Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial

Masunori Matsuzaki; Toshio Ogihara; Seiji Umemoto; Hiromi Rakugi; Hiroaki Matsuoka; Kazuyuki Shimada; Keishi Abe; Norihiro Suzuki; Tanenao Eto; Jitsuo Higaki; Sadayoshi Ito; Akira Kamiya; Kenjiro Kikuchi; Hiromichi Suzuki; Chuwa Tei; Yasuo Ohashi; Takao Saruta; Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial Group

doi:10.1097/HJH.0b013e328348345d

Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial

J Hypertens. 2011 Aug;29(8):1649-59. doi: 10.1097/HJH.0b013e328348345d.

Authors

Masunori Matsuzaki¹, Toshio Ogihara, Seiji Umemoto, Hiromi Rakugi, Hiroaki Matsuoka, Kazuyuki Shimada, Keishi Abe, Norihiro Suzuki, Tanenao Eto, Jitsuo Higaki, Sadayoshi Ito, Akira Kamiya, Kenjiro Kikuchi, Hiromichi Suzuki, Chuwa Tei, Yasuo Ohashi, Takao Saruta; Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial Group

Collaborators

Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial Group:
T Fujita, H Kumagai, K Shimamoto, S Takishita, K Hayashi, K Kario, M Kawana, K Kitagawa, H Makino, M Matsumoto, J Yoshikawa, H Matsuura, Y Ohashi, K Otsuka, K Tanabe, S Nogawa, K Utsunomiya, T Yoshikawa, W Yumura, K Kiluchi, N Hasebe, M Bunya, W Fujii, N Funayama, K Hashizume, Y Hirayama, H Matsuhashi, H Morimoto, T Myojo, K Ohori, H Omiay, T Ota, A Sato, T Shiokoshi, H Tanaka, K Yamazaki, H Yoshie, K Shimamoto, M Abiru, M Adachi, Y Fujise, K Hanawa, K Ishii, Y Kadono, T Kaku, S Kaneta, M Kato, N Kato, H Kobayashi, T Komakine, T Matsumoto, T Mita, N Miura, H Mukai, K Nagao, H Nakagawa, M Nakagawa, N Nakajima, T Nishimiya, Y Nishino, A Nunokawa, J Ohata, H Ooiwa, R Sato, S Satoh, S Shibata, M Takada, Y Takagawa, Y Takagi, S Takeichi, S Tanaka, N Togashi, N Ura, C Wakabayashi, D Yoshida, H Yoshida, K Yoshida, A Kitabatake, H Tsutsui, M Akutsu, S Fujii, T Furumoto, S Kakinoki, H Kawasaki, T Kimura, M Makiguchi, H Matsuo, H Okamoto, Y Oyama, J Shimokawa, N Tsuzuki, S Ito, Y Imai, R Domon, H Ebina, S Egawa, T Haruyama, H Hashimoto, T Hayakawa, H Inomata, Y Katahira, T Katakura, R Kikuchi, H Kimura, S Kyogoku, Y Kyogoku, K Matsuo, H Nakazawa, H Odakura, F Okuguchi, E Ohtomo, H Ouchi, M Seino, M Tadokoro, Y Tanno, N Uchida, T Yamanaka, K Yunomura, K Okumura, T Hatayama, Y Kanehira, H Kaneko, M Kimura, N Maeda, A Mikuniya, H Narita, M Ono, T Osanai, M Sato, H Yoshino, S Momomura, M Ono, M Inoue, T Iwase, K Miyazaki, M Taki, T Aizawa, Y Hasunuma, H Makino, H Okabayashi, S Hosoda, T Sumiyoshi, M Abe, Y Kira, M Nagayama, K Sakai, O Yoshikawa, M Ide, N Kimura, S Matsuzaka, Y Miyajima, K Sawai, R Takada, Y Yamada, K Yoda, T Yokokawa, S Yokoyama, K Kanmatsuse, T Kushiro, T Anazawa, T Migita, T Osada, Y Otsuka, F Saito, S Shimoda, K Sugino, A Takahashi, S Tani, K Yumi, H Daida, T Arino, T Iesaki, Y Inomata, H Nakahara, H Shiraishi, H Sudo, T Degawa, T Araki, H Itaya, H Komatsu, H Kuwana, T Mikawa, H Nomoto, N Ogawa, H Sato, H Takase, H Toyoda, K Obayashi, I Akabane, H Hamamoto, R Kanbara, H Kato, H Kimura, N Mori, K Yamada, O Inaba, T Inazawa, H Inomata, K Isobe, Y Ito, M Komura, H Kosuge, Y Maejima, N Miwa, T Nishimori, K Otomo, K Sakurai, T Takagi, K Tanaka, D Tezuka, T Tokunaga, A Yagishita, A Yamashina, T Hara, S Hayashi, Y Hirayama, Y Hirooka, M Iitaka, T Ishiyama, F Kijima, H Kobayashi, Y Kobayashi, K Kondo, T Kuwabara, M Mugishima, Y Nakayama, Y Nishizato, Y Osamura, Y Sakomura, S Saneshige, N Shindo, N Takao, Y Takata, H Tomiyama, S Ishimaru, Y Obitsu, H Shigematsu, T Baba, H Fukushima, T Hirayama, K Magari, S Makimura, T Nagae, K Osada, T Osada, T Shimizu, K Tamura, T Yamazaki, A Hirai, T Fukasawa, H Ono, M Yamakado, T Shiba, S Otomi, A Uehata, K Takazawa, A Aizawa, T Iketani, M Kino, H Kobayashi, T Morishima, N Sakamoto, T Sakamoto, H Kasanuki, R Nagai, T Kadowaki, J Tanaka, T Yamazaki, M Takagi, S Ui, S Baba, K Fujita, T Hasegawa, K Tajima, M Tanaka, N Yamato, I Kuwajima, K Harada, H Miyata, S Mizuno, S Ueda, K Sugi, H Ando, K Mishima, S Nishizawa, S Suzuki, J Yamazaki, R Nakanishi, H Nakano, K Tokuyasu, T Aoyagi, M Fujioka, N Kobayakawa, K Nakajima, A Hirayama, K Tsukamoto, Y Araki, H Hara, K Hara, T Saruya, S Umemura, M Arima, T Endo, K Furumi, Y Hatori, Y Ikeda, Y Ikeya, T Kaneda, T Kawada, T Kawano, T Kawashima, M Kihara, M Kikuta, A Kitamura, H Kobayashi, S Kobayashi, T Kuji, S Masuda, Y Minamimoto, K Minamisawa, T Mitsuhashi, N Miyazaki, Z Nagashima, T Nakatogawa, R Nakayama, N Nyui, M Ogawa, T Onishi, K Saka, T Sano, A Sato, K Shiba, F Shionoiri, H Sugiyama, H Suzuki, I Takasaki, K Tamura, Y Tokita, M Umemura, S Yamaguchi, G Yasuda, S Nakamura, K Takayanagi, T Hayashi, M Ichihara, S Kobayashi, Y Sakai, T Uchida, I Yaguchi, I Komuro, S Aoki, Y Hashimoto, C Ibuki, Y Isobe, R Kumasaka, M Matsuda, K Mizuno, D Murakami, S Nakamura, M Nakatani, T Ohba, T Ohara, T Okumura, A Saito, T Sakurai, S Sato, W Sato, K Seimiya, Y Seino, K Shimizu, K Tokuyama, D Uchida, K Yodogawa, S Oshima, M Kurabayashi, N Baba, Y Furushima, T Goto, T Hosoi, T Iijima, K Ito, Y Iwata, H Kubo, M Matsumoto, M Miyazaki, F Naganuma, K Nakada, M Tokushima, K Tsunoda, S Wakamatsu, Y Yagihara, Y Aizawa, M Aizawa, M Aizawa, N Hayashi, T Hori, H Kobayashi, M Kodama, K Maeda, K Miura, K Okada, Y Okura, Y Sasagawa, S Takizawa, M Tamura, T Yamamoto, T Murohara, Y Awaji, H Funahashi, D Hayashi, M Iida, D Ishihara, S Ishikawa, S Kamide, M Kanashiro, N Kurebayashi, S Kyo, H Matsui, K Matsuo, M Morishima, H Noda, T Noda, N Okumura, T Ota, S Shimizu, F Somura, Y Takada, Y Takeichi, H Takezawa, T Uchikawa, D Yoshikawa, G Kimura, Y Ando, M Hoshiai, N Okuda, S Suzuki, K Takada, N Takada, K Yamada, H Hishida, T Furuta, H Hayashi, K Ito, K Kato, M Nomura, T Ota, M Ohtsuki, T Tabata, S Taga, R Tateishi, T Ito, M Fukuda, T Iwa, Y Wakida, T Yonemoto, Y Murata, S Nomoto, K Takemoto, N Tsuboi, Y Yoshida, N Inoue, M Ishikawa, M Matsumoto, T Muramatsu, R Yoshida, M Ono, Y Hanaki, H Sano, Y