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2	Background and Context Dennis Cotter President of Medical Technology and Practice Patterns Institute (MTPPI) 4733 Bethesda Avenue #510 Bethesda, MD 20814
3	Decade-long study of EPO Identified Medicare and non-Medicare use of EPO Quantified total EPO use among dialysis patients Currently, PI on R01 grant focusing on the role of EPO dosing and patient outcomes
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5	Widespread EPO use based on 2000 DOQI findings including:
6	However, survival findings might have been confounded by EPO treatment itself
7	Application of causal modeling techniques Received R01 grant (5R01DK066011-02 Epoetin Therapy and Survival of Hemodialysis Patients) to examine the role of EPO treatment in patient outcomes
8	Introduction to Causal Modeling Miguel Hernán Associate Professor of Epidemiology Department of Epidemiology Harvard School of Public Health 677 Huntington Avenue Boston, MA 02115
9	Goal
10	Problem with observational studies
11	Actually, there are 2 problems
12	Problem 1 Unmeasured confounding
13	Problem 2 Inappropriately adjusting for confounding
14	IPW: Utility
15	IPW: Technical details
16	IPW: Examples of application
17	IPW: Our application
18	Research Findings Yi Zhang Senior Analyst MTPPI
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25	Study variables Censoring events change of dialysis modality, transplantation, 30 days after change of dialysis provider, gap in outpatient dialysis services, or death Exposure: Average EPO dose in the first 3 months of dialysis Outcome: HCT at month 4
26	Statistical methods Estimated inverse probability weights to adjust for measured confounders, and then fit a weighted regression model Constructed a dose-response curve Each hematocrit-EPO dose point in the curve shows the estimated average hematocrit if subjects had been randomly assigned to that EPO dose 95% CI were based on bootstrap techniques
27	Distribution of patients by initial EPO doses
28	Distribution of patients by hematocrit group
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30	Dose response curve based on standard adjustment
31	Study limitations Potential for unmeasured confounding Monthly HCT and EPO dose Unobserved clinical factors (iron level, blood pressure, nutritional status...) EPO use in the hospital, route of EPO administration Did not consider dynamic EPO dosing regimes Restriction of study period and population
32	Conclusions Dose-response curve is S-shaped HCT plateaus at 38.5% for average EPO doses greater than 20,000 units/week Normal HCT target might not be achievable for dialysis population Starting doses recommended by FDA are appropriate and are in the linear portion of the curve
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35	Previous research A plethora of observational studies have shown that higher hematocrit is associated with better survival for dialysis patients However, results of clinical trials demonstrated that patients targeted to higher hematocrit levels did not show survival benefits led to a recent FDA black box warning The EPO dose-survival relationship has not been empirically determined
36	Study design 20,580 incident hemodialysis patients Eligibility criteria Age 65 and older First ESRD service in 2003 Attend freestanding facilities Complete baseline (first 3 months of dialysis) data Exposure: cumulative average EPO dose Outcome: death during months 4-12 Censored if change of provider/modality, or loss to follow-up
37	Methods Estimated inverse probability weights to adjust for measured confounders, and then fit a weighted Cox model Constructed survival curves for each EPO dose Each curve shows the survival if subjects had been randomly assigned to that EPO dose 95% CI were based on bootstrap techniques
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41	Study limitations Potential for unmeasured confounding as always Did not consider dynamic EPO dosing regimes One-year survival only
42	"Lowest mortality found for average..." Lowest mortality found for average EPO doses of 8,500-15,000 units per week Treating all patients with higher EPO doses (>15,000 U/wk) might decrease average survival
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