Clinical and Experimental Hypertension, 2012; 34(3): 191–200

Copyright © Informa Healthcare USA, Inc.

ISSN 1064-1963 print /1525-6006 online
DOI: 10.3109/10641963.2011.601377

Assessment on Antihypertensive Effect and Safety of Nifedipine

Controlled-Release Tablet Administered at 80 mg/day in Practical
Clinic

Naohiko Kobayashi, Toshihiko Ishimitsu

Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University School of Medicine, Mibu,
Tochigi, Japan

Abstract
In this study, the effect of nifedipine controlled-release tablets at a dose of 80 mg/day (NCR80) on blood pressure (BP)
and safety was investigated. In essential hypertension (n = 50, >140/90 mm Hg) despite a combined therapy with
antihypertensive agents, NCR80 was administered instead of the previous antihypertensive agents and changes in BP
and pulse rate (PR), side effects, and changes in laboratory test values were examined for 24 months. Thirty-three
patients switched to NCR80 as the initial dose from the previous antihypertensive agents (Initial), while 17 patients
started treatment at NCR40 and increased to NCR80 after 1–3 months (Up-titration). In the Initial group, BP decreased
significantly and this significant reduction continued for 24 months, but not in the case of PR. In the Up-titration group,
BP decreased significantly during the treatment with NCR40, and further reduced in 1–2 month(s) after NCR80. This
significant reduction continued for 12 months, but not in the case of PR. The mean change in BP after increasing
NCR40 to NCR80 was −16/–6 mm Hg at 6 months. When patients who received NCR80 were stratified into three
grades according to the baseline systolic blood pressure level (SBP) (≥180, 160–179, and 140–159 mm Hg), the mean
change in BP at 1 month was −55, −27, and −16 mm Hg, respectively. None of the 50 patients treated with NCR80
experienced any side effects and no abnormal change was observed in their laboratory test values. These findings
suggested that NCR80 demonstrated the ability to control BP appropriately depending on the severity with favorable
safety.

Keywords: calcium antagonist, essential hypertension, nifedipine

INTRODUCTION flow to organs; therefore, they are convenient for the

treatment in patients with a complication or in elderly
In the guidelines for the management of hypertension
patients and have been used as first-line therapy in
by the Japanese Society of Hypertension (JSH2009) (1),
many patients along with angiotensin receptor blockers
strict control of blood pressure (BP) is proposed since
(ARBs). Above all, nifedipine controlled-release tablets
protective effects of antihypertensive agents against
(nifedipine CR tablet), which have a special slow-release
cardiovascular diseases are mostly determined by the
system, successfully achieved to retain both the pow-
reduction in BP rather than their classes. However, with
erful antihypertensive effect and the antianginal effect
current agents of BP control in practice, it has been
of nifedipine while reducing side effects and improving
reported that only half of all hypertensive patients being
compliance by single daily administration (3,4). This
treated with antihypertensive agents have achieved BPs
agent is expected to be useful for the treatment in severe
to the target lower level (2). Therefore, the guidelines
patients whose BP could not be controlled with other
also state that agents that have a greatest antihyperten-
antihypertensive agents or have refractory hyperten-
sive effect and are appropriate for concomitant diseases
sion or high-risk patients including those with diabetes,
should be used, and in high-risk patients, BP should be
chronic kidney disease (CKD), and a history of myocar-
lowered to the target level as soon as possible. Among
dial infarction. Although the approved indication of this
the existing antihypertensive agents, dihydropyridine
agent is once daily administration at doses of 20–40 mg
calcium (Ca) antagonists have the strongest antihy-
for antihypertensive therapy, in patients whose BP could
pertensive effect as well as an effect to protect blood

Address correspondence to Naohiko Kobayashi, Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University
School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail: naokky@me.com
Received 16 January 2011; revised 19 March 2011; accepted 25 March 2011.

191
192 N. Kobayashi and T. Ishimitsu

not be controlled sufficiently at 40 mg/day, the agent is Table 1. Patient background (n = 50)
sometimes administered with an increased dose of up Age (y) 59.5 ± 12.5
to 80 mg/day. However, since there is concern that a
≥65 19
high dose of the agent may cause excessive reduction <65 31
of BP or increase in pulse rate (PR), no study on the
efficacy and safety of 80 mg/day administration in a Sex Male: 24 (48%)
With complication
large population has been conducted. In patients who Diabetes 8
received nifedipine CR tablet at a dose of 80 mg/day Renal disease 6
after the failure of treatment with a high dose of other Arrhythmia (including atrial 2
Ca antagonists or several other antihypertensive agents, fibrillation)
the reduction in BP and safety including patient back- Angina 7
Hyperlipidemia 5
ground are evaluated and the results are presented in Others 6
this report. Dosing schedule of nifedipine CR tablets
Initial dose of 80 mg/day 33
Initial dose of 40 mg/day 17
SUBJECTS AND METHODS SBP/DBP (mm Hg)
Initial dose of 80 mg/day 173 ± 24/100 ± 15
Among patients with essential hypertension who had Initial dose of 40 mg/day 165 ± 16/98 ± 13
been referred by other institutions because of uncon- Pulse rate (per min)
trolled BP or had been newly diagnosed with hyper- Initial dose of 80 mg/day 78 ± 17
tension from September 2000 to November 2009, 50 Initial dose of 40 mg/day 69 ± 5
Previous antihypertensive agent
patients with essential hypertension who still presented
ARB 18
systolic blood pressure (SBP) ≥140 mm Hg and/or ACE inhibitor 3
diastolic blood pressure (DBP) ≥90 mm Hg after β-blocker 3
monotherapy or combined therapy with antihyperten- α-blocker 6
sive agents such as Ca antagonists except ARBs, diuret- Calcium antagonist 19
Amlodipine at 2.5–10 mg/day 10
ics, and nifedipine were extracted. In these patients,
Benidipine at 8 mg/day 3
monotherapy with nifedipine CR tablet was started at Azelnidipine at 8–16 mg/day 2
a dose of 80 mg/day (40 mg twice daily, after breakfast Others 4
and dinner) instead of previous antihypertensive agents
Abbreviations: SBP – systolic blood pressure; DBP – diastolic
and changes in BP and PR, presence of side effects, blood pressure; ARB – angiotensin receptor blocker; CR –
and changes in laboratory test values were examined. controlled-release. Values are denoted as mean ± SD.
Based on their clinical conditions, previous response
to Ca antagonists, and allergic history, some patients
were initially given nifedipine CR tablets at a dose of had no complication with diabetes or renal disease, and
40 mg/day (once daily, after breakfast) and later the that BP was stage I (140–159/90–99 mm Hg) or stage
dose was increased to 80 mg/day, while other patients II (160–179/100–109 mm Hg) despite mid-dose of ARB
received 80 mg/day from the beginning. Patient back- or Ca antagonist other than nifedipine CR.
ground is shown in Table 1. Of the 50 patients, 24 As previous antihypertensive therapy, ARBs had been
patients (48%) were male with the mean age of 60 years used in 18 patients, ACE inhibitors in 3 patients, diuret-
(19 patients aged 65 y or older) and 24 patients (48%) ics in 3 patients, α- or β-blockers in 9 patients, and Ca
had a complication including 8 patients with diabetes antagonists in 19 patients. Amlodipine had been used
(16%), 6 with CKD (12%), and 7 with angina (14%). in 10 patients (2.5 mg: n = 1, 5 mg: n = 7, and 10 mg:
Thirty-one patients had received other antihyperten- n = 2). Dose titration schedule of nifedipine CR tablets
sive agents before the treatment with the nifedipine CR was, for 33 patients, single administration of 80 mg/day
tablet and the remaining 19 patients had newly diag- from the beginning, but for the remaining 17 patients,
nosed hypertension. Fifteen patients (30%) had been initial dose was set at 40 mg/day and the dose was
treated with two or more antihypertensive agents. increased to single administration of 80 mg/day after
In principle, the selection criteria to start the dos- failure of 1–3 months treatment was confirmed. Clinical
ing from 80 mg/day were that patients were complicated BP and PR were measured before start of the treat-
with diabetes mellitus, renal disease, or cardiac disease, ment and after 1, 2, 3, 6, 12, and up to 24 month(s)
that BP at the time of hospital visit was higher than of treatment with nifedipine CR tablets. For patients
150/90 mm Hg despite ARBs or Ca antagonist treat- who started the treatment at 40 mg, clinical BP and PR
ment other than nifedipine CR as prior treatment, or were measured before start of the treatment and after
that BP was at stage II (160–179/100–109 mm Hg) or 1–3 months of 40 mg administration, and then 1, 2, 3,
stage III (≥180/110 mm Hg) despite high-dose treat- 6, 12, and 24 months of 80 mg administration. General
ment with Ca antagonist other than nifedipine CR as laboratory testing was also performed before the treat-
prior treatment. On the other hand, the selection crite- ment with nifedipine CR tablets, and after 6, 12, and
ria for the starting dose of 40 mg/day were that patients 24 months of treatment, if possible.
Clinical and Experimental Hypertension
 Safety and Effect of Nifedipine CR at 80 mg/day 193

(A)
STATISTICS 210 SBP
DBP
Primary endpoints of this study were reduction in BP 190
PR
after administration of nifedipine CR tablets at a dose 170
**

mm Hg, beat/min
of 80 mg/day, reduction in BP after increasing the 150
** ** ** **
dose from 40 mg to 80 mg, and the percentage of **
130
patients who achieved the target BP after the treat- 110
ment when treated with these doses. Values including 90 **
** **
BP and PR were presented as mean ± standard devi- ** ** **
70
ation and the one-way repeated measures analysis of
50
variance (ANOVA) was used for statistical analysis and 0M 1M 2M 3M 6M 12M 24M

t test was performed by the Bonferroni method. Cor- (B) 200

relation between baseline BP level and reduction in BP 180

*
was examined using the Pearson correlation. Also, SBP 160 ** ** **
** **
140
level at baseline was stratified into three grades, that is,

grade I (140–159 mm Hg), grade II (160–179 mm Hg),
and grade III (≥180 mm Hg), and reduction in BP after
administration of CR tablets was calculated for each
grade. Furthermore, as secondary analysis, antihyper-
tensive effect of the nifedipine CR tablet was assessed in
the patient population aged 65 or older and the popula-
tion aged less than 65, as well as in patients with diabetes
or CKD and patients who switched from a moderate
to high dose of amlodipine. As safety assessment, side
effects such as changes in PR, tachycardia, palpitation,
and abnormal changes in laboratory test values were
examined.
RESULTS
Changes in BP and PR, and Measured Reduction in BP
Changes in BP and PR for 24 months in patients who
started the treatment at a dose of 80 mg/day are shown
in Figure 1A. Blood pressure level was 173 ± 24/100 ±
15 mm Hg at baseline and significantly reduced to
138 ± 15/80 ± 9 mm Hg 1 month after switching
therapy (P < .001, P < .001, respectively), and the
significant reduction continued during the period from
2 to 24 months (P < .001, P < .001, respectively). The
mean reduction in BP after the treatment with 80 mg
as the initial dose was −36 ± 23/–20 ± 17 mm Hg at
1 month, −45 ± 25/–26 ± 14 mm Hg at 2 months, −43
± 26/–22 ± 14 mm Hg at 3 months, −47 ± 25/–23 ±
24 mm Hg at 6 months, −45 ± 33/–21 ± 28 mm Hg
at 12 months, and −51 ± 24/–22 ± 27 mm Hg at
24 months. Pulse rate was reduced significantly from
the baseline value of 78 ± 17/minute to 71 ± 8/minute
at 2 months after switching treatment (P = .04), and
the significant reduction continued from 3 to 24 months
(P = .005, .016, .005, and .01).
Changes in BP and PR in patients who started the
treatment with nifedipine CR at a dose of 40 mg/day
are shown in Figure 1B. Blood pressure level was 165 ±
16/98 ± 13 mm Hg at baseline and significantly reduced
to 151 ± 14/89 ± 9 mm Hg 1–3 months after switch-
ing treatment to 40 mg/day (P = .017); and when it
was switched to 80 mg/day for further reduction, the
BP level was reduced to 142 ± 15/87 ± 12 mm Hg
© 2012 Informa Healthcare USA, Inc.
mm Hg, beat/min
120
100 ** ** ** ** **
80
**
60
SBP
40 DBP
20
PR
0
0M 40 m g 80 m g1M 80 m g2M 80 m g3M 80 m g6M 80 m g12M
(1–3M)
Figure 1. (A) Change in BP and pulse rate in patients who
received nifedipine CR tablets of 80 mg/day as the initial dose
(n = 33). **P < .001. Bonferroni t test. (B) Changes in BP and
pulse rate in patients who increased the dose of nifedipine CR
tablets from 40 mg/day to 80 mg/day (n = 17). * and ** denote P
< .05 and P < .001, respectively. Bonferroni t test. Abbreviations:
SBP – systolic blood pressure; DBP – diastolic blood pressure; PR
– pulse rate; BP – blood pressure.
at 1 month (P < .001) and 136 ± 13/83 ± 9 mm Hg
at 2 months (P < .001) and the significant reduc-
tion continued from 3 to 12 months (P < .001). The
mean reduction in BP was −13 ± 16/–11 ± 9 mm Hg
1–3 months after switching treatment to 40 mg/day and
−22 ± 19/–13 ± 11 mm Hg 1 month after switching
treatment to 80 mg, −27 ± 19/–17 ± 11 mm Hg at
2 months, −32 ± 17/–20 ± 11mm Hg at 3 months,
−29 ± 23/–16 ± 13 mm Hg at 6 months, −38 ±
18/–26 ± 17 mm Hg at 12 months, and −51 ± 19/–22
± 8 mm Hg at 24 months, which tended to gradually
increase with no significance.
Changes in BP reduction by increasing the dose from
40 mg/day to 80 mg/day are shown in Figure 2. There
was a significant reduction in SBP by −16 ± 15/–6 ±
11 mm Hg 2 months after increasing the dose from
40 mg/day to 80 mg/day (P = .007) and significant
reduction in both SBP and DBP was observed during
the period from 3 to 24 months.
Pulse rate was 69 ± 5/minute at baseline, 69 ± 4/
minute 1–3 months after the treatment was switched
to 40 mg/day and 70 ± 9/minute 1 month after the
treatment was switched to 80 mg/day, and there was
no significant change during the period from 2 to 24
months.
The percentages of patients who achieved the target
BP are shown in Table 2. All of the patients who had
194 N. Kobayashi and T. Ishimitsu

1 mo after 2 mo after 3 mo after 6 mo after

dose increase dose increase dose increase dose increase
0

–5

–10

–15
–2.4
–*6.1 –*
–*6.7
mm Hg
–20 9.4

–25
*
–10.9
–30
*
–15.9
–35 *
–17.9
–40
*
–15.9
–45 No significant change during treatment period

Mean reduction in SBP

Mean reduction in DBP

Figure 2. Blood pressure reduction by increasing the dose of nifedipine CR tablets from 40 mg/day to 80 mg/day (n = 17). Abbreviations:
SBP – systolic blood pressure; DBP – diastolic blood pressure. *P < .01 versus 40 mg/day.

Table 2. Percentage of achieving the target blood pressure after
the treatment with nifedipine CR
At 2 At 3
Dosing schedule At 1 mo mon mon
Initial dose of 19 (58) 26 (79) 25 (76)
80 mg/day (n = 33)
Increased dose from 7 (41) 11 (65) 12 (71)
40 mg/day to
80 mg/day (n = 17)
Whole patients 26 (52) 37 (74) 37 (74)
(n = 50)
Abbreviation: CR – controlled-release. Target blood pressure:
<140/90 mm Hg and <130/80 mm Hg (complicated by diabetes
or renal disease). Values are denoted as number (%).
diabetes or CKD were included in the Initial group con-
sisting 33 patients. The percentage of target BP achieve-
ment in these patients was high as 58% at 1 month
after switching treatment, 79% at 2 months, and 73% at
6 months. In 17 patients in the Up-titration group who
initially received 40 mg/day, the percentage was only
41% at the time when the treatment was switched to
40 mg/day but the percentage of target achievement was
higher after increasing the dose to 80 mg/day with 65%
at 1 month, 71% at 3 months, and 59% at 6 months.
Next, whether there is a difference in PR changes
after nifedipine CR tablet 80 mg/day administra-
tion between severe hypertension group and mild
hypertension group at baseline is evaluated. Because
the strong BP-lowering effect in severe hypertensive
patients may increase PR, the relationship between
BP at baseline and PR changes was examined. The
patients have been stratified based on the severity of
SBP (stage I, II, and III) at the time of the initi-
ation of the treatment, calculated PR changes after
nifedipine CR tablet 80 mg/day treatment in 1–3
months interval, and have made comparison based
At 6 on the severity of hypertension. As a result, there
mon was no significant change in the PR irrespective
24 (73) of groups. In addition, no correlation was observed
between SBP at the time of the initiation of treat-
10 (59) ment and the degree of PR change after nifedipine
CR tablet 80 mg/day treatment (n = 27, γ = 0.011,
34 (68)
P = .955, Pearson product moment correlation). Thus,
there was no increase of PR associated with strong
BP-lowering effects of concern (Table 3).
Moreover, whether there is a difference in BP and
PR after nifedipine CR tablet 80 mg/day administra-
tion between with and without Ca antagonists as a
previous antihypertensive drug is estimated. Among
treated patients, 19 patients were pretreated with other
Ca antagonists prior to the initiation of the treatment
with nifedipine, while 31 patients were not previously
treated with Ca antagonist. Patients were stratified
based on with or without prior use of Ca antago-
nist and chronological changes of BP and PR were
compared. In both groups, significant BP-lowering
effect in both SBP and DBP was observed throughout
12 months treatment period, while no significant change
was observed in PR. In addition, there was no signifi-
cant difference in BP and PR at each treatment stage
between both groups. However, baseline SBP value in
patients previously treated by Ca antagonist was signif-
icantly lower. Prior to the initiation of nifedipine CR
tablet 80 mg/day treatment, the number of previous
antihypertensive drugs was 1.25 ± 0.62 in patients with-
out prior use of Ca antagonist and 2.00 ± 0.88 in
patients with prior use of Ca antagonist. This might
have reflected to the difference in the baseline values
(Table 4).

Clinical and Experimental Hypertension

 Safety and Effect of Nifedipine CR at 80 mg/day 195

Table 3. Differences in PR stratified by SBP grade

SBP grade At 1 mon P At 2 mons P At 3 mons P
I (n = 11) −2.5 ± 16.7 .621 −3.0 ± 9.3 .466 −3.8 ± 19.0 .985
II (n = 26) −6.3 ± 19.6 −10.3 ± 22.0 −6.3 ± 18.8
III (n = 11) 0.0 ± 16.7 3.0 ± 9.6 −1.6 ± 6.1
Abbreviations: PR – pulse rate; SBP – systolic blood pressure. Values are denoted as mean ± SD
(unit: bpm).

Table 4. Comparison of BP and PR between pre-CCB (n = 19) and pre-non-CCB (n = 31)

Items Group 0 mon P 1 mon P 3 mons P 6 mons P 12 mons P
SBP (mm Hg) CCB 161 ± 15 .012 141 ± 17 .853 132 ± 11 .810 134 ± 12 .050 132 ± 14 .423
NCCB 176 ± 23 138 ± 14 133 ± 13 127 ± 10 127 ± 10
DBP (mm Hg) CCB 93 ± 10 .014 82 ± 11 .761 76 ± 6 .347 78 ± 10 .470 76 ± 6 .725
NCCB 100 ± 22 83 ± 9 78 ± 6 76 ± 6 75 ± 6
PR (per min) CCB 73 ± 15 .519 73 ± 12 .371 70 ± 6 .450 68 ± 4 .521 70 ± 4 .426
NCCB 74 ± 13 70 ± 8 69 ± 8 70 ± 7 68 ± 5
Abbreviations: BP – blood pressure; SBP – systolic blood pressure; DBP – diastolic blood pressure; CCB – calcium channel blocker;
PR – pulse rate. Values are denoted as mean ± SD, Mann–Whitney U test.

Correlation between BP at Baseline and Reduction in BP to 80 mg/day, 133 ± 15/73 ± 6 mm Hg at 2 months,

In 50 patients who received nifedipine CR tablet
80 mg/day, the correlation between BP level at base-
line (before the treatment) and reduction in BP ()
was examined. This assessment on the correlation was
performed using BP values at 6 months since the avail-
able matched data from before and after treatment were
greatest for this time point. As a result (Figure 3), there
was a significant negative correlation between SBP and
SBP (R = −0.847, P < .001, n = 43). A significant
correlation between DBP and DBP was also observed
(R = −0.756, P < .001, n = 42).
For the three groups stratified according to the sever-
ity of baseline SBP as grade I (140–159 mm Hg), grade
II (160–179 mm Hg), and grade III (≥180 mm Hg),
the mean SBP at baseline and mean reduction in BP are
shown in Figure 4. The mean reduction in BP for the
grade I hypertension (n = 11) was −16 ± 15 mm Hg
at 1 month, −18 ± 8 mm Hg at 2 months, and −20 ±
8 mm Hg at 3 months after switching treatment. The
mean reduction in BP for the grade II hypertension
(n = 26) was −28 ± 18 mm Hg at 1 month, −34 ± 16
mm Hg at 2 months, and −36 ± 14 mm Hg at 3 months
after switching treatment. The mean reduction in BP
for the grade III hypertension (n = 12) was −55 ± 21
mm Hg, −66 ± 23 mm Hg, and −65 ± 27 mm Hg,
respectively, for 1 month, 2 months, and 3 months, and
observed reduction in BP significantly increased with
the increase in the severity of hypertension at each time
point (at 1 mo, 2 mo, and 3 mo; P < .001, P < .001,
and P < .001, ANOVA).
Antihypertensive Effect in Elderly Patients
and Non-Elderly Patients
There were 19 elderly hypertensive patients who aged
65 or older and their BP level was 167 ± 16/91 ±
12 mm Hg before the treatment, 140 ± 16/80 ±
11 mm Hg at 1 month after switching the treatment
© 2012 Informa Healthcare USA, Inc.
132 ± 13/73 ± 5 mm Hg at 3 months, 130 ± 12/73
± 6 mm Hg at 6 months, 132 ± 17/75 ± 7 mm Hg at
12 months, and 120 ± 5/71 ± 2 mm Hg at 24 months,
and a significant antihypertensive effect continued for
24 months after 1 month of treatment (for all measured
points; P < .001/P < .001).
There were 31 patients who aged less than 65, and
their BP level was 172 ± 24/102 ± 21 mm Hg before
the treatment, 138 ± 15/80 ± 11 mm Hg at 1 month
after switching the treatment to 80 mg/day, 131 ± 9/80
± 7 mm Hg at 2 months, 131 ± 10/80 ± 5 mm Hg at
3 months, 130 ± 11/79 ± 8 mm Hg at 6 months, 128
± 8/76 ± 6 mm Hg at 12 months, and 129 ± 13/77 ±
8 mm Hg at 24 months, and a significant antihyperten-
sive effect continued for 24 months after 1 month of the
treatment (for all measured points; P < .001/P < .001).
With regard to PR, there was no significant change in
both elderly group and non-elderly group.
Antihypertensive Effect in Patients with Diabetes or CKD
There were 12 patients who were complicated with
diabetes or CKD and all the patients received 80 mg/day
as their initial dose. Their BP level was 168 ± 19/97 ±
14 mm Hg before the treatment, 136 ± 13/79 ±
10 mm Hg 1 month after switching the treatment,
134 ± 15/73 ± 7 mm Hg at 2 months, 132 ±
14/74 ± 6 mm Hg at 3 months, 130 ± 6/76 ±
9 mm Hg at 6 months, 137 ± 17/78 ± 9 mm Hg
at 12 months, and 121 ± 9/71 ± 7 mm Hg at 24
months, and a significant antihypertensive effect con-
tinued for 24 months after 1 month of the treatment
(for all measured points; P < .001/P < .001). The per-
centage of patients who achieved the target BP (i.e.,
<130/80 mm Hg) was 36% at 1 month, 55% at 2
months, 50% at 3 months, 56% at 6 months, 38%
at 12 months, and 71% at 24 months. Compared to
196 N. Kobayashi and T. Ishimitsu

Baseline SBP Baseline DBP

n = 43 n = 42
0 10
100 150 200 250 300
–20 0
50 70 90 110 130 150
–40 –10

ΔDBP (mm Hg)

ΔSBP (mm Hg)

–60 –20

–80 –30
–100 –40

–120 –50
y = –0.9938x + 128.37
–140 –60 y = –0.9016x + 66.821
γ = –0.847 γ = –0.756
–160 –70
Spearman correlation, P < .001 Spearman correlation, P < .001

Figure 3. Antihypertensive property of nifedipine controlled-release tablets at 80 mg/day – correlation between baseline blood pressure
and blood pressure reduction. Abbreviations: SBP – systolic blood pressure; DBP – diastolic blood pressure.

Grade I (140–159) Grade II (160–179) Grade III (≥ 180)

147.1 ± 4.8 mm Hg 168.5 ± 5.4 mm Hg 198.8 ± 21.0 mm Hg
1M 2M 3M 1M 2M 3M 1M 2M 3M
0
–10
–20
–30 –18.4 –19.5
–16.0
–40
(mm Hg)

–50 –27.7
–34.3 –35.5
–60
–70
Values indicate the mean SBP reduction
–80 –54.8
ANOVA: P < .01 between three groups at each month
–90
–66.3 –64.9
–100

Figure 4. Systolic blood pressure reduction stratified according to the severity of baseline value. Abbreviations: SBP – systolic blood
pressure; ANOVA – analysis of variance.

the PR at 80 ± 12/minutes before the treatment, PR In addition, there was no significant change in PR for
also tended to decrease significantly after switching the 12 months from the baseline rate at 71 ± 5/minute.
treatment (P < .05).
Safety
Antihypertensive Effect in Patients Who Failed the Changes in major laboratory test values are shown
Treatment with Amlodipine (5–10 mg) in Table 5. For all items, no significant change was
In nine patients, who had been treated with a mod- observed after switching the treatment to nifedipine CR
erate to high dose of amlodipine, the BP, which was tablets at 80 mg/day. For estimated-glomerular filtra-
160 ± 16/89 ± 11 mm Hg before the treatment, was tion rate (e-GFR), there was an insignificant tendency
significantly reduced after switching the treatment to to increase during the 24-month treatment period from
80 mg/day, and DBP was significantly reduced and the the baseline level of 67.5 ± 24.5, and renal function was
reduction continued with 144 ± 18/79 ± 11 mm Hg well preserved. As indicated by the reduction in PR, no
at 1 month (P = .022), 135 ± 14/76 ± 9 mm Hg at 2 patients reported palpitation or tachycardia as subjective
months (P = .005/P = .02), 131 ± 10/74 ± 7 mm Hg symptoms and the safety was favorable.
at 3 months (P < .001/P < .001), 136 ± 13/75 ±
10 mm Hg at 6 months (P = .004/P = .001), and
DISCUSSION
139 ± 16/76 ± 7 mm Hg at 12 months (P = .025/
P = .02). Of these, four patients started the treatment In this study, nifedipine CR tablet, administered at
at 40 mg/day and were observed for 1–3 months but a dose of 80 mg/day, is demonstrated to be a good
since BP was unstable in all patients, the dose was BP controller in hypertensive patients whose BPs were
increased to 80 mg/day, which resulted in good control. uncontrolled despite several antihypertensive agents and
Clinical and Experimental Hypertension
 Safety and Effect of Nifedipine CR at 80 mg/day 197

Table 5. Changes in laboratory test values

Baseline (before
n nifedipine CR) At 6 mo At 12 mo At 24 mo
AST (U) 41 27.5 ± 25.9 28.3 ± 25.4 30.5 ± 34.1 27.7 ± 29.2
ALT (U) 41 29.7 ± 33.0 28.5 ± 26.9 30.1 ± 30.3 27.1 ± 38.0
ALP (IU) 40 261.0 ± 117.9 271.9 ± 78.5 278.1 ± 81.5 307.2 ± 81.4
LDH 40 240.6 ± 95.9 229.2 ± 46.2 218.2 ± 49.0 211.0 ± 24.8
γ-GTP (U) 40 48.1 ± 48.4 46.4 ± 36.9 53.3 ± 32.9 27.5 ± 12.3
Total bilirubin (mg/dL) 39 0.6 ± 0.4 0.7 ± 0.4 0.6 ± 0.3 0.5 ± 0.2
BUN (mg/dL) 41 17.5 ± 8.5 19.7 ± 6. 16.6 ± 5.9 15.6 ± 4.9
Na (mEq/dL) 41 141.1 ± 2.2 141.0 ± 1.8 140.8 ± 1.5 141.9 ± 1.5
K (mEq/dL) 41 4.3 ± 0.6 4.2 ± 0.4 4.3 ± 0.5 4.5 ± 0.5
Cl (mEq/dL) 41 102.9 ± 16.1 104.6 ± 2.5 104.6 ± 3.0 104.9 ± 1.9
Uric acid (mg/dL) 38 7.0 ± 6.5 5.8 ± 1.3 6.6 ± 1.5 5.4 ± 1.4
Serum creatinine (mg/dL) 41 1.0 ± 1.0 0.9 ± 0.6 0.9 ± 0.6 0.7 ± 0.2
e-GFR (mL/min/1.73 m2 ) 41 67.5 ± 24.5 66.9 ± 22.6 71.5 ± 26.0 78.2 ± 26.3
Fasting blood glucose (mg/dL) 41 118.0 ± 45.8 106.9 ± 20.2 109.9 ± 13.7 104.4 ± 16.0
Total cholesterol (mg/dL) 37 203.1 ± 36.8 205.0 ± 27.7 194.8 ± 25.2 210.8 ± 40.2
Triglyceride (mg/dL) 35 150.2 ± 66.4 145.2 ± 76.4 139.4 ± 59.4 122.3 ± 61.9
HDL-C (mg/dL) 32 52.5 ± 8.9 60.8 ± 12.0 56.3 ± 12.0 66.0 ± 22.0
LDL-C (mg/dL) 32 118.8 ± 32.5 118.8 ± 26.6 114.1 ± 22.7 115.8 ± 28.4
HbA1c (%) 27 5.5 ± 1.0 5.4 ± 0.7 5.4 ± 0.5 5.4 ± 0.6
WBC count (per mm3 ) 41 6.8 ± 3.5 6.4 ± 2.5 6.1 ± 2.8 6.8 ± 3.3
RBC count (×104 /mm3 ) 41 4.7 ± 0.8 4.5 ± 0.8 4.6 ± 0.7 4.6 ± 0.4
Hemoglobin (g/dL) 41 14.0 ± 2.3 13.5 ± 2.0 13.8 ± 2.5 13.5 ± 1.6
Hematocrit (%) 41 41.8 ± 5.9 43.9 ± 14.1 41.8 ± 6.6 41.3 ± 4.3
Plt count (×104/mm3 ) 41 22.6 ± 7.5 20.8 ± 7.9 23.1 ± 7.6 23.4 ± 9.2
Abbreviations: CR – controlled-release; AST – aspartate transaminase; ALT – alanine transaminase; ALP – alkaline phosphatase; LDH
– lactate dehydrogenase; γ-GTP – gamma-glutamyl transpeptidase; BUN – blood urea nitrogen; e-GFR – estimated-glomerular filtration
rate; Na – sodium; K – potassium; Cl – chloride; HDL-C – high density lipoprotein cholesterol; LDL-C – low density lipoprotein
cholesterol; HbA1c – hemoglobin A1c; WBC – white blood cell; RBC – red blood cell; Plt – platelet. No significant changes were
detected from baseline values for each item.

who were at high risk with a complications such as
diabetes or CKD, and had severe hypertension pre-
senting SBP of >180 mm Hg. After 2 years of treat-
ment, the BP level in the 50 patients, which was more
than 170/100 mm Hg at baseline, was reduced to
126/75 mm Hg and no attenuation of the effect was
observed. Of these patients, 70% achieved the target
BP defined by the JSH2009 guidelines within 3 months.
The PR in these patients was not increased by switching
the treatment to nifedipine CR tablets at 80 mg/day, and
any side effects such as headache and tachycardia were
not observed.
The results of this study has showed that dose
increase of nifedipine CR tablets from 40 mg/day to
80 mg/day could reduce BP by 16.6 mm Hg for SBP
and by 7.4 mm Hg for DBP in an average of 6 months
as one of its antihypertensive properties. Previously pub-
lished data analysis on this agent reported that dose
increase from 20 mg/day to 40 mg/day reduced SBP
by 15 mm Hg and DBP by 7.5 mm Hg, and this
study also demonstrated comparable BP reductions by
dose increase, suggesting that the strong antihyperten-
sive effect is dose-dependent. Furthermore, a strong
negative correlation between baseline BP and BP reduc-
tion after treatment was observed for both SBP and
DBP, which suggests that the agent may exert a stronger
antihypertensive effect in patients with higher BP but
the antihypertensive effect may be lower in patients
with relatively mild hypertension. When patients were
classified by severity of BP and compared for BP reduc-
tion, it was found that the agent showed appropriate
effects depending on the severity as reducing SBP by
−18 mm Hg in mild patients, −33 mm Hg in moderate
patients, and −62 mm Hg in severe patients. Landmark
(5) has already reported that long-acting nifedipine
formulations hardly influence the BP and PR in nor-
motensive people and that if the BP is higher before
the treatment, they will exert a stronger antihypertensive
effect. Because, from in vivo study using spontaneously
hypertensive rats, it has been estimated that the inhi-
bition of Ca2+ influx by Ca antagonists was more
pronounced in hypertensive patients than in normoten-
sive people, suggesting that there may be a systemic
disorder of Ca kinetics in hypertensive patients and
nifedipine may inhibit only the excessive Ca2+ influx
into smooth muscle (6,7). The results of our study
are consistent with these previous reports. Nifedipine
has a strong antihypertensive effect, however, there is a
concern about the possible side effects such as tachy-
cardia and palpitation due to sympathetic hyperactivity
caused by rapid BP reduction and therefore some peo-
ple are hesitant to use its high doses. When patients
with uncontrolled hypertension are referred from other
institutions to our department, a nifedipine CR tablet

© 2012 Informa Healthcare USA, Inc.