Shibata, K Sakai, M Ajioka, H Asano, R Okamoto, H Osanai, Y Uemura, K Yokoi, T Tanaka, H Kamiya, K Miki, M Niwa, H Fujiwara, S Minatoguchi, T Arai, S Kato, H Kobayashi, T Minagawa, N Mori, K Nakahara, Y Shimizu, M Tadokoro, N Takahashi, T Shigemasa, I Kobayashi, T Nakano, M Ito, A Fukui, Y Higashi, T Ito, U Kano, K Makino, K Nakai, M Nakajima, T Nakajima, K Sekoguchi, T Tanaka, T Tanigawa, N Takekoshi, H Enyama, T Hirakawa, J Ito, T Ito, H Kakuda, T Kigoshi, K Kondo, K Masuya, M Matoba, A Nakagawa, T Nakahashi, H Nakato, H Okada, Y Takeuchi, H Tsugawa, T Urata, M Yasuhara, M Shimizu, H Ino, T Araki, N Fujino, T Haraki, K Hayashi, S Hifumi, T Konno, M Minamoto, S Miyamoto, M Mori, C Nakanishi, Y Sakamoto, K Sakata, S Takeda, K Ueda, K Uchiyama, S Takata, S Kaneko, I Aburadani, I Inoki, K Kitano, D Kobayashi, K Kontani, M Maekawa, M Maruyama, K Matsunuma, Y Nagai, Y Nagata, M Okajima, K Otowa, Y Sekiguchi, K Shinmura, S Usui, H Yokoyama, M Yoneji, K Nakao, N Hiraiwa, T Ko, I Masuda, T Nagae, K Nishino, M Sakamoto, T Kita, Y Nakagawa, T Kimura, T Doi, H Horiuchi, M Kinoshita, M Mizuno, M Ohnishi, K Shigemoto, A Wada, T Yamada, M Nakagawa, H Matsubara, K Furukawa, T Hatta, A Inoue, H Katsume, A Masui, S Matsumoto, T Seki, K Takeda, Y Taniguchi, H Tsuji, Y Saito, Y Fukuoka, M Iwano, T Katsuyama, A Nakatani, Y Sakaguchi, T Konishi, T Izumi, I Toda, A Kamimoto, Y Nagai, E Matsuwaka, R Matsuwaka, K Takei, R Ueda, N Wakaki, T Iwasaka, H Hamada, S Hamada, H Koga, H Koito, K Kono, H Kurihara, J Maeda, S Morimoto, Y Takayama, T Aoyama, S Kashii, M Maenaka, H Ohashi, T Suyama, M Matsuda, Y Aoyagi, K Kunisada, T Mori, T Mori, J Uemura, Y Yokoi, N Morioka, T Ozaki, K Kanamasa, K Ishikawa, S Miyazaki, S Arima, T Kai, A Kurooka, I Shimada, M Takewa, M Taniguchi, R Hattori, K Haba, R Yokota, H Matsui, E Tone, H Yamahira, T Kawarabayashi, H Inaba, Y Sakaguchi, Y Yamamoto, H Ito, M Date, M Dodo, K Fujii, M Imai, K Inoue, Y Kanoh, N Komura, S Senpuku, H Tateyama, K Yasui, R Yoneda, H Morita, M Kawanami, A Tahara, T Sado, T Takamura, M Taniwa, Y Kitaura, M Fukuda, H Hanada, K Nakamura, K Sawada, M Yamaguchi, K Kodama, T Higo, A Hirata, M Kanzaki, S Komatsu, K Matsuo, T Murakawa, H Nakanishi, T Nemoto, M Nishio, N Ogasawara, Y Okuyama, Y Ueda, M Imanishi, Y Kitamura, T Sakakibara, H Yoshida, H Yoshimi, T Ogihara, H Rakugi, M Akiyama, Y Ikuno, N Imai, Y Imamura, T Inoyama, K Kamide, K Katahira, S Katsuya, T Katsuya, Y Kurokawa, O Matsuki, M Matsuo, T J Tachi, H Tanaka, T Tsunetoshi, M Yoshino, M Hori, N Awata, T Fukukawa, Y Iimori, S Iwamoto, K Sawami, M Okamura, Y Kanayama, F Nagano, H Nakayama, H Suzuki, T Amano, K Tachibana, Y Arita, M Kirino, K Sakuyama, M Shukawa, Y Nishida, T Sakamoto, S Yanagi, K Hirota, T Majima, T Ota, T Tanaka, R Nohara, T Funauchi, O Isogai, S Takashima, H Koike, M Nishimoto, Y Kawase, O Tojo, Y Chimori, H Harada, H Takeoka, S Kishi, M Yokoyama, K Hirata, J Ejiri, R Emoto, Y Furuta, K Hattori, R