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

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

2. Targeting Hemoglobin and the Use of Erythropoietin and Transfusion in Cardiac PatientsPeter A. McCullough, MD, MPH, FACC, FACPChief, Division of Nutrition and Preventive MedicineMedical Director, Preventive CardiologyConsultant CardiologistWilliam Beaumont HospitalRoyal Oak, MI

3. Anemia Correction and CVD Trials Peter A. McCullough, MD, MPH, FACC, FACP, FAHA, FCCP Consultant Cardiologist and ChiefDivision of Nutrition and Preventive MedicineWilliam Beaumont HospitalBeaumont Health CenterRoyal Oak, Michigan

4. Anemia Begins at a GFR <60 mL/min 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 old 57.1 60 Diabetic 50 Nondiabetic 42.9 40 Anemia prevalence (%) 30 20 16.5 10 6.8 6.4 6.7 6.6 5.3 0 <30 30-59 60-89 >89 Estimated GFR (mL/min/1.73 m2) El Achkar TM, et al. The Kidney Early Evaluation Program (KEEP 2.0). Accepted for publication, 2005.

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

6. - - Monocyte/Macrophage Aging Excess LDL cholesterol Micro-organisms Auto-immunity Malignancies? + IL-1 TNF Bone marrow Interferon T-Cell Erythropoietin IL-6? VEGF Endothelial progenitor cells Kidney + Arteries Injury Inflammation IL-6 VEGF T-Cell Monocyte/Macrophage O2 IL-6? {

7. 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 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

8. Effect of Darbepoetin Alfa q 2 Weekly on Hb in 463 CKD Patients 14.0 Dose to achieve target: 64  17 mcg Time to target: 40  32 days 13.5 13.0 12.5 Target range 12.0 11.5 Hemoglobin (g/dL) 11.0 10.5 10.0 9.5 60% received oral iron 16% received IV iron 9.0 8.5 N= 483 447 463 456 455 456 451 458 454 453 451 452 453 447 8.0 BL 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 Toto et al. Am J Nephrol. 2004;24:453-460.

9. EPO and Mortality J Am Soc Nephrol 15: 3154–3165, 2004

10. EPO and HTN J Am Soc Nephrol 15: 3154–3165, 2004

11. Hemoglobin Targets in CKD Patients ↑Thrombosis (↑Plt activity, ↑thrombin) ↑HTN (ET↑, ADMA↑) ↑Oxidative Stress (Fe) ↑Quality of Life ↑Physical Functioning ↓LVH ?Morbidity ?Mortality 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)

12. CREATE Trial: Randomized Controlled Trial of Anemia Treatment in Pre-Endstage Renal Failure CREATE 600 predialysis subjects, CrCl 15-35 mL/min 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 • 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 CrCl=creatinine clearance; GFR=glomerular filtration rate; Hb=hemoglobin. Stevens et al. Clin Med. 2003;3:503-508.

13. Median Hemoglobin Levels in the Intention-to-Treat Population During the Study 16 Group 1 15 14 13 12 Hemoglobin (g/dl) 11 Group 2 10 9 8 0 0 6 12 18 24 30 36 42 48 Months Drüeke, T. et al., N Engl J Med 2006;355:2071-84.

14. Time to Primary End Point of First Cardiovascular Event Before Censoring Data on Patients at Initiation of Dialysis Group 2 Lower Hb Group 1 Higher Hb Event-Free Survival (%) Month Drüeke, T. et al., N Engl J Med 2006;355:2071-84.

15. CHOIR Trial 1432 patients enrolled 717 assigned to low-Hb group (11.3 g/dL) 715 assigned to high-Hb group (13.5 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.

16. 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.

17. CHOIR ResultsComponents of the Primary Endpoint Singh AK, et al. N Engl J Med. 2006;355:2085-2098.

18. N = 2000 Aranesp Group (Target Hemoglobin 13 g/dL) • Study Population • Hemoglobin 11 g/dL • GFR 20-60 mL/min • Type 2 DM Design – randomized (1:1), double blind, controlled N = 2000 Control Group Enrollment = 1.5 years Follow-up period = 2.5 years 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 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)

19. Ongoing Trial: RED-HF™ Trial: Hypothesis And Study Design 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 Darbepoetin alfa group(target Hb 13.0, not to exceed 14.5 g/dL) N = 1700 • Study Population • Hb 9 to 12 g/dL • LVEF < 35% • NYHA Class II to IV 1:1 randomization Placebo group N = 1700 Began enrolling June 2006 Timelines Event driven: ~3 years to complete

20. Transfusion andClinical Outcome in ACS Rao SV, et al. JAMA. 2004;292(13):1555-1562.

21. Blood Transfusions Mortality Effects Hb 7-9 All patients Restrictive-transfusion strategy Survival (%) P = 0.11 Liberal-transfusion strategy Hb 10-12 Days Hébert et al. N Engl J Med 1999;340:409–17

22. 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

23. Question & Answer

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