Transcript Effect of High-dose Angiotensin II Receptor Blocker (ARB) Monotherapy versus ARB plus Calcium Channel Blocker Combination on Cardiovascular Events in Japanese Elderly High-risk Hypertensive.

Effect of High-dose Angiotensin II Receptor
Blocker (ARB) Monotherapy versus ARB plus
Calcium Channel Blocker Combination on
Cardiovascular Events in Japanese Elderly
High-risk Hypertensive Patients (OSCAR): a
Randomized Trial
Hisao Ogawa1, Shokei Kim-Mitsuyama2, Tomio Jinnouchi3,
Hideaki Jinnouchi3, Kunihiko Matsui4 and Kikuo Arakawa5, for
the OSCAR Study Group
1
Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical
Sciences, Kumamoto, Japan; 2 Department of Pharmacology and Molecular Therapeutics,
Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; 3 Jinnouchi
Clinic, Diabetes Care Center, Kumamoto, Japan; 4 Department of General Medicine,
Yamaguchi University Hospital, Ube, Japan; 5 Second Department of Internal Medicine, School
of Medicine, Fukuoka University, Fukuoka, Japan
Study Background
 ARBs are effective for the treatment of not
only hypertension but also stroke, MI, HF,
diabetic nephropathy, etc
 High-dose ARB is more effective than lowdose ARB in the prevention of CVD in
patients with diabetic nephropathy or HF.
 However, it remains to be determined which
therapeutic strategy is more effective, highdose ARB or ARB plus CCB.
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
OSCAR Study
 OSCAR Study compared high-dose ARB vs.
ARB plus CCB in the prevention of
cardiovascular events in high-risk Japanese
elderly hypertensive patients
 Multicenter, active-controlled, two-arm,
parallel group comparison using PROBE
method
 Enrolment from June 2005 to May 2007
with 3yrs. follow-up
 Conducted at 134 institutions in Japan
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Study Design
Registration/
randomization
High-dose ARB group
Other drugs**
Olmesartan (40 mg)
Screening
Step 1
Olmesartan (20 mg)
Run-in treatment
Step 2
Olmesartan (20 mg)
Calcium channel blocker*
ARB plus CCB group
Other drugs**
* Azelnidipine or Amlodipine.
**Other than ARBs, ACEIs, and CCBs.
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Inclusion Criteria
 Outpatients aged 65-84 years
 Single antihypertensive drug
with SBP ≥140 mmHg and/or DBP ≥90
mmHg
 At least one of the following CV risk
factors:
–
–
–
–
–
Cerebrovascular disease
Cardiac disease
Vascular disease
Renal dysfuntion
Type 2 DM
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Primary Endpoints
 Composite of fatal and nonfatal CV events
–
–
–
–
–
–
Cerebrovascular disease
Coronary artery disease
HF
Other arteriosclerotic diseases
Diabetic microvascular diseases
Renal dysfunction
 All cause death
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Secondary Endpoints
 Incidence of each CV event
 Blood pressure (SBP, DBP, mean BP) change
 Serious AEs other than primary endpoints
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Statistical analysis
 ITT principle
 Primary endpoint: Log-rank test stratified
by gender, age, and risk factors (baseline
CV disease and type2 DM)
 HR and 95%CI were calculated by
stratified Cox proportional hazards model.
 Subgroup analysis (predefined)
Interaction-P between CV disease
(Cerebrovascular disease, Cardiac disease,
Vascular disease, Renal dysfunction) and
type2 DM alone was estimated.
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Overview of Disposition
of Patients
1,217 pts. randomized
53 pts. excluded
-17 withdrew consent before trial phase
-36 no data after randomization
1,164 pts. evaluable
BP≧140/90 mmHg by olmesartan 20 mg
578 assigned
high-dose ARB group
(olmesartan 40 mg)
39 withdrew consent
31 lost to follow-up
11 refused follow-up
from sites
578 available for
ITT analyses
586 assigned
ARB (olmesartan 20 mg)
plus CCB (azelnidipine or
amlodipine) group
31 withdrew consent
28 lost to follow-up
10 refused follow-up
from sites
586 available for
ITT analyses
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Baseline Characteristics
Male, n (%)
High-dose ARB
(n=578)
254 (43.9)
ARB plus CCB
(n=586)
261 (44.5)
Age (years)
73.65.3
73.65.5
0.8627
BMI (kg/m2)
24.33.7
23.83.5
0.0216
Systolic BP (mmHg)
158.212.6
157.211.3
0.1512
Diastolic BP (mmHg)
85.210.1
84.69.8
0.3182
73.99.7
72.99.4
0.0920
eGFR (mL/min/1.73 m2)
66.518.6
67.918.8
0.2323
Current smoker, n (%)
62 (10.8)
53 (9.0)
0.3313
Current alcohol, n (%)
178 (31.0)
193 (33.0)
0.4454
History of cardiovascular disease
Stroke
Myocardial infarction
Heart failure
405
111
16
41
(70.1)
(19.2)
(2.8)
(7.1)
407 (69.5)
96 (16.4)
21 (3.6)
48 (8.2)
0.8192
0.2081
0.4278
0.4810
Type 2 diabetes
309 (53.5)
319 (54.4)
0.7382
Heart rate (bpm)
P value*
0.8382
Data are mean±SD (%)
*t-tests or χ2-tests
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Time-course of SBP and DBP
(mmHg)
180
Systolic BP
160
*
140
*
*
*
*
*
120
100
Diastolic BP
80
*
*
*
*
*
60
40
High-dose ARB
20
ARB plus CCB
0
0
6
12
18
24
30
36 (months)
*P<0.05 between groups (adjusted by Holm’s method)
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Differences in BP between Groups
(mmHg)
5
Systolic BP
Diastolic BP
4
3
2
1
0
0
6
12
18
24
30
36 (months)
Difference in means (High-dose ARB – ARB plus CCB)
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Primary Composite Endpoint
(%)
Patients with primary events
20
No. at risk
High-dose ARB
ARB plus CCB
High-dose ARB (58 events)
ARB plus CCB (48 events)
HR=1.31 (95%CI, 0.89-1.92)
P=0.1717
10
0
0
6
12
18
24
30
578
586
559
579
526
553
505
533
477
507
460
494
36 (months)
450
478
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Primary and Secondary Endpoints
No. patients with event
High-dose ARB ARB plus CCB HR (95%CI)
(n=578)
(n=586)
P value
Primary composite endpoint
58
48
1.31 (0.89-1.92)
0.1717
Fatal and nonfatal
cardiovascular event
Cerebrovascular disease
49
37
1.44 (0.94-2.21)
0.0910
24
15
1.75 (0.92-3.35)
0.0848
Coronary artery disease
6
7
0.92 (0.31-2.75)
0.8842
12
8
1.56 (0.64-3.83)
0.3251
Other arteriosclerotic disease
3
2
1.88 (0.31-11.25)
0.4842
Diabetic complications
2
4
0.54 (0.10-2.94)
0.4657
Renal dysfunction
2
1
2.39 (0.21-26.71)
0.4653
9
11
0.85 (0.35-2.06)
0.7203
Heart failure
All-cause death *
* Non-CV death
0
1
2
3
4
High-dose ARB ARB plus CCB
better
better
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Primary Composite Endpoint
in Patients with Cardiovascular Disease
(%)
Patients with primary events
20
No. at risk
High-dose ARB
ARB plus CCB
High-dose ARB (51 events)
ARB plus CCB (34 events)
HR=1.63 (95%CI, 1.06-2.52)
p=0.0261 （log-rank test）
10
0
0
6
12
18
24
30
405
407
391
404
364
387
346
369
329
352
315
344
36 (months)
306
331
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Primary Composite Endpoint in Subgroup
of Patients with CVD or only Type 2 DM
Cardiovascular Disease
(%)
20
Only Type 2 Diabetes
(%)
20
High-dose ARB (51 events)
ARB plus CCB (14 events)
Patients with primary events
ARB plus CCB (34 events)
Patients with primary events
High-dose ARB (7 events)
HR=1.63 (95%CI, 1.06-2.52)
P=0.0261
10
HR=0.52 (95% CI 0.21-1.28)
P=0.1445
10
Interaction P = 0.0241
0
0
6
12
18
24
30
36
(months)
0
0
6
12
18
24
30
36
(months)
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Serious AEs
High-dose ARB
ARB plus CCB
P value
Serious AEs
47 (8.1%)
51 (8.7%)
0.7523
Cancer incidence
10 (1.7%)
21 (3.6%)
0.0672
P values derived from Fisher’s exact test.
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Summary
 In the OSCAR study, BP was significantly lower in the ARB plus
CCB group than in the high-dose ARB group.
 There were no significant differences in primary endpoint rate
between the high-dose ARB and the ARB plus CCB groups.
 In subgroup of patients with CVD at baseline, primary composite
endpoint was significantly higher in the high-dose ARB group
than ARB plus CCB group (P=0.0261).
 Conversely, in the subgroup of patients with T2DM but with no
other comorbid conditions, the rate of composite primary
endpoint was lower in the high-dose ARB group than in the ARB
plus CCB group (P=0.1445).
 There was a significant treatment-by-subgroup interaction for
the primary endpoints for the subgroup between cardiovascular
disease and only the presence of diabetes (P = 0.0241).
Conclusion
The OSCAR study, first large clinical trial to
investigate the efficacy of high-dose ARB vs. ARB plus
CCB in high-risk elderly hypertensive patients, did not
show any differences in reducing CV events/all cause
death.
ARB plus CCB was superior in reducing CV events/
all cause death in subgroup of patients with CV
disease.
High-dose ARB seemed to prevent CV events/
all cause death in patients with diabetes alone in
spite of the weakness in antihypertensive effect.
Further study is needed.
Membership of Committees
 Steering Committee:
Kikuo Arakawa (Chair), Hisao Ogawa, Shokei Kim-Mitsuyama,
Tomio Jinnouchi
 Endpoint Committee:
Shuichi Oshima, Yoichiro Hashimoto, Takamichi Nakamura
 Data and Safety Monitoring Committee:
Yasuhiro Ogata, Toshiro Yonehara
 Ethics Committee:
Takao Hashimoto, Ryo Nagao, Satoshi Asai, Wataru Shimizu,
Hideko Agui
 Study Statistician: Kunihiko Matsui
 Study Secretary: Hisao Ogawa
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OSCAR Study Group
Aichi; Kenji Yamada. Akita; Goro Namekawa, Yasushi Suzuki, Aomori; Kenichi Kimura, Morio Aihara. Chiba; Akiko
Soyama, Michiko Yonemitsu, Tomotane Shishikura, Toshiyuki Imasawa. Ehime; Masahiro Hasui. Fukuoka;
Hidenori Urata, Hiroshi Ikezono, Masahiko Seki, Masaki Munekiyo, Takatoshi Otonari, Tetsuya Ohtsubo, Yasunori
Sawayama, Yoichi Hanaoka, Yoshinori Takajo, Yuji Taira. Fukushima; Kuniyoshi Shima. Gifu; Hiroyuki Ohbayashi.
Hiroshima; Kazuya Shigenobu. Hokkaido; Chieko Imamoto, Hiromitsu Yokota, Kazuo Yamagata, Kouichi Kanda,
Tateo Ogura, Toshio Tsubokura. Hyogo; Akira Kosaka, Akira Tabuchi, Masaharu Shigenobu, Takatoshi Takamiya,
Yasuki Makino, Yoshikazu Irie. Kagawa; Hideyasu Kiyomoto, Hirofumi Hitomi. Kagoshima; Yasuhiro Hashiguchi,
Yoshihiro Fukuoka, Yoshitaka Shintomi. Kanagawa; Fusahiro Nonaka, Hiroshi Takeda, Masato Nishimura, Nariaki
Kanemoto, Takayuki Furuki. Kumamoto; Akira Maki, Akira Sato, Eiichiro Tanaka, Etsuro Tsutsumi, Hajime Shono,
Haruo Takeda, Hideaki Jinnouchi, Hirofumi Kann, Hiromi Fujii, Hiroyuki Shono, Hisao Fujimoto, Hisayasu Terazaki,
Junichi Matsubara, Kazuhiko Yamada, Kazuhiro Nishigami, Keiichiro Tsuruta, Kenichi Koyama, Kenji Azuma,
Koichiro Kataoka, Koji Sasaki, Kouji Honjio, Kunihiro Ohmori, Kunio Idegami, Masakazu Matsukawa, Masamitsu
Toihata, Mikiko Suematsu, Motoko Tanaka, Osamu Hashiguchi, Ryo Fukami, Seiko Fujimoto, Shinichi Uemura,
Shiro Mimori, Shojiro Naomi, Shouji Maruta, Shuichi Matsuo, Sunao Kojima, Taiji Sekigami, Takashi Fukunaga,
Takashi Kudoh, Takashi Ono, Takeshi Koga, Tomio Wakita, Tomohiro Sawada, Toshihiko Sakanashi, Toshihiro
Higashi, Yasuhiro Nagayoshi, Yasuhiro Sakamoto, Yoshihiro Kimura, Yuji Miyao, Yutaka Horio, Kyoto; Ken
Takenaka. Miyazaki; Hiroshi Senokuchi, Hirotsugu Ohta, Juniti Miyata, Naoto Yokota, Takeshi Yamamoto.
Nagasaki; Hiroyuki Oka, Yoshito Tanioka, Niigata; Toshihide Shu. Okayama; Hirohiko Asonuma, Naoki Kashihara,
Naruya Tomita, Takehiko Tokura, Tamaki Sasaki. Osaka; Hidenori Koyama, katsuo Suyama, Kenei Shimada,
Masahito Imanishi, Masanori Emoto, Masayuki Hosoi, Masayuki Nagata, Nobuo Wakaki, Shiro Yanagi, Takao
Yoshioka, Takeshi Horio, Tetsuya Hayashi. Saga; Kazuo Moroe, Shiro Hata. Saitama; Hideto Muranaka, Masaru
Arai, Shouji Mashiba, Souichirou Ishimoto, Tadahiko Ogasawara, Tomoya Fujino, Tomoyuki Okudaira. Shimane;
Yuko Yamane. Shizuoka; Masako Waki. Tokushima; Akira Ota. Kazuto Okagawa, Kenzo Motoki, Takashi Iwase.
Tokyo; Akihiko Hachiya, Hiromi Takekawa, Kenzo Matsumura, Masato Yamamoto, Minoru Hojo, Shiho Kaku,
Tetsuya Taniguchi, Yasunaga Hiyoshi, Yutaka Shimizu. Yamaguchi; Hideaki Hanamiya.
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OSCAR Overview
 Design: Multicentre, active-controlled, two-arm, parallel
group comparison using a prospective, randomized open-label
method with blinded endpoint assessment (PROBE).
– Patients randomized to high-dose ARB group (olmesartan
40mg/day) or ARB (olmesartan 20mg/day) plus CCB (amlodipine
or azelnidipine) group
– Conducted at 134 institutions in Japan from June 2005 to May
2007 with follow-up to May 2010
 Inclusion Criteria: Outpatients aged 65-84 years, receiving
treatment with a single antihypertensive drug in principle and
showing SBP ≥140 mmHg and DBP ≥90 mmHg
 Exclusion Criteria: Secondary hypertension or malignant
hypertension, severe heart failure (NYHA class III or IV),
malignancy requiring treatment, serious hepatic or renal
dysfunction
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans