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Combinations of Olmesartan and A Calcium Channel.21 PDF
Combinations of Olmesartan and A Calcium Channel.21 PDF
INTRODUCTION
Some data from this report were presented as a late-breaking clinical trial at the 23rd
European Meeting on Hypertension and Cardiovascular Protection (Milan, Italy), 16
June 2013.
Received 14 November 2013 Revised 20 May 2014 Accepted 20 May 2014
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Study protocol
METHODS
The target SBP and DBP were less than 140 and less than
90 mmHg, respectively, in both groups. For patients with
BP exceeding these targets, the dose of each drug was to be
increased. If the target BP was not achieved with maximal
doses of the allocated drug, the other class of antihypertensive drug was added, followed by the addition of other
antihypertensive drugs, including b-blockers, a-blockers,
and angiotensin-converting enzyme (ACE) inhibitors. If
the BP decreased excessively, the doses of antihypertensive
agents other than the study drugs were reduced, or the
other drugs were discontinued with the aim of continuing
the combination for as long as possible [14].
Study design
Outcomes
Patients
Hypertensive patients aged at least 65 to less than 85 years
with a history of cardiovascular disease or risk factors for
cardiovascular disease, including diabetes mellitus or dyslipidemia, were eligible for the study. Patients were
enrolled if their clinic-measured SBP was at least 140 mmHg
and/or their DBP was at least 90 mmHg during treatment
with one or more antihypertensive drugs at enrolment, or if
their SBP was at least 160 mmHg and/or DBP was at least
100 mmHg without antihypertensive treatment. All patients
provided written informed consent.
Sample size
The rationale for the sample size is reported elsewhere [14].
Briefly, the incidence of cardiovascular events (i.e., the
primary endpoint) was estimated to be 2% per year, and
the relative difference in the incidence of cardiovascular
events between the two groups was estimated to be 33%.
Therefore, more than 2000 patients were needed for each
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Ogihara et al.
Statistical methods
All analyses were conducted according to the intention-totreat principle. Time-to-event curves for cardiovascular
events were plotted using the KaplanMeier method. Stratified log-rank tests were conducted with sex, age, and
history of cardiovascular disease as strata. Hazard ratios
and 95% confidence intervals (CIs) were calculated using
the stratified proportional hazards model. Exploratory
analyses of prespecified subgroup analyses were conducted, and interactions between treatment group and each
subgroup were investigated. Patient characteristics at baseline, BP at the end of the trial, and the frequency of adverse
events between two groups were compared using the t-test
(for continuous variables) and Fishers exact test (for categorical variables). The t-test was used to compare the change
in BP, and the analysis of covariance adjusted by baseline
data was conducted to compare the average change in heart
rate between two groups. Two interim analyses were
planned to either continue or discontinue the study on
the basis of ethical and scientific considerations, with
adjustment for repeated comparisons using the OBrien
Fleming a-spending function, and the results were evaluated by the Independent Data Monitoring Committee. The
prespecified significant levels for stopping criteria were
0.00001 for the first interim analysis and 0.003 for the
second interim analysis. If these were met, the Data
Monitoring Committee would ask the Steering Committee
to either amend the study protocol or discontinue the study.
For the primary endpoint, the significance level for the final
analysis was set at 0.049 (two-sided) considering the two
RESULTS
Patients
Of 5658 patients assessed for eligibility, 489 patients met the
exclusion criteria and 28 patients withdrew consent before
enrolment. Therefore, 5141 patients were randomized.
Overall, 46 patients in the olmesartan plus CCB group
and 72 patients in the olmesartan plus diuretic group were
lost to follow-up, leaving 2568 and 2573 patients in these
groups, respectively (Fig. 1). The results of two interim
analyses in October 2009 and December 2010 did not meet
the prespecified early stopping criteria. The median followup period was 3.3 years (range 1 day to 4.3 years), and the
follow-up rate was 98.0%. The baseline characteristics,
including BP at randomization, are shown in Table 1.
The mean age of patients was 73.6 years, and 51.6% were
men. There were no significant differences in baseline
characteristics between the two groups. Approximately
24% of patients had a history of cardiovascular diseases,
including stroke (14.6%) and ischaemic heart disease
(11.0%). Approximately 81% of patients were treated with
antihypertensive agents at enrolment; the most common
types were ARBs (49%) and CCBs (37%).
At 3 years, the mean number of antihypertensive drugs
used, including the allocated drugs, was 2.1 in the olmesartan plus CCB group and 2.1 in the olmesartan plus
diuretic group (P 0.64). The median number of drugs
was two in both groups.
Excluded: 517
Did not meet eligibility criteria: n = 489
Withdrew consent before randomization: n = 28
Randomized
n = 5141
n = 2568
n = 2573
Lost to follow-up: n = 46
Withdrew consent: n = 89
Lost to follow-up: n = 72
Withdrew consent: n = 93
n = 2568
n = 2573
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Sex
Men
Women
Age (years)
75 years old
<75 years old
BMI (kg/m2)
eGFR (ml/min per 1.73 m2)
SBP (mmHg)
DBP (mmHg)
Heart rate (bpm)
Cardiovascular history
Stroke
Ischaemic heart disease
Cardiovascular risk factors
Dyslipidemia
Diabetes mellitus
Smoking
Drinking
Use of antihypertensive drugs at enrolmenta
ARB
CCB
b-Blockers
ACE inhibitors
Diuretics
a-Blockers
Concomitant use of other drugs
Statin
Antiplatelet drugs
Antidiabetic drugs
P-Value
1323 (51.5)
1245 (48.5)
73.6 5.3
1109 (43.2)
1459 (56.8)
24.3 3.5
67.6 19.0
158.0 12.7
87.1 10.8
73.1 9.9
1330 (51.7)
1243 (48.3)
73.6 5.4
1114 (43.3)
1459 (56.7)
24.2 3.4
67.3 18.3
158.0 12.5
86.9 10.8
72.9 9.3
0.91
0.26
0.62
0.96
0.58
0.49
369 (14.4)
286 (11.1)
382 (14.9)
277 (10.8)
0.63
0.68
0.74
0.95
1165
684
641
1090
(45.5)
(26.6)
(25.1)
(42.8)
1172
678
648
1086
(45.8)
(26.4)
(25.4)
(42.5)
0.84
0.82
0.84
0.88
1262
977
231
149
146
71
(49.2)
(38.1)
(9.0)
(5.8)
(5.7)
(2.8)
1254
916
191
154
168
70
(48.9)
(35.8)
(7.5)
(6.0)
(6.6)
(2.7)
0.84
0.08
0.04
0.76
0.20
1.00
719 (28.1)
561 (21.9)
497 (19.4)
0.64
0.83
0.37
704 (27.5)
555 (21.7)
472 (18.4)
Data are n (%) or mean standard deviation. ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; eGFR: estimated glomerular
filtration rate, calculated using the Japanese formula 194 Cr 1.094 age 0.287 (0.739 for women).
a
Excludes 16 patients for whom data were not collected after randomization (n 2563 in the olmesartan plus CCB group, n 2562 in the olmesartan plus diuretic group).
Primary outcome
KaplanMeier analysis of the time to the first primary
endpoint is shown in Fig. 3. The incidence and hazard
ratio of the primary endpoint are shown in Fig. 4. The
primary endpoint occurred in 116/2568 patients (4.5%) in
the olmesartan plus CCB group, and in 135/2573 patients
(5.3%) in the olmesartan plus diuretic group (hazard ratio
0.83, 95% CI 0.651.07, P 0.16). The incidence of the
primary endpoint per 1000 patient-years was 14.8 in
the olmesartan plus CCB group and 17.6 in the olmesartan
plus diuretic group. There were no significant differences
in the rates of each type of event between the two groups
(Fig. 4).
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Ogihara et al.
Olmesartan plus CCB
180
160
SBP
140
120
100
DBP
80
60
0
12
18
24
30
36
42
Time (months)
No. at risk
Olmesartan
plus CCB
Olmesartan
plus diuretic
2568
2456
2454
2424
2363
2269
2211
2110
2065
643
2573
2440
2433
2404
2326
2219
2143
2071
2020
641
8
P = 0.16 (log-rank test)
HR 0.83 (95% CI: 0.651.07)
0
0
No. at risk
Olmesartan
plus CCB
Olmesartan
plus diuretic
12
18
24
30
36
42
Time (months)
2568
2497
2381
2285
2214
2154
2114
793
2573
2475
2352
2245
2162
2098
2043
776
FIGURE 3 KaplanMeier curves for the primary composite endpoint of fatal and nonfatal cardiovascular events.
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Outcome
Olmesartan Olmesartan
plus CCB plus diuretic
(n = 2568)
(n = 2573)
HR (95% CI)
CCB
better
Diuretic
better
1.0
P-value
2.0
116 (4.5)
135 (5.3)
0.83 (0.651.07)
0.16
Sudden death
6 (0.2)
11 (0.4)
0.53 (0.191.44)
0.20
63 (2.5)
66 (2.6)
0.93 (0.661.32)
0.70
37 (1.4)
47 (1.8)
0.76 (0.501.18)
0.23
Renal events
14 (0.6)
14 (0.5)
0.98 (0.472.06)
0.96
All-cause mortality
64 (2.5)
76 (3.0)
0.83 (0.591.15)
0.27
72 (2.8)
88 (3.4)
0.80 (0.581.09)
0.16
Cardiovascular death
13 (0.5)
18 (0.7)
0.70 (0.341.43)
0.33
Non-fatal stroke
60 (2.3)
62 (2.4)
0.95 (0.661.35)
0.78
9 (0.4)
16 (0.6)
0.55 (0.241.24)
0.14
Atrial fibrillation
43 (1.7)
32 (1.2)
1.33 (0.842.10)
0.21
New-onset diabetes
10 (0.4)
15 (0.6)
0.66 (0.291.47)
0.30
Secondary endpoints
FIGURE 4 Incidence rates and hazard ratios of the primary composite endpoint, of individual components of the primary endpoint, and of the secondary endpoints.
The hazard ratios and 95% CIs were determined using a stratified Cox proportional hazards model taking into account sex, age, and baseline cardiovascular disease.
The P-values were derived from a log-rank test, stratified by sex, age, and baseline cardiovascular disease. CCB, calcium channel blocker; CI, confidence interval.
Hazard ratio
(95% CI)
P-Value
P-Value
(interaction)
63/1323 (4.8)
53/1245 (4.3)
76/1330 (5.7)
59/1243 (4.7)
0.82 (0.581.14)
0.87 (0.601.26)
0.24
0.46
0.81
58/1459 (4.0)
58/1109 (5.2)
55/1459 (3.8)
80/1114 (7.2)
1.03 (0.711.49)
0.70 (0.500.99)
0.85
0.04
0.14
76/1525 (5.0)
40/1022 (3.9)
93/1527 (6.1)
41/1018 (4.0)
0.81 (0.591.09)
0.94 (0.601.45)
0.17
0.78
0.74
43/622 (6.9)
47/1230 (3.8)
52/642 (8.1)
55/1224 (4.5)
0.82 (0.551.24)
0.83 (0.561.23)
0.35
0.37
0.94
48/684 (7.0)
68/1884 (3.6)
42/678 (6.2)
93/1895 (4.9)
1.12 (0.741.69)
0.71 (0.520.97)
0.58
0.03
0.06
68/1165 (5.8)
48/1398 (3.4)
66/1172 (5.6)
69/1390 (5.0)
1.01 (0.721.41)
0.68 (0.470.98)
0.94
0.03
0.08
55/610 (9.0)
61/1958 (3.1)
59/615 (9.6)
76/1958 (3.9)
0.90 (0.621.30)
0.78 (0.561.10)
0.58
0.16
0.61
Data are n of patients reaching the primary endpoint/total n (%). CCB, calcium channel blocker; CI, confidence interval; eGFR, estimated glomerular filtration rate.
group than in the olmesartan plus CCB group (6.5 vs. 2.6%,
P < 0.001).
DISCUSSION
Over a median follow-up period of 3.3 years, there were no
differences in the cardiovascular risk reduction conferred
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current clinical guidelines for the management of hypertension advocate the use of multiple antihypertensive drugs
in combination to help reach BP targets. Although there is
abundant evidence supporting the use of combination
therapy, very few studies have compared different combinations of drugs. We found no marked differences in the
cardiovascular risk reduction by using olmesartan together
with either a CCB or a diuretic. When considering the safety
aspects, however, a regimen consisting of olmesartan and a
CCB may be preferable to olmesartan in combination with a
diuretic. Well designed studies are needed to compare the
cardiovascular risk reduction profiles and safety profiles of
combination regimens based on an ARB, ACE inhibitor,
or CCB.
ACKNOWLEDGEMENTS
We thank the collaborators and members of the COLM
Study Group.
The present work was supported by a grant from Japan
Heart Foundation. The Japan Heart Foundation had no
input into the study design; in the collection, analysis,
and interpretation of data; in the writing of the report; or
in the decision to submit the paper for publication.
Conflicts of interest
T.O., T.S., H.R., I.S., K.Shimamoto., H.M., K.Shimada, S.I.,
M.H., T.I., S.T., J.H., S.K., G.K., N.U., K.H., M.O., N.T., T.I.,
S.U., N.K., and S.T. have received travel expenses, payment
for speaking at meetings, or funding for research from one
or more pharmaceutical companies that market antihypertensive drugs, including Daiichi Sankyo Co. Ltd. S.M. has no
conflicts of interest to disclose.
Appendix
COLM study committees
Executive and Writing Committee: T. Saruta (Co-Chair, Keio
University), T. Ogihara (Co-Chair, Morinomiya University
of Medical Sciences), H. Rakugi (Secretary, Osaka University Graduate School of Medicine), and I. Saito (Keio
University).
Steering Committee: K. Shimamoto (Sapporo Medical
University), S. Ito (Tohoku University Graduate School of
Medicine), H. Matsuoka (Dokkyo Medical University), K.
Shimada (Shin-Oyama City Hospital), M. Horiuchi (Ehime
University Graduate School of Medicine), T. Imaizumi
(Kurume University School of Medicine), and S. Takishita
(University of the Ryukyus School of Medicine).
Protocol Committee: K. Shimada (Shin-Oyama City
Hospital), N. Ura (Sapporo Nishimaruyama Hospital), K.
Hayashi (Keio University), and H. Rakugi (Osaka University
Graduate School of Medicine).
Endpoint Committee: J. Higaki (Ehime University Graduate School of Medicine), M. Odawara (Tokyo Medical
University), N. Tanahashi (Saitama Medical University),
and G. Kimura (Asahi Rousai Hospital).
Independent Data Monitoring Committee: S. Katayama
(Saitama Medical University), S. Umemura (Yokohama City
University Graduate School of Medicine), T. Ishimitsu
(Dokkyo Medical University), N. Kashihara (Kawasaki
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12.
13.
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