Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis
Hiroaki Ogata, Masafumi Fukagawa, Hideki Hirakata, Tatsuo Kagimura, Masanori Fukushima, Tadao Akizawa, Masashi Suzuki, Yoshiki Nishizawà, 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, M. Fukushima, Takashi Sekiguchi, Kazuyoshi Nakamura, Ryuji Suzuki, Teruo Kowatari, Ikuto Masakane, Minoru Ito, Hirofumi Hashimoto, Hiroaki Ogata, Ryuji Aoyagi, Sumi Hidaka, J. Mizuguchi, Toshio Shinoda, Kenji Tanaka, Shohei Sawada, Takahiro Kawakami, Masayuki Iyoda, Yuki Shindo, Yoshiko Tanaka, Masakazu Otsuka, Makoto M. 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
Abstract
Importance: 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. Objective: To determine whether lanthanum carbonate reduces cardiovascular events compared with calcium carbonate in patients with hyperphosphatemia at risk of vascular calcification undergoing hemodialysis. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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], P = .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]; P = .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]; P = .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]; P = .045) and secondary hyperparathyroidism (difference, 1.34 [95% CI, 0.49 to 2.19]; HR, 1.62 [95% CI, 1.19 to 2.20]; P = .002). Adverse events occurred in 282 (25.7%) in the lanthanum carbonate group and 259 (23.4%) in the calcium carbonate groups. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT01578200; UMIN Clinical Trial Registry Identifier: UMIN000006815.