New Aspects to Optimize Epoetin Treatment with Intravenous Iron Therapy in Hemodialysis Patients

Transcription

1 23. Berliner DialyseSeminar Dezember 2010 New Aspects to Optimize Epoetin Treatment with Intravenous Iron Therapy in Hemodialysis Patients George R. Aronoff, MD, MS, FACP Professor of Medicine and Pharmacology Vice Chair, Department of Medicine University of Louisville School of Medicine Louisville, Kentucky USA

2 Educational Objectives Review pharmacology of IV iron Evaluate safety and efficacy of IV iron Examine new methods for IV iron dosing

3 Normal Erythropoiesis Bone Marrow Circulation ERYTHROPOIETIN IRON IRON Stem Cell BFU-E CFU-E Pro-erythroblast Reticulocytes RBCs & erythroblast Day 0 Day 12 Day 18 Day 20 Day 22 Day 25 Red Blood Cell Development: Time to Mature BFU-E: burst-forming units-erythroid; CFU-E: colony-forming units-erythroid; RBC: red blood cells Adapted from Kalantar-Zadeh K et al. Adv Chronic Kidney Dis 16: , 2009.

4 Iron Metabolism: Before and After Advent of ESAs Iron metabolism in pre-esa era Blood transfusions used to manage anemia 1 IV iron supplementation unnecessary; transfused blood contained adequate iron supply Transfusion-related issues Increases infection risk 2 Allergic reactions 2 Adverse immunologic effects Iron overload 1 Serum ferritin levels > µg/l Tissue deposition and cell damage Increased risk of infection 1 Nephrol Dial Transplant2004;19(Suppl2):ii6 ii15; 2 Henry D. The Oncologist 3:275-8, 1998.

5 Iron Metabolism: Before and After Advent of ESAs Iron metabolism in post-esa era Transfusion-related issues avoided Iron directed to Hgb formation ESA stimulated erythropoiesis Functional iron deficiency often occurs Oral ironcannot keep up with iron losses IV iron supplementation required Eschbach JW. Best Practice & Research Clinical Haematology 18(2): , 2005.

6 Iron Deficiency Anemia: Average Annual Iron Losses Up to 3 grams of iron may be lost annually in each chronic hemodialysis (HD) patient 3 Repeated laboratory test Annual Iron Loss (gram ms) Accidental losses during HD Blood retention in dialyzer and tubing Normal iron losses REMEMBER: You lose twice the iron with a Hgbof 12 gm/dl as with a Hgbof 6 gm/dl Maintenance HD Patients Adapted from Kalantar-Zadeh K et al. Adv Chronic Kidney Dis 16:143-51, 2009.

7 Scanning EM of IV Iron Iron-dextran Iron-sucrose Iron-gluconate Kudashevaand Cowman, Polytechnic University, Brooklyn, NY

8 IV Iron Iron Core and Carbohydrate Shell iron oxyhydroxide core carbohydrate shell

9 Order of Core Size & Particle Size: Iron Dextran >> Iron Sucrose > Ferric Gluconate Iron sucrose Ferric gluconate Iron dextran

10 Intravenous Iron Free Iron 2Fe 2Fe Labile Iron

11 RES Processing of IV Iron Sucrose Fe 59 Uptake 20 Spleen Liver Marrow Time after IV Iron Sucrose (min) Source: Beshara S, et al. Br J Hematol 104: , 1999

12 Prompt RBC Utilization of Iron Sucrose Nearly Complete within 1 Month RBC Iron Utilization (%) Time after IV Iron Sucrose (days) Source: Beshara S, et al. Br J Hematol 104: , 1999

13 Increased HgbCorresponded to Reduction in Mean EPO Dose Epoetin Dose (units thr ree times a week) Hgb Epoetin 100 mg dose of iron sucrose 12 (g/dl) Hemoglobin ( Days After Initiating Iron Therapy Charytan C, Levin N, Al-Saloum M, et al. Am J Kidney Dis 2001;37:

14 Maintenance Iron Dosing Compared facility level data from 24 Fresenius dialysis facilities Group mg every other week (n=16) Group 2 25 mg every week (n=8) % pts with Group Tsat20-50 (%) Mean Tsat (%) Mean Ferritin (ng/ml) Mean Hgb (g/dl) % Pts Hgb g/dl Epounitsper Administration , ,665 Aronoff GR, Brier ME, MullonC., et al. Iron Sucrose Injection Maintenance Therapy in Hemodialysis Patients and Erythropoiesis-Stimulating Agent Sparing. Abstract ASN 2010.

