OSCAR

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					     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
               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 low-
  dose 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, high-
  dose 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/
                                High-dose ARB group                 Other drugs**
               randomization

Screening                       Olmesartan (40 mg)
            Step 1

 Olmesartan (20 mg)             Step 2                                        3 years

        Run-in treatment
                                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
 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



                                                            586 assigned
              578 assigned
                                                      ARB (olmesartan 20 mg)
          high-dose ARB group
                                                      plus CCB (azelnidipine or
          (olmesartan 40 mg)
                                                         amlodipine) group
39 withdrew consent                                                        31 withdrew consent
31 lost to follow-up                                                       28 lost to follow-up
11 refused follow-up                                                       10 refused follow-up
    from sites                                                               from sites

            578 available for                              586 available for
              ITT analyses                                   ITT analyses

              Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans
                       Baseline Characteristics
                                                High-dose ARB           ARB plus CCB
                                                                                                 P value*
                                                   (n=578)                (n=586)
Male, n (%)                                       254 (43.9)             261 (44.5)               0.8382
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
Heart rate (bpm)                                    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                  405 (70.1)             407 (69.5)              0.8192
 Stroke                                            111 (19.2)              96 (16.4)              0.2081
 Myocardial infarction                              16 (2.8)               21 (3.6)               0.4278
 Heart failure                                      41 (7.1)               48 (8.2)               0.4810
Type 2 diabetes                                    309 (53.5)             319 (54.4)              0.7382
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
                                      (%)
                                      20
                                                      High-dose ARB (58 events)
       Patients with primary 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             36 (months)
   No. at risk
High-dose ARB 578                                       559            526           505           477            460           450
 ARB plus CCB 586                                       579            553           533           507            494           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)
                                                                                                          P value
                               (n=578)      (n=586)

Primary composite endpoint          58              48      1.31 (0.89-1.92)                              0.1717
 Fatal and nonfatal                 49              37      1.44 (0.94-2.21)                              0.0910
 cardiovascular event
 Non-CV death                        9              11      0.85 (0.35-2.06)                              0.7203


Secondary endpoint
 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
 Heart failure                      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


                                                                            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
                                      (%)
                                      20
                                                     High-dose ARB (51 events)
       Patients with primary 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             36 (months)
   No. at risk
High-dose ARB 405                                      391            364           346           329            315           306
 ARB plus CCB 407                                      404            387           369           352            344           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(+)                                                               Cardiovascular Disease(-)
                               (%)                                                                                     (%)              (Only Type 2 Diabetes)
                                20                                                                                      20
                                           High-dose ARB (51 events / 405 pts.)                                                    High-dose ARB (7 events / 173 pts.)
                                           ARB plus CCB (34 events / 407 pts.)                                                     ARB plus CCB (14 events / 179 pts.)




                                                                                        Patients with primary events
                                        HR=1.63 (95%CI, 1.06-2.52)                                                               HR=0.52 (95% CI 0.21-1.28)
Patients with primary events




                                        P=0.0261                                                                                 P=0.1445




                               10                                                                                      10




                                                                      Interaction P = 0.0241

                                0                                                                                       0
                                    0      6     12      18     24     30        36                                         0       6      12    18     24       30      36
                                                                             (months)                                                                                 (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.

				
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posted:10/19/2012
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