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A randomized, open-label study to evaluate the efficacy and safety of esaxerenone compared to angiotensin receptor blockers in older patients with hypertension

ESCORT-HT Study

419

In the full analysis set (FAS; n=402), the mean age +/- standard deviation was 75.5 +/- 7.1 years in the esaxerenone group and 75.5 +/- 7.0 years in the angiotensin II receptor blocker (ARB) group. The proportion of male participants was 47.5% in the esaxerenone group and 43.5% in the ARB group, whereas the proportion of female participants was 52.5% and 56.5%, respectively. The mean body mass index (BMI +/- standard deviation) was 24.020 +/- 3.438 kg/m2 in the esaxerenone group and 24.337 +/- 3.508 kg/m2 in the ARB group. With regard to comorbid conditions, the prevalence of type 2 diabetes mellitus was 32.2% in the esaxerenone group and 27.5% in the ARB group, while the prevalence of chronic kidney disease was 9.9% and 7.0%, respectively. The mean duration of hypertension (+/- standard deviation) was 7.92 +/- 6.82 years in the esaxerenone group and 6.86 +/- 6.33 years in the ARB group. Baseline blood pressure values (mean +/- standard deviation) were as follows: the morning home systolic blood pressure was 144.4 +/- 9.4 mmHg in the esaxerenone group and 145.2 +/- 10.1 mmHg in the ARB group, and the corresponding diastolic blood pressure was 85.1 +/- 8.3 mmHg and 85.4 +/- 8.0 mmHg, respectively. The bedtime home systolic blood pressure was 135.7 +/- 11.5 mmHg in the esaxerenone group and 135.0 +/- 12.0 mmHg in the ARB group, with diastolic blood pressure values of 78.4 +/- 7.7 mmHg and 78.3 +/- 8.5 mmHg, respectively. Office systolic blood pressure was 144.7 +/- 16.8 mmHg in the esaxerenone group and 145.6 +/- 16.8 mmHg in the ARB group, and office diastolic blood pressure was 78.7 +/- 10.8 mmHg and 78.2 +/- 10.9 mmHg, respectively. Overall, no clinically meaningful differences were observed in baseline demographic or clinical characteristics between the two treatment groups.

Participant enrollment for this study began in September 2024, enrollment was completed in April 2025, and follow-up of all study participants was completed in June 2025. Of the 721 participants initially registered in the primary enrollment, 419 participants (209 in the esaxerenone group and 210 in the angiotensin II receptor blocker [ARB] group) proceeded to secondary enrollment. Among the 402 participants included in the full analysis set (FAS; 202 in the esaxerenone group and 200 in the ARB group), 383 participants completed the study during the treatment period (191 in the esaxerenone group and 192 in the ARB group), while 19 participants discontinued the study during the treatment period (11 in the esaxerenone group and 8 in the ARB group). Among the 365 participants included in the per protocol set (PPS; 185 in the esaxerenone group and 180 in the ARB group), which comprised participants who met the criteria specified in the study protocol, 347 participants completed the study during the treatment period (174 in the esaxerenone group and 173 in the ARB group), and 18 participants discontinued the study during the treatment period (11 in the esaxerenone group and 7 in the ARB group). For the safety analysis set, 415 participants were included (207 in the esaxerenone group and 208 in the ARB group). Of these, 386 participants completed the study during the treatment period (193 in the esaxerenone group and 193 in the ARB group), whereas 29 participants discontinued the study during the treatment period (14 in the esaxerenone group and 15 in the ARB group).

Adverse events was 25.1% (52/207 participants) in the esaxerenone group and 30.8% (64/208 participants) in the angiotensin II receptor blocker (ARB) group. The incidence of serious adverse events was 1.0% (2/207 participants) in the esaxerenone group and 3.4% (7/208 participants) in the ARB group. Details of the serious adverse events were as follows: gastrointestinal stromal tumor and acute respiratory failure each occurred in 0.5% (1/207 participants) of the esaxerenone group. In the ARB group, bacterial prostatitis, gastrointestinal submucosal tumor, anaphylactic shock, dehydration, cerebral infarction, atrial fibrillation, pelvic organ prolapse, and femoral neck fracture each occurred in 0.5% (1/208 participants). Among these serious adverse events, the outcome was death in the case of acute respiratory failure, not recovered in the case of dehydration, and recovered with sequelae in the case of cerebral infarction. All other adverse events resulted in either improvement or recovery. Adverse drug reactions was 2.9% (6/207 participants) in the esaxerenone group and 3.8% (8/208 participants) in the ARB group. No serious adverse drug reactions were observed in either group, and the incidence of adverse drug reactions was comparable between the two groups. The incidence of diseases and related conditions was 3.9% (8/207 participants) in the esaxerenone group and 3.8% (8/208 participants) in the ARB group. No serious diseases or conditions were observed in either group, and the incidence was similar between the two groups.

<Primary Endpoint> With respect to the change from baseline in morning home systolic blood pressure, the point estimate of the between-group difference (esaxerenone group minus ARB group) and its two-sided 95% confidence interval was -1.6 mmHg (-3.7, 0.5). The upper bound of the two-sided 95% confidence interval was below the prespecified non-inferiority margin at the end of treatment, defined as 3.8 mmHg for the upper limit of the between-group difference (esaxerenone group minus ARB group). Therefore, non-inferiority of esaxerenone to the ARB was demonstrated. As the upper bound of the two-sided 95% confidence interval did not fall below 0 mmHg, superiority of esaxerenone over the ARB was not demonstrated. <Secondary Endpoints> Morning Home Blood Pressure With respect to morning home blood pressure, the mean change from baseline to end of treatment (+/- standard deviation) in systolic and diastolic blood pressure was -10.1 +/- 11.2 mmHg (95% confidence interval -11.6, -8.5; p < 0.0001) and -4.6 +/- 6.3 mmHg (95% CI: -5.5, -3.7; p < 0.0001) in the esaxerenone group, and -8.7 +/- 10.5 mmHg (95% CI: -10.2, -7.2; p < 0.0001) and -4.4 +/- 5.8 mmHg (95% CI: -5.2, -3.6; p < 0.0001) in the ARB group, respectively. In both groups, morning home systolic and diastolic blood pressure at end of treatment was significantly reduced compared with baseline. Bedtime Home Blood Pressure For bedtime home blood pressure, the mean change from baseline to end of treatment (+/- standard deviation) in systolic and diastolic blood pressure was -8.3 +/- 11.0 mmHg (95% CI: -9.8, -6.7; p < 0.0001) and -3.4 +/- 6.1 mmHg (95% CI: -4.3, -2.5; p < 0.0001) in the esaxerenone group, and -7.4 +/- 10.5 mmHg (95% CI: -8.9, -5.9; p < 0.0001) and -3.9 +/- 6.1 mmHg (95% CI: -4.8, -3.0; p < 0.0001) in the ARB group, respectively. Bedtime home blood pressure at end of treatment was significantly decreased from baseline in both treatment groups. Office Blood Pressure Regarding office blood pressure, the mean change from baseline to end of treatment (+/- standard deviation) in systolic and diastolic blood pressure was -7.38 +/- 17.23 mmHg (95% CI: -9.80, -4.95; p < 0.0001) and -3.44 +/- 9.48 mmHg (95% CI: -4.78, -2.11; p < 0.0001) in the esaxerenone group, and -8.29 +/- 14.60 mmHg (95% CI: -10.35, -6.22; p < 0.0001) and -4.88 +/- 8.71 mmHg (95% CI: -6.11, -3.65; p < 0.0001) in the ARB group, respectively. In both groups, office systolic and diastolic blood pressure at end of treatment was significantly reduced compared with baseline. Proportion of Participants Achieving Blood Pressure Targets At end of treatment, the proportion of participants achieving a systolic blood pressure <135 mmHg and diastolic blood pressure <85 mmHg for morning home blood pressure was 47.0% (95/202 participants; 95% CI: 40.0, 54.2) in the esaxerenone group and 36.5% (73/200 participants; 95% CI: 29.8, 43.6) in the ARB group. For bedtime home blood pressure, the corresponding proportions were 65.8% (133/202 participants; 95% CI: 58.9, 72.4) and 67.0% (134/200 participants; 95% CI: 60.0, 73.5), respectively. The proportion of participants achieving a systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg for office blood pressure at end of treatment was 55.0% (111/202 participants; 95% CI: 47.8, 61.9) in the esaxerenone group and 58.0% (116/200 participants; 95% CI: 50.8, 64.9) in the ARB group. Overall, no clinically meaningful differences were observed between the two groups in the proportion of participants achieving blood pressure targets. Percent Change in Urine Albumin-to-Creatinine Ratio (UACR) The point estimates of percent change from baseline in UACR were -15.6% (95% CI: -24.9, -5.2; p = 0.0044) in the esaxerenone group and -16.4% (95% CI: -25.0, -6.9; p = 0.0013) in the ARB group at Week 4; -18.8% (95% CI: -27.2, -9.6; p = 0.0002) and -21.7% (95% CI: -29.9, -12.5; p < 0.0001), respectively, at Week 8; and -20.9% (95% CI: -29.7, -10.9; p = 0.0001) and -19.4% (95% CI: -28.3, -9.4; p = 0.0004), respectively, at Week 12. In both groups, UACR was significantly reduced after treatment compared with baseline. Percent Change in Serum N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) At Week 12, the point estimate of percent change from baseline in serum NT-proBNP was -16.7% (95% CI: -22.4, -10.7; p < 0.0001) in the esaxerenone group and -6.5% (95% CI: -13.1, 0.6; p = 0.0713) in the ARB group. The percent change in serum NT-proBNP at Week 12 was significantly reduced from baseline in the esaxerenone group. <Safety Endpoints> Changes and Time Course of Serum Potassium, Serum Sodium, and eGFR_creat The mean change from baseline in serum potassium levels (+/- standard deviation) at end of treatment was 0.22 +/- 0.40 mEq/L in the esaxerenone group (n = 198) and 0.11 +/- 0.39 mEq/L in the ARB group (n = 196). The mean change from baseline in estimated glomerular filtration rate based on serum creatinine (eGFR_creat; +/- standard deviation) at end of treatment was -4.46 +/- 7.43 mL/min/1.73m2 in the esaxerenone group (n = 197) and -0.48 +/- 7.83 mL/min/1.73m2 in the ARB group (n = 197). A decreasing trend in eGFR_creat was observed in the esaxerenone group from Week 4 of the treatment period onward, whereas little change was observed in the ARB group throughout the treatment period. Proportion of Participants with Serum Potassium Levels >=5.5 mEq/L and >=6.0 mEq/L The proportions of participants according to measured serum potassium levels during the treatment period were as follows. Serum potassium levels <3.5 mEq/L were observed in 4 of 204 participants (2.0%; 95% confidence interval 0.5, 4.9) in the esaxerenone group and in 10 of 200 participants (5.0%; 95% CI: 2.4, 9.0) in the ARB group. Serum potassium levels >=5.5 mEq/L were observed in 1 of 204 participants (0.5%; 95% CI: 0.0, 2.7) in the esaxerenone group and in none of the 200 participants (0.0%; 95% CI: 0.0, 1.8) in the ARB group. Serum potassium levels >=6.0 mEq/L were observed in 1 of 204 participants (0.5%; 95% CI: 0.0, 2.7) in the esaxerenone group and in none of the 200 participants (0.0%; 95% CI: 0.0, 1.8) in the ARB group.

This study compared the antihypertensive efficacy and safety of esaxerenone versus ARBs in older hypertensive patients with inadequate BP control on CCB monotherapy. Over a 12-week treatment period, this study demonstrated the non-inferiority of esaxerenone to ARBs in reducing morning home SBP. And no unexpected safety concerns were observed. The results of this study suggest this regimen could be a feasible alternative G2 option for older patients with uncontrolled hypertension.

Aug. 07, 2026

April. 24, 2026

https://www.nature.com/articles/s41440-026-02634-4

Yes

The datasets generated and/or analyzed during the current study will be available from the corresponding author and Daiichi Sankyo.Co.,Ltd. on reasonable request.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031240300

Kario Kazuomi

Jichi Medical University (Jichi Medical University Hospital)

3311-1, Yakushiji, Shimotsuke City, Tochigi

kkario@jichi.ac.jp

Kario Kazuomi

Jichi Medical University

3311-1, Yakushiji, Shimotsuke City, Tochigi

+81-285-44-2111

kkario@jichi.ac.jp

Complete

Aug. 27, 2024

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

Patients will be included if they meet all of the following inclusion criteria:
1)Patients (=> 65 year of age) at the time of informed consent
2)Hypertensive patients treated with Amlodipine Besilate 2.5 mg or 5 mg for at least 4 weeks before the start of the observation period
3) Patients with mean systolic blood pressure =>135 mmHg in the last 5 days of early morning home blood pressure measured by a brachial sphygmomanometer.

Patients who meet any of the following criteria will be excluded:
1)Patients diagnosed with secondary hypertension (endocrine hypertension, etc.)
2)Hyperkalemia patients
3)Patients with serum potassium level over 4.8 mEq/L
4)Patients with eGFRcreat less than 45 mL/min/1.73m2
5)Patients with extremely poor bile secretion or severe liver impairment
6)Patients with a history of clinically significant adverse reactions to esaxerenone or ARB
7)Pregnant, possibly pregnant or planning to become pregnant
8)Patients who are inappropriate for this study judged by primary investigators

Both

Older patients with hypertension

[Dosage and administration of the research drug]
Esaxerenone is given orally at 2.5 mg once daily.
Patients with moderate renal dysfunction (eGFRcreat is 30 or more and less than 60 mL/min/1,73m2) and diabetic patients with albuminuria should start with 1.25mg of esaxerenone, and the dose is increased to 2.5 mg after 4 week of the administration period, depending on the patient's condition including serum potassium level.

[Dosage and administration of the comparator drug]
ARB is given orally once daily, according to the dosage on the electronic package insert.
ARB is given either Azilsartan, Irbesartan, Olmesartan Medoxomil, Candesartan Cilexetil, Telmisartan, Valsartan or Losartan Potassium.
If the dose is started from a low dose according to each electronic supplement, the dose should be increased to the standard dose after the 4th week of administration. The dosage may be adjusted depending on patient's age and symptoms.

[Dosage considerations]
In principle, patients started at low dose increase tothe standard dose after the 4th week of the treatment period based on the dose criteria. After increasingto the standard dose, neither reducing the dose below the standard dose nor administering the maximum dose is acceptable.

Hypertension

Change from baseline in morning home blood pressure (systolic blood pressure)

1.Efficacy
1) Change from baseline in morning home, bedtime home and office blood pressure (systolic and diastolic blood pressure)
2) Changes in each blood pressure (morning home ,bedtime home and office(systolic and diastolic blood pressure))
3) Achieving rate of target blood pressure (morning home, bedtime home and office)
4) Change,%change from baseline and change from baseline in UACR
5) Change and %change in NT-proBNP
6) Change from baseline in PAC, PRA and ARR
7) Changes and change from baseline in urinary biomarkers (Na,K, Na/K and Cr)

2.Safety
1) Adverse events (event name, number of events and incidence rate)
2) Change and Change from baseline in serum potassium levels, serum sodium level and eGFRcreat
3) Change from baseline in laboratory test values(HbA1c)
4) Percentage of study subjects with serum potassium levels: 5.5 mEq/L or moreand 6.0 mEq/L or more
5) Percentage of study subjects with serum sodium level : less than 135.0 mEq/L
6) Pulse rate

+81-3-3470-3360

Aug. 02, 2024

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