Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

Targeting Hemoglobin and the Use of Erythropoietin and Transfusion in Cardiac Patients Targeting Hemoglobin and the Use of Erythropoietin and Transfusion in Cardiac Patients Peter A. McCullough, MD, MPH, FACC, FACP Chief, Division of Nutrition and Preventive Medicine Medical Director, Preventive Cardiology Consultant Cardiologist William Beaumont Hospital Royal Oak, MI

Anemia Correction and CVD Trials Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP Consultant Cardiologist and Chief Division of Nutrition and Preventive Medicine William Beaumont Hospital Beaumont Health Center Royal Oak, Michigan

El Achkar TM, et al. The Kidney Early Evaluation Program (KEEP 2.0). Accepted for publication, Anemia prevalence (%) < >89 Estimated GFR (mL/min/1.73 m 2 ) Anemia prevalence by K/DOQI category of kidney function Hb 50 years <11.0 g/dl for women <51 years old Diabetic Nondiabetic Anemia Begins at a GFR <60 mL/min

1. Androne AS. Circulation. 2003;107: Pathogenesis of Anemia Associated With CKD  Erythropoietin (epoetin alfa) deficiency  Epoetin alfa resistance  Hemodilution 1  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

Aging Excess LDL cholesterol Micro-organisms Auto-immunity Malignancies? Monocyte/Macrophage Bone marrow Endothelial progenitor cells Arteries Injury Inflammation IL-6 VEGF T-Cell Monocyte/Macrophage { + Kidney Erythropoietin Interferon IL-1 TNF IL-6? VEGF T-Cell O 2 IL-6?

McCullough PA, Lepor NE. The deadly triangle of anemia, renal insufficiency, and cardiovascular disease: implications for prognosis and treatment. Rev Cardiovasc Med Winter;6(1):1-10. NLM CIT. ID: Deadly Triangle Erythropoietin (Epoetin alfa) deficiency Chronic disease (diabetes) Elevated cytokines Malnutrition LVH HF morbidity/mortality MI mortality PCI complications All-cause death CKDAnemia 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 iron 16% received IV iron Toto et al. Am J Nephrol. 2004;24: Hemoglobin (g/dL) BL Study Week N=

USRDS Patient Distribution, by Mean Monthly Hemoglobin (g/dL) Percent of Patients –<12 10–<11 9–<10 <9 Mean Monthly Hemoglobin (g/dL) and Mean EPO Dose per Week Hemoglobin (g/dL) Mean EPO Dose (in 1000s of Units) EPO: Previous Method EPO: New Method Hemoglobin ESRD Anemia Treatment

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)

13 CREATE Trial: Randomized Controlled Trial of Anemia Treatment in Pre-Endstage Renal Failure CrCl=creatinine clearance; GFR=glomerular filtration rate; Hb=hemoglobin. Stevens et al. Clin Med. 2003;3: predialysis subjects, CrCl mL/min Early intervention group, IIb g/dL target Hb g/dL Late intervention group, Hb 10 g/dL target Hb 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

Hemoglobin (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: Group 2 Group 1

Event-Free Survival (%) Time to Primary End Point of First Cardiovascular Event Before Censoring Data on Patients at Initiation of Dialysis Month Drüeke, T. et al., N Engl J Med 2006;355: Group 2 Lower Hb Group 1 Higher Hb

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: CHOIR Trial

17 CHOIR Results – Primary Endpoint Composite 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:

18 CHOIR Results Components of the Primary Endpoint Singh AK, et al. N Engl J Med. 2006;355:

Ongoing Trial: TREAT: Trial to Reduce Cardiovascular Events with Aranesp  (Darbepoetin alfa) Therapy 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 mL/min Type 2 DM N = 2000 Enrollment = 1.5 yearsFollow-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 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 2006 Timelines Ongoing Trial: RED-HF™ Trial: Hypothesis And Study Design

Transfusion and Clinical Outcome in ACS Rao SV, et al. JAMA. 2004;292(13):

Hébert et al. N Engl J Med 1999;340:409–17 Blood Transfusions Mortality Effects Survival (%) Days All patients Restrictive-transfusion strategy Liberal-transfusion strategy 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

Question&Answer

Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive