Cardiovascular Drugs and Therapy 17 335341 2003

C 2003 Kluwer Academic Publishers. Manufactured in The Netherlands

CLINICAL PHARMACOLOGY AND DRUG STUDIES

Differential Effects of Morning or Evening Dosing of

Amlodipine on Circadian Blood Pressure and Heart Rate
Yuan-Gang Qiu, Jun-Zhu Chen, Jian-Hua Zhu,
and Xue-Yan Yao
Department of Cardiology, The First Affiliated Hospital,
Zhejiang University, College of Medicine, Hangzhou, P.R. China

Summary. Objectives: To compare the effects of morning

and evening dosing of amlodipine on both circadian blood
pressure (BP) and heart rate (HR) in mild-to-moderate essential hypertension.
Design: A perspective, double-blind, randomized,
crossover design with dose titration.
Patients and methods: Sixty-two patients recruited in
the study were aged 2177 years and had mild-to-moderate
essential hypertension. At the end of a 2-week single-blind,
placebo run-in period, eligible patients were randomly assigned to morning (7 AM) and evening (9 PM) amlodipine treatment. The initial dose was 5 mg. After 2 weeks of
double-blind therapy, patients with a seated diastolic blood
pressure 90 mm Hg had their doses titrated upward to
10 mg, while the other patients remained on their original
5 mg doses for another 4 weeks period, than crossover to
the alternate dosing regimen for 6 additional weeks. The
24-h ambulatory monitoring was performed at baseline and
at 6 and 12 weeks after randomization.
Results: 24-h diastolic BP load (11.0 17.5% vs.
6.5 9.1%, P < 0.05) and night-time BP load (28.5 31.4%/
17.7 28.2% vs. 20.0 27.9%/9.2 17.8%, P < 0.05/0.05)
were significantly greater with evening dosing compared
with morning dosing. 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 mm Hg, P < 0.01/0.05). Percentage
of nocturnal BP fall was greater with morning dosing versus 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).
Conclusions: Morning administered amlodipine had a
better effect on the circadian BP compared with evening
administrated amlodipine in mild-to-moderate essential hypertension.
Key Words. hypertension, ambulatory blood pressure monitoring, circadian rhythm, amlodipine, morning and evening
administration

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

This study was supported in part by a research grant (20020825)

from The Education Department of Zhejiang Province, China.

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.

the average of 3 seated office diastolic blood pressure

(DBP) measurements after 10 min of rest was 95 mm
Hg and 114 mm Hg at the end of single-blind, placebo
run-in period. Additionally, patients were eligible for
randomization only if the mean ambulatory daytime
(6 AM to 9:59 PM) systolic blood pressure (SBP) was
135 mm Hg or diastolic blood pressure 85 mm Hg.
These additional ambulatory BP criteria were used to
assure inclusion of patients with sustained hypertension into the study [8].
Key exclusion criteria were any known form of secondary hypertension, SBP > 200 mm Hg or DBP
115 mm Hg, bradycardia (heart rate <45 beats/min)
or tachycardia (heart rate >100 beats/min), stroke or
myocardial infarction in the previous 6 months, congestive heart failure (left ventricular ejection fraction
<40%), clinically significant hepatic or renal disease,
uncontrolled diabetes mellitus, life-style factors such
as night-shift work, history of drug and alcohol abuse,
neurologic and psychiatric illnesses, and women who
were pregnant or breast-feeding.
The study protocol was approved by the ethical committee of the hospital and all subjects provided informed consent.

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

were currently receiving antihypertensive therapy; (2)

