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Hisao Ogawa 1 , Shokei Kim-Mitsuyama 2 , Tomio Jinnouchi 3 , Hideaki Jinnouchi 3 , Kunihiko Matsui 4 and Kikuo Arakawa

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.

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Hisao Ogawa 1 , Shokei Kim-Mitsuyama 2 , Tomio Jinnouchi 3 , Hideaki Jinnouchi 3 , Kunihiko Matsui 4 and Kikuo Arakawa

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  1. 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; 2Department 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

  2. 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.

  3. 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

  4. 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

  5. Study Design High-dose ARB group Other drugs** Registration/ randomization Olmesartan (40 mg) Screening Step 1 Olmesartan (20 mg) 3 years Step 2 Run-in treatment Olmesartan (20 mg) Calcium channel blocker* Other drugs** ARB plus CCB group * Azelnidipine or Amlodipine. **Other than ARBs, ACEIs, and CCBs. Ogawa H, et al. Hypertens Res. 2009; 32: 575-580

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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. evaluableBP≥140/90 mmHg by olmesartan 20 mg 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 31 withdrew consent 28 lost to follow-up 10 refused follow-up from sites 578 available for ITT analyses 586 available for ITT analyses Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  11. Baseline Characteristics Data are mean±SD (%) *t-tests or χ2-tests Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  12. Time-course of SBP and DBP High-dose ARB ARB plus CCB (mmHg) 180 Systolic BP 160 * * * * * * 140 120 100 Diastolic BP * * * * 80 * 60 40 20 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

  13. Primary Composite Endpoint High-dose ARB (58 events) ARB plus CCB (48 events) (%) 20 HR=1.31 (95%CI, 0.89-1.92) P=0.1717 Patients with primary events 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

  14. Primary and Secondary Endpoints No. patients with event High-dose ARB (n=578) ARB plus CCB (n=586) HR (95%CI) P value Primary composite endpoint 58 48 1.31 (0.89-1.92) 0.1717 Fatal and nonfatal cardiovascular event 49 37 1.44 (0.94-2.21) 0.0910 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 better ARB plus CCB better Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  15. Primary Composite Endpoint in Patients with Cardiovascular Disease High-dose ARB (51 events) ARB plus CCB (34 events) (%) 20 HR=1.63 (95%CI, 1.06-2.52) P=0.0261 （log-rank test） Patients with primary events 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

  16. High-dose ARB (51 events / 405 pts.) High-dose ARB(7 events / 173 pts.) ARB plus CCB (14 events/ 179 pts.) ARB plus CCB (34 events / 407 pts.) Primary Composite Endpoint in Subgroupof Patients with CVD or only Type 2 DM Cardiovascular Disease(+) Cardiovascular Disease(-) (Only Type 2 Diabetes) (%) (%) 20 20 HR=1.63 (95%CI, 1.06-2.52) P=0.0261 HR=0.52 (95% CI 0.21-1.28) P=0.1445 Patients with primary events Patients with primary events 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

  17. 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).

  18. 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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