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Powerpoint presentation of a talk I gave in World Congress of Nephrology 2009 in Milan about subdistribution hazard regression models as a method of analyzing ESRD clinical trials in the setting of ...

Powerpoint presentation of a talk I gave in World Congress of Nephrology 2009 in Milan about subdistribution hazard regression models as a method of analyzing ESRD clinical trials in the setting of informative censoring (due to transplantation or drop-out).

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    Transplantation, Drop Out And Analysis Of Outcomes In Transplantation, Drop Out And Analysis Of Outcomes In Presentation Transcript

    • TRANSPLANTATION, DROP-OUT AND ANALYSIS OF OUTCOMES IN THE HEMO TRIAL Christos Argyropoulos MD, PhD Renal and Electrolyte Division University of PittsburghWorld Congress of Nephrology 2009 Milan, Italy, May 22nd – 26th
    • Financial DisclosureThis research was supported by the Renal Discoveries – Baxter Extramural Grant Program 2007.World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Features of Clinical Studies in ESRDClinical Studies (randomized clinical trials/observational cohorts) in ESRD are complicated by high rates of early treatment termination:1. Transplantation2. Modality Switches3. Changes in living situations that interfere with delivery of treatment (e.g. change in residence)World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Complications of Early TreatmentTermination1. Incomplete Follow Up of Survival Time2. Difficulty in proportioning “benefit” and “harm” between the time spent receiving a treatment and the time spent off treatment3. When survival is an outcome, the specific answer to question 2 can dramatically influence the clinical question the statistics answer.World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Solutions and Pitfalls1. Per-Protocol (PP) : censor individuals at the time they prematurely end their treatment • ↑ chance of false positive associations2. “Intent-To-Treat” (ITT) : censor individuals ONLY if they are alive at the planned termination date of the study: • ↑ chance of false negatives associationsIn Nephrology the most common interpretation of theITT leads to censoring of transplants but not drop-outs at the time these events occurWorld Congress of Nephrology 2009, Milan, May 22nd-26th
    • Solutions from Competing Outcomes• Premature Study Termination is analogous to risk analysis in the presence of competing outcomes• Methods for competing outcomes work by estimating simultaneously the cumulative incidence of these competing outcomes and the factors that affect them.• Informally such methods construct and analyze “multiple” Kaplan Meier curves one for each competing outcome in the study.World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Solutions from Competing Outcomes• In studies of survival in ESRD one can attempt to use such methods to simultaneously adjust for the following (potentially informative) causes of early treatment termination :1. Transplantation2. Patient withdrawal from the studyWorld Congress of Nephrology 2009, Milan, May 22nd-26th
    • Case Study: HEMO trial• NIH sponsored 2 x 2 randomized clinical trial of dialysis dose (Kt/V of 1.4 vs 1.6) and flux (“high” vs “low”) with all cause mortality as a primary outcome• Study run from May 10th 1995 until December 21st 2001 in 15 academic centers across the United States• Enrolled 1846 prevalent dialysis patients with minimal residual renal function• Primary analysis of HEMO: higher Kt/V targets or high flux dialysis do not lead to a reduced all cause mortality.World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Statistical methodology1. ITT: Adjusted Proportional Hazard Model for all cause mortality by Flux and Kt/V interventions censoring transplants.2. PP: Adjusted Proportional Hazard Model for all cause mortality by Flux and Kt/V interventions censoring drop-outs and transplants.3. CI: Adjusted Proportional (sub-distribution) Hazard model for 3 mutually exclusively outcomes: • Death while