198 N. Kobayashi and T. Ishimitsu
of 40 mg is usually given to those patients under the
trough condition at the hospital on the day and their
conditions after 2–3 hours is checked, and if they do
not have any symptoms or do not feel sick, nifedip-
ine CR at a dose of 80 mg/day is prescribed and then
they are permitted to go home. In this study, none of
the 50 patients experienced expected side effects and an
excessive reduction in BP was observed, which ensured
security and reliability of the patients. Compared with
existing formulations, this agent does not cause exces-
sive reductions in BP and the sympathetic hyperactivity
(8,9) because of its unique slow-release system (4), and
as a result, it probably could stabilize PR. Recently,
as a survey on the postmarketing drug use investiga-
tion of nifedipine CR tablets, assessment on the safety
and efficacy in patients with uncontrolled hyperten-
sion was published (10). In this survey, many cases
of hypertension that had failed treatment with other
Ca antagonists but could be controlled by switching to
nifedipine CR tablets at 40 mg/day were collected. In
our study, there were nine patients who failed treatment
with a middle to high dose of amlodipine and half of
them received 40 mg/day initially but remained uncon-
trolled and then switched to nifedipine CR tablets at a
dose of 80 mg/day, which resulted in sufficient reduction
in BP and a reduction in PR.
The Ohkubo research (2), which investigated the
status of the management of BP in treated hyperten-
sive patients, found out that BP was not controlled
well in about half of the patients. In the research, the
home BP was studied as a main theme and the tar-
get home BP was set at a lower level than the office
BP (1). In addition, it has also been reported that in
high-risk patients with diabetes or CKD, the incidence
of masked hypertension such as early-morning hyper-
tension is higher and the percentage of achieving the
target is only 27% for diabetes and 18% for CKD in
big cities (11), thus, the current situation is far from
the rapid and strict management of hypertension pro-
posed by the JSH2009 guidelines. Also, the incidence of
refractory hypertension is sometimes more than 50% in
outpatient clinics due to kidney diseases and hyperten-
sion (12). In our study, the whole percentage of patients
who achieved the target BP including those with refrac-
tory hypertension exceeded 70% within 3 months, and
although the number of patients with aforementioned
complications was limited, the achievement percentage
in those patients was more than 50%, thus it can be
considered that BP was successfully controlled. With
regard to laboratory test values, no significant change
or exacerbation was observed in any items. Especially,
e-GFR was maintained at a good level or improved
for 24 months. Bakris et al. (13) conducted a meta-
analysis and showed that if the BP were lowered more,
the decline of e-GFR could be delayed longer, there-
fore, there is a possibility that the high percentage of
achieving target with nifedipine CR tablets at a dose 80
mg/day might contribute to the well-maintained e-GFR
level. It is proposed that the target should be less than
140/90 mm Hg for elderly hypertensive patients, too.
In this study, about 40% of patients were 65 years or
older and BPs were reduced to the mean level at 128/76
mm Hg after 12 months, however, no change in PR and
no excessive reduction in BP were observed. Since a
large clinical trial conducted in Japan also demonstrated
the importance of strict BP control in elderly patients
(14), this agent that showed an excellent antihyperten-
sive effect in patients regardless of their age is expected
to be useful.
As an option of therapy for uncontrolled hyperten-
sion, the JSH2009 guidelines have proposed to increase
doses of antihypertensive agents or change dosing
schedules from once daily to twice daily administra-
tion (1). Nifedipine is a Ca antagonist that is dependent
on blood concentration and once daily administration of
CR tablets at 40 mg for 7 days can keep the maximum
drug concentration at 68.5 ng/mL and the minimal
effective concentration at 14.0 ng/mL for 24 hours (5).
However, since the plasma half-life is short, the trough
level should be raised as high as possible. Therefore, for
hypertension that is refractory but reactive to nifedip-
ine, it may be important to keep the minimal effective
concentration for a long time rather than raise the
maximum drug concentration, and twice daily admin-
istration of this agent at 40 mg is considered as an
appropriate dosing schedule.
In fact, by switching from several antihypertensive
agents to twice daily administration of nifedipine CR
tablets at 40 mg as monotherapy, BP can be controlled
successfully and the target BP can be achieved. Poor
adherence due to the use of multiple antihypertensive
agents can also be another factor. Especially, in patients
with refractory hypertension who receive several anti-
hypertensive agents concomitantly, it is very difficult
to adjust the doses of multiple antihypertensive agents
in order to address seasonal variations as well as to
reduce side effects. In that regard, the agent allows
us to control BP sufficiently and shows favorable tol-
erance, which may results in patient’s reliability and
eventually improve adherence as well as medical econ-
omy. In Japan, amlodipine which is also classified as
Ca antagonist has been approved for an additional dose
of 10 mg/day (15,16). This approval was based on the
standard doses of large clinical trials and the status of
the use in Japan (17–19). Among our patients, there
were two patients who had failed the treatment with
amlodipine at 10 mg/day, and both showed substantial
BP reduction after switching to nifedipine CR tablets at
80 mg/day. Since amlodipine of 10 mg appears to be
comparable to nifedipine CR tablet at 40 mg for anti-
hypertensive effect, it may be a good option to switch
to nifedipine CR tablets at 80 mg/day for patients with
CKD or diabetic nephropathy who failed the treatment
with amlodipine 10 mg. The standard dosage of long-
acting nifedipine formulations is 30–60 mg/day in large
trials in high-risk patients such as INSIGHT (20) and
Clinical and Experimental Hypertension

