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Nephrology 20 (2015) 257–265
Original Article
Design and participant baseline characteristics of ‘A Clinical Trial of IntensiVE Dialysis’: The ACTIVE Dialysis Study MEG J JARDINE,1,2 LI ZUO,3 NICHOLAS A GRAY,4,5 JANAK DE ZOYSA,6,7 CHRISTOPHER T CHAN,8 MARTIN P GALLAGHER,1,9 KIRSTEN HOWARD,10 STEPHANE HERTIER,11 ALAN CASS1,12 and VLADO PERKOVIC1,13 on behalf of the ACTIVE Dialysis Steering Committee* 1 The George Institute for Global Health, 9Concord Clinical School, Sydney Medical School, 10School of Public Health, University of Sydney, 2Renal Unit, Concord Repatriation General Hospital, 13Department of Renal Medicine, Royal North Shore Hospital, Sydney, New South Wales, 4Renal Medicine, Nambour General Hospital, 5Sunshine Coast Clinical School, The University of Queensland, Nambour, Queensland, 11School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, 12Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia; 3Department of Nephrology, Peking University People’s Hospital, Beijing, China; 6Renal Services, North Shore Hospital, 7Department of Medicine, University of Auckland, Auckland, New Zealand; and 8Division of Medicine, University Health Network, Toronto, Ontario, Canada
KEY WORDS: extended dialysis, H(a)emodialysis, left ventricular mass index, quality of life, randomized controlled trial. Correspondence: Dr Meg Jardine, The George Institute for Global Health, PO Box M201, Missenden Road, NSW, 2050, Australia. Email: [email protected] Accepted for publication 16 December 2014. Accepted manuscript online 22 December 2014. doi:10.1111/nep.12385 Conflict of Interest Statement Meg Jardine has received an unconditional research grant from Gambro AB. Nick Gray has received speaker’s fees from Baxter Healthcare. Janak de Zoysa has received an unrestricted educational grant from Baxter Healthcare. Chris Chan has received funding from NIDDK, Baxter Extramural Grant Program and the Clinical Evidence Council program. Zuo Li, Martin Gallagher, Kirsten Howard, Stephane Hertier, Alan Cass and Vlado Perkovic declare that there are no conflicts of interest.
*Members listed in Appendix S1. Funding: The primary funding of the ACTIVE Dialysis Study was a National Health and Medical Research Council (NHMRC) of Australia Project Grant (571045). Additional funding included a Baxter Clinical Evidence Council Investigator Initiated Research Grant (2012), an unrestricted grant from Baxter with funding for the vanguard phase from an NHMRC Program Grant (358395). Trial registration: clinicaltrials.gov NCT00649298 MESH terms Chronic Kidney Failure; Clinical Trial, Phase IV; Hypertrophy, Left Ventricular; Quality of Life; Renal Dialysis
ABSTRACT: Aims: Observational reports suggest extended dialysis hours are associated with improved outcomes. These findings are confounded by better prognostic characteristics among people practising extended hours. The aim of this article is to provide an overview of the methods and baseline characteristics for ACTIVE Dialysis Study participants. Methods: This multicentre, randomized, open-label, blinded endpointassessment trial randomized participants receiving maintenance haemodialysis therapy to either extended (≥24 h) or standard (12–18 h) weekly haemodialysis for 12 months. A web-based randomization system used minimization to ensure balanced allocation across regions, dialysis setting and dialysis vintage. The primary outcome is the change in quality of life over 12 months of study treatment assessed by EQ-5D. Secondary outcomes include change in left ventricular mass index assessed by magnetic resonance imaging and safety outcomes including dialysis access events. Results: A total of 200 participants were recruited between 2009 and 2013 from Australia (29.0%), China (62.0%), Canada (5.5%) and New Zealand (3.5%). Participants had a mean age of 52 (± 12) years and 11.5% were dialysing at home, with a mean duration of 13.9 h per week over a median of three sessions. At baseline, 32.5% had a history of cardiovascular disease and 36.5% had diabetes. Conclusion: The ACTIVE Dialysis Study has met its planned recruitment target. The participant population are drawn from a range of health service settings in a global context. The study will contribute important evidence on the benefits and harms of extending weekly dialysis hours. The trial is registered at clinicaltrials.gov (NCT00649298).
SUMMARY AT A GLANCE This paper forms the background for the soon to be released ACTIVE Dialysis Study – an important study comparing quality of life in patients randomly assigned to conventional or extended hours haemodialysis.
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BACKGROUND In the 1960s, dialysis therapies were introduced into routine clinical practice as a life-preserving intervention for people with end-stage kidney disease (ESKD). Fifty years on, over 430 000 people are being treated with dialysis therapies in the US alone.1 People requiring maintenance dialysis therapies continue to have poorer outcomes and survival than people without ESKD with adjusted all-cause mortality rates being 6.5–7.9 times that of the general US population.1 Unadjusted annual mortality rates are over 20% in the USA,1 approximately 10–15% in Australia, New Zealand and Canada2 and 5–10% in China.3 The twin observations that mortality and cardiovascular events increase with declining kidney function4 and that dramatic improvements in these outcomes are seen following renal transplantation5 have driven the hypothesis that improving dialysis clearances will improve cardiovascular and survival outcomes. Observational studies also report better dialysis survival using extended hours haemodialysis as seen in the Centre de Rein Artificiel in France, with 5 years actuarial mortality approximately halved.6 Subsequent observational reports have shown excellent patient outcomes including 5 years survival rates of over 80% for cohorts receiving extended hours dialysis in Australia7 and Canada,8 and 3 years survival of 70–80% in the USA.9,10 However, a recent analysis from The International Quotidian Dialysis Registry that included propensity score matching and attempts to control for survival and immortal time bias found that daily in-centre haemodialysis was associated with worse survival {HR 1.6 (95% confidence interval [CI] 1.1, 2.3) P = 0.023}.11 Beyond survival, smaller studies have shown people receiving extended weekly haemodialysis hours may have improvements in multiple other parameters including quality of life, cardiac structure and function, phosphate control, anaemia and blood pressure control.12,13 Concerns have, however, been raised regarding an increase in adverse arteriovenous fistula events.7 The major limitation of the observational studies is the better baseline characteristics of patients receiving extended hours dialysis patients. Two randomized controlled trials testing the impact of extended dialysis hours have been reported. In Alberta, Canada, 52 participants randomized for 6 months to daily nocturnal haemodialysis compared with conventional thrice-weekly haemodialysis demonstrated improved left ventricular mass (reduction of 15.3 g), some improvement in quality of life domains and lower requirements for blood pressure and phosphate binder medications, whereas hospitalization rates and vascular access complications were unchanged.14 The Frequent Hemodialysis Network (FHN) Nocturnal Trial randomized 87 of a planned 250 participants to six nocturnal dialysis sessions compared with thrice-weekly conventional dialysis.15 While the nocturnal group exhibited improved blood pressure and phos258
phate control, there was no difference in left ventricular mass or physical quality of life, although the trial was underpowered to reliably assess the impact on most outcomes. The parallel Frequent Daily trial randomized 245 participants to six short compared with three standard dialysis sessions per week16 for 12 months, and demonstrated a reduction in left ventricular mass of 13.8 g, an improvement in physical quality of life score, improved blood pressure and phosphate control but a higher rate of vascular access interventions. Extended follow up survival analyses of the FHN studies, reported thus far in abstract form, suggest a survival advantage with frequent daily dialysis (Relative risk [RR] 0.54, 95% CI 0.32, 0.93, P = 0.024),17 and disadvantage with nocturnal dialysis (RR 3.82, 95% CI 1.26, 11.63, P = 0.011).18 Uncertainty therefore persists regarding the relative benefits and harms of extended hours haemodialysis regimens. The multicentre ACTIVE Dialysis Study is a prospective randomized study that will assess the effect of extended compared with standard weekly haemodialysis hours upon patient quality of life, along with a range of clinical and economic outcomes, in participants receiving maintenance haemodialysis over 12 months.
METHODS/DESIGN Study design ACTIVE Dialysis is a multicentre, randomized trial where participants and treating physicians were aware of treatment allocation; however, the central study team and endpoint assessors were blinded. Two hundred participants were randomized to the two arms: extended (≥24 h per week) or standard haemodialysis therapy (≤18 h per week) for 12 months. The primary hypothesis being tested is that increasing weekly haemodialysis hours will improve quality of life for individuals receiving maintenance haemodialysis for ESKD.
Setting and participants Incident and prevalent maintenance haemodialysis patients meeting the inclusion criteria (Table 1) and providing informed consent were eligible to participate. Study treatment was provided either in home or institution-based settings with the setting determined prior to randomization to avoid confounding by dialysis location. Forty dialysis centres located in Australia, China, Canada and New Zealand participated in the study. Some centres recruited institutionbased participants only, others home-based patients only with the remainder having a mix of both.
Intervention Participants randomized to standard weekly haemodialysis hours have continued their usual treatment regimen over a minimum of three sessions per week and not exceeding 18 h of haemodialysis per week, with the expectation most would receive between 12 and 15 h of haemodialysis. Participants randomized to extended weekly haemodialysis hours were to receive at least 24 h of haemodialysis © 2014 Asian Pacific Society of Nephrology
ACTIVE Dialysis design and characteristics
Table 1 Inclusion and exclusion criteria of the ACTIVE Dialysis Study Inclusion criteria 1. 2. 3. 4. 5.
Incident or prevalent patients requiring maintenance haemodialysis therapy for end-stage kidney disease Aged 18 years or older Undergoing dialysis for 18 h per week or less Suitable for either extended or standard dialysis in the view of the treating physician Agreeable to randomization
Exclusion criteria 1. 2. 3. 4. 5.
Life expectancy of less than 6 months Definite plans to undergo renal transplantation within 12 months of entry to the study Inability to complete quality of life questionnaire Concomitant major illness that would limit assessments and follow-up High chance that the patient will not adhere to study treatment and follow-up in the view of the treating physician.
weekly, using a minimum three sessions per week. The interventions were designed to be as flexible as possible while maintaining a separation in weekly haemodialysis hours between the study groups. All other treatment is provided according to routine practice at participating sites. A summary of expectations for routine care and monitoring of patients undergoing standard or extended weekly dialysis hours has been provided to sites (Appendix S2).
Participant intervention period duration After randomization, participants commenced their allocated treatment within 1 month, continuing until any of the following occurred: completion of the 12 month study period, cessation of haemodialysis (e.g. kidney transplantation and transfer to peritoneal dialysis), transfer to a setting where both randomized therapies are not available (e.g. transferring to an institution dialysis setting where both randomized treatments are not available), participant death or withdrawal of consent.
Observational follow-up and data linkage Following the conclusion of their participation in the intervention study, participants will continue to be followed remotely for at least 5 years in a cohort phase to collect information on vital status, dialysis modality and haemodialysis weekly hours. During the observational phase weekly dialysis hours will be determined by physician discretion and local practice. Data linkage to health-care and dialysis registries will be performed in jurisdictions where this is possible.
randomization with the details of the randomization schedule remaining confidential, known to only a limited number of persons including the unblinded statistician who otherwise had no role in the study.
Study endpoints The primary endpoint is change in quality of life from baseline, (pre-randomization) to the end of the 12 month trial period as measured by the EQ-5D 3 L score, a questionnaire designed to measure health status available and validated in all languages used in the study.19 The quality of life instrument is administered by a central blinded interviewer via telephone with participants provided with a written copy of the questionnaire prior to the interview. The visual analog score was not included because of the use of telephone-based administration of the instrument. The questionnaires and interview are conducted in the dominant language of the participant’s country. Translation services are provided if required so that lack of fluency in the dominant language of the participant’s country of residence is not a contraindication to participation. A range of secondary endpoints are described in Table 2 and within the prespecified Statistical Analysis Plan available on The George Institute for Global Health website (http:// www.georgeinstitute.org/projects/active-dialysis-a-clinical-trial-ofintensive-dialysis). The study will have substantial power to detect clinically important differences in secondary endpoints based on data from the Canadian randomized pilot trial of daily long dialysis14 and registries. Change in left ventricular mass index is assessed using cardiac magnetic resonance imaging (MRI) at baseline and 12 months. Cardiac MRIs are performed at local MRI centres and analysed centrally. Participants are excluded from cardiac MRI assessment if they have individual contraindications or have been recruited from an MRI-exempted site. Sites were exempted from the requirement for cardiac MRI assessment if they were geographically distant from a MRI centre with capacity to participate. Adequacy of scanning capacity at each site was assessed on a test scan or the first study scan for each site before approval for ongoing scans. The study has 90% power to detect a difference between the groups in the change in left ventricular mass index from baseline to 12 months of 8.7 g/m2 if 100 participants complete cardiac MRI imaging, and of 7.7 g/m2 if 125 participants complete cardiac MRI imaging. Differences in left ventricular mass index in other randomised controlled trials of extended weekly haemodialysis hours have ranged between −4.4 and −8.1 g/m2.14–16 Endpoints beyond the 12 month study period will be assessed during the observational follow-up period of the study. Outcomes will be assessed using data linkage to routinely collected data sources and registries or, where this is not possible, through data on participant vital status and dialysis modality collected by sites.
Economic evaluation Randomization Randomization (1:1) was performed centrally via a passwordprotected, encrypted web-based interface using a minimization algorithm to balance treatment allocation across geographical regions (Australia and New Zealand vs China and Canada), dialysis location (institution vs home) and dialysis vintage (≤6 months vs >6 months). Treatment allocation concealment was ensured prior to © 2014 Asian Pacific Society of Nephrology
If the intervention is demonstrated to be effective for the primary outcome, cost utility analyses will be performed from the perspective of the healthcare provider (base case), to estimate the cost effectiveness of long dialysis with respect to standard care in terms of cost per quality adjusted life year (QALY) gained. The total costs of providing standard and extended dialysis will be collected during the course of the trial, including all aspects of healthcare utilisation in the follow259
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Table 2 Secondary outcomes in the ACTIVE Dialysis Study 1) Survival and cardiovascular outcomes a) Cardiovascular structure b) Blood pressure
c) Requirement for blood pressure lowering
d) Clinical cardiovascular events
e) Survival 2) Quality of life and patient acceptability a) Quality of life
i) i) ii)
Change in left ventricular mass index from baseline to the end of the trial period Change in systolic blood pressure from baseline to end of the trial period† Change in systolic blood pressure from baseline to all follow-up visits occurring during the trial period† i) Change in number and dose of blood pressure lowering agents from baseline to the end of the trial period‡ ii) Change in number and dose of blood pressure lowering agents from baseline to all follow-up visits occurring during the trial period‡ iii) Change in the percentage of people on no blood pressure lowering medications at the end of the trial period iv) Change in the percentage of people on no blood pressure lowering medications at all follow-up visits during the trial period i) Time to the occurrence of a combined end-point consisting of new onset of documented acute myocardial infarction, stroke or death due to cardiovascular causes§ ii) Time to the occurrence of a combined end-point consisting of new onset of documented acute myocardial infarction, stroke, death due to cardiovascular causes and cardiovascular SAEs during the trial period i) Difference in survival between the two groups at 24, 36 and 60 months and when survival in the standard treatment arm reaches 25%§ i) ii) iii) iv) v)
b) Patient acceptability
i) ii)
iii) 3) Changes in biochemical and haematological markers a) Mineral metabolism
b) Erythropoiesis stimulating agent requirement
4) Safety outcomes a) Survival b) Serious adverse events (SAEs) 5) Vascular access
6) Hospitalizations
Change in quality of life from baseline to the follow-up visits occurring during the trial period as measured by the EQ-5D instrument Change in quality of life as measured by the SF-36 two composite scores (physical-health composite and mental-health composite) from baseline to the end of the trial period Change in quality of life as measured by the SF-36 two composite scores (physical-health composite and mental-health composite) from baseline to the follow-up visits occurring during the trial period Change in quality of life as measured by the individual eight domains of the SF-36 from baseline to the end of the trial period Change in quality of life as measured by the individual eight domains of the SF-36 from baseline to the follow-up visits occurring during the trial period Relative adherence assessed at the end of the trial period Relative adherence assessed at each of the trial period follow-up visits. (1) Full adherence at the end of the trial period (2) Full adherence at each of the follow-up visits Relative and full adherence at 24, 36 and 60 months§
Change in the percentage at optimal phosphate target defined as a phosphate < 1.5 mmol/L AND no use of phosphate binders at the follow-up visits occurring during the trial period. ii) Change in the number of phosphate binder tablets during the trial period iii) Number of patients on phosphate supplementation during the trial period¶ iv) Change in the dose of phosphate binders from baseline to the end of the trial period v) Number of patients on phosphate supplementation (oral or intravenous) at the end of the trial period¶. i) Change in the dose of erythropoiesis stimulating agents (ESA) during the trial period compared with baseline†† ii) Change in the dose of erythropoiesis stimulating agents (ESA) from baseline to the end of the trial period compared with baseline†† i)
i) i) i)
Survival measured using proportional hazards Comparison of SAEs by diagnostic group Time to first vascular access failure defined as thrombosis or fistula revision where revision is defined as a procedure that requires a new anastomosis ii) Time to first vascular access intervention or failure iii) Time to first vascular access infection iv) Number of reported access-related AEs. i) Number of reported hospitalizations from randomization to end of trial period ii) Total duration of hospitalizations from randomization to end of trial period
†Blood pressure is taken as the average of the 2nd and 3rd of three measurements taken after 5 min rest and measured immediately prior to a dialysis session. ‡Dose of blood pressure-lowering agents is defined in terms of the number of maximum BP-lowering medication dose equivalents’ calculated as described in the Statistical Analysis Plan (available at http://www.georgeinstitute.org/projects/active-dialysis-a-clinical-trial-of-intensive-dialysis). §Some outcomes will be assessed over the trial and the following cohort observational period. ¶Phosphate supplementation is defined as a medication/supplement administered with the primary goal of replacing phosphate. ††Further information on the conversion formula for ESAs is described in the Statistical Analysis Plan.
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ACTIVE Dialysis design and characteristics
ing broad categories: (i) provision of dialysis services; (ii) inpatient healthcare utilisation; (iii) out of hospital healthcare utilisation; and (iv) the financial household impact of dialysis treatment.
Ethics and oversight All participants provided informed consent. The study was approved by the Harbour Human Research Ethics Committee of Northern Sydney Central Coast Health, NSW, Australia (Ref: HREC/09/ HARBR/26) with each centre obtaining additional ethics approval in accordance with local practice. The study and all its related procedures are being performed in compliance with the Guidelines for Good Clinical Practice. The study is being overseen by an independent Data Safety Monitoring Board, which undertook regular review of predefined safety parameters and overall study conduct. Predefined safety parameters included total mortality and serious adverse effects without formal testing of a treatment effect.
All continuous secondary endpoints will be analysed using linear regression adjusted for baseline values. Change in left ventricular mass index on magnetic resonance imaging analysis will be restricted to the subgroup of participants with both baseline and 12 month measurements available. Secondary outcomes repeatedly measured over time will also be modelled using a linear mixed model. Treatment effect will be tested using their Wald type test P-value from the model. Binary repeated measurement will be analysed using logistic generalized estimating equations to take into account the correlation due the repeated measurement effect. Count secondary endpoints will be modelled using a negative binomial model. All time to event variables will be censored at the time of study completion if the event of interest has not been observed. Survival curves and estimated median survival time will be generated according to the Kaplan–Meier method and differences assessed using the Log-rank test. Recurrent secondary endpoints will be analysed using the Andersen and Gill approach that is a generalization of a Cox proportional hazard model.
RESULTS Power The total sample size of 200 was chosen to provide 90% power (with alpha = 0.05) to detect an absolute difference of 0.10 in the change in health-related quality of life (utility or QALY weights, measured on a scale of 0 to 1) over 12 months between the intervention and control groups. We assumed a mean EQ-5D score of 0.70 at baseline with no change in the standard dialysis group, an improvement of 0.10 in the extended dialysis group, and a common standard deviation of 0.22. These values underlying the assumptions were obtained from the Canadian study of long dialysis with a comparable patient population.14 Using these assumptions, ACTIVE is not powered to detect smaller differences in EQ-5D-measured quality of life with 82% power to detect a difference of 0.09 and 73% power to detect a difference of 0.08.
Statistics All analyses will be performed on an intention-to-treat basis and according to the detailed pre-specified statistical analysis plan. In brief, the primary outcome will be assessed using linear regression to test the effectiveness of extended dialysis over standard dialysis (control) adjusted for the baseline score. Our primary analysis will be conducted using a pragmatic single imputation performed as follows: (i) if the participant died during the 12 month trial period, the quality of life score allocated will be zero from the date of death, and (ii) if the patient reaches the end of the study trial period before 12 months (e.g. due to receipt of a renal transplant) or if the quality of life score at 12 month is missing, then the last available score will be used. To ensure our results are robust to the handling of missing data we will conduct two sensitivity analyses: the first one by excluding those who do not complete a 12 month quality of life assessment and the second one by using a repeated-measure model including all data available during the follow-up. The primary endpoint will also be assessed according to the following subgroups: (i) participant region (China vs Australia, New Zealand and Canada), (ii) participant dialysis location (home vs centre dialysis), and (iii) participant vintage on dialysis (less or equal to 6 months vs more than 6 months dialysis duration at baseline). © 2014 Asian Pacific Society of Nephrology
Nearly 1200 patients were screened to recruit 200 participants between 2009 and 2013 from Australia (29.0%), China (62.0%), Canada (5.5%) and New Zealand (3.5%) (Table 3). Some centres recruited participants from institution-based programmes only (27 centres, 69.5% of participants), others home-based patients only (11 centres, 19.0% of participants) with the remaining two sites having a mix of both (11.5% of participants with 5.0% being institution based and 6.5% home based). Sites recruited participants entirely from institution-based programmes in China and from home-based programmes in New Zealand. In Australia, 11.5% of participants were recruited from institution-based programmes and 17.5% from home-based programmes. The relative figures for recruitment in Canada were 1.0% and 4.5%. The institution-based programmes did not routinely offer extended dialysis hours outside the trial. The median number of participants per site was 4, with an interquartile range of 2–7. The baseline characteristics of study participants are shown in Table 3. The mean age at baseline was 52 years, 69.5% were male, and 37% had diabetes. At baseline, 33% had a history of cardiovascular disease including 18% with a history of ischaemic heart disease, 8% with a history of cerebrovascular disease and 8% with a history of peripheral vascular disease. At baseline, 88.5% were dialysing in an institutional setting and 11.5% were dialysing at home. Some of those dialysing in an institution were planning for home dialysis with 25.5% intending to dialysis at home during the study. Participants were dialysing a mean of 14 h per week (median 12 h) over median three sessions at baseline.
DISCUSSION The ACTIVE Dialysis Study has met its planned recruitment target, and all participants will have completed the 12 month 261
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Table 3 Baseline characteristics Characteristics
Age at randomization (years) Mean (SD) Median (Q1, Q3) Gender Male Female Primary cause of renal disease Diabetic nephropathy Hypertension/vascular nephrosclerosis Glomerulonephritis Reflux nephrology Polycystic kidney disease Other Unknown Comorbidity Diabetes mellitus Hypertension Any cardiovascular disease Symptomatic ischaemic heart disease Angina Acute myocardial infarction Previous coronary artery bypass graft/percutaneous transluminal coronary angioplasty Congestive heart failure Cerebrovascular disease Peripheral vascular disease Smoking status Never smoked Past cigarette smoker Current cigarette smoker Country Australia Canada China New Zealand Ethnicity Caucasian Aboriginal or Torres Strait Islander Maori Pacific Islander Asian Indian Other Not reported Number of dialysis sessions per week 2 3 4 or more Total number of hours on dialysis per week Mean (SD) Median (Q1, Q3) Dialysis site at enrolment Home Institution Intended dialysis site for study treatment Home Institution Dialysis session During the day Overnight Combination of both Dialysis access Native arteriovenous fistula Synthetic fistula Tunnelled dialysis catheter Other
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Standard (n = 100)
Extended (n = 100)
Total (n = 100)
51.6 (11.50) 52.6 (45.2, 60.3)
52.1 (12.72) 53.2 (40.7, 62.6)
51.8 (12.10) 52.8 (42.0, 61.2)
70 (70.0%) 30 (30.0%)
69 (69.0%) 31 (31.0%)
139 (69.5%) 61 (30.5%)
34 (34.0%) 11 (11.0%) 34 (34.0%) 5 (5.0%) 7 (7.0%) 8 (8.0%) 1 (1.0%)
27 (27.0%) 11 (11.0%) 41 (41.0%) 3 (3.0%) 5 (5.0%) 10 (10.0%) 3 (3.0%)
61 (30.5%) 22 (11.0%) 75 (37.5%) 8 (4.0%) 12 (6.0%) 18 (9.0%) 4 (2.0%)
39 (39.0%) 85 (85.0%) 32 (32.0%) 18 (18.0%) 11 (11.0%) 2 (2.0%) 6 (6.0%) 13 (13.0%) 8 (8.0%) 8 (8.0%)
34 (34.0%) 82 (82.0%) 33 (33.0%) 18 (18.0%) 9 (9.0%) 2 (2.0%) 7 (7.0%) 19 (19.0%) 7 (7.0%) 6 (6.0%)
73 (36.5%) 167 (83.5%) 65 (32.5%) 36 (18.0%) 20 (10.0%) 4 (2.0%) 13 (6.5%) 32 (16.0%) 15 (7.5%) 14 (7.0%)
56 (56.0%) 23 (23.0%) 21 (21.0%)
60 (60.0%) 20 (20.0%) 20 (20.0%)
116 (58.0%) 43 (21.5%) 41 (20.5%)
28 (28.0%) 6 (6.0%) 62 (62.0%) 4 (4.0%)
30 (30.0%) 5 (5.0%) 62 (62.0%) 3 (3.0%)
58 (29.0%) 11 (5.5%) 124 (62.0%) 7 (3.5%)
24 (24.0%) 0 (0.0%) 3 (3.0%) 4 (4.0%) 66 (66.0%) 1 (1.0%) 2 (2.0%) 0 (0.0%)
23 (23.0%) 1 (1.0%) 3 (3.1%) 4 (4.0%) 65 (65.0%) 0 (0.0%) 2 (2.0%) 2 (2.0%)
47 (23.5%) 1 (0.5%) 6 (3.0%) 8 (4.0%) 131 (65.5%) 1 (0.5%) 4 (4.0%) 2 (1.0%)
1 (1.0%) 82 (82.0%) 17 (17.0%)
1 (1.0%) 86 (86.0%) 13 (13.0%)
2 (1.0%) 168 (84.0%) 30 (15.0%)
14.1 (2.8) 12.4 (12.0, 16.0)
13.6 (2.6) 12.0 (12.0, 15.0)
13.9 (2.7) 12.0 (12.0, 15.0)
12 (12.0%) 88 (88.0%)
11 (11.0%) 89 (89.0%)
23 (11.5%) 177 (88.5%)
25 (25%) 75 (75.0%)
26 (26%) 74 (74.0%)
51 (25.5%) 149 (74.5%)
94 (94.0%) 2 (2.0%) 4 (4.0%)
96 (96.0%) 3 (3.0%) 1 (1.0%)
190 (95.0%) 5 (2.5%) 5 (2.5%)
81 (81.0%) 4 (4.0%) 14 (14.0%) 1 (1.0%)
87 (87.0%) 3 (3.0%) 9 (9.0%) 1 (1.0%)
168 (84.0%) 7 (3.5%) 23 (11.5%) 2 (1.0%)
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ACTIVE Dialysis design and characteristics
Table 3 Continued Characteristics
Dialysis cannulation method The Buttonhole technique The Rope Ladder technique Dialysis Catheter Systolic blood pressure (mmHg) Mean (SD) Median (Q1, Q3) Diastolic blood pressure (mmHg) Mean (SD) Median (Q1, Q3) Quality of life measured using EQ-5D (score)
trial period during 2014. As with all randomized studies in this area,15 participant recruitment was difficult and required expansion to additional sites (40 rather than 10) across four countries to complete. As such, ACTIVE Dialysis is the largest randomized trial of extended hours dialysis, and the first multicentre trial of this intervention to successfully achieve its randomization goal. The range of geographies and dialysis settings involved in the trial will also enhance the generalizability of its findings to most dialysis environments around the world. Subgroup analyses by setting, region (Asia vs other), frequency and session duration will further allow exploration of the impact of these aspects on outcomes associated with extended hours dialysis. Overall, the ACTIVE cohort appears to have similarities with other extended dialysis randomized and cohort studies, with mean age between 50 and 55 and ESKD due to diabetic nephropathy in around one-third (Table 4). It is younger than the Australian and New Zealand general haemodialysis populations with less diabetic nephropathy than the New Zealand cohort although is broadly similar in age and cause of ESKD to the general Beijing haemodialysis population. More people in the ACTIVE study were dialysing with an arteriovenous fistula than the other extended dialysis randomized studies that appeared to reflect higher background rates of arteriovenous fistula access in the Australian and Beijing haemodialysis populations. The most compelling primary outcome for a trial of extended hours dialysis would be patient survival, but a trial of this outcome would require thousands of participants. Although there are at least hundreds, and probably thousands, of patients being treated with extended hours dialysis around the world,11 a trial of this size does not currently appear feasible without a substantial change in patient and physician willingness to support the generation of clinical trial evidence before embracing treatment approaches. Similar issues of practice uptake prior to trial demonstration of benefit have arisen with renal denervation for resistant hypertension, where thousands of people around the world were treated based on one small trial, prior to a larger, sham-controlled trial casting doubt on the efficacy of the © 2014 Asian Pacific Society of Nephrology
Standard (n = 100)
Extended (n = 100)
Total (n = 100)
14 (14.0%) 71 (71.0%) 15 (15.0%)
22 (22.0%) 68 (68.0%) 10 (10.0%)
36 (18.0%) 139 (69.5%) 25 (12.5%)
139 (21.0) 138 (126, 156)
141 (20.7) 140 (130, 156)
140 (20.8) 139 (128, 156)
79 (13.6) 80 (70, 88) 0.76 (0.25)
81 (13.9) 81 (73, 90) 0.79 (0.23)
80 (13.8) 80 (71, 89) 0.78 (0.24)
procedure.23 As a community, we must resist the lure of exciting new therapies until the benefits and risks have been clearly assessed in appropriately designed and powered randomized trials. In this light, a strength of the current trial is the plan to prospectively collect longitudinal outcome data for at least 5 years. Although it is expected that treatment drop-out and drop-in rates may be high soon after completion of the 12 month treatment period, this will allow assessment of the legacy effects of the ACTIVE study treatments. The importance of quality of life, as well as quantity, is regularly identified by consumer and patient groups as being similar or even greater to that of survival.24 As such, quality of life is an appropriate and important primary outcome for this trial and would represent a compelling reason for changes in practice if a beneficial effect is demonstrated, contingent upon the findings of the planned economic evaluation. A range of quality of life instruments have been used to assess quality of life in people with kidney disease.25 The EQ-5D instrument was selected for the ACTIVE Dialysis trial for a number of reasons. Firstly, it provides quality of life years that can be employed in cost utility analyses in the event of demonstration of benefit. Secondly, it allowed comparison with the Alberta trial that was the only published trial of extended weekly dialysis hours in maintenance hemodialysis at the time ACTIVE was designed. The ACTIVE Dialysis Study has successfully recruited the largest randomized study cohort to examine the effect of increasing haemodialysis weekly hours upon changes in quality of life. The study population represents a range of haemodialysis settings globally so the findings will be generalizable and represent a major contribution to our understanding of the benefits and harms of extended weekly dialysis hours therapy.
