Anemia in CKD Part 2 of 2

Division of Nephrology and HypertensionEast Carolina University Brody School of Medicine

Objectives

• Review key aspects of anemia from Part 1• Be aware of regulatory and fiscal policy

surrounding anemia management in CKD• Understand key features of anemia trials

that have led to lowering of hemoglobin targets when patients are treated with ESA’s

Review from last presentation:

• Normocytic and normochromic• Reduced production of erythropoietin by the kidney

– Due to reduction of functioning renal mass

• Shortened RBC survival in CKD• We must be sure to exclude non-renal causes of

anemia in a patient with diminished GFR• Erythropoiesis stimulating agents include:

– Erythropoietin (=Epogen, Procrit)– Darbepoetin (=Aranesp) = 3x longer half-life

• Iron before ESA’s (goal Tsat >20%, ferritin > 100)

Review from last presentation: Evaluation of anemia in CKD

• Evaluation of anemia in CKD:– When Hgb < 12 g/dL in females and < 13.5

g/dL in males– Evaluation should include:

• RBC indices• Absolute reticulocyte count• Serum iron• Total iron binding capacity• % transferrin saturation• Serum ferritin• WBC count and differential; platelet count• Testing for blood in stool

History of US Regulatory and Fiscal Policy

• Erythropoietin FDA-approved 1989 with target Hct 30-33%

• Upper limit increased to 36% in 1994

• Hematocrit Measurment Audit Program– Any month Hct >36% only reimbursed if

previous 3 mos rolling average < 36.5%– Medical justification for Hct>36% ended– Short-lived program 1997-1998

History of US Regulatory and Fiscal Policy

• Post-payment review of “atypical” number of 3 month rolling averages >37.5%

• In 2006, mandatory 25% reduction in ESA dose for Hct>39%, 3 month rolling averages discontinued, caps on total monthly doses (500,000 units for Erythropoietin and 1500 mcgs for Darbepoetin alfa)

• WHO defines anemia as– <13 g/dL in men and post-menopausal women– <12 g/dL in pre-menopausal women

• Nearly 90% of individuals with GFR < 25cc/min have anemia, many < 10g/dL

• Over 90% of dialysis patients in the U.S. are maintained on ESA’s

but less than 35% of pre-dialysis CKD pts

receive ESAs

The Prevalence of Anemia in CKD

13

33

42

54

76

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10

20

30

40

50

60

70

80

>90 Stage 1

60-90 Stage 2

30-60 Stage 3

15-30 Stage 4

< 15 Stage 5

GFR (mL/min/1.73m2)

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Curr Med Res Opin. 2004;20:1501-1510.

Hemoglobin Targets

• Controversial• Higher hemoglobin levels have been associated

with adverse cardiovascular outcomes• Probably target hemoglobin of 11 – 12 g/dL is

acceptable in predialysis CKD patients– Though since 2006, following a series of FDA alerts,

titrating ESAs to a hemoglobin in the 10 – 12 g/dL range is becoming more acceptable

• If hemoglobin > 12 g/dL on ESA’s, should:– Decrease the dose OR– Increase the dosing interval

What is the evidence?

• Many retrospective population-based studies have explored outcomes associated with Hemoglobin levels in hemodialysis (HD) patients– Some variability but overall better outcomes

with Hgb 11-13 g/dL

What is the evidence?

• Normal Hematocrit trial in HD patients• CHOIR trial in pre-dialysis CKD patients• CREATE trial in pre-dialysis CKD patients

• Suggest that hemoglobin levels approaching the normal range are associated with significant adverse outcomes

• Also no convincing long-term benefits

CHOIR study

• 1432 patients with eGFR 15-50 cc/min and Hgb < 11 g/dL

• Assigned to target Hgb of either 11.3 g/dL or 13.5 g/dL

• Endpoints: composite of death/MI/stroke/CHF hospitalization

• Recommended target Hgb of 11-12 g/dL• Increased CV risk in this study without benefit in

quality of life among the group who achieved mean Hgb level of 12.6 g/dL (assigned to target of 13.5 g/dL)

• Terminated early, after a median duration of 16 months

CREATE study

• 603 patients with eGFR 15-35 cc/min and anemia• Assigned to a normal (13-15 g/dL) or subnormal

(10.5-11.5 g/dL) Hgb level• Endpoints: composite of 8 CV events (sudden

death, MI, acute CHF, stroke/TIA, hospitalization for angina pectoris or arrhythmia or complications of PVD)

• During the trial, hgb levels were 1.5-2 g/dL higher in the “normal” group (13.5 g/dL vs. 11.5 g/dL)

• At 3 years, similar risk of experiencing primary endpoint in both groups, similar changes in LV mass and rates of CKD progression but did show enhanced QOL in the “normal” group

2007 K/DOQI Anemia guideline update

• Recommended target Hgb of 11-12 g/dL

• Recommended target Hgb should not exceed 13 g/dL