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Targeting Hemoglobin and the Use Targeting Hemoglobin and the Use of Erythropoietin and Transfusion of Erythropoietin and Transfusion

in Cardiac Patientsin Cardiac Patients

Peter A. McCullough, MD, MPH, FACC, FACP

Chief, Division of Nutrition and Preventive MedicineMedical Director, Preventive Cardiology

Consultant CardiologistWilliam Beaumont Hospital

Royal Oak, MI

Anemia Correction and CVD Trials

Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP

Consultant Cardiologist and ChiefDivision of Nutrition and Preventive Medicine

William Beaumont HospitalBeaumont Health Center

Royal Oak, Michigan

El Achkar TM, et al. The Kidney Early Evaluation Program (KEEP 2.0). Accepted for publication, 2005.

57.1

42.9

16.5

6.8 6.7 5.3 6.4 6.6

0

10

20

30

40

50

60

An

emia

pre

vale

nce

(%

)

<30 30-59 60-89 >89

Estimated GFR (mL/min/1.73 m2)

Anemia prevalence by K/DOQI category of kidney function

Hb <12.0 g/dl for men and women >50 years

<11.0 g/dl for women <51 years oldDiabetic

Nondiabetic

Anemia Begins at a GFR <60 mL/min

1. Androne AS. Circulation. 2003;107:226-229.

Pathogenesis of Anemia Associated With CKD

Erythropoietin (epoetin alfa) deficiency

Epoetin alfa resistance

Hemodilution1

Chronic disease

Shortened RBC lifespan from 120 to 64 days

Iron losses (iron deficiency)– GI bleeding– Reduced intake

Malnutrition

Anemia related to ACE inhibitors/ARBs– Increased epoetin alfa consumption– Decreased glomerular stimulus for release– Inhibition of hemopoetic progenitor cells

AgingExcess LDL cholesterolMicro-organismsAuto-immunityMalignancies?

Monocyte/Macrophage

Bone marrow

Endothelial progenitor cells

Arteries

Injury InflammationIL-6VEGFT-CellMonocyte/Macrophage

{

+

Kidney

ErythropoietinErythropoietin

+

-

-Interferon

IL-1

TN

F

IL-6

?

VE

GF

T-Cell

O2

IL-6?

McCullough PA, Lepor NE. The deadly triangle of anemia, renal insufficiency, and cardiovascular disease: implications for prognosis and treatment. Rev Cardiovasc Med. 2005 Winter;6(1):1-10. NLM CIT. ID: 15741920

Deadly Triangle

Erythropoietin (Epoetin alfa) deficiency

Chronic disease (diabetes)

Elevated cytokines

Malnutrition

LVH

HF morbidity/mortality

MI mortality

PCI complications

All-cause death

CKD Anemia

CVD

Effect of Darbepoetin Alfa q 2 Weekly on Hb in 463 CKD Patients

Dose to achieve target: 64 17 mcg

Time to target: 40 32 days

Target range

60% received oral iron16% received IV iron60% received oral iron16% received IV iron

Toto et al. Am J Nephrol. 2004;24:453-460.

Hem

og

lob

in (

g/d

L)

14.0

13.5

13.0

12.5

12.0

11.5

11.0

10.5

10.0

9.5

9.0

8.5

8.0BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Study Week

N= 483 447 463456 455 456 451 458 454 453 451 452 453 447

EPO and Mortality

J Am Soc Nephrol 15: 3154–3165, 2004

EPO and HTN

J Am Soc Nephrol 15: 3154–3165, 2004

Hemoglobin Targets in CKD Patients

↑Quality of Life↑Physical Functioning↓LVH?Morbidity?Mortality

↑Thrombosis (↑Plt activity, ↑thrombin)↑HTN (ET↑, ADMA↑)↑Oxidative Stress (Fe)

Hb 11 g/dL to 13 g/dL

Tojo MK, etal, Hyertens Res 2004;27:79-84; Scalera F, J Am Soc Nephrol 2005;16:892-8.; Tobu M, et al, Clin Appl Thromb Hemost. 2004;10:225-32)

1313

CREATE Trial: Randomized Controlled Trial of CREATE Trial: Randomized Controlled Trial of Anemia Treatment in Pre-Endstage Renal FailureAnemia Treatment in Pre-Endstage Renal FailureCREATE Trial: Randomized Controlled Trial of CREATE Trial: Randomized Controlled Trial of

Anemia Treatment in Pre-Endstage Renal FailureAnemia Treatment in Pre-Endstage Renal Failure

CrCl=creatinine clearance; GFR=glomerular filtration rate; Hb=hemoglobin.CrCl=creatinine clearance; GFR=glomerular filtration rate; Hb=hemoglobin.Stevens et al. Stevens et al. Clin Med.Clin Med. 2003;3:503-508. 2003;3:503-508.

