| Eligibility criteria |
End‐stage renal disease (ESRD) patients undergoing outpatient hemodialysis in U.S. dialysis facilities between 2006 and 2011. Congestive heart failure (CHF) in 2 years before study entry or ischemic heart disease (IHD) in previous 2 years. ESA use in the previous month. At least 6 months on dialysis. No myocardial infarction (MI), pericardial disease, cardiac amyloidosis, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass grafting (CABG) in previous 3 months. No severe cardiac disability in previous 6 months. No use of darbepoetin in previous 3 months. Compliance with dialysis in previous 3 months.
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Defined as the presence in USRDS during the month of June of any of those years. CHF defined as one or more inpatient claims with CHF as primary/secondary reason for hospitalization or as >15 dialysis sessions in a month (nonroutine ultrafiltration). IHD defined as one or more inpatient claims with IHD as primary/secondary reason for hospitalization, or >1 outpatient, physician/supplier claims for IHD. EPO does not equal to zero in previous month. Months since first ESRD service date ≥6. Defined as one or more inpatient claims with MI, pericardial disease, or cardiac amyloidosis as primary reason for hospitalization in previous 3 months; PTCA and CABG are identified using ICD‐9 procedure codes from inpatient claims. Defined as >2 hospital admissions for CHF in previous 6 months. Defined as darbepoetin dose equal to zero. Defined as no missing dialysis sessions for an entire month.
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| Treatment strategies |
Patients are randomly assigned to one of the following three dynamic treatment strategies:
Low hematocrit: intravenous EPO to achieve and maintain hematocrit values of 30–33% Mid hematocrit: intravenous EPO to achieve and maintain hematocrit values of 33–36% High hematocrit: intravenous EPO to achieve and maintain hematocrit values of 36–39%.
Under all strategies, EPO dose (units per administration) is changed according to the following rules: Dose is increased 15%, maintained, or decreased 15% if hematocrit is below, within, or above the target range, respectively. EPO is withheld during the first 4 days of hospitalization and set to the EPO dose received before hospitalization after the first 4 days.
The administration of IV iron is left to the discretion of the treating physician, but no use of darbepoetin is allowed.
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To emulate these strategies, we used:
Average EPO dose (units per administration) for each month. Inpatient EPO use was not reported so we assume 0 dose for the first 4 days of hospitalization and the most recent prehospitalization dose level for longer hospitalizations. Hematocrit value reported at the beginning of each month. When dose was withheld, hematocrit was not reported, so we carry forward the most recent value in the primary analysis. In sensitivity analyses, the missing hematocrit is assumed to increase or decrease by 10% compared with the previous reported level.
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| Outcomes |
Primary: all‐cause mortality or nonfatal MI
Secondary: mortality alone
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MI date was defined as the date of first inpatient claim during the follow‐up with MI as primary/secondary reason for hospitalization. Death date was identified from USRDS Patients File. |
| Follow‐up |
From eligibility and treatment assignment until the earliest of 18 months, death, or loss to follow‐up |
Same. Loss to follow‐up was defined as the earlier of (1) data anomaly (e.g., EPO dose >0 even though hematocrit value was not reported in the claim), (2) switch to darbepoetin, and (3) 30‐day gap in outpatient dialysis or inpatient claims. |
| Causal contrasts |
Per‐protocol effect |
Same. |
| Statistical analysis |
Parametric g‐formula to estimate survival curves under each strategy |
Same. See Appendix SA2 for SAS code. |