15 Iron Sucrose North American Clinical Trial 665 Hemodialysis patient received iron sucrose Replacement 100 mg each treatment x 10 Maintenance 100 mg weekly x 10 Repeated as necessary to achieve and maintain K/DOQI targets 8,583 doses of iron sucrose 239 patient years Aronoff, et al. Iron Sucrose in Hemodialysis Patients: Safety and Efficacy of Iron Replacement and Maintenance Therapy. KI 2004;66:

16 Iron Sucrose Adverse Events No serious drug-related adverse effects No hypersensitivity reactions 29 non-serious drug-related events Taste disturbance most common Transient Not dose related Aronoff, et al. Iron Sucrose in Hemodialysis Patients: Safety and Efficacy of Iron Replacement and Maintenance Therapy. KI 2004;66:

17 Iron sucrose North American Clinical Trial Infection 500 Hospitalization Rate 40 Death Rate (per 1000 patie ent years) P= P< USRDS NACT USRDS NACT Aronoff, et al. Iron Sucrose in Hemodialysis Patients: Safety and Efficacy of Iron Replacement and Maintenance Therapy. KI 2004;66:

18 Hypersensitivity Reactions to Intravenous Iron Retrospective Review of Adverse Events FOI surveillance database (FDA) Jan 1997-Sept 2002 Iron dextran, SFG, IS Anaphylaxis, anaphylactoid rxn, urticaria, angioedema Normalized to 100 mg dose equivalents Bailie G, et al. Neph Dial Trans. April 2005.

19 Hypersensitivity Reactions to Intravenous Iron 100 mg lents Reports/million dose equival Iron Dextran SFG IS Bailie G, et al. Neph Dial Trans. April 2005.

20 All-Cause Fatal Reactions to Intravenous Iron 100 mg lents Reports/million dose equival 1,4 1,2 1 0,8 0,6 0,4 0,2 0 Iron Dextran SFG IS Bailie G, et al. Neph Dial Trans. April 2005.

21 Inclusion criteria <11 g/dl, DRIVE Study Design ferritin 500 to 1200 ng/ml TSAT <25% epoetin dosage >225 IU/kg per wk or >22,500 IU/wk Participants (n 134) randomized to no iron (control) or to ferric gluconate1,000 mg IV in eight doses EPO was increased 25% at baseline Comparisons made using ANCOVA Coyne DW. KapoianT. SukiW. Singh AK. Moran JE. Dahl NV. RizkalaAR. DRIVE Study Group. JASN 18(3):975-84, 2007

22 DRIVE Study Design Coyne DW. KapoianT. SukiW. Singh AK. Moran JE. Dahl NV. RizkalaAR. DRIVE Study Group. JASN 18(3):975-84, 2007

23 DRIVE Study Results Iron gluconate No iron Coyne DW. KapoianT. SukiW. Singh AK. Moran JE. Dahl NV. RizkalaAR. DRIVE Study Group. JASN 18(3):975-84, 2007

24 Effect Modification of Iron on EPO Response Retrospective data from 209 hemodialysis patients for months Monthly measurements Predialysis Hgb Tsat Serum albumin Kt/V; Quarterly measurements predialysis serum ferritin intact parathyroid hormone Analyzed the dynamic relationship between hemoglobin and Epodose Gaweda AE. Goldsmith LJ. Brier ME. Aronoff GR. CJASN 5(4):576-81, 2010 Apr.

25 Effect Modification of Iron on EPO Response Fe ++ Deficiency Inflammation Gaweda AE. Goldsmith LJ. Brier ME. Aronoff GR. CJASN 5(4):576-81, 2010 Apr.

26 Control Engineering Approach to Anemia Management Model Predictive Controller Epo Hgb pred Dose Optimizer Model Reinforcement Learning Epo* Penalty Fxn Hgboff target Epo adjustment Patient Hgb Brier ME, GawedaAE, Dailey A, Aronoff GR, and Jacobs AA. Randomized Trial of Model Predictive Control for Improved Anemia Management. CJASN. 5(5):814-20, 2010 May.

27 Hemoglobin Response to Model Predictive Control vs Algorithmic Anemia Management Protocol Brier ME, GawedaAE, Dailey A, Aronoff GR, and Jacobs AA. Randomized Trial of Model Predictive Control for Improved Anemia Management. CJASN. 5(5):814-20, 2010 May.

28 Control Engineering Approach to Anemia Management Model Predictive Controller Dose Optimizer Epo Iron Model Hgb pred Epo and Iron Penalty Fxn Hgboff target Epo adjustment Patient Hgb Brier ME, GawedaAE, Dailey A, Aronoff GR, and Jacobs AA. Randomized Trial of Model Predictive Control for Improved Anemia Management. CJASN. 5(5):814-20, 2010 May.

29 Conclusions Iron deficiency impedes erythropoiesis EPO resistance Intravenous iron replacement is almost always needed in hemodialysis patients Iron replacement is safe and effective Iron maintenance therapy decreases EPO dose Giving iron in excess amounts does not improve EPO sensitivity Individualized anemia management requires simultaneous modeling of iron and EPO

30 Thanks to: Michael E. Brier, PhD Alfred A. Jacobs, MD, PhD Adam E. Gaweda, PhD, MSPHS Patients and Staff of the Kidney Disease Program University of Louisville School of Medicine Louisville Kentucky