Kuroda, N Maehashi, H Monnaka, Y Ohashi, T Okada, H Suzuki, M Takeuchi, M Ohyanagi, M Masai, T Masuyama, M Kawabata, T Kajiya, N Daito, T Fujisawa, S Fujita, M Hasegawa, M Hirakoba, T Hirano, Y Ikeda, N Imai, K Marumoto, S Masuda, T Miki, M Mitsunaga, H Mitsuoka, Y Miyachi, N Mukohara, T Nagao, K Nakada, K Nishian, S Nishioka, T Ogura, Y Onishi, K Sakaguchi, E Ogura, M Ohishi, R Sasaki, K Sugimoto, I Sano, W Sano, M Shigenobu, A Tabuchi, J Takashima, Y Taniguchi, H Uchida, T Ueda, N Urabe, H Makino, S Harada, S Hirakawa, H Hirata, J Ishii, K Koten, Y Nagake, T Nakajima, Y Nakamura, T Terami, K Mitsudo, M Fujii, K Fujita, E Iwano, K Kadota, Y Nishihara, Y Takaya, T Yamamoto, C Shigemasa, I Hisatome, T Kato, H Miyakoda, M Sakamoto, M Shimoyama, T Shimada, K Tanabe, Y Goto, Y Hanada, K Kawakami, J Kitamura, K Kitamura, M Matsuzaki, S Umemoto, S Aoyagi, H Aoyama, T Fujino, S Fukuta, N Hiroyama, Y Ikeda, Y Inamoto, R Kametani, A Kamiya, Y Kanamaru, S Kotoku, A Matsushima, J Morita, Y Murano, M Nakatsuka, S Nishimura, Y Nisnimura, T Okamura, F Okuda, U Onaka, M Ozaki, A Shimizu, C Takata, T Watada, T Watada, K Yamamoto, M Yamauchi, T Yorozu, H Yoshikane, F Yoshino, J Higaki, J Doiuchi, T Fukuoka, H Hashimoto, H Kadota, H Kaneko, S Komatsu, Y Matsubara, K Miyoshi, K Murakami, S Murao, T Ochi, A Satoh, T Seki, H Takahashi, T Yamashita, T Yoshino, M Kohno, N Fujita, T Fukui, T Hamamoto, K Hasegawa, H Hitomi, K Ihara, H Kiyomoto, H Masugata, I Matsumoto, N Takahashi, K Yoshikawa, Y Doi, M Arisawa, T Egawa, M Fukuda, Y Kawada, H Kusunose, T Maeda, N Minami, M Nishinaga, T Noguchi, K Okabayashi, K Sato, T Satomi, J Takada, S Tamura, T Usui, M Yamada, M Irahara, H Azuma, M Fujimura, H Fujino, M Fujino, E Harada, S Harada, Y Hiasa, S Hosokawa, K Kawahara, K Koshiba, M Murakami, Y Nakaya, H Nii, S Nozaki, A Ota, T Ozaki, K Sone, Y Tsutsui, S Ueta, M Nobuyoshi, Y Fujishima, K Hisano, H Ikezono, R Imawatari, Y Izumi, H Kanai, T Nakamura, T Nakamura, T Noda, E Ono, S Tanaka, T Tsuiki, T Yanai, T Sasaguri, S Akimitsu, K Dohmen, K Fujisawa, K Fukuyo, S Harashima, T Hayashi, M Hirata, Y Hirata, N Ikeda, H Ikematsu, W Ikematsu, W Kajiyama, Y Kawakami, I Kawasaki, H Kondo, H Kusuhara, N Maeda, H Miyahara, A Motomura, K Nakamura, T Noguchi, T Okinaga, M Sato, I Shimada, H Shin, K Soejima, K Sugi, T Taniguchi, T Uwatoku, S Yamaga, K Yamaji, J Yanagi, H Yano, K Saku, M Enomoto, T Hiratsuka, K Imoto, R Kamei, H Kanaya, M Kohara, M Kusuda, H Nishikawa, H Sako, T Imaizumi, K Yano, K Maemura, N Ashizawa, M Hazama, Y Ishida, T Ito, M Kanda, M Kimura, T Noguchi, Y Oku, S Seto, S Suzuki, H Ogawa, K Goto, K Honjio, Y Horio, H Jinnouchi, Y Kaku, S Kawano, T Kimura, Y Kiyohara, A Maki, K Misumi, T Sakamoto, K Sasaki, S Sugiyama, E Tanaka, S Uemura, C Tei, K Arima, Y Daitoku, H Eto, T Hashino, K Ichinari, Y Ikeda, A Iriki, K Kiyonaga, K Kubota, Y Makise, S Masuzaki, M Miyata, H Mizoguchi, T Niiyama, Y Samejima, S Yonezawa

