Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis
Authors: Hiroaki Ogata, Masafumi Fukagawa, Hideki Hirakata, Tatsuo Kagimura, Masanori Fukushima, Tadao Akizawa, Masashi Suzuki, Yoshiki Nishizawa, Chikao Yamazaki, Shiro Tanaka, Shuzo Kobayashi, Issei Komuro, Kazuhiko Tsuruya, Hideki Fujii, Hirotaka Komaba, Masatomo Taniguchi, Takeshi Hasegawa, Takayuki Hamano, Masahide Mizobuchi, Takashi Akiba, Ryoichi Ando, Kunitoshi Iseki, Masaaki Inaba, Takatoshi Kakuta, Hitoshi Kato, Hideki Kawanishi, Eriko Kinugasa, Fumihiko Koiwa, Takashi Shigematsu, Tetsuo Shoji, Yoshiharu Tsubakihara, Yoshihiro Tominaga, Masaaki Nakayama, Ichiei Narita, Shinichi Nishi, Kosaku Nitta, Jun Minakuchi, Keitaro Yokoyama, Yuzo Watanabe, Noritomo Itami, Tetsuo Komota, Kenji Yuasa, Akimi Uehata, Ikuo Takahashi, Mikihiko Fujishima, Kazutaka Kukita, Ibuki Yajima, Kanji Shishido, Noriko Toshima, Masato Oroku, Tomoki Yonaha, Koshi Goto, Kazuyuki Maeno, Motoko Tanaka, Tomoko Okuda, Hiroyuki Tamura, Tokihiko Sawada, Senji Okuno, Masaki Fukushima, Takashi Sekiguchi, Kazuyoshi Nakamura, Ryuji Suzuki, Teruo Kowatari, Ikuto Masakane, Minoru Ito, Hirofumi Hashimoto, Hiroaki Ogata, Ryuji Aoyagi, Sumi Hidaka, Jun Mizuguchi, Toshio Shinoda, Kenji Tanaka, Shohei Sawada, Takahiro Kawakami, Masayuki Iyoda, Yuki Shindo, Yoshiko Tanaka, Masakazu Otsuka, Makoto Watanabe, Yoshihiro Tsujimoto, Yoshihiko Ohtsubo, Shigeki Okada, Akio Yokochi, Naoto Kobayashi, Tomoki Morikawa, Harumichi Higashi, Hiroshi Asakura, Masanori Mukai, Hidetoshi Kanai, Tateki Kitaoka, Masaki Kobayashi, Ryo Karasawa, Toru Sanai, Michio Kuwahara, Satomi Shikuma, Keiko Takahashi, Masuo Tokoo, Shoji Koga, Yoko Hayami, Tetsuro Michihata, Zenzo Fujii, Yasushi Suto, Kazunori Ogiu, Yoshiko Chida, Tetsuro Takeda, Yuji Takatori, Soichi Uekihara, Keiji Kono, Ken Kitamura, Yuriko Yonekura, Akira Okuyama, Naoki Hamazaki, Tatsuo Iizumi, Kenichiro Shigemoto, Hideki Ikenaga, Toru Kawai, Kenichi Saito, Noriko Minamisono, Masahiro Tominaga, Takashi Miyamoto, Hideo Kobayashi, Hajime Yamazaki, Takashi Ishimatsu, Dai Matsuo, Hirofumi Ikeda, Kei Hori, Nobuaki Shinozaki, Norimitsu Kurogi, Noriyuki Ozawa, Shizuo Hatashita, Akio Imada, Tomohiko Naruse, Isoji Sasagawa, Kanyu Miyamoto, Masabumi Yoshino, Akihiko Shirahama, Chihiro Shirahama, Katsufumi Sakata, Tatsuji Kashiki, Shohei Nakanishi, Muneo Tomizawa, Hideki Ueno, Kazuhiro Harada, Toyonori Saiki, Keita Kimura, Yasuhiro Horii, Kazuhiro Suzuki, Naoki Hamaguchi, Akira Nakamura, Morihiro Kondo, Seikon Kin, Shoji Sanma, Yoshinori Tanaka, Shin Hasegawa, Satoru Fujimi, Akira Takehara, Yasuko Yuasa, Yuko Shibuya, Naoaki Hayama, Yasunori Nakashima, Tomoko Teramura, Yoshifumi Inada, Yuji Oyabu, Naofumi Ikeda, Fumiaki Kumagai, Tetsuhiko Yoshida, Takahito Nasu, Yutaka Watanabe, Naoyuki Kobayashi, Masaki Kohara, Yoshihiro Tani, Kei Fukami, Akira Onozaki, Yutaka Nakajima, Masahito Tamura, Kenjiro Kumakawa, Kiyoshi Ikeda, Jun Suzuki, Tsutomu Sanaka, Yoshikazu Onda, Kazo Kaizu, Futoshi Oikawa, Hiromitsu Noto, Takahiko Sato, Akihisa Yamazaki, Yoshiyuki Oshiro, Shuzo Yamamoto, Chie Ogawa, Fumiyoshi Nakayama, Kenichi Motomura, Takao Tanaka, Ryoji Hagiwara, Kazuaki Takahashi, Nobukazu Suzuki, Shinya Kobayashi, Koji Tomori, Keigo Shibagaki, Tatsuhiko Kamata, Takashi Ariyoshi, Hiroyuki Hyakutake, Suguru Matsui, Makoto Takano, Kenji Ito, Toshiaki Murata, Hidekazu Okamoto, Masahiko Ogihara, Hisashi Terajima, Takashi Uchida, Sohei Morita, Masato Nishioka, Hironori Nakamura, Yutaka Kanno, Kazuhiro Fujisawa, Yutaka Tachiki, Mitsunori Yasuda, Motoko Yanagita, Kimio Tomita, Naoaki Kanamori, Hideki Takano, Fukuji Takeda, Masashi Kaneko, Yoshihisa Inukai, Akifumi Hirata, Hirotake Kasuga, Tatsuaki Watanabe, Hironobu Miyai, Kunihiko Natori, Toshimitsu Sato, Joji Takada, Yasunori Suga, Kazuo Miyatani, Keitaro Iijima, Tsutomu Tanaka, Teruhiro Nakada, Takashi Sato, Fumiko Fukuchi, Yoshinobu Hamasaki, Yoshifumi Wada, Nobuyuki Suzuki, Masami Hashimoto, Noriko Kaburagi, Matsuhiko Suenaga, Tomohide Nomura, Toshihito Haba, Kazutaka Murakami, Keizo Kitano, Keiichi Kono, Tomio Suzuki, Fusae Deguchi, Tatsuya Nonaka, Yuko Ozawa, Kenji Maeda, Satoshi Sugiyama, Gen Konemori, Masao Mizuno, Yasunobu Shimano, Kunihiro Nabeshima, Sadahiko Hiramatsu, Yoshiyasu Iida, Yoshinari Tsuruta, Naoto Kawamura, Etsuko Kumagai, Masato Tsuboi, Wataru Tsukada, Yoshihiro Nakamura, Makoto Miyasaka, Hironori Kawamura, Takeyuki Hiramatsu, Susumu Uda, Haruki Wakai, Yasue Obi, Tetsuya Imai, Shigeru Miyahara, Kazuto Sato, Shunji Miura, Kazunobu Sugimura, Takashi Miyazaki, Kiichiro Ueno, Kazuhiro Yoshimine, Tetsuya Hashimoto, Satoru Yamazaki, Hiroyuki Kobayashi, Masuo Terashima, Tomomasa Oguchi, Masahiro Mori, Manabu Kuse, Tetsuo Chiba, Takayasu Taira, Yasuo Futoo, Takayoshi Hamada, Masanobu Horie, Kohei Miura, Tetsushi Nagai, Takehiko Muramatsu, Shuhei Tozawa, Hiroya Mukai, Kosei Kurosawa, Junko Takahashi, Naoki Matsuhashi, Aiji Yajima, Takeshi Furukawa, Yuji Ishida, Masahiro Miyata, Yukihiko Miyata, Takako Ohtsuka, Makoto Hasegawa, Hirofumi Tamai, Tetsuro Yoshioka, Hiroshi Shiozaki, Toru Takemura, Takashi Mori, Isao Aoyama, Takako Sawasaki, Daisuke Nakayama, Katsuhide Toyama, Sumiko Ito, Mayuri Ichinose, Kyoko Inoue, Kazuyoshi Kataoka, Shinji Ako, Akihiro Nagamoto, Tatsuro Arii, Kosuke Masutani, Yoshie Sasatomi, Naoki Tachibana, Atsuhiko Kawamoto, Hideaki Kaneda, Shinsuke Kojima, Miyuki Matsuo, Mikio Yoshidomi, Yoko Nakagawa, Kenichi Kohno, Emiko Uno, Tomoko Shinno, Yoji Nagai, Kaori Kuronaka, Yoichiro Nishimura, Satoshi Nakagawa, Mitsuru Maeda, Hideki Nogi, Masanori Nishi
Journal: JAMA (2021)

<h3>Importance</h3> Among patients with hyperphosphatemia undergoing dialysis, it is unclear whether non–calcium-based phosphate binders are more effective than calcium-based binders for reducing cardiovascular events. <h3>Objective</h3> To determine whether lanthanum carbonate reduces cardiovascular events compared with calcium carbonate in patients with hyperphosphatemia at risk of vascular calcification undergoing hemodialysis. <h3>Design, Setting, and Participants</h3> Open-label, randomized, parallel-group clinical trial with blinded end point adjudication performed in 2374 patients with chronic kidney disease from 273 hemodialysis facilities in Japan. Eligible patients had hyperphosphatemia and 1 or more risk factors for vascular calcification (ie, ≥65 years, postmenopausal, diabetes). Enrollment occurred from November 2011 to July 2014; follow-up ended June 2018. <h3>Interventions</h3> Patients were randomized to receive either lanthanum carbonate (n = 1154) or calcium carbonate (n = 1155) and titrated to achieve serum phosphate levels of between 3.5 mg/dL and 6.0 mg/dL. <h3>Main Outcomes and Measures</h3> The primary outcome was a composite cardiovascular event (cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina, transient ischemic attack, or hospitalization for heart failure or ventricular arrhythmia). Secondary outcomes included overall survival, secondary hyperparathyroidism-free survival, hip fracture–free survival, and adverse events. <h3>Results</h3> Among 2309 randomized patients (median age, 69 years; 40.5% women), 1851 (80.2%) completed the trial. After a median follow-up of 3.16 years, cardiovascular events occurred in 147 of 1063 patients in the lanthanum calcium group and 134 of 1072 patients in the calcium carbonate group (incidence rate, 4.80 vs 4.30 per 100 person-years; difference 0.50 per 100 person-years [95% CI, −0.57 to 1.56]; hazard ratio [HR], 1.11 [95%, CI, 0.88 to 1.41],<i>P</i> = .37). There were no significant differences in all-cause death (difference, 0.43 per 100 person-years [95% CI, −0.63 to 1.49]; HR, 1.10 [95% CI, 0.88 to 1.37];<i>P</i> = .42) or hip fracture (difference, 0.10 per 100 person-years [95% CI, −0.26 to 0.47]; HR, 1.21 [95% CI, 0.62 to 2.35];<i>P</i> = .58). The lanthanum carbonate group had an increased risk of cardiovascular death (difference, 0.61 per 100 person-years [95% CI, 0.02 to 1.21]; HR, 1.51 [95% CI, 1.01 to 2.27];<i>P</i> = .045) and secondary hyperparathyroidism (difference, 1.34 [95% CI, 0.49 to 2.19]; HR, 1.62 [95% CI, 1.19 to 2.20];<i>P</i> = .002). Adverse events occurred in 282 (25.7%) in the lanthanum carbonate group and 259 (23.4%) in the calcium carbonate groups. <h3>Conclusions and Relevance</h3> Among patients undergoing hemodialysis with hyperphosphatemia and at least 1 vascular calcification risk factor, treatment of hyperphosphatemia with lanthanum carbonate compared with calcium carbonate did not result in a significant difference in composite cardiovascular events. However, the event rate was low, and the findings may not apply to patients at higher risk. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01578200; UMIN Clinical Trial Registry Identifier:UMIN000006815