Comparative Effects of an Angiotensin II Receptor Blocker (ARB)/Diuretic vs. ARB/Calcium-Channel Blocker Combination on Uncontrolled Nocturnal Hypertension Evaluated by Information and Communication Technology-Based Nocturnal Home Blood Pressure Monitoring　― The NOCTURNE Study ―

Abstract

Background: Nocturnal blood pressure (BP) is an independent risk factor of cardiovascular events. The NOCTURNE study, a multicenter, randomized controlled trial (RCT) using our recently developed information and communication technology (ICT) nocturnal home BP monitoring (HBPM) device, was performed to compare the nocturnal HBP-lowering effects of differential ARB-based combination therapies in 411 Japanese patients with nocturnal hypertension (HT).

Methods and Results: Patients with nocturnal BP ≥120/70 mmHg at baseline even under ARB therapy (100 mg irbesartan daily) were enrolled. The ARB/CCB combination therapy (irbesartan 100 mg+amlodipine 5 mg) achieved a significantly greater reduction in nocturnal home systolic BP (primary endpoint) than the ARB/diuretic combination (daily irbesartan 100 mg+trichlormethiazide 1 mg) (−14.4 vs. −10.5 mmHg, P<0.0001), independently of urinary sodium excretion and/or nocturnal BP dipping status. However, the change in nocturnal home systolic BP was comparable among the post-hoc subgroups with higher salt sensitivity (diabetes, chronic kidney disease, and elderly patients).

Conclusions: This is the first RCT demonstrating the feasibility of clinical assessment of nocturnal BP by ICT-nocturnal HBPM. The ARB/CCB combination was shown to be superior to ARB/diuretic in patients with uncontrolled nocturnal HT independently of sodium intake, despite the similar impact of the 2 combinations in patients with higher salt sensitivity.

Nocturnal blood pressure (BP) and non-dipper (reduced nocturnal BP dipping)/riser (higher nocturnal BP than daytime BP) patterns of nocturnal BP are significant risk factors for organ damage and future cardiovascular events.^1–8 In a population-based prospective study, the nocturnal BP level was the most potent predictor of cardiovascular prognosis among office BP, home BP, and daytime and nocturnal ambulatory BPs.⁴ The IDACO (International Database on Ambulatory BP monitoring in relation to Cardiovascular Outcomes), a large international database of prospective studies using ambulatory BP monitoring (ABPM), demonstrated that the effect of nocturnal BP on cardiovascular prognosis was much greater than that of daytime BP in on-treatment patients,⁵ indicating that uncontrolled nocturnal hypertension (HT) is an important remaining cardiovascular risk that should be targeted in medicated hypertensive patients.

Editorial p 938

The nocturnal BP closely depends on the circulating volume.⁹ Diuretics and salt restriction achieve a significant and extensive reduction in nocturnal BP compared with daytime BP, resulting in a shift from a non-dipper to a dipper pattern of nocturnal BP.^10,11 Asians tend to have a genetic predisposition to salt sensitivity and to consume more salt than Westerners.⁸ Because some angiotensin II receptor blockers (ARBs) may improve salt sensitivity,¹² the combination of diuretics with an ARB might be synergistically more effective than a calcium-channel blocker (CCB) with an ARB for additively reducing nocturnal BP,^13,14 especially in Asian patients with nocturnal HT that is uncontrolled by an ARB, who are likely to have high salt-sensitivity and high salt intake.

Traditionally, nocturnal BP has been assessed by ABPM. However, we recently developed a nocturnal home BP monitoring (HBPM) device and demonstrated that nocturnal home BP measured with this device was comparable to nocturnal ABP,^7,8 and was significantly correlated with various measures of organ damage, such as the urinary albumin/creatinine ratio (UACR), N-terminal pro-B-type natriuretic peptide level (NT-proBNP), carotid intima-media thickness, and left ventricular hypertrophy (LVH) diagnosed by echocardiography.^15,16 We have also demonstrated using this device that the change in nocturnal HBP by antihypertensive drug treatment significantly correlated with the reduction in LVH.¹⁷ However, there has not been a randomized controlled trial (RCT) using nocturnal HBPM to compare the nocturnal home BP-lowering effects of different antihypertensive drugs on nocturnal HT.

Here we used our recently developed ICT-based nocturnal HBPM device^7,8 to conduct the NOCTURNE study, the first multicenter RCT to compare the nocturnal home BP-lowering effect of differential ARB-based combination therapies (ARB/diuretic vs. ARB/CCB) in patients with nocturnal HT that was uncontrolled even by an ARB.

Methods

Study Design

The NOCTURNE study is a prospective, multicenter, randomized, open-label, parallel-group design clinical trial investigating the efficacies and safety of 2 fixed-dose drug combinations (ARB (irbesartan)+CCB (amlodipine), or ARB (irbesartan)+diuretic (trichlormethiazide)) on nocturnal home BP and target organ damage in patients with uncontrolled nocturnal HT. This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by an ethics committee of the Jichi Medical University School of Medicine (Shimotsuke, Japan), and all patients gave written informed consent. The protocol of the NOCTURNE study was registered on the University Trials Registry (UMIN-CTR) website (trial no. UMIN000016629).

The study design is illustrated in Figure 1. At visit 1 between March 2015 and May 2016, unmedicated hypertensive outpatients with office BP >140/90 mmHg and/or home BP >135/85 mmHg, or medicated hypertensive patients with 1 or 2 antihypertensive drugs were enrolled. The patients with renal dysfunction (serum creatinine >2.0 mg/dL), severe liver dysfunction, heart failure (New York Heart Association functional class ≥II), or coronary artery disease or stroke within the past 6 months were excluded. Those who were already being medicated were instructed to switch their regimen of any current antihypertensive medications to treatment with irbesartan 100 mg only. Patients were administered oral irbesartan 100 mg/day once in the morning over a 4-week run-in period, during which any patients (n=64, 10.4%) who could not measure or declined to measure their nocturnal home BP with a 3G- (3rd generation of wireless mobile telecommunications technology) enabled HBPM were also excluded. After the run-in period, eligible patients who had uncontrolled nocturnal HT with nocturnal home BP ≥120/70 mmHg were enrolled in the study. After stratification by sex, age (<65 years, ≥65 years), and baseline nocturnal home systolic BP (HSBP) (<130 mmHg, ≥130 mmHg), patients were randomly allocated to an ARB/CCB group (irbesartan 100 mg+amlodipine 5 mg) or an ARB/diuretic group (irbesartan 100 mg+trichlormethiazide 1 mg), and took their allocated treatment once in the morning for 8 weeks.

Figure 1.

Design of the NOCTURNE study. BP, blood pressure.

Concomitant use of non-study drugs that could affect BP was prohibited. Other drugs currently in use for lifestyle diseases were allowed, but the doses were not changed during the study period in principle.

BP Measurements

Home BP The nocturnal HBPM was performed using a cuff oscillometric device equipped with a mobile network communication function (HEM-7252G-HP; Omron Healthcare Co., Ltd., Kyoto, Japan). All data obtained by the device were transmitted automatically to a cloud-based remote monitoring system, the Medical LINK program provided by Omron Healthcare.

In keeping with the Japanese Society of Hypertension 2014 Guidelines for the Management of Hypertension,¹⁸ patients were instructed to measure their morning home BP (measured twice within 1 h after waking; both measurements taken after urination, before taking morning medications and after 1–2 min of seated rest), evening home BP (measured twice before bedtime after 1–2 min of seated rest), and nocturnal home BP (measured at 2:00 AM, 3:00 AM, and 4:00 AM during sleep)^7,8,15–17 for 5 successive days before their next scheduled visit (at 4, 8, and 12 weeks). To measure their nocturnal home BP, patients were instructed to wear the BP cuff and press the button to start the timer when they went to bed.

Office BP Office BP was measured after resting for ≥5 min while seated in a chair with the arm cuff level with the heart.¹⁸ Smoking was prohibited 30 min before the measurement. Several measurements were consecutively taken at intervals of ≥1 min, and the average of 2 measurements was used to define the seated office BP. After that, BP measurements were taken twice at 1-min intervals in a standing position with the arm down, and the average of these values was used to define standing office BP.

Primary and Secondary Endpoints

The primary endpoint was defined as a change in nocturnal HSBP from 4 to 12 weeks after the start of the study. The secondary efficacy endpoints were defined as changes in the following parameters from 4 to 12 weeks: nocturnal home diastolic BP (HDBP); morning and evening home BPs; seated and standing office BPs; day-by-day and diurnal variabilities of nocturnal, morning, and evening home BPs; rate of achievement of the target BP (nocturnal home BP <120/70 mmHg; office BP <140/90 mmHg); UACR; NT-proBNP; estimated urinary sodium excretion (as a measure of salt intake) and urinary Na/K ratio calculated from 1-day spot urine collected at the office visits.¹⁹ Patients with NT-proBNP ≥125 pg/mL were classified as the high NT-proBNP group according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure.²⁰

Sample Size

Based on the findings of the J-CORE study, which used an olmesartan 20 mg+azelnidipine 16 mg group and an olmesartan 20 mg+hydrochlorothiazide 12.5 mg group,²¹ 176 patients per group would guarantee 80% power at P=0.05 (2-sided) to conclude the superiority of combination therapy with irbesartan 100 mg+trichlormethiazide 1 mg over irbesartan 100 mg+amlodipine 5 mg, assuming a difference in nocturnal SBP of 3.0 mmHg between the groups. Further assuming SD of 10 mmHg and a 10% dropout, the final sample size was fixed at 200 patients per treatment group, so 400 patients were needed in total.

Statistical Analysis

Patients who were non-compliant with the Ethical Guidelines for Clinical Research were excluded from all analyses, including those on efficacy and safety. The data sets to be analyzed were defined as follows. The full analysis set (FAS) was defined as all enrolled participants who had received the investigational drug at least once after randomization and who had measured their nocturnal HSBP at least once. The safety analysis set was defined as all randomized participants who had received the investigational drug at least once during the study period.

A 2-sided test was used, and values of P<0.05 were considered statistically significant. Intergroup comparisons were tested with a t-test for continuous variables, and Pearson’s chi-squared test or Fisher’s exact test for dichotomous data.

In the efficacy analyses for BP values, the outcomes were determined using the FAS. Mixed-effects model repeated-measures (MMRM) analysis was used to compare the changes in nocturnal HSBP from 4 to 12 weeks after the start of the study. MMRM included the allocated study group, the time points (4, 8, and 12 weeks), the interaction between the study group and time points as fixed effects, and ages and sex as covariates. Safety was determined using a safety analysis set. Data were analyzed using SAS version 9.4 (SAS Institute, Cary, NC, USA) at the Jichi Medical University Center of Global Home and Ambulatory BP Analysis (GAP), Shimotsuke, Japan.

Results

Patient Disposition and Baseline Characteristics

Of the 616 patients registered in this study, 416 were randomized to a group administered the combination of irbesartan 100 mg+amlodipine 5 mg (ARB/CCB) and a group receiving irbesartan 100 mg+trichlormethiazide 1 mg (ARB/diuretic) (Figure 2). After randomization, 5 patients dropped out and the efficacy analysis was conducted using the data from 411 patients (ARB/CCB group, n=203; ARB/diuretic group, n=208) (Figure 2). A total of 381 (91.6%) patients completed the study (Figure 2). The mean age of the randomized population was 62.7 years, and 55.3% were men. There were no significant differences in the characteristics of patients at baseline except for nocturnal and evening home pulse rates (Table 1).

Figure 2.

Flowchart of patient participation in the NOCTURNE study. ARB, angiotensin-receptor blocker; CCB, calcium-channel blocker.

Table 1. Baseline Characteristics of Participants in the NOCTURNE Study

	ARB/CCB group (n=203)	ARB/diuretic group (n=208)	P value for intergroup comparisons
Age, years	63.0±11.6	62.5±11.7	0.70
Male, %	55.2	55.8	0.92
BMI, kg/m2	25.4±4.1	25.3±4.0	0.95
Type II diabetes, %	22.2	23.1	0.91
Dyslipidemia, %	44.3	42.8	0.77
Peripheral artery disease, %	3.9	1.9	0.26
Coronary artery disease, %	3.5	1.0	0.10
Stroke, %	4.4	4.8	1.00
Nocturnal home SBP, mmHg	128.2±12.7	128.4±14.2	0.87
Nocturnal home DBP, mmHg	79.2±8.7	79.4±8.5	0.79
Nocturnal home PR, beats/min	63.3±10.0	61.3±8.6	0.03
Evening home SBP, mmHg	136.6±15.3	137.2±16.4	0.75
Evening home DBP, mmHg	83.7±10.5	83.6±11.1	0.91
Evening home PR, beats/min	72.9±11.8	70.4±10.3	0.03
Morning home SBP, mmHg	143.8±14.3	143.7±15.9	0.93
Morning home DBP, mmHg	90.1±10.5	89.4±10.6	0.56
Morning home PR, beats/min	67.1±10.2	65.6±8.8	0.15
Seated office SBP, mmHg	146.7±18.5	146.0±17.6	0.69
Seated office DBP, mmHg	87.0±12.8	87.3±12.3	0.78
Seated office PR, beats/min	71.4±10.6	70.1±11.0	0.22
Standing office SBP, mmHg	145.1±18.6	146.5±19.5	0.46
Standing office DBP, mmHg	89.0±12.8	90.1±12.5	0.38
Standing office PR, beats/min	74.6±11.4	73.6±12.4	0.41

Data are shown as the mean±SD or a percentage. ARB, angiotensin-receptor blocker; BP, blood pressure; CCB, calcium-channel blocker; DBP, diastolic blood pressure; PR, pulse rate; SBP, systolic blood pressure.

Changes in BP

During the treatment period, there were significant BP reductions (P<0.0001 for all BP parameters) from baseline (week 4) to the end of the 8-week treatment period (week 12) in both groups. Nocturnal HSBP (primary endpoint) and HDBP respectively decreased from 128.3/79.2 mmHg to 113.9/71.9 mmHg in the ARB/CCB group and from 128.4/79.2 mmHg to 117.9/73.7 in the ARB/diuretic group (Table 2). In the ARB/CCB group, the changes in nocturnal HSBP and HDBP from baseline to the end of the 8-week treatment period were −14.4±0.7 mmHg and −7.3±0.5 mmHg, respectively, and in the ARB/diuretic group the corresponding changes were −10.5±0.7 mmHg and −5.6±0.4 mmHg. Nocturnal HSBP and HDBP were more greatly reduced in the ARB/CCB group compared with the ARB/diuretic group (P=0.0001 for HSBP, P=0.0056 for HDBP; Table 2). In addition, the range of nocturnal HSBP in patients given the ARB/diuretic combination was broader than that in patients treated with the ARB/CCB combination (Figure 3). The SD of nocturnal HSBP measurements at weeks 8 and 12 were greater in the subjects receiving the ARB/diuretic combination than in those receiving ARB/CCB (P<0.0001).

Table 2. Changes in BP and Rate of Achievement of target BP Among Participants in the NOCTURNE Study

Variable	ARB/CCB group (n=203)	ARB/diuretic group (n=208)	P value for intergroup comparisons
BP level, mmHg
Nocturnal home SBP
Baseline (visit 2; week 4)	128.3±1.0	128.4±0.9	0.95
Visit 3 (week 8)	115.3±0.9*	119.9±0.9*	0.0005
Visit 4 (week 12)	113.9±0.9*	117.9±0.9*	0.0018
Change between weeks 4 and 12	−14.4±0.7	−10.5±0.7	0.0001
Nocturnal home DBP
Baseline (visit 2; week 4)	79.2±0.6	79.2±0.6	0.97
Visit 3 (week 8)	72.8±0.6*	74.7±0.6*	0.018
Visit 4 (week 12)	71.9±0.6*	73.7±0.6*	0.027
Change between weeks 4 and 12	−7.3±0.5	−5.6±0.4	0.0056
Morning home SBP
Baseline (visit 2; week 4)	144.1±1.1	143.7±1.1	0.83
Visit 3 (week 8)	129.7±1.1*	135.6±1.0*	<0.0001
Visit 4 (week 12)	129.0±1.1*	134.3±1.1*	0.0007
Change between weeks 4 and 12	−15.0±0.9	−9.4±0.9	<0.0001
Morning home DBP
Baseline (visit 2; week 4)	90.0±0.8	89.3±0.7	0.48
Visit 3 (week 8)	82.3±0.7*	85.2±0.7*	0.0027
Visit 4 (week 12)	82.1±0.7*	84.5±0.7*	0.012
Change between weeks 4 and 12	−8.0±0.6	−4.8±0.5	<0.0001
Evening home SBP
Baseline (visit 2; week 4)	136.5±1.2	137.3±1.2	0.64
Visit 3 (week 8)	124.2±1.1*	128.9±1.1*	0.0035
Visit 4 (week 12)	123.5±1.2*	128.4±1.1*	0.0028
Change between weeks 4 and 12	−13.0±1.1	−8.9±1.0	0.006
Evening home DBP
Baseline (visit 2; week 4)	83.7±0.8	83.3±0.7	0.78
Visit 3 (week 8)	77.0±0.7*	79.4±0.7*	0.023
Visit 4 (week 12)	77.2±0.7*	79.3±0.7*	0.039
Change between weeks 4 and 12	−6.5±0.6	−4.1±0.6	0.0048
Seated office SBP
Baseline (visit 2; week 4)	146.7±1.3	146.0±1.3	0.69
Visit 3 (week 8)	132.3±1.1*	136.5±1.1*	0.006
Visit 4 (week 12)	129.3±1.1*	134.3±1.1*	0.0019
Change between weeks 4 and 12	−17.4±1.2	−11.7±1.2	0.0009
Seated office DBP
Baseline (visit 2; week 4)	87.0±0.8	87.2±0.8	0.90
Visit 3 (week 8)	79.2±0.7*	82.4±0.7*	0.0019
Visit 4 (week 12)	78.3±0.7*	81.8±0.7*	0.0007
Change between weeks 4 and 12	−8.7±0.8	−5.4±0.7	0.0015
Standing office SBP
Baseline (visit 2; week 4)	145.2±1.3	146.4±1.3	0.53
Visit 3 (week 8)	130.6±1.2*	137.7±1.2*	<0.0001
Visit 4 (week 12)	128.6±1.2*	136.0±1.2*	<0.0001
Change between weeks 4 and 12	−16.7±1.2	−10.4±1.2	0.0002
Standing office DBP
Baseline (visit 2; week 4)	89.0±0.9	89.9±0.8	0.41
Visit 3 (week 8)	80.8±0.8*	85.5±0.7*	<0.0001
Visit 4 (week 12)	80.1±0.8*	84.3±0.8*	0.0001
Change between weeks 4 and 12	−8.9±0.8	−5.6±0.8	0.0038
Rate of achievement target BP, %
Nocturnal home BP (<120/70 mmHg)
Visit 3 (week 8)	35.3	21.5	0.0039
Visit 4 (week 12)	40.0	27.0	0.0086
Morning home BP (<135/85 mmHg)
Visit 3 (week 8)	54.6	31.6	<0.0001
Visit 4 (week 12)	59.3	34.9	<0.0001
Evening home BP (<135/85 mmHg)
Visit 3 (week 8)	77.1	57.9	0.0003
Visit 4 (week 12)	77.4	61.2	0.0018
Seated office BP (<140/90 mmHg)
Visit 3 (week 8)	67.0	53.0	0.0055
Visit 4 (week 12)	75.8	56.9	0.0001

Data are adjusted for age and sex and shown as the mean±SE, or percentage of the achievement rate for both SBP and DBP. *P<0.0001 vs. baseline for within-group changes. HR, heart rate. Other abbreviations as in Table 1.

Figure 3.

Changes in nocturnal home systolic blood pressure among participants in the NOCTURNE study. (A) The points represent the mean±SE, (B) ARB/CCB group, and (C) ARB/diuretic group. SBP, systolic blood pressure. Other abbreviations as in Figure 2.

