Comparative Effectiveness of Two Anemia Management Strategies for Complex Elderly Dialysis Patients

Introduction

Anemia affects nearly all end-stage renal disease (ESRD) patients and is associated with diminished quality of life, decreased survival, and adverse cardiovascular outcomes.^1,2,3 Dialysis patients receive erythropoiesis-stimulating agents (ESAs) to elevate their hematocrit levels. The optimal hematocrit target is unknown. Four randomized trials in patients with chronic kidney disease (CKD) have shown that patients targeted to near normal hematocrit values (39% for TREAT,⁴ 39-45% for CREATE,⁵ 40.5% for CHOIR,⁶ and 42% for the Normal Hematocrit Trial (NHT)⁷) had worse clinical outcomes than patients targeted to low hematocrit values (27%-34.5%)^5,6,7 or placebo.⁴ For example, in the NHT study, the only trial that included dialysis (vs. predialysis) patients,⁷ the high hematocrit arm experienced a 27% increase in mortality compared with the control arm.

Safety concerns and lack of proven benefits for targeting patients to normal hematocrit levels prompted the FDA to recommend that physicians “reduce or interrupt the dose” of epoetin if hematocrit exceeds 33%. However, until 2011, the majority of ESRD patients in the U.S. were targeted to a middle hematocrit range of 34 – 39%.⁸ No randomized trials have compared the FDA-recommended strategy of hematocrit <33% with the commonly used strategy of hematocrit 34-39%, which requires higher epoetin doses. In addition to higher mortality and cardiovascular risks of targeting normal hematocrits, the cost implications of using higher doses are significant; epoetin is the single largest Medicare drug expenditure: ∼$2 billion annually between 2005 and 2010 and∼11% of all ESRD costs.⁹

In this research, we use observational data to compare the effects of a low hematocrit strategy of 30 - 34.5%, similar to the FDA-recommended strategy, with a commonly used mid range hematocrit strategy of 34.5 - 39%. Like the NHT and TREAT trials, we focused on elderly ESRD dialysis patients at high risk for adverse cardiovascular outcomes.

Methods

We used observational data from the United States Renal Data System (USRDS) to emulate a randomized clinical trial¹⁰ among elderly hemodialysis patients with both diabetes and cardiovascular disease. The USRDS includes 93% of U.S. dialysis patients with Medicare coverage.¹¹ Most claims cover a service period of approximately one month (average duration is 24 days).¹² We used the USRDS standard analytic files for 2006-2009 that contained variables from patient, medical evidence, and facility data files. Figure 1 represents the patient selection process.

We considered two dynamic treatment strategies for ESA use:

1. Mid Hct Strategy: intravenous epoetin alfa to achieve and maintain hematocrit values between 34.5 and 39.0% or

2. Low Hct Strategy: intravenous epoetin alfa to achieve and maintain hematocrit values between 30.0 and 34.5%.

Under both strategies, epoetin dose is (i) increased by at least 10% if previous hematocrit is below the target range, (ii) decreased by no more than 10% times [previous hematocrit minus lower end of range] or increased by no more than 10% times [upper end of range minus hematocrit] if previous hematocrit is within target range, (iii) decreased by at least 25% (or withheld) if previous hematocrit is above the target range. For simplicity we did not consider strategies that vary according to the evolving clinical characteristics of the patients.

Similar to previous RCTs, the two endpoints of interest were all-cause mortality and a composite outcome including death and hospitalization for myocardial infarction (MI), stroke, or congestive heart failure (CHF).^{5, 6} Previous studies have verified that ICD-9 codes used to define MI, CHF, and stroke have specificity higher than 90% and sensitivity between 67% and 86%.^13,14,15,16

Table 1 summarizes the characteristics of the hypothetical randomized trial and how we emulated it using the observational data. Supplemental Digital Content 1a and 1b describe the monthly assignment to each strategy.

Results

Of 22,474 eligible patients (Figure 1), 5,395 were classified as following the Mid Hct Strategy only, 7,439 following the Low Hct Strategy only, and 9,640 as following both strategies. Compared with patients only in the Low Hct Strategy, patients in the Mid Hct Strategy had higher predialysis and baseline hematocrit, lower doses of epoetin and iron before baseline, a higher Charlson score, fewer inpatient days before baseline, and were more likely to receive dialysis services from Fresenius (the nation's largest dialysis chain) (Table 2). Patients following both strategies had shorter inpatient stays before baseline and had the highest average hematocrit value in the first 3 months of dialysis.

In the expanded dataset with duplicates, there were 2,738 deaths (3,825 composite events) under the Mid Hct Strategy and 2,292 deaths (3,281 composite events) under the Low Hct Strategy. The HRs (95% CI) were 1.05 (0.99, 1.11) for death and 1.03 (0.98, 1.08) for the composite event in the intention-to-treat analysis, and 0.98 (0.78, 1.24) and 1.00 (0.81, 1.24), respectively, in the per-protocol analysis (Table 3). In analyses restricted to the 87% of patients with Hct>30% at baseline (considered epoetin responsive patients), the HRs were similar. Unadjusted and partially adjusted estimates were also similar (Supplemental Digital Content 2). The 6-month risk difference between the Mid and Low Hct strategies was 0.0% in all analyses (Figure 2).

Our estimates did not change when we restricted our analysis to patients with serum albumin level <3.5 g/dL, who might be expected to have worse outcomes, when IP weights were estimated under a gamma or truncated normal distribution for the log of epoetin dosage, when we used different knot locations for splines of log epoetin dosage and hematocrit values, when we used cubic splines of iron dose, and when we applied different dosing algorithms to define hematocrit target strategies (i.e. 10%, 15%, 20%, and 25% dose titration rate). To test the robustness of our estimates to longer follow-up, we followed patients through the end of their first year on dialysis (i.e., treatment strategies and patient outcomes were evaluated during the 9-month period after baseline). Intention-to-treat and per-protocol analysis resulted in essentially null estimates, although there was substantial attrition due to artificial censoring in the latter(data not shown)

Discussion

Previous randomized trials of epoetin therapy – three in predialysis chronic kidney disease patients^4,5,6 and one in dialysis patients⁷ – found increased mortality or no benefits for higher, near normal, hematocrit targets compared with lower targets (Appendix Table). After the publication of the TREAT trial, the FDA changed the epoetin label and advised reducing or interrupting the dose of epoetin if the hematocrit exceeded 33%. While targeting hematocrit above 39% appears to be harmful compared to targeting below 34.5%, the effect of commonly clinically targeted middle range has not been examined in clinical trials to date. Using observational data, we emulated a randomized trial in a high risk population of elderly dialysis patients with both diabetes and cardiovascular disease assigned to either a mid (34.5 to 39%) or a low (30 to 34.5%) hematocrit target strategy to be achieved through epoetin therapy. We found no differences in the rates of mortality and a cardiovascular composite endpoint between these two clinical strategies, which supports the current FDA recommendations for a target hematocrit level up to 33% in hemodialysis patients.

It has been suggested²⁰ that hematocrit targets higher than those recommended by the FDA might help some patients (e.g. those who respond to epoetin and achieve a high hematocrit) and harm others (e.g., hyporesponsive patients). We found no indication of benefit for a higher hematocrit target after removing poor responders from our analyses, which supports FDA's target hematocrit recommendation for all patients.

Until January 2011, nearly all nephrologists and dialysis providers targeted a hematocrit level above 33%. In 2011, the enhanced ESRD Prospective Payment System (PPS) bundled epoetin therapy into the dialysis composite rate.²¹ Preliminary indications suggest that both epoetin use²² and hematocrit levels have been dramatically reduced since implementation of the ESRD PPS, and hematocrit targets appear to be more consistent with current FDA recommendations.^23,24

We used the largest and most complete observational database available for ESRD research. Our study, however, has several limitations. First, the validity of our estimates depends on the assumption that all confounding factors were correctly included in the model.^25,26 We used statistical methods that appropriately adjust for measured time-varying confounders, but residual confounding could still remain. Second, claims data are collected primarily for billing purposes, and their quality for research might be suboptimal. However, the information on health outcomes used in our study has been previously validated.²⁷ Finally, our approach made it hard to find differences in the intention-to-treat analysis (because most patients were assigned to both strategies), and it was difficult to study a longer follow-up period in the per-protocol analysis because many patients were artificially censored. Additional analysis based on the parametric g-formula might help alleviate these problems.

Our results support the FDA's most recent advisories recommending a hematocrit target of less than 33% when treating hemodialysis patients, including those with serious co-morbidities. The statistical methods employed can be applied to USRDS and other observational databases to examine different hematocrit strategies in specific populations and provide preliminary data for planning randomized clinical trials.

Supplementary Material