Anemia Guidelines and The Use of Erythropoietin in Turkey Kenan ATEŞ, MD Department of Nephrology Ankara University Faculty of Medicine

Anemia in chronic renal failure Erythropoietin deficiency GFR <40 ml/min Erythropoesis inhibition Hemolysis ANEMİA Blood loss Iron deficiency Normocytic normochromic Folate/Vitamin B12 deficiency Inflammation Aluminium overload

Anemia is important Reduced quality of life Decreased tissue oxygen delivery and utilization Decreased cognition and mental acuity Increased cardiac output Altered menstrual cycles Ventricular hypertrophy Decreased sexual function Cardiac enlargement Impaired immune responsiveness Angina pectoris Growth retardation Congestive heart failure Decreased intellectual performance Reduced quality of life Poor patient rehabilitation Decreased survival

Treatment of secondary Treatment of anemia Iron supplementation Adequate dialysis Adequate nutrition Target Hb/Hct Level Treatment of secondary hyperparathyroidism Prevention of inflammation ERYTHROPOIETIN

Not all dialysis patients will require treatment with EPO Adequate dialysis HD 20% Adequate nutrition Iron supplementation PD 40% Other measures

C O S T EPO therapy is a very expensive treatment One month cost 900 $ HEMODIALYSIS 900 $ EPO (6000 U/wk) 500 $

ANEMIA GUIDELINES

EUROPEAN BEST PRACTICE GUIDELINES Anemia Guidelines The aim of guidelines is to provide an evidence-based standard of care for management of anemia in patients with chronic renal failure 1996 NKF-DOQI GUIDELINES 1999 EUROPEAN BEST PRACTICE GUIDELINES 2003 TSN ANEMIA GUIDELINES

When to initiate the work-up of anemia Pre-menopausal females Pre-pubertal patients Hb <11 g/dl (Hct <33%) Post-menopausal females Adult males Hb <12 g/dl (Hct <37%) NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

EUROPEAN BEST PRACTICE GUIDELINES Evaluation of anemia Hemoglobin and/or hematocrit Red blood cell indices Serum iron Reticulocyte count TIBC Iron parameters Serum ferritin Transferrin saturation Occult blood in stool Percen. of hypochromic red cells CRP NKF-DOQI GUIDELINES TSN ANEMIA GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES

Evaluation of anemia A fuller work-up should also include the following, as indicated Serum vitamin B12 and folic acid Differential white blood count Tests for hemolysis Serum protein electroforesis Hemoglobin electroforesis TSN ANEMIA GUIDELINES Bone marrow examination EUROPEAN BEST PRACTICE GUIDELINES Serum aluminium

Erythropoietin deficiency EUROPEAN BEST PRACTICE GUIDELINES Anemia is most likely due to EPO deficiency If Impairment of renal function is present A normocytic, normochromic anemia is present No cause for anemia is detected by the work-up NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

Indications for starting treatment with Erythropoietin EPO treatment should be considered when the Hb concentration is consistently less than 11 g/dl on repeating testing (Hct <33%) when other causes of anemia have been excluded NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES

Indications for starting treatment with Erythropoietin TSN ANEMIA GUIDELINES ASYMPTOMATIC PATIENTS SYMPTOMATIC PATIENTS Heart failure, angina Hb <10 g/dl Htc <30% Higher Hb and/or Hct levels EPO TREATMENT

Hematology work-up Treat with EPO if indicated Serum creatinine 2 mg/dl Check Hb <12 g/dl in males and post-menopausal females <11 g/dl in pre-menopausal females and pre-pubertal patients Work-up No Hematology work-up Normal Fe deficiency Treat with EPO if indicated Treat with iron Anemia not corrected Anemia corrected

Target hematocrit/hemoglobin for erythropoietin therapy 11-12 g/dl Hematocrit 33-36% Variations in the target Hb may be required in patients with co-morbidity NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

Assesment of iron status BEST PRACTICE GUIDELINES Serum iron Total iron binding capacity Transferrin saturation Percentage of hypochromic red cells Serum ferritin Iron stores in bone marrow NKF-DOQI GUIDELINES RBC ferritin concentration BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

EUROPEAN BEST PRACTICE GUIDELINES Target iron level The patients should have sufficient iron to achieve and maintain an Hb (Hct) of 11-12 g/dl (33-36%) OPTIMAL Serum ferritin >100 ng/ml 200-500 ng/ml Transferrin saturation >20% 30-40% Hypochromic red cells <10% <2.5% (<5%) NKF-DOQI GUIDELINES TSN ANEMIA GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES

Monitoring iron status BEST PRACTICE GUIDELINES Patients treated with Epo Patients not treated with Epo Hb/Hct stable Hb <11 g/dl Hct <33% Hb 11-12 g/dl Hct 33-36% Ferritin 100 ng/ml TSAT 20% Every 3 months Every 3-6 months Not receiving IV iron Receiving IV iron NKF-DOQI GUIDELINES BEST PRACTICE GUIDELINES Every month Every 3 months TSN ANEMIA GUIDELINES

Administration of supplemental iron TSAT <20% Ferritin <100 ng/ml 100-125 mg IV iron at every HD seans for 8-10 doses TSAT <20% Ferritin <100 ng/ml TSAT >20% Ferritin >100 ng/ml TSAT >50% Ferritin >800 ng/ml 100-125 mg IV iron at every HD seans for 8-10 doses 25-125 mg IV iron per week IV iron therapy should be withheld for 3 months

EUROPEAN BEST PRACTICE GUIDELINES Oral iron therapy When oral iron is used It should be given as 200 mg of elemental iron per day, in two to three divided doses in the adult patient, and 2-3 mg/kg/day in the pediatric patient NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

Route of administration of erythropoietin INTRAVENOUS INTRAPERITONEAL SUBCUTANEOUS INTRADERMAL EPO should be administered SC in PD patients The most effective route of EPO is SC in HD patients NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES TSN ANEMIA GUIDELINES

Initial erythropoietin administration SC 80-120 units/kg/week, in two to three doses per week IV 120-180 units/kg/week, in three doses per week NKF-DOQI GUIDELINES

Initial erythropoietin administration The starting dose of EPO should be 50-150 units/kg/week SC The starting dose should be in the lower range IV The starting dose should be in the upper range EUROPEAN BEST PRACTICE GUIDELINES

Initial erythropoietin administration SC The starting dose should be 75 units/kg/week IV The starting dose should be 150 units/kg/week TSN ANEMIA GUIDELINES

Monitoring of Hb/Hct during erythropoietin therapy Target Hb/Hct is not achieved NKF-DOQI GUIDELINES Every 1-2 weeks BEST PRACTICE GUIDELINES Every 1-2 weeks TSN ANEMIA GUIDELINES Every 2 weeks Target Hb/Hct is achieved NKF-DOQI GUIDELINES Every 2-4 weeks BEST PRACTICE GUIDELINES Every 4-6 weeks TSN ANEMIA GUIDELINES Every 4 weeks

Titration of erythropoietin dosage After initation of EPO After a dose increase If the increase in Hb (Hct) is <0.7 g/dl (<2%) over a 2-4 week period If the increase in Hb/Hct is >2.5 g/dl (>8%) per month If the Hb (Hct) exceeds the target levels Dose should be increased by 50% Dose should be decreased by 25-50% NKF-DOQI GUIDELINES BEST PRACTICE GUIDELINES

Titration of erythropoietin dosage After initation of EPO After a dose increase If the increase in Hb (Hct) is <1.0 g/dl (<3%) over a 4-6 week period If the increase in Hb/Hct is >1.5 g/dl (>5%) per month Dose should be decreased by 50% Dose should be increased by 12.5-25 units/kg/week TSN ANEMIA GUIDELINES

Inadequate response to erythropoietin DEFINITION NKF-DOQI GUIDELINES Failure to achieve target Hb/Hct in the presence of adequate iron stores at dose of 450 units/kg/wk IV or 300 units/kg/wk SC within 4-6 months or failure to maintain target Hb/Hct subsequently at that dose EUROPEAN BEST PRACTICE GUIDELINES Failure to attain the target Hb concentration while receiving more than 300 units/kg/wk (~20.000 units/wk) of EPO SC or a continued need for such dosage to maintain the target

Inadequate response to erythropoietin DEFINITION TSN ANEMIA GUIDELINES Despite the EPO therapy at dose of 300 units/kg/week, no increase in Hb more than 2 g/dl within 12 weeks

Causes of inadequate response to erythropoietin Iron deficiency Osteitis fibrosa Infection/inflamation Aluminium overload Chronic blood loss Folate/Vitamin B12 deficiency Malnutrition Hemoglobinopathies Hemolysis Multiple myeloma NKF-DOQI GUIDELINES EUROPEAN BEST PRACTICE GUIDELINES

EPO RESISTANCE Infection Inflammation Malignancy CRP Non-compliance Occult blood in stool Blood loss Iron stores Reticulocyte LDH Bilirubin Blood smear Hemolysis Inadequate Adequate Vitamin deficiency Vitamin B12/Folate Blood smear PTH Bone marrow examination Bone marrow fibrosis Aluminium overload Serum aluminium TSN ANEMIA GUIDELINES Hemoglobinopathies Hb electrof.

LEGAL ARRANGEMENTS

Ministry of Finance 2003 Fiscal Year Budget Application Directions Official Gazette: Date 01.02.2003, Number 25011 Use of erythropoietin in patients with chronic renal failure The target Hct level for EPO therapy is 30-35% If the target Hct is achieved, EPO dose should be decreased If the Hct level exceeds 40%, EPO therapy should be interrupted until Hct is decreased to target level If failure to achieve the target Hct within 3 months, EPO therapy should be interrupted and causes of resistance should be examined EPO should be administered subcutaneously

Social Insurance Institution (SSK) 2002 Year Drug Application Directions Item 30 Principles of erythropoietin usage EPO therapy should be used when the Hb (Hct) is less than 8 g/dl (24%) If the following conditions is determined during the initial evaluation, EPO therapy should not be used Iron deficiency Chronic infection Ischemic vascular disease Blood loss Aluminium overload Uncontrolled hypertension Hemolysis Hyperparathyroidism Vascular access thrombosis

Social Insurance Institution (SSK) 2002 Year Drug Application Directions The target Hb (Hct) level is 10-11 g/dl (30-33%) If the Hb (Hct) level exceeds the 11 g/dl (33%), EPO therapy should be interrupted EPO Resistance: Despite the EPO therapy at dose of 150 units/kg/week, no increase in Hb/Hct within 3 months If no increase in Hb/Hct level within two months, EPO therapy should be interrupted EPO should be administered subcutaneously

CURRENT ASPECTS OF ANEMIA THERAPY AND USE OF ERYTHROPOIETIN IN TURKEY

Use of erythropoietin in dialysis patients in Turkey % TSN Registry

Use of erythropoietin in hemodialysis patients in Turkey % Ministry of Health Data

Mean hemoglobin level in dialysis patients in Turkey TSN Registry-2002

Percent of patients with hemoglobin 11 g/dl in Turkey % TSN Registry

The success rate with erythropoietin in dialysis patients in Turkey % TSN Registry-2002

Use of iron therapy in dialysis patients in Turkey % TSN Registry-2002

Serum ferritin level in dialysis patients in Turkey % TSN Registry-2002

Data of United Kingdom Renal Registry %

CONCLUSION Anemia is present in the majority of the patients with CRF, and when untreated, it is associated with poor clinical outcomes Today, anemia treatment and use of erythropoietin is guided by social security organisations in Turkey Directions of erythropoietin usage suggested by these organisations are cost-based but not evidence-based Principles of anemia treatment in Turkey should be rearranged according to TSN Anemia Guidelines