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Updates From Kidney Week Chronic Kidney Disease and Associated Anemia Moderator Steven N. Fishbane, MD Professor of Medicine Hofstra Northwell School of Medicine Chief, Division of Kidney Diseases and Hypertension North Shore University Hospital Long Island Jewish Medical Center Great Neck, New York Panelists Jeffrey S. Berns, MD Myles S. Wolf, MD Professor of Medicine Associate Dean for Graduate Medical Education University of Pennsylvania Director Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Professor of Medicine Chief of Nephrology Duke University School of Medicine Durham, North Carolina This program will include a discussion of off-label treatment options and investigational agents not yet approved by the FDA for use in the United States. There will also be a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal. Introduction • Anemia is a frequent and significant complication of CKD – Associated with a high prevalence of cardiovascular disease in this patient population • There are a number of options for treating anemia in this patient population; however, there continue to be limitations with current treatments Pattern Changes in Anemia Treatment in Patients With NDD-CKD Objective • Evaluate the use and time to use of ESA, IV iron, and RBC transfusion after diagnosis of anemia during baseline year Methods • Two study cohorts of Medicare patients with stage 3 to 5 NDD-CKD and anemia • 2008: 71,744 • 2012: 109,251 • Consistent ESA treatment: ≥1 ESA monthly administration in ≥80% of 12 follow-up months Results • ESA use decreased by 57% from 2008 to 2012 • IV iron use and RBC transfusions remained stable • Patients received transfusions sooner, corresponding to decline in ESA use St Peter WL, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO767. Changes in ESA Labels • 2011 FDA update for ESA use in patients with CKD – Start ESA treatment when the hemoglobin level is <10 g/dL – Does not specify if goal is Hb of ≥10 g/dL – Dosing should be individualized – Use lowest dose of ESA sufficient to reduce the need for RBC transfusions – Adjust dosing as appropriate FDA website. Unexpected Medical Consequences of Revised ESA Label – – – – HE ↑ 100% DVT ↑31% PE ↑45% All-cause death and MACE incidence did not decline 2008 (n = 71,744) 2012 (n = 109,251) 35 30 Patients, % • Objective: Examine the changes in treatment of anemia, comorbidities and outcomes after FDA label revisions for ESA use in patients with NDD-CKD and anemia • CV outcomes in the 2012 cohort: 25 20 15 10 5 0 ESA Li S, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO795. IV Iron RBC Transfusion Decrease in Adverse Events Post-FDA Label Changes to ESA Treatment Patient population Reduction in events Chertow, et al[a] Wang, et al[b] ≈ 250,000 patients receiving maintenance dialysis between 2005 and 2012 69,718 patients who had undergone incident hemodialysis between 2008 and 2013 Absolute deviation from trend per 100 patient-years (95% CI): • Stroke: -0.24 (-0.08, -0.37) • VTE: -2.43 (-1.35, -3.70) • Heart failure: -0.77 (-0.28, -1.27) Decreased risk of stroke (HR: 0.77, 95% CI: 0.64, 0.93; P = .01) a. Chertow GM, et al. J Am Soc Nephrol. 2016;27:3129-3138. b. Wang C, et al. JAMA Intern Med. 2016;176:1818-1825. Use of High ESA Doses in Patients With NDD-CKD Objective Methods • Looked at the association of increased adverse events, comorbidities, and healthcare resource utilization in patients with NDD-CKD and anemia 2011-2013 Medicare data • 12,901 patients with stage 3-5 NDD-CKD with anemia receiving ESAs • Definition of high dose ESA: average monthly ESA dose >90th percentile of monthly doses Gilbertson DT, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO794. Results High dose ESA was associated with: • Significantly increased burden of CV and thromboembolic events – 60% ↑ risk of death – 46% ↑ risk of major cardiac event – 52% ↑ in Medicare payments Role of HIF and HIF-PH in Erythropoiesis HIF-α Low Oxygen Normal Oxygen (eg, high altitude) HIF-PH Enzymes HIF-α HIF-α HIF-PH Enzymes HIF-α degrades rapidly HIF-α Gene Transcription Degradation HIF-β Effect of Vadadustat* on Hemoglobin Levels in Patients With DD-CKD • Randomized, phase 2 open-label study • Objective: assess Hb response to 3 starting doses of vadadustat over 16 weeks in 94 DD-CKD patients who were maintained on ESAs prior to study entry • Hb response and vadadustat dose requirements for Hb maintenance are independent of underlying systemic inflammation and baseline ESA dose in patients with DD-CKD *This agent is not approved by the FDA for use in the United States. Haase VH, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO960. Effect of Daprodustat* on Hemoglobin Maintenance • Objective: examine the relationship between the dose of daprodustat and hemoglobin at 4 weeks, and safety and efficacy over 24 weeks • Participants: 216 subjects on HD previously receiving recombinant human EPO • Results – Switching from a stable dose of EPO to daprodustat produced dosedependent mean changes in Hb from baseline after week 4 – Hepcidin levels were reduced at week 24 (20.6% in daprodustat group vs 3.6% in control group) – Adverse event profile in daprodustat group was consistent with the HD population *This agent is not approved by the FDA for use in the United States. Cobitz, AR, et al. J Am Soc Nephrol. 2016;27. Abstract SA-OR114. Treatment of CKD-Associated Anemia With Roxadustat* in Patients Not on Dialysis – – Dose-dependent increase in hemoglobin No MACE occurred in roxadustat group Change in Hemoglobin, g/dL/wk • Phase 2, double-blind, 24-week study • Objective: evaluate safety and efficacy of roxadustat • Participants: 107 Japanese patients with NDD-CKD and anemia • Results P < .0001 for all doses of roxadustat compared with placebo 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 -0.1 Roxadustat Roxadustat Roxadustat 50 mg 70 mg 100 mg n=27 n=26 *This agent is not approved by the FDA for use in the United States. Akizawa T, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO1142. n=27 Placebo n=27 Potential Future of HIF-PH Inhibitors • Individuals living at high altitudes have HIF stabilization and elevated erythropoietin levels[a] – Can HIF-PH inhibitors used concomitantly with ESAs diminish adverse events of ESAs and increase erythropoietin? • Larger phase 3 trials are necessary to determine safety of this drug class – Potential to increase VEGF production (can enhance tumor progression)[b] – HIF is also involved in vascular tone and blood pressure regulation (concern for development of pulmonary hypertension)[c] a. Hopfl G, et al. Hypoxia: Through the Lifecycle. 2003:89-115; b. Krock BL, et al. Genes Cancer. 2011;2:1117-1133; c. Semenza GL. Annu Rev Pathol. 2014;9:47-71. HIF-PH Inhibitors and Hepcidin Levels • Hepcidin is a small peptide produced in the liver • Regulates iron homeostasis • In CKD, hepcidin levels go up as a result of decreased renal clearance and inflammation – Decrease in duodenal absorption of iron – Iron release from storage sites blocked • HIF-PH inhibitors play a role in decreasing levels of hepcidin Ganz T, et al. Semin Nephrol. 2016;36:87-93. Maxwell PH, et al. Nat Rev Nephrol. 2016;12:157-168. Effects of Ferric Citrate* in the Treatment of Iron Deficiency Anemia in Patients With NDD-CKD • 234 patients with NDD-CKD stages 3 to 5 and iron deficiency anemia randomized to ferric citrate or placebo for 16 weeks – 52.1% (ferric citrate) vs 19.1% (placebo) achieved ≥1 g/dL increase in hemoglobin – 48.7% (ferric citrate) vs 14.8% (placebo) achieved a sustained increase in hemoglobin • Most common adverse events are GI (diarrhea, nausea, constipation) *This drug is currently not approved by the FDA for this indication. Fishbane S, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO901. Regulation of FGF23 and Iron Status • FGF23 is an endocrine hormone secreted by osteocytes and osteoblasts • It is involved in regulating serum phosphate – Increases fractional phosphate excretion and reduces serum phosphate levels • Levels increase as kidney function declines • FGF23 plays a role in the pathogenesis of left ventricular hypertrophy, a risk factor for mortality in CKD • Iron deficiency, as well as some IV iron preparations, can lead to an increase in FGF23 production Wolf M. Kidney Int. 2012;82:737-747. Iron Therapy and Fibroblast Growth Factor-23 in Hemodialysis Objective • Evaluate effect of IV iron on levels of iFGF23 and cFGF23 in hemodialysis patients – Serum hepcidin, ferritin, and PO4 were also measured Results • IV ferric carboxymaltose group (n=22) – Ferritin and hepcidin levels increased significantly – cFGF23 increased – iFGF23 and PO4 decreased • Iron sucrose group (n=20) – Ferritin and hepcidin levels increased significantly Roberts MA, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO539. Concluding Remarks • Over the years there have been treatment pattern changes seen with the use of ESAs • HIF-PH inhibitors are a newer class of drugs with potential for treating anemia • Ferric citrate currently acts as a phosphate binder but can potentially be used for the treatment of anemia • Recent data suggest that iron deficiency and elevated phosphate levels stimulate FGF23 production Thank you for participating in this activity. 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