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antihypertensive agents may have a clinically meaningful effect on circadian BP [3,4]. In addition, some
agents given once daily may not provide adequate BP
control, and the antihypertensive effect of some agents
may taper off by the end of 24-h period [5,6]. Thus, it is
appropriate to perform studies with once-daily hypertensive therapies to evaluate the effects of dosing time
on circadian BP and heart rate.
Amlodipine is a potent vascular-selective dihydropyridine calcium antagonist used in the treatment of hypertension. After oral administration of amlodipine,
drug concentration would reach its peak value between
5 and 7 h. The plasma half-life of amlodipine ranges
from 35 to 45 h [7]. This agent is usually given once
a day in the morning. To investigate whether time of
administration influences the 24-h efficacy of amlodipine, we performed a prospective, double blind, randomized, crossover study using ambulatory monitoring of
BP and HR in patients with mild-to-moderate essential hypertension. In an effort to simulate usual clinical
practice, each patients dose of study drug could be adjusted based on his or her blood pressure.
Methods
Study patients
Patients were screened and studied in hypertension
and cardiology clinics of the First Affiliated Hospital,
Zhejiang University, College of Medicine. Sixty-two patients recruited in the study were aged 2177 years and
had mild-to-moderate essential hypertension. If they
were previously treated, all antihypertensive medications were stopped for at least five elimination half-lives
(and no less than one week) before they entered a 2week placebo run-in period. Patients were included if
Introduction
The effects of time of dosing on the pharmacodynamics
of long-acting, once-daily antihypertensive drugs are
an important consideration for antihypertensive therapeutics [1,2]. It should not be assumed that a drug
dosed in the morning will have the same antihypertensive effect as dosed in the evening [1]. Studies using ambulatory monitoring of blood pressure (BP) and heart
rate (HR) have shown that altering the dosing time of
Address for correspondence and requests for reprints: Dr. YuanGang Qiu, MD, Department of Cardiology, The First Affiliated
Hospital, Zhejiang University, College of Medicine, 79 Qingchun
Road, Hangzhou 310003, P.R. China. Tel.: 86 571 87236500; Fax:
86 571 87236618; E-mail: qiuyuangang@yahoo.com.cn
335
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Qiu et al.
Study design
The study had a prospective, double blind, randomized,
crossover design with dose titration that included a 2week, single-blind placebo run-in phase and an 12 week
active treatment period. There are three periods for
patients who were currently receiving antihypertensive therapy (Fig. 1): (1) a 1- to 2-week (more than 5
elimination half-lives) washout periods for patients who
Fig. 1. The study design was randomized, double-blind, crossover with dose titration, ambulatory blood pressure recordings were
performed at the end of placebo baseline and after 6 and 12 weeks of double-blind morning or evening amlodipine treatment.
337
Statistical analysis
The primary objective of the present study is to evaluate whether 24-h BP changes with amlodipine are independent of the time of amlodipine administration, thus
mean reductions in diastolic 24-h ambulatory BP were
equivalent for both morning and evening dosing. On
the basis of a maximum difference in response between
dosing schedules acceptable for clinical equivalence of
3.4 mm Hg, with 0.05 level significance and 80% testing
power, the total sample size required was 60 patients.
The sample size was based on an estimated within subject standard deviation of 6.3 mm Hg for 24-h diastolic
ambulatory BP [9].
Data are expressed as mean standard deviation. For continuous variables (including office BP, 24-h
mean BP, daytime mean BP, night-time mean BP, 24-h
BP peak value, nocturnal fall of BP, and the percentage
of nocturnal BP fall), comparison among three groups
was made by analysis of variance (ANOVA). An analysis of variance model for a crossover design was used to
demonstrate equivalence between the two treatment
regimens. For discrete variables (including 24-h BP
load, daytime BP load and night-time BP load), the nonparametric Friedman test was used in the comparison
among three groups. Wilcoxon sighed ranks test was
used to compare the two treatment regimens.
A P value of <0.05 was considered statistically significant. A P < 0.01 was considered highly significant.
Results
Demographics
Sixty-two patients were randomized to the treatment
with morning or evening administration of amlodipine.
Sixty patients have completed two active treatment
period (Table 1) and were included in the analysis. Two
Table 1. Baseline characteristics of patients
Gender, n (%)
Women
Men
Mean age, year (SD)
Mean weight (SD)
Women
Men
16 (27)
44 (73)
57.5 (10.5)
58.5 (8.4)
69.4 (10.1)
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Qiu et al.
patients were withdrawn from the study after randomization for the adverse symptoms: one patient for insomnia, another for peripheral edema.
Efficacy
Doses of amlodipine were titrated up to 10 mg if the
office seated DBP was 90 mm Hg after 2 weeks of
treatment. Sixty percent of the patients remained on
their original 5 mg doses throughout the study. In both
regimens, fifty-one of sixty (85%) patients had a reduction in DBP of 10 mm Hg and an endpoint DBP of
<90 mm Hg. More than 98% patients had an endpoint
DBP < 90 mm Hg. Compared with the baseline value
(171.2 12.2/99.6 8.0 mm Hg), office blood pressure
was reduced significantly by administration of amlodipine either in the morning (135.3 9.8/80.6 6.5 mm Hg,
P < 0.01/0.01) or in the evening (133.7 9.1/80.7 6.0
mm Hg, P < 0.01/0.01). No significant difference was
found between morning and evening administration.
The 1-hourly ambulatory blood pressure and pulse
profiles of baseline and that at the end of two periods
of active treatments are shown in Figure 2. Heart rate
(including 24-h average, daytime average and nighttime average heart rate) was not affected by morning or
evening administration, and there were no differences
in heart rate according to dosing times (Table 2). 24-h
mean BP, daytime mean BP, night-time mean BP, 24-h
peak BP value and daytime BP load during both regimens were lower than baseline (P all <0.01) but did not
differ from each other (Table 2). The 24-h BP load and
night-time BP load during both regimens were lower
than that before treatment (P all <0.01). An evaluation
of sleep and awake periods revealed differential 24-h
DBP load, night-time BP load, nocturnal fall of BP and
the percentage of nocturnal BP fall for morning dosing compared with evening dosing (Table 2). 24-h DBP
load was higher with evening dosing than with morning
dosing (11.0 17.5% vs. 6.5 9.1%, P < 0.05). Nighttime BP load was higher with evening dosing compared
with morning dosing (28.5 31.4%/17.7 28.2% vs.
20.0 27.9%/9.2 17.8%, P < 0.05/0.05). Nocturnal
fall of BP was greater with morning dosing than with
evening dosing (9.8 6.7/7.4 5.3 vs. 6.7 6.6/5.4
5.4, P < 0.014/ <0.05). Similarly, percentage of nocturnal BP fall was greater with morning dosing than with
evening dosing (7.9 5.3%/9.6 6.8% vs. 5.4 7.0%/7.0
6.9%, P < 0.01/ <0.05, Table 2)
Discussion
The aim of our study is to investigate the potential
difference in effects of morning and evening dosing of
amlodipine on circadian BP and heart rate.
The results of the study showed that the two regimens have similar effects on 24-h mean BP, daytime
mean BP, night-time mean BP, 24-h BP peak value,
24-h SBP load, daytime BP load and heart rate (24-h
mean, daytime mean and night-time mean). However,
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Table 2. Summary data for the amlodipine morning versus night-time administration study
Office BP
SBP (mmHg)
DBP (mmHg)
24-h mean
SBP (mmHg)
DBP (mmHg)
HR (beats/min)
Daytime mean
SBP (mmHg)
DBP (mmHg)
HR (beats/min)
Night-time mean
SBP (mmHg)
DBP (mmHg)
HR (beats/min)
24-h BP Peak value
SBP (mmHg)
DBP (mmHg)
24-h BP load
SBP (%)
DBP (%)
Daytime BP load
SBP (%)
DBP (%)
Night-time BP load
SBP (%)
DBP (%)
Nocturnal BP fall
SBP (mmHg)
DBP (mmHg)
% Nocturnal BP fall
SBP (%)
DBP (%)
Baseline
Morning ingestion
Night-time ingestion
171.2 12.2
99.6 8.0
135.3 9.8
80.6 6.5
133.7 9.1
80.7 6.0
135.3 9.0
85.1 9.0
72.7 9.3
118.0 9.4
73.8 6.2
71.7 9.3
117.3 10.1
74.0 8.1
71.0 9.2
139.0 10.1
88.2 10.2
76.3 10.1
121.3 10.4
76.3 6.7
75.4 9.8
119.5 11.1
75.8 8.5
74.7 10.4
128.0 10.3
78.9 8.5
65.4 8.6
111.5 8.6
68.9 6.7
64.2 9.4
112.8 10.5
70.3 8.4
63.6 7.9
147.7 12.9
94.6 11.4
128.0 10.8
81.9 7.5
128.8 11.8
82.0 8.9
53.9 25.8
44.4 28.6
12.5 22.6
6.5 9.1
15.5 22.0
11.0 17.5
45.8 27.6
44.6 31.3
8.8 22.1
5.2 8.2
9.0 22.3
7.7 15.2
70.0 32.2
44.2 35.1
20.0 27.9
9.2 17.8
28.5 31.4
17.7 28.2
11.0 10.0
9.2 7.4
9.8 6.7
7.4 5.3
6.7 6.6
5.4 5.4
7.7 7.2
10.1 8.1
7.9 5.3
9.6 6.8
5.4 7.0
7.0 6.9
Values are expressed as means SD, n = 60. BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. P < 0.05,
P < 0.01 versus baseline; P < 0.05, P < 0.01 versus morning administration.
Previous studies
Studies have shown that altering the dosing time of
antihypertensive agents may have a clinically meaningful effect on nocturnal BP [4,10,13,14]. Palatini et al.
[4] in a group of 18 hypertensives found a more sustained antihypertensive action with the evening administration compared with the morning administration of
quinapril: as with the morning administration, a partial
loss of effectiveness was observed during night-time
hours. Witte et al. [14] evaluated 12 hypertensive patients and observed that the treatment of enalapril at
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Qiu et al.
Present Study
In this study, either when amlodipine was given in the
moring or in the evening, fifty-one out of sixty (85%)
patients had a reduction in DBP of 10 mm Hg and an
endpoint DBP < 90 mm Hg, more than 98% patients had
an endpoint of DBP < 90 mm Hg. Those data indicated
that amlodipine is a powerful antihypersive drug.
What we are interested in most is which time when
amlodipine is administered will achieve a better effect
on circadian blood pressure. Recognition of the characteristics of the circadian variation of BP and heart rate
led to increased numbers of clinical trials that evaluate
the effects of antihypertensive therapy on early morning, awake, and sleep pressure. The circadian pattern of
BP is typically characterized by an increase of BP during early morning and a nocturnal BP decrease during
sleep. However, this nocturnal decline in BP is blunted
or absent in some hypertensive patients and their cardiovascular risk may be excessive [16,17]. Thus, it has
become of interest to determine the effects of antihypertensive drugs on nocturnal BP in patients of hypertension. The present study indicates that nocturnal fall
of BP and percentage nocturnal BP fall are greater with
morning dosing than with evening dosing. A reduced
extent of a nocturnal BP fall is associated with greater
left ventricular hypertrophy and left ventricular diastolic impairment, increased carotid intima-media thickness, and prevalence of carotid plaque [1822]. Other
studies [16,2325] suggested that too great a decline
in BP during sleep (>20 mg from the daytime mean),
particularly in elderly hypertensive individuals with
small-vessel disease of the brain, increases the risk for
stroke. No patient, however, has been found to have an
excessive nocturnal fall (i.e. more than 20% nocturnal
BP fall, data not shown) in our study.
Our study also showed that 24-h DBP load and nighttime BP load were higher with evening dosing than with
morning dosing. Previous studies, either of hypertensive adults [26] or of hypertensive children [27], have
reported that elevated BP load was associated with decreased cardiac function and increased left ventricular
mass index.
The presence of left ventricular hypertrophy on either the ECG or the echocardiogram is a risk factor
for major cardiovascular events, including the development of coronary heart disease (angina, myocardial infarction, sudden death), congestive heart failure, stoke,
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