ESAs and Outcomes in CKD Patients

Philip Lui PharmDThe 13th Annual Contemporary Therapeutic

Issues in Cardiovascular DiseaseMay 8, 2010

Anemia in CKD Patients

• Associated with impairment in quality of life, reduced energy, neurocognitive decline, decreased exercise capacity, and increased mortality

• Erythropoiesis-stimulating agents (ESAs): epoetin alfa, epoetin beta, darbepoetin alfa

Hemoglobin Targets

Significantly higher primary end point of death, MI, hospitalization for CHF, or stroke in higher hemoglobin target group

No significant difference

NEJM 2006;355:2071-84, NEJM 2006;355:2085-98

Normal Hematocrit study

NEJM 1998;339:584-90

NEJM 2009;361:2019-32

TREAT

• Randomized, double-blind, placebo-controlled trial

• 4038 patients with type 2 diabetes, chronic kidney disease not on dialysis and anemia

• Darbepoetin to increase Hb to 130g/L versus placebo with rescue darbepoetin if Hb < 90g/L

TREAT

NEJM 2009;361:2019-32

TREATDarbepoetin (n=2012)

N (%)Placebo (n=2026)

N (%)P value

CV composite 632 (31.4) 602 (29.7) 0.41

Death from any cause 412 (20.5) 395 (19.5) 0.48

Myocardial infarction 124 (6.2) 129 (6.4) 0.73

Stroke 101 (5.0) 53 (2.6) <0.001

Heart failure 205 (10.2) 229 (11.3) 0.24

Myocardial ischemia 41 (2.0) 49 (2.4) 0.40

Renal composite 652 (32.4) 618 (30.5) 0.29

TREAT

Darbepoetin group• More thromboembolism (2.0% vs. 1.1%)• More deaths from cancer among patients with

history of cancer (7.4% vs. 0.6%)• Fewer transfusions (14.8% vs. 24.5%)• Quality of life scores

Implications

• Placebo controlled• Largest trial with the most adjudicated events• Did not confirm the higher rates of death and

hospitalization for CHF in CHOIR• Darbepoetin confers no benefit in mortality or

cardiovascular or renal outcomes compared to placebo

Stroke Risks

CHOIR, CREATE• No difference

Normal Hematocrit study• High Hct 6.3% vs. low Hct 4.7% (p=ns)

Canadian-European Normalization of Hemoglobin with Erythropoietin trial• High Hb 4% vs. low Hb 1% (p<0.05)

NEJM 1998;339:584-90, J Am Soc Neph 2005;16:2180-9

Potential Mechanisms

• Increased viscosity and wall shear stress• Thrombocytosis• Increased platelet reactivity, adhesion, and

aggregation• Increased arterial pressure

Am J Kidney Dis 2009;53(5):733-6, Adv Chronic Kidney Dis 2009;16(2):131-42

TREAT Quality of Life

• FACT–Fatigue • Improvement in mean score - darbepoetin 4.2 vs.

placebo 2.8• Clinically meaningful change of 3 points -

darbepoetin 55% vs. placebo 50%• SF-36

• No significant difference

Quality of Life

CHOIR (LASA, KDQ, SF-36)• Both groups improved, no significant difference

CREATE (SF-36)• Significant improvements in high Hb target group

Outstanding Unknowns

• Dose• Hemoglobin target• ESA hyporesponsiveness• Different dosing strategy• Class effect• Patient population• Quality of Life

Treatment of Anemia

CKD patients not on dialysis• Minimize ESA use for mild to moderate anemia

(90-110g/L) especially for those with minimal fatigue

• Minimize ESA use for those with history of cancer or stroke

• Transplant candidates or those with severe anemia (<90g/L) may consider long term ESA to maintain Hb between 90g/L and 110g/L

J Am Soc Neph 2010;21:1-13

Treatment of Anemia

Dialysis patients• Use lowest dose to maintain Hb above 90g/L• Pursue other strategies to lower ESA dose (eg. SC

instead of IV, peritoneal dialysis, iron, treat inflammation)

• Minimize ESA use in patients who are within 2 years of diagnosis of malignancy

J Am Soc Neph 2010;21:543-55