Disclosures for Michael Auerbach MD, FACP In compliance with ACCME policy, ASH requires disclosures to the session audience:

Transcription

1 Treatment of Iron Deficiency: Who, When, With What Michael Auerbach MD, FACP Private Practice, Baltimore, Maryland Clinical Professor of Medicine Georgetown University School of Medicine Washington, DC Disclosures for Michael Auerbach MD, FACP In compliance with ACCME policy, ASH requires disclosures to the session audience: Research Funding: AMAG Pharma; Pharmacosmos Discussion of off label drug use: Use of IV iron 1

2 Learning Objectives 1. Distinguish the need for oral or intravenous iron for the treatment of iron deficiency 2. Familiarize and become comfortable with the available IV iron formulations 3. Be able to differentiate the symptoms associated with minor infusion reactions with IV iron and the rare symptoms of severe hypersensitivity which can lead to anaphylaxis 4. Review evidence based treatment approaches with iron supplementation in specific conditions associated with iron lack Use of Oral Iron Sydenham first used iron filings in cold wine to treat green sickness (described by Lange) in 1687 Blaud renamed chlorosis in 1832, First to use ferrous sulfate By time of American Civil War iron was used to treat war wounds Today iron deficiency is the most common micronutrient deficiency on the planet estimated to affect >35% of world s population, >50% of gravidas 100 times more prevalent than cancer >300 years later, the often ineffective, usually poorly tolerated oral iron continues to be frontline Beard JL, et al. Annu Rev Nutr. 2001:23:

3 Major Causes of Iron Deficiency Abnormal Uterine Bleeding Pregnancy Multiparity Post partum blood loss Gastrointestinal (Inflammatory Bowel Disease) Bariatric Surgery Multiple Surgeries Angiodysplasia CKD Diabetes Blood loss from trauma Hereditary Hemorrhagic Telangiectasia Comorbid conditions (Iron restricted erythropoiesis) Malabsorption (should never be considered without excluding others) Symptoms of Iron Deficiency Fatigue often independent of hemoglobin Pagophagia and forms of pica Restless Legs Syndrome Brittle Integument 3

4 10/3/2018 Iron Deficiency Anemia of Anemia Inflammation Diagnosis Iron deficiency Anemia of Inflammation CHr Low Low TIBC High Low Low Low Very low N/High Transferrin saturation Ferritin Mees Lines 4

5 Pretreatment Tongue Healed Tongue 5

6 Oral or Intravenous Iron Indications for oral iron Mild, uncomplicated iron deficiency without active bleeding First trimester of pregnancy Second trimester of pregnancy if Hb>10.0 g/dl Indications for IV iron Intolerance of, or unresponsiveness to oral iron Second trimester of pregnancy if Hb<10.0 g/dl Third trimester of pregnancy After bariatric surgery Abnormal uterine bleeding Inflammatory bowel disease Angiodysplasia (HHT) Iron restricted erythropoiesis Co morbid inflammatory condition Adverse Events with Iron Supplementation ORAL (70%) Constipation (less often diarrhea) Metallic taste Nausea Gastric Cramping Thick, green, tenacious stool INTRAVENOUS Infusion Reactions (1 3%) Pressure in chest Arthralgia or myalgia Headache Flushing Severe Hypersensitivity (<1:250,000) Hives or urticaria Hypotension Wheezing Stridor Periorbital edema 6

7 Labile Iron Content in Parenteral Iron Produc Used with permission from: Jahn MR, Andreasen HB, Fütterer S, Nawroth T, Schünemann V, Kolb U, Hofmeister W, Muñoz M, Bock K, Meldal M, Langguth P. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm Aug;78(3):

8 Premedication and Serious Adverse Events Patients SHOULD NOT be premedicated with diphenhydramine which can cause hypotension, flushing, somnolence and supraventricular tachycardia Inappropriate intervention can cause severe SAE Minor chest and back tightness, usually after test dose, first described by Steve Fishbane is NOT a serious AE Resolves without treatment: Do NOT intervene with epinephrine or diphenhydramine An SAE should consist of hypotension, tachypnea, tachycardia, wheezing, stridor or periorbital edema Premedication with steroids only for allergic diatheses Auerbach M, Ballard H, Glaspy J. Lancet. 2007;369:

9 Study ID Other Baykan et al, 2006 Cook et al, 1990 Davis et al, 2000 Fouad et al, 2013 Ganzoni and Rhyner, 1974 Gordeuk et al, 1987 Hallberg et al, Hallberg et al, Hallberg et al, Levy et al, 1978 Maghsudlu et al, 2008 Mirrezaie et al, 2008 Pereira et al, 2014 Sutton et al, 2004 Tuomainen et al, 1999 Vaucher et al, 2012 Waldvogel et al, 2012 Yalcin et al, 2009 Subtotal (I squared = 27.0%, p = 0.140). Pregnant Makrides et al, 2003 Meier et al, 2003 Subtotal (I squared = 0.0%, p = 0.367). Overall (I squared = 53.6%, p = 0.002) Note: Weights are from random effects analysis OR (95% CI) % Weight 1.32 (0.63, 2.79) (1.49, 6.84) (0.83, ) (0.65, 10.97) (2.32, 8.59) (1.59, ) (1.07, 3.31) (1.23, 4.69) (1.45, 4.45) (2.41, 8.05) (1.06, 5.84) (0.86, 5.57) (1.20, ) (0.35, 3.26) (0.41, ) (0.47, 2.79) (1.67, 9.68) (0.40, 4.99) (2.02, 3.30) (0.63, 1.47) (0.61, 3.88) (0.71, 1.53) (1.74, 3.08) Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects in placebocontrolled RCTs. With Permission: Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One Feb 20;10(2):e IV Iron Safety A total of 103 trials performed between 1965 and 2013 were included. Pooled together, 10,391 patients were treated with IV iron and were compared to: - 4,044 patients treated with oral iron - 1,329 with no iron - 3,335 with placebo with IM iron Avni et al, Mayo Clin 2015;90:

10 IV Iron Safety Overall, there was no increase in the risk of severe adverse events (SAEs) with IV iron compared to control, RR 1.04 (95% CI , 97 trials, I 2 =9%) No difference in either efficacy or toxicity among the formulations was observed Avni et al, Mayo Clin 2015;90:12-23 Cumulative fractional and total iron absorption in study 1 Stoffel N, Cercamondi C, Brittenham G, Zeder C, Geurts Moespot A, Swinkels D, Moretti D, Zimmermann, M. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice daily split dosing in iron depleted women: two open label, randomised controlled trials. The Lancet Haematology 2017; 4: doi: /s (17)

11 Intravenous Iron Preparations Carbohydrate Total Dose Infusion (TDI) Test Dose Required Boxed warning Availability LMW Iron dextran YES Yes Yes US/Eur Ferric gluconate NO No No US/Eur Iron sucrose NO No No US/Eur Ferumoxytol YES No Yes US Carboxymaltose YES No No US/Eur Isomaltoside YES No No Europe 1. INFeD. Available at: 2. Ferrlecit. Available at: 3. Venofer. Available at: 4. Feraheme. Available at: 5. Injectafer. Available at: 6. Monofer. Available at: Formulation Approved Dosing Maximum Safe Dose IV Iron Dosing LMW Iron dextran 100mg over 2 min TDI over 1-4 hours 1-2 Ferumoxytol (US only) Ferric carboxymaltose (FCM) 510mg in 15 min 510mg over seconds or 1020mg over 15 min 3 750mg over 15 min 1000mg over 15 min 4 Iron isomaltoside (Europe only) 20mg/kg over 15 min <1000mg and 60 min for > mg over 15 min 5,6 1.Auerbach et al. Am J Kidney Dis. 1998;31: Auerbach et al. Presented at American Society of Hematology, December 2009, New Orleans, LA. 3.Ferumoxytol [prescribing information]. Lexington, MA: AMAG Pharmaceuticals, Inc; FCM [summary of product characteristics]. France: Vifor Pharma; Iron isomaltoside [summary of product characteristics]. Denmark: Pharmacosmos; Dahlerup et al. Scand of Gastroenterol 2016;21:1-7 11

12 TDI LMWID 1000 mg in One Hour Data were collected from consecutive unselected patients (888) with iron deficiency anemia who met the following criteria: - Confirmed iron deficiency (TSAT 20% and/or serum ferritin 100 ng/ml) - Previously failed or intolerant of oral iron - No ESA therapy or chemotherapy 1000 mg LMWID diluted in 250 ml normal-saline infusion over 1 hour after a test dose (n=1266) Auerbach M, et al. Am J Hematol. 2011;86: Hgb and Transfusion Requirements Hgb (g/dl) Pre-infusion baseline Post-infusion followup* Change from baseline Hgb increase of 1 g/dl: 51% of patients Hgb increase of 2 g/dl: 26% of patients Mean ± SD 10.8± ± ±1.4 LMWID (n=434) 95% CI One patient transfused following severe gastrointestinal bleed secondary to angiodysplasia *Median time to follow-up for change in Hgb = 4 weeks. Auerbach M, et al. Am J Hematol. 2011;86:

13 Case Presentations Iron Deficiency plus active inflammation Iron Deficiency with Anemia of Cancer Iron Deficiency with Inflammatory bowel disease Iron Deficiency after bariatric surgery Iron Deficiency in Pregnancy Case Presentation #1 A 58 year old otherwise well exercise enthusiast suffered a tear of her right obturator internus muscle after vigorous stretching. A large hematoma ensued which became infected, required treatment with intravenous antibiotics and hospitalization. Healing commenced with discharge and at four weeks the hemoglobin was 9.3 grams/dl, MCV 83 fl, serum ferritin 34 ng/ml, TIBC 296 ug/ml, TSAT 8%. Initial therapy should be: A. 325 mg Oral ferrous sulfate every other day B. 325 mg oral ferrous sulfate followed by IV iron if intolerant C. Intravenous iron D. B12 and folate 0% 0% 0% 0% A. B. C. D. 13

14 Hepcidin cvauidiko increases iron absorption, liver iron, decreased RE iron Over expression leads to severe Fe def in mice, Iron refractory anemia of hepatic adenomas Mutated in juvenile hemochromatosis Vaulont S et al. J Clin Invest 2005;115: Vaulont S et al. J Clin Invest 2005;115: Why IV Iron Works There is no in vitro data for this slide IV iron immediately saturates circulating transferrin which then brings the iron via the transferrin receptor to the surface of erythroblasts Circulating macrophage iron increases in these iron avid cells Macrophages load with iron which upregulates IRP1 and 2 which upregulates ferroportin overcoming some of hepcidin block The benefit in ESA reduction and decreased time to targets in anemias of CKD and CIA provide support for these hypotheses. 14

15 Answer: (C) Intravenous Iron It is likely absolute and functional iron deficiency are present Unlike oral iron, intravenous iron will overcome the inhibition of erythropoiesis of the inflammatory state Intravenous iron will treat the iron deficiency anemia and replenish stores. Since a single treatment is likely to completely correct the defect, LMWID as 1000 mg in one hour, ferumoxytol as two 510 mg infusions over 15 minutes (or one 1020 mg infusion if covered by insurance (US only)), iron isomaltoside as one gram in 15 minutes (Europe only) or ferric carboxymaltose as two 750 mg infusions in 15 minutes (US) or one gram in 15 minutes (Europe only) are the preferred choices. Case Presentation #2: Chemotherapy Induced Anemia A 58 year old man with metastatic colon cancer to liver developed anemia during treatment. The hemoglobin was 8.8, MCV 94, retics 68,000 /mm, ferritin 1186 ng/ml, TSAT 7%. B12 >2000 pg/ml. LDH 410 U/mL. Intervention for the anemia should be: A. Ferrous sulfate one tablet every other day B. Intravenous iron C. Intravenous iron plus ESA D. Blood transfusion E. Psychiatry consult to assist in dealing with fatigue 0% 0% 0% 0% 0% A. B. C. D. E. 15

16 Hematopoietic response RR 1.31 [95% CI 1.15 to 1.49] Intravenous iron versus standard of care: Rate of patients who achieved a hematopoietic response Blue squares represent the point estimate. Their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate Gafter-Gvili et al, Acta Oncologica, 2012 Need for blood Transfusions RR 0.74 [95% CI 0.61 to 0.89] Intravenous iron versus standard of care: Number of patients who required blood transfusions. Gafter-Gvili et al, Acta Oncologica,

17 IV Iron Optimizes the Response to Recombinant Human EPO in Patients with CIA: Mean Change in Hgb Mean Change in Hgb, g/dl ITT population No iron Oral iron Bolus TDI a,b a,b Overall changes from baseline, P< Overall difference between groups, P< a Differs from no iron group, P<0.05. b Differs from oral iron group, P<0.05. Auerbach M, et al. J Clin Oncol. 2004;22: IV Iron Optimizes the Response to Recombinant Human EPO in Patients with CIA: Erythropoietic Response Percentage of Patients With Peak Hgb 12 g/dl or Hgb Increase of 2 g/dl Patients (%) ITT population 75% 25% a,b a,b 32% 32% 64% 68% 68% 36% No iron Oral iron Bolus TDI Responders Nonresponders a Differs from no iron group, P<0.01. b Differs from oral iron group, P<0.01. Auerbach M, et al. J Clin Oncol. 2004;22:

18 Cochrane Systematic Review of IV Iron in Chemotherapy and Cancer Induced Anemia Addition of IV iron to ESAs offers superior hematopoietic response Risk of RBC transfusions is reduced Hemoglobin levels are improved Well tolerated Mhaskar et al. Cochrane Database of Systematic Reviews Answer: (C) Intravenous Iron plus ESA This is severe iron restricted erythropoiesis. The ferritin is due to the liver metastases and should be ignored. ESