Association of Quarterly Average Achieved Hematocrit With Mortality in Dialysis Patients: A Time-Dependent Comorbidity-Adjusted Model Joseph M. Messana, MD, 1 Chien-Chia Chuang, MAE, 2 Marc Turenne, PhD, 2 John Wheeler, PhD, 2 Jason Turner, MAE, 3 Kathryn Sleeman, MS, 2 Philip Tedeschi, PhD, 2 and Richard Hirth, PhD 2 Background: Recent publications suggest that increased mortality is associated with high hematocrit targets in erythropoietin-stimulating agent–treated patients with chronic kidney disease. We aim to further inform the debate about optimal hematocrit targets, advancing the hypothesis that the current hematocrit target may not optimize the survival of patients with end-stage renal disease. Study Design: Cross-sectional observational study. Setting & Participants: Medicare dialysis patients from 2002 to 2004 (n = 393,967). Factors: Quarterly average hematocrit and erythropoietin alfa (EPO) dose. Outcomes: Mortality hazard ratios from time-dependent Cox proportional hazard models, adjusting for comorbidities. Results: N = 2,712,197 patient-facility quarters. During the study, 100,086 deaths were identified. Percentages of patient quarters within each hematocrit category: hematocrit less than 27% (2.0%), 27% to 28.49% (1.7%), 28.5% to 29.9% (2.9%), 30% to 31.49% (5.2%), 31.5% to 32.99% (9.0%), 33% to 34.49% (14.9%), 34.5% to 35.99% (19.2%), 36% to 37.49% (18.0%), 37.5% to 38.99% (12.0%), 39% to 40.49% (6.4%), 40.5% to 41.99% (3.0%), and 42% or greater (3.1%). Mortality hazard ratios from the fully adjusted model: hematocrit less than 27% (3.11), 27% to 28.49% (2.60), 28.5% to 29.9% (2.14), 30% to 31.49% (1.80), 31.5% to 32.99% (1.44), 33% to 34.49% (1.17), 34.5% to 35.99% (reference), 36% to 37.49% (0.98), 37.5% to 38.99% (1.01), 39% to 40.49% (1.13), 40.5% to 41.99% (1.32), and 42% or greater (1.57). Limitations: First, potential confounding by indication related to associations between underlying illness and mortality, anemia, and EPO responsiveness. Second, Medicare claims data reflect a range of conditions and degrees of severity not easily translated into the clinical context. Third, for Medicare claims, EPO reporting is not required if EPO is not billed. Greater than 95% of “missing hematocrit” quarters are “EPO = 0” patient quarters. Interpretation of results for the missing hematocrit and EPO = 0 use categories is complicated by data source limitations. Conclusions: We show an association between mortality and low hematocrit in dialysis patients, in part reflecting the presence of comorbidities. We also show an association between increased mortality and high hematocrit. Additional interventional trials should be undertaken to better define the optimal target for anemia management in patients with end-stage renal disease, with careful prospective identification of underlying comorbidities and clinical factors contributing to high erythropoietin- stimulating agent requirement. Am J Kidney Dis 53:503-512. © 2009 by the National Kidney Foundation, Inc. INDEX WORDS: Hematocrit; erythropoietin-stimulating agent (ESA); mortality; hemodialysis. T he introduction of erythropoietin alfa (EPO) in 1989 as a treatment for anemia in pa- tients with end-stage renal disease (ESRD) re- sulted in profound changes in clinical ESRD care. Initial clinical trials reported few adverse clinical events, and early observational studies showed associations between higher hematocrit or hemoglobin level and improved survival in long-term dialysis patients. 1,2 These observa- tions and other factors resulted in progressively higher targeted and achieved hematocrits in the nearly 2 decades since EPO became available. 3-5 A recent study using data from one large dialysis organization showed an association be- tween hemoglobin level of 13.5 g/dL or greater and increased mortality in long-term dialysis From the 1 Division of Nephrology, University of Michi- gan Health System; 2 Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, MI; and 3 Department of Health Management and Policy, School of Public Health, St Louis University, St Louis, MO. Received May 30, 2008. Accepted in revised form October 24, 2008. Originally published online as doi: 10.1053/j.ajkd.2008.10.047 on February 2, 2009. Address correspondence to Joseph M. Messana, MD, 3914 Taubman Center, Box 5364, Division of Nephrology, University of Michigan Health System, Ann Arbor, MI 48109- 5364. E-mail: jmessana@med.umich.edu © 2009 by the National Kidney Foundation, Inc. 0272-6386/09/5303-0018$36.00/0 doi:10.1053/j.ajkd.2008.10.047 American Journal of Kidney Diseases, Vol 53, No 3 (March), 2009: pp 503-512 503