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 Ogawa 1, Shokei Kim-Mitsuyama 2, Tomio Jinnouchi 3, Hideaki Jinnouchi 3, Kunihiko Matsui 4 and Kikuo Arakawa 5, 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 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: Japan Heart Foundation Grant support for OSCAR from Japan Heart Foundation (Japan) Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Kowa, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and Takeda, 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 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. 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. 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:

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 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 Multicenter, active-controlled, two-arm, parallel group comparison using PROBE method Enrolment from June 2005 to May 2007 with 3yrs. follow-up Enrolment from June 2005 to May 2007 with 3yrs. follow-up Conducted at 134 institutions in Japan Conducted at 134 institutions in Japan Ogawa H, et al. Hypertens Res. 2009; 32:

Other drugs** Study Design Registration/randomization High-dose ARB group Step 2 Step 1 Screening Olmesartan (20 mg) Run-in treatment Olmesartan (40 mg) Olmesartan (20 mg) Calcium channel blocker* ARB plus CCB group * Azelnidipine or Amlodipine. **Other than ARBs, ACEIs, and CCBs. Ogawa H, et al. Hypertens Res. 2009; 32: years

Inclusion Criteria Outpatients aged years Outpatients aged years Olmesartan 20 mg/day monotherapy with SBP ≥140 mmHg and/or DBP ≥90 mmHg Olmesartan 20 mg/day monotherapy with SBP ≥140 mmHg and/or DBP ≥90 mmHg At least one of the following CV risk factors: 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:

Primary Endpoints Composite of : Fatal and nonfatal CV events Fatal and nonfatal CV events –Cerebrovascular disease –Coronary artery disease –HF –Other arteriosclerotic diseases –Diabetic microvascular diseases –Renal dysfunction Non-CV death Non-CV death Ogawa H, et al. Hypertens Res. 2009; 32:

Secondary Endpoints Incidence of each CV event Incidence of each CV event Blood pressure (SBP, DBP) change Blood pressure (SBP, DBP) change Serious AEs other than primary endpoints Serious AEs other than primary endpoints Ogawa H, et al. Hypertens Res. 2009; 32:

Statistical analysis ITT principle ITT principle Primary endpoint: Log-rank test stratified by gender, age, and risk factors (baseline CV disease and type2 DM) 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. 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. 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:

Overview of Disposition of Patients 1,217 pts. randomized 53 pts. excluded -17 withdrew consent before trial phase -36 no data after randomization 578 assigned high-dose ARB group (olmesartan 40 mg) 586 assigned ARB (olmesartan 20 mg) plus CCB (azelnidipine or amlodipine) group 39 withdrew consent 31 lost to follow-up 11 refused follow-up from sites 578 available for ITT analyses 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 1,164 pts. evaluable BP≥140/90 mmHg by olmesartan 20 mg

High-dose ARB (n=578) ARB plus CCB (n=586) (n=586) P value* Male, n (  ) 254 (43.9) 261 (44.5) Age (years) 73.6   BMI (kg/m 2 ) 24.3   Systolic BP (mmHg)   Diastolic BP (mmHg) 85.2   Heart rate (bpm) 73.9   eGFR (mL/min/1.73 m 2 ) 66.5   Current smoker, n (  ) 62 (10.8) 53 (9.0) Current alcohol, n (  ) 178 (31.0) 193 (33.0) History of cardiovascular disease Stroke Myocardial infarction Heart failure 405 (70.1) 111 (19.2) 16 (2.8) 41 (7.1) 407 (69.5) 96 (16.4) 21 (3.6) 48 (8.2) Type 2 diabetes 309 (53.5) 319 (54.4) Baseline Characteristics Data are mean±SD (  ) *t-tests or χ 2 -tests Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

Time-course of SBP and DBP Time-course of SBP and DBP (mmHg)0 High-dose ARB ARB plus CCB Systolic BP Diastolic BP (months) Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans *P<0.05 between groups (adjusted by Holm’s method) * * * * * ** * * * *

Primary Composite Endpoint Primary Composite Endpoint 10 Patients with primary events (%)0 High-dose ARB (58 events) ARB plus CCB (48 events) HR=1.31 (95%CI, ) P= (months) ARB plus CCB High-dose ARB No. at risk Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

Primary and Secondary Endpoints Primary and Secondary Endpoints High-dose ARB (n=578) ARB plus CCB (n=586) No. patients with event HR (95  CI) P value High-dose ARB better ARB plus CCB better Primary composite endpoint Fatal and nonfatal cardiovascular event Cerebrovascular disease Coronary artery disease Heart failure Other arteriosclerotic disease Diabetic complications Renal dysfunction Non-CV death ( ) 1.44 ( ) 1.75 ( ) 0.92 ( ) 1.56 ( ) 1.88 ( ) 0.54 ( ) 2.39 ( ) 0.85 ( ) Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans Secondary endpoint

Primary Composite Endpoint in Patients with Cardiovascular Disease ARB plus CCB High-dose ARB No. at risk Patients with primary events High-dose ARB (51 events) ARB plus CCB (34 events) HR=1.63 (95%CI, ) P= （ log-rank test ） (%)(months) Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

(months) Patients with primary events (months) 20 0 (%) 10 HR=1.63 (95%CI, ) P= High-dose ARB (51 events / 405 pts.) ARB plus CCB (34 events / 407 pts.) Cardiovascular Disease(+) Patients with primary events 10 HR=0.52 (95% CI ) P= High-dose ARB (7 events / 173 pts.) ARB plus CCB (14 events/ 179 pts.) ARB plus CCB (14 events / 179 pts.) 20 0 (%) Interaction P = Primary Composite Endpoint in Subgroup of Patients with CVD or only Type 2 DM Cardiovascular Disease(-) (Only Type 2 Diabetes)

In the OSCAR study, BP was significantly lower in the ARB plus CCB group than in the high-dose ARB group. 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. 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). 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). 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 = ). There was a significant treatment-by-subgroup interaction for the primary endpoints for the subgroup between with and without CV disease (only T2DM) (P = ). Summary

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. 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. 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. The OSCAR study suggest that the relative effect of the two therapies depends on the presence of CV disease or T2DM. Conclusion