Presentation is loading. Please wait.

Presentation is loading. Please wait.

Breaking the Vicious Cycle – Efficacy of Anemia Therapies

Similar presentations


Presentation on theme: "Breaking the Vicious Cycle – Efficacy of Anemia Therapies"— Presentation transcript:

1 Breaking the Vicious Cycle – Efficacy of Anemia Therapies
Peter Bárány Division of Renal Medicine Department of Clinical Science, Intervention and Technology Karolinska Institutet, Stockholm, Sweden 1 1

2 Learning Objectives Understand the importance of anemia treatment in patients with chronic kidney disease (CKD) Review the efficacy of erythropoiesis-stimulating agents (ESAs) and intravenous (i.v.) iron to correct anemia Understand the limitations of previous trials and how these are being addressed in forthcoming studies

3 Outline Anemia in CKD Anemia treatment Further studies are needed
Blood transfusions ESAs Iron Further studies are needed Conclusions 3 3

4 Reduced Kidney Function is Associated with Worsening Anemia
National Health and Nutrition Examination Survey (NHANES) Population-based epidemiological study 15,419 participants aged ≥20 years Conducted from 1988–1994 17 17 15 15 13 13 Hb level in men (g/dL) 11 Hb level in women (g/dL) 11 9 95th Percentile Median 5th Percentile 9 95th Percentile Median 5th Percentile 7 7 30 60 90 120 150 30 60 90 120 150 Estimated GFR, (mL/min/1.73 m2) Estimated GFR, (mL/min/1.73 m2 ) GFR, glomerular filtration rate Astor BC et al. Arch Intern Med 2002;162:1401–1408 4 4

5 Anemia is Associated with Poor Survival of Patients with CKD
Due to the negative effects of anemia,1–3 early diagnosis and treatment in patients with CKD is recommended4,5 25.0 Dynamic, retrospective cohort study among 8761 patients with CKD at Kaiser Permanente Northwest2 Assessment of outcomes2 Death Cardiovascular (CV) hospitalization End-stage renal disease (ESRD) 23.4 Death CV hospitalization ESRD 20.0 17.4 15.5 15.0 14.5 Rate per 100 patient-years 12.6 11.6 11.3 10.3 10.1 10.0 9.6 9.0 8.5 8.9 7.6 7.4 6.5 5.9 6.2 5.3 4.8 5.0 4.0 2.6 1.3 1.3 1.0 0.8 0.5 0.4 0.4 0.3 0.0 9.4 11.0 11.8 12.3 12.8 13.2 13.5 13.9 14.5 15.8 Mean hemoglobin (g/dL) per decile 1. Fishbane S. Heart Fail Clin 2008;4:401–410; 2. Thorp ML et al. Nephrology 2009;14:240–246; 3. Kovesdy CP et al. Kidney Int 2006;69:560–564; 4. Hörl WH et al. Nephrol Dial Transplant 2007;22(suppl 3):iii2–6; 5. Gouva C et al. Kidney Int 2004;66:753–760 5 5

6 Blood Transfusions – Restricted Use is Still Needed
6 6

7 Transfusion Use in the CKD Population
Transfusion use is decreasing in the CKD population1 Data from Medicare patients 301,000 CKD and 15,772,039 non-CKD ESA usage increased from 2.5% in 1998 to 7.5% in 2004 150 100 Transfusion rate (per 1000 patients) CKD Non-CKD 50 1998 1999 2000 2001 2002 2003 2004 Cohort year 1. Ibrahim HN et al. Nephrol Dial Transplant 2009;24:3138–3143 7 7

8 Hemoglobin Targets and Blood Transfusions in HD Patients
Randomized multicenter, international trial 596 hemodialysis (HD) patients without symptomatic cardiac disease Treated with epoetin alfa and randomized to a low (9.5–11.5 g/dL) or high (Hb 13.5–14.5 g/dL) hemoglobin (Hb) target ‘High hemoglobin target was a significant predictor of time to first transfusion independent of baseline associations’ Low Hb target High Hb target p Transfusion rate (per patient per year) 0.66 (95% CI=0.59–0.74) 0.26 (95% CI=0.22–0.32) <0.0001 Pretransfusion Hb level (g/dL) 7.7 (95% CI=7.5–7.9) 8.1 (95% CI=7.6–8.5) 0.09 Transfusion HR 1 (reference) 0.46 (95% CI=0.29–0.72) 0.0007 HR, Hazard Ratio Foley RN et al. Clin J Am Soc Nephrol 2008;3:1669–1675 8 8

9 The Efficacy of ESA Therapy
9 9

10 Numerous ESAs are Currently Available with more Development
Epoetin a t1/2 6–24 hours Epoetin b t1/2 6–24 hours Darbepoetin a t1/2 25–72 hours Epoetin d Methoxy PEG-epoetin b (CERA) t1/2 130 hours Biosimilar epoetins 20XX Hematide 1989 1990 2002 2007 Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115 Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130 CERA, continuous erythropoietin receptor activator 10 10

11 Numerous Studies have Demonstrated the Efficacy of ESAs to Improve and Maintain Hemoglobin Levels in Patients with Anemia and CKD at all Stages Size (n) Hemoglobin (g/dL) 500 1000 1500 6 7 8 9 10 11 12 13 14 15 16 Placebo/control mean Hb Lower target mean achieved Hb Higher target mean achieved Hb Ritz (2007) Singh (2006) Drüeke (2006) Rossert (2006) Levin (2005) Parfrey (2005) Roger (2004) Gouva (2004) Furuland (2003) Foley (2000) McMahon (1999) Besarab (1998) Kuriyama (1997) Nissenson (1995) Roth (1994) Sikole (1993) Morris (1993) Clyne (1992) Bahlman (1991) CanEPO (1990) Watson (1990) Abraham (1990) Suzuki (1989) KDOQITM. Am J Kidney Dis 2007;50:471–530 11 11

12 ESAs have a Modest Effect on Aerobic Capacity in HD Patients with Severe Anemia and Low Target
21 HD patients with severe anemia (15 control healthy subjects) ESA therapy to partially correct anemia (Hb 10–11 g/dL) has a modest effect on aerobic capacity 800 700 600 500 400 300 200 1 2 3 4 5 Total hemoglobin (g) VO2 max (L/min) Mean healthy subjects ± 2SD of mean p<0.001 Before ESA therapy After ESA therapy VO2 max, maximum oxygen uptake Bárány P et al. Clin Sci 1993;84:441–447 12 12

13 Change in LVMi (mean with 95% CI)
Patients with Severe Anemia have a Substantial Improvement in Cardiac Function when Targeted to an Hb ≤12 g/dL Systematic review of studies relating ESA therapy and cardiac outcomes January 1990–February 2007 15 unique studies 1731 patients with CKD and ESRD Anemia at baseline defined as: Severe: Hb <10 g/dL Moderate: Hb ≥10 g/dL <12 g/dL Target Hb Low: Hb ≤12 g/dl or ≤Hct 36% High: Hb >12 g/dl or >Hct 36% Cannella 1990 Pascual 1991 (i) Pascual 1991 (ii) Portoles 1997 Massimetti 1998 Hayashi 2000 London 2001 Sikole 2002 Ayus 2005 Combined -100 -80 -60 -40 -20 20 40 60 Change in LVMi (mean with 95% CI) Patients with severe anemia had a substantial improvement in LVMi when assigned to a target Hb ≤12 g/dL Hct, hematocrit; LVMi, left ventricular mass index Parfrey PS et al. Clin J Am Soc Nephrol 2009;4:755–762 13

14 Correction of Moderate Anemia has No Effect on LVMi
Moderate anemia and low Hb target Moderate anemia and high Hb target Foley 2000 (i) Foley 2000 (ii) Foley 2000 (iv) Foley 2000 (iii) Frank 2004 Roger 2004 (i) Roger 2004 (ii) Levin 2005 (ii) Hampl 2005 Parfrey 2005 (i) Levin 2005 (ii) Parfrey 2005 (ii) Ritz 2007 (ii) Ritz 2007 (ii) Combined Combined -100 -80 -60 -40 -20 20 40 60 -100 -80 -60 -40 -20 20 40 60 Change in LVMi (mean with 95% CI) Change in LVMi (mean with 95% CI) Patients with moderate anemia had no improvement in LVMi, irrespective of target Hb Parfrey PS et al. Clin J Am Soc Nephrol 2009;4:755–762 14

15 Four Large Trials have Examined the Efficacy and Safety of ESAs to Achieve High or Low Hb Targets
Normal HCT1 CHOIR2 CREATE3 TREAT4 Region USA Europe Americas, Europe, Australia N 1233 1432 603 4038 Patients CKD5D with cardiac disease CKD 3–4 CKD 3–4 with Type 2 DM eGFR, mL/min/1.73 m2 HD patients 15–50 15–35 20–60 Target/achieved Hb, g/dL Low High Hct 30±3 % Hct 42±3 % 11.3 13.5/12.6 10.5–11.5 13.0–15.0 Placebo/ESA at ≥9.0 13.0 Follow-up, months 30 16 35 48 Primary outcome Death, MI Death, MI, stroke, CHF hospitalization CV events Death, CV events, ESRD HR (95 % CI) 1.3 (0.9–1.8) 1.34 (1.03–1.74) 0.78 (0.53–1.14) 1.05 (0.94–1.17) DM, diabetes mellitus; MI, myocardial infarction; CHF, chronic heart failure 1. Besarab A et al. N Engl J Med 1998;339:584–590; 2. Singh AK et al. N Engl J Med 2006;355:2085–2098; 3. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 4. Pfeffer MA et al. N Engl J Med 2009;361:2019–2032 15 15

16 Diabetes and CV Disease were Common Comorbidities in the Four Major Trials of ESAs
Normal HCT1 CHOIR2 CREATE3 TREAT4 Region USA Europe Americas, Europe, Australia N 1233 1432 603 4038 Patients CKD5D with cardiac disease CKD 3–4 CKD 3–4 with Type 2 DM DM, % 56 N/A 26 100 History of CV disease, % MI CHF Cerebrovascular disease Peripheral vascular disease 24 46 39 16 10 1 32 3 2 18 33 11 21 1. Besarab A et al. N Engl J Med 1998;339:584– Singh AK et al. N Engl J Med 2006;355:2085–2098; 3. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 4. Pfeffer MA et al. N Engl J Med 2009;361:2019–2032 16 16

17 Higher Hb Targets are Associated with Improvements in QoL Parameters
CV risk reduction by early anemia treatment with epoetin beta (CREATE) study 603 patients with CKD and anemia treated with ESA Randomized to Hb target of: 13–15 g/dL (group 1) 10.5–11.5 g/dL (group 2) Primary endpoint: composite of eight CV events No reduced risk of CV events was observed,1 reflecting the fact that CREATE was underpowered2 Group 1 Group 2 5 p=0.003 p<0.001 p<0.001 p=0.01 p=0.006 p<0.001 4 3 2 1 Change from baseline in quality of life score -1 -2 -3 -4 -5 -6 -7 General Health MentalHealth Physical Function Physical Role Social Function Vitality Higher Hb targets in pre-dialysis CKD patients are associated with significant improvements in quality of life (QoL) parameters 1. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 2. Levin A. Nephrol Dial Transplant 2007;22:309–312 17 17

18 Mean epoetin dose x 103 (units/patient/wk)
Greater ESA Doses are Significantly Associated with Greater Hb Concentrations Dialysis Outcomes and Practice Patterns Study (DOPPS) Analysis of data from 11,041 HD patients in 12 countries Seven countries 1996–2001 and 12 countries 2001–2004 12.5 Sweden 12.0 Spain US Canada Belgium AUS/NZ 11.5 Germany Italy Mean Hb level (g/dL) 11.0 UK France 10.5 Japan 10.0 9.5 4 6 8 10 12 14 16 18 Mean epoetin dose x 103 (units/patient/wk) Van Wyck D et al. Clin J Am Soc Nephrol 2007;2:13–14; Pisoni RL et al. Am J Kidney Dis 2004;44:94–111 18