In the ARB/CCB group, the changes in morning HSBP and HDBP from baseline to the end of the 8 week treatment were −15.0±0.9 mmHg and −8.0±0.6 mmHg, respectively, and in the ARB/diuretic group, the corresponding changes were −9.4±0.9 mmHg and −4.8±0.5 mmHg. Morning HSBP and HDBP were more greatly reduced in the ARB/CCB group compared with the ARB/diuretic group (both P<0.0001) (Table 2). In the ARB/CCB group, the changes in evening SBP and DBP from baseline to the end of the 8-week treatment period were −13.0±1.1 mmHg and −6.5±0.6 mmHg, respectively, and in the ARB/diuretic group, the corresponding changes were −8.9±1.0 mmHg and −4.1±0.6 mmHg. Evening HSBP and HDBP were more greatly reduced in the ARB/CCB group compared with the ARB/diuretic group (P<0.006 for HSBP, P<0.005, for HDBP; Table 2).

Seated and standing office SBP/DBP were more greatly reduced in the ARB/CCB group compared with the ARB/diuretic group (Table 2). Achievement rates for the target of nocturnal home and other BPs in the ARB/CCB group were significantly higher than those in the ARB/diuretic group (Table 2).

UACR and NT-proBNP

Changes in NT-proBNP and UACR during the study are shown in Table 3. Changes in UACR were not significantly different (P=0.14) between the ARB/diuretic group (−27.4%) and the ARB/CCB group (−15.6%), whereas changes in NT-proBNP were significantly greater in the ARB/CCB group (−28.1%) compared with the ARB/diuretic group (−18.1%) (P=0.019).

Table 3. Changes in NT-ProBNP and UACR Among Participants in the NOCTURNE Study

Variable	ARB/CCB group	ARB/diuretic group	P valuea
Overall group
n	203	208
UACR, mg/gCr
4 weeks (baseline)	31.2 (25.0, 38.9)	35.2 (27.9, 44.7)
12 weeks	26.8 (21.1, 34.1)*	25.0 (19.9, 31.8)**
Change (95% CI), %b	−15.6 (−27.4, −1.4)	−27.4 (−37.5, −16.5)	0.14
NT-proBNP, pg/mL
4 weeks (baseline)	61.6 (53.0, 71.5)	50.9 (43.8, 59.7)
12 weeks	45.2 (39.3, 52.5)**	42.1 (36.2, 49.4)**
Change (95% CI), %b	−28.1 (−33.6, −22.1)	−18.1 (−23.7, −11.3)	0.019
High UACR group (≥30 mg/gCr)
n	97	100
UACR, mg/gCr
4 weeks (Baseline)	111.1 (87.4, 141.2)	142.6 (108.9, 186.8)
12 weeks	69.4 (49.4, 96.5)**	70.8 (50.4, 98.5)**
Change (95% CI), %b	−37.5 (−49.8, −22.1)	−50.3 (−60.9, −36.9)	0.16
High NT-ProBNP group (≥125pg/mL)
n	47	38
NT-proBNP, pg/mL
4 weeks (Baseline)	247.2 (202.4, 301.9)	267.7 (214.9, 337.0)
12 weeks	154.5 (122.7, 192.5)**	202.4 (156.0, 265.1)*
Change (95% CI), %b	−38.1 (−46.2, −28.8)	−26.7 (−40.0, −10.8)	0.15

Values are expressed as the mean (95% confidence interval [CI]) and are converted to the original scale using the inverse transformation or a percentage. We used the natural-log transformation of the NT-proBNP and UACR levels because of the highly skewed distribution of these levels. ^aP value for between-group differences in the change from 4 to 12 weeks. ^bChange shows a reduction (%) between weeks 4 and 12. *P<0.01, **P<0.001 vs. baseline for within-group changes. NT-proBNP, N-terminal pro-B-type natriuretic peptide; UACR, urinary albumin/creatinine ratio. Other abbreviations as in Table 1.

Safety

During the treatment period, 31 adverse events occurred (22 in the ARB/CCB group vs. 9 in the ARB/diuretic group) and of them, 8 were serious (7 vs. 1) (Table 4). However, there were no causal relationships between serious adverse events and the drugs. Laboratory abnormalities were observed in both the ARB/CCB group (4) and the ARB/diuretic group (10) (Table 4).

Table 4. Safety Data for the NOCTURNE Study

AEs during the treatment period	Total (n=411)	ARB/CCB group (n=203)	ARB/diuretic group (n=208)
Total AEs	31 (28)	22 (20)	9 (8)
Serious AEs†	8 (8)	7 (7)	1 (1)
Abdominal aneurysm	1	1	0
Appendicitis	1	1	0
Atherothrombotic brain infarction	1	1	0
Dizziness	1	1	0
Gastric cancer	1	0	1
Intestinal obstruction	1	1	0
Radius fracture	1	1	0
Vitreous surgery	1	1	0
Non-serious AEs	23 (20)	15 (13)	8 (7)
Acute upper respiratory tract infection	1	1	0
Ankle sprain	1	0	1
Benign paroxysmal positional vertigo	1	1	0
Cellulitis	1	0	1
Chronic neck pain	1	1	0
Cold	4	2	2
Hemorrhoids	1	1	0
External otitis	1	1	0
Drop in BP requiring a dose reduction of antihypertensive drug	1	0	1
Hypotension	1	1	0
Knee joint inflammation	1	0	1
Increase in transaminase	1	0	1
Lower-limb edema	1	1	0
Ocular pain	1	1	0
Otitis media	1	1	0
Pharyngitis	2	1	1
Reflux esophagitis	1	1	0
Sudden hearing loss	1	1	0
Weakness	1	1	0
Laboratory abnormalities	14 (12)	4 (4)	10 (8)
Uric acid	5	2	3
Potassium	3	0	3
Alanine aminotransferase	2	1	1
γ-glutamyl transpeptidase	1	0	1
White blood cell	2	0	2
Hemoglobin A1c	1	1	0

*Data are shown as the number of events (patients). ^†Serious AEs showed no causal relationship with each drug. AE, adverse event; BP, blood pressure.

Post-Hoc Subgroup Analysis

We created a forest plot to present the effect size in specific subgroups (Figure 4). The nocturnal HSBP-lowering effect of the ARB/CCB combination was greater than that of the ARB/diuretic combination in this subgroup analysis. However, the difference in the nocturnal HSBP-lowering effect was not significant between the 2 groups in the diabetic, chronic kidney disease, and elderly subgroups.

Figure 4.

Forest plot of nocturnal blood pressure-lowering effects of combination therapy with ARB/diuretic vs. ARB/CCB in the NOCTURNE study. CKD, chronic kidney disease (eGFR <60 mL/min/1.73 m²); UACR, urinary albumin/creatinine ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide. Sodium intake (g/day) was estimated by urinary sodium and creatinine concentrations; Na/K ratio, urinary sodium/potassium ratio. Other abbreviations as in Figure 2.

When we stratified the study subjects based according to their estimated salt intake based on the Na/Cr ratio derived from 1-day spot urine, there were no significant differences in the nocturnal HSBP-lowering effect of the ARB-based combinations between the higher sodium intake group (≥9.6 g/day) and the lower sodium intake group (<9.6 g/day) (Figure 4). Similar results were found in the 2 groups stratified by urinary Na/K ratio.

There were no significant differences in the changes in UACR or NT-proBNP between the 2 groups of those with microalbuminuria (UACR >30 mg/g Cr) or those with high NT-proBNP (≥125 pg/mL) (Table 3).

Discussion

This is the first study to target uncontrolled nocturnal HT defined as a nocturnal home BP ≥120/70 mmHg, regardless of the control status of office BP, morning home BP or evening home BP. In this study, a combination of ARB/CCB combination was found to be superior to an ARB/diuretic combination for reducing nocturnal home BP in Japanese patients with uncontrolled nocturnal HT. This is also the first RCT to use ICT-based nocturnal HBPM; the results showed that an ICT-based approach is feasible in a clinical trial to obtain objective nocturnal BP measurements during sleep directly from the patient’s home.

Uncontrolled Nocturnal HT

In this study, the first to target uncontrolled nocturnal HT irrespective of the control status of office BP and morning or evening home BP, the ARB/CCB combination was superior to the ARB/diuretic combination for reducing nocturnal home BP, the primary endpoint. Nocturnal HT is considered to be associated with increased circulating volume, which is partly determined by higher salt intake, especially in those with high salt-sensitivity.⁹ Because the ARB restores salt sensitivity,¹² we speculated that the synergistic nocturnal BP-lowering effect of the ARB/diuretic combination would be greater than the additive nocturnal BP-lowering effect of the ARB/CCB combination. Unexpectedly, however, we found that a diuretic (daily trichlormethiazide 1 mg) was less effective for reducing nocturnal BP than a CCB (daily amlodipine 5 mg) when the respective drugs were administered together with an ARB (daily irbesartan 100 mg) in patients with uncontrolled nocturnal HT in the NOCTURNE study. Nonetheless, the follow-up duration may have been too short to determine whether the ARB/diuretic combination has a sufficient BP-lowering effect; that is, the follow-up period in the NOCTURNE study was only 2 months (8 weeks). In our previous J-CORE study, which demonstrated that ABPM-measured nocturnal BP tended to be greater in the ARB/diuretic group (olmesartan 20 mg+hydrochlorothiazide 12.5 mg) than in the ARB/CCB group (olmesartan 20 mg+azelnidipine 16 mg), the follow-up was 6 months.²¹ Another trial of ARB-based combination therapy demonstrated that an ARB/CCB combination (the same ARB as that in the screening phase+amlodipine 5 mg) reduced office BP more extendedly than an ARB/diuretic combination (losartan 50 mg+hydrochlorothiazide 12.5 mg) at 3 months after randomization, but the BP-lowering effects were the same after 6, 9, and 12 months.²² Thus, to achieve the stable maximum BP-lowering effect, the ARB/diuretic combination may require a longer duration of administration than the ARB/CCB combination. The range of individual nocturnal BP-lowering effects by the ARB/diuretic combination was broader than that of the ARB/CCB, as shown in Figure 3. The broader range of the home BP-lowering effects of the ARB/diuretic combination indicates the importance of individual-based, HBPM-guided antihypertensive approach to nocturnal HT for the management of HT throughout a 24-h period.

