Anemia and Iron Management With CKD: The Challenge

1. Anemia and Iron Management With CKD: The Challenge Connie Gilet, ANP UNC Healthcare/Kidney Center May 23, 2012

2. Outline • Brief history of anemia management • Guidelines: what they are and what they are not • Research about anemia management • Research about iron administration • Gaps in the research anemia & iron research • Information about ESA and Iron medications • Using the new guidelines: case studies

3. Brief History • Epogen approved for treatment of anemia of CKD, June 1989 • Prior to 1989, blood transfusions used to treat anemia (about 15% received blood) >Blood transfusions increased the likelihood of developing antibodies that could make a kidney donor transplant difficult/impossible >Adverse effects, including vol. & iron overload

4. Comparing ESAs

5. Peginesatide: New ESA • Studied in USA/Europe. Mean f/u 67.4 weeks • Studies funded by Affymax and Takeda • Drug was approved by FDA 3/2012 >Greater than 25,000 received medication • Pulled from the market 2/2013 >0.2% dialysis pts have severe allergic rx >0.02% fatal rx with first dose, 30 mins after administration (N = 3) >Reasons for reactions are unclear

6. Definitions: KDOQI and KDIGO • KDOQI >Kidney Disease Outcomes Quality Initiatives >Created 1995 by National Kidney Foundation >Publish practice guidelines • KDIGO >Kidney Disease Improving Global Outcomes >Created 2003 >Independent, non profit organization governed by multi-discipline international board and managed by the National Kidney Foundation

7. Brief History of Treatment Guidelines

8. Guidelines: What They Are And Are Not

9. Consequences Of Using Treatment Guidelines • Guidelines supported increasing Epogen doses >>> Hgbvalues increased… >Hgb 9.6 in 1991 >>>>> >Hgb 12.0 in 2006 (90% of those receiving epogen on dialysis) >Hypothesis: higher Hgb would decrease cardiovascular complications (e.g. LVH) >Improved quality of life (e.g. functional status) • How did the research support the guidelines?

10. Evolution of Guidelines: Is More Better? • Since Epogen successful to increase Hgb, why not treat anemia to targeted “normal” levels? >Women ~ 12 g/dl and men ~13 g/dl or Hct 30% vs 42% • Larger doses of Epogen given to achieve these higher Hgb (without much research to support)

11. What Does the Research Tell Us How To Treat Anemia?

12. How Does One Interpret Research Data? • Few important facts about research studies…. • Randomized control trial (RCT) done prospectively with a large number of subjects followed for a long time produces the most reliable data. May want to base therapy on results. VS • Observational study done retrospectively with a few subjects, may provide ‘food for thought’ but don’t want to base therapy on results • Can not generalize research results to groups other than the one(s) studied

13. Normal Hematocrit Trial • RCT, prospective study (1998) of 1233 people on HD with cardiac disease compared “low” Hct (30%) vs “normal” Hct (42%) >Average age 65 >Many with diabetes >Followed for average 14 months >Epogen doses 160u/kg/week for “low” group vs “normal” group 460u/kg/week Besarab, et al, 1998

14. Normal Hematocrit Trial • Although difference did not meet statistical significance, greater mortality, MI and vascular clots in group with “normal” Hct values, trial was stopped before all enrolled • No improvement in QOL with higher Hct levels Besarab, et al, 1998

15. “CHOIR” StudyCorrection of Hemoglobin and Outcomes in Renal Insufficiency • RCT study (2006) looked at 1432 patients with CKD, stage 3 and 4 >Compared Hgb >= 13 to 11.3 gm/d: Group with Hgb >= 13 had increased risk of MI, hospitalization, stroke, and death. >Terminated early >Similar improvements in quality of life • After the study, goal Hgb reverted 11-12 g/dl Singh, et al 2006

16. “CREATE” StudyCV Risk Reduction by Early Anemia Treatment with Epoetin Beta • RCT (2006) of 603 CKD-ND (c/s diabetes) people >Compared Hgb 13-15 to 10.5 to 11.5: risk of CV events not lowered by correcting the anemia >Epogen doses 5,000 VS 2,000 units per week >After about 3 years, Hgb 13-15 group 22% greaterfirst CV event (not statistically significant) >Renal function declined faster >Higher QOL scores Drueke, et al, 2006

17. “Treat” StudyTrial to Reduce CV Events with Aranesp Therapy • RCT study (2009) of 4, 038 CKD 3 & 4 with diabetes. Compared treatment with placebo with Aranesp to achieve a Hgb of 13 gm/d >No difference death or progression to ESRD >Greater doses increased risk for stroke, venous clots and possibly, malignancy. >Reported a small improvement in fatigue and QOL >54% of those had Hgb of 13 >49% of those receiving placebo also reported improvements in fatigue and QOL Pfeffer, et al, 2009

18. Children/PD And Anemia Studies? • None

19. Research About Anemia Management And Transplant? • Retrospective study (2009), non randomized. >1794 transplant recipients >Hgb > 12.5 g/dl associated with increased mortality

20. What Are The Outcomes If Hgb Is High Without ESA? • DOPPS study >DOPPS = Dialysis Outcomes and Practice Patterns Study >Prospective, observational with 20 counties >545 of 29,796 (1.8%) folks on HD maintained a Hgb >12.0 g/dl for 4 months without ESA >No increase in mortality noted Goodwin, et al, 2009

21. Anemia Management With ESA Resistance? • About 15% of ESRD are ESA resistance • “Choir” Study >High dose Epogen associated with 57% increased risk death, MI, HF and stroke • “Treat” Study >Poor response to Aranesp >>increase risk of CV adverse events

22. Summary Of Research Findings For Anemia Management • Most research done on adults with CKD-ND and some with those receiving HD • “Reasonable” dose of ESA probably has some benefits • Do not want Hgb >= 13 with ESA dosing • Individualize epogen therapy balancing the pros(feeling better/dec blood transfusions) vs the cons (inc chance MI, stroke and death)

23. Summary Of Research Findings • Those who are ESA resistant and treated with high ESA doses may have more adverse outcomes (e.g CV and death). • Naturally occurring high Hgb probably less risky than a high Hgb achieved with ESA

24. Gaps In Research Data • Most of the research done on those with CKD, not on dialysis, older than 60 years with many comorbitities (e.g. DM, HTN) >Apply findings to groups not studied with caution. For example,how much Epogen do you give to a 25 year old who was started on HD due to IgA nephropathy and has no comorbidities? • Little info on PD, children or those transplanted

25. Gaps In Research Data • What is the optimal Epogen dose frequency; one a week, twice a week, three times per week? • While research demonstrates Hgb > 13.0 are associated with adverse outcomes, no data on the benefits vs. adverse outcomes of Hgb between 11.5 and 13.0 g/dl

26. Gaps In Research Data • Doses of Epogen varied widely to obtain Hgb values greater than 13. >ESA resistant patients received the highest Epogen doses? How do we better ID those who are resistant? How much Epogen is too much? How does one decide how much Epogen to administer in this group?

27. Most Recent KDIGO Guidelines: CKD-ND • Individualize dose; use the lowest dose that reduces need for blood transfusion >Target Hgb range not provided >Consider starting ESA when Hgb below 10 and reduce or stop ESA when Hgb above 10

28. Most Recent FDA Guidelines: CKD-ND • Consider ESA when Hgb < 10 g/dl. If Hgb > 10, reduce or interrupt dose

29. UNC CKD-ND Anemia Guidelines • Outpatient anemia clinic guidelines for CKD III to V >Start Aranesp at 50mg/kg >Goal Hgb between 9.5 and 10.4 >If Hgb >= 11.0 hold Ananesp

30. Most Recent KDIGO Guidelines: CKD-HD • Use ESA therapy to avoid Hgb below 9.0 Start ESA between 9 & 10. • Initiate therapy less than 10 and reduce or interrupt if Hgb exceeds 11.5

31. Most Recent FDA Guidelines: CKD-HD • CKD-D: start ESA when Hgb < 10. >Reduce or interrupt when Hbg > 11.0

32. Recent KDIGO GuidelinesFor Both CKD-ND and CKD-HD • Base dosing decision/initiation of ESA >How rapidly Hgbdecreasing >Response to Iron administration >Risks of transfusion and ESA therapy >Symptoms due to anemia • Don’t use ESA to maintain Hgb > 11.5, unless willing to take the risk • Don’t use ESA to incHgb > 13 g/dl

33. Recent KDIGO GuidelinesFor Both CKD-ND and CKD-HD • Prefer decreasing dose vs holding dose ESA • Use ESA’s with GREAT caution in people with CKD if malignancy, past or current, or history of stroke • Blood transfusions may be preferred if > Hemoglobinopathies, ESA resistance, Malignancy, Stroke • Address all correctable causes of anemia before starting ESA

34. Guidelines For Anemia Management With ESA Resistance • FDA-inadequate response to ESA over 12 week escalation period, no further dose increases • Per KDOQI: Evaluate “for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered.”

35. KDIGO Guidelines For ESA Hyporesponsiveness • Initial >No incHgb from baseline after 1 month of weight-based dosing = hyporesponsive > If hyporesponsive, suggest no inc dose beyond doubling initial weight-based dose (50 to 100 u/kg) • Subsequent (acquired) >If previously stable Hgb, may inc50% beyond dose at which stable (no data to support) >Avoid inc dose beyond 2 x dose at which Hgb had been stable

36. KDIGO GuidelinesFor ESA Hyporesponsiveness • Management >Treat cause of poor ESA response >If poor response remains, balance benefits/ burden of >Decrease in Hgb >Continuing ESA >Blood transfusions (All 2D = Suggest and very low quality evidence)

37. Correctable Vs Not Correctable Causes of Anemia

38. Oral Iron Medications

39. IV Iron Medications

40. Anemia Management and Iron • FDA Black Box warning is 2007 >> decreased Epogen doses >As Epogen doses decreased, IV iron usage increased >% dialysis patients receiving IV iron increased from 57% to 71% between 8/2010 to 8/2011.* *Pisoni, et al 2011

41. Iron: Where It’s Found And How It’s Measured • Most iron found in liver and red blood cells. Also present in bone marrow, spleen and in all cells >Body hoards and recycles iron • Two tests used to estimate iron stores, ferritin and transferrin saturation (TSAT) >Ferritin: measures protein inside cells that store iron > TSAT: % serum iron and total iron binding capacity. 20% sats = 20% of the binding sites of transferrin occupied by iron

42. Why We Care About How to Measure Iron Stores • Can have too much of a good thing >>> iron toxicity • Iron toxicity >> organ damage >Lungs - fluid >Liver failure - n/v and bleeding >CV - hypotension >Neuro - drowiness, seizures and coma >Death

43. What Do Iron Tests Tell You? • If sats <30% and ferritin <500 = iron deficiency • If sats 25% and ferritin 650 ??? >Increase in ferritin can be due neoplasm, inflammatory (including autoimmune dx) or infectious state OR >Iron overload • Should iron be given if sats low and ferritin high?

44. Research About Iron and CKD • Observational study (2004) >No relationship between IV iron & mortality >Subjects had depleted iron stores and no systemic inflammation * • Several studies claim people on dialysis have iron overload per labs, yet no clinical symptoms of iron overload ** *Feldman, et al, 2004 **Conavese, et al, 2004. Ferrari, et al, 2001. Rostocker, et al, 2012

45. More Research About Iron and CKD: Drive I (2007) • RCT, prospective study of CKD-hemodialysis >Low sats (<=25%) and high ferritin (500- 1200) >Hgb <= 11 and Epogen >= 225u/kg/week

46. DRIVE I and II • Drive I >Showed no adverse effect when ferritin levels high (up to 1200) and sats low >Only followed 134 people for 6 wks • Drive II >Observational study: Those who received iron maintained Hgb for 12 weeks despite lower Epogen doses

47. Other Iron Studies • Study (2011), prospective study with 25 people with CKD III to VI found, after infusion of IV iron, increases of iron in liver don’t correlate with increases in serum ferritin or TSATs • Little data on long-term clinical benefit of iron administration other than increasing Hgb Ferrari 2011

48. Summary of Iron Research Data • If the sats are low (< = 30) and ferritin < = 500, ok to give oral or IV iron • If the sats are low and ferritin > 500, unclear status of iron stores >>> dosing??? >Individualize care: balance pros and cons of giving IV iron

49. KDIGO Guidelines For Iron Administration • Balance potential benefits with risks of harm • For adults with CKD-ND, trial of iron if TSAT is <=30% & ferritin is <=500 ng/ml • CKD-HD: If Hb increase or Epogen dose decrease desired, try iron. • Avoid administering IV iron to patients with active systemic infections. (Not Graded)

50. KDIGO Guidelines For Iron Administration • For CKD ND patients who require iron supplementation, select route of iron administration based on severity of iron deficiency, availability of venous access, response to prior oral iron, side effects with prior oral or IV iron therapy, patient compliance, and cost. (Not Graded) • Guide subsequent iron administration in CKD patients based on Hbresponses to recent iron therapy, as well as ongoing blood losses, iron status tests (TSAT and ferritin), Hb concentration, ESA responsiveness and ESA dose in ESA treated patients, trends in each parameter, and the patient’s clinical status. (Not Graded)