Presentation on theme: "Anemia and Iron Management With CKD: The Challenge"— Presentation transcript:
1Anemia and Iron Management With CKD: The Challenge Connie Gilet, ANPUNC Healthcare/Kidney CenterMay 23, 2012
2Outline Brief history of anemia management Guidelines: what they are and what they are notResearch about anemia managementResearch about iron administrationGaps in the research anemia & iron researchInformation about ESA and Iron medicationsUsing the new guidelines: case studies
3Brief HistoryEpogen approved for treatment of anemia of CKD, June 1989Prior to 1989, blood transfusions used to treat anemia (about 15% received blood)>Blood transfusions increased the likelihoodof developing antibodies that could make akidney donor transplant difficult/impossible>Adverse effects, including vol. & iron overload
4Comparing ESAs Chemical Structure Epotein alfa (Epogen, Procrit) Darbepoetin (Aranesp) Approved 9/2001PeginesatideSynthesisGenetically engineered from Chinese hamster ovary cellsSyntheticRoute of administrationIV/SCCKD-NDCKD-HDInitial Dosing Amountsunits/kg0.45 mcg/kg0.04 – 0.08 mg/kgDosing ScheduleAdapted from Dutka 20123 times/weekWeekly – 2-8 wksEvery 4 weeks
5Peginesatide: New ESA Studied in USA/Europe. Mean f/u 67.4 weeks Studies funded by Affymax and TakedaDrug was approved by FDA 3/2012>Greater than 25,000 received medicationPulled from the market 2/2013>0.2% dialysis pts have severe allergic rx>0.02% fatal rx with first dose, 30 mins afteradministration (N = 3)>Reasons for reactions are unclearEmerald 1 & 2 (n=1626) = peginesatide and epogen for HD pts. Pearl 1 & 2 (n = 983) = peginestatide and aranesp for non dialysis pts. CV outcomes greater in peginestatide group than aranesp.
6Definitions: KDOQI and KDIGO >Kidney Disease Outcomes Quality Initiatives>Created 1995 by National Kidney Foundation>Publish practice guidelinesKDIGO>Kidney Disease Improving Global Outcomes>Created 2003>Independent, non profit organization governedby multi-discipline international board andmanaged by the National Kidney Foundation
7Brief History of Treatment Guidelines KDOQI/KDIGOFederal Drug Administration (FDA)Hemoglobin Goal YearHemoglobin Goal Year11-12 g/dl10-11 g/dl Year?- initialrecommendationUp to 13 g/dl10-12 g/dl11-12 g/dl10-11 g/dlMore complex (KDIGO)More complex guidelines:-Lowest dose to avoid PRBC-No epogen to treat anemiasymptoms or QOL-Dec dose if Hgb inc > 1gm2 wksNo longer recommendHgb range
8Guidelines: What They Are And Are Not What They Are NotProvides informationNot a standard of careBased on evidence and expert advice, helps with making informed decisionNot suitable for all; can not account for all variations in people (age, co-morbidities, genetics), provider, and system variantsHave been shown to improve quality of care for a populationOne size DOES NOT fits all , while a guideline can apply to the population, it may not apply to an individual
9Consequences Of Using Treatment Guidelines Guidelines supported increasing Epogendoses >>> Hgb values increased…>Hgb 9.6 in 1991 >>>>>>Hgb 12.0 in 2006(90% of those receiving epogen on dialysis)>Hypothesis: higher Hgb would decreasecardiovascular complications (e.g. LVH)>Improved quality of life (e.g. functionalstatus)How did the research support the guidelines?
10Evolution 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 orHct 30% vs 42%Larger doses of Epogen given to achieve these higher Hgb (without much research to support)
11What Does the Research Tell Us How To Treat Anemia?
12How 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.VSObservational study done retrospectively with afew subjects, may provide ‘food for thought’ butdon’t want to base therapy on resultsCan not generalize research results to groups other than the one(s) studied
13Normal Hematocrit Trial RCT, prospective study (1998) of 1233 people onHD 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/weekBesarab, et al, 1998
14Normal Hematocrit Trial Although difference did not meet statisticalsignificance, greater mortality, MI andvascular clots in group with “normal” Hctvalues, trial was stopped before all enrolledNo improvement in QOL with higher Hct levelsBesarab, et al, 1998
15“CHOIR” Study Correction 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: Groupwith Hgb >= 13 had increased risk of MI,hospitalization, stroke, and death.>Terminated early>Similar improvements in quality of lifeAfter the study, goal Hgb reverted g/dlSingh, et al 2006
16“CREATE” Study CV Risk Reduction by Early Anemia Treatment with Epoetin Beta RCT (2006) of 603 CKD-ND (c/s diabetes) people>Compared Hgb to 10.5 to 11.5: risk ofCV events not lowered by correcting the anemia>Epogen doses 5,000 VS 2,000 units per week>After about 3 years, Hgb group 22%greater first CV event (not statisticallysignificant)>Renal function declined faster>Higher QOL scoresDrueke, et al, 2006
17“Treat” Study Trial 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 clotsand possibly, malignancy.>Reported a small improvement in fatigue and QOL>54% of those had Hgb of 13>49% of those receiving placebo also reportedimprovements in fatigue and QOLPfeffer, et al, 2009
19Research About Anemia Management And Transplant? Retrospective study (2009), non randomized.>1794 transplant recipients>Hgb > 12.5 g/dl associated with increasedmortality
20What Are The Outcomes If Hgb Is High Without ESA? DOPPS study>DOPPS = Dialysis Outcomes and PracticePatterns Study>Prospective, observational with 20 counties>545 of 29,796 (1.8%) folks on HD maintaineda Hgb >12.0 g/dl for 4 months without ESA>No increase in mortality notedGoodwin, et al, 2009
21Anemia 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 ofCV adverse events
22Summary 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 benefitsDo not want Hgb >= 13 with ESA dosingIndividualize epogen therapy balancingthe pros (feeling better/dec blood transfusions)vsthe cons (inc chance MI, stroke and death)
23Summary Of Research Findings Those who are ESA resistant and treatedwith high ESA doses may have moreadverse outcomes (e.g CV and death).Naturally occurring high Hgb probably less risky than a high Hgb achieved with ESA
24Gaps In Research DataMost 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 withcaution. For example, how much Epogen do yougive to a 25 year old who was started on HD dueto IgA nephropathy and has no comorbidities?Little info on PD, children or those transplanted
25Gaps In Research DataWhat 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
26Gaps In Research Data Doses of Epogen varied widely to obtain Hgb values greater than 13.>ESA resistant patients received the highestEpogen doses? How do we better ID thosewho are resistant? How much Epogen istoo much? How does one decide how muchEpogen to administer in this group?
27Most 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 10and reduce or stop ESA when Hgb above 10
28Most Recent FDA Guidelines: CKD-ND Consider ESA when Hgb < 10 g/dl.If Hgb > 10, reduce or interrupt dose
29UNC 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
30Most Recent KDIGO Guidelines: CKD-HD Use ESA therapy to avoid Hgb below 9.0Start ESA between 9 & 10.Initiate therapy less than 10 and reduceor interrupt if Hgb exceeds 11.5
31Most Recent FDA Guidelines: CKD-HD CKD-D: start ESA when Hgb < 10.>Reduce or interrupt when Hbg > 11.0
32Recent KDIGO Guidelines For Both CKD-ND and CKD-HD Base dosing decision/initiation of ESA>How rapidly Hgb decreasing>Response to Iron administration>Risks of transfusion and ESA therapy>Symptoms due to anemiaDon’t use ESA to maintain Hgb > 11.5, unless willing to take the riskDon’t use ESA to inc Hgb > 13 g/dl
33Recent KDIGO Guidelines For Both CKD-ND and CKD-HD Prefer decreasing dose vs holding dose ESAUse ESA’s with GREAT caution in people with CKD if malignancy, past or current, or history of strokeBlood transfusions may be preferred if> Hemoglobinopathies, ESA resistance,Malignancy, StrokeAddress all correctable causes of anemia before starting ESA
34Guidelines For Anemia Management With ESA Resistance FDA-inadequate response to ESA over 12week escalation period, no further doseincreasesPer KDOQI: Evaluate “for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered.”
35KDIGO Guidelines For ESA Hyporesponsiveness Initial>No inc Hgb from baseline after 1 month ofweight-based dosing = hyporesponsive> If hyporesponsive, suggest no inc dose beyonddoubling initial weight-based dose (50 to 100 u/kg)Subsequent (acquired)>If previously stable Hgb, may inc 50% beyonddose at which stable (no data to support)>Avoid inc dose beyond 2 x dose at which Hgb hadbeen stable
36KDIGO Guidelines For 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)
37Correctable Vs Not Correctable Causes of Anemia “Easily” CorrectablePotentially CorrectableNot CorrectableNon-adherenceHyperparathyroidsmPRCA (pure red cell aplasia)MalignancyMalnutritionHemoglobinopathies(group of disorders affecting the red blood cells)B12/Folate deficiencyUnder dialyzedBone Marrow DisordersHypothyroidismHemolysisACE-inhibitorsBleedingIron deficiencyInfection/inflammationAdapted from Drueki & Parfrey 2012PRCA-red cells don’t form normally in the bone marrow
38Oral Iron Medications Dose Elemental Iron Side Effects Ferrous Fumarate (buy on-line: 100 pills for about $30)325 mg108 mg ironUpset stomach, constipationFerrous Sulfate65 mg ironFerrous GluconateVitamin C increases absorption of iron. Take between meals with 8 oz water.35 mg iron
39IV Iron Medications Elemental Iron Dosing Side Effects Ferrlecit (Sodium ferric gluconate)62.5 mg/ml125 mg for 8 dosesFlushing, HA, fever, chills, dec BPVenofer (Iron sucrose)20 mg/ml100 mg for 10 dosesFerraheme (Ferumoxytol)39 mg/ml510 mg; 2 doses 3 to 8 days apartINFed (Dextran)50 mg/mlUse formulaTest dose used. Can cause severe allergic reactionsFerrlecit and Venofer had the lowest reported adverse events of this group.Dailie 2012
40Anemia Management and Iron FDA Black Box warning is >> decreased Epogen doses>As Epogen doses decreased, IV iron usageincreased>% dialysis patients receiving IV ironincreased from 57% to 71% between8/2010 to 8/2011.**Pisoni, et al 2011
41Iron: 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 ironTwo tests used to estimate iron stores, ferritin and transferrin saturation (TSAT)>Ferritin: measures protein inside cells thatstore iron> TSAT: % serum iron and total iron bindingcapacity. 20% sats = 20% of the binding sites oftransferrin occupied by iron
42Why We Care About How to Measure Iron Stores Can have too much of a good thing >>>iron toxicityIron toxicity >> organ damage>Lungs - fluid>Liver failure - n/v and bleeding>CV - hypotension>Neuro - drowiness, seizures and coma>Death
43What Do Iron Tests Tell You? If sats <30% and ferritin <500 = iron deficiencyIf sats 25% and ferritin 650 ???>Increase in ferritin can be due neoplasm,inflammatory (including autoimmune dx) orinfectious stateOR>Iron overloadShould iron be given if sats low and ferritin high?
44Research About Iron and CKD Observational study (2004)>No relationship between IV iron & mortality>Subjects had depleted iron stores and nosystemic 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, Ferrari, et al, Rostocker, et al, 2012
45More 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/weekGroupInterventionOutcomesOne1 gm ferric gluconate + 25% increase epogen1.6 g/dl inc HgbTwo25% inc epogen and no iron1.1 g/dl inc Hgb
46DRIVE I and IIDrive I>Showed no adverse effect when ferritin levelshigh (up to 1200) and sats low>Only followed 134 people for 6 wksDrive II>Observational study: Those who receivediron maintained Hgb for 12 weeks despitelower Epogen doses
47Other 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 withincreases in serum ferritin or TSATsLittle data on long-term clinical benefit of iron administration other than increasing HgbFerrari 2011
48Summary of Iron Research Data If the sats are low (< = 30) and ferritin< = 500, ok to give oral or IV ironIf the sats are low and ferritin > 500, unclear status of iron stores >>> dosing???>Individualize care: balance pros and cons ofgiving IV iron
49KDIGO Guidelines For Iron Administration Balance potential benefits with risks of harmFor adults with CKD-ND, trial of iron if TSAT is <=30% & ferritin is <=500 ng/mlCKD-HD: If Hb increase or Epogen dose decrease desired, try iron.Avoid administering IV iron to patients with active systemic infections. (Not Graded)
50KDIGO Guidelines For Iron Administration For CKD ND patients who require iron supplementation, selectroute of iron administration based on severity of iron deficiency,availability of venous access, response to prior oral iron, side effectswith prior oral or IV iron therapy, patient compliance, and cost.(Not Graded)Guide subsequent iron administration in CKD patients based onHb responses to recent iron therapy, as well as ongoing blood losses,iron status tests (TSAT and ferritin), Hb concentration, ESAresponsiveness and ESA dose in ESA treated patients, trends in eachparameter, and the patient’s clinical status. (Not Graded)
51Iron Management And Children For all pediatric CKD patients with anemia not oniron or ESA therapy, we recommend oral iron (or IViron in CKD HD patients) administration whenTSAT is <=20% and ferritin is <=100 ng/ml 100 ug/l).(1D)For all pediatric CKD patients on ESA therapy who are not receiving iron supplementation, we recommend oral iron (or IV iron in CKD HD patients) administration to maintain TSAT >20% and ferritin >100 ng/ml. (1D)(1D = Recommended but very low quality of evidence)
52Anemia Management And Children Data lacking for adults/very little data, if any, for children. KDIGO = Hgb between 11 & 12UNC Kidney Center: Goal = Hgb 10-12HDPD/CKDChildren < 5yrsunits/kg/weekunits/kg/weekChildren > 5 yrs150 units/kg/week100 units/kg/weekIron goals (give enough iron to achieve values)Ferritin > 100 ngTSAT > 20%
53Case Study #1 Mr. C.C. is a 70 year old male with >Hx: CKD IV, IDDM, CAD with two stents, TIA>Meds = 3 HTN, Zocor, oral iron bid, ASA, insulin>VS/Labs: BP 135/82, Creatinine 2.6, GFR 25 mlHgb 9.4, Ferritin 110 ng, Saturation 19%Weight = 70 kgShould Mr. C.C. receive an ESA? IV iron?
54Case Study #1 Mr. C.C. receives IV iron, repeat labs are… >Ferritin 350, Sats 35%, Hgb 9.5Should Mr. C.C. receive epogen ?>When Hgb below 10, consider…>Rate of Hgb decrease>Prior response to iron>Risk of needing transfusion>Symptoms 2/2 anemia
55Case Study #1Mr. C.C. was started on Aranesp 40 mcg. Labs drawn 2 weeks after dose given:>Hgb inc from 9.5 to 9.6>Ferritin inc from 350 to 500 ,>Sats dec from 35 to 31%>No c/o SOB or change in energy level>With a history of TIA, CAD, do you want toincrease the Aranesp dose?
56Case Study #2 Ms. A.A. is a 52 year old on HD with >Hx: DM, HTN, CAD, PVD and SVC syndrome>Meds: 4 HTN, ASA, Warfarin, Lantus>VS/Labs: BP 150/90, Weight 60 kgHgb 9.6, Ferritin 750, Sats 29%>Receiving Epogen 3,000 units 3 x per wkJust completed 1000 mg of ferrlecit IV
57Case Study #2 Ms. A.A. is a 52 year old on HD with >Hx: DM, HTN, CAD, PVD and SVC syndrome>Hgb 9.6, Ferritin 750, Sats 29%Do the guidelines support giving additional iron?Do the guidelines support increasing the Epogen dose?
58Unanswered Questions Is there a maximum or toxic dose of ESA? What makes someone ESA resistant?How does one manage ESA resistance?Does dosing frequency matter?>Is it better to give 2,000 units 3 x per week or6,000 units once per week?How does Hgb variability due to ESA dosing changes affect outcomes?
59What Is The Optimal Hgb Goal? Is this the question we should be asking?Our patients are all different; different genes,comorbidities, functional abilities, needs andexpectations>Should the question not be ?….>For each individual, at what Hgb level arethe risks minimized (e.g. CV) and thebenefits maximized (less fatigue, feel “better”)>Intern’l task force examining this question
61ReferencesBailie, G.R. (2012). Comparison of rates of reported adverse events associated with I.V. iron products in the United States. American Journal of Health-System Pharmacy, 69,(4),Besarab, A., Bolton, W.K., Browne, J.K., Egrie, J.C., Nissenson, A.R., Okamoto, D.M., Schwab, S.J., & Goodkin, D.A. (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin (Normalized Hct). New England Journal of Medicine, 339, (9),
62ReferencesCavanese, C., et al. (2004). Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney International, 65,Coyne, D.W. et al. (2007). Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results from the dialysis patients’ response to IV iron with elevated ferrin (DRIVE) study. Journal of American Society of Nephrology, 18,
63ReferencesDrueke, T.B., Locatelli, F., & Clyne, N. (2006). Normalization of hemoglobin level in patients with chronic kidney disease and anemia(CREATE). New England Journal of Medicine, 355,Drueke, T.B., Parfrey, P.S. (2012). Summary of the KDIGO guideline on anemia and comment: reading between the guideline(s). Kidney International, 82,Dutka, P. (2012). Erythorpoiesis-stimulating agents for the management of anemia of chronic kidney disease: Past Advancements and Current Innovations. Nephrology Nursing Journal, 39 (6),
64ReferencesFeldman, H., et al. (2004). Administration of parenteral iron and mortality among hemodialysis patients. Journal of American Society of Nephrology, 15,Ferrari, P, et al. (2011). Serum iron markers are inadequate for guiding iron depletion in chronic kidney disease. Clinical Journal of American Society of Nephrology, 6,Goodkin, D.A. et al. (2011). Naturally occurringhigher hemoglobin concentration does not increasemortality among hemodialysis patients. Journal ofAmerican Society of Nephrology, 20,
65References Heinz, G., Kainz, A., Horl, W., & Oberbauer, R. (2009). Mortality in renal transplantrecipients given erythropoietins to increasehaemoglobin concentration: cohort study.British Medical Journal, 339, 4081.Kalantar-Zadeh, K. et al (2006). The fascinating but deceptive ferritin: to measure of not to measure it in chronic kidney disease. Clinical Journal of American Society of Nephrology, 1 (Supple 1), S9-S18.
66ReferencesKapalon, T. et al (2008). Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Journal of American Society of Nephrology, 19,Pisoni, R.L. et al (2011). The DOPPS practice monitor for US dialysis care: trends throught August The American Journal of Kidney Diseases, 60, ,
67ReferencesPfeffer, M. A., Burdmann,E.A., Chen, C.Y., Cooper, M.E., de Zeeuw, D., Eckardt, K., Ivanovich, P., Kewalramani, R., Levey, A.S., Lewis, E.F., McGill, J., McMurray, J., Parfrey, P., Parving, H., Remuzzi, G., Singh, A.K., Solomon, S.D., Toto, R., Uno, H. (2009). Baseline characteristics in the trial to reduce cardiovascular events with aranesp therapy (TREAT). American Journal of Kidney Diseases, 54 (1),
68ReferencesRostocker, G. et al. (2012). Hemodialysis-associated hemosiderosis in the era of erythropoisis-stimulating agents. American Journal of Medicine, 125,Singh, A.K., Szczech, L., Tang, K.L., Burnhart, H., Sapp, S., Wolfson, M., Reddan, D. (2006). Correction of anemia with epoetin alfa in chronic kidney disease, New England Journal of Medicine, 355,