ACTION (21) using 60–90 mg/day of nifedipine as the
mean dose demonstrated protective effects against cere-
brovascular and cardiovascular events by a long-term
administration. Since the formulations of nifedipine CR
tablets have been designed differently from those of
overseas nifedipine gastrointestinal therapeutic system
(GITS), the situation is not the same as amlodipine, but
those results may be useful in the assessment of the need
for high doses. Miyakawa (22) reported that adminis-
tration of nifedipine CR tablets at 40 mg at bedtime
was significantly more effective in suppressing early-
morning BP than amlodipine. Antihypertensive effect
of nifedipine CR 40 mg tablets has been demonstrated
to be significantly stronger than amlodipine 5 mg in
the litrature (23,24). There is no article that demon-
strated equivalence of antihypertensive effect between
amlodipine 10 mg and nifedipine CR tablet of 40 mg.
In order to achieve BP-lowering effect greater than that
of amlodipine 5 mg, nifedipine CR 40 mg should be
selected. Accordingly, it was considered that it might be
better to change amlodipine 10 mg/day to nifedipine CR
80 mg/day.
Nifedipine CR may temporarily increase heart rate
in patients with no prior treatment with Ca antagonist
or those highly sensitive to Ca antagonist. For these
patients, through review of medical record and health
interview, history of adverse events will be checked. In
addition, when a patient first visits our hospital, single
tablet of nifedipine CR is given to the patient to monitor
any abnormalities. After the confirmation of the absence
of abnormal findings such as tachycardia, a patient is
allowed to leave the clinic. Because of these procedures,
patients who tend to become tachycardia or sensitive
to Ca antagonist may be excluded, which may explain
the result of the current study. As potential other rea-
sons, patients with confirmed diagnosis of heart failure
were not included. Furthermore, although there were
19 patients who were 65 or older, these patients did not
show significant fluctuation of heart rate following dos-
ing. Thirty-one patients who were 65 or younger also
did not show changes. Therefore, it is speculates that
these factors did not influence the decreasing trend of
heart rate.
In 10 patients the dose of nifedipine CR 80 mg/day
reduced during the course of the treatment. Among
10 patients, the dose of 4 patients was adjusted from
80 mg/day to 60 mg/day. Six patients were reduced from
80 mg/day to 40 mg/day. Reasons for dose reduction
were not patient’s complaints of excessive hyperten-
sive effect or tachycardia. However, since the BP at
clinical visit was far below the target value, doctor in
charge voluntarily decided to reduce the dose, taking
into consideration seasonal fluctuation that may occur
in the future. After the dose adjustment, no patients
were discontinued. Accordingly, the current analysis has
already included these 10 patients for efficacy and safety
assessment.
© 2012 Informa Healthcare USA, Inc.
Safety and Effect of Nifedipine CR at 80 mg/day 199
Table 6. e-GFR changes between pre-RAS group and pre-non-
RAS group
e-GFR (mL/min/ At 0 At 12 At 24
1.73 m2 ) mo mo mo ANOVA
Pre-RAS-I (n = 18) 59 ± 23 57 ± 26 67 ± 18 0.754
Pre-non-RAS (n = 24) 74 ± 24 59 ± 23 59 ± 23 0.427
P value .044 .077 .193 –
Mann–Whitney
rank sum
Abbreviations: ANOVA – analysis of variance; e-GFR – estimated-
glomerular filtration rate; RAS – renin-angiotensin system. Values
are denoted as mean ± SD.
LIMITATION
This is a retrospective study on 50 patients who were
given nifedipine CR tablets at a dose of 80 mg/day. Of
those, 12 patients had diabetes or CKD and 10 patients
had failed the treatment with amlodipine, therefore, the
study was limited due to the small number of sub-
jects. In addition, because the follow-up period and
the laboratory testing items were not predefined and
data could be collected from only half of the patients
at 24 months, it cannot be said that all patients were
treated for a long term. Therefore, it may be necessary
to conduct an interventional study with predefined sub-
jects and control agents using the results of this study as
a hypothesis. Also, only three patients received diuret-
ics in our study. The JSH2009 guidelines positively
recommend the concomitant use of low-dose diuret-
ics in uncontrolled patients or in patients with ARBs
showing a lingering effect. Considering this point as
well, the management of BP in patients with refrac-
tory hypertension should be addressed as the future
challenge.
As shown in Results section, tendency of the increase
in e-GFR was observed after nifedipine CR treatment.
However, e-GFR was not measured in all patients. In
addition, the number of 2-year value data is limited.
Accordingly, it cannot be concluded that clear renal pro-
tective effect was demonstrated. As indicated, e-GFR
values of 18 patients who were treated with renin–
angiotensin System (RAS) inhibitor and diuretic prior
to nifedipine CR tablet 80 mg/day treatment and 24
patients who were not were compared. In both groups,
significant increase in e-GFR was not observed after
nifedipine CR tablet 80 mg/day treatment. In addition,
in group comparison of 1-year and 2-year values, no
difference was detected. However, e-GFR value prior
to the initiation of the treatment was lower in the RAS
plus diuretic group and this difference was considered
due to use of RAS inhibitor in patients with tendency of
decreased renal function (Table 6).
As a result of this study, nifedipine CR tablets
administered at a dose of 80 mg (40 mg, twice daily)
as a monotherapy have demonstrated the ability of
controlling BP appropriately in patients with refractory
hypertension to other antihypertensive agents or severe
200 N. Kobayashi and T. Ishimitsu
hypertension depending to the severity with favorable
safety. This agent can be considered as a significant
option for patients with uncontrolled hypertension.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are responsible
for the content and writing of the paper.
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