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Cardiology

Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing HemodialysisThe LANDMARK Randomized Clinical Trial

Educational Objective
To understand the treatment of hyperphosphatemia in patients who are undergoing dialysis.

1 Credit CME

JAMA

Published Online: May 18, 2021

Original Investigation

Article Information and Disclosures

Hiroaki Ogata, MD¹;

Masafumi Fukagawa, MD²;

Hideki Hirakata, MD³;

Tatsuo Kagimura, PhD⁴;

Masanori Fukushima, MD⁴;

Tadao Akizawa, MD⁵;

for the LANDMARK Investigators and Committees

Author Affiliations

¹Division of Nephrology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Tsuzuki, Yokohama, Kanagawa, Japan
²Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
³Fukuoka Renal Clinic, Chuo-ku, Fukuoka, Japan
⁴The Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-ku, Kobe, Hyogo, Japan
⁵Division of Nephrology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan

LANDMARK Investigators and Committeesfor the

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Key Points

Question Does lanthanum carbonate–based treatment without calcium-based phosphate binders reduce cardiovascular events compared with calcium carbonate–based treatment in patients with hyperphosphatemia undergoing hemodialysis?

Findings In this open-label randomized clinical trial that included 2135 patients undergoing hemodialysis with at least 1 risk factor for vascular calcification, there was no significant difference in composite cardiovascular events between lanthanum carbonate–based treatment with and without calcium-based phosphate binders after a median follow-up of 3.16 years (4.80 vs 4.30 per 100 person-years).

Meaning Lanthanum carbonate–based treatment without calcium-based phosphate binders did not significantly reduce the composite outcome of cardiovascular events in patients with hyperphosphatemia undergoing hemodialysis.

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

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Article Information

Corresponding Author: Hiroaki Ogata, MD, Division of Nephrology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Chigasaki-chuo 35-1, Tsuzuki, Yokohama 224-8503, Kanagawa, Japan (ogatah@med.showa-u.ac.jp).

Accepted for Publication: March 12, 2021.

Author Contributions: Dr Kagimura had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Fukagawa, Hirakata, Akizawa.

Acquisition, analysis, or interpretation of data: Ogata, Hirakata, Kagimura, Fukushima, Akizawa.

Drafting of the manuscript: Ogata, Kagimura.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kagimura.

Obtained funding: Hirakata, Akizawa.

Supervision: Ogata, Fukagawa, Hirakata, Fukushima, Akizawa.

Conflict of Interest Disclosures: Dr Ogata reported receiving lecture fees from Bayer Yakuhin, Kyowa Kirin, Torii Pharmaceutical, Otsuka, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Sumitomo Dainippon Pharm, Daiichi Sankyo, Kowa, Ono Pharmaceutical; grants from Torii Pharmaceutical and Ono Pharmaceutical; and consulting fees from YL Biologics. Dr Fukagawa reported receiving personal fees from Bayer Yakuhin and grants from Kyowa Kirin. Dr Hirakata reported receiving personal fees from Kyowa-Kirin, Chugai Pharma, Torii, Japan Tobacco, and Ono Yakuhin. Dr Kagimura reported receiving grants from Bayer Yakuhin. Dr Akizawa reported receiving consulting and lecture fees from Bayer Yakuhin, Astellas, Kyowa Kirin, Kissei Pharmaceutical, Ono Pharmaceutical, Fuso Pharmaceutical Industry, Torii Pharmaceutical; consulting fees from GlaxoSmithKline, JT Pharmaceutical, Nipro Corporation, Otsuka, and Sanwa Chemical; and lecture fees from Chugai Pharmaceutical. No other disclosures were reported.

Funding/Support: This trial was funded by Bayer Yakuhin Ltd.

Role of the Funder/Sponsor: Bayer Yakuhin Ltd had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. However, the company was kept informed of the progress of the study. There were no confidentiality agreements regarding the data.

Group Information: the LANDMARK Investigators and Committees appear in Supplement 4.

Meeting Presentation: Presented at the American Society of Nephrology Annual Kidney Week meeting, October 27, 2018, San Diego, California.

Additional Contribution: Editorial support, in the form of medical writing, assembling tables, and creating high-resolution images based on authors’ detailed directions, collating author comments, copyediting, fact-checking, and referencing, was provided by Editage, Cactus Communications, and funded by the Department of Internal Medicine, Showa University Northern Yokohama Hospital.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME [and Self-Assessment requirements] of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.