Higher versus Lower Phosphate Targets for Patients Undergoing In-Center Hemodialysis

Key Points The HiLo pragmatic, multicenter randomized trial compared a higher versus lower serum phosphate target in patients undergoing maintenance hemodialysis. The HiLo trial was terminated early due to insufficient enrollment and inadequate phosphate separation between groups. HiLo demonstrated the feasibility of embedding a randomized intervention in routine dialysis care and identified challenges to inform future trials. Background Serum phosphate targets in maintenance hemodialysis are based on observational studies. The Pragmatic Trial of Higher versus Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis (HiLo) trial aimed to compare the effect of a higher versus a lower phosphate target on clinical events in patients receiving maintenance hemodialysis. Methods HiLo was a pragmatic, multicenter randomized trial that compared higher (≥6.5 mg/dl; “Hi”) versus lower (<5.5 mg/dl; “Lo”) phosphate targets in patients undergoing maintenance hemodialysis. The goal was to enroll 4400 cluster-randomized patients to assess the primary hierarchical composite outcome of all-cause mortality, followed by all-cause hospitalization using the win ratio. Owing to an imbalance in baseline serum phosphate between groups, raising concern for biased recruitment due to postrandomization consent, HiLo transitioned to individual randomization 23 months after the trial began. Ultimately, HiLo was stopped early due to insufficient enrollment and inadequate phosphate separation between groups. For this report, we combined the cluster-randomized and individually randomized cohorts, analyzing the individually randomized cohort as two additional clusters and applying a variance inflation factor to account for site-level clustering effects. Results Between March 2020 and November 2023, 352 patients in the Hi group and 441 in the Lo group were enrolled. After a median follow-up of 1.4 years (quartiles 1–3: 0.5–2.8 years), there were 11 deaths per 100 person-years in the Hi group and 13 per 100 person-years in the Lo group. The Hi group experienced 134 hospitalizations per 100 person-years compared with 96 per 100 person-years in the Lo group. The primary hierarchical composite outcome did not differ between groups (win ratio for Hi versus Lo targets was 0.97; 95% confidence interval, 0.55 to 1.71). Conclusions Insufficient enrollment and inadequate phosphate separation between groups preclude inferences about the effects of phosphate targets on clinical outcomes. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04095039.