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Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH study)

ESES-LVH study (ESES-LVH study)

60

Overall in the Full Analysis Set (FAS) (58 subjects), the number of men (41 subjects) was more than that of women (17 subjects), with mean age (SD) was 64.8 (12.7) years (range: 37 to 92 years), mean weight (SD) at the time of starting of esaxerenone administration was 66.88 (14.19) kg, mean BMI was 25.20 (4.09) kg/m2, mean duration of hypertension (SD) was 6.73 (8.44) years. Mean baseline SBP/DBP (SD) were 142.8 (8.1)/85.0 (10.0) mmHg for home BP (early morning), 141.0 (8.4)/81.9 (10.5) mmHg for home BP (bedtime), and 145.9 (14.3)/85.3 (12.8) mmHg for office BP. Eighteen (18) subjects (31.0%) had smoking habit, 52 subjects (89.7%) had complications, and 11 subjects (19.0%) had diabetes complications.

Enrollment had started since June 2020, and the follow-up period for all subjects was finished in March 2022. Disposition of subjects is shown below. Enrolled: 60 subjects (21 subjects in renin-angiotensin [RA] inhibitor combination cohort, 39 subjects in calcium channel blocker [CCB] combination cohort). Esaxerenone treated: 60 subjects (21 subjects in RA inhibitor combination cohort, 39 subjects in CCB combination cohort). Completed esaxerenone treatment period: 57 subjects (18 subjects in RA inhibitor combination cohort, 39 subjects in CCB combination cohort). Safety Analysis Population: 60 subjects FAS: 58 subjects Population following label instructions of esaxerenone: 46 subjects

In the Safety Analysis Population (60 subjects), 21 subjects (35.0%) experienced a total of 40 adverse events (AEs). Of these, 2 events in 2 subjects (3.3%) were reported as adverse drug reaction (ADR). The PT of 2 ADRs were both blood potassium increased (1 subject each in RA inhibitor combination cohort and CCB combination cohort). No serious study-related adverse events were reported.

Primary efficacy endpoint: In the FAS, overall mean (SD) change from baseline at the end of treatment for home BP (early morning) was -11.5 (12.3) mmHg (95% CI: -14.8, -8.3 mmHg, P < 0.001) for SBP and -4.7 (7.7) mmHg (95% CI: -6.7, -2.7 mmHg, P < 0.001) for DBP, demonstrating statistically significant reduction in both SBP/DBP. By basal antihypertensive agent, the mean home BP (early morning) at the end of treatment (SBP and DBP) also showed statistically significant reductions in both RA inhibitor combination cohort and CCB combination cohort, demonstrating hypotensive effect of esaxerenone regardless of combination treatment (i.e., basal antihypertensive agent). Overall mean (SD) change from baseline at the end of treatment for left ventricular mass index (LVMI) was -9.9 (20.5) g/m2 (95% CI: -15.5, -4.3 g/m2, P < 0.001) and mean (SD) percentage change from baseline at the end of treatment for LVMI was -8.5 (20.0)% (95% CI: -13.0, -3.9%, P < 0.001), demonstrating statistically significant reduction in LVMI. By basal antihypertensive agent, the mean LVMI at the end of treatment also showed statistically significant reductions in both RA inhibitor combination cohort and CCB combination cohort, demonstrating regression effect of left ventricular hypertrophy of esaxerenone regardless of combination treatment (i.e., basal antihypertensive agent). Major secondary efficacy endpoints: Similar to the primary results, the mean home BP (bedtime) and office BP at the end of treatment (SBP and DBP) showed statistically significant reductions in overall and both RA inhibitor combination cohort and CCB combination cohort. The home BP (early morning and bedtime) was generally decreasing tendency until Week 6 and maintained decreased BP throughout the 24-week treatment period. The office BP was generally decreasing tendency until Week 12 and maintained decreased BP throughout the 24-week treatment period. Similar tendency was observed in both RA inhibitor combination cohort and CCB combination cohort. For echocardiogram parameters, statistically significant reduction was observed at the end of treatment in the FAS for left ventricular posterior wall thickness (LVPWT), the ratio between the E-wave velocity and A-wave velocity of the pulsed-wave Doppler mitral flow image (E/A), the ratio between E-wave velocity and the average early diastolic velocity of the lateral and septum at the mitral annulus level (E/e'), E-wave height, myocardial strain (Left Atrial peak Longitudinal Strain [LA peak LS]), left ventricular volume (left ventricular end-diastolic volume [LVEDV] and left ventricular end-systolic volume [LVESV]) and left atrial volume (LAV), double product (DP) and triple product (TP). For pharmacodynamic parameters, statistically significant elevation was observed at the end of treatment in the FAS for plasma aldosterone concentration (PAC) and plasma renin activity (PRA). Three subjects (1 subject in RA inhibitor combination cohort, 2 subjects in CCB combination cohort) had 5.5 mEq/L or more of serum potassium levels, but no subjects reported 6.0 mEq/L or more.

