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

C. Marijn Hazelbag, Sanne A.E. Peters, Peter J. Blankestijn, Michiel L. Bots, Bernard Canaud, Andrew Davenport, Muriel P.C. Grooteman, Fatih Kircelli, Francesco Locatelli, Francisco Maduell, Marion Morena, Menso J. NubÉ, Ercan Ok, Ferran Torres, Arno W. Hoes, Rolf H.H. Groenwold

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 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-totreat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PPexcl; exclusion of patients who receive transplantation), PPcens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TAext) 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 hazardsmodels 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 (PPcens, PPexcl, 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 participantsmay receive additional treatments.

Original languageEnglish
Pages (from-to)ii31-ii39
JournalNephrology Dialysis Transplantation
Volume32
DOIs
Publication statusPublished - 1 Apr 2017

Cite this

Hazelbag, C. Marijn ; Peters, Sanne A.E. ; Blankestijn, Peter J. ; Bots, Michiel L. ; Canaud, Bernard ; Davenport, Andrew ; Grooteman, Muriel P.C. ; Kircelli, Fatih ; Locatelli, Francesco ; Maduell, Francisco ; Morena, Marion ; NubÉ, Menso J. ; Ok, Ercan ; Torres, Ferran ; Hoes, Arno W. ; Groenwold, Rolf H.H. / The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials : The example of renal transplantation in hemodialysis trials. In: Nephrology Dialysis Transplantation. 2017 ; Vol. 32. pp. ii31-ii39.
@article{ba5ad992cc2b48e8a663b3ac0e026348,
title = "The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: The example of renal transplantation in hemodialysis trials",
abstract = "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 Hemodiafiltraci{\'o}n 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-totreat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PPexcl; exclusion of patients who receive transplantation), PPcens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TAext) 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 hazardsmodels 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 (PPcens, PPexcl, 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 participantsmay receive additional treatments.",
keywords = "End-stage renal disease, Hemodiafiltration, Randomized controlled trial, Renal transplantation, Time-varying exposure",
author = "Hazelbag, {C. Marijn} and Peters, {Sanne A.E.} and Blankestijn, {Peter J.} and Bots, {Michiel L.} and Bernard Canaud and Andrew Davenport and Grooteman, {Muriel P.C.} and Fatih Kircelli and Francesco Locatelli and Francisco Maduell and Marion Morena and Nub{\'E}, {Menso J.} and Ercan Ok and Ferran Torres and Hoes, {Arno W.} and Groenwold, {Rolf H.H.}",
year = "2017",
month = "4",
day = "1",
doi = "10.1093/ndt/gfw458",
language = "English",
volume = "32",
pages = "ii31--ii39",
journal = "Nephrology, Dialysis, Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press",

}

Hazelbag, CM, Peters, SAE, Blankestijn, PJ, Bots, ML, Canaud, B, Davenport, A, Grooteman, MPC, Kircelli, F, Locatelli, F, Maduell, F, Morena, M, NubÉ, MJ, Ok, E, Torres, F, Hoes, AW & Groenwold, RHH 2017, 'The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials: The example of renal transplantation in hemodialysis trials' Nephrology Dialysis Transplantation, vol. 32, pp. ii31-ii39. https://doi.org/10.1093/ndt/gfw458

The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials : The example of renal transplantation in hemodialysis trials. / Hazelbag, C. Marijn; Peters, Sanne A.E.; Blankestijn, Peter J.; Bots, Michiel L.; Canaud, Bernard; Davenport, Andrew; Grooteman, Muriel P.C.; Kircelli, Fatih; Locatelli, Francesco; Maduell, Francisco; Morena, Marion; NubÉ, Menso J.; Ok, Ercan; Torres, Ferran; Hoes, Arno W.; Groenwold, Rolf H.H.

In: Nephrology Dialysis Transplantation, Vol. 32, 01.04.2017, p. ii31-ii39.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - The importance of considering competing treatment affecting prognosis in the evaluation of therapy in trials

T2 - The example of renal transplantation in hemodialysis trials

AU - Hazelbag, C. Marijn

AU - Peters, Sanne A.E.

AU - Blankestijn, Peter J.

AU - Bots, Michiel L.

AU - Canaud, Bernard

AU - Davenport, Andrew

AU - Grooteman, Muriel P.C.

AU - Kircelli, Fatih

AU - Locatelli, Francesco

AU - Maduell, Francisco

AU - Morena, Marion

AU - NubÉ, Menso J.

AU - Ok, Ercan

AU - Torres, Ferran

AU - Hoes, Arno W.

AU - Groenwold, Rolf H.H.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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 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-totreat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PPexcl; exclusion of patients who receive transplantation), PPcens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TAext) 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 hazardsmodels 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 (PPcens, PPexcl, 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 participantsmay receive additional treatments.

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 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-totreat (ITT) analysis (i.e. not taking renal transplantation into account), per protocol exclusion (PPexcl; exclusion of patients who receive transplantation), PPcens (censoring patients at the time of transplantation), transplantation-adjusted (TA) analysis and an extension of the TA analysis (TAext) 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 hazardsmodels 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 (PPcens, PPexcl, 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 participantsmay receive additional treatments.

KW - End-stage renal disease

KW - Hemodiafiltration

KW - Randomized controlled trial

KW - Renal transplantation

KW - Time-varying exposure

UR - http://www.scopus.com/inward/record.url?scp=85019067700&partnerID=8YFLogxK

U2 - 10.1093/ndt/gfw458

DO - 10.1093/ndt/gfw458

M3 - Article

VL - 32

SP - ii31-ii39

JO - Nephrology, Dialysis, Transplantation

JF - Nephrology, Dialysis, Transplantation

SN - 0931-0509

ER -