a 2-week single-blind placebo run-in period to establish
baseline clinical and ambulatory BPs and HRs; (3) a 12week, double-blind, crossover treatment period during
which patients took amlodipine either in the morning
(7 AM) or in the evening (9 PM) by a randomization
schedule, with matching placebo in either the evening
or morning (Fig. 1). The initial dose of amlodipine was
5 mg. After 2 weeks of therapy, if the BP response
was not satisfactory (defined as seated DBP 90 mm
Hg), the dosage was titrated upward to 10 mg. For
the other patients, the dosage was remained on their
original 5 mg. Treatment continued for 4 more weeks.
After having received total 6 weeks of active therapy,
patients then received amlodipine by the alternating
dosing schedules for another 6 weeks. Patients were
instructed to fast for 1 h before and after taking study
medication, and to take their medication at the same
time each day, regardless of scheduled office visiting or
ambulatory BP monitoring.
The effects of amlodipine administrated in the morning or in the evening were assessed by determining
changes in 24-h ambulatory BP and heart rate and office BP.
Patients visited the clinic at 2-week intervals during the placebo run-in and the 12-week treatment period. Patients were requested to continue eating their
usual diet but no restriction on their intakes of fluid
throughout the study. However, the patients were allowed any medication for concomitant diseases, as far
as those treatments would not interfere with regulation
of blood pressure and metabolism of the drugs being
studied.

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.

Differential Effects of Morning or Evening Dosing

Office (causal) blood pressure measurements

On the day of the clinic visit, the patients were instructed to present at the clinic in the morning between 8 AM to 9 AM. Each blood pressure assessment
was the mean of three office measurements, obtained
3 minutes apart, with a standard mercury sphygmomanometer. Blood pressure was measured after the patient was seated for a 10-minute rest period with the
blood pressure cuff placed at heart level. The sphygmomanometer was inflated to 30 mm Hg above the
expected SBP and subsequently deflated at approximately 2 mm Hg/s. DBP was recorded as Korotkoff V. If
the Korotkoff V tone is 0 mm Hg, the Korotkoff IV value
will be recorded. Coffee and tea were not allowed during the hour preceding blood pressure measurement,
and smoking was not allowed during the 30 minutes
before blood pressure measurement. Blood pressures
were recorded at the same time of day and by the same
individual.
Ambulatory blood pressure recordings
The 24-h ambulatory BP and heart rate were measured with SpaceLabs 90207 monitors (Spacelabs Ltd,
Redmond, Washington, USA). The ambulatory BP was
measured 24-h before randomization and 24-h before
the last day of the two active treatment periods. Patients were fitted with a monitor on the same arm used
for office BP determinations, with cuff size adapted to
the arm circumference. All monitors were compared
with a standard mercury sphygmomanometer to ensure that office DBP and ambulatory DBP were in
agreement (7 mm Hg). BP and heart rate were measured at 20 min intervals during the day (6 AM9:59
PM) and at 30 min intervals during the night (10 PM
5:59 AM). The monitoring was performed on a working day starting at around 810 AM. The blood pressure profile was screened for artefactual recording
by the spacelabs computer program, which excluded
blood pressure outside the following defined limits: SBP
<70 mm Hg or >260 mm Hg, DBP < 40 mm Hg or
>150 mm Hg, pulse pressure <40 mm Hg or >110 mm
Hg; and heart rate <40 beats/min or >120 beats/min.
Successful monitoring occurred when 80% of readings were valid over the monitoring period, including a
minimum of one valid reading/h. If these criteria were
not satisfied, the monitoring study would be repeated.
Blood pressures measured within each hour were averaged hourly for each patient and then were pooled for
evaluation. The time of dosing of medication, sleep, and
awakening were recorded on diary cards.
The following specific parameters, abstracted from
the data, were evaluated for the two therapeutic regimens and compared with placebo: office BP, 24-h mean
BP, night-time (10 PM5:59 AM) mean BP, daytime
(6 AM9:59 PM) mean BP, 24-h BP peak value, nocturnal fall of BP, percentage of nocturnal BP fall, 24-h BP
load, daytime BP load and night-time BP load. Elevated
BP values during the awake hours (>140/90 mm Hg)
and sleeping hours (>120/80 mm Hg) were used to

337

calculate the BP load, the percentage of abnormal BP

value (including 24-h BP load, daytime BP load and
night-time BP load) in each patient.
At the end of the placebo and of the two periods of active treatments, echocardiography, cardiac
roentgenography, routine laboratory tests (including
tests for levels of hemoglobin, red blood cells, creatine,
bilirubin, transaminase, alkaline phosphatase, glucose,
total and low-density lipoprotein cholesterol, triglyceride, plasma sodium and potassium as well as urinalysis) were performed.

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)

338

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,

Fig. 2. Effect of morning versus evening dosing of amlodipine

on SBP, DBP and heart rate over 24 hours. SBP, systolic blood
pressure; DBP, diastolic blood pressure. , baseline;
, morning
dosing; , evening dosing.

differential effects were observed in some parameters

with different time of administration. Those could be
characterized as less reduction in 24-h DBP load, nighttime BP load, nocturnal fall of BP and the percentage of
nocturnal BP fall after morning dosing compared with
evening dosing.

Sample size considerations

Recently, investigators have begun to evaluate the effects of timing of antihypertensive drugs on the circadian rhythms of blood pressure [10,11]. Although a
fairly large number of studies have been performed to
assess the impact of timing of dosing of therapy, most
have had small sample sizes, open-label design, or may
not have used a crossover design that allows for reduced error variability [12]. In this study, we prospectively calculated the sample size requirements for the
present crossover design and took into consideration

Differential Effects of Morning or Evening Dosing

339

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.

the variability of ambulatory BP as well as the desire

to be able to detect 3.4-mm Hg differences between the
dosing regimens on 24-h DBP. This power calculation
demonstrated that 60 patients were required to demonstrate a 3.4-mm Hg difference in ambulatory DBP between groups. To date, most studies evaluating the effect of dosing time of several class of agents on circadian
BP rhythms had small sample size of less than 30 patients [4,1214]. Thus, most studies in this field have
been greatly underpowered.

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

7 AM significantly reduced blood pressure during the

day but have less effect at night. On the other hand, dosing of enalapril at 7 PM significantly decreased nighttime blood pressure followed by a slow increase during
the day, with no effect on elevated afternoon values, and
some pharmacokinetics differences were reported, such
as a higher peak concentration of drug in the plasma after the morning dose. A study by Morgan et al. [13]
assessed the effect of a single dose of perindopril administrated at 9 AM or 9 PM by ambulatory BP monitoring. The results showed that the early morning blood
pressure rise is reduced more when 4 mg perindopril
is administered at 9 PM. However, the 9 PM dose regimen does not reduce blood pressure over 24 h whereas
24 h control is achieved with the 9 AM dose. White
et al. [10] evaluated 75 hypertensive patients, and found
that the timing of nisoldipine ER administration had
no effect on mean changes in BP and heart rate over a
24-h period. However, a significantly greater effect on
awake diastolic BP was observed with morning dosing
compared with evening dosing. In addition, smaller increases in sleep and early morning heart rate were seen

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Qiu et al.

with evening compared with morning administration of

nisoldipine SR. In a nifedipine trial [15], patients were
studied using 30 mg nifedipine GITs at either 10 AM or
10 PM. The treatment period was 1 and 2 weeks, respectively. Nifedipine GITs did induce a 3- to 5-beats/min increase in ambulatory heart rate compared with placebo,
however, this was not statistically significant. Morning
dosing lowered daytime BP slightly more than evening
dosing, but this did not achieve statistical significance,
too.

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,

transient ischemic attacks, and intermittent claudication [2831].

Those studies and our results imply that morning
administrated amlodpine have a better effect on the
circadian BP compared with evening administrated amlodipine.
In conclusion, our results indicate that heart rate and
overall 24-h BP control were similar when amlodipine
was dosed in the morning or in the evening. However,
the present data also suggests that there is less reduction in 24-h DBP load and night-time BP load after
morning dosing compared with evening dosing. Nocturnal fall of BP and the percentage of nocturnal fall of BP
were greater with morning dosing than evening dosing. Those data imply that morning dosing of amlodipine has a better effect on the circadian BP compared
with evening dosing. Our results and those of other
chronopharmacology studies show that, some agents
may have substantially different effects on nocturnal
BP when given at bedtime versus upon awakening. It
is particularly noteworthy that a difference has been
found where it is not expected, i.e. with amlodipine, a
drug with a long half life of 3545 hours [7]. Thus, we
suggest that all long-lasting antihypertensive agents
should be properly studied to assess the safety and efficacy of the agent when they are administrated in the
morning or in the evening.

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