receiving Treatment • Terminate Treatment while receiving Treatment (Drop-Out) • Receive a Transplant while receiving Treatment (Transplantation) Patients alive at the end of the study are censored by all three approaches (administrative censoring) World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Classification of Survival Times ITT PP CIDeaths 871 792 792Censored 875 1054 666Transplants - - 194Drop-Outs* - - 194* Reasons: Change in residence: 84/194, modalityswitch 39/194 World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Probability of Death : ITT & PPWorld Congress of Nephrology 2009, Milan, May 22nd-26th
    • Cumulative Incidence of Death, Transplantation and Drop OutWorld Congress of Nephrology 2009, Milan, May 22nd-26th
    • Adjusted Analyses ITT PP CI HR 95% CI p HR 95% CI p HR 95% CI pHigh Flux vs. Low Flux 0.91 0.79-1.04 0.15 0.89 0.78-1.0 0.12 0.86 0.75-0.99 0.04High Kt/V vs. StandardKt/V 0.94 0.82-1.08 0.41 0.93 0.81-1.1 0.32 0.93 0.81-1.07 0.28Age (per decade) 1.4 1.32-1.49 * 1.37 1.28-1.5 * 1.48 1.38-1.58 *Females vs. Males 0.84 0.73-0.97 0.02 0.86 0.74-1.0 0.05 0.84 0.72-0.97 0.02NonBlack vs. Black 1.27 1.08-1.50 ‡ 1.31 1.11-1.6 ‡ 1.28 1.10-1.50 ‡Diabetics vs.Non-Diabetics 1.27 1.09-1.47 ‡ 1.26 1.08-1.5 ‡ 1.25 1.07-1.46 ‡ICED 1.37 1.25-1.49 * 1.35 1.23-1.5 * 1.35 1.24-1.48 *Duration of ESRD 1.04 1.02-1.05 * 1.04 1.02-1.1 * 1.04 1.02-1.06 *Albumin (per 0.5 g/dLincrease) 0.63 0.57-0.70 * 0.63 0.56-0.7 * 0.64 0.57-0.72 * ‡p-value<0.01,* p-value<0.001; ICED, Index of Co-Existent Diseases World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Transplantation & Drop Outs Drop out: Transplantation: HR 95% CI pThe only statistically significant Age (per decade) 0.64 0.58-0.69 *predictor was age with a HR of0.81 (95% CI 0.73-0.89, p<0.001) Females vs. Males 1.34 1.00-1.78 0.05per decade. Non Black vs. Black 1.37 1.03-1.83 0.03 ICED 0.74 0.61-0.90 0.003 Duration of ESRD 0.93 0.90-0.97 0.001 Albumin (per 0.5 g/dL increase) 1.40 1.15-1.71 0.001 (Older people were more (Younger, white, female patients, with likely to stay on the study fewer comorbidities, higher albumin protocol than younger people) and shorter duration of ESRD were more likely to receive a transplant) p-value<0.001; ICED, Index of Co-Existent Diseases World Congress of Nephrology 2009, Milan, May 22nd-26th
    • Conclusions1. Patient drop-out and transplantation may be potentially informative censoring events in ESRD trials.2. Simultaneous consideration of such informative censoring events may support different conclusions, compared to PP and ITT analyses.3. In HEMO, predictors of survival differed from predictors of causes of early treatment termination4. Recently described statistical methods may facilitate a better understanding of complex clinical trials in ESRD World Congress of Nephrology 2009, Milan, May 22nd-26th
    • References1. Lagakos SW, Lim LL, Robins JM. Adjusting for early treatment termination in comparative clinical trials. Stat Med. 1990 Dec;9(12):1417-242. Eknoyan G et al,; Hemodialysis(HEMO) Study Group, Effect of dialysis dose and membrane flux in maintenance hemodialysis, N Engl J Med, 2002 Dec 19;347(25):2010-93. Jaar B et al. Comparing the risk for death with peritoneal dialysis and hemodialysis in a national cohort of patients with chronic kidney disease. Ann Intern Med. 2005 Aug 2;143(3):174-834. Locatelli F et al. ; Membrane Permeability Outcome (MPO) Study Group. Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol. 2009 Mar;20(3):645-54.5. Kalbfleisch, J.D. and Prentice R.L. The statistical analysis of failure time data, p248-9, Wiley 20026. Fine J and Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association (1999) 94:496–509 World Congress of Nephrology 2009, Milan, May 22nd-26th
    • AcknowledgementsRenal and Electrolyte Division,Department of MedicineMark Unruh MD, MSMaria Eleni Roumelioti MDDepartment of Biostatistics, Graduate School of Public HealthLisa Weissfeld, PhDAbdus Sattar, MSDepartment of Critical Care MedicineJohn A. Kellum, MD, FACP FACCM World Congress of Nephrology 2009, Milan, May 22nd-26th