UACR and NT-proBNP

Although the nocturnal home BP reduction was greater in the ARB/CCB group than in the ARB/diuretic group, the reduction in UACR was comparable between the 2 treatment groups in both the entire group and the subgroup with microalbuminuria. The reduction in NT-proBNP was greater in the ARB/CCB group than in the ARB/diuretic group in the entire group, but this difference was comparable in those with a higher NT-proBNP level. A previous population-based study demonstrated that even in normotensive community-dwelling subjects, non-dipper status was associated with concentric LVH and increased plasma levels of BNP.³ In our previous subanalysis of the J-TOP (Japan Morning Surge-Target Organ Protection) study, the change in ABPM-measured nocturnal ABP was more closely associated with a change in the plasma BNP level than a change in the daytime ABP.²³ Even among those with well-controlled morning and evening home BPs, those who remained as isolated nocturnal hypertensive with ABPM-measured nocturnal ABP ≥120/70 mmHg exhibited higher UACR and higher serum BNP than those with well-controlled nocturnal ABP <120/70 mmHg.²⁴ Thus, control of nocturnal HT is important for organ protection in the management of HT.

ICT-Based Nocturnal HBPM

We recently developed an ICT-based device for measuring nocturnal HBPM.^7,8 In the present study, we confirmed that the ICT-based approach successfully yielded objective nocturnal BP measurements directly from patients at sleep in their homes, and demonstrated that antihypertensive medication significantly reduced nocturnal home BP as well as morning and evening home BPs in this clinical trial. In previous clinical trials, ABPM was more frequently used than HBPM, because the home BP values are self-reported by patients and HBPM cannot measure nocturnal BP during sleep. In our previous clinical practice-based registry, the JHOP (Japan Morning Surge-Home Blood Pressure) study, we used nocturnal HBPM (Medinote), which has the capacity to store data but lacks an ICT transmission system, and found that nocturnal home BP significantly correlated with measures of organ damage.^15,16 In the NOCTURNE study, we assessed for the first time whether an ICT-based nocturnal HBPM^7,8 device could be successfully used by hypertensive patients who had no prior experience with the device. During the run-in period, 552 (89.6%) of the 616 registered patients measured their nocturnal home BP with 3G-enabled HBPM. At the end of the treatment period (12 weeks), 374 (91.0%) of 411 patients had successfully measured their nocturnal home BP with the device. Thus, HBPM could be used as an alternative to ABPM in both clinical trials and clinical practice to assess nocturnal BP.

Post-Hoc Subgroup Analysis and Limitations

The post-hoc subanalysis demonstrated that there were no significant differences in the nocturnal BP-lowering effect between the ARB/CCB and the ARB/diuretic groups in the diabetic, chronic kidney disease, or elderly subgroups. These 3 subgroups are known to have increased salt sensitivity.⁹ Thus, in these subgroups, the nocturnal BP-lowering effect of ARB/diuretic combination may not be significantly different from that of the ARB/CCB combination. Accordingly, when such salt-sensitive patients are medicated using the combination of an ARB/diuretic, strict salt restriction is recommended in order to enhance the nocturnal BP-lowering effect.

Neither the salt-intake estimate based on urinary sodium excretion, nor the urinary sodium/potassium ratio had any effect on the nocturnal BP-lowering effect in the NOCTURNE study. This may have been partly because of the specific method used to estimate salt intake (i.e., estimated from the Na/Cr ratio in 1-day spot urine samples collected in the office). Although this method is simple, it is also somewhat unreliable.¹⁹ Further study of the relationship between salt intake evaluated by a more precise method such as 24-h urine collection over several days and nocturnal BP-lowering effect is required.

The nocturnal BP dipping status did not affect the nocturnal BP-lowering effect of the 2 groups in the NOCTURNE study. In general, patients with a non-dipper/riser pattern of nocturnal BP are considered to be more salt-sensitive than dippers.⁹ Salt restriction and diuretic monotherapy have been shown to reduce nocturnal ABP more extensively than daytime ABP, resulting in a shift from non-dipper to dipper status.^10,11 However, those previous studies used ABPM to define the status of non-dippers and dippers. As there is no consensus on the non-dipper/dipper classification of nocturnal home BP, we defined it according to the percentage of nocturnal HSBP dip against the average of morning and evening HSBPs in the NOCTURNE study. In the future, we will study the clinical implications of the different definitions of home BP-defined non-dipper status.

Conclusion and Perspectives

Uncontrolled nocturnal HT could be detected by HBPM, and both the ARB/CCB and ARB/diuretic combinations significantly reduced nocturnal home BP. The nocturnal BP-lowering effect of the ARB/CCB combination was greater than that of the ARB/diuretic combination.

Acknowledgments

This study was carried out as a joint research effort by the Jichi Medical University School of Medicine and Shionogi & Co., Ltd. This study was funded by Shionogi & Co., Ltd, which was involved in creating the design, but not involved in data collection, did not have date access rights, and did not play a role in the statistical analysis.

The independent study control center was managed and all the data were collected by a contract research organization (CRO), Satt Co., Ltd. (Tokyo, Japan). All data and procedures of this study were regularly audited independently by another CRO, Selene Science Co., Ltd. (Tokyo, Japan).

