PMID- 28339826 OWN - NLM STAT- MEDLINE DCOM- 20171025 LR - 20181202 IS - 1460-2385 (Electronic) IS - 0931-0509 (Linking) VI - 32 IP - suppl_2 DP - 2017 Apr 1 TI - The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: the example of renal transplantation in hemodialysis trials. PG - ii31-ii39 LID - 10.1093/ndt/gfw458 [doi] AB - BACKGROUND: During the follow-up in a randomized controlled trial (RCT), participants may receive additional (non-randomly allocated) treatment that affects the outcome. Typically such additional treatment is not taken into account in evaluation of the results. Two pivotal trials of the effects of hemodiafiltration (HDF) versus hemodialysis (HD) on mortality in patients with end-stage renal disease reported differing results. We set out to evaluate to what extent methods to take other treatments (i.e. renal transplantation) into account may explain the difference in findings between RCTs. This is illustrated using a clinical example of two RCTs estimating the effect of HDF versus HD on mortality. METHODS: Using individual patient data from the Estudio de Supervivencia de Hemodiafiltracion On-Line (ESHOL; n = 902) and The Dutch CONvective TRAnsport STudy (CONTRAST; n = 714) trials, five methods for estimating the effect of HDF versus HD on all-cause mortality were compared: intention-to-treat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PP excl ; exclusion of patients who receive transplantation), PP cens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TA ext ) with additional adjustment for variables related to both the risk of receiving a transplant and the risk of an outcome (transplantation-outcome confounders). Cox proportional hazards models were applied. RESULTS: Unadjusted ITT analysis of all-cause mortality led to differing results between CONTRAST and ESHOL: hazard ratio (HR) 0.95 (95% CI 0.75-1.20) and HR 0.76 (95% CI 0.59-0.97), respectively; difference between 5 and 24% risk reductions. Similar differences between the two trials were observed for the other unadjusted analytical methods (PP cens, PP excl , TA) The HRs of HDF versus HD treatment became more similar after adding transplantation as a time-varying covariate and including transplantation-outcome confounders: HR 0.89 (95% CI 0.69-1.13) in CONTRAST and HR 0.80 (95% CI 0.62-1.02) in ESHOL. CONCLUSIONS: The apparent differences in estimated treatment effects between two dialysis trials were to a large extent attributable to differences in applied methodology for taking renal transplantation into account in their final analyses. Our results exemplify the necessity of careful consideration of the treatment effect of interest when estimating the therapeutic effect in RCTs in which participants may receive additional treatments. CI - (c) The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. FAU - Hazelbag, C Marijn AU - Hazelbag CM AD - Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands. FAU - Peters, Sanne A E AU - Peters SAE AD - Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands. AD - George Institute for Global Health, University of Oxford, Oxford, UK. FAU - Blankestijn, Peter J AU - Blankestijn PJ AD - Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands. FAU - Bots, Michiel L AU - Bots ML AD - Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands. FAU - Canaud, Bernard AU - Canaud B AD - Nephrology, Dialysis and Intensive Care Unit, CHRU, Montpellier, France. AD - Dialysis Research and Training Institute, Montpellier, France. FAU - Davenport, Andrew AU - Davenport A AD - University College London, Centre for Nephrology, Royal Free Hospital, London, UK. FAU - Grooteman, Muriel P C AU - Grooteman MPC AD - Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Kircelli, Fatih AU - Kircelli F AD - Division of Nephrology, Ege University School of Medicine, Izmir, Turkey. FAU - Locatelli, Francesco AU - Locatelli F AD - Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy. FAU - Maduell, Francisco AU - Maduell F AD - Nephrology Department, Hospital Clinic, Barcelona, Spain. FAU - Morena, Marion AU - Morena M AD - Dialysis Research and Training Institute, Montpellier, France. AD - Biochemistry and Hormonology Department Laboratory, CHRU, Montpellier, France; PhyMedExp, University of Montpellier, ISERM U1046, CNRS UMR 9214, Montpellier, France. FAU - Nube, Menso J AU - Nube MJ AD - Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands. FAU - Ok, Ercan AU - Ok E AD - Division of Nephrology, Ege University School of Medicine, Izmir, Turkey. FAU - Torres, Ferran AU - Torres F AD - Biostatistics Unit, School of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain. AD - Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona, Spain. FAU - Hoes, Arno W AU - Hoes AW AD - Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands. FAU - Groenwold, Rolf H H AU - Groenwold RHH AD - Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands. CN - HDF Pooling Project investigators LA - eng PT - Journal Article PL - England TA - Nephrol Dial Transplant JT - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association JID - 8706402 SB - IM MH - Aged MH - Cause of Death MH - Female MH - Humans MH - Intention to Treat Analysis MH - Kidney Failure, Chronic/*therapy MH - *Kidney Transplantation MH - Male MH - Middle Aged MH - *Mortality MH - Prognosis MH - Proportional Hazards Models MH - Randomized Controlled Trials as Topic MH - *Renal Dialysis MH - *Research Design OTO - NOTNLM OT - end-stage renal disease OT - hemodiafiltration OT - randomized controlled trial OT - renal transplantation OT - time-varying exposure EDAT- 2017/03/25 06:00 MHDA- 2017/10/27 06:00 CRDT- 2017/03/25 06:00 PHST- 2016/05/31 00:00 [received] PHST- 2016/12/20 00:00 [accepted] PHST- 2017/03/25 06:00 [pubmed] PHST- 2017/10/27 06:00 [medline] PHST- 2017/03/25 06:00 [entrez] AID - 3056568 [pii] AID - 10.1093/ndt/gfw458 [doi] PST - ppublish SO - Nephrol Dial Transplant. 2017 Apr 1;32(suppl_2):ii31-ii39. doi: 10.1093/ndt/gfw458.