ACKNOWLEDGEMENTS We gratefully acknowledge the contribution of the ACTIVE Dialysis Investigators and Study Co-ordinators, the project 263
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Male gender Diabetic nephropathy Hypertension/vascular nephrosclerosis Glomerulonephritis Diabetes mellitus Ischaemic heart disease Acute myocardial infarction Congestive heart failure Cerebrovascular disease Peripheral vascular disease Australia New Zealand Canada USA/Canada China United States France Caucasian Asian Aboriginal or Torres Strait Islander Maori Pacific Islander Black Native arteriovenous fistula Synthetic fistula Tunnelled dialysis catheter Non-tunnelled dialysis catheter Unknown 17.6% 25.5%
3.5% 11.5% 1.0%
56.9%
86.3%
84.0%
3.0% 4.0%
23.5% 65.5% 0.5%
62.0%
100%
21.6% 15.7% 15.7%
16.0% 7.5% 7.0% 29.0% 3.5% 5.5%
25.5% 41.2% 39.2% –
37.5% 36.5% 18.0% 2.0%
7% 47%
26.4% 45%
55.2% 13.8%
100%
13.8% 2.3% 17.2%
35.6% 42.5% – 10.3%
52.8 (mean) 66.5% 34.5% 8.0%
87 –
FHN Nocturnal15,20
18% 19%
41.6% 63%
36.3% 6.5%
100%
20.0% 7.3% 10.2%
19.2% 40.8% – 11.0%
50.4 (mean) 61.6% 34.3% 20.8%
245 –
FHN Daily16,20
∼6% 2–3%
92%
90%
100%
– – –
38% 24% – –
52 (median) 77% 12% –
Australian extended hours cohort7 286 – –
16.9%
5.5% 21.7%§§
56.0%
11.9% 14.8% 77.4%
73.3%
13.1% 5.0% 10.7%
– 24.0% – 11.4%
49.6 (mean) 71.7 – –
420
International Quotidian Registry11
Cohorts practising extended hours
1.0% 3.6%
77.2% 7.5% 8.8%
100%
– 11.6% 23.7%‡‡
37.9% 30.5% 38.6%‡‡ –
55–64 (mode) 58.6% 18.7% 8.8%
1048 9.2%
Australian 201221
27.7% 17.9%
50.1% 4.1% 0.0%
100%
– 9.2% 18.8%‡‡
38.8% 34.3% 36.0%‡‡ –
45–54 (mode)§ 67.8% 28.6% 6.6%
469 19.0%
New Zealand 201221
Registry home haemodialysis cohorts
1%
7% 13%
78%
0.9% 2.5%
72.2% 8.4% 13.9%
100%
– 21.2% 35.4%‡‡
25.2% 47.8% 53.4%‡‡ –
62 (median) 59.8% 34.2% 12.5%
9219‡ 80.5%
Australia 201221
3%
4% 20%
73%
31.4% 28.9%
32.1% 7.0% 0.0%
100%
– 15.4% 24.5%‡‡
26.9% 52.7% 42.3%‡‡ –
58 (median) 61.2% 45% 6.8%
1697‡ 68.7%
New Zealand 201221
0.9%†† 81.1%††,§§
15.8%††
100%
– – –
13.7% 53.6%†† – –
45–64 (mode range)§ 59.3% 35.6% 16.3%
19 638 82.5%
Canada 201222
Registry haemodialysis cohorts
27.0%††
7.5%††
62.5%††
100%
– – –
34.1% – – –
59.2 (mean)¶ 52.9%¶ 27.9% 14.2%
10 072 –
Beijing 20103
†Proportion of relevant national prevalent dialysis cohort listed for Australia, New Zealand and Canada. ‡Numbers for haemodialysis patients include both institution-based and home-based patients. §Data reported in age ranges. The modal range is listed here. ¶Unpublished communication, Prof Zuo Li, President, Blood Purification Center Management Branch of Chinese Hospital Association. ††Figures for incident haemodialysis patients listed as prevalent figures not available in the published report. ‡‡Known or suspected disease. §§Catheter type (tunnelled or non-tunnelled) not specified.
Dialysis access
Ethnicity
Country
Cause end-stage kidney disease Comorbidities
Demography
52 – 54.1 (mean) 62.7% 29.4% 7.8%
200 –
n Proportion of total dialysis population† Age in years
Alberta trial14
51.8 (mean) 69.5% 30.5% 11.0%
ACTIVE Dialysis
Study
Report
Randomized trials of extended hours
Table 4 Comparative characteristics at entry into randomized trials of extended hours, cohorts practising extended haemodialysis hours, home haemodialysis cohorts and general prevalent haemodialysis populations
MJ Jardine et al.
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ACTIVE Dialysis design and characteristics
coordinating central team and the MRI centres (listed in Appendix S1), and most particularly the study participants. Meg Jardine is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and the National Heart Foundation. Alan Cass is supported by a NHMRC Senior Research Fellowship. Vlado Perkovic is supported by a New South Wales Cardiovascular Research Network Fellowship.
FUNDING This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Project Grant [ID:571045] and a Baxter Clinical Evidence Council Investigator Initiated Research Grant [2012]. Additional support came from an unrestricted grant from Baxter International Inc. with funding for the vanguard phase from an NHMRC Program Grant (358395). The funding sources had no role in the design of this study nor its execution and will not have any role during its analyses, interpretation of the data, or decision to submit results for publication.
11.
12. 13.
14.
15.
16.
17.
18.
REFERENCES 1. U.S. Renal Data System. USRDS. Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013. 2. McDonald S. Deaths, ANZDATA Registry Report 2012: [3.1–3.9 pp.]. 3. The Expert Team of Beijing Blood Purification Quality Control and Improvement Center. Annual Data Report of Beijing Blood Purification Quality Control and Improvement Center. Zhongguo Xueye Jinghua. 2013; 12 (Suppl): 1–70. 4. Gansevoort RT, Matsushita K, van der Velde M et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011; 80: 93–104. 5. McDonald S. Deaths, ANZDATA Registry Report 2011, Australia and New Zealand Dialysis and Transplant Registry. Adelaide, South Australia. 2011. 6. Innes A, Charra B, Burden RP, Morgan AG, Laurent G. The effect of long, slow haemodialysis on patient survival. Nephrol. Dial. Transplant. 1999; 14: 919–22. 7. Jun M, Jardine MJ, Gray N et al. Outcomes of extended-hours hemodialysis performed predominantly at home. Am. J. Kidney Dis. 2013; 61: 247–53. 8. Pierratos A. Daily nocturnal home hemodialysis. Kidney Int. 2004; 65: 1975–86. 9. Johansen KL, Zhang R, Huang Y et al. Survival and hospitalization among patients using nocturnal and short daily compared to conventional hemodialysis: A USRDS study. Kidney Int. 2009; 76: 984–90. 10. Weinhandl ED, Liu J, Gilbertson DT, Arneson TJ, Collins AJ. Survival in daily home hemodialysis and matched thrice-weekly
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19. 20.
