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The Journal of Clinical Hypertension logoLink to The Journal of Clinical Hypertension
. 2013 Apr 29;15(7):465–472. doi: 10.1111/jch.12113

Effect of a Novel Calcium Channel Blocker on Abnormal Nocturnal Blood Pressure in Hypertensive Patients

Kazuomi Kario 1,✉, Jin Nariyama 2, Hidenori Kido 3, Shin‐ichi Ando 4, Shin Takiuchi 5, Kazuo Eguchi 1, Yawara Niijima 6, Toshiaki Ando 6, Makoto Noda 7
PMCID: PMC8033971  PMID: 23815534

Abstract

The authors examined the effect of cilnidipine, a unique L/N‐type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE), a large‐scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24‐hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12‐week treatment with cilnidipine significantly reduced 24‐hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were −17.9 mm Hg from 154.6 mm Hg in risers and −11.9 mm Hg from 142.1 mm Hg, −6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but −7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (−0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

A number of studies have demonstrated that nocturnal nondipping1, 2, 3 and extreme dipping of blood pressure (BP)4, 5, 6 are associated with organ damage. A lack of nocturnal dipping has also been related to risk of cardiovascular events,7, 8, 9, 10, 11 even if BP measured at the clinic or at home is normal. Diuretics, angiotensin‐converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists are partially effective in restoring normal BP dipping.12, 13, 14 However, evidence‐based studies of antihypertensive medication for the treatment of abnormal nocturnal dipping are lacking. In current daily medical practice, antihypertensive medication for reducing 24‐hour BP as well as normalizing dipping status need to be individualized and optimized in each hypertensive patient with different backgrounds such as age and comorbidities.

Cilnidipine is a unique L/N‐type calcium channel blocker (CCB) that inhibits norepinephrine release at sympathetic nerve endings by blocking N‐type calcium channels and directly dilates vascular vessels by blocking L‐type calcium channels.15, 16, 17, 18 Recently, we demonstrated that cilnidipine reduced BP and pulse rate (PR) in patients with morning hypertension suggested to be characterized by increased sympathetic activity using data measured at home obtained from the Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by the N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE) trial.19 The investigation is a large‐scale clinical study designed to evaluate the effects of cilnidipine in daily medical practice on BP and PR in patients with essential hypertension measured at the clinic and at home. In a portion of these patients, measurement was performed by 24‐hour ambulatory BP (ABP) monitoring (ABPM).

In the present study, we examined the effects of cilnidipine on abnormal nocturnal dipping in hypertensive patients.

Methods

Patients and Study Design

The ACHIEVE‐ONE trial was an observational study approved by the institutional review board of Jichi Medical University and was registered in the University Hospital Medical Information Network, Japan (UMIN000003695). This study was conducted in conformity with the Japanese Good Post‐Marketing Study Practice, which is a guideline that specifies acceptable post‐marketing surveillance activities. Clinical practitioners were openly recruited from across Japan. Patients were diagnosed as having hypertension by each clinical practitioner according to the guidelines for the management of hypertension in the Japanese Society of Hypertension and were prescribed cilnidipine in daily medical practice during the period from October 2008 to September 2010. Each clinical practitioner participating in this study transcribed patient data to an electric data–capturing system (PostMaNet; Fujitsu F.I.P. Corporation, Tokyo, Japan) as unlinkable anonymized records. Pregnant women and women suspected of being pregnant were excluded from this study. No restriction was set on age or complications. Cilnidipine is a CCB approved in Japan for its use according to the following administration and dosage regimens: (1) for patients with hypertension, once‐daily oral treatment after breakfast at a dose of 5 to 10 mg; and (2) for patients with severe hypertension, the dose can be increased up to 20 mg. Regimens for cilnidipine and other concomitant drugs had been decided by practitioners and were not changed until the study was finished, except for patients with therapeutic disadvantages. Adverse effects encountered in this study were collected in the electronic data capture system based on reports from practitioners.

24‐Hour BP Monitoring

Before starting treatment and after 12 weeks of treatment, 24‐hour ABPM was performed in a subset of patients who participated in the ACHIEVE‐ONE trial.19 Practitioners trained each patient on how to measure 24‐hour ABP as recommended by the guidelines of the Japanese Circulation Society.20 ABP was monitored every 30 minutes with a cuff‐oscillometric device approved by the Ministry of Health, Labor, and Welfare, Japan. Each patient recorded daily activities including the time of going to bed and waking up. Incomplete BP datasets retaining <5 monitoring points during either daytime or nighttime were excluded from this analysis.

Day and night BP and PR were defined as the mean BP and PR in the interval from waking up to going to bed, and from going to bed to waking up, respectively. Morning BP and PR were defined as the mean BP and PR during the first 2 hours after awakening. The nighttime low systolic BP (SBP) was defined as the lowest value among the 1‐hour moving averages of SBP measured during the total sleep period. Morning surge was calculated by subtracting the nighttime low SBP from the morning SBP (sleep‐trough morning surge). Nocturnal SBP reduction rate (%) was calculated as (day SBP – night SBP)/day SBP×100.

Patient Classification

Hypertensive patients were classified into 4 groups using the following criteria: extreme dippers, a nocturnal SBP reduction rate of ≥20%; dippers, a nocturnal SBP reduction rate of 10% to <20%; nondippers, a nocturnal SBP reduction rate of 0% to <10%; and risers, a nocturnal SBP reduction rate of <0%.

Statistical Analysis

Data are expressed as mean±standard deviation (SD) except as otherwise noted. After one‐way analysis of variance (ANOVA) or chi‐square test, a Dunnett test or Fisher exact test was used to evaluate differences between dippers and other groups. A Wilcoxon signed rank test was also used for comparison of BP and PR values between pretreatment and posttreatment. Two‐way ANOVA was used for evaluation of daytime and nighttime SBP changes in the patients stratified into quartiles based on the baseline 24‐hour SBP. All statistical tests were performed using two‐tailed designs with a significance level (P value) <.05, which was adjusted using the Bonferroni method when performing multiple comparisons (the original P value was divided by the number of tests performed to obtain an adjusted significance threshold). Analyses were performed using SAS statistical software (version 9.1; SAS Institute, Inc, Cary, NC).

Results

Baseline Characteristics of Patients in Each Nocturnal Dipping Status Group

ABPM was performed in 615 patients before and after cilnidipine treatment, but 54 patients were excluded from this analysis because of incomplete or poor‐quality ABP data. No significant difference was observed in the baseline mean 24‐hour SBP between the remaining included 561 patients and the excluded 54 patients (146.2±16.1 mm Hg vs 148.0±16.1 mm Hg, respectively; P=.437). There were also no significant differences between these groups regarding changes in 24‐hour SBP from baseline after 12 weeks of treatment (−10.3±15.3 mm Hg vs −13.0±14.8 mm Hg, respectively; P=.223). Among the 561 patients, 269 patients was unmedicated, and 159, 85, and 48 patients were medicated with 1, 2, and ≥3, respectively, kinds of antihypertensive drugs at baseline. All the 561 patients had been prescribed cilnidipine during the study period, but 45 patients had a change in medication excluding cilnidipine. Daytime and nighttime SBP values after treatment between groups of the 45 patients and the other 516 patients were not significantly different (140.4±19.1 mm Hg vs 138.9±13.9 mm Hg, P=.757 and 124.5±20.1 mm Hg vs 126.4±17.5 mm Hg P=.238, respectively). Cilnidipine was administrated once a day in the morning for 410 (73.1%) patients, once a day in the evening for 99 (17.6%) patients, and twice a day in the morning and evening for 52 (9.3%) patients. The average daily dose of cilnidipine was 10.5±3.9 mg.

As shown in Table 1, 561 patients were classified into the 4 nocturnal dipping groups, extreme dippers (n=74), dippers (n=200), nondippers (n=206), and risers (n=81). Significant differences were observed among 4 groups in age, sex, daytime SBP and diastolic BP (DBP), daytime PR, nighttime SBP and DBP, morning SBP, morning surge, prevalence of chronic kidney disease (CKD), and percentage of concomitant use of diuretics and αβ‐blockers. When compared with dippers, extreme dippers showed a significantly higher morning surge and use of diuretic medication, as well as significantly lower mean nighttime BPs; nondippers had higher nighttime BP and a lower morning BP surge; risers were older, had higher comorbidity of CKD and nighttime BPs, and were lower in daytime BPs and morning surge. In addition, the prevalence of risers among patients with CKD was significantly higher than in those without CKD (23.6% vs 13.4%, respectively; P=.041).

Table 1.

Baseline Characteristics of Patients

Total Extreme Dippers Dippers Nondippers Risers ANOVA or Chi‐Square
N=561 n=74 n=200 n=206 n=81
Age, y 66.1±12.2 62.7±11.1 65.2±12.5 65.5±12.4 72.5±10.0 a P<.0001
Men, % 50.3 41.9 57.0 50.5 40.7 P=.0344
Body mass index, kg/m2 23.9±3.8 23.4±3.8 23.9±3.5 24.3±4.3 23.5±3.3 P=.4395
Comorbidity, %
Dyslipidemia 26.0 23.0 23.0 25.7 37.0 P=.0929
Ischemic heart disease 3.6 1.4 2.5 5.3 3.7 P=.3072
Diabetes mellitus 15.0 17.6 13.0 16.0 14.8 P=.7574
Cerebral vascular disorder 8.9 8.1 9.5 9.2 7.4 P=.9414
Chronic kidney disease 9.8 4.1 6.0 13.1 16.0 a P=.0069
Concomitant antihypertensive drug, %
Angiotensin II receptor blocker 41.9 39.2 39.0 43.7 46.9 P=.5679
Angiotensin‐converting enzyme inhibitor 4.6 5.4 3.0 4.9 7.4 P=.4335
Calcium channel blocker 6.4 5.4 6.0 7.3 6.2 P=.9301
Diuretic 13.2 25.7 b 9.0 11.7 16.0 P=.0027
β‐Blocker 8.2 5.4 9.0 7.8 9.9 P=.7311
αβ‐Blocker 7.5 2.7 4.5 11.2 9.9 P=.0212
α‐Blocker 4.1 4.1 2.0 4.4 8.6 P=.0884
Mean 24‐h SBP, mm Hg 146.2±16.1 143.8±14.7 144.8±14.8 148.1±16.9 147.2±18.0 P=.0999
Mean 24‐h DBP, mm Hg 86.5±12.1 84.3±11.8 87.6±11.1 86.8±12.9 85.0±12.4 P=.1403
Mean 24‐h PR, beats per min 70.5±9.2 72.9±9.4 70.3±8.7 70.2±9.0 69.4±10.3 P=.1030
Day SBP, mm Hg 149.7±16.4 152.8±15.9 150.1±15.2 150.0±16.9 144.8±17.8 a P=.0182
Day DBP, mm Hg 88.8±12.5 89.0±12.4 91.0±11.4 88.3±12.9 84.5±12.8 b P=.0009
Day PR, beats per min 72.9±9.7 76.0±10.0 72.9±9.3 72.5±9.3 71.4±10.9 P=.0221
Night SBP, mm Hg 135.6±19.4 115.8±11.9 b 128.5±13.6 142.1±16.5 b 154.6±19.6 b P<.0001
Night DBP, mm Hg 79.2±12.9 69.6±10.5 b 77.1±11.1 82.0±13.1 b 86.2±12.5 b P<.0001
Night PR, beats per min 63.0±9.2 62.9±9.0 62.5±9.0 63.3±9.2 63.5±9.9 P=.7504
Morning SBP, mm Hg 152.2±19.1 147.8±19.6 150.7±18.2 154.1±18.5 154.7±21.2 P=.0386
Morning DBP, mm Hg 90.9±14.1 87.1±13.6 92.1±13.1 91.4±14.4 90.2±15.5 P=.0654
Morning PR, beats per min 71.4±11.3 74.4±10.6 70.9±10.8 71.1±11.5 71.0±12.4 P=.1359
Morning surge, mm Hg 30.4±17.5 44.9±16.0 b 35.5±14.9 26.2±14.6 b 15.4±16.8 b P<.0001
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Abbreviations: ANOVA, analysis of variance; DBP, diastolic blood pressure; PR, pulse rate; SBP, systolic blood pressure. a P<.05. b P<.001 vs dippers.

BP‐Lowering Effects of Cilnidipine on Patients in each Nocturnal Dipping Status Group

The BP‐lowering effects of cilnidipine were determined by 24‐hour ABP measurements in 561 patients classified according to the 4 nocturnal dipping types. SBP and DBP were significantly decreased at all time points during the 24 hours of recording in the total patient sample (Figure 1). To characterize the BP‐lowering effects of cilnidipine, we examined the changes in daytime and nighttime SBPs, stratified according to mean 24‐hour SBP at baseline (Figure 2). Two‐way ANOVA revealed that a trend in SBP changes between daytime and nighttime were not different in total patients (P=.143). Then, these patients were classified into 4 groups by nocturnal dipping types (Figure 3). In extreme dippers, SBP and DBP were significantly reduced, except during the sleep period. In dippers and nondippers, SBP and DBP were significantly decreased at all time points during the 24‐hour recording. In risers, SBP and DBP were significantly reduced during nighttime and morning. The trends in SBP changes between daytime and nighttime were different in extreme dippers, dippers, and risers (P<.001), but not in nondippers (P=.122) (Figure 4). In risers, the daytime SBP change reached almost a plateau between Q3 and Q4 of baseline mean 24‐hour SBP.

Figure 1.

Figure 1

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Effect of cilnidipine on 24‐hour blood pressure (BP) variation in the total study population. Data are shown as hourly averages of systolic BP (SBP) and diastolic BP (DBP) in the total patient sample (n=561).○ and • indicate SBP at baseline and after 12 weeks of cilnidipine treatment, respectively. ▵ and ▲indicate DBP at baseline and after 12 weeks of cilnidipine treatment, respectively. ‡P<.001, Wilcoxon test. [Correction added after online publication 29‐Apr‐2013: Figure has been updated.]

Figure 2.

Figure 2

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Effects of cilnidipine on daytime and nighttime systolic blood pressure (SBP) changes in total patients. □ and ■ indicate as average daytime and nighttime SBP changes between baseline and after 12 weeks of cilnidipine treatment in the total patients stratified into quartiles, according to baseline mean 24‐hour SBP. Two‐way analysis of variance was used for the analysis.

Figure 3.

Figure 3

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Effect of cilnidipine on 24‐hour blood pressure (BP) variation in patients with different dipping patterns. SBP indicates systolic BP; DBP, diastolic blood pressure. Data are shown as hourly averages of SBP and DBP in extreme dippers (n=74), dippers (n=200), nondippers (n=206), and risers (n=81).○ and • indicate SBP at baseline and after 12 weeks of cilnidipine treatment, respectively. ▵ and ▲indicate DBP at baseline and after 12 weeks of cilnidipine treatment, respectively. *P<.05. †P<.01. ‡P<.001 vs baseline by Wilcoxon test. [Correction added after online publication 29‐Apr‐2013: Figure has been updated.]

Figure 4.

Figure 4

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Effects of cilnidipine on daytime and nighttime systolic blood pressure (SBP) changes in patients with different dipping patterns. □ and ■ indicate as average daytime and nighttime SBP changes between baseline and after 12 weeks of cilnidipine treatment in extreme dippers (n=74), dippers (n=200), nondippers (n=206), and risers (n=81) stratified into quartiles, according to baseline mean 24‐hour SBP. Two‐way analysis of variance was used for the analysis.

Mean 24‐hour SBPs were significantly reduced in the total patient sample, extreme dippers, dippers, nondippers, and risers (Table 2). Changes from baseline of nighttime SBP were 0.1±13.2 mm Hg, −6.6±15.2 mm Hg, −11.9±18.3 mm Hg, and −17.9±23.3 mm Hg in extreme dippers, dippers, nondippers, and risers, respectively. Changes from baseline of daytime SBP were −12.8±11.7 mm Hg, −12.7±14.3 mm Hg, −9.6±16.9 mm Hg, and −6.1±18.7 mm Hg in extreme dippers, dippers, nondippers, and risers, respectively. In risers, the changes in SBP between measurements made before and after treatment were greater at nighttime (−17.9±23.3 mm Hg) than the mean 24‐hour recording (−9.0±19.0 mm Hg), day (−6.1±18.7 mm Hg), and morning (−11.1±22.2 mm Hg) SBPs. In contrast, in extreme dippers, cilnidipine significantly reduced SBP and DBP in the mean 24‐hour, daytime, and morning, but not at nighttime.

Table 2.

Changes in SBP, DBP, and PR During the 24‐Hour Awake, Sleep, and Morning Recordings in Patients of Different Dipping Types

Total Extreme Dippers Dippers Nondippers Risers ANOVA
N=561 n=74 n=200 n=206 n=81
Mean 24‐h SBP, mm Hg Changes −10.3±15.3 −9.8±10.8 −11.2±13.7 −10.1±16.4 −9.0±19.0 P=.6932
vs baseline P<.0001 P<.0001 P<.0001 P<.0001 P<.0001
Mean 24‐h DBP, mm Hg Changes −5.7±8.9 −4.9±7.0 −6.4±8.5 −5.6±9.3 −5.1±10.2 P=.4564
vs baseline P<.0001 P<.0001 P<.0001 P<.0001 P<.0001
Mean 24‐h PR, beats per min Changes −0.6±6.3 −2.3±6.9 −0.6±6.6 −0.1±6.1 −0.3±5.3 P=.0662
vs baseline P=.0309 P=.0055 P=.1935 P=.8987 P=.6697
Day SBP, mm Hg Changes −10.6±15.8 −12.8±11.7 −12.7±14.3 −9.6±16.9 −6.1±18.7 b P=.0068
vs baseline P<.0001 P<.0001 P<.0001 P<.0001 P=.0041
Day DBP, mm Hg Changes −5.8±9.5 −6.1±7.9 −7.1±9.2 −5.2±9.8 −3.8±10.7 a P=.0417
vs baseline P<.0001 P<.0001 P<.0001 P<.0001 P=.0020
Day PR, beats per min Changes −0.5±7.1 −2.6±8.1 −0.5±7.3 0.1±6.7 0.0±6.2 P=.0304
vs baseline P=.1036 P=.0062 P=.3109 P=.7962 P=.9588
Night SBP, mm Hg Changes −9.3±18.2 0.1±13.2 a −6.6±15.2 −11.9±18.3 b −17.9±23.3 c P<.0001
vs baseline P<.0001 P=.9415 P<.0001 P<.0001 P<.0001
Night DBP, mm Hg Changes −5.3±10.4 −0.8±8.0 a −4.3±9.9 −6.5±10.3 −9.0±12.2 c P<.0001
vs baseline P<.0001 P=.3842 P<.0001 P<.0001 P<.0001
Night PR, beats per min Changes −0.9±7.1 −0.9±5.7 −0.8±7.4 −0.7±7.2 −1.5±6.9 P=.8553
vs baseline P=.0029 P=.1952 P=.1120 P=.1633 P=.0509
Morning SBP, mm Hg Changes −9.7±21.3 −7.6±18.7 −10.6±20.2 −9.0±23.0 −11.1±22.2 P=.6713
vs baseline P<.0001 P=.0011 P<.0001 P<.0001 P<.0001
Morning DBP, mm Hg Changes −5.7±13.6 −4.1±13.1 −6.5±13.4 −5.6±14.2 −5.5±13.2 P=.6590
vs baseline P<.0001 P=.0109 P<.0001 P<.0001 P=.0004
Morning PR, beats per min Changes −1.1±10.8 −2.7±9.8 −1.6±10.9 −0.7±11.0 0.4±10.5 P=.1359
vs baseline P=.0188 P=.0226 P=.0563 P=.3771 P=.7403
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Abbreviations: ANOVA, analysis of variance; DBP, diastolic blood pressure; PR, pulse rate; SBP, systolic blood pressure. a P<.05. b P<.01. c P<.001 vs dippers.

As shown by the nighttime SBP reduction rate in Table 3 and Figure 3, cilnidipine significantly, but not completely, restored abnormal nocturnal dipping toward a dipping pattern. Changes from baseline in nighttime SBP reduction rate were −7.0%±8.2% in extreme dippers, 1.8%±8.7% in nondippers, and 8.2%±10.2% in risers, while no change was observed in the nighttime SBP reduction rate for the total sample of 561 patients (−0.2%±9.6%).

Table 3.

Changes in Nocturnal SBP Reduction Rate

Total Nocturnal SBP Reduction, % ANOVA
Extreme Dippers Dippers Nondippers Risers
N=561 n=74 n=200 n=206 n=81
Baseline 9.3±9.6 24.1±3.6 14.4±2.8 5.3±2.7 −6.8±5.0
Changes from baseline −0.2±9.6 −7.0±8.2 a −3.2±7.5 1.8±8.7 b 8.2±10.2 b P<.0001
vs baseline P=.6174 P<.0001 P<.0001 P=.0028 P<.0001
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Abbreviations: ANOVA, analysis of variance; SBP, systolic blood pressure. a P<.01. b P<.001. vs dippers.

Adverse Reactions Related to Cilnidipine

A total of 4 episodes of adverse reactions occurred in 4 patients (0.65%). Adverse reactions included abnormal hepatic function, peripheral edema, decreased blood pressure, and abdominal discomfort.

Discussion

Effects of Cilnidipine in Risers

Cilnidipine reduced nighttime BP more than daytime BP in risers, nighttime and daytime BPs equally in nondippers, and daytime BP more than nighttime BP in dippers (Figures 3 and 4, Table 2). These effects may be a reflection of dual actions that cilnidipine blocks both L‐type and N‐type calcium channels. An L‐type CCB, amlodipine showed similar effects on BP excluding risers, since BP data in risers was lacking.21 An α‐adrenergic blocker, doxazocin, suppressing sympathetic nerve activity, reduced nighttime BP more than daytime BP in risers.22, 23 Therefore, we speculate that cilnidipine can restore abnormal nocturnal dipping status in risers predominantly by blocking N‐type calcium channels, although cilnidipine also reduces 24‐hour BP by blocking L‐type calcium channels. ARBs, ACE inhibitors, aldosterone antagonists, diuretics, and salt restriction, which decrease preload as well as nighttime ABP,24 partially restore nocturnal BP dipping status from nondippers to dippers.12, 13, 14 Recently, Aritomi and colleagues25 showed that cilnidipine inhibited aldosterone production dose‐dependently in H295R adrenocarcinoma cells expressing N‐type calcium channels. This novel action of cilnidipine may also play a role in restoring nocturnal BP dipping status. In the present study, risers were older and had more frequent comorbidity with CKD than dippers (Table 1), and nondippers also showed a similar trend. These findings coincide with reports that risers are highly prevalent among hypertensive patients with comorbid CKD,26 and that aging is associated with increased prevalence of nondipping status in CKD patients.27 Risers as well as nondippers among CKD patients are known to be at risk for cardiovascular events, end‐stage renal disease, or death.28 We also reported that risers have a 2.7‐fold higher risk of stroke than dippers,29 and that CKD and nondipping in elderly hypertensive patients increase the risk for cardiovascular events.30 In addition, sympathetic activity is increased in risers,31, 32 the elderly,33 and CKD patients.34, 35 Therefore, the risers classified in this study were not an unusual subpopulation and are suggested to have increased sympathetic activity.

Effects of Cilnidipine on Extreme Dippers

The morning BP surge in extreme dippers (Table 1)10 and prevalence of extreme dippers in the top decile of the morning BP surge group29 are the highest among the dipping patterns. An exaggerated morning BP surge has been shown to be a cardiovascular risk10, 29, 36 and is associated with increased sympathetic activity early in the morning.37, 38, 39 In addition, it has been suggested that extreme dipping may provoke cerebral and cardiac ischemia caused by excessive lowering of nocturnal BP, leading to hypoperfusion in elderly patients29 or in patients receiving antihypertensive treatment.24 We previously demonstrated that amlodipine21 and doxazocin22 reduced daytime BP but not nighttime BP in extreme dippers. In this study, cilnidipine also improved dipping status in extreme dippers as a result of BP reduction during the daytime, but BP reduction was not observed during nighttime (Figures 3 and 4, Table 2). We speculated that cilnidipine would not worsen organ damage risk in extreme dippers but is more likely to reduce cardiovascular risk, especially in extreme dippers with an exaggerated morning BP surge.

Study Limitations

This study did not set a control group. We speculate that the BP‐lowering effect of cilnidipine could be at least partially explained by the effects of cilnidipine itself, not only by the regression to the mean, when the patients were stratified or classified into subgroups, as exemplified by the result that trends in SBP changes between daytime and nighttime were significantly different in dippers, risers, and extreme dippers, but not in nondippers (Figure 4); however, a randomized controlled trial will be needed to conclude the effects of cilnidipine in patients with abnormal dipping status.

The percentage of the patients with diuretic treatment in extreme dippers was higher than that in dippers. The possibility that diuretic use may affect dipping status and nocturnal BP were not excluded, because diuretics have been shown to shift the nocturnal BP rhythm from nondipping to dipping.13 Diuretics including loop diuretics, thiazide diuretics, and aldosterone antagonists were administrated to 34, 39, and 6 patients, respectively.

We did not set an exclusion criterion about sleep quality in patients during ABPM. Sleep quality during performing ABPM may influence their nocturnal dipping status.

Conclusions

Cilnidipine partially but significantly restored the abnormal nocturnal dipping status of patients categorized as risers, nondippers, and extreme dippers toward a more normal dipper pattern in a real‐world setting.

Disclosures

None.

Acknowledgments

This study was financially supported by Ajinomoto Pharmaceuticals Co., LTD, Tokyo Japan, and Mochida Pharmaceutical Co., LTD, Tokyo, Japan.

J Clin Hypertens (Greenwich). 2013;15:465–472. ©2013 Wiley Periodicals, Inc.23815534

A part of this study was presented at the 22nd Scientific Meeting of the European Society of Hypertension, London, UK, April 27, 2012.

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