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

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.

Conflict of interest statement

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.

Figures

Figure 1.. Flow of Participants Through the Study of the Effect of Lanthanum Carbonate and Calcium Carbonate in Patients Undergoing Hemodialysis

aRandomization was stratified by age, sex, the presence of diabetes, and study site. bOne person had a history of bowel obstruction and 10 had inappropriately obtained consent. cOne person had a history of bowel obstruction; 2, recent history of malignancy; and 11, inappropriately obtained consent. dThe 1099 patients included 1098 in the lanthanum carbonate group and 1 assigned to the calcium carbonate group who received lanthanum carbonate by mistake. eThe 1108 patients included 1106 in the calcium carbonate group and 2 assigned to the lanthanum carbonate group who received calcium carbonate by mistake. fOne patient had a stroke; 2, pneumonia; 1, skin abscess; 1, gangrene; and 1, colon perforation. gThree patients for an adverse event and 1 by physician decision. hThree patients had strokes; 1, coronary artery bypass graft; 1, spinal canal stenosis; 2, injury; and 1, gait disturbance. iOne patient for an adverse event; 1, consent withdrawal; 1, physician decision; and 2, kidney transplant.

Figure 2.. Primary Composite and All-Cause Mortality Outcomes

The median observation time was 3.16 years (interquartile range [IQR], 2.41-3.89 years) for the lanthanum carbonate group and 3.16 years (IQR, 2.55-3.85 years) for the calcium carbonate group. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina, and hospitalization for heart failure or ventricular arrhythmia.