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in-center hemodialysis patients. J. Am. Soc. Nephrol. 2012; 23: 895–904. Suri RS, Lindsay RM, Bieber BA et al. A multinational cohort study of in-center daily hemodialysis and patient survival. Kidney Int. 2013; 02//print; 83: 300–7. Pierratos A. Nocturnal home haemodialysis: An update on a 5-year experience. Nephrol. Dial. Transplant. 1999; 14: 2835–40. Chazot C, Wabel P, Chamney P, Moissl U, Wieskotten S, Wizemann V. Importance of normohydration for the long-term survival of haemodialysis patients. Nephrol. Dial. Transplant. 2012; 27: 2404–10. Culleton BF, Walsh M, Klarenbach SW et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: A randomized controlled trial. JAMA 2007; 298: 1291–9. Rocco MV, Lockridge RS, Jr, Beck GJ et al. The effects of frequent nocturnal home hemodialysis: The Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011; 80: 1080–91. F. H. N. Trial Group, Chertow GM, Levin NW et al. In-center hemodialysis six times per week versus three times per week. N. Engl. J. Med. 2010; 363: 2287–300. Chertow GM, Levin NW, Beck GJ et al., The FHN Trial Group. Effects of randomization to frequent in-center hemodialysis on long-term mortality: Frequent hemodialysis daily trial [Abstract]. J. Am. Soc. Nephrol. 2013; 24: 442A. Rocco MV, Daugirdas JT, Greene T et al., The FHN Trial, Group. Effects of randomization to frequent nocturnal hemodialysis on long-term mortality: Frequent hemodialysis network nocturnal trial [Abstract]. J. Am. Soc. Nephrol. 2013; 24: 443A. EuroQol G. EuroQol – A new facility for the measurement of health-related quality of life. Health Policy 1990; 16: 199–208. Suri RS, Larive B, Sherer S et al. Risk of vascular access complications with frequent hemodialysis. J. Am. Soc. Nephrol. 2013; 24: 498–505. Blair Grace KH, McDonald S, Clayton P. 36th Annual ANZDATA Report (2013)2013. Canadian Institute for Health Information. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada, 2003 to 2012. 2014. Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 2014; 370: 1393–401. Tong A, Sainsbury P, Carter SM et al. Patients’ priorities for health research: Focus group study of patients with chronic kidney disease. Nephrol. Dial. Transplant. 2008; 23: 3206–14. Cagney KA, Wu AW, Fink NE et al. Formal literature review of quality-of-life instruments used in end-stage renal disease. Am. J. Kidney Dis. 2000; 36: 327–36.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1 ACTIVE Dialysis Study Group. Appendix S2 Routine Monitoring of ACTIVE Dialysis Participants. Appendix S3 Suggested aseptic procedure for patients using button hole cannulation.
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Nephrology 20 (2015) 257–265
Original Article
Design and participant baseline characteristics of ‘A Clinical Trial of IntensiVE Dialysis’: The ACTIVE Dialysis Study MEG J JARDINE,1,2 LI ZUO,3 NICHOLAS A GRAY,4,5 JANAK DE ZOYSA,6,7 CHRISTOPHER T CHAN,8 MARTIN P GALLAGHER,1,9 KIRSTEN HOWARD,10 STEPHANE HERTIER,11 ALAN CASS1,12 and VLADO PERKOVIC1,13 on behalf of the ACTIVE Dialysis Steering Committee* 1 The George Institute for Global Health, 9Concord Clinical School, Sydney Medical School, 10School of Public Health, University of Sydney, 2Renal Unit, Concord Repatriation General Hospital, 13Department of Renal Medicine, Royal North Shore Hospital, Sydney, New South Wales, 4Renal Medicine, Nambour General Hospital, 5Sunshine Coast Clinical School, The University of Queensland, Nambour, Queensland, 11School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, 12Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia; 3Department of Nephrology, Peking University People’s Hospital, Beijing, China; 6Renal Services, North Shore Hospital, 7Department of Medicine, University of Auckland, Auckland, New Zealand; and 8Division of Medicine, University Health Network, Toronto, Ontario, Canada
KEY WORDS: extended dialysis, H(a)emodialysis, left ventricular mass index, quality of life, randomized controlled trial. Correspondence: Dr Meg Jardine, The George Institute for Global Health, PO Box M201, Missenden Road, NSW, 2050, Australia. Email: [email protected] Accepted for publication 16 December 2014. Accepted manuscript online 22 December 2014. doi:10.1111/nep.12385 Conflict of Interest Statement Meg Jardine has received an unconditional research grant from Gambro AB. Nick Gray has received speaker’s fees from Baxter Healthcare. Janak de Zoysa has received an unrestricted educational grant from Baxter Healthcare. Chris Chan has received funding from NIDDK, Baxter Extramural Grant Program and the Clinical Evidence Council program. Zuo Li, Martin Gallagher, Kirsten Howard, Stephane Hertier, Alan Cass and Vlado Perkovic declare that there are no conflicts of interest.
*Members listed in Appendix S1. Funding: The primary funding of the ACTIVE Dialysis Study was a National Health and Medical Research Council (NHMRC) of Australia Project Grant (571045). Additional funding included a Baxter Clinical Evidence Council Investigator Initiated Research Grant (2012), an unrestricted grant from Baxter with funding for the vanguard phase from an NHMRC Program Grant (358395). Trial registration: clinicaltrials.gov NCT00649298 MESH terms Chronic Kidney Failure; Clinical Trial, Phase IV; Hypertrophy, Left Ventricular; Quality of Life; Renal Dialysis
ABSTRACT: Aims: Observational reports suggest extended dialysis hours are associated with improved outcomes. These findings are confounded by better prognostic characteristics among people practising extended hours. The aim of this article is to provide an overview of the methods and baseline characteristics for ACTIVE Dialysis Study participants. Methods: This multicentre, randomized, open-label, blinded endpointassessment trial randomized participants receiving maintenance haemodialysis therapy to either extended (≥24 h) or standard (12–18 h) weekly haemodialysis for 12 months. A web-based randomization system used minimization to ensure balanced allocation across regions, dialysis setting and dialysis vintage. The primary outcome is the change in quality of life over 12 months of study treatment assessed by EQ-5D. Secondary outcomes include change in left ventricular mass index assessed by magnetic resonance imaging and safety outcomes including dialysis access events. Results: A total of 200 participants were recruited between 2009 and 2013 from Australia (29.0%), China (62.0%), Canada (5.5%) and New Zealand (3.5%). Participants had a mean age of 52 (± 12) years and 11.5% were dialysing at home, with a mean duration of 13.9 h per week over a median of three sessions. At baseline, 32.5% had a history of cardiovascular disease and 36.5% had diabetes. Conclusion: The ACTIVE Dialysis Study has met its planned recruitment target. The participant population are drawn from a range of health service settings in a global context. The study will contribute important evidence on the benefits and harms of extending weekly dialysis hours. The trial is registered at clinicaltrials.gov (NCT00649298).
SUMMARY AT A GLANCE This paper forms the background for the soon to be released ACTIVE Dialysis Study – an important study comparing quality of life in patients randomly assigned to conventional or extended hours haemodialysis.
© 2014 Asian Pacific Society of Nephrology
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BACKGROUND In the 1960s, dialysis therapies were introduced into routine clinical practice as a life-preserving intervention for people with end-stage kidney disease (ESKD). Fifty years on, over 430 000 people are being treated with dialysis therapies in the US alone.1 People requiring maintenance dialysis therapies continue to have poorer outcomes and survival than people without ESKD with adjusted all-cause mortality rates being 6.5–7.9 times that of the general US population.1 Unadjusted annual mortality rates are over 20% in the USA,1 approximately 10–15% in Australia, New Zealand and Canada2 and 5–10% in China.3 The twin observations that mortality and cardiovascular events increase with declining kidney function4 and that dramatic improvements in these outcomes are seen following renal transplantation5 have driven the hypothesis that improving dialysis clearances will improve cardiovascular and survival outcomes. Observational studies also report better dialysis survival using extended hours haemodialysis as seen in the Centre de Rein Artificiel in France, with 5 years actuarial mortality approximately halved.6 Subsequent observational reports have shown excellent patient outcomes including 5 years survival rates of over 80% for cohorts receiving extended hours dialysis in Australia7 and Canada,8 and 3 years survival of 70–80% in the USA.9,10 However, a recent analysis from The International Quotidian Dialysis Registry that included propensity score matching and attempts to control for survival and immortal time bias found that daily in-centre haemodialysis was associated with worse survival {HR 1.6 (95% confidence interval [CI] 1.1, 2.3) P = 0.023}.11 Beyond survival, smaller studies have shown people receiving extended weekly haemodialysis hours may have improvements in multiple other parameters including quality of life, cardiac structure and function, phosphate control, anaemia and blood pressure control.12,13 Concerns have, however, been raised regarding an increase in adverse arteriovenous fistula events.7 The major limitation of the observational studies is the better baseline characteristics of patients receiving extended hours dialysis patients. Two randomized controlled trials testing the impact of extended dialysis hours have been reported. In Alberta, Canada, 52 participants randomized for 6 months to daily nocturnal haemodialysis compared with conventional thrice-weekly haemodialysis demonstrated improved left ventricular mass (reduction of 15.3 g), some improvement in quality of life domains and lower requirements for blood pressure and phosphate binder medications, whereas hospitalization rates and vascular access complications were unchanged.14 The Frequent Hemodialysis Network (FHN) Nocturnal Trial randomized 87 of a planned 250 participants to six nocturnal dialysis sessions compared with thrice-weekly conventional dialysis.15 While the nocturnal group exhibited improved blood pressure and phos258
phate control, there was no difference in left ventricular mass or physical quality of life, although the trial was underpowered to reliably assess the impact on most outcomes. The parallel Frequent Daily trial randomized 245 participants to six short compared with three standard dialysis sessions per week16 for 12 months, and demonstrated a reduction in left ventricular mass of 13.8 g, an improvement in physical quality of life score, improved blood pressure and phosphate control but a higher rate of vascular access interventions. Extended follow up survival analyses of the FHN studies, reported thus far in abstract form, suggest a survival advantage with frequent daily dialysis (Relative risk [RR] 0.54, 95% CI 0.32, 0.93, P = 0.024),17 and disadvantage with nocturnal dialysis (RR 3.82, 95% CI 1.26, 11.63, P = 0.011).18 Uncertainty therefore persists regarding the relative benefits and harms of extended hours haemodialysis regimens. The multicentre ACTIVE Dialysis Study is a prospective randomized study that will assess the effect of extended compared with standard weekly haemodialysis hours upon patient quality of life, along with a range of clinical and economic outcomes, in participants receiving maintenance haemodialysis over 12 months.
METHODS/DESIGN Study design ACTIVE Dialysis is a multicentre, randomized trial where participants and treating physicians were aware of treatment allocation; however, the central study team and endpoint assessors were blinded. Two hundred participants were randomized to the two arms: extended (≥24 h per week) or standard haemodialysis therapy (≤18 h per week) for 12 months. The primary hypothesis being tested is that increasing weekly haemodialysis hours will improve quality of life for individuals receiving maintenance haemodialysis for ESKD.
Setting and participants Incident and prevalent maintenance haemodialysis patients meeting the inclusion criteria (Table 1) and providing informed consent were eligible to participate. Study treatment was provided either in home or institution-based settings with the setting determined prior to randomization to avoid confounding by dialysis location. Forty dialysis centres located in Australia, China, Canada and New Zealand participated in the study. Some centres recruited institutionbased participants only, others home-based patients only with the remainder having a mix of both.
Intervention Participants randomized to standard weekly haemodialysis hours have continued their usual treatment regimen over a minimum of three sessions per week and not exceeding 18 h of haemodialysis per week, with the expectation most would receive between 12 and 15 h of haemodialysis. Participants randomized to extended weekly haemodialysis hours were to receive at least 24 h of haemodialysis © 2014 Asian Pacific Society of Nephrology
ACTIVE Dialysis design and characteristics
Table 1 Inclusion and exclusion criteria of the ACTIVE Dialysis Study Inclusion criteria 1. 2. 3. 4. 5.
Incident or prevalent patients requiring maintenance haemodialysis therapy for end-stage kidney disease Aged 18 years or older Undergoing dialysis for 18 h per week or less Suitable for either extended or standard dialysis in the view of the treating physician Agreeable to randomization
Exclusion criteria 1. 2. 3. 4. 5.
Life expectancy of less than 6 months Definite plans to undergo renal transplantation within 12 months of entry to the study Inability to complete quality of life questionnaire Concomitant major illness that would limit assessments and follow-up High chance that the patient will not adhere to study treatment and follow-up in the view of the treating physician.
weekly, using a minimum three sessions per week. The interventions were designed to be as flexible as possible while maintaining a separation in weekly haemodialysis hours between the study groups. All other treatment is provided according to routine practice at participating sites. A summary of expectations for routine care and monitoring of patients undergoing standard or extended weekly dialysis hours has been provided to sites (Appendix S2).
Participant intervention period duration After randomization, participants commenced their allocated treatment within 1 month, continuing until any of the following occurred: completion of the 12 month study period, cessation of haemodialysis (e.g. kidney transplantation and transfer to peritoneal dialysis), transfer to a setting where both randomized therapies are not available (e.g. transferring to an institution dialysis setting where both randomized treatments are not available), participant death or withdrawal of consent.
Observational follow-up and data linkage Following the conclusion of their participation in the intervention study, participants will continue to be followed remotely for at least 5 years in a cohort phase to collect information on vital status, dialysis modality and haemodialysis weekly hours. During the observational phase weekly dialysis hours will be determined by physician discretion and local practice. Data linkage to health-care and dialysis registries will be performed in jurisdictions where this is possible.
randomization with the details of the randomization schedule remaining confidential, known to only a limited number of persons including the unblinded statistician who otherwise had no role in the study.
Study endpoints The primary endpoint is change in quality of life from baseline, (pre-randomization) to the end of the 12 month trial period as measured by the EQ-5D 3 L score, a questionnaire designed to measure health status available and validated in all languages used in the study.19 The quality of life instrument is administered by a central blinded interviewer via telephone with participants provided with a written copy of the questionnaire prior to the interview. The visual analog score was not included because of the use of telephone-based administration of the instrument. The questionnaires and interview are conducted in the dominant language of the participant’s country. Translation services are provided if required so that lack of fluency in the dominant language of the participant’s country of residence is not a contraindication to participation. A range of secondary endpoints are described in Table 2 and within the prespecified Statistical Analysis Plan available on The George Institute for Global Health website (http:// www.georgeinstitute.org/projects/active-dialysis-a-clinical-trial-ofintensive-dialysis). The study will have substantial power to detect clinically important differences in secondary endpoints based on data from the Canadian randomized pilot trial of daily long dialysis14 and registries. Change in left ventricular mass index is assessed using cardiac magnetic resonance imaging (MRI) at baseline and 12 months. Cardiac MRIs are performed at local MRI centres and analysed centrally. Participants are excluded from cardiac MRI assessment if they have individual contraindications or have been recruited from an MRI-exempted site. Sites were exempted from the requirement for cardiac MRI assessment if they were geographically distant from a MRI centre with capacity to participate. Adequacy of scanning capacity at each site was assessed on a test scan or the first study scan for each site before approval for ongoing scans. The study has 90% power to detect a difference between the groups in the change in left ventricular mass index from baseline to 12 months of 8.7 g/m2 if 100 participants complete cardiac MRI imaging, and of 7.7 g/m2 if 125 participants complete cardiac MRI imaging. Differences in left ventricular mass index in other randomised controlled trials of extended weekly haemodialysis hours have ranged between −4.4 and −8.1 g/m2.14–16 Endpoints beyond the 12 month study period will be assessed during the observational follow-up period of the study. Outcomes will be assessed using data linkage to routinely collected data sources and registries or, where this is not possible, through data on participant vital status and dialysis modality collected by sites.
Economic evaluation Randomization Randomization (1:1) was performed centrally via a passwordprotected, encrypted web-based interface using a minimization algorithm to balance treatment allocation across geographical regions (Australia and New Zealand vs China and Canada), dialysis location (institution vs home) and dialysis vintage (≤6 months vs >6 months). Treatment allocation concealment was ensured prior to © 2014 Asian Pacific Society of Nephrology
If the intervention is demonstrated to be effective for the primary outcome, cost utility analyses will be performed from the perspective of the healthcare provider (base case), to estimate the cost effectiveness of long dialysis with respect to standard care in terms of cost per quality adjusted life year (QALY) gained. The total costs of providing standard and extended dialysis will be collected during the course of the trial, including all aspects of healthcare utilisation in the follow259
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Table 2 Secondary outcomes in the ACTIVE Dialysis Study 1) Survival and cardiovascular outcomes a) Cardiovascular structure b) Blood pressure
c) Requirement for blood pressure lowering
d) Clinical cardiovascular events
e) Survival 2) Quality of life and patient acceptability a) Quality of life
i) i) ii)
Change in left ventricular mass index from baseline to the end of the trial period Change in systolic blood pressure from baseline to end of the trial period† Change in systolic blood pressure from baseline to all follow-up visits occurring during the trial period† i) Change in number and dose of blood pressure lowering agents from baseline to the end of the trial period‡ ii) Change in number and dose of blood pressure lowering agents from baseline to all follow-up visits occurring during the trial period‡ iii) Change in the percentage of people on no blood pressure lowering medications at the end of the trial period iv) Change in the percentage of people on no blood pressure lowering medications at all follow-up visits during the trial period i) Time to the occurrence of a combined end-point consisting of new onset of documented acute myocardial infarction, stroke or death due to cardiovascular causes§ ii) Time to the occurrence of a combined end-point consisting of new onset of documented acute myocardial infarction, stroke, death due to cardiovascular causes and cardiovascular SAEs during the trial period i) Difference in survival between the two groups at 24, 36 and 60 months and when survival in the standard treatment arm reaches 25%§ i) ii) iii) iv) v)
b) Patient acceptability
i) ii)
iii) 3) Changes in biochemical and haematological markers a) Mineral metabolism
b) Erythropoiesis stimulating agent requirement
4) Safety outcomes a) Survival b) Serious adverse events (SAEs) 5) Vascular access
6) Hospitalizations
Change in quality of life from baseline to the follow-up visits occurring during the trial period as measured by the EQ-5D instrument Change in quality of life as measured by the SF-36 two composite scores (physical-health composite and mental-health composite) from baseline to the end of the trial period Change in quality of life as measured by the SF-36 two composite scores (physical-health composite and mental-health composite) from baseline to the follow-up visits occurring during the trial period Change in quality of life as measured by the individual eight domains of the SF-36 from baseline to the end of the trial period Change in quality of life as measured by the individual eight domains of the SF-36 from baseline to the follow-up visits occurring during the trial period Relative adherence assessed at the end of the trial period Relative adherence assessed at each of the trial period follow-up visits. (1) Full adherence at the end of the trial period (2) Full adherence at each of the follow-up visits Relative and full adherence at 24, 36 and 60 months§
Change in the percentage at optimal phosphate target defined as a phosphate < 1.5 mmol/L AND no use of phosphate binders at the follow-up visits occurring during the trial period. ii) Change in the number of phosphate binder tablets during the trial period iii) Number of patients on phosphate supplementation during the trial period¶ iv) Change in the dose of phosphate binders from baseline to the end of the trial period v) Number of patients on phosphate supplementation (oral or intravenous) at the end of the trial period¶. i) Change in the dose of erythropoiesis stimulating agents (ESA) during the trial period compared with baseline†† ii) Change in the dose of erythropoiesis stimulating agents (ESA) from baseline to the end of the trial period compared with baseline†† i)
i) i) i)
Survival measured using proportional hazards Comparison of SAEs by diagnostic group Time to first vascular access failure defined as thrombosis or fistula revision where revision is defined as a procedure that requires a new anastomosis ii) Time to first vascular access intervention or failure iii) Time to first vascular access infection iv) Number of reported access-related AEs. i) Number of reported hospitalizations from randomization to end of trial period ii) Total duration of hospitalizations from randomization to end of trial period
†Blood pressure is taken as the average of the 2nd and 3rd of three measurements taken after 5 min rest and measured immediately prior to a dialysis session. ‡Dose of blood pressure-lowering agents is defined in terms of the number of maximum BP-lowering medication dose equivalents’ calculated as described in the Statistical Analysis Plan (available at http://www.georgeinstitute.org/projects/active-dialysis-a-clinical-trial-of-intensive-dialysis). §Some outcomes will be assessed over the trial and the following cohort observational period. ¶Phosphate supplementation is defined as a medication/supplement administered with the primary goal of replacing phosphate. ††Further information on the conversion formula for ESAs is described in the Statistical Analysis Plan.
