1. Clinical Trial Results. org Tilman B. Drüeke, M.D.; Francesco Locatelli, M.D.; Naomi Clyne, M.D.; Kai-Uwe Eckardt, M.D.; Iain C. Macdougall, M.D.; Dimitrios Tsakiris, M.D.; Hans-Ulrich Burger, Ph.D.; and Armin Scherhag, M.D. for the CREATE Investigators Published in The New England Journal of Medicine November 16, 2006 Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia

2. Clinical Trial Results. org Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84. Anemia is a common complication of chronic kidney disease and is highly predictive of complications and death from cardiovascular causes in patients with chronic kidney disease.Anemia is a common complication of chronic kidney disease and is highly predictive of complications and death from cardiovascular causes in patients with chronic kidney disease. In prospective trials, normalizing hemoglobin in patients receiving hemodialysis did not improve left ventricular indexes or decrease the risk of death.In prospective trials, normalizing hemoglobin in patients receiving hemodialysis did not improve left ventricular indexes or decrease the risk of death. Anemia is a common complication of chronic kidney disease and is highly predictive of complications and death from cardiovascular causes in patients with chronic kidney disease.Anemia is a common complication of chronic kidney disease and is highly predictive of complications and death from cardiovascular causes in patients with chronic kidney disease. In prospective trials, normalizing hemoglobin in patients receiving hemodialysis did not improve left ventricular indexes or decrease the risk of death.In prospective trials, normalizing hemoglobin in patients receiving hemodialysis did not improve left ventricular indexes or decrease the risk of death. Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Background

3. Clinical Trial Results. org Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84. The effect of correcting anemia may differ among those patients that require dialysis and those that do not.The effect of correcting anemia may differ among those patients that require dialysis and those that do not. This study tested whether complete correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes as compared with partial correction of anemia.This study tested whether complete correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes as compared with partial correction of anemia. The effect of correcting anemia may differ among those patients that require dialysis and those that do not.The effect of correcting anemia may differ among those patients that require dialysis and those that do not. This study tested whether complete correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes as compared with partial correction of anemia.This study tested whether complete correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes as compared with partial correction of anemia. Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Background

4. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Study Design  Primary Endpoint: Time to first cardiovascular event (including sudden death, myocardial infarction (MI), acute heart failure, stroke, transient ischemic attack (TIA), angina pectoris resulting in hospitalization > 24 h or prolongation of hospitalization, complication of peripheral vascular disease (PVD) (amputation or necrosis), or cardiac arrhythmia resulting in hospitalization > 24 h).  Secondary Endpoint: All-cause mortality  Primary Endpoint: Time to first cardiovascular event (including sudden death, myocardial infarction (MI), acute heart failure, stroke, transient ischemic attack (TIA), angina pectoris resulting in hospitalization > 24 h or prolongation of hospitalization, complication of peripheral vascular disease (PVD) (amputation or necrosis), or cardiac arrhythmia resulting in hospitalization > 24 h).  Secondary Endpoint: All-cause mortality Group 1 Intermediate treatment with epoetin beta To reach hemoglobin value in normal range (13.0-15.0 g/dL) n=301 Group 1 Intermediate treatment with epoetin beta To reach hemoglobin value in normal range (13.0-15.0 g/dL) n=301 Group 2 Treatment with epoetin beta triggered by ↓ in hemoglobin level to <10.5 g/dL Target hemoglobin value in subnormal range (10.5-11.5 g/dL) n=302 Group 2 Treatment with epoetin beta triggered by ↓ in hemoglobin level to <10.5 g/dL Target hemoglobin value in subnormal range (10.5-11.5 g/dL) n=302 603 patients >18 yrs w/estimated glomerular filtration rate (GFR) 15.0-35.0 ml/min/1.73m 2 of body-surface area, mild-to-moderate anemia, & blood pressure <170/95 mmHg Excluding those with need for renal replacement therapy within 6 months, advanced CV disease, nonrenal causes of anemia, blood transfusions in the preceding 3 months, serum ferritin level 15 mg/L, & previous treatment with erythropoietin Open-label. Randomized. Two-group. Parallel-group design. 603 patients >18 yrs w/estimated glomerular filtration rate (GFR) 15.0-35.0 ml/min/1.73m 2 of body-surface area, mild-to-moderate anemia, & blood pressure <170/95 mmHg Excluding those with need for renal replacement therapy within 6 months, advanced CV disease, nonrenal causes of anemia, blood transfusions in the preceding 3 months, serum ferritin level 15 mg/L, & previous treatment with erythropoietin Open-label. Randomized. Two-group. Parallel-group design. R mos. or yrs. follow-up Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

5. Clinical Trial Results. org Characteristic Group 1 (n=301) Group 2 (n=302) P value Weight (kg) 74.7  15.6 71.8  14.2 0.05 Body-mass index 26.6  4.5 26.2  4.8 0.42 Age (yr) 59.3  14.6 58.8  13.7 0.36 Male sex, no (%) 171 (57) 154 (51) 0.16 Estimated GFR (ml/min†) 24.9  6.3 24.2  6.0 0.30 Diabetes mellitus (%) 80 (27) 77 (25) 0.64 Hypertension (%) 275 (91) 269 (89) 0.38 Blood Pressure (mm Hg) Systolic Systolic Diastolic Diastolic 139  17 79  10 139  16 80  9 0.870.28 Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia : Baseline Characteristics † The percentages are the number of patients divided by the total number of patients receiving at least one does of epoetin beta (300 in group 1 and 302 in group 2) Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

6. Clinical Trial Results. org Upon completion of the study, 105 patients had had a first cardiovascular event (58 in group 1 vs. 47 in group 2, hazard ratio, 0.78, 95% CI, 0.53 to 1.14, adjusted p=0.20).Upon completion of the study, 105 patients had had a first cardiovascular event (58 in group 1 vs. 47 in group 2, hazard ratio, 0.78, 95% CI, 0.53 to 1.14, adjusted p=0.20). # of Patients Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Primary Endpoint n = p =0.20 Primary Endpoint of First Cardiovascular Event (# patients) Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

7. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Secondary Endpoint There were no significant differences among the two groups in frequency and incidence of death from any cause (10% group 1 vs. 7% group 2; p=0.14), incidence of death from cardiovascular causes (4% vs. 3%; p=0.48), percentage of patients undergoing cardiovascular intervention (7% vs. 6%) incidence of hospital admission (61% vs. 59%), mean time to worsening of NYHA class (p=0.97), or mean duration of hospitalization for cardiovascular reasons (33.0 vs 28.2 days).There were no significant differences among the two groups in frequency and incidence of death from any cause (10% group 1 vs. 7% group 2; p=0.14), incidence of death from cardiovascular causes (4% vs. 3%; p=0.48), percentage of patients undergoing cardiovascular intervention (7% vs. 6%) incidence of hospital admission (61% vs. 59%), mean time to worsening of NYHA class (p=0.97), or mean duration of hospitalization for cardiovascular reasons (33.0 vs 28.2 days). p = 0.14 p = 0.48 Endpoint (%) n=31n=21 All-Cause Mortality, Cardiovascular Death, Need for Cardiac Intervention, Any Hospitalization (% of patients) Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

8. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Quality of Life The quality of life was significantly better in group 1 compared with group 2 at 1 year regarding the following: general health (p=0.003), mental health (p<0.001), physical function (p<0.001), physical role (p=0.01), social function (p=0.006), and vitality (p<0.001).The quality of life was significantly better in group 1 compared with group 2 at 1 year regarding the following: general health (p=0.003), mental health (p<0.001), physical function (p<0.001), physical role (p=0.01), social function (p=0.006), and vitality (p<0.001). The significant difference between groups was maintained at 2 years with regard to general health (p=0.008) and vitality (p=0.01).The significant difference between groups was maintained at 2 years with regard to general health (p=0.008) and vitality (p=0.01). Quality of Life At 1 Year p-value General Health General Health0.003 Mental Health Mental Health<0.001 Physical Function Physical Function<0.001 Physical Role Physical Role0.01 Social Function Social Function0.006 Vitality Vitality<0.001 Quality of Life At 2 Years General Health General Health0.008 Vitality Vitality0.01 Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

9. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Limitations Upon study completion, only half of the predicted number of cardiovascular events (105 actual events vs. 200 expected) had occurred and almost half of the patients were receiving dialysis.Upon study completion, only half of the predicted number of cardiovascular events (105 actual events vs. 200 expected) had occurred and almost half of the patients were receiving dialysis. The lack of benefit from complete hemoglobin correction appears to be driven not by the lack of events but by the lack of an effect, which is possibly attributable to the nephrologists increasing their awareness of and protection against CVD combined with the usually better prognosis of patients enrolled in randomized controlled trials.The lack of benefit from complete hemoglobin correction appears to be driven not by the lack of events but by the lack of an effect, which is possibly attributable to the nephrologists increasing their awareness of and protection against CVD combined with the usually better prognosis of patients enrolled in randomized controlled trials. Upon study completion, only half of the predicted number of cardiovascular events (105 actual events vs. 200 expected) had occurred and almost half of the patients were receiving dialysis.Upon study completion, only half of the predicted number of cardiovascular events (105 actual events vs. 200 expected) had occurred and almost half of the patients were receiving dialysis. The lack of benefit from complete hemoglobin correction appears to be driven not by the lack of events but by the lack of an effect, which is possibly attributable to the nephrologists increasing their awareness of and protection against CVD combined with the usually better prognosis of patients enrolled in randomized controlled trials.The lack of benefit from complete hemoglobin correction appears to be driven not by the lack of events but by the lack of an effect, which is possibly attributable to the nephrologists increasing their awareness of and protection against CVD combined with the usually better prognosis of patients enrolled in randomized controlled trials. Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

10. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Summary The lack of benefit from the normalization of hemoglobin levels in this study suggests that although the degree of anemia is a strong indicator of poor prognosis, complete correction of it does not improve outcomes.The lack of benefit from the normalization of hemoglobin levels in this study suggests that although the degree of anemia is a strong indicator of poor prognosis, complete correction of it does not improve outcomes. It also suggests that factors causing the anemia, rather than the anemia itself, have adverse consequences.It also suggests that factors causing the anemia, rather than the anemia itself, have adverse consequences. The lack of benefit from the normalization of hemoglobin levels in this study suggests that although the degree of anemia is a strong indicator of poor prognosis, complete correction of it does not improve outcomes.The lack of benefit from the normalization of hemoglobin levels in this study suggests that although the degree of anemia is a strong indicator of poor prognosis, complete correction of it does not improve outcomes. It also suggests that factors causing the anemia, rather than the anemia itself, have adverse consequences.It also suggests that factors causing the anemia, rather than the anemia itself, have adverse consequences. Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.

11. Clinical Trial Results. org Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia: Summary As in previous studies, this study showed significant benefits of higher hemoglobin targets on the quality of life, which generally deteriorate with the progression of chronic kidney disease.As in previous studies, this study showed significant benefits of higher hemoglobin targets on the quality of life, which generally deteriorate with the progression of chronic kidney disease. In conclusion, the CREATE study adds direct evidence that confirms the current best practice guidelines which recommends partial correction of anemia and not routine normalization of hemoglobin levels.In conclusion, the CREATE study adds direct evidence that confirms the current best practice guidelines which recommends partial correction of anemia and not routine normalization of hemoglobin levels. As in previous studies, this study showed significant benefits of higher hemoglobin targets on the quality of life, which generally deteriorate with the progression of chronic kidney disease.As in previous studies, this study showed significant benefits of higher hemoglobin targets on the quality of life, which generally deteriorate with the progression of chronic kidney disease. In conclusion, the CREATE study adds direct evidence that confirms the current best practice guidelines which recommends partial correction of anemia and not routine normalization of hemoglobin levels.In conclusion, the CREATE study adds direct evidence that confirms the current best practice guidelines which recommends partial correction of anemia and not routine normalization of hemoglobin levels. Drüeke et al., N Engl J Med. 2006 Nov; 335(20):2071-84.