Japanese Hypertensive Patients Research Articles

Coexistence of periodic limb movements during sleep with restless legs syndrome and its association with hypertension in Japanese patients

BackgroundCaucasian patients with restless legs syndrome (RLS) frequently exhibit periodic limb movements during sleep (PLMS), which may increase the risk of hypertension. We evaluated the positivity rate of PLMS and factors associated with positivity in Japanese patients with RLS, and tested whether the complications of PLMS are associated with the presence of hypertension. MethodsWe retrospectively investigated polysomnographic data and the presence or absence of hypertension in patients with RLS. Patients with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or those taking antihypertensive medication were categorized as the group with hypertension. ResultsAmong 468 patients, 200 (42.7%) had periodic limb movement index (PLMI) values ≥ 15/h and 108 (23.1%) met the criteria of positivity for hypertension. Multiple logistic regression analysis revealed that only higher age was significantly associated with PLMI values ≥ 15/h. Multiple linear regression analyses of factors associated with an increased PLMI also showed that increased PLMI was significantly correlated with higher age and male sex, but not with the international restless legs scale scores. Multiple logistic regression analysis also revealed that higher age and body mass index, not PLMI values ≥ 15/h, were significantly associated with the presence of hypertension. ConclusionThe PLMS-positivity rate may be lower in Japanese patients with RLS than in Caucasian patients, and it increases with age and male sex, but not with the severity of the disorder. Furthermore, PLMS complications were not associated with the risk of hypertension in Japanese patients with RLS.

PS-P15-9: EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON HOME BLOOD PRESSURE AND CARDIAC HYPERTROPHY IN HYPERTENSIVE PATIENTS WITH LVH (ESES-LVH STUDY)

Objective: Cardiac hypertrophy is a prognostic factor in hypertensive patients, and attenuation of the hypertrophy with sustained antihypertensive treatment is important to delay the progression to heart failure. Although most classes of antihypertensive agents have evidence of cardiac hypertrophy regression, there is insufficient evidence for mineralocorticoid receptor blockers (MRB); only one report states that MRB has a more pronounced regressive effect when used in combination with a renin-angiotensin system (RAS) inhibitor. Esaxerenone is a novel selective nonsteroidal MRB which has been recently approved for the treatment of hypertension, to date however, there is little evidence of the effectiveness and safety of esaxerenone in hypertensive patients with cardiac hypertrophy. The study was aimed to evaluate the effectiveness and safety of esaxerenone in Japanese hypertensive patients with left ventricular hypertrophy (LVH) whose blood pressure (BP) was inadequately controlled with a RAS inhibitor or calcium channel blocker (CCB). Design and method: ESES-LVH study (jRCTs071190043) was a multicenter, open-label, interventional study. Main inclusion criteria were hypertensive patients (20 years) with morning and bedtime home BP: 135–159 mmHg systolic BP (SBP) and/or 85–99 mmHg diastolic BP (DBP) taking a RAS inhibitor or CCB, and patients with LVH (diagnosed with echocardiography, ECG, or left ventricular mass index [LVMI]). Over the 24-week study period, the initial dose of esaxerenone was started at 1.25 or 2.5 mg/day, and increased to 5 mg/day at weeks 4 and 8, based on the individual patient's condition. The primary endpoints were change from baseline in morning home BP, and change and %change in LVMI, at the end of treatment (EOT). Secondary endpoints included changes in bedtime home and office BP, proportion of patients achieving target BP, changes in echocardiographic parameters, and safety variables including adverse events, eGFR, and serum potassium levels. Results: Baseline characteristics of the 58 enrolled patients were mean age, 64.8 years; male, 70.7%; RAS inhibitor/CCB, 32.8/67.2%; mean morning home SBP/DBP, 142.8/85.0 mmHg; mean LVMI 118.1 g/m2; left ventricular ejection fraction 62.8%; serum potassium level 4.1 mEq/L; and mean eGFRcreat 71.3 mL/min/1.73m2. Mean change from baseline at EOT was -11.5/-4.7 mmHg in the morning home BP, and mean change and % change in LVMI were -9.9 g/m2 and-8.5%, respectively (p < 0.001 each). Detailed effectiveness and safety results will be presented. Conclusions: ESES-LVH study will provide the first clinical evidence of not only the antihypertensive and LVH-regressive effects of esaxerenone, but also its safety in Japanese hypertensive patients with cardiac hypertrophy.

