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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.

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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 CV disease (Cerebrovascular disease, Cardiac disease, Vascular disease, Renal dysfunction) andonly 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(-) (Only Type 2 Diabetes) Cardiovascular Disease(+) (%) (%) 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. Serious AEs P values derived from Fisher’s exact test. Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  18. 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 history of CV disease, primary composite endpoint was significantly higher in the high-dose ARB group than ARB plus CCB group (P=0.0261). • Conversely, in the subgroup of patients with T2DM but with no other comorbid conditions, the rate of composite primary endpoint was 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 cardiovascular disease and only the presence of diabetes (P = 0.0241).

  19. Conclusion • The OSCAR study, first large clinical trial to investigate the efficacy of high-dose ARB vs. ARB plus CCB in high-risk elderly hypertensive patients, did not show any differences in reducing CV events/non CV death. • ARB plus CCB was superior in reducing CV events/non CV death in subgroup of patients with history of CV disease. • High-dose ARB seemed to prevent CV events/non CVdeath in patients with diabetes alone in spite of the weakness in antihypertensive effect. Further study is needed.

  20. Back up slides

  21. Achieved Blood Pressure *at 36 months Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  22. Differences in BP between Groups Systolic BP Diastolic BP (mmHg) 5 4 3 2 1 0 0 6 12 18 24 30 36 (months) Difference in means (High-dose ARB – ARB plus CCB) Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  23. Membership of Committees Steering Committee: Kikuo Arakawa (Chair), Hisao Ogawa, Shokei Kim-Mitsuyama, Tomio Jinnouchi Endpoint Committee: Shuichi Oshima, Yoichiro Hashimoto, Takamichi Nakamura Data and Safety Monitoring Committee: Yasuhiro Ogata, Toshiro Yonehara Ethics Committee: Takao Hashimoto, Ryo Nagao, Satoshi Asai, Wataru Shimizu, Hideko Agui Study Statistician: Kunihiko Matsui Study Secretary: Hisao Ogawa Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

  24. OSCAR Study Group Aichi; Kenji Yamada. Akita; Goro Namekawa, Yasushi Suzuki, Aomori; Kenichi Kimura, Morio Aihara. Chiba; Akiko Soyama, Michiko Yonemitsu, Tomotane Shishikura, Toshiyuki Imasawa. Ehime; Masahiro Hasui. Fukuoka; Hidenori Urata, Hiroshi Ikezono, Masahiko Seki, Masaki Munekiyo, Takatoshi Otonari, Tetsuya Ohtsubo, Yasunori Sawayama, Yoichi Hanaoka, Yoshinori Takajo, Yuji Taira. Fukushima; Kuniyoshi Shima. Gifu; Hiroyuki Ohbayashi. Hiroshima; Kazuya Shigenobu. Hokkaido; Chieko Imamoto, Hiromitsu Yokota, Kazuo Yamagata, Kouichi Kanda, Tateo Ogura, Toshio Tsubokura. Hyogo; Akira Kosaka, Akira Tabuchi, Masaharu Shigenobu, Takatoshi Takamiya, Yasuki Makino, Yoshikazu Irie. Kagawa; Hideyasu Kiyomoto, Hirofumi Hitomi. Kagoshima; Yasuhiro Hashiguchi, Yoshihiro Fukuoka, Yoshitaka Shintomi. Kanagawa; Fusahiro Nonaka, Hiroshi Takeda, Masato Nishimura, Nariaki Kanemoto, Takayuki Furuki. Kumamoto; Akira Maki, Akira Sato, Eiichiro Tanaka, Etsuro Tsutsumi, Hajime Shono, Haruo Takeda, Hideaki Jinnouchi, Hirofumi Kann, Hiromi Fujii, Hiroyuki Shono, Hisao Fujimoto, Hisayasu Terazaki, Junichi Matsubara, Kazuhiko Yamada, Kazuhiro Nishigami, Keiichiro Tsuruta, Kenichi Koyama, Kenji Azuma, Koichiro Kataoka, Koji Sasaki, Kouji Honjio, Kunihiro Ohmori, Kunio Idegami, Masakazu Matsukawa, Masamitsu Toihata, Mikiko Suematsu, Motoko Tanaka, Osamu Hashiguchi, Ryo Fukami, Seiko Fujimoto, Shinichi Uemura, Shiro Mimori, Shojiro Naomi, Shouji Maruta, Shuichi Matsuo, Sunao Kojima, Taiji Sekigami, Takashi Fukunaga, Takashi Kudoh, Takashi Ono, Takeshi Koga, Tomio Wakita, Tomohiro Sawada, Toshihiko Sakanashi, Toshihiro Higashi, Yasuhiro Nagayoshi, Yasuhiro Sakamoto, Yoshihiro Kimura, Yuji Miyao, Yutaka Horio, Kyoto; Ken Takenaka. Miyazaki; Hiroshi Senokuchi, Hirotsugu Ohta, Juniti Miyata, Naoto Yokota, Takeshi Yamamoto. Nagasaki; Hiroyuki Oka, Yoshito Tanioka, Niigata; Toshihide Shu. Okayama; Hirohiko Asonuma, Naoki Kashihara, Naruya Tomita, Takehiko Tokura, Tamaki Sasaki. Osaka; Hidenori Koyama, katsuo Suyama, Kenei Shimada, Masahito Imanishi, Masanori Emoto, Masayuki Hosoi, Masayuki Nagata, Nobuo Wakaki, Shiro Yanagi, Takao Yoshioka, Takeshi Horio, Tetsuya Hayashi. Saga; Kazuo Moroe, Shiro Hata. Saitama; Hideto Muranaka, Masaru Arai, Shouji Mashiba, Souichirou Ishimoto, Tadahiko Ogasawara, Tomoya Fujino, Tomoyuki Okudaira. Shimane; Yuko Yamane. Shizuoka; Masako Waki. Tokushima; Akira Ota. Kazuto Okagawa, Kenzo Motoki, Takashi Iwase. Tokyo; Akihiko Hachiya, Hiromi Takekawa, Kenzo Matsumura, Masato Yamamoto, Minoru Hojo, Shiho Kaku, Tetsuya Taniguchi, Yasunaga Hiyoshi, Yutaka Shimizu. Yamaguchi; Hideaki Hanamiya. Late-breaking clinical trial ACC 60th Annual Scientific session, April 5, 2011, in New Orleans

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