CLINICAL RESEARCH www.jasn.org A Trial of Extending Hemodialysis Hours and Quality of Life † ‡ | Meg J. Jardine,* Li Zuo, Nicholas A. Gray ,§ Janak R. de Zoysa ,¶ †† Christopher T. Chan ,** Martin P. Gallagher ,* Helen Monaghan,* ‡‡ | †††† Stuart M. Grieve , §§ Rajesh Puranik, ¶¶ Hongli Lin,*** Josette M. Eris , ‡‡‡ |||||| Ling Zhang, Jinsheng Xu,§§§ Kirsten Howard, ¶¶¶ Serigne Lo,* Alan Cass,**** and †††† Vlado Perkovic,* on behalf of the ACTIVE Dialysis Steering Committee *The George Institute for Global Health, ††Concord Clinical School, ‡‡Sydney Translational Imaging Laboratory, Charles Perkins Centre, Sydney Medical School, and ||||||School of Public Health, University of Sydney, Sydney, Australia; †Department of Renal Medicine, Concord Repatriation General Hospital, Sydney, Australia; ‡Department of Nephrology, Peking University People’s Hospital, Beijing, China; §Department of Renal Medicine, Nambour General Hospital, Nambour, Australia; |Sunshine Coast Clinical School, The University of Queensland, Brisbane, Australia; ¶Department of Nephrology, North Shore Hospital, University of Auckland, Auckland, New Zealand, **Division of Nephrology, University Health Network, Toronto, Canada; Departments of §§Radiology, |Cardiology, and †††Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia; ¶¶Specialist Magnetic Resonance Imaging, Newtown, Australia; ***First Affiliated Hospital of Dalian Medical University, Dalian, China; ‡‡‡Department of Nephrology, China-Japan Friendship Hospital, Beijing, China; §§§Fourth Hospital Affiliated to Hebei Medical University, Shijiazhuang, China; ¶¶¶Institute for Choice, University of South Australia, Sydney, Australia; ****Menzies School of Health Research, Charles Darwin University, Darwin, Australia; and ††††Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia ABSTRACT The relationship between increased hemodialysis hours and patient outcomes remains unclear. We randomized (1:1) 200 adult recipients of standard maintenance hemodialysis from in-center and home-based hemodialysis programs to extended weekly ($24 hours) or standard (target 12–15 hours, maximum 18 hours) hemodialysis hours for 12 months. The primary outcome was change in quality of life from baseline assessed by the EuroQol 5 di- mension instrument (3 level) (EQ-5D). Secondary outcomes included medication usage, clinical laboratory values, vascular access events, and change in left ventricular mass index. At 12 months, median weekly hemodialysis hours were 24.0 (interquartile range, 23.6–24.0) and 12.0 (interquartile range, 12.0–16.0) in the extended and standard groups, respectively. Change in EQ-5D score at study end did not differ between groups (mean difference, 0.04 [95% confidence interval, 20.03 to 0.11]; P=0.29). Extended hours were associated with lower phosphate and potassium levels and higher hemoglobin levels. Blood pressure (BP) did not differ between groups at study end. Extended hours were associated with fewer BP-lowering agents and phosphate-binding medications, but were not associated with erythropoietin dosing. In a substudy with 95 patients, we detected no difference between groups in left ventricular mass index (mean difference, 26.0 [95% confidence interval, 214.8 to 2.7] g/m2;P=0.18). Five deaths occurred in the extended group and two in the standard group (P=0.44); two participants in each group withdrew consent. Similar numbers of patients experienced vascular access events in the two groups. Thus, extending weekly hemodialysis hours did not alter overall EQ-5D quality of life score, but was associated with improvement in some laboratory parameters and reductions in medication burden. (Clinicaltrials.gov identifier: NCT00649298). J Am Soc Nephrol 28: 1898–1911, 2017. doi: https://doi.org/10.1681/ASN.2015111225 Outcomes for patients receiving maintenance dial- Received November 12, 2015. Accepted November 28, 2016. ysis are poor, with mortality rates many times Published online ahead of print. Publication date available at greater than the general population1 and a substan- www.jasn.org. 20 tially reduced quality of life. The rise in mortality Correspondence: Prof. Meg Jardine, The George Institute for and cardiovascular events as kidney function falls,3 Global Health, PO Box M201, Missenden Road, NSW 2050, with amelioration after renal transplantation,4 has Australia. Email: [email protected] driven the hypothesis that increasing dialysis Copyright © 2017 by the American Society of Nephrology 1898 ISSN : 1046-6673/2806-1898 JAmSocNephrol28: 1898–1911, 2017 www.jasn.org CLINICAL RESEARCH exposure will improve outcomes for people with kidney group (Figure 2). First treatment commenced a mean of 37.4 failure. Observational studies from several countries5–9 have (median, 27) days