S-17-5: EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON HOME BLOOD PRESSURE AND ALBUMINURIA IN JAPANESE HYPERTENSIVE PATIENTS WITH DKD (EX-DKD STUDY)

Objective: To investigate the effect of esaxerenone on home blood pressure (BP) and albuminuria in Japanese hypertensive patients with diabetic kidney disease (DKD) who had an inadequate response to BP-lowering treatment with a renin angiotensin system (RAS) inhibitor or a RAS inhibitor plus a calcium channel blocker (CCB). Design and method: The EX-DKD study (jRCTs061190027) was a multicenter, open-label study conducted in Japan. The study enrolled hypertensive patients with DKD who had previously received a RAS inhibitor or a RAS inhibitor plus CCB for < 12 weeks, and had sitting office systolic BP (SBP) 130 to < 180 mmHg and/or diastolic BP (DBP) 80 to < 110 mmHg, UACR < 1000 mg/g creatinine, and eGFRcreat 30 to < 60 mL/min/1.73m2 at baseline. Based on baseline UACR, the patients were divided into 3 subcohorts: UACR < 30, 30 to < 300, and 300 to < 1000 mg/g creatinine. Esaxerenone was incrementally dosed for 12 weeks: 1.25, 2.5, and 5 mg/day at the start of treatment, Week4, and Week8, respectively, based on each patient's condition. The primary efficacy endpoint was change in morning home SBP/DBP from baseline to end of treatment (EOT). Secondary endpoints included the proportion of patients achieving target BP at Week12, change in UACR from baseline to EOT, and safety (including serum potassium level). Results: The baseline characteristics of the overall study population (n = 109) were mean age, 72.6 years; male, 54.1%; morning home SBP/DBP, 135.6/75.9 mmHg; UACR < 30, 30 to < 300, and 300 to < 1000 mg/g creatinine, 41.3%, 37.6%, and 21.1%, respectively; eGFRcreat, 49.4 mL/min/1.73m2; RAS inhibitor, 33.0%; RAS inhibitor plus CCB, 67.0%. Morning home SBP/DBP decreased significantly from baseline to EOT in the total population (-11.6/-5.2 mmHg, both p < 0.001) and all UACR subcohorts (all p < 0.001). Similar results were obtained for bedtime home and office BP. At Week12, 38.5% of the total population had achieved target morning home BP. UACR improved significantly from baseline to EOT in the total population and UACR subcohorts; the overall percentage change was -50.9% (p < 0.001). Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 23.2% and 7.1%, respectively. The percentage of patients with serum potassium <5.5 mEq/L during the study period was 2.7%, and no patients had serum potassium < 6.0 mEq/L. Conclusions: Esaxerenone significantly reduced morning home BP as well as bedtime home and office BP and significantly halved albuminuria in Japanese hypertensive patients with DKD. The effects were consistent regardless of their UACR severity without clinically relevant serum potassium elevation.

PS-C29-2: AZELNIDIPINE IMPROVES INSULIN RESISTANCE IN JAPANESE HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

Objective: Metabolic syndrome is related with insulin resistance and the close relation between hypertension and insulin resistance has been demonstrated. On ant-hypertensive drugs, organ-protective action other than antihypertensive action is important and should be considered when we select antihypertensive drugs. Long-acting calcium antagonists have action of improving insulin resistance other than antihypertensive action. In this study, we examined effect of improving insulin resistance in azelnidipne of long-acting calcium antagonist in Japanese hypertensive patients with metabolic syndrome. Design and method: This study included 25 patients (14 men and 11 women; mean age 54.6 years) of Japanese hypertensive patients with metabolic syndrome who had prior antihypertensive treatment with ARB (poor BP control with BP > 140/90 mmHg) or no treatment. These patients were given azelnidipine 16 mg/day and the following indices were measured before and 3–6 months of azelnidipine therapy to compare their variations: systolic BP, diastolic BP, heart rate, fasting plasma glucose, fasting immunoreactive insulin(F-IRI), homeostasis model assessment for insulin resistance(HOMA-R) and HbA1c. Results: The mean BP was 153/90 mmHg before azelnidipine therapy but significantly decreased to 137/80 mmHg after therapy. Heart rate also significantly decreased from 88bpm to 81bpm. F-IRI significantly decreased from 15.0 microIU/ml to 10.1 microIU/ml. HOMA-R significantly decreased from 3.66 to 2.40. Other parameters had no significant changes. Conclusions: In Japanese hypertensive patients with metabolic syndrome who had prior antihypertensive treatment with ARB (poor BP control) or no treatment, azelnidipine therapy significantly decreased BP and heart rate and improved insulin resistance. It is speculated that this phenomenon is caused by azelnidipine effect of inhibiting the sympathetic nervous system. This study showed that azelnidipine therapy is useful for hypertensive patients with metabolic syndrome.

PS-P15-8: EFFICACY AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH TYPE 2 DIABETES AND RECEIVING SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS (EAGLE-DH STUDY)

Objective: Hypertensive patients with type 2 diabetes mellitus (T2DM) who respond inadequately to antihypertensive therapy are at high risk for cardiorenal events and require effective treatment options. Clinical trials have shown that esaxerenone, a non-steroidal mineralocorticoid receptor blocker, has favorable antihypertensive and renoprotective effects in hypertensive patients with various characteristics including T2DM and albuminuria. However, clinical evidence is lacking regarding the concomitant use of esaxerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors in hypertensive patients with T2DM. The study aimed to evaluate the efficacy and safety of esaxerenone and SGLT2 inhibitor combination therapy in Japanese hypertensive patients with T2DM who had an inadequate response to blood pressure (BP)-lowering treatment with renin angiotensin system (RAS) inhibitor or calcium channel blocker (CCB) monotherapy or combined therapy. Design and method: EAGLE-DH (jRCTs031200273) was a multicenter, open-label, interventional study in hypertensive patients (age, ≧ 20 years) with T2DM. Inclusion criteria were previous use of antihypertensive therapy (a RAS inhibitor, CCB, or RAS inhibitor plus CCB) and oral hypoglycemic drugs (a SGLT2 inhibitor with or without one or two other oral hypoglycemic drugs) for ≧ 12 weeks; morning home systolic BP (SBP) 125 to < 160 mmHg and/or diastolic BP (DBP) 75 to < 100 mmHg; and eGFRcreat ≧ 30 mL/min/1.73m2 at baseline. Over the 24-week study period, esaxerenone dose was started at 1.25 or 2.5 mg/day, and based on the individual patient's condition, the dose could be titrated at weeks 4 and 8 to a maximum of 5 mg/day. The primary endpoints were change in morning home BP from baseline to weeks 12 and 24. Secondary endpoints included change in bedtime home BP and office BP, proportion of patients achieving target SBP/DBP (home, < 125/75 mmHg; office, < 130/80 mmHg), change in urine albumin-to-creatinine ratio (UACR), and safety variables including adverse events, eGFR, and serum potassium. Results: The study population comprised 93 patients. Baseline characteristics were mean age, 66.3 years; male, 68.8%; mean morning home SBP/DBP, 136.4/82.3 mmHg; mean UACR 145.3 mg/g creatinine; one RAS inhibitor use, 33.3%; one CCB inhibitor use, 19.4%; RAS inhibitor plus CCB, 47.3%; mean HbA1c 6.8%; mean serum potassium, 4.2 mEq/L; and mean eGFRcreat 66.8 mL/min/1.73m2. Efficacy and safety results will be presented at the conference. Conclusions: EAGLE-DH will provide the first evidence from clinical practice for the efficacy of esaxerenone plus SGLT2 inhibitor in reducing morning/bedtime home and office BP with improving albuminuria as well as for its safety profile in Japanese hypertensive patients with T2DM.

PS-BPC11-6: USEFULNESS OF BONE BROTH SOUP FOR THE REDUCTION OF SALT INTAKE

Objective: Salt reduction is most important in guidance regarding lifestyle modifications in Japanese hypertensive patients as well as for the health of the general population. However, low-salt diets have not been preferred because they are not delicious. Thus, we investigated the influence of bone broth soup on the saltiness and palatability in this study. Design and method: Subjects comprised 103 staffs working at Kokura Daiichi Hospital (22 males, 81 females, mean age 35 ± 12 years old). They tested 0.9% NaCl solutions (A), 0.6% NaCl solutions (B) and 0.6% NaCl solutions with bone broth soup (C). Evaluations of saltiness and palatability for each solution were conducted using a visual analog scale in a double-blinded randomized manner. We estimated 24-hour salt excretion using spot urine samples and also assessed BP, the awareness of salt intake using self-description questionnaire score (range 0 to 35, from the lowest to the highest), medication and other confounding factors including lifestyles. Results: In all subjects, average estimated salt intake was 9.0 ± 2.0 g/day and each rate of achievement of salt intake was 15.1% in 73 female without hypertension (< 6.5 g/day), 23.5% in 17 male without hypertension (< 7.5 g/day), 0.0% in 13 hypertension (< 6.0 g/day). Both in saltiness and palatability, B was significantly lower than A, but C was significantly higher than B. Salt intake levels were categorized into quantile (Q1, lowest; Q3, highest). C in palatability was significantly higher in the Q1 group than in the Q3 group (0.6 ± 1.4 vs -0.2 ± 1.1, p < 0.01). Urinary sodium-to-potassium ratio and total average score for the awareness of salt intake on the questionnaire in the Q1 group was significantly lower and compared to that in the Q3 group (2.34 ± 2.34 vs 4.54 ± 2.16, p < 0.01; 11.7 ± 5.1 vs 13.5 ± 4.5, p < 0.05). Conclusions: Most subjects failed to achieve the goal of salt intake. Group with high salt intake might be able to feel less palatable. Our results indicate that bone broth soup seems effective in reducing salt intake without loss of palatability.

Current antihypertensive treatment and treatment-resistant hypertension in Japanese patients with chronic kidney disease.

Hypertension is an important prognostic predictor in patients with chronic kidney disease (CKD), and the recommended target blood pressure has been continuously revised. This study aimed to reveal the current antihypertensive practices in Japanese patients with CKD. In the Fukuoka Kidney disease Registry, we extracted 3664 non-dialysis-dependent patients with CKD. Apparent treatment-resistant hypertension (aTRH) was defined as a failure of blood-pressure control treated with three antihypertensive medication classes or a treatment with ≥ 4 classes regardless of blood pressure. The blood-pressure control complied with the target blood pressure recommended by the KDIGO 2012 guideline. The median age of the patients was 67years, body mass index (BMI) was 23kg/m2, and estimated glomerular filtration rate (eGFR) was 40mL/min/1.73 m2. The number of patients with unachieved blood-pressure control was 1933, of whom 26% received ≥ 3 classes of antihypertensive medications. The first choice of medication was renin-angiotensin system inhibitors, followed by calcium-channel blockers. The rate of thiazide use was low in all CKD stages (3-11%). The prevalence of aTRH was 16%, which was significantly associated with BMI (odds ratio [95% confidence interval] per 1-standard deviation change, 1.38 [1.25-1.53]), decreased eGFR (1.87 [1.57-2.23]), as well as age, diabetes mellitus, and chronic heart disease. Renal dysfunction and obesity are important risk factors of aTRH. Even under nephrologist care, most patients were treated with insufficient antihypertensive medications. It is important to prescribe sufficient classes of antihypertensive medications, including diuretics, and to improve patients' lifestyle habits.

Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: A retrospective study.

Esaxerenone, a mineralocorticoid receptor blocker (MRB), is a new antihypertensive agent. However, esaxerenone-related data with respect to hypertension with heart failure are limited. We investigated the safety and efficacy of esaxerenone in hypertensive patients with heart failure with reduced ejection fraction (HFrEF). Hypertensive patients with HFrEF treated with esaxerenone were retrospectively analyzed at two timepoints (short-term: 35±15 days; mid-term: 167±45 days). Adverse events including hyperkalemia (K+ >5.5 mEq/L), worsening renal function (WRF; estimated glomerular filtration rate (eGFR) reduction by ≥20%), and hypotension (systolic blood pressure <90 mmHg) were evaluated. eGFR and K+, serum creatinine, and brain natriuretic peptide (BNP) levels at baseline, short-term, and mid-term assessments were compared. Patients administered esaxerenone as their first MRB (first-MRB cohort) and those who converted from another MRB (conversion cohort) were separately analyzed. There were 50 (56±10 years old, 26% female) patients. At the short-term assessment, hyperkalemia or hypotension was not observed at a dose of 2.0±0.9 mg/day. Seven patients (14%) showed WRF. K+ was slightly elevated (4.12±0.41 to 4.25±0.39 mmol/L, p = 0.07) and eGFR was significantly reduced (66.9±19.6 mL/min/1.73 m2 to 62.4±19.7 mL/min/1.73 m2, p = 0.006). In the conversion cohort, significant changes in K+ and eGFR from baseline were not observed at the short-term assessment. BNP levels were consistently improved regardless of the cohorts (first-MRB cohort, 310 [110-370] pg/mL to 137 [47-152] pg/mL, p = 0.001; conversion cohort, 181 [30-203] pg/mL to 108 [26-146] pg/mL, p = 0.028). At the mid-term assessment, there were no significant changes in K+ and eGFR compared with the short-term assessment. In conclusion, esaxerenone was safe for hypertensive patients with HFrEF. Hyperkalemia and hypotension were rarely noted, while eGFR was marginally reduced. Moreover, esaxerenone might be beneficial for HFrEF in terms of BNP level reduction.

Protocol: Prospective observational study investigating the prevalence and clinical outcome of portopulmonary hypertension in Japanese patients with chronic liver disease.

BackgroundPortopulmonary hypertension (PoPH) is a subtype of the pulmonary arterial hypertension (PAH) associated with portal hypertension. There is a dissociation between the proportion of PoPH in PAH and that of PoPH in patients with liver cirrhosis, suggesting PoPH underdiagnosis and an incomplete understanding of this entity in the clinical setting. Specifically, real-world data in Japan is largely unknown as compared with in Europe and the United States. The present study aims to elucidate the prevalence and etiology of PoPH in Japanese patients with chronic liver disease.Methods and designIn this prospective, single-center, observational investigation of PoPH patients with chronic liver disease, a targeted 2,500 Japanese adult patients regularly visiting Shinshu University Hospital in Matsumoto, Japan, for chronic liver disease will complete a standardized questionnaire on the presence of PoPH symptoms. If the respondent has signs of possible PoPH, ultrasound echocardiography (UCG) will be performed as a primary screening. In the case that UCG findings indicate pulmonary hypertension, the patient will be referred to a cardiologist for further evaluation, whereby a definitive diagnosis PoPH can be made. PoPH prevalence and etiology will be investigated at the time of diagnosis. Afterwards, patients with PoPH will be followed for five years for determination of survival rate.DiscussionThis study will reveal the prevalence, etiology, and 5-year survival rate of PoPH in Japanese patients with chronic liver disease.Trial registrationThis study is being performed at Shinshu University following registration as UMIN 000042287 on October 29, 2020.

EFFECT OF MINERALOCORTICOID RECEPTOR BLOCKER, ESAXERENONE, ON NOCTURNAL HYPERTENSION: A POST HOC ANALYSIS OF ESAX-HTN STUDY

Objective: Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure variability and a known risk marker for target organ damage and cardiovascular events. Esaxerenone is a novel, first non-steroidal mineralocorticoid receptor blocker (MRB) with a dose-dependent antihypertensive effect. We investigated the efficacy of esaxerenone on nocturnal hypertension in Japanese hypertensive patients. Design and method: The ‘Esaxerenone compared to Eplerenone in Patients with Essential Hypertension (ESAX-HTN)’ study was a phase 3, multicenter, randomized, controlled, double-blind, and parallel-group clinical study conducted in Japan. Patients were eligible for enrolment in the study if they had trough systolic BP (SBP) &gt; = 140 and &lt; 180 mmHg, trough diastolic BP (DBP) &gt; = 90 and &lt; 110 mmHg, 24-hour mean BP (ABPM) &gt; = 130/80 mmHg. This post hoc analysis used ABPM data to evaluate the effects of esaxerenone and eplerenone on nocturnal blood pressure in patients with essential hypertension. Results: Patients (n = 1001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Esaxerenone significantly lowered blood pressure from baseline throughout the 24-hour dosing interval; reductions in nighttime systolic blood pressure (95% confidence interval [CI]) were significantly greater with 2.5 and 5 mg/day esaxerenone versus eplerenone (-2.6 mmHg [-5.0, -0.2] and -6.4 mmHg [-8.8, -4.0], respectively). Esaxerenone 2.5 and 5 mg/day significantly reduced nighttime blood pressure from baseline compared with eplerenone in non-dipper patients (-4.4 mmHg [-8.6, -0.2] and -10.8 mmHg [-15.0, -6.7], respectively). In addition, esaxerenone did not markedly alter nighttime blood pressure in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime blood pressure were greater than eplerenone-induced decreases in older patients. Conclusions: Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with non-dipping patterns of nocturnal blood pressure.

ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION

Objective: Mineralocorticoid receptor blockers (MRB) adding to renin–angiotensin system (RAS) inhibitors should be an effective treatment option for the strict blood pressure (BP) control of the hypertensive patients with moderate kidney dysfunction. Esaxerenone is a novel, first non-steroidal MRB with a dose-dependent antihypertensive effect and renal protective potential. We investigated the efficacy and safety of esaxerenone in Japanese hypertensive patients with moderate kidney dysfunction. Design and method: Two multicenter, open-label, non-randomized, dose-escalation studies were conducted to assess the efficacy and safety of esaxerenone monotherapy and add-on therapy to RAS inhibitor. Esaxerenone therapy started from 1.25 mg/day, titrated to 5 mg/day and continued until 12 weeks. Primary endpoint was change from baseline in sitting BP. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also evaluated. Results: Of 91 patients, 33 received monotherapy and 58 received add-on therapy; mean baseline estimated glomerular filtration rates were 52 and 51 mL/min/1.73m2, respectively. The esaxerenone dose was increased to 2.5 mg/day and above in 100% (n = 33) and 93% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. After the initiation of treatment, significant reduction in sitting SBP/DBP at the end of treatment was observed in both studies (monotherapy: 19/9 mmHg; add-on therapy: 18/8 mmHg; both P &lt; 0.001); 64% and 48% of patients achieved target blood pressure (&lt;140/90 mmHg). The antihypertensive effects were consistent across patient subgroups by age, BMI, and eGFR. The UACR decreased significantly from baseline to Week 12: by 26% in the monotherapy study (P &lt; 0.01) and 29% in the add-on therapy study (P &lt; 0.001). An increased serum K+ level of 5.5 mEq/L and above occurred in 7 patients (12%) receiving add-on therapy, but in none receiving monotherapy. All increases in serum K+ were transient and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment due to kidney function decline. Conclusions: Esaxerenone demonstrated sufficient antihypertensive effects and was well tolerated in hypertensive patients with moderate kidney dysfunction, both as monotherapy and add-on therapy to a RAS inhibitor.

Effects of Isometric Handgrip Training on Home Blood Pressure Measurements in Hypertensive Patients: A Randomized Crossover Study.

Objective We aimed to examine the effects of isometric handgrip (IHG) training on home blood pressure (BP) levels in hypertensive Japanese patients undergoing treatment. Methods Fifty-three hypertensive patients (mean age, 61.7 years; 56.6% men) with a home systolic BP ≥135 mmHg and/or a home diastolic BP ≥85 mmHg were randomly assigned to either group A or B. As per the crossover design, group A performed 8 weeks of IHG training, followed by an equivalent training-free, control period, while the reverse protocol was performed by group B. The baseline characteristics were similar between both groups. The individualized daily IHG training comprised four sets of 2-min isometric contractions at 30% of the individual’s maximum voluntary contraction capacity, including 1 min of rest between sets, for ≥3 days/week. The outcome measure was morning and evening home BP readings taken over the last 2 weeks of the training and control periods. Results A combined data analysis for both groups showed that IHG training was significantly associated with the lowering of both systolic and diastolic BP in the morning (137.9±9.3 vs. 135.3±9.5 mmHg, p=0.007 and 83.0±9.5 vs. 81.2±9.3 mmHg, p＜0.001, respectively) and evening (130.0±10.7 vs. 127.6±10.1 mmHg, p=0.003 and 75.8±10.4 vs. 73.8±9.2 mmHg, p＜0.001, respectively), while no significant change was observed after the control period. A larger increase in the maximum grip strength due to IHG training was associated with greater BP reductions. Conclusion An 8-week period of IHG training significantly lowered both the morning and evening home BP in hypertensive Japanese patients undergoing treatment.

Relation between Oscillometric Measurement of Central Hemodynamics and Left Ventricular Hypertrophy in Hypertensive Patients

Introduction: The augmentation index (AIx) or central systolic blood pressure (SBP), measured by radial applanation tonometry, has been reported to be independently associated with left ventricular hypertrophy (LVH) in Japanese hypertensive patients. Cuff-based oscillometric measurement of the AIx using Mobil-O-Graph® showed a low or moderate agreement with the AIx measurement with other devices. Methods: The AIx measured using the Mobil-O-Graph was validated against the tonometric measurements of the radial AIx measured using HEM-9000AI in 110 normotensive healthy individuals (age, 21–76 years; 50 men). We investigated the relationship between the central hemodynamics assessed using the Mobil-O-Graph and LVH in 100 hypertensive patients (age, 54–75 years; 48 men), presenting a wall thickness of ≥11 mm and ≥10 mm in men and women, respectively. Results: Although the Mobil-O-Graph-measured central AIx showed no negative values, it correlated moderately with the HEM-9000AI-measured radial AIx (r = 0.602, p < 0.001) in the normotensive individuals. The hypertensive patients did not show a significant difference in the central SBP between the sexes, but the central AIx was lower in men than in women. The independent determinants influencing left ventricle (LV) mass index (LVMI) (R² = 0.362; adjusted R² = 0.329, p < 0.001) were heart rate (β = −0.568 ± 0.149, p < 0.001), central SBP (β = 0.290 ± 0.100, p = 0.005), and aortic root diameter (β = 1.355 ± 0.344, p = 0.001). Age (β = −0.025 ± 0.124, p = 0.841) and the central AIx (β = 0.120 ± 0.131, p = 0.361) were not independently associated with the LVMI. The area under the receiver operator characteristic curve to evaluate the diagnostic performance of the central AIx for the presence of LVH (LVMI >118 g/m² in men or >108 g/m² in women) was statistically significant in men (0.875, p < 0.001) but not in women (0.622, p = 0.132). In men, a central AIx of 28.06% had a sensitivity of 83.3% and specificity of 80.0% for detecting LVH. Conclusions: AIx measurement in men provided useful prognostic information for the presence of LVH. Pulse-wave analysis assessed using the Mobil-O-Graph may be a valuable tool for detecting LVH in hypertensive patients.

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

Esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker (MRB) in hypertension and chronic kidney disease.

The steroidal mineralocorticoid receptor (MR) antagonists, spironolactone and eplerenone, decrease blood pressure, and attenuate the progression of chronic kidney disease (CKD). However, their use is limited by the fear of inducing hyperkalemia, gynecomastia, impotence, and amenorrhea. Esaxerenone is a novel nonsteroidal MR blocker (MRB) that has been recently developed. In vitro studies have revealed that esaxerenone has a high potency and selectivity for MR compared with spironolactone and eplerenone. Further studies have shown that esaxerenone elicits a strong blood pressure-lowering effect in hypertensive animals. Following the results from phase III clinical trials that esaxerenone is an effective and well-tolerated MRB in Japanese hypertensive patients, esaxerenone became clinically available in Japan from May 2019 for hypertensive patients. Thus, esaxerenone is a promising treatment option for patients with hypertension. In addition, both preclinical studies and phase II clinical trials have shown that esaxerenone elicits renoprotection independent of its antihypertensive effect. Recently, a phase III clinical trial (ESAX-DN study) has also demonstrated the safety and efficacy of esaxerenone in patients with type 2 diabetes and microalbuminuria. These data support future clinical development of esaxerenone for the treatment of renal disease.

Highlights of the 2019 Japanese Society of Hypertension Guidelines and perspectives on the management of Asian hypertensive patients.

Unlike other international guidelines but in accord with the earlier Japanese Society of Hypertension (JSH) guidelines, the 2019 JSH guidelines ("JSH 2019") continue to emphasize the importance of out-of-office blood pressure (BP) measurements obtained with a home BP device. Another unique characteristic of JSH 2019 is that it sets clinical questions about the management of hypertension that are based on systematic reviews of updated evidence. JSH 2019 states that individuals with office BP<140/90mmHg do not have normal BP. The final decisions regarding the diagnosis and treatment of hypertension should be performed based on out-of-office BP values together with office BP measurements. For hypertensive adults with comorbidities, the office BP goal is usually <130/80mmHg and the home BP goal is <125/75mmHg. Recommendations of JSH 2019 would be valuable for not only Japanese hypertensive patients but also Asian hypertensive patients, who share the same features including higher incidence of stroke compared with that of myocardial infarction and a steeper blood pressure-vascular event relationship.

COMPARISON OF UNATTENDED AUTOMATED OFFICE BLOOD PRESSURE WITH HOME BLOOD PRESSURE AND ITS RELATION TO PULSE WAVE VELOCITY

Objective: We assessed whether Unattended automated office blood pressure (UAOBP) was equal to Home blood pressure (HBP) and extended to explore the difference in the correlation between each blood pressure (BP) measure and pulse wave velocity (PWV).Design and method: Study patients were 70 essential hypertensives (mean age 67.0 ± 9.4; male 48.6%; antihypertensive medication use 87.8%). Medical staff measured Attended automated office BP (AAOBP), and 5 minutes later since medical staff left the room, UAOBP was measured. AAOBP, UAOBP, and HBP were recorded as the average of triplicate measurements taken at 30-s intervals. HBP was measured 5 consecutive days in the morning and evening. In this study, we used each systolic BP values. Brachial-ankle PWV (baPWV) was measured to evaluate subclinical organ damage. Results: Average of each systolic BP values were AAOBP 127.6 ± 14.5 mmHg; UAOBP 122.5 ± 13.7 mmHg; Average of morning and evening HBP 129.3 ± 11.7 mmHg; Morning HBP 133.1 ± 12.8 mmHg, Evening HBP 125.6 ± 13.6 mmHg. Average of morning and evening HBP and Morning HBP were significantly higher compared with UAOBP (all P < 0.001). AAOBP (r = 0.246, P = 0.040), Average of morning and evening HBP (r = 0.323, P = 0.006), Morning HBP (r = 0.372, P = 0.002), and Evening HBP (r = 0.204, P = 0.091) were associated with baPWV, whereas UAOBP (r = 0.151, P = 0.211) was not. Among these BP values, only Morning HBP was significantly correlated with baPWV after adjusted for age, gender, body mass index, current smoking, habitual drinking, diabetes, and hyperlipidemia (β = 6.001, P = 0.020). Conclusions: In Japanese hypertensive patients, UAOBP was significantly lower compared with Average of morning and evening HBP and Morning HBP. Morning HBP was associated with subclinical organ damage after adjusted for conventional cardiovascular risk, whereas this association was not found in UAOBP. To evaluate clinical utility of UAOBP in Japanese, follow-up survey is needed.

Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin–angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin–angiotensin system inhibitor.

Influence of blood pressure on the effects of low-dose asprin in elderly patients with multiple atherosclerotic risks.

We examined whether the efficacy of low-dose acetylsalicylic acid (aspirin) for primary prevention of cardiovascular events is influenced by blood pressure (BP) using data from patients aged 60-85 years with hypertension, dyslipidemia, and/or diabetes, but without cardiovascular disease of the Japanese Primary Prevention Project. All patients had received aspirin (100 mg/day) or no aspirin. BP subgroups were defined as low (average SBP from the baseline to the year of the events <130 mmHg), moderate (≥130 and <140 mmHg), and high (≥140 mmHg). The mean duration of follow-up was 5.02 years. In hypertensive patients (n = 12 278) aspirin had no significant impact on the primary outcome of death from cardiovascular disease, nonfatal stroke, and nonfatal myocardial infarction. On the other hand, aspirin increased the incidence of serious extracranial hemorrhage [hazard ratio, 1.81; 95% confidence interval (CI), 1.18-2.77; P = 0.0064] and tended to increase hemorrhagic stroke (hazard ratio, 1.75; CI, 0.99-3.07; P = 0.053). Aspirin had no effect on the primary outcome in any of the BP subgroups, and was associated with increased hemorrhagic stroke in the high BP group (hazard ratio, 3.51; CI, 1.29-9.51; P = 0.014); serious extracranial hemorrhage was elevated or tended to elevate in the moderate (hazard ratio, 2.53; CI, 1.18-5.45; P = 0.017) and high (hazard ratio, 2.14; CI, 1.00-4.56; P = 0.050) BP groups. In aged Japanese hypertensive patients, these data demonstrated no overall benefit of low-dose aspirin therapy although treatment was associated with an elevated risk of hemorrhagic events.

Antihypertensive treatment for hypertensive patients with heart failure using real-world Japanese data: subanalysis of the Retrospective study of antihypertensives for lowering blood pressure (REAL) study

ABSTRACTThe number of patients with heart failure (HF) is rapidly increasing. Although hypertension is related to onset of HF, antihypertensive treatment status for these patients has not been fully examined. We conducted a claims-based study to discern the treatment status of Japanese hypertensive patients with HF. Two Japanese databases (2008–2016) from acute care hospitals and health insurance societies were used to analyze prescription rates for antihypertensive drug class or category of diuretics in all hypertensive patients and the subset of patients with HF. Totals of hypertensive patients and those with HF in each database in 2015 were 4,191,666 and 1,404,008 patient-months, and 1,382,732 and 148,194 patient-months, respectively. In the acute care hospitals database, calcium channel blockers (CCBs) (55.0–56.5%) and angiotensin II receptor blockers (49.4–54.7%) were prescribed most. β-blockers (38.7–48.0%) and diuretics (42.3–45.6%) were prescribed more for hypertensive patients with HF than for all hypertensive patients (21.5–24.8% and 25.5–26.7%, respectively). Loop diuretics were also prescribed more often for hypertensive patients with HF (68.3–76.0% from acute care hospitals and 47.8–55.8% from health insurance societies) than for all hypertensive patients (56.7–61.7% and 16.4–18.3%). The size of medical institution had a greater effect on drug selection than patient age in both patient groups. Given recommendations in guidelines for hypertensive patients with HF, the differences in drug choice in comparison with all hypertensive patients appear reasonable. However, some deviations, such as the high rate of CCBs in frontline and preference for angiotensin II receptor blockers over angiotensin-converting enzyme inhibitors, did not appear to follow guidelines.