600 predialysis subjects, CrCl 15-35 mL/min600 predialysis subjects, CrCl 15-35 mL/min

Early intervention group, IIb 11-2.5 g/dLtarget Hb 13-15 g/dL

Early intervention group, IIb 11-2.5 g/dLtarget Hb 13-15 g/dL

Late intervention group, Hb 10 g/dLtarget Hb 10.5-11.5 g/dL

Late intervention group, Hb 10 g/dLtarget Hb 10.5-11.5 g/dL

CREATE

• The primary end point was a composite of 8 cardiovascular

events; secondary end points included left ventricular mass

index, quality-of-life scores, and the progression of chronic

kidney disease

He

mo

glo

bin

(g

/dl)

Median Hemoglobin Levels in the Intention-to-Treat Population During the Study

Months

Drüeke, T. et al., N Engl J Med 2006;355:2071-84.

0

8

9

10

11

12

13

14

15

16

0 6 12 18 24 30 36 42 48

Group 2

Group 1

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48

Ev

ent-

Fre

e S

urv

iva

l (%

)Time to Primary End Point of First Cardiovascular Event

Before Censoring Data on Patients at Initiation of Dialysis

MonthDrüeke, T. et al., N Engl J Med 2006;355:2071-84.

Group 2 Lower Hb

Group 1 Higher Hb

16

1432 patients enrolled

715 assigned to high-Hb group (13.5 g/dL)

717 assigned to low-Hb group (11.3 g/dL)

• 312 completed 36 months or withdrew at study termination without having primary event

• 125 had a primary event• 278 withdrew before early

termination of study 131 required renal

replacement therapy (RRT) 147 withdrew for other

reasons

• 349 completed 36 months or withdrew at study termination without having primary event

• 97 had a primary event• 271 withdrew before early

termination of study 111 required RRT 160 withdrew for other reasons

Singh AK, et al. N Engl J Med. 2006;355:2085-98.

CHOIR Trial

17

CHOIR Results – Primary EndpointComposite Events

• 222 composite events (death, MI, hospitalization for CHF, stroke) High Hb (13.5 g/dL): 125 events (18%) Low Hb (11/3 g/dL): 97 events (14%) Hazard ratio = 1.34; 95% CI, 1.03 to 1.74 (P = 0.03)

Singh AK, et al. N Engl J Med. 2006;355:2085-2098.

18

CHOIR ResultsComponents of the Primary Endpoint

Singh AK, et al. N Engl J Med. 2006;355:2085-2098.

Ongoing Trial: TREAT: Ongoing Trial: TREAT: TTrial to rial to RReduce Cardiovascular educe Cardiovascular EEvents with vents with AAranespranesp (Darbepoetin alfa) (Darbepoetin alfa) TTherapyherapy

Hypothesis:

Treatment of anemia with Aranesp reduces the risk of mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes

Aranesp Group (Target Hemoglobin 13 g/dL)

Control Group

Study Population• Hemoglobin 11 g/dL• GFR 20-60 mL/min• Type 2 DM

N = 2000

N = 2000

Enrollment = 1.5 years Follow-up period = 2.5 years

Design – randomized (1:1), double blind, controlled

1˚ Endpoint• Time to:

– All-cause mortality– CV mortality – Myocardial ischemia– Myocardial infarction– Cerebrovascular accident– Congestive heart failure

2˚ Endpoint• Time to end stage renal disease • Rate of decline in eGFR   • Change in patient reported fatigue (FACT-fatigue)

Darbepoetin alfa group (target Hb 13.0, not to exceed 14.5 g/dL)

Placebo group

Study Population Hb 9 to 12 g/dL LVEF < 35% NYHA Class II to IV

N = 1700

N = 1700

Hypothesis:

Treatment of anemia with darbepoetin alfa in subjects with symptomatic left ventricular systolic dysfunction and anemia decreases the risk of all-cause mortality or hospital admission for

worsening HF

1:1 randomization

Event driven: ~3 years to complete

Began enrolling June 2006Timelines

Ongoing Trial: RED-HF™ Trial: Hypothesis And Ongoing Trial: RED-HF™ Trial: Hypothesis And Study DesignStudy Design

Transfusion andTransfusion andClinical Outcome in ACSClinical Outcome in ACS

Rao SV, et al. JAMA. 2004;292(13):1555-1562.

Hébert et al. N Engl J Med 1999;340:409–17Hébert et al. N Engl J Med 1999;340:409–17

Blood Transfusions Mortality Effects S

urvi

val (

%)

Days

All patientsRestrictive-transfusion

strategy

Liberal-transfusionstrategy

P = 0.11

Hb 7-9

Hb 10-12

Conclusions

Use of erythocyte stimulating agents (EPO, darbepoetin, others) may worsen CVD outcomes in renal patients– Higher Hb targets?

– Higher doses of the agents?

– More iron given to achieve these targets?

Current trials in CKD and HF should give important additional guidance

Transfusion in ACS patients is associated with independently worse outcomes

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