after randomization in the extended group supported this hypothesis and suggest a strong relationship and 24.2 (median, 15) days in the standard group. between weekly dialysis hours and survival. The few random- An estimate of small molecule clearance, predominantly ized studies assessing increasing dialysis hours have suggested urea reduction ratio, was available in 152 (75.1%) participants improvements in a number of surrogate outcomes, but have also according to usual site practices (Supplemental Table 3) and raised concerns about possible adverse effects on dialysis vascu- included measures conducted within the 3-month time win- lar access,10 residual renal function,11 and long-term mortality.12 dow for baseline assessment in 117 participants (Supplemen- Quality of life is substantially worse in patients receiving tal Table 4). The mean urea reduction ratio, the measured dialysis compared with the general population,13 whereas in- single pool Kt/V, and the calculated standardized Kt/V were creased weekly dialysis hours are associated with better quality greater in the extended group than the standard group at each of life in observational studies; however, recent trials have not postrandomization assessment (average difference of 7.1% clearly defined the effects of dialysis hours on this outcome.14,15 [95% confidence interval (95% CI), 4.9 to 9.3; P,0.001], The presence and magnitude of any benefit is central to the 0.48 [95% CI, 0.27 to 0.68; P,0.001], and 1.29 [95% CI, assessment of cost-effectiveness for quality of life outcomes, 0.61 to 1.96; P=0.001], respectively). such as quality-adjusted life years, as extending dialysis hours increases treatment costs in most settings.16 Outcomes Quality of Life Objective In the extended dialysis hours group, quality of life assessed by Weaimed to conduct a prospectiverandomizedtrial to evaluate EQ-5D at 12 months decreased by 0.018, as compared with the effect of increasing weekly hemodialysis hours on quality 0.055 in the standard group (between-group difference at study of life over 12 months compared with standard hemodialysis. endadjustedforbaseline:0.037;95%CI,20.03 to 0.11; P=0.33; Figure 3, Supplemental Figure 1). The results were similar for the prespecified subgroup analyses defined by re- RESULTS gion, dialysis location, and dialysis vintage (Figure 4, P het- erogeneity all .0.2). In addition, no effect from increased Patients dialysis hours was seen when EQ-5D scores from all follow-up From 2009 to 2013, 200 participants were randomized from 40 visits throughout the intervention period were considered sites. Baseline characteristics were similar across randomized using a linear mixed model (mean difference, 0.03 [95% CI, groups (Table 1). Treatment was discontinued before 12 20.03 to 0.09]; P=0.30), in the sensitivity analyses excluding months in 16 participants because of death (seven partici- participants who did not complete an end of study quality pants), transplantation (five participants), and withdrawal of of life assessment (mean difference, 0.03; 95% CI, 20.04 to consent (four participants) (Figure 1). Analyzable results from 0.10; P=0.33), or in the post hoc sensitivity analysis adjusted the EuroQol 5 dimension instrument (3 level) (EQ-5D) qual- for baseline presence of chronic heart failure, diabetes, di- ity of life assessments were performed in 195 participants, alysis vintage, or catheter use (mean difference, 0.03; 95% excluding the four who withdrew consent, and one who de- CI, 20.04 to 0.01; P=0.36). There was no suggestion of clined to answer one part of the questionnaire at baseline. trend in the evolution of quality of life scores (Supplemental Figure 2). Delivered Treatment There was a small but statistically significant improvement Median weekly dialysis hours received were doubled in the in the Physical Component Summary (PCS) score with ex- extended group (median, 24 hours; interquartile range tended hours, but no effect on Mental Component Summary [IQR], 24–24 hours) compared with standard group (median, (MCS) score of the 36-Item Short Form Health Survey (SF-36) 12 hours; IQR, 12–16 hours) at 12 months, which was pre- quality of life measure in the prespecified analysis from baseline dominantly achieved by longer treatment sessions rather than to 12 months (between-group difference at 12 months adjusted increased session frequency (Table 2). Both blood and dialysis for baseline: 2.68 [95% CI, 0.39 to 4.97; P=0.02] and 1.53 flow rates were lower in the extended group (Supplemental [95% CI, 21.17 to 4.23; P=0.27], respectively). Both PCS Table 1). Most patients were treated with high flux, synthetic and MCS significantly improved with extended hours when membranes (Supplemental Table 2). No participant was treated