Anemia Guidelines

Anemia Guidelines

Şehsuvar Ertürk, MD, FASN

Ankara University School of Medicine

Across seacoast is motherland

I shout fromDo you hear me? Memet, Memet!

Nazım Hikmet

Goals of the lecture

To know impact of anemia on clinical outcomes in patients with chronic kidney disease.

To approach management of anemia of chronic kidney disease in terms of evidence-based medicine.

Plan

BackgroundEpidemiological aspectsPathophysiologyConsequences of anemia management

Guidelines/recommendations Current practice patterns

Bright-1830s

“Anemia is a characteristic manifestation of chronic kidney disease”

Levin A. Kidney Int 61 (Suppl 80):S35-S38, 2002.

Prevalence of anemia in CKD

Etiology of anemia

Bone marrow depressionRelative EPO deficiency / resistance to EPOInflammatory cytokinesApopitosis / decreased eryhtroid progenitors

Reduced availability of ironMalnutritionDecreased absorptionGIS losses (ASA, NSAID)Iatrogenic (repeated blood testing)

Hemodilution (water and sodium retention)

Rao M and Pereira BJG. Kidney Int 68:1432-38, 2005Lewis BS, et al. Nephrol Dial Transplant 20(Suppl 7):vii3-6, 2005

Hemodynamic (Increased Cardiac Output)

Systemic arterial dilatationDecreased TPRReduced afterloadIncreased stroke volume

Decreased blood viscosityIncreased venous returnIncreased preload

Symphatetic activationIncreased heart rate

Non-hemodynamic(Increased O2 extraction)

Increased EPO production (?)Increased 2,3-DPG

Pereira AA and Sarnak MJ. Kidney Int 64(Suppl 87):S32-S39, 2003Silverberg D. Nephrol Dial Transplant 18(Suppl 2):ii7-12, 2003Levin A. Kidney Int 61(Suppl 80):S35-S38, 2002

Pathophysiology of anemia

Consequences of anemia

Exercise capacityCoagulation

Immune responseCognitive function

Sexual functionAppetite/Nutrition

Growth (in children) Quality of life

DepressionAngina

LVHCardiac failure

MyopathyRenal disease progression

MorbidityMortality

Gomez JML and Carrera F. Kidney Int 61 (Suppl 80):S39-S43, 2002

Impact of anemia on outcomes General population

>1 Million Medicare subjects, Age>67y

1-y mortality Anemia 8% CKD 8% CHF 13% None 4% All 23%

Herzog CA, et al. J Card Fail 10:467-72, 2004

Anemia and clinical outcomes CKD (pre-dialysis)

Increased risk for

MortalityCVD (LVH, LVD, CHF)

Progression of kidney disease

Anemia and clinical outcomes CKD (pre-dialysis)

246 patients, 12 months follow-up,>20% increase in LVMI OR

Hb 0.5 g/dL 1.32

853 male patients, Mortality and ESRD

Hb<12 g/dL 1.97Hb<11 g/dL 2.57

Levin A, et al. Am J Kidney Dis 27:347-54, 1996

Kovesdy CP, et al. Kidney Int 69:560-64, 2006

Anemia and clinical outcomes CKD (pre-dialysis) (RENAAL Study)

Shahinfar S, et al. Kidney Int 67(Suppl 93):S48-S51, 2005

Anemia and clinical outcomes ESRD

Mortality 432 patients

Hb 1 g/dL 14%

Foley RN, et al. Am J Kidney Dis 28:53-61, 1996.

93.087 patients Hb (g/dL) <10 64% Hb (g/dL) 12-13 21%

Roberts TL, et al. Nephrol Dial Transplant 21:1652-62,

2006.


12.733 patients Mortality HR (95% CI)

WhitesHb (g/dL) <10 1.32 (1.16-1.48)

AAs

Hb (g/dL) <10 1.50 (1.27-1.76) 10-<11 1.60 (1.37-1.84)

Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.


Longer time to target Hb levels HR (95% CI)Hospitalization 1.15 (1.12–1.19) Mortality 1.26 (1.20–1.33)Ishani A, et al. Nephrol Dial Transplant 22:2247-55, 2007.

More months below target Hb levels RR (95% CI)Hospitalization 1.70 (1.63–1.76)Mortality 2.48 (2.28–2.69)Ishani A, et al. Nephrol Dial Transplant 23:1682-89, 2008.

Economic issues

Cost difference between anemic and non-anemic patients:

CHF 29.511 USD / patient / yearCKD 20.529Cancer 18.418

Ershler WB, et al. Value Health 8:629-38, 2005

Potential benefits/risks of treatment of anemia with ESAs and iron

Benefits

Improved quality of life (QOL)

Decrease in LVMISlowing the progressionDecrease in hospitalizationsImproved survival

Risks

HypertensionThrombosis

Increase in mortality

?

