Transcript OSCAR

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
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
1
Disclosure Information
Hisao Ogawa, MD, PhD
 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
Financial Disclosures:
 Grant support for OSCAR from Japan Heart Foundation (Japan)
 Grant support from Astellas, AstraZeneca, Bayer, Boehringer
Ingelheim, Daiichi-Sankyo, Eisai, Kowa, Kyowa Hakko Kirin,
MSD, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and
Takeda, for the past 5 years. No other potential conflict of
interest relevant to this study was reported.
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
3 years
Step 2
Olmesartan (20 mg)
Calcium channel blocker*
ARB plus CCB group
* Azelnidipine or Amlodipine.
**Other than ARBs, ACEIs, and CCBs.
Other drugs**
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Inclusion Criteria
 Outpatients aged 65-84 years
 Olmesartan 20 mg/day monotherapy
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
Non-CV death
Ogawa H, et al. Hypertens Res. 2009; 32: 575-580
Secondary Endpoints
 Incidence of each CV event
 Blood pressure (SBP, DBP) 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 Treatment and Pts
with CV disease (Cerebrovascular disease,
Cardiac disease, Vascular disease, Renal
dysfunction) and Pts without CV disease
(only type2 DM) 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
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
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)
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Primary Composite Endpoint
(%)
Patients with primary events
20
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
No. at risk
High-dose ARB 578
ARB plus CCB 586
6
12
18
24
30
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)
Primary composite endpoint
P value
58
48
1.31 (0.89-1.92)
0.1717
49
37
1.44 (0.94-2.21)
0.0910
9
11
0.85 (0.35-2.06)
0.7203
Cerebrovascular disease
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
Fatal and nonfatal
cardiovascular event
Non-CV death
Secondary endpoint
Heart failure
0
1
2
3
4
High-dose ARB ARB plus CCB
better
better
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Primary Composite Endpoint
in Patients with Cardiovascular Disease
(%)
Patients with primary events
20
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
No. at risk
High-dose ARB 405
ARB plus CCB 407
6
12
18
24
30
391
404
364
387
346
369
329
352
315
344
36 (months)
306
331
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
Primary Composite Endpoint in Subgroup
of Patients with CVD or only Type 2 DM
Cardiovascular Disease(+)
(%)
20
Cardiovascular Disease(-)
(%)
20
High-dose ARB (51 events / 405 pts.)
High-dose ARB (7 events / 173 pts.)
ARB plus CCB (14 events / 179 pts.)
Patients with primary events
ARB plus CCB (34 events / 407 pts.)
Patients with primary events
(Only Type 2 Diabetes)
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)
Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
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 CV disease, primary endpoint rate
was significantly higher in the high-dose ARB group than ARB
plus CCB group (P=0.0261).
 Conversely, in the subgroup of patients without CV disease (only
with T2DM), the rate of composite primary endpoint tended to
be 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 with and
without CV disease (only T2DM) (P = 0.0241).
Conclusion
The OSCAR study is the first large clinical trial to
investigate the effect of high-dose ARB vs. ARB plus
CCB in high-risk elderly hypertensive patients.
We did not observe any differences in reducing CV
events/non CV death between the groups.
The OSCAR study suggest that the relative effect of
the two therapies depends on the presence of CV
disease or T2DM.