NN&I - January 2012

Renal Policy all were thus given ever higher ESA doses e g 400 475 units kg week in hopes of achieving the designated target Many did not In each study patients in the higher hemoglobin target group experienced greater morbidity and death rates The studies did not consider correlations between patients achieved hemoglobin levels and outcomes Furthermore each trial focused almost exclusively on ESA administration often using unconventional dosing regimens in an attempt to achieve their assigned targets Despite the known complexity of anemia none of the trials pursued or documented a systematic multi factorial anemia management approach including the use of intravenous But the financial penalties under the QIP program give us little choice We exceed the QIP upper threshold Our work must IV iron In fact the almost exclusive preoccupation with ESAs in ameliorating anemia may be misplaced entirely our studies show The FDAs own Acting Deputy Director for Science Office of Surveillance and Epidemiology debunked the basis for the black box warning in 20072 Since then the methodology underlying the three pivotal RCTs have been called into question with one formally recanted Among other fundamental flaws two distinct populations were treated as one the results tending towards the mean Once delineated it was clear there was a positive correlation between higher achieved hemoglobin levels and lower mortality and morbidity It was true the acting deputy director demonstrated to the FDA committees in 2007 for ESA responders and non responders alike Seen in this light the three randomized trials mirror the preponderance of observational evidence worldwide 3 13 Higher hemoglobin levels are associated with improved clinical outcomes i e lower mortality morbidity and hospitalization rates Contrary to popular belief observational studies may be more appropriate for evaluating the merits of different treatment regimens in complex heterogeneous populations not conducive to proper experimental controls 14 In point of fact the quality of welldesigned observational studies either a cohort or case control design rivals the very best randomized trials on the same topic 15 Moreover as Yale epidemiologist Alvan Feinstein wisely observed Because randomized trials cannot serve as a basic foundation for stop we must downgrade our care science in clinical management clinical investigators who want to get scientific answers to important clinical questions will have to reach beyond the constraints of the paradigm that requires formal experimentation as the sole method of science 14 The role of iron Our keen interest in anemia started with an observation more than 15 years ago at the Upper Manhattan Dialysis Center UMDC A longstanding patients hemoglobin suddenly plummeted A quick analysis revealed that the patient was highly iron deficient despite taking oral supplements Further analysis revealed that more than half the patients were highly iron deficient From that moment we started to explore the complex role of iron deficiency and other variables in anemia and the merits of alternative therapeutic approaches first at UMDC and from 1998 at The Rogosin Institute In both cases a comprehensive coded and analyzable patient record for practice management and clinical research enabled the conduct of retrospective and prospective practicebased studies at little additional cost Our first practice based anemia study published in 2001 showed how iron repletion in managing anemia leads to significant improvements in serum albumin serum creatinine Kg a measure of muscle mass as well as pre and post dialysis blood pressure 16 For the unit as a whole subject to the anemia protocol along with the study patients hospitalization and mortality rates fell by 29 and 31 respectively excluding those with AIDS and myeloma Our second practicebased study a 95 year multi factorial survival analysis published in 2009 demonstrates that best patient survival occurs with Hb 12 g dL TSAT 25 serum ferritin 600μg L and EPO 12000 units weekly 17 Critically for this discussion ESA use without IV iron did not benefit survival and with IV iron the benefit was small Based on our observational studies we implemented a new anemia management protocol in 2010 in Rogosins Manhattan dialysis center n 250 patients 18 19 The objective was to achieve stable and sustainable reductions in anemia Replete iron deficiency and maintaining iron sufficiency was the starting point ESAs were used in a sparing step wise fashion based on improvements in hemoglobin with adequate intervals between dose changes 6 8 weeks The practice protocol was then tailored to patients individual needs and modified in response to the waxing and waning impacts of medications disease flare ups e g inflammation and ancillary therapies Our outcomes by months 13 18 of the study showed a 35 reduction in ESA use to 9400 units per patient Nephrology News Issues January 2012 Subscribe to our free eNewsletter at www NephrologyNews com 32