Esaxerenone versus angiotensin II receptor blockers as second-line therapy in older Japanese patients with uncontrolled hypertension on calcium channel blockers: the randomized, open-label ESCORT-HT study

Hypertension Research https://doi.org/10.1038/s41440-026-02634-4 ARTICLE Esaxerenone versus angiotensin II receptor blockers as second-line therapy in older Japanese patients with uncontrolled hypertension on calcium channel blockers: the randomized, open-label ESCORTHT study Kazuomi Kario1 Hiroyuki Ohbayashi2 Hajime Ishii3 Mitsutoshi Kato4 Minoru Nozaki5 Norio Abiru6 Toshiki Fukui7 Kazushi Nomura8 Yasushi Fukushima9 Naoki Itabashi10 Kazuaki Uchiyama11 Masafumi Nishizawa12 Yoshiki Hata13 Noriko Nakamura14 Satoshi Kodono15 Kunio Hirano16 Tomohiro Katsuya17 Tatsuo Shimosawa18 Kazuhito Shiosakai19 Go Kato20 Takashi Taguchi20 Mitsuru Ohishi21 on behalf of the ESCORT-HT investigators ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 1234567890();,: 1234567890();,: Received: 6 February 2026 / Revised: 16 March 2026 / Accepted: 26 March 2026 © The Author(s) 2026. This article is published with open access Abstract Mineralocorticoid receptor blockers (MRBs) are positioned as second-line antihypertensive agents in the 2025 Japanese Society of Hypertension guidelines, yet evidence in older patients remains limited. This 12-week, multicenter, randomized, open-label, parallel-group, non-inferiority ESCORT-HT study (jRCTs031240300; September 2024–June 2025) compared esaxerenone with angiotensin II receptor blockers (ARBs) as add-on therapy to amlodipine in Japanese patients aged ≥65 years whose morning home systolic blood pressure (SBP) remained ≥135 mmHg despite stable amlodipine. The mean age was 75.5 years in both the esaxerenone (n = 202; female: 52.5%) and ARB (n = 200; female: 56.5%) groups. At the end of treatment, the least squares mean change from baseline in morning home SBP (primary endpoint) was −10.6 (95% confidence interval: −12.0, −9.1) mmHg with esaxerenone treatment and −9.0 (−10.4, −7.5) mmHg with ARB treatment; the between-group difference was −1.6 (−3.7, 0.5) mmHg, meeting the pre-defined non-inferiority margin (3.8 mmHg). Both treatments lowered the urine albumin-to-creatinine ratio, whereas only esaxerenone significantly reduced N-terminal pro-B-type natriuretic peptide. Treatment-emergent adverse events occurred in 25.1% and 30.8% of the esaxerenone and ARB groups; serious events were reported in 2 versus 7 patients, including one death (esaxerenone group). Hyperkalemia occurred in one esaxerenone-treated patient and none who received ARBs. No serious adverse event was judged to be drugrelated. Esaxerenone was non-inferior to ARBs in lowering morning home SBP and showed a favorable safety profile in older Japanese patients with inadequately controlled hypertension on amlodipine. These data support the clinical use of esaxerenone as an effective second-line treatment option for this population. Keywords Angiotensin II receptor blockers Esaxerenone Mineralocorticoid-receptor blockers Morning hypertension Randomized comparative study ● ● ● ● Introduction A list of members and their affiliations appears in the Supplementary Information. Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41440026-02634-4. * Kazuomi Kario Extended author information available on the last page of the article Hypertension is the most prevalent chronic condition in Japan, affecting approximately 43 million individuals [1]. According to the Japanese 2019 National Health and Nutrition Survey, 29.9% of men and 24.9% of women surveyed had a systolic blood pressure (SBP) ≥ 140 mmHg [2, 3]. Despite treatment, an estimated 12.5 million patients in Japan fail to attain guideline-recommended blood pressure (BP) targets [4]. Given that both the prevalence and severity of hypertension increase with age [5] and that K. Kario et al. Graphical Abstract Japan is the world’s most rapidly aging society [6], there is an urgent need for effective, age-appropriate strategies to manage hypertension. The 2025 Japanese Society of Hypertension (JSH 2025) guidelines recommend the use of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors, calcium channel blockers (CCBs), thiazide diuretics, and beta blockers as first-line (step 1 [G1]) treatments for adults of any age [4]. When monotherapy is insufficient, early initiation of combination antihypertensive therapy is recommended to achieve adequate BP control [4]. Notably, mineralocorticoid receptor blockers (MRBs) have been reclassified in the JSH 2025 guidelines from the fourth-line to the preferred second-line (G2) agents, reflecting the increasing recognition of their potent antihypertensive, kidney-protective, and cardioprotective effects. In Japan, an analysis of prescription data found that 38% of treated patients are managed on monotherapy, while 36% require two antihypertensive agents [7]. Among those on dual therapy, CCBs + ARBs account for approximately 60% of all combinations. Thus, MRBs can now be selected as the G2 agents in a substantial proportion of patients. In routine clinical practice in Japan, ARBs and CCBs (both classified as G1a agents) are the most frequently prescribed first- and second-line combination therapies, and CCBs are the most frequently prescribed therapy in older adults [8]. Age-related declines in renin–angiotensin system activity may attenuate the efficacy of ARBs in this population [9, 10]. In contrast, MRBs effectively lower BP in salt-sensitive or low-renin states, which are common in older patients [11, 12]. However, direct comparative evidence evaluating MRBs versus ARBs as add-on therapy to CCBs in older Japanese patients is limited, and further investigation into their benefits in this population is warranted. Esaxerenone versus angiotensin II receptor blockers as second-line therapy in older Japanese patients. . . Esaxerenone is a selective, non-steroidal MRB with higher selectivity and potency, a longer half-life, and more favorable bioavailability than other MRBs [13, 14]. In the EXCITE-HT study, esaxerenone added to either an ARB or a CCB demonstrated non-inferior morning home BP reductions versus trichlormethiazide and showed superior efficacy in patients with uncontrolled essential hypertension [15]. Additionally, subgroup analyses based on the type of baseline antihypertensive agent used (ARB or CCB) and patient age (<65 and ≥65 years) showed similar results regardless of the type of baseline antihypertensive agent [16] or patient age [17]. Additionally, the combination of ARB and CCB has been reported to be superior to an ARB plus a diuretic in patients with uncontrolled nocturnal hypertension [18]. However, it remains unclear whether esaxerenone is comparable to ARBs when each is added to CCBs in older patients with uncontrolled hypertension. Therefore, the ESCORT-HT study was conducted to determine whether esaxerenone is non-inferior to ARBs, when each is combined with the CCB amlodipine, for lowering morning home SBP in Japanese patients aged ≥ 65 years with uncontrolled hypertension. The saf (...truncated)