Esaxerenone showed stable antihypertensive effect and regression effect on left ventricular hypertrophy (reduction of LVMI) regardless of the kind of basal antihypertensive agent (RA inhibitor or CCB). No new unpredictable AEs or ADRs were observed, and safety of esaxerenone have been confirmed. It is suggested that esaxerenone can be clinically useful option as the second-line treatment for hypertensive patients with cardiac hypertrophy who had uncontrolled BP under treatment with RA inhibitor or CCB.

June. 30, 2023

Feb. 04, 2024

https://pubmed.ncbi.nlm.nih.gov/38310194/

Yes

The datasets generated and/or analyzed during the current study will be available from the corresponding author and the study sponsor on reasonable request.

https://jrct.niph.go.jp/latest-detail/jRCTs071190043

Tsujita Kenichi

Kumamoto University Hospital

1-1-1 Honjo, Chuo-ku, Kumamoto,Japan

tsujita@kumamoto-u.ac.jp

Sueta Daisuke

Kumamoto University Hospital

1-1-1 Honjo, Chuo-ku, Kumamoto,Japan

+81-96-373-5175

Sueta-d@kumamoto-u.ac.jp

Complete

Jan. 24, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1) Patients with hypertension (early morning home blood pressure [BP]: =>135 mmHg and <=159 mmHg of systolic blood pressure and/or =>85 mmHg and <=99 mmHg of diastolic blood pressure)
2) Patients with left ventricular hypertrophy.
3) Patients treated with renin-angiotensin inhibitor or Ca-antagonist.
4) Patients aged 20 years or older.

1) Patients with a diagnosis of secondary hypertension or malignant hypertension.
2) Patients with orthostatic hypotension or a history of orthostatic hypotension.
3) Patients with any of the cerebro-cardiovascular diseases.
4) Patients with type 1 diabetes.
5) Hyperkalemia patients, patients whose serum potassium level exceeds 5.0 mEq/L, etc.
6) Patients who the investigator judges to be unsuitable for the study.

Both

Hypertensive Patients with Left Ventricular Hypertrophy

The duration of treatment with Esaxelenone is 24 weeks. Esaxelenone is given orally once daily. The initial daily doses will be started at 2.5 mg and titrated (if the effect is insufficient, the dose may be increased up to 5 mg) depending on the patient's condition. Dose reduction criteria patients should be started with 1.25 mg of Esaxelenone.

Hypertensive Patients with Left Ventricular Hypertrophy

Esaxerenone

1) Change in sitting BP (early morning home BP) between baseline values and values at the end of administration of Esaxerenone.
2) Amount and rate of change in left ventricular mass index (LVMI) between baseline values and values at the end of administration of Esaxerenone.

1) Change in sitting BP (early morning home BP) between baseline and 12 weeks after the start of Esaxerenone administration.
2) Change in sitting BP (home BP before bedtime) between baseline values and values at the end of administration of Esaxerenone.
3) Proportion of patients achieving the target of sitting BP reduction.
4) Left Ventricular Mass (LVM) and Rate of change in left ventricular mass index (LVMI) between baseline and 12 weeks after the start of Esaxerenone administration.
5) Change in Left Ventricular posterior Wall Thickness (LVPWT), Relative Wall Thickness (RWT), the ratio between the E-wave velocity and A-wave velocity of the pulsed-wave Doppler mitral flow image (E/A), the ratio between E-wave velocity and the average early diastolic velocity of the lateral and septum at the mitral annulus level (E/e'), E-wave height, mitral annulus early diastolic velocity (e'), a', tricuspid regurgitation velocity (TRV), left atrial volume index (LAVI), left ventricular end-diastolic dimension (LVDd), deceleration time (DT), left ventricular ejection fraction (LVEF), vascular function test (baPWV or CAVI), myocardial strain, myocardial strain rate, left ventricular volume, left atrial volume,double product (DP), triple-product (TP), coefficient of variation of R-R Interval (CVR-R), NT-proBNP, CRP, PAC, PRA, and urinary (Na, K, albumin, creatinine, protein) between baseline and 12 weeks after the start of Esaxerenone administration.

+81-96-373-5966

Jan. 10, 2020

none