Presentation is loading. Please wait.

Presentation is loading. Please wait.

Breaking the Vicious Cycle – Efficacy of Anemia Therapies Peter Bárány Division of Renal Medicine Department of Clinical Science, Intervention and Technology.

Similar presentations


Presentation on theme: "Breaking the Vicious Cycle – Efficacy of Anemia Therapies Peter Bárány Division of Renal Medicine Department of Clinical Science, Intervention and Technology."— 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

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 –Blood transfusions –ESAs –Iron Further studies are needed Conclusions

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 Astor BC et al. Arch Intern Med 2002;162:1401–1408 GFR, glomerular filtration rate 17 0 Hb level in men (g/dL) Estimated GFR, (mL/min/1.73 m 2 ) th Percentile Median 5 th Percentile 17 0 Estimated GFR, (mL/min/1.73 m 2 ) th Percentile Median 5 th Percentile Hb level in women (g/dL)

5 Anemia is Associated with Poor Survival of Patients with CKD Dynamic, retrospective cohort study among 8761 patients with CKD at Kaiser Permanente Northwest 2 Assessment of outcomes 2 –Death –Cardiovascular (CV) hospitalization –End-stage renal disease (ESRD) 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 Due to the negative effects of anemia, 1–3 early diagnosis and treatment in patients with CKD is recommended 4, Rate per 100 patient-years Mean hemoglobin (g/dL) per decile Death CV hospitalization ESRD

6 Blood Transfusions – Restricted Use is Still Needed

7 Transfusion Use in the CKD Population Transfusion use is decreasing in the CKD population 1 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 Ibrahim HN et al. Nephrol Dial Transplant 2009;24:3138– Cohort year Transfusion rate (per 1000 patients) CKD Non-CKD

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 Foley RN et al. Clin J Am Soc Nephrol 2008;3:1669–1675 Low Hb targetHigh Hb targetp Transfusion rate (per patient per year) 0.66 (95% CI=0.59–0.74) 0.26 (95% CI=0.22–0.32) < Pretransfusion Hb level (g/dL) 7.7 (95% CI=7.5–7.9) 8.1 (95% CI=7.6–8.5) 0.09 Transfusion HR1 (reference)0.46 (95% CI=0.29–0.72) HR, Hazard Ratio

9 The Efficacy of ESA Therapy

10 Numerous ESAs are Currently Available with more Development 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 Darbepoetin t 1 / 2 25–72 hours Epoetin t 1 / 2 6–24 hours Methoxy PEG-epoetin (CERA) t 1 / hours Epoetin t 1 / 2 6–24 hours 20XX Hematide Biosimilar epoetins

11 Numerous Studies have Demonstrated the Efficacy of ESAs to Improve and Maintain Hemoglobin Levels in Patients with Anemia and CKD at all Stages KDOQI TM. Am J Kidney Dis 2007;50:471–530 0 Suzuki (1989) Size (n) Placebo/control mean Hb Lower target mean achieved Hb Higher target mean achieved Hb Hemoglobin (g/dL) Abraham (1990) Watson (1990) CanEPO (1990) Bahlman (1991) Clyne (1992) Morris (1993) Sikole (1993) Roth (1994) Nissenson (1995) Kuriyama (1997) Besarab (1998) McMahon (1999) Foley (2000) Furuland (2003) Gouva (2004) Roger (2004) Parfrey (2005) Levin (2005) Rossert (2006) Drüeke (2006) Singh (2006) Ritz (2007)

12 VO 2 max (L/min) Total hemoglobin (g) 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 Bárány P et al. Clin Sci 1993;84:441–447 VO 2 max, maximum oxygen uptake Before ESA therapy Mean healthy subjects ± 2SD of mean After ESA therapy p<0.001

13 Parfrey PS et al. Clin J Am Soc Nephrol 2009;4:755–762 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% Patients with severe anemia had a substantial improvement in LVMi when assigned to a target Hb 12 g/dL Change in LVMi (mean with 95% CI) -100 Combined Ayus 2005 Sikole 2002 London 2001 Hayashi 2000 Massimetti 1998 Portoles 1997 Pascual 1991 (ii) Pascual 1991 (i) Cannella 1990 Hct, hematocrit; LVMi, left ventricular mass index

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

15 Four Large Trials have Examined the Efficacy and Safety of ESAs to Achieve High or Low Hb Targets Normal HCT 1 CHOIR 2 CREATE 3 TREAT 4 Region USA Europe Americas, Europe, Australia N Patients CKD5D with cardiac disease CKD 3–4 CKD 3–4 with Type 2 DM eGFR, mL/min/1.73 m 2 HD patients15–5015–3520–60 Target/achieved Hb, g/dL Low High Hct 30±3 % Hct 42±3 % / – –15.0 Placebo/ESA at Follow-up, months 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) 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 DM, diabetes mellitus; MI, myocardial infarction; CHF, chronic heart failure

16 Diabetes and CV Disease were Common Comorbidities in the Four Major Trials of ESAs Normal HCT 1 CHOIR 2 CREATE 3 TREAT 4 Region USA Europe Americas, Europe, Australia N Patients CKD5D with cardiac disease CKD 3–4 CKD 3–4 with Type 2 DM DM, % 56N/A26100 History of CV disease, % MI CHF Cerebrovascular disease Peripheral vascular disease – 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

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 underpowered 2 1. Drüeke TB et al. N Engl J Med 2006;355:2071–2084; 2. Levin A. Nephrol Dial Transplant 2007;22:309–312 Higher Hb targets in pre-dialysis CKD patients are associated with significant improvements in quality of life (QoL) parameters Group 1Group 2 General Health Change from baseline in quality of life score Mental Health Physical Function Physical Role Social Function Vitality p=0.003p<0.001 p=0.01p=0.006p<0.001

18 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 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 Mean Hb level (g/dL) Mean epoetin dose x 10 3 (units/patient/wk) Spain Germany Japan AUS/NZ CanadaBelgium US Italy Sweden France UK

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 Pfeffer MA et al. N Engl J Med 2009;361:2019–2032 ESA therapy effectively corrected Hb levels compared with placebo, however, no difference was observed in disease progression or mortality Renal composite (ESRD or death) ESRD Months since randomization 0 Mean Hb (g/dL) Darbepoetin alfa Placebo Months since randomization 0 Patients with event (%) Darbepoetin alfa Placebo Hazard ratio, 1.06 (95% CI, 0.95–1.19) p=0.29 Months since randomization 0 Patients with event (%) Darbepoetin alfa Placebo Hazard ratio, 1.02 (95% CI, 0.87–1.18) p=0.83

20 The Efficacy of Iron Therapy

21 Numerous I.v. Iron Preparations are Available Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115 Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117– s1990s1950s Ferric carboxymaltose 150 kDa t 1 / 2 16 hours Ferumoxytol 308–750kDa t 1 / 2 9.3–14.5 hours Low MW iron dextran 72–90 kDa t 1 / 2 5–35 hours Sodium ferric gluconate 12 kDa t 1 / 2 1–2 hours Iron sucrose 45 kDa t 1 / 2 5 hours 2010 MW, molecular weight 20XX Hematide High MW iron dextran 265 kDa t 1 / 2 60 hours 1970s Darbepoetin t 1 / 2 25–72 hours Epoetin t 1 / 2 6–24 hours Methoxy PEG-epoetin (CERA) t 1 / hours Epoetin t 1 / 2 6–24 hours Biosimilar epoetins

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 Eschbach JW et al. N Engl J Med 1987;316:73– –2007 One of the clinical features seen with this form of treatment was a state of functional iron deficiency 45 Reticulocytes Corrected (%) Weeks Anephric Hematocrit (%) 200 mL RBCs 1000 mg i.v. iron dextran rHuEPO 50 U/kg 3x/wk % saturated ferritin

23 Besarab A et al. J Am Soc Nephrol 1999;10:2029–2043 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 Change in hemoglobin (%) PrePost Ferritin (ng/mL) 209±40447±50 TSAT (%)22±235± Reduction in ESA dose (%) r=0.56 p<0.05

24 1. Kalantar-Zadeh K et al. J Am Soc Nephrol 2005;16:3070–3080 I.v. Iron Therapy is Associated with Improved Survival in HD Patients Epidemiological study conducted in the US 1 –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 All-cause mortality hazard ratio – – Unadjusted Case mix Case mix and MICS I.v. iron dose (mg/month) CV mortality hazard ratio – – Unadjusted Case mix Case mix and MICS I.v. iron dose (mg/month) MICS; malnutrition-inflammation complex syndrome

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) *p<0.05; **p<0.01; ***p<0.001 from baseline +p<0.05 after 42 weeks between groups Patients achieving 1 g/dL increase in Hb (%) Change in Hb (g/dL) Time after start of treatment (days) ** *** * * I.v. ironOral iron I.v. ironOral iron Adapted from Van Wyck DB et al. Kidney Int 2005;68:2846–2856

26 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) Adapted from Charytan C et al. Nephron Clin Pract 2005;100:c55-62 Patient response* (%) Mean Hb change from baseline (g/dL) p= Baseline Study day p< p=0.002 p=0.017 I.v. ironOral iron I.v. ironOral iron *Achieving Hb >11.0 g/dL p values are versus baseline values

27 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) Spinowitz BS et al. J Am Soc Nephrol 2008;19:1599–1605 Mean change in Hb from baseline (g/dL) Patient response* (%) p=0.001 I.v. iron (n=83) Oral iron (n=33) I.v. iron (n=83) Oral iron (n=33) *Achieving 1g/dL increase from baseline

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 m 2 ) with anemia –I.v. ferric carboxymaltose (n=152) versus oral ferrous sulfate (n=103) p<0.001 I.v. iron (n=144) 60.4 Oral iron (n=101) Patient response* (%) *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 SAPO2422

29 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 Benjamin J & Qunibi W. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SAPO2422 p<0.008; p<0.002 *Achieving 1g/dL increase from baseline at any time during the study I.v. iron + ESA (n=33) 50.0 Oral Iron + ESA (n=24) 53.2 I.v. iron only (n=11) 29.9 Oral iron only (n=77) Patient response* rate (%)

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 *p<0.05 versus baseline Baseline12 months* Patients achieving targets (%) Hb >10 g/dL Serum ferritin >100 ng/mL and TSAT >20% Mircescu G et al. Nephrol Dial Transplant 2006;21:120–

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 Coyne DW et al. J Am Soc Nephrol 2007;18:975– Week 0 Study week Hb level (g/dL) Week 1Week 2Week 3Week 4Week 5Week 6 (LOCF) ** I.v. iron Control *p = LOCF, last observation carried forward

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

33 Where Do We Go From Here?

34 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

35 FIND-CKD Visits: every 2 weeks (weeks 0–8), then every 4 weeks (weeks 8–52), dosing every 4 weeks Screening (up to 4 weeks) ND-CKD ESA-naïve Hb 9–10.5 g/dL Ferritin <100 µg/L 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 Rescreening permitted R Ferric carboxymaltose: high dose (ferritin target= 400–600 µg/L) 254 patients Ferric carboxymaltose: low dose (ferritin target= 100–200 µg/L) 254 patients Oral iron, daily ferrous sulphate 508 patients No ESA (weeks 0–8) Macdougall IC et al. 42nd ASN Renal Week, 27 October–1 November 2009, San Diego, USA. Poster SA–PO2402

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


Download ppt "Breaking the Vicious Cycle – Efficacy of Anemia Therapies Peter Bárány Division of Renal Medicine Department of Clinical Science, Intervention and Technology."

Similar presentations


Ads by Google