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ing broad categories: (i) provision of dialysis services; (ii) inpatient healthcare utilisation; (iii) out of hospital healthcare utilisation; and (iv) the financial household impact of dialysis treatment.
Ethics and oversight All participants provided informed consent. The study was approved by the Harbour Human Research Ethics Committee of Northern Sydney Central Coast Health, NSW, Australia (Ref: HREC/09/ HARBR/26) with each centre obtaining additional ethics approval in accordance with local practice. The study and all its related procedures are being performed in compliance with the Guidelines for Good Clinical Practice. The study is being overseen by an independent Data Safety Monitoring Board, which undertook regular review of predefined safety parameters and overall study conduct. Predefined safety parameters included total mortality and serious adverse effects without formal testing of a treatment effect.
All continuous secondary endpoints will be analysed using linear regression adjusted for baseline values. Change in left ventricular mass index on magnetic resonance imaging analysis will be restricted to the subgroup of participants with both baseline and 12 month measurements available. Secondary outcomes repeatedly measured over time will also be modelled using a linear mixed model. Treatment effect will be tested using their Wald type test P-value from the model. Binary repeated measurement will be analysed using logistic generalized estimating equations to take into account the correlation due the repeated measurement effect. Count secondary endpoints will be modelled using a negative binomial model. All time to event variables will be censored at the time of study completion if the event of interest has not been observed. Survival curves and estimated median survival time will be generated according to the Kaplan–Meier method and differences assessed using the Log-rank test. Recurrent secondary endpoints will be analysed using the Andersen and Gill approach that is a generalization of a Cox proportional hazard model.
RESULTS Power The total sample size of 200 was chosen to provide 90% power (with alpha = 0.05) to detect an absolute difference of 0.10 in the change in health-related quality of life (utility or QALY weights, measured on a scale of 0 to 1) over 12 months between the intervention and control groups. We assumed a mean EQ-5D score of 0.70 at baseline with no change in the standard dialysis group, an improvement of 0.10 in the extended dialysis group, and a common standard deviation of 0.22. These values underlying the assumptions were obtained from the Canadian study of long dialysis with a comparable patient population.14 Using these assumptions, ACTIVE is not powered to detect smaller differences in EQ-5D-measured quality of life with 82% power to detect a difference of 0.09 and 73% power to detect a difference of 0.08.
Statistics All analyses will be performed on an intention-to-treat basis and according to the detailed pre-specified statistical analysis plan. In brief, the primary outcome will be assessed using linear regression to test the effectiveness of extended dialysis over standard dialysis (control) adjusted for the baseline score. Our primary analysis will be conducted using a pragmatic single imputation performed as follows: (i) if the participant died during the 12 month trial period, the quality of life score allocated will be zero from the date of death, and (ii) if the patient reaches the end of the study trial period before 12 months (e.g. due to receipt of a renal transplant) or if the quality of life score at 12 month is missing, then the last available score will be used. To ensure our results are robust to the handling of missing data we will conduct two sensitivity analyses: the first one by excluding those who do not complete a 12 month quality of life assessment and the second one by using a repeated-measure model including all data available during the follow-up. The primary endpoint will also be assessed according to the following subgroups: (i) participant region (China vs Australia, New Zealand and Canada), (ii) participant dialysis location (home vs centre dialysis), and (iii) participant vintage on dialysis (less or equal to 6 months vs more than 6 months dialysis duration at baseline). © 2014 Asian Pacific Society of Nephrology
Nearly 1200 patients were screened to recruit 200 participants between 2009 and 2013 from Australia (29.0%), China (62.0%), Canada (5.5%) and New Zealand (3.5%) (Table 3). Some centres recruited participants from institution-based programmes only (27 centres, 69.5% of participants), others home-based patients only (11 centres, 19.0% of participants) with the remaining two sites having a mix of both (11.5% of participants with 5.0% being institution based and 6.5% home based). Sites recruited participants entirely from institution-based programmes in China and from home-based programmes in New Zealand. In Australia, 11.5% of participants were recruited from institution-based programmes and 17.5% from home-based programmes. The relative figures for recruitment in Canada were 1.0% and 4.5%. The institution-based programmes did not routinely offer extended dialysis hours outside the trial. The median number of participants per site was 4, with an interquartile range of 2–7. The baseline characteristics of study participants are shown in Table 3. The mean age at baseline was 52 years, 69.5% were male, and 37% had diabetes. At baseline, 33% had a history of cardiovascular disease including 18% with a history of ischaemic heart disease, 8% with a history of cerebrovascular disease and 8% with a history of peripheral vascular disease. At baseline, 88.5% were dialysing in an institutional setting and 11.5% were dialysing at home. Some of those dialysing in an institution were planning for home dialysis with 25.5% intending to dialysis at home during the study. Participants were dialysing a mean of 14 h per week (median 12 h) over median three sessions at baseline.
DISCUSSION The ACTIVE Dialysis Study has met its planned recruitment target, and all participants will have completed the 12 month 261
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Table 3 Baseline characteristics Characteristics
Age at randomization (years) Mean (SD) Median (Q1, Q3) Gender Male Female Primary cause of renal disease Diabetic nephropathy Hypertension/vascular nephrosclerosis Glomerulonephritis Reflux nephrology Polycystic kidney disease Other Unknown Comorbidity Diabetes mellitus Hypertension Any cardiovascular disease Symptomatic ischaemic heart disease Angina Acute myocardial infarction Previous coronary artery bypass graft/percutaneous transluminal coronary angioplasty Congestive heart failure Cerebrovascular disease Peripheral vascular disease Smoking status Never smoked Past cigarette smoker Current cigarette smoker Country Australia Canada China New Zealand Ethnicity Caucasian Aboriginal or Torres Strait Islander Maori Pacific Islander Asian Indian Other Not reported Number of dialysis sessions per week 2 3 4 or more Total number of hours on dialysis per week Mean (SD) Median (Q1, Q3) Dialysis site at enrolment Home Institution Intended dialysis site for study treatment Home Institution Dialysis session During the day Overnight Combination of both Dialysis access Native arteriovenous fistula Synthetic fistula Tunnelled dialysis catheter Other
262
Standard (n = 100)
Extended (n = 100)
Total (n = 100)
51.6 (11.50) 52.6 (45.2, 60.3)
52.1 (12.72) 53.2 (40.7, 62.6)
51.8 (12.10) 52.8 (42.0, 61.2)
70 (70.0%) 30 (30.0%)
69 (69.0%) 31 (31.0%)
139 (69.5%) 61 (30.5%)
34 (34.0%) 11 (11.0%) 34 (34.0%) 5 (5.0%) 7 (7.0%) 8 (8.0%) 1 (1.0%)
27 (27.0%) 11 (11.0%) 41 (41.0%) 3 (3.0%) 5 (5.0%) 10 (10.0%) 3 (3.0%)
61 (30.5%) 22 (11.0%) 75 (37.5%) 8 (4.0%) 12 (6.0%) 18 (9.0%) 4 (2.0%)
39 (39.0%) 85 (85.0%) 32 (32.0%) 18 (18.0%) 11 (11.0%) 2 (2.0%) 6 (6.0%) 13 (13.0%) 8 (8.0%) 8 (8.0%)
34 (34.0%) 82 (82.0%) 33 (33.0%) 18 (18.0%) 9 (9.0%) 2 (2.0%) 7 (7.0%) 19 (19.0%) 7 (7.0%) 6 (6.0%)
73 (36.5%) 167 (83.5%) 65 (32.5%) 36 (18.0%) 20 (10.0%) 4 (2.0%) 13 (6.5%) 32 (16.0%) 15 (7.5%) 14 (7.0%)
56 (56.0%) 23 (23.0%) 21 (21.0%)
60 (60.0%) 20 (20.0%) 20 (20.0%)
116 (58.0%) 43 (21.5%) 41 (20.5%)
28 (28.0%) 6 (6.0%) 62 (62.0%) 4 (4.0%)
30 (30.0%) 5 (5.0%) 62 (62.0%) 3 (3.0%)
58 (29.0%) 11 (5.5%) 124 (62.0%) 7 (3.5%)
24 (24.0%) 0 (0.0%) 3 (3.0%) 4 (4.0%) 66 (66.0%) 1 (1.0%) 2 (2.0%) 0 (0.0%)
23 (23.0%) 1 (1.0%) 3 (3.1%) 4 (4.0%) 65 (65.0%) 0 (0.0%) 2 (2.0%) 2 (2.0%)
47 (23.5%) 1 (0.5%) 6 (3.0%) 8 (4.0%) 131 (65.5%) 1 (0.5%) 4 (4.0%) 2 (1.0%)
1 (1.0%) 82 (82.0%) 17 (17.0%)
1 (1.0%) 86 (86.0%) 13 (13.0%)
2 (1.0%) 168 (84.0%) 30 (15.0%)
14.1 (2.8) 12.4 (12.0, 16.0)
13.6 (2.6) 12.0 (12.0, 15.0)
13.9 (2.7) 12.0 (12.0, 15.0)
12 (12.0%) 88 (88.0%)
11 (11.0%) 89 (89.0%)
23 (11.5%) 177 (88.5%)
25 (25%) 75 (75.0%)
26 (26%) 74 (74.0%)
51 (25.5%) 149 (74.5%)
94 (94.0%) 2 (2.0%) 4 (4.0%)
96 (96.0%) 3 (3.0%) 1 (1.0%)
190 (95.0%) 5 (2.5%) 5 (2.5%)
81 (81.0%) 4 (4.0%) 14 (14.0%) 1 (1.0%)
87 (87.0%) 3 (3.0%) 9 (9.0%) 1 (1.0%)
168 (84.0%) 7 (3.5%) 23 (11.5%) 2 (1.0%)
© 2014 Asian Pacific Society of Nephrology
ACTIVE Dialysis design and characteristics
Table 3 Continued Characteristics
Dialysis cannulation method The Buttonhole technique The Rope Ladder technique Dialysis Catheter Systolic blood pressure (mmHg) Mean (SD) Median (Q1, Q3) Diastolic blood pressure (mmHg) Mean (SD) Median (Q1, Q3) Quality of life measured using EQ-5D (score)
trial period during 2014. As with all randomized studies in this area,15 participant recruitment was difficult and required expansion to additional sites (40 rather than 10) across four countries to complete. As such, ACTIVE Dialysis is the largest randomized trial of extended hours dialysis, and the first multicentre trial of this intervention to successfully achieve its randomization goal. The range of geographies and dialysis settings involved in the trial will also enhance the generalizability of its findings to most dialysis environments around the world. Subgroup analyses by setting, region (Asia vs other), frequency and session duration will further allow exploration of the impact of these aspects on outcomes associated with extended hours dialysis. Overall, the ACTIVE cohort appears to have similarities with other extended dialysis randomized and cohort studies, with mean age between 50 and 55 and ESKD due to diabetic nephropathy in around one-third (Table 4). It is younger than the Australian and New Zealand general haemodialysis populations with less diabetic nephropathy than the New Zealand cohort although is broadly similar in age and cause of ESKD to the general Beijing haemodialysis population. More people in the ACTIVE study were dialysing with an arteriovenous fistula than the other extended dialysis randomized studies that appeared to reflect higher background rates of arteriovenous fistula access in the Australian and Beijing haemodialysis populations. The most compelling primary outcome for a trial of extended hours dialysis would be patient survival, but a trial of this outcome would require thousands of participants. Although there are at least hundreds, and probably thousands, of patients being treated with extended hours dialysis around the world,11 a trial of this size does not currently appear feasible without a substantial change in patient and physician willingness to support the generation of clinical trial evidence before embracing treatment approaches. Similar issues of practice uptake prior to trial demonstration of benefit have arisen with renal denervation for resistant hypertension, where thousands of people around the world were treated based on one small trial, prior to a larger, sham-controlled trial casting doubt on the efficacy of the © 2014 Asian Pacific Society of Nephrology
Standard (n = 100)
Extended (n = 100)
Total (n = 100)
14 (14.0%) 71 (71.0%) 15 (15.0%)
22 (22.0%) 68 (68.0%) 10 (10.0%)
36 (18.0%) 139 (69.5%) 25 (12.5%)
139 (21.0) 138 (126, 156)
141 (20.7) 140 (130, 156)
140 (20.8) 139 (128, 156)
79 (13.6) 80 (70, 88) 0.76 (0.25)
81 (13.9) 81 (73, 90) 0.79 (0.23)
80 (13.8) 80 (71, 89) 0.78 (0.24)
procedure.23 As a community, we must resist the lure of exciting new therapies until the benefits and risks have been clearly assessed in appropriately designed and powered randomized trials. In this light, a strength of the current trial is the plan to prospectively collect longitudinal outcome data for at least 5 years. Although it is expected that treatment drop-out and drop-in rates may be high soon after completion of the 12 month treatment period, this will allow assessment of the legacy effects of the ACTIVE study treatments. The importance of quality of life, as well as quantity, is regularly identified by consumer and patient groups as being similar or even greater to that of survival.24 As such, quality of life is an appropriate and important primary outcome for this trial and would represent a compelling reason for changes in practice if a beneficial effect is demonstrated, contingent upon the findings of the planned economic evaluation. A range of quality of life instruments have been used to assess quality of life in people with kidney disease.25 The EQ-5D instrument was selected for the ACTIVE Dialysis trial for a number of reasons. Firstly, it provides quality of life years that can be employed in cost utility analyses in the event of demonstration of benefit. Secondly, it allowed comparison with the Alberta trial that was the only published trial of extended weekly dialysis hours in maintenance hemodialysis at the time ACTIVE was designed. The ACTIVE Dialysis Study has successfully recruited the largest randomized study cohort to examine the effect of increasing haemodialysis weekly hours upon changes in quality of life. The study population represents a range of haemodialysis settings globally so the findings will be generalizable and represent a major contribution to our understanding of the benefits and harms of extended weekly dialysis hours therapy.
ACKNOWLEDGEMENTS We gratefully acknowledge the contribution of the ACTIVE Dialysis Investigators and Study Co-ordinators, the project 263
264
Male gender Diabetic nephropathy Hypertension/vascular nephrosclerosis Glomerulonephritis Diabetes mellitus Ischaemic heart disease Acute myocardial infarction Congestive heart failure Cerebrovascular disease Peripheral vascular disease Australia New Zealand Canada USA/Canada China United States France Caucasian Asian Aboriginal or Torres Strait Islander Maori Pacific Islander Black Native arteriovenous fistula Synthetic fistula Tunnelled dialysis catheter Non-tunnelled dialysis catheter Unknown 17.6% 25.5%
3.5% 11.5% 1.0%
56.9%
86.3%
84.0%
3.0% 4.0%
23.5% 65.5% 0.5%
62.0%
100%
21.6% 15.7% 15.7%
16.0% 7.5% 7.0% 29.0% 3.5% 5.5%
25.5% 41.2% 39.2% –
37.5% 36.5% 18.0% 2.0%
7% 47%
26.4% 45%
55.2% 13.8%
100%
13.8% 2.3% 17.2%
35.6% 42.5% – 10.3%
52.8 (mean) 66.5% 34.5% 8.0%
87 –
FHN Nocturnal15,20
18% 19%
41.6% 63%
36.3% 6.5%
100%
20.0% 7.3% 10.2%
19.2% 40.8% – 11.0%
50.4 (mean) 61.6% 34.3% 20.8%
245 –
FHN Daily16,20
∼6% 2–3%
92%
90%
100%
– – –
38% 24% – –
52 (median) 77% 12% –
Australian extended hours cohort7 286 – –
16.9%
5.5% 21.7%§§
56.0%
11.9% 14.8% 77.4%
73.3%
13.1% 5.0% 10.7%
– 24.0% – 11.4%
49.6 (mean) 71.7 – –
420
International Quotidian Registry11
Cohorts practising extended hours
1.0% 3.6%
77.2% 7.5% 8.8%
100%
– 11.6% 23.7%‡‡
37.9% 30.5% 38.6%‡‡ –
55–64 (mode) 58.6% 18.7% 8.8%
1048 9.2%
Australian 201221
27.7% 17.9%
50.1% 4.1% 0.0%
100%
– 9.2% 18.8%‡‡
38.8% 34.3% 36.0%‡‡ –
45–54 (mode)§ 67.8% 28.6% 6.6%
469 19.0%
New Zealand 201221
Registry home haemodialysis cohorts
1%
7% 13%
78%
0.9% 2.5%
72.2% 8.4% 13.9%
100%
– 21.2% 35.4%‡‡
25.2% 47.8% 53.4%‡‡ –
62 (median) 59.8% 34.2% 12.5%
9219‡ 80.5%
Australia 201221
3%
4% 20%
73%
31.4% 28.9%
32.1% 7.0% 0.0%
100%
– 15.4% 24.5%‡‡
26.9% 52.7% 42.3%‡‡ –
58 (median) 61.2% 45% 6.8%
1697‡ 68.7%
New Zealand 201221
0.9%†† 81.1%††,§§
15.8%††
100%
– – –
13.7% 53.6%†† – –
45–64 (mode range)§ 59.3% 35.6% 16.3%
19 638 82.5%
Canada 201222
Registry haemodialysis cohorts
27.0%††
7.5%††
62.5%††
100%
– – –
34.1% – – –
59.2 (mean)¶ 52.9%¶ 27.9% 14.2%
10 072 –
Beijing 20103
†Proportion of relevant national prevalent dialysis cohort listed for Australia, New Zealand and Canada. ‡Numbers for haemodialysis patients include both institution-based and home-based patients. §Data reported in age ranges. The modal range is listed here. ¶Unpublished communication, Prof Zuo Li, President, Blood Purification Center Management Branch of Chinese Hospital Association. ††Figures for incident haemodialysis patients listed as prevalent figures not available in the published report. ‡‡Known or suspected disease. §§Catheter type (tunnelled or non-tunnelled) not specified.
Dialysis access
Ethnicity
Country
Cause end-stage kidney disease Comorbidities
Demography
52 – 54.1 (mean) 62.7% 29.4% 7.8%
200 –
n Proportion of total dialysis population† Age in years
Alberta trial14
51.8 (mean) 69.5% 30.5% 11.0%
ACTIVE Dialysis
Study
Report
Randomized trials of extended hours
Table 4 Comparative characteristics at entry into randomized trials of extended hours, cohorts practising extended haemodialysis hours, home haemodialysis cohorts and general prevalent haemodialysis populations
MJ Jardine et al.
© 2014 Asian Pacific Society of Nephrology
ACTIVE Dialysis design and characteristics
coordinating central team and the MRI centres (listed in Appendix S1), and most particularly the study participants. Meg Jardine is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia and the National Heart Foundation. Alan Cass is supported by a NHMRC Senior Research Fellowship. Vlado Perkovic is supported by a New South Wales Cardiovascular Research Network Fellowship.
FUNDING This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Project Grant [ID:571045] and a Baxter Clinical Evidence Council Investigator Initiated Research Grant [2012]. Additional support came from an unrestricted grant from Baxter International Inc. with funding for the vanguard phase from an NHMRC Program Grant (358395). The funding sources had no role in the design of this study nor its execution and will not have any role during its analyses, interpretation of the data, or decision to submit results for publication.
11.
12. 13.
14.
15.
16.
17.
18.
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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1 ACTIVE Dialysis Study Group. Appendix S2 Routine Monitoring of ACTIVE Dialysis Participants. Appendix S3 Suggested aseptic procedure for patients using button hole cannulation.
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