Affiliation

¹ Yamaguchi University, Ube, Japan.

PMID: 21610513
DOI: 10.1097/HJH.0b013e328348345d

Abstract

Objectives: Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events.

Methods: We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), β-blocker, or thiazide diuretic in addition to benidipine.

Results: Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-β-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-β-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P = 0.3505) and 1.54 in the benidipine-β-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and β-blocker. All trial treatments were safe and well tolerated.

Conclusion: CCB combined with ARB, β-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.

Trial registration: ClinicalTrials.gov NCT00135551.

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adrenergic beta-Antagonists / therapeutic use*
Adult
Aged
Aged, 80 and over
Angiotensin Receptor Antagonists / therapeutic use*
Calcium Channel Blockers / therapeutic use*
Dihydropyridines / therapeutic use*
Drug Therapy, Combination
Female
Follow-Up Studies
Humans
Hypertension / complications
Hypertension / drug therapy*
Incidence
Japan
Kaplan-Meier Estimate
Male
Middle Aged
Outcome Assessment, Health Care
Prospective Studies
Risk Factors
Single-Blind Method
Sodium Chloride Symporter Inhibitors / therapeutic use*
Stroke / epidemiology
Stroke / prevention & control*
Treatment Outcome

Substances

Adrenergic beta-Antagonists
Angiotensin Receptor Antagonists
Calcium Channel Blockers
Dihydropyridines
Sodium Chloride Symporter Inhibitors
benidipine

Associated data

ClinicalTrials.gov/NCT00135551