19 ESA Therapy Effectively Corrects Hb Levels Compared with Placebo
Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT) Randomized, double-blind, placebo-controlled trial 4038 pre-dialysis CKD patients with diabetes and anemia (Hb ≤11 g/dL) randomized to receive ESA (n=2012) or placebo (n=2026) Primary endpoint: composite outcomes of death, CV events or ESRD Renal composite (ESRD or death) 50 Darbepoetin alfa 40 Hazard ratio, 1.06 (95% CI, 0.95–1.19) p=0.29 Placebo 30 Patients with event (%) 20 10 13.5 6 12 18 24 30 36 42 48 13.0 Darbepoetin alfa Months since randomization 12.5 ESRD 12.0 50 11.5 Mean Hb (g/dL) 40 Placebo Hazard ratio, 1.02 (95% CI, 0.87–1.18) p=0.83 11.0 30 Darbepoetin alfa 10.5 Patients with event (%) 20 Placebo 10.0 9.5 10 0.0 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48 Months since randomization Months since randomization ESA therapy effectively corrected Hb levels compared with placebo, however, no difference was observed in disease progression or mortality Pfeffer MA et al. N Engl J Med 2009;361:2019–2032 19 19

20 The Efficacy of Iron Therapy
20 20

21 Numerous I.v. Iron Preparations are Available
Epoetin a t1/2 6–24 hours Epoetin b t1/2 6–24 hours Darbepoetin a t1/2 25–72 hours Epoetin d Methoxy PEG-epoetin b (CERA) t1/2 130 hours Biosimilar epoetins 20XX Hematide 1950s 1970s 1990s 2000s 2010 Iron sucrose 45 kDa t1/2 5 hours Sodium ferric gluconate 12 kDa t1/2 1–2 hours Ferumoxytol 308–750kDa t1/2 9.3–14.5 hours Ferric carboxymaltose 150 kDa t1/2 16 hours High MW iron dextran 265 kDa t1/2 60 hours Low MW iron dextran 72–90 kDa t1/2 5–35 hours Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115 Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130 MW, molecular weight 21 21

22 Functional Iron Deficiency was Described Early in Epoetin-treated CKD5D Patients
Combined Phase I and II trial data for recombinant human erythropoietin (rHuEPO) in 25 HD patients with anemia rHuEPO administration induced a fall in transferrin saturation (TSAT) and serum iron levels 45 1000 mg i.v. iron dextran Anephric 1933–2007 35 Hematocrit (%) 200 mL RBCs 25 15 6.0 Reticulocytes Corrected (%) 4.0 2.0 -12 -8 -4 +4 +8 +12 +16 +20 +24 Weeks ‘One of the clinical features seen with this form of treatment was a state of functional iron deficiency’ rHuEPO 50 U/kg 3x/wk % saturated ferritin Eschbach JW et al. N Engl J Med 1987;316:73–78 22 22

23 Parenteral Iron Therapy is Effective in Hemodialysis Patients
Regression analysis of 13 studies of parenteral iron in ESRD patients demonstrated improvements in iron status (ferritin and TSAT) On average, the ESA dose was decreased by 42% with an 18% increase in Hb Pre Post Ferritin (ng/mL) 209±40 447±50 TSAT (%) 22±2 35±4 70 60 50 40 Change in hemoglobin (%) r=0.56 p<0.05 30 20 10 10 20 30 40 50 60 70 80 Reduction in ESA dose (%) Besarab A et al. J Am Soc Nephrol 1999;10:2029–2043 23

24 I.v. Iron Therapy is Associated with Improved Survival in HD Patients
Epidemiological study conducted in the US1 Prospectively collected data over 2 years from an historical cohort from the DaVita database 58,058 maintenance HD patients Three types of i.v. iron Iron sucrose Sodium ferric gluconate Iron dextran 2.0 2.0 Unadjusted Case mix Case mix and MICS Unadjusted Case mix Case mix and MICS 1.5 1.5 1.0 1.0 All-cause mortality hazard ratio CV mortality hazard ratio 0.8 0.8 0.6 0.6 0.4 0.4 1–199 200–399 ≥400 1–199 200–399 ≥400 I.v. iron dose (mg/month) I.v. iron dose (mg/month) MICS; malnutrition-inflammation complex syndrome 1. Kalantar-Zadeh K et al. J Am Soc Nephrol 2005;16:3070–3080 24

25 Greater Increase in Hb with I.v. Iron Sucrose Versus Oral Iron
Randomized controlled multicenter trial Pre-dialysis CKD patients Stage 3–5 I.v. iron sucrose (n=79) versus oral ferrous sulfate (n=82) I.v. iron Oral iron I.v. iron Oral iron 60 1.0 *** *** 0.8 40 Patients achieving ≥1 g/dL increase in Hb (%) + *** 0.6 Change in Hb (g/dL) + + + 0.4 * 20 0.2 ** * ** 0.0 14 28 42 56 14 28 42 56 Time after start of treatment (days) Time after start of treatment (days) *p<0.05; **p<0.01; ***p<0.001 from baseline +p<0.05 after 42 weeks between groups Adapted from Van Wyck DB et al. Kidney Int 2005;68:2846–2856 25 25 25 25

26 Mean Hb change from baseline (g/dL)
More Patients Achieve Target Hb Level with i.v. Iron Sucrose Versus Oral Iron Randomized open-label, multicenter trial 96 pre-dialysis CKD patients I.v. iron sucrose (n=48) versus oral ferrous sulfate (n=48) 1.2 60 p=0.028 I.v. iron Oral iron 54.2 p<0.0001 1.0 50 p<0.0001 0.8 40 Mean Hb change from baseline (g/dL) 31.3 0.6 Patient response* (%) p<0.0001 30 p=0.017 p<0.0001 0.4 20 0.2 10 p=0.002 Baseline 15 36 43 I.v. iron Oral iron Study day *Achieving Hb >11.0 g/dL p values are versus baseline values Adapted from Charytan C et al. Nephron Clin Pract 2005;100:c55-62 26 26 26

27 Mean change in Hb from baseline (g/dL)
Greater Increase in Hb with I.v. Ferumoxytol Versus Oral Iron in ESA-treated Patients Randomized open-label, multicenter trial 304 pre-dialysis CKD patients (Stage 1–5) with anemia I.v. ferumoxytol (n=228) versus oral ferrous fumerate (n=76) p=0.001 1.16 1.2 60 55.4 1.0 50 0.8 40 Mean change in Hb from baseline (g/dL) 0.6 Patient response* (%) 30 24.2 0.4 20 0.19 0.2 10 0.0 I.v. iron (n=83) Oral iron (n=33) I.v. iron (n=83) Oral iron (n=33) *Achieving ≥1g/dL increase from baseline Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605 27 27 27

28 Efficacy is Higher with I.v. Ferric Carboxymaltose Versus Oral Iron
Randomized multicenter trial 255 pre-dialysis CKD patients (creatinine clearance ≤45 mL/min/1.73 m2) with anemia I.v. ferric carboxymaltose (n=152) versus oral ferrous sulfate (n=103) 100 p<0.001 75 Patient response* (%) 60.4 50 34.7 25 I.v. iron (n=144) Oral iron (n=101) *Achieving ≥1g/dL increase from baseline at any time during the study Benjamin J & Qunibi W. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA−PO2422 28 28 28

29 Patient response* rate (%)
Efficacy is Higher with I.v. Ferric Carboxymaltose Versus Oral Iron + ESA I.v. ferric carboxymaltose administration alone achieves a greater Hb response rate (≥1 g/dL increase from baseline at any time during the study) than either oral iron alone or oral iron + ESA 100 80 84.8† I.v. iron + ESA (n=33) 60 Patient response* rate (%) 53.2‡ I.v. iron only (n=11) 50.0† 40 29.9‡ 20 Oral Iron + ESA (n=24) Oral iron only (n=77) †p<0.008; ‡p<0.002 *Achieving ≥1g/dL increase from baseline at any time during the study Benjamin J & Qunibi W. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA−PO2422 29 29 29

30 I.v. Iron is Effective without ESAs in Patients with CKD
Longitudinal open-label, single-arm, prospective study in a single nephrology centre 60 pre-dialysis CKD patients 58 completed the study Treated with i.v. iron sucrose for 12 months 100 80 75 76 Patients achieving targets (%) 50 49 44 Hb >10 g/dL 25 Serum ferritin >100 ng/mL and TSAT >20% Baseline 12 months* *p<0.05 versus baseline Mircescu G et al. Nephrol Dial Transplant 2006;21:120–124 30 30

31 I.v. Ferric Gluconate Improves Anemia more than ESA alone in HD Patients
Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) trial Randomized, controlled, open-label, multicenter trial 134 HD-CKD patients with anemia Ferritin 500–1200 ng/mL, TSAT <25% I.v. sodium ferric gluconate (n=68) versus no iron (n=66) Primary endpoint: Hb change from baseline 12.2 * * 12.0 I.v. iron Control 11.8 11.9 11.9 11.6 11.7 11.4 Hb level (g/dL) 11.2 11.3 11.3 11.2 11.0 11.1 10.8 10.8 10.9 10.7 *p = 0.028 10.6 10.7 10.4 10.4 10.5 10.2 10.2 10.0 Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 (LOCF) LOCF, last observation carried forward Study week Coyne DW et al. J Am Soc Nephrol 2007;18:975–984 31 31

32 Past I.v. Iron Trials have Limitations
Lack of endpoint studies Several studies demonstrating the efficacy of i.v. iron alone or in combination with ESAs are low powered with small cohorts and limited follow-up periods Not all CKD stages studied Studies in HD are not representative of CKD 3–4 populations Patients with comorbidity excluded Most anemia therapy studies in patients with CKD exclude individuals with comorbidities such as inflammatory disease and heart failure 32 32

33 Where Do We Go From Here? 33

34 Where Do We Go From Here? Endpoint studies of i.v. iron and ESA
Are the reduced ESA doses beneficial? Studies in patients with ‘cardio-renal syndrome’ I.v. iron in early anemia FIND-CKD study Observational studies of patients with comorbidity 34 34

35 FIND-CKD Screening (up to 4 weeks) R ND-CKD ESA-naïve
Ferric carboxymaltose: high dose (ferritin target= 400–600 µg/L) 254 patients Screening (up to 4 weeks) Ferric carboxymaltose: low dose (ferritin target= 100–200 µg/L) 254 patients R ND-CKD ESA-naïve Hb 9–10.5 g/dL Ferritin <100 µg/L Oral iron, daily ferrous sulphate 508 patients Visits: every 2 weeks (weeks 0–8), then every 4 weeks (weeks 8–52), dosing every 4 weeks Rescreening permitted No ESA (weeks 0–8) Anemia management per standard practice Primary objective: To evaluate the long-term efficacy of ferric carboxymaltose (using targeted ferritin levels to determine dosing) or oral iron to delay and/or reduce ESA use in ND-CKD patients with iron-deficiency anemia Secondary objectives: To evaluate the ESA requirements, to evaluate the long-term safety and tolerability of iron therapy and evaluate the health resource and economic burden of the treatment of anemia of ND-CKD Macdougall IC et al. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA–PO2402 35 35

36 Conclusions Iron first
Early treatment of anemia in patients with CKD should include effective iron supplementation Most studies demonstrate the superiority of i.v. versus oral iron Low Hb levels are associated with poor prognosis and increased mortality However, interventional ESA trials have not shown a beneficial effect of anemia correction on survival ESA treatment to a low target (10–12 g/dL) is associated with positive effects on QoL and physical function A restrictive transfusion policy is recommended 36 36


Download ppt "Breaking the Vicious Cycle – Efficacy of Anemia Therapies"

Similar presentations


Ads by Google