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) 73.65.3 73.65.5 0.8627 BMI (kg/m2) 24.33.7 23.83.5 0.0216 Systolic BP (mmHg) 158.212.6 157.211.3 0.1512 Diastolic BP (mmHg) 85.210.1 84.69.8 0.3182 73.99.7 72.99.4 0.0920 eGFR (mL/min/1.73 m2) 66.518.6 67.918.8 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.