1. MTPPI EPO Outcomes Research
Presented to FDA /CDER
Joint Meeting of the Cardiovascular and Renal Drugs & Drug Safety and Risk Management Advisory Committees
September 11, 2007
Hilton Washington
Gaithersburg, MD

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

4. Hemoglobin values have increased steadily after EPO introduced
Today, nearly all dialysis patients receive EPO therapy
Source: USRDS 2006 Annual Data Report

5. Widespread EPO use based on 2000 DOQI findings including:
Survival benefits
Decreased incidence of hospitalization
Partial regression of left ventricular hypertrophy (LVH)
Improved quality of life
Increased exercise capacity

6. However, survival findings might have been confounded by EPO treatment itself

7. Application of causal modeling techniques
Received R01 grant (5R01DK 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
To estimate the effect of EPO on hematocrit and survival among renal failure patients with anemia
A RCT would be ideal
Next best thing is an observational study that mimics an RCT

10. Problem with observational studies
Patients with worse prognosis tend to receive higher EPO doses (confounding by indication)
Not a problem in ITT analyses of RCTs

11. Actually, there are 2 problems
1. Confounding may be unmeasured
2. Confounding may be measured but inappropriately adjusted for

12. Problem 1 Unmeasured confounding
THE fundamental problem
Need measurements of all important prognosis factors that are also indications for treatment but can never prove you have all confounders
We used monthly hematocrit, hospitalization, prior EPO dose, iron use, blood transfusions, dialysis sessions, urea reduction ratio; and baseline age at ESRD onset, race, gender, initial EPO dose per administration, underlying cause of ESRD, pre-dialysis hematocrit, presence of cardiovascular and noncardiovascular co- morbidities, geographic region, dialysis chain membership, hypertension, body mass index, GFR, and serum creatinine

13. Problem 2 Inappropriately adjusting for confounding
Conventional statistical methods cannot appropriately adjust for confounding
When the prognosis factors (e.g., hematocrit) that affect treatment decisions (e.g., EPO dose) are themselves affected by prior treatment decisions
A solvable problem: just use inverse probability weighting (IPW)

14. IPW: Utility Can be used to mimic an RCT using observational data
Under the assumption of no unmeasured confounding
Even in the presence of time-varying confounders affected by prior treatment

15. IPW: Technical details
Each subject is weighted by the inverse of the estimated probability of receiving the EPO dose that he actually received
Essentially equivalent to standardization
The corresponding weighted models estimate the parameters of marginal structural models

16. IPW: Examples of application
IPW extensively used in HIV/AIDS research
In fact, NIH required expertise on IPW when requesting applications for estimating the effects of antiretrovirals from observational data
IPW replicated estimates from RCTs in the HIV/AIDS field

17. IPW: Our application
We used IPW to estimate the survival and mean hematocrit of subjects randomly assigned to different EPO doses
We needed IPW because hematocrit is a time-dependent confounder (predicts both EPO dose and outcome) and is affected by prior EPO dose

18. Yi Zhang Senior Analyst MTPPI
Research Findings
Yi Zhang
Senior Analyst
MTPPI
Thank you, Dr. Herann. I will now present our research findings.

19. The effect of EPO dose on hematocrit response among elderly hemodialysis patients in the U.S. Cotter D, Zhang Y, Thamer M, Kaufman J, Hernán MA. Kidney International 2007 [in press]
In this study, we examined the relationship between Epo dose and population HCT response. This research is supported by R01 NIDDK grant and has been accepted by Kidney International.

20. Mean monthly hemoglobin and mean EPO dose per week
This figure shows mean haemoglobin concentrations and weekly EPO doses in prevalent dialysis patients. The red line is for EPO dose and the blue is for Haemoglobin. Between and 2005, the mean administered dose of epoetin increased more than 300% in the US. However, the effect of epo dose and average HCT response in the ESRD population has not been evaluated.

21. Prior research
Dose response relationship has not been examined since Phase II trials
Stringent patient eligibility criteria
Limited dose
Observational studies have shown an inverse relationship between EPO dose and hematocrit
Confounding by indication
The only exsiting clinical study that examined dose and HCT relationship is the Phase II trials. However, phase II did not fully capture the population dose response because of its strict patient selection criteria and that non-responsive patients were not included.
Subsequent studies examining the relationship between EPO dose and hematocrit (or hemoglobin) have primarily used administrative databases. However, these studies often showed an inverse association between dose and HCT due to bias by indication. The true relationship between EPO dose and HCT should not be negative.

22. Research goals
To mimic an RCT in which subjects are randomly assigned to different arms, each receiving a different EPO dose
To compare the achieved hematocrit in each arm
So our aim was to estimate the relationship between EPO dose and hematocrit by using causal inference techniques to control for treatemnt-by-indication bias. In doing so, we tried to mimic an RCT in which patients are randomized on EPO dose and then we compared the achieved hematocrit in each arm.

23. Data source United States Renal Data System (USRDS)
administrative database on ESRD patients whose care is covered by Medicare
include extensive baseline and follow-up demographic and clinical data
outpatient EPO claims include monthly total EPO dose and hematocrit values
most recent USRDS data available for researchers
We used the 2003 and 2004 USRDS data, which are the most recent available data for researchers. USRD is an administrative database that contains EPO dose and HCT info based on monthly claims.

24. Patient population Retrospective cohort study.
14,001 patients who started EPO and dialysis in
>=65 years of age
had first claim with 90 days of their first ESRD service date
had not used EPO before
did not have a kidney transplant, HIV or cancer before starting dialysis.
were not censored during the first complete dialysis month
We restricted our analysis to patients who were ≥65 years of age (because EPO use before the initiation of dialysis can be reliably determined in this group), started hemodialysis and EPO treatment within 90 days after their first ESRD service date to avoid left censoring. Patients who used predialysis epo were excluded to ensure we have complete EPO therapy information, did not have a kidney transplant, HIV or cancer before starting dialysis (because these patients might respond differently to EPO therapy).

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
Patients were censored on these censoring events, whichever occurred first. We estimated the effect of average EPO dose in the first three months on dialysis on the achieved hematocrit at month four among incident dialysis patients who were EPO naïve. By choosing EPO naïve patients and limiting the observation period to the first three months of treatment, we selected the period in which change in hematocrit would be greatest. The outcome was chosen at the end of the fourth month period because a 2 – 4 week lag period has been reported for EPO to affect hematocrit.

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
We used margianl structural models to adjust for confounding by indication and we contructed a dose-response curve. Since Dr. Hernan has just presented an overview of how MSM works, I will focus on the results.

27. Distribution of patients by initial EPO doses
This is the distribution of patients by initialntial EPO doses.30% patients used initial doses recommend by FDA, while more than 60% received dose higher than recommended starting doses.

28. Distribution of patients by hematocrit group
26,000
21,500
Average EPO dose (U/week)
21,100
21,000
This is the distribution of patients by hematocrit at the end of first 3 months. More than 30% of patient achieved HCT greater than 39% and received highest epo doses in the first 3 months..
23,400

29. Dose response curve and 95% confidence intervals based on MSM4
This is the estimated dose-response curve. x-axis is--. Y axis is --. The dotted lines indicate 95% percent confidence intervals. A starting dose of 13,500 units/week would result in an average hematocrit of 36%, the greatest increases in the average hematocrit of the population take place with EPO doses between 9,000 and 22,500 units/week. At higher doses of EPO, the average population hematocrit plateaus at 38.5%. Red dots indicate the fda-recommended starting doses. which are located on the linear portion of the curve.

30. Dose response curve based on standard adjustment
the curve based on standard linear regression analysis is flatter, plateaus lower and is is less biologically plausible than our estimated curve.

31. Study limitations Did not consider dynamic EPO dosing regimes
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
This study has several limitations. First, there might be residule confounding introducced by unmeasured clininal factors. It's ideal for us to have treatment-to treatment data/from one epo administration to another. However, what we have in the claims data are HCT taken at the end of the month and the total monthly EPO dose. So we may not necessarily have the HCT that physicians are actually based upon when making dosing decisions. To the extent therefore that the residual confounding by unmeasured factors exists, it might underestimate the average hematocrit for large EPO doses, thus shifting the curve downwards. Inaddition, this administrative data source does not contain laboratory results such as nutritional status, blood pressure or inflammatory state, although in practice, decisions on EPO dosing are largely based on the archived hematocrit level. Other caveats include that the research question may not reflect current anemia management strategies and the study conclusions may not be generilizeble to different patient 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
Conclusions
Dose-response is S-shaped. HCT plateaus at 38.5%. Normal HCT target might not be achievable for dialysis population, and starting doses recommended by FDA are appropriate.

33. Zhang Y, Thamer, Cotter D, Kaufman J, Hernán MA
The relationship between EPO dose and survival among hemodialysis patients
Zhang Y, Thamer, Cotter D, Kaufman J, Hernán MA
Joint Statistical Meetings 2007 [Abstract]

34. Research goals
To mimic an RCT in which subjects are randomly assigned to different arms, each receiving a different average dose of EPO
To compare the survival in each arm

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

38. Mortality hazard ratios by EPO dose (quartiles)

39. Mortality rate by EPO dose

40. Survival for EPO doses based on 3 different doses

41. Study limitations Potential for unmeasured confounding as always
Did not consider dynamic EPO dosing regimes
One-year survival only

42. Conclusions
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

43. Relevance of research findings to FDA labeling decisions
INITIAL DOSE
In our study cohort, 61% of all incident elderly dialysis patients received
an initial EPO dose higher than the FDA-approved U/kg range
DOSE-RESPONSE
Based on our dose-response model, a population average EPO dose higher than 12,000 U/week would result in exceeding the FDA-approved HCT target of 36%
RISK
Based on our dose-survival model, a population average EPO dose higher than 15,000 U/week would result in progressively higher mortality risks
HYPORESPONSIVE PATIENTS
The risk of increased mortality is greatest among hyporesponsive patients
who receive the largest EPO doses
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