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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
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.


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.

Data Sharing Statement: See Supplement 5.

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.

Ganesh  SK , Stack  AG , Levin  NW , Hulbert-Shearon  T , Port  FK .  Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.   J Am Soc Nephrol. 2001;12(10):2131-2138.PubMedGoogle ScholarCrossref
Block  GA , Klassen  PS , Lazarus  JM , Ofsthun  N , Lowrie  EG , Chertow  GM .  Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.   J Am Soc Nephrol. 2004;15(8):2208-2218. doi:10.1097/01.ASN.0000133041.27682.A2PubMedGoogle ScholarCrossref
Hruska  KA , Mathew  S , Lund  R , Qiu  P , Pratt  R .  Hyperphosphatemia of chronic kidney disease.   Kidney Int. 2008;74(2):148-157. doi:10.1038/ki.2008.130PubMedGoogle ScholarCrossref
Tentori  F , Blayney  MJ , Albert  JM ,  et al.  Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS).   Am J Kidney Dis. 2008;52(3):519-530. doi:10.1053/j.ajkd.2008.03.020PubMedGoogle ScholarCrossref
McGovern  AP , de Lusignan  S , van Vlymen  J ,  et al.  Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study.   PLoS One. 2013;8(9):e74996. doi:10.1371/journal.pone.0074996PubMedGoogle Scholar
Floege  J , Kim  J , Ireland  E ,  et al; ARO Investigators.  Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population.   Nephrol Dial Transplant. 2011;26(6):1948-1955. doi:10.1093/ndt/gfq219PubMedGoogle ScholarCrossref
Cozzolino  M , Mangano  M , Stucchi  A , Ciceri  P , Conte  F , Galassi  A .  Cardiovascular disease in dialysis patients.   Nephrol Dial Transplant. 2018;33(suppl_3):iii28-iii34. doi:10.1093/ndt/gfy174PubMedGoogle ScholarCrossref
Chertow  GM , Burke  SK , Raggi  P ; Treat to Goal Working Group.  Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients.   Kidney Int. 2002;62(1):245-252. doi:10.1046/j.1523-1755.2002.00434.xPubMedGoogle ScholarCrossref
Ohtake  T , Kobayashi  S , Oka  M ,  et al.  Lanthanum carbonate delays progression of coronary artery calcification compared with calcium-based phosphate binders in patients on hemodialysis: a pilot study.   J Cardiovasc Pharmacol Ther. 2013;18(5):439-446. doi:10.1177/1074248413486355PubMedGoogle ScholarCrossref
Zhang  C , Wang  S , Zhao  S , Zhang  X .  Effect of lanthanum carbonate on coronary artery calcification and bone mineral density in maintenance hemodialysis patients with diabetes complicated with adynamic bone disease: a prospective pilot study.   Medicine (Baltimore). 2017;96(45):e8664. doi:10.1097/MD.0000000000008664PubMedGoogle Scholar
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group.  KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).   Kidney Int Suppl (2011). 2017;7(1):1-59. doi:10.1016/j.kisu.2017.04.001PubMedGoogle ScholarCrossref
Ruospo  M , Palmer  SC , Natale  P ,  et al.  Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD).   Cochrane Database Syst Rev. 2018;8:CD006023. doi:10.1002/14651858.CD006023.pub3PubMedGoogle Scholar
Goodman  WG , Goldin  J , Kuizon  BD ,  et al.  Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis.   N Engl J Med. 2000;342(20):1478-1483. doi:10.1056/NEJM200005183422003PubMedGoogle ScholarCrossref
Spoendlin  J , Paik  JM , Tsacogianis  T , Kim  SC , Schneeweiss  S , Desai  RJ .  Cardiovascular outcomes of calcium-free vs calcium-based phosphate binders in patients 65 years or older with end-stage renal disease requiring hemodialysis.   JAMA Intern Med. 2019;179(6):741-749. doi:10.1001/jamainternmed.2019.0045PubMedGoogle ScholarCrossref
Ogata  H , Fukagawa  M , Hirakata  H , Kaneda  H , Kagimura  T , Akizawa  T ; LANDMARK Study Group.  Design and baseline characteristics of the LANDMARK study.   Clin Exp Nephrol. 2017;21(3):531-537. doi:10.1007/s10157-016-1310-8PubMedGoogle ScholarCrossref
Fukagawa  M , Yokoyama  K , Koiwa  F ,  et al; CKD-MBD Guideline Working Group; Japanese Society for Dialysis Therapy.  Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder.   Ther Apher Dial. 2013;17(3):247-288. doi:10.1111/1744-9987.12058PubMedGoogle ScholarCrossref
Nakai  S , Iseki  K , Itami  N ,  et al.  An overview of regular dialysis treatment in Japan (as of 31 December 2010).   Ther Apher Dial. 2012;16(6):483-521. doi:10.1111/j.1744-9987.2012.01143.xPubMedGoogle ScholarCrossref
Block  GA , Wheeler  DC , Persky  MS ,  et al.  Effects of phosphate binders in moderate CKD.   J Am Soc Nephrol. 2012;23(8):1407-1415. PubMedGoogle ScholarCrossref
Di Iorio  B , Bellasi  A , Russo  D ; INDEPENDENT Study Investigators.  Mortality in kidney disease patients treated with phosphate binders: a randomized study.   Clin J Am Soc Nephrol. 2012;7(3):487-493. doi:10.2215/CJN.03820411PubMedGoogle ScholarCrossref
Di Iorio  B , Molony  D , Bell  C ,  et al; INDEPENDENT Study Investigators.  Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial.   Am J Kidney Dis. 2013;62(4):771-778. doi:10.1053/j.ajkd.2013.03.023PubMedGoogle ScholarCrossref
Block  GA , Spiegel  DM , Ehrlich  J ,  et al.  Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis.   Kidney Int. 2005;68(4):1815-1824. doi:10.1111/j.1523-1755.2005.00600.xPubMedGoogle ScholarCrossref
Block  GA , Raggi  P , Bellasi  A , Kooienga  L , Spiegel  DM .  Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.   Kidney Int. 2007;71(5):438-441. doi:10.1038/sj.ki.5002059PubMedGoogle ScholarCrossref
Suki  WN , Zabaneh  R , Cangiano  JL ,  et al.  Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.   Kidney Int. 2007;72(9):1130-1137. doi:10.1038/sj.ki.5002466PubMedGoogle ScholarCrossref
Chertow  GM , Raggi  P , Chasan-Taber  S , Bommer  J , Holzer  H , Burke  SK .  Determinants of progressive vascular calcification in haemodialysis patients.   Nephrol Dial Transplant. 2004;19(6):1489-1496. PubMedGoogle ScholarCrossref
Raggi  P , Chertow  GM , Torres  PU ,  et al; ADVANCE Study Group.  The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.   Nephrol Dial Transplant. 2011;26(4):1327-1339. doi:10.1093/ndt/gfq725PubMedGoogle ScholarCrossref
Ogata  H , Fukagawa  M , Hirakata  HN , Kagimura  T , Akizawa  T .  Comparison of lanthanum carbonate with calcium carbonate for the progression of coronary artery calcification in hemodialysis.  Abstract.  J Am Soc Nephrol. 2017;28:B7.Google ScholarCrossref
Jovanovich  A .  Time to reconsider calcium-based phosphate binders in dialysis? a call for a well-designed randomized controlled trial.   Am J Kidney Dis. 2020;75(3):453-455. doi:10.1053/j.ajkd.2019.08.008PubMedGoogle ScholarCrossref
Goodkin  DA , Bragg-Gresham  JL , Koenig  KG ,  et al.  Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS).   J Am Soc Nephrol. 2003;14(12):3270-3277. doi:10.1097/01.ASN.0000100127.54107.57PubMedGoogle ScholarCrossref
Stirnadel-Farrant  HA , Karaboyas  A , Cizman  B ,  et al.  Cardiovascular event rates among hemodialysis patients across geographical regions—a Snapshot from the Dialysis Outcomes and Practice Patterns Study (DOPPS).   Kidney Int Rep. 2019;4(6):864-872. doi:10.1016/j.ekir.2019.03.016PubMedGoogle ScholarCrossref
Robinson  BM , Akizawa  T , Jager  KJ , Kerr  PG , Saran  R , Pisoni  RL .  Factors affecting outcomes in patients reaching end-stage kidney disease worldwide: differences in access to renal replacement therapy, modality use, and haemodialysis practices.   Lancet. 2016;388(10041):294-306. doi:10.1016/S0140-6736(16)30448-2PubMedGoogle ScholarCrossref
St Peter  WL , Liu  J , Weinhandl  E , Fan  Q .  A comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity in hemodialysis: a secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) randomized trial using claims data.   Am J Kidney Dis. 2008;51(3):445-454. doi:10.1053/j.ajkd.2007.12.002PubMedGoogle ScholarCrossref
Masakane  I , Taniguchi  M , Nakai  S ,  et al  Annual dialysis data report 2015, JSDT renal data registry.   Ren Replace Ther. 2018;4(1):19. doi:10.1186/s41100-018-0149-8Google ScholarCrossref
Kumssa  DB , Joy  EJ , Ander  EL ,  et al.  Dietary calcium and zinc deficiency risks are decreasing but remain prevalent.   Sci Rep. 2015;5:10974. doi:10.1038/srep10974PubMedGoogle ScholarCrossref
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