The authors thank Mrs. Ayako Okura, Department of Cardiovascular Medicine, Jichi Medical University School of Medicine, for her editorial support.

Conflicts of Interests / Disclosures

K. Kario has received honoraria from Omron Healthcare Co., Ltd., Daiichi Sankyo Co., Ltd., and Takeda Pharmaceutical Co, Ltd., as well as research grants from Fukuda Denshi Co., Ltd., Omron Healthcare Co., Ltd., Bayer Yakuhin Co., Ltd., Medtronic Japan Co., Ltd. (for participation in SYMPLICITY HTN-Japan), Otsuka Pharmaceutical Co., Ltd., and Teijin Pharma Co. Ltd. K. Kanda is an employee of Shionogi & Co., Ltd. Shinji Hasegawa is an employee and stock/shareholder of Shionogi & Co., Ltd. The other authors declare no conflicts of interest.

Sources of Funding

This work was supported by Shionogi & Co., Ltd. Trial registration URL: http://www.umin.ac.jp; University Hospital Medical Information Network Clinical Trials Registry, UMIN000016629.

Appendix

Participants and Participating Centers

Akira Kurai, Kurai Naika Clinic; Akira Hirosaka, Hirosaka Cardiology Medical Clinic; Akitoshi Kawakubo, Ikeura Clinic; Atsushi Hasegawa, Hasegawa Clinic; Chikako Ito, Grand Tower Medical Court Life Care Clinic; Fumio Naganuma, Tsurugaya Hospital; Fumishi Tomita, Tomita Medical Clinic Internal Medicine Cardiovascular Medicine; Hajime Ishii, Kashinoki Internal Medicine; Haruki Takahashi, Okubo Iin; Hideki Kikuchi, Kikuchi Clinic; Hiroaki Omori, Shizukuishi Omori Clinic; Hiroaki Seino, Seino Internal Medicine Clinic; Hiroshi Ohtani, Iwase General Hospital; Hiroshi Nishimura, Nishimura Clinic; Hiroshi Takeda, Medical Corp. Takeda Clinic; Hirotaka Kubo, Sekishindo Clinic; Hiroto Takezawa, Takezawa Clinic; Issei Sano, Sano Heart Clinic; Jun Yamagami, Yamagami Naika; Kazuomi Kario, Jichi Medical University Hospital; Kayo Yamagiwa, Yamagiwa Clinic; Kazuaki Uchiyama, Uchiyama Clinic; Kazumi Akiyama, Akiyama Clinic; Kazuo Ikeda, Ikeda Clinic; Kazuo Maeda, Maeda Medical Clinic; Kei Kotani, Kotani Diabetes Clinic; Kengo Matsumoto, Ishite Matsumoto Internal Medicine Cardiology Clinic; Kensuke Kimura, Kimura Naika Clinic; Makiko Kono, Owada Naika Ichouka; Makio Tani, Tani Naika Clinic; Masahiro Tohaya, Tohaya Iin; Masaki Akahata, Hosoda Clinic; Masatoshi Yanagisawa, Yanagisawa Iin; Masayuki Otaki, Tenjinmae Clinic; Mizuki Kaneshiro, Kaneshiro Diabetes Clinic; Motoyuki Ishiguro, Ishiguro Clinic; Munenori Miyake, Nagisa Clinic; Naonobu Nishino, KEIJU Hospital; Naoto Minamitani, Minamitani Clinic; Naoto Yokota, Yokota Naika; Nobuo Takahashi, Takahashi Family Clinic; Norihiro Tsuchiya, Omotesando Clinic; Reiko Majima, Hayashi Clinic; Ryusaku Shionoya, Shionoya Clinic; Shigeki Nishizawa, Nishizawa Medical Clinic; Shigeki Moritani, Moritani Clinic; Shigeru Nakano, Shika Clinic; Shigeru Sekiguchi, Sekiguchi Clinic; Shigeru Tai, Tai Internist Clinic; Shinya Okamoto, Iwasaki Hospital; Shinya Hiramitsu, Hiramitsu Heart Clinic; Shuichi Kawano, Kawano Clinic; Takao Nagasu, Nagasu Clinic; Takeshi Okuda, Okuda Clinic; Takuo Ogawa, Ogawa-naika Clinic; Taro Asakura, Kaneshiro Diabetes Clinic; Tetsuro Yoshida, Onga Nakama Medical Association Onga Hospital; Tetsuya Kogawa, Nakanoshima Kitaguchi Kogawa Clinic; Tomohiro Katsuya, Katsuya Iin; Toshihiko Shiraiwa, Shiraiwa Medical Clinic; Toshio Tamaki, Tamaki Clinic; Toshiro Matsunaga, Suizenji Touya Hospital; Yasuhiro Hashiguchi, Tempozan Naika Clinic; Yasuhiro Horii, Seiwadai Clinic; Yasuyuki Maruyama, Iwatsuki-minami Hospital; Yojiro Kurihara, Kondo Clinic; Yoko Emura, Medical Corporation emura ityoukanaikaiin; Yoshiki Noda, Noda Clinic; Yutaka Wakasa, Wakasa Medical Clinic.

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