The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: the example of renal transplantation in hemodialysis trials.
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.



Using individual patient data from the Estudio de Supervivencia de Hemodiafiltración 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.



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.



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.
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
C Marijn
CM
Hazelbag
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.|George Institute for Global Health, University of Oxford, Oxford, UK.
Sanne A E
SAE
Peters
Department of Nephrology, University Medical Center Utrecht, Utrecht, The Netherlands.
Peter J
PJ
Blankestijn
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
Michiel L
ML
Bots
Nephrology, Dialysis and Intensive Care Unit, CHRU, Montpellier, France.|Dialysis Research and Training Institute, Montpellier, France.
Bernard
B
Canaud
University College London, Centre for Nephrology, Royal Free Hospital, London, UK.
Andrew
A
Davenport
Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Muriel P C
MPC
Grooteman
Division of Nephrology, Ege University School of Medicine, Izmir, Turkey.
Fatih
F
Kircelli
Department of Nephrology, Alessandro Manzoni Hospital, Lecco, Italy.
Francesco
F
Locatelli
Nephrology Department, Hospital Clinic, Barcelona, Spain.
Francisco
F
Maduell
Dialysis Research and Training Institute, Montpellier, France.|Biochemistry and Hormonology Department Laboratory, CHRU, Montpellier, France; PhyMedExp, University of Montpellier, ISERM U1046, CNRS UMR 9214, Montpellier, France.
Marion
M
Morena
Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
Menso J
MJ
Nubé
Division of Nephrology, Ege University School of Medicine, Izmir, Turkey.
Ercan
E
Ok
Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.|Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona, Spain.
Ferran
F
Torres
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
Arno W
AW
Hoes
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
Rolf H H
RHH
Groenwold
D000368:Aged; D002423:Cause of Death; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D007676:Kidney Failure, Chronic / Q000628:therapy*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009026:Mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D006435:Renal Dialysis; D012107:Research Design
end-stage renal disease; hemodiafiltration; randomized controlled trial; renal transplantation; time-varying exposure