?

Effect of treatmentCKD-predialysis (RCTs)

Increased exercise capacity, QOL

Teehan BP, et al. Am J Kidney Dis 18:50-9, 1991.Revicki DA, et al. Am J Kidney Dis 25:548-54, 1995.Ritz E, et al. Am J Kidney Dis 49:194-207, 2007.

Effect of treatmentCKD-predialysis (RCTs)

No effect on LVMI 155 patients, Hb 12.1 vs. 10.8 g/dLRoger SD, et al. JASN 15:148-56, 2004.

No effect on LVMI,prevention of new LVH172 patients, DM Type 1 and 2,Hb 13.5 vs.12.1 g/dLRitz E, et al. AJKD 49:194-207, 2007.

Decrease in LVMI101 patients, Hb 11.3 vs. 9.1g/dLAyus JC, et al. Kidney Int 68:788-95, 2005.

Effect of treatmentCKD-predialysis (Recent RCTs)

CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency)

CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epo beta)

TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy)

No cardiovascular or renal benefits or even detrimental outcomes of higher targets.

Singh AK, et al. N Engl J Med 355:2085-98, 2006.Drüeke TB, et al. N Engl J Med 355:2071-84, 2006.Pfeffer MA, et al. N Engl J Med 2009 (doi: 10.1056/NEJMoa0907845)

Effect of treatmentESRD-dialysis (RCTs)

Increase in mortality (1.236 pts., Hb 14 vs. 10 g/dL)

Besarab A, et al. N Engl J Med 339, 584-90, 1998.

No effect on LVMI, prevention of new LVD (146 pts., Hb 13 vs. 10 g/dL)

Foley RN, et al. Kidney Int 58:1325-35, 2000.

No effect on LVMI, improvement in QOL (596 pts., Hb 13.3 vs. 10.9 g/dL)

Parfrey PS, et al. J Am Soc Nephrol 16:2180-89, 2005.

Effect of treatment(CKD-predialysis+dialysis) (Metaanalysis)

A: Study cohorts with severe anemia at baseline and lower target Hb. B: Study cohorts with moderate anemia at baseline and lower target Hb.

Parfrey PS, et al. CJASN 4:755-62, 2009.

High Hb vs. ESA dose

Goodkin DA. Semin Dial 22:495-502, 2009.


Regidor DL, et al. JASN 17:1181-91, 2006.


Mortality HR (95% CI)

WhitesEPO dose (UI/wk) <4,500 0.82 (0.72-0.93)

AAsEPO dose (UI/wk) >20,000 1.32 (1.12-1.53)



Szczech LA, et al. Kidney Int 74:791–98, 2008.

Ağaoğlu Ö. Train, Yenice, 2001

Clinical Practice Guidelines/Recommendations

ERBP ERBP

Diagnosis/Evaluation/Target Hb/Using ESAs-Iron-Adjuvants/Resistance

EBPG KDOQI

Diagnosis of anemia Hb levels should be measured at least

annually in all patients with CKD (regardless of stage or cause).

Diagnosis of anemia should be made if Hb concentrations

<13.5 g/dL in adult males.<12.0 g/dL in adult females.

Evaluation of anemia Hb concentration, white blood cell count and

platelet count Red blood cell indices

mean corpuscular volume [MCV] mean corpuscular hemoglobin [MCH] mean corpuscular hemoglobin concentration [MCHC])

Absolute reticulocyte count Serum ferritin Serum TSAT or

Content of Hb in reticulocytes (CHr)

Target Hb levels

Hb levels of 11-12 g/dL should be sought, without intentionally exceeding 13 g/dL.

Using ESAs ESAs should be given to all patients

with CKD with Hb levels consistently (i.e., measured twice at least 2 weeks apart) below 11 g/dL, where all other causes of anemia have been excluded.

Using ESAs The initial ESA dose and ESA dose

adjustments should be determined by

Patient’s Hb level Target Hb levelObserved rate of increase in Hb level

The frequency of Hb monitoring in patients treated with ESAs should be at least monthly.

Using ESAs The objective of initial ESA therapy

is a rate of increase in Hb levels of 1-2 g/dL per month.

ESA doses should be decreased by 25%, but not necessarily held, when a downward adjustment of Hb level is needed.

Using ESAs The route and frequency of ESA administration

Non–HD-CKD patients Subcutaneous HD-CKD patients Intravenous

Less frequent administration, particularly in non–HD-CKD patients.

Using iron agents Iron status should be evaluated every month

during initial ESA treatment and at least every 3 months during stable ESA treatment or in patients with HD-CKD not treated with an ESA.

Targets levels:TSAT >20% andSerum ferritin >200 ng/mL HD-CKD >100 ng/mL ND-CKD, PD-CKD

Upper limit of ferritin level?

Using iron agents Route of administration

HD-CKD I.V. ND-CKD or PD-CKD I.V. or oral

Hypersensitivity reactionsIron dextran Resuscitative medication

and personnel

All forms of IV iron (iron dextran, gluconate, and sucrose) may beassociated with acute adverse events.

Using adjuvants to ESA

There is insufficient evidence to recommend the use of vitamin C (ascorbate) and L-carnitine.

Androgens should not be used as

an adjuvant to ESA treatment in the management of anemia in patients with CKD.

Transfusion therapy

No specific Hb concentration justifies or requires transfusion.

DefinitionA significant increase in the ESA dose requirement to maintain a certain Hb level or a significant decrease in Hb level at a constant ESA dose, A failure to increase the Hb level to >11 g/dL despite an ESA dose equivalent to epoetin > 500 IU/kg/wk.

CausesPersistent iron deficiencyInfection/Inflammatory disease/Catheter insertion/ Hypoalbuminemia/Elevated C-reactive protein levelPancytopenia/aplastic anemia/hemolytic anemiaCancer/Chemotherapy/RadiotherapyAcquired immune deficiency syndrome

Causes of hyporesponsivenessHyporesponse

Antibody-mediated PRCA Diagnosis

Sudden rapid decline in Hb level at the rate of 0.5 to 1.0 g/dL/wk, or requirement of red blood cell transfusions at the rate of approximately 1 to 2 per week; normal platelet and white blood cell counts; and absolute reticulocyte count less than 10,000/L.The definitive diagnosis is dependent upon demonstration of the presence of neutralizing antibodies against erythropoietin.

ManagementDiscontinue the administration of any ESA productTransfusion supportTreatment with immunosuppressive approaches

Retreatment with ESAs can be considered if anti-EPO antibodies are not detectable.

Music therapy Sultan Bayezid II Medical School, 17th Century

Health Museum, Trakya University, Edirne, Turkey

Are the guidelines useful?

------------------------------------------------------------------------------------------------------------Hematocrit Frequency Mortality(33 to 36%) (%) HR (95% CI) ------------------------------------------------------------------------------------------------

0 of 3 28.1 1.00 1 of 3 36.5 0.88 (0.82 to 0.94) 2 of 3 25.4 0.81 (0.75 to 0.87) 3 of 3 10.0 0.68 (0.61 to 0.76)

------------------------------------------------------------------------------------------------

Tentori F, et al. JASN 18:2377-84, 2007.

Satisfying KDOQI guidelines and mortality risk:(Hematocrit, Serum albumin, Phosphorus, Calcium, PTH, and spKt/V)

Frequency, 1% HR (95% CI) 0.11 (0.06-0.19)

Current practicePredialysis

24.778 patients, age>67y

Claims for anemia testing during 2 years prior to dialysis <50%

Kausz AT, et al. J Am Soc Nephrol 16:3092-101, 2005.

Current practiceDOPPS

Locatelli F, et al. Am J Kidney Dis 44(Suppl 2):S27-S33, 2004.

Current practiceUSRDS 2006

Foley RN and Collins AJ. JASN 18:2644-48, 2007.

Percentage of monthly rHuEPO claims when Hb>13 g/dL

2.0% to 16.7%

Monthly rHuEPO dose

38,687 to 54,299 units

Practice vs. Guidelines

Collins AJ, et al. Am J Kidney Dis 49:135-42, 2006.

Differences between the dialysis providers:

Not Receiving Epoetin (%)

Median Epoetin Dose (U/wk)

Overall 2.3 11,270

Hb (g/dL)<1010-<1111-<1212-<13>13

1.90.80.61.4

21.7

25,12216,42710,9829,1628,097


Practice vs. Guidelines

FDA vs. Guidelines

……The new boxed warning advises physicians

to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions. Physicians and patients should carefully weigh the risks of ESAs against transfusion risks.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108864.htm(Accessed on November 15th, 2009).

Practice vs. FDADialysis-Medicare

Percentage of patients receiving at least one transfusion (left Y axis), and mean hemoglobin (dark red line, right Y axis) from 1987 through 2006.

Coyne DW and Brennan DC. Semin Dial 22:590-91, 2009.

Conclusion Anemia is common among patients with

chronic kidney disease, and is associated with higher morbidity and mortality rates.

Individualized treatment with the use of moderate ESA doses in conjunction with iron therapy to keep hemoglobin between target levels of the currently available guidelines seems to be reasonable.

Conclusion Further studies to understand the

relationships between target hemoglobin level, ESA dose, and outcomes is essential in designing effective anemia management and reimbursement policies.

Documents

Anemia Guidelines