 50 mg of captopril); physiological saline challenge test (PAC >60 pg/mL 4 h after loading 0.9% saline); furosemide standing test (plasma renin activity (PRA) <2.0 ng/mL·h 2 hours after loading 40 mg of furosemide). All tests adhered to the Japan Endocrine Society guidelines [25]. Te exclusion criteria were as follows: having other forms of secondary hypertension (e.g., renovascular hypertension, Cushing's syndrome, subclinical Cushing's syndrome, pheochromocytoma, or hypertension associated with a single kidney) or hypertensive crisis. Te following measurements were taken before and after treatment with esaxerenone: (1) systolic and diastolic blood pressure (BP), (2) potassium level, (3) estimated glomerular fltration rate (eGFR), (4) B-type natriuretic peptide (BNP) level, and (5) urine albumin-to-creatinine ratio (UACR). Serum creatinine levels were used to calculate eGFRs, using the following equation: eGFR � 194 × serum creatinine − 1.904 × age − 0.287. A number of blood pressure stabilizers were permitted to be used during the study period: calcium channel blockers, angiotensin II receptor blockers, thiazides, beta-blockers, alpha-blockers, furosemide, renin inhibitors, and methyldopa. Te PA patients included in this study received treatment with esaxerenone at varying doses, depending on new treatment group, dose of pretreatment MRB, and eGFR less than 60 ml/min/1.73 m 2 . Tey received either 1.25 mg/day, 2.5 mg/day, or 5 mg/day.
Since the observation period was defned as the period from the date of initiation of treatment to the date of continuation of esaxerenone without change of antihypertensive medication, the period of esaxerenone administration was the same as the follow-up period.
Tis study was approved by the ethics review board of the Chiba University Hospital, and it complied with the principles of the Helsinki Declaration.

Statistical
Analyses. Data were analyzed with GraphPad Prism 7, version X (GraphPad Software, San Diego, CA, USA), and SAS version 9.4 (SAS Institute, Cary, NC, USA). Data are expressed as means ± standard deviation (SD), median, and interquartile range. Te normality of the distribution was confrmed with Shapiro-Wilk's test. In case of normally distributed data, the two groups were compared using an unpaired or paired t-test. In case of nonnormally distributed data, the data were compared using Mann-Whitney U test or Wilcoxon test. Dose-stratifed analysis were performed using ANOVA test. P-values of <0.05 denoted statistical signifcance. Subgroup analysis were performed for (1) concomitant group or noncomitant group of antihypertensive drugs and (2) ESA as the frst therapy group and the switch from another MRA group.

Results
Te average age of the patients was 56 ± 11.9 years (females, 50.6%). Te median follow-up values were 9.1 weeks. Information regarding the subtype diagnosis for all patients was as follows: out of 87 cases, 53 cases are N.D. (not determined), 14 are unilateral, and 20 are bilateral. To stabilize their blood pressure, most patients were taking calcium channel blockers (66.7%). Tere were 33 patients in the treatment group with esaxerenone as frst-line therapy, while 55 patients switched from another MRA to esaxerenone. Detailed information on the number of patients that took an antihypertensive agent and on the daily dose of esaxerenone can be found in Table 1.   2 International Journal of Hypertension Systolic BP and diastolic BP decreased after treatment with esaxerenone (P � 0.025 and 0.096, respectively). UACR and BNP decreased; however, there were no signifcant reductions during the observation period. Te serum potassium levels increased, while the eGFR decreased (P � 0.047 and 0.043, respectively) ( Table 2). Two patients (2.3%) had slightly elevated serum potassium levels of ≥5.0 mEq/L. No patient needed a dose reduction or the discontinuation of esaxerenone based on their serum potassium level and eGFR.
Te blood pressure (BP) of 32 patients was measured before and after treatment, and those who had systolic or diastolic BP reductions of 10 mmHg, or more, were considered responders. Systolic BP before treatment was signifcantly higher in responders compared to nonresponders (P � 0.025) (Figure 1(a)). Changes in systolic and diastolic, BP and ΔBP, after treatment were signifcantly greater in responders compared to nonresponders (P � 0.00012 and P � 0.00099, respectively) ( Figure 1(b)). Similar changes were observed in longer-term treatment with esaxerenone ( Figure 1(b) right). No signifcant diferences between responders and nonresponders were observed with esaxerenone dose (Figure 1(c)). Changes in systolic and diastolic BP were studied in each dose of esaxerenone; however, the diference in dose-dependent efects was not signifcant (Figure 1(d)). Te responders were signifcantly older than the nonresponders (P � 0.0035) (Figure 2(a)). Biochemical parameters did not difer signifcantly between these two groups other than serum creatinine and estimated glomerular fltration rate (Figures 2(b)-2(h)). Clinical data of nonresponders and responders, and subtype diagnosis were shown in Table 3. Age was studied in the subgroups according to the presence or absence of antihypertensive drugs other than MRAs (Table 4). A subgroup analysis in patients who received esaxerenone as initial therapy and in patients who switched from other MRAs, and the results are shown in Table 5. Most of the parameters were similar to the overall observations with signifcant diferences (P < 0.05).

Discussion
MRA is the recommended treatment for patients with PA who are unwilling to undergo surgery or who have contraindications for surgery [26]. In this study, we investigated the characteristics that maximize the efect of esaxerenone in hypertensive patients with PA, and assessed age, renal function, potassium levels, BNP, UACR, PAC, and PRA of the responders and nonresponders for esaxerenone. We found that the responders were signifcantly older than the nonresponders.
Conversely, the investigated biochemical parameters did not difer signifcantly between these two groups. Nevertheless, the observed changes of those measurements of PA patients after the treatment phase suggest an overall positive response. As such, both systolic and diastolic BP decreased in patients with PA after treatment with esaxerenone. Satoh et al. showed that signifcant reductions in systolic and diastolic BPs were observed from week 2 and continued through week 8 after treatment with esaxerenone for patients with PA [22]. A signifcant decrease was observed only in systolic BP in our study, most likely because approximately 60% of the cases had received pretreatment with other MRAs and were switched to a treatment with esaxerenone. Ito et al. reported that esaxerenone treatment showed persistent 24-hour antihypertensive efects and positive changes in diurnal BP in patients with essential hypertension [21]. We generally observed antihypertensive efects of esaxerenone in patients with PA, although the study period was limited and there were restrictions such as dose variation. Te proportions of patients achieving the target sitting BP were 31.5% and 41.2% after being treated with esaxerenone 2.5 and 5 mg/day, respectively [21].
In our study, the serum potassium level signifcantly increased on average, and the efect of aldosterone was considered suppressed. Hyperkalemia with a serum potassium level of >5.0 mEq/L was observed in two cases; however, they were transient. Ito et al. reported that a serum potassium level of ≥5.5 mEq/L was observed in 12.1% of the patients with moderate kidney dysfunction receiving add-on treatment with esaxerenone. All increments in serum potassium levels were transient, and no patients met predefned serum potassium criteria for dose reduction or treatment discontinuation [24]. Furthermore, in the present analysis, the PRA increased to 1.0 ng/mL·h more on average. Previous reports indicated that PA patients with a PRA of <1.0 ng/ mL·h had a higher incidence of cardiovascular events than those with a PRA of ≥1.0 ng/mL·h after surgery or medication, suggesting that the PRA of 1.0 ng/mL·h or higher in our study was desirable [27][28][29][30].     UACR and BNP values decreased in our study; however, there were no signifcant reductions. Tis result is not surprising. Adding esaxerenone to the existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria has shown to increase the likelihood of the normalization of the albumin levels and   International Journal of Hypertension reduced progression of albuminuria [23]. In this study, eGFR decreased signifcantly, suggesting that the treatment with esaxerenone was efective for the patients with PA. Previously, BP, albuminuria, and eGFR decreased after 1 year of surgery or medical treatment with MRAs, and BP and albuminuria continued to decrease after 5.3 and 6.8 years, respectively, but eGFR remained stable without any further decrease [31]. While the biochemical parameters suggest the esaxerenone treatment is suitable as such for the chosen type of PA patients, the only prominent factor that determined an excellent response to the treatment was age. Older patients showed signifcantly better response than younger patients. Consistent with our fndings, greater hypotensive efects were observed in older adults (>65 years old) by subgroup analyses on previous clinical trials of esaxerenone for the patients with EHT in the Japanese population [7]. However, although the precise mechanisms behind these fndings are still unclear, several murine models on vascular aging have been studied. Krug et al., for example, reported an increased expression of the mineralocorticoid receptor (MR) in the aorta and enhanced sensitivity to aldosterone-mediated extracellular signal-regulated kinase 1/2 activation in aged rats. Tey also suggested that an increased MR signaling promoted age-associated infammation, which in turn accompanies arterial aging [32,33]. Interestingly, McCurley et al. showed that a deletion of smooth muscle cell-specifc MR signifcantly decreased the systolic BP in aged mice (more than 7 months old) but not in young adult mice (4 to 7 months old) [32,33]. Further studies are needed to address whether MR signaling is enhanced in blood vessels in aged humans and why the BP of older patients tends to decrease after a MR blockade. Excessive hypotension in older adults should be prevented. However, with careful observation, it is worth considering to lower BP or suppress the efects of aldosterone via a MR blockade in older patients.
We also studied blood pressure in longer-term treatment with esaxerenone (median follow-up: 13 months, mean: 14.7 months, S.D.: 10.2 months, 25% quartile: 4.8 months, 75% quartile: 23.3 months, nonresponders: 12.6 ± 9.3 months, responders: 15.2 ± 10.2 months). Nevertheless, SBP and DBP were signifcantly lower in responders than in nonresponders at  Tese results suggest that the high proportion of elderly patients in the responder group was not due to the short observation period. Also, according to clinical data of nonresponders and responders, and subtype diagnosis, there seemed to be no apparent diference in the proportion of subtype diagnoses between the two groups. In this cohort, there are many patients that switched from other MRAs, and some comparisons did not have signifcant diferences, especially in the switching group, due to the smaller sample size. In contrast, the mean results show a trend similar to that seen in the whole group.
Retrospective studies are generally limited in the sense that the data have already been collected and the study design cannot be adjusted anymore in retrospective. Hence, we were limited by the relatively small sample size and short observational period. Finally, there was no washout period for other MRAs administered as pretreatment. Nonetheless, the strength of our study is that it led to candidate predictors of efectiveness regarding the treatment with esaxerenone in patients with PA.

Conclusions
We found that U-ACR and BNP decreased after treatment with esaxerenone. Further, esaxerenone was more efective in older patients with PA.

Data Availability
Te data that support the fndings of this study can be obtained from the corresponding author upon reasonable request.

Ethical Approval
All procedures were performed according to the principles of the Declaration of Helsinki, and this study was approved by the Committee on Ethics in Human Research of the Chiba University Hospital, Japan (no. 4125).