Anemia Guidelines and The Use of Erythropoietin in Turkey

Anemia Guidelines and The Use of Anemia Guidelines and The Use of

Erythropoietin in TurkeyErythropoietin in Turkey

Kenan ATEŞ, MD

Department of NephrologyAnkara University Faculty of Medicine

Anemia in chronic renal failure

GFR <40 ml/minGFR <40 ml/min

ANEMİAANEMİA

Normocytic normochromic Normocytic normochromic

Erythropoietin deficiencyErythropoietin deficiency

Iron deficiencyIron deficiency

Folate/Vitamin BFolate/Vitamin B1212 deficiency deficiency

InflammationInflammation

Aluminium overloadAluminium overload

Blood lossBlood loss

HemolysisHemolysis

Erythropoesis inhibitionErythropoesis inhibition

Anemia is importantAnemia is important

Decreased tissue oxygenDecreased tissue oxygendelivery and utilizationdelivery and utilization

Increased cardiac outputIncreased cardiac output

Ventricular hypertrophyVentricular hypertrophy

Cardiac enlargementCardiac enlargement

Angina pectorisAngina pectoris

Congestive heart failureCongestive heart failure

Decreased cognition andDecreased cognition andmental acuitymental acuity

Altered menstrual cyclesAltered menstrual cycles

Decreased sexual functionDecreased sexual function

Impaired immune responsivenessImpaired immune responsiveness

Growth retardationGrowth retardation

Decreased intellectual performanceDecreased intellectual performance

Reduced quality of lifeReduced quality of life

Decreased survivalDecreased survival

Poor patient rehabilitationPoor patient rehabilitation

Treatment of anemia

Adequate dialysisAdequate dialysis

Adequate nutritionAdequate nutrition

Treatment of secondaryTreatment of secondaryhyperparathyroidismhyperparathyroidism

Prevention of inflammationPrevention of inflammation

Iron supplementationIron supplementation

TargetTargetHb/Hct LevelHb/Hct Level

ERYTHROPOIETINERYTHROPOIETIN

Not all dialysis patients will require treatment with EPONot all dialysis patients will require treatment with EPO

HDHD

PDPD

20%20%

40%40%

Adequate dialysisAdequate dialysis

Adequate nutritionAdequate nutrition

Iron supplementationIron supplementation

Other measuresOther measures

C O S T

EPO therapy is a very expensive treatmentEPO therapy is a very expensive treatment

One month costOne month cost

HEMODIALYSISHEMODIALYSIS 900 $900 $

EPO (6000 U/wk)EPO (6000 U/wk) 500 $500 $

ANEMIA GUIDELINES

Anemia Guidelines

The aim of guidelines is to provide an evidence-basedThe aim of guidelines is to provide an evidence-basedstandard of care for management of anemia in patientsstandard of care for management of anemia in patientswith chronic renal failurewith chronic renal failure

NKF-DOQI GUIDELINESNKF-DOQI GUIDELINES

EUROPEAN BEST PRACTICE GUIDELINESEUROPEAN BEST PRACTICE GUIDELINES

19961996

19991999

20032003 TSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINES

When to initiate the work-up of anemia

Hb <11 g/dl (Hct <33%)Hb <11 g/dl (Hct <33%)Pre-menopausal femalesPre-menopausal femalesPre-pubertal patientsPre-pubertal patients

Post-menopausal femalesPost-menopausal femalesAdult malesAdult males

Hb <12 g/dl (Hct <37%)Hb <12 g/dl (Hct <37%)



TSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINES

Evaluation of anemia

Hemoglobin and/or hematocritHemoglobin and/or hematocrit

Red blood cell indicesRed blood cell indices

Reticulocyte countReticulocyte count

Occult blood in stoolOccult blood in stool

Serum ironSerum iron

TIBCTIBC

Transferrin saturationTransferrin saturation

Serum ferritinSerum ferritin

Percen. of hypochromic red cellsPercen. of hypochromic red cells

Iron parametersIron parameters



CRPCRP


Evaluation of anemia

Serum vitamin BSerum vitamin B1212 and folic acid and folic acid

Differential white blood countDifferential white blood count

Tests for hemolysisTests for hemolysis

Serum protein electroforesisSerum protein electroforesis

Bone marrow examinationBone marrow examination

Serum aluminiumSerum aluminium

A fuller work-up should also include the following, as indicatedA fuller work-up should also include the following, as indicated

Hemoglobin electroforesisHemoglobin electroforesis TSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINES

EUROPEAN BESTEUROPEAN BEST PRACTICE GUIDELINESPRACTICE GUIDELINES

No cause for anemia is detected by the work-upNo cause for anemia is detected by the work-up

Erythropoietin deficiency

Anemia is most likely due to EPO deficiencyAnemia is most likely due to EPO deficiency

IfIf

A normocytic, normochromic anemia is presentA normocytic, normochromic anemia is present

Impairment of renal function is presentImpairment of renal function is present




Indications for starting treatment with Erythropoietin

EPO treatment should be consideredEPO treatment should be considered when the Hb concentration is consistently less thanwhen the Hb concentration is consistently less than 11 g/dl on repeating testing (Hct <33%) 11 g/dl on repeating testing (Hct <33%) when other causes of anemia have been excludedwhen other causes of anemia have been excluded



Indications for starting treatment with Erythropoietin


Hb <10 g/dlHb <10 g/dlHtc <30%Htc <30%

EPO TREATMENTEPO TREATMENT

Higher Hb and/or Hct levelsHigher Hb and/or Hct levels

ASYMPTOMATICASYMPTOMATICPATIENTSPATIENTS

SYMPTOMATICSYMPTOMATICPATIENTSPATIENTS

Heart failure, anginaHeart failure, angina

Serum creatinine Serum creatinine 2 mg/dl2 mg/dl

Check HbCheck Hb

Work-upWork-up

NormalNormal Fe deficiencyFe deficiency

Treat with EPOTreat with EPOif indicatedif indicated

Anemia not correctedAnemia not corrected

<12 g/dl in males and post-menopausal females<12 g/dl in males and post-menopausal females<11 g/dl in pre-menopausal females and pre-pubertal patients<11 g/dl in pre-menopausal females and pre-pubertal patients

Treat with ironTreat with iron

Anemia correctedAnemia corrected

HematologyHematologywork-upwork-up

NoNo

Target hematocrit/hemoglobin for erythropoietin therapy

HemoglobinHemoglobin

HematocritHematocrit

11-12 g/dl11-12 g/dl

33-36%33-36%




Variations in the target Hb may be requiredVariations in the target Hb may be requiredin patients with co-morbidityin patients with co-morbidity

Assesment of iron status

Serum ironSerum iron

Total iron binding capacityTotal iron binding capacity



Percentage of hypochromic red cellsPercentage of hypochromic red cells

Iron stores in bone marrowIron stores in bone marrow

RBC ferritin concentrationRBC ferritin concentration



BEST PRACTICE GUIDELINESBEST PRACTICE GUIDELINES

Target iron level



>20%>20%

>100 ng/ml>100 ng/ml

30-40%30-40%

200-500 ng/ml200-500 ng/ml

The patients should have sufficient iron to achieve andmaintain an Hb (Hct) of 11-12 g/dl (33-36%)

Hypochromic red cellsHypochromic red cells <10%<10% <2.5% (<5%)<2.5% (<5%)

OPTIMALOPTIMAL

TSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINESNKF-DOQI GUIDELINESNKF-DOQI GUIDELINES


Monitoring iron status

Every monthEvery month

Every 3 monthsEvery 3 months Every 3-6 monthsEvery 3-6 months

Patients treated with EpoPatients treated with Epo Patients not treated with EpoPatients not treated with Epo

Hb/Hct stableHb/Hct stable

Ferritin Ferritin 100 ng/ml100 ng/mlTSAT TSAT 20%20%

Hb <11 g/dlHb <11 g/dlHct <33%Hct <33%

Hb 11-12 g/dlHb 11-12 g/dlHct 33-36%Hct 33-36%

Every 3 monthsEvery 3 months




ReceivingReceivingIV ironIV iron

Not receivingNot receivingIV ironIV iron

Administration of supplemental iron

TSAT <20%TSAT <20%Ferritin <100 ng/mlFerritin <100 ng/ml

100-125 mg IV iron100-125 mg IV ironat every HD seansat every HD seans

for 8-10 dosesfor 8-10 doses

25-125 mg IV iron25-125 mg IV ironper weekper week

100-125 mg IV iron at every HD seans100-125 mg IV iron at every HD seansfor 8-10 dosesfor 8-10 doses

TSAT <20%TSAT <20%Ferritin <100 ng/mlFerritin <100 ng/ml

TSAT >20%TSAT >20%Ferritin >100 ng/mlFerritin >100 ng/ml

IV iron therapyIV iron therapyshould be withheldshould be withheld

for 3 monthsfor 3 months

TSAT >50%TSAT >50%Ferritin >800 ng/mlFerritin >800 ng/ml

Oral iron therapy

It should be given as 200 mg of elemental iron per day,It should be given as 200 mg of elemental iron per day,in two to three divided doses in the adult patient, andin two to three divided doses in the adult patient, and2-3 mg/kg/day in the pediatric patient2-3 mg/kg/day in the pediatric patient

When oral iron is usedWhen oral iron is used




Route of administration of erythropoietin

EPO should be administered SC in PD patientsEPO should be administered SC in PD patients

The most effective route of EPO is SC in HD patientsThe most effective route of EPO is SC in HD patients

INTRAVENOUSINTRAVENOUS

SUBCUTANEOUSSUBCUTANEOUS

INTRAPERITONEALINTRAPERITONEAL

INTRADERMALINTRADERMAL




Initial erythropoietin administration

SCSC 80-120 units/kg/week, in two to three doses per week80-120 units/kg/week, in two to three doses per week

IVIV 120-180 units/kg/week, in three doses per week120-180 units/kg/week, in three doses per week



SCSC The starting dose should be in the lower rangeThe starting dose should be in the lower range

IVIV The starting dose should be in the upper rangeThe starting dose should be in the upper range


The starting dose of EPO should be 50-150 units/kg/weekThe starting dose of EPO should be 50-150 units/kg/week


SCSC The starting dose should be 75 units/kg/weekThe starting dose should be 75 units/kg/week

IVIV The starting dose should be 150 units/kg/weekThe starting dose should be 150 units/kg/week


Monitoring of Hb/Hct during erythropoietin therapy

Every 1-2 weeksEvery 1-2 weeks


Target Hb/Hct is achievedTarget Hb/Hct is achieved

Target Hb/Hct is not achievedTarget Hb/Hct is not achieved


BEST PRACTICE GUIDELINESBEST PRACTICE GUIDELINES Every 1-2 weeksEvery 1-2 weeks

TSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINES Every 2 weeksEvery 2 weeks





Every 4 weeksEvery 4 weeks

Titration of erythropoietin dosage

Dose should be increased byDose should be increased by50%50%

Dose should be decreased byDose should be decreased by25-50%25-50%

After initation of EPOAfter initation of EPOAfter a dose increaseAfter a dose increase

If the increase in Hb (Hct) isIf the increase in Hb (Hct) is<0.7 g/dl (<2%) over a 2-4 <0.7 g/dl (<2%) over a 2-4 week periodweek period

If the increase in Hb/Hct isIf the increase in Hb/Hct is>2.5 g/dl (>8%) per month>2.5 g/dl (>8%) per month



If the Hb (Hct) exceedsIf the Hb (Hct) exceedsthe target levelsthe target levels

Titration of erythropoietin dosage

Dose should be increased byDose should be increased by12.5-25 units/kg/week12.5-25 units/kg/week

Dose should be decreased byDose should be decreased by50%50%

After initation of EPOAfter initation of EPOAfter a dose increaseAfter a dose increase

If the increase in Hb (Hct) isIf the increase in Hb (Hct) is<1.0 g/dl (<3%) over a 4-6 <1.0 g/dl (<3%) over a 4-6 week periodweek period


If the increase in Hb/Hct isIf the increase in Hb/Hct is>1.5 g/dl (>5%) per month>1.5 g/dl (>5%) per month

Inadequate response to erythropoietin

Failure to achieve target Hb/Hct in the presence of adequateiron stores at dose of 450 units/kg/wk IV or 300 units/kg/wkSC within 4-6 months or failure to maintain target Hb/Hct subsequently at that dose

DEFINITIONDEFINITION

Failure to attain the target Hb concentration while receivingmore than 300 units/kg/wk (~20.000 units/wk) of EPO SC ora continued need for such dosage to maintain the target



Inadequate response to erythropoietin

DEFINITIONDEFINITION


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


Infection/inflamationInfection/inflamation

Chronic blood lossChronic blood loss

Osteitis fibrosaOsteitis fibrosa


Folate/Vitamin BFolate/Vitamin B1212 deficiency deficiency

HemoglobinopathiesHemoglobinopathiesMalnutritionMalnutrition

HemolysisHemolysis Multiple myelomaMultiple myeloma



EPO RESISTANCEEPO RESISTANCE

Non-complianceNon-compliance

Iron storesIron stores

AdequateAdequate

CRPCRP

ReticulocyteReticulocyteLDHLDHBilirubinBilirubinBlood smearBlood smear

Occult bloodOccult bloodin stoolin stool

Vitamin BVitamin B1212/Folate/FolateBlood smearBlood smear

PTHPTHBone marrowBone marrowexaminationexamination

Serum aluminiumSerum aluminium

Hb electrof.Hb electrof.

InadequateInadequate

InfectionInfectionInflammationInflammationMalignancyMalignancy


HemolysisHemolysis

VitaminVitamindeficiencydeficiency

AluminiumAluminiumoverloadoverload

Bone marrowBone marrowfibrosisfibrosis

HemoglobinopathiesHemoglobinopathiesTSN ANEMIA GUIDELINESTSN ANEMIA GUIDELINES

LEGAL ARRANGEMENTS

Ministry of Finance2003 Fiscal Year

Budget Application Directions

Official Gazette: Date 01.02.2003, Number 25011 Official Gazette: Date 01.02.2003, Number 25011

Use of erythropoietin in patients with chronic renal failureUse of erythropoietin in patients with chronic renal failure

The target Hct level for EPO therapy is 30-35%The target Hct level for EPO therapy is 30-35%

If the target Hct is achieved, EPO dose should be decreasedIf the target Hct is achieved, EPO dose should be decreased

If the Hct level exceeds 40%, EPO therapy should beIf the Hct level exceeds 40%, EPO therapy should beinterrupted until Hct is decreased to target levelinterrupted until Hct is decreased to target level

EPO should be administered subcutaneouslyEPO should be administered subcutaneously

If failure to achieve the target Hct within 3 months, EPOIf failure to achieve the target Hct within 3 months, EPOtherapy should be interrupted and causes of resistancetherapy should be interrupted and causes of resistanceshould be examinedshould be examined

Social Insurance Institution (SSK)2002 Year Drug Application Directions

EPO therapy should be used when the Hb (Hct) is less thanEPO therapy should be used when the Hb (Hct) is less than8 g/dl (24%) 8 g/dl (24%)

If the following conditions is determined during the initialIf the following conditions is determined during the initialevaluation, EPO therapy should not be usedevaluation, EPO therapy should not be used



HemolysisHemolysis

Chronic infectionChronic infection


HyperparathyroidismHyperparathyroidism

Uncontrolled hypertensionUncontrolled hypertension

Vascular access thrombosisVascular access thrombosis

Ischemic vascular diseaseIschemic vascular disease

Item 30 Principles of erythropoietin usage

Social Insurance Institution (SSK)2002 Year Drug Application Directions

EPO Resistance:EPO Resistance: Despite the EPO therapy at dose of Despite the EPO therapy at dose of150 units/kg/week, no increase in Hb/Hct within 3 months150 units/kg/week, no increase in Hb/Hct within 3 months

The target Hb (Hct) level is 10-11 g/dl (30-33%)The target Hb (Hct) level is 10-11 g/dl (30-33%)

If the Hb (Hct) level exceeds the 11 g/dl (33%), EPO therapyIf the Hb (Hct) level exceeds the 11 g/dl (33%), EPO therapyshould be interruptedshould be interrupted

If no increase in Hb/Hct level within two months, EPOIf no increase in Hb/Hct level within two months, EPOtherapy should be interruptedtherapy should be interrupted

EPO should be administered subcutaneouslyEPO should be administered subcutaneously

CURRENT ASPECTS OF ANEMIA THERAPY AND USE OF

ERYTHROPOIETIN IN TURKEY

Use of erythropoietin in dialysis patients in Turkey

0

20

40

60

80

100

1996 1997 1998 1999 2000 2001 2002

HD

PD%

TSN RegistryTSN Registry

Use of erythropoietin in hemodialysis patients in Turkey

52,9 56,6

71,1 75

0

20

40

60

80

100

Universityhospital

SSK hospital Ministry ofHealth

hospital

Privateenterprise

%

Ministry of Health DataMinistry of Health Data

Mean hemoglobin level in dialysis patients in Turkey

7

8

9

10

11

12

Mea

n H

b (

g/d

l)

HD PD

TSN Registry-2002TSN Registry-2002

Percent of patients with hemoglobin 11 g/dl in Turkey

0

20

40

60

80

100

2001 2002

HDPD

%

TSN RegistryTSN Registry

The success rate with erythropoietin in dialysis patients in Turkey

0

20

40

60

80

100

Hb >11 g/dl withEPO

EPO resistance

HDPD

%


Use of iron therapy in dialysis patients in Turkey

0

20

40

60

80

100

Oral Parenteral

HDPD

%


Serum ferritin level in dialysis patients in Turkey

0

10

20

30

40

50

60

70

<100 100-399 400-800 >800

HD

PD%


Data of United Kingdom Renal Registry

0

20

40

60

80

100

Use of EPO Hb >11 g/dl

HD PD

7

8

9

10

11

12

13

Mean Hb

%

CONCLUSION

Today, anemia treatment and use of erythropoietin is guidedToday, anemia treatment and use of erythropoietin is guidedby social security organisations in Turkey by social security organisations in Turkey

Anemia is present in the majority of the patients with CRF, andAnemia is present in the majority of the patients with CRF, andwhen untreated, it is associated with poor clinical outcomeswhen untreated, it is associated with poor clinical outcomes

Directions of erythropoietin usage suggested by theseDirections of erythropoietin usage suggested by theseorganisations are cost-based but not evidence-basedorganisations are cost-based but not evidence-based

Principles of anemia treatment in Turkey should be rearrangedPrinciples of anemia treatment in Turkey should be rearrangedaccording to TSN Anemia Guidelinesaccording to TSN Anemia Guidelines

Documents

Anemia Guidelines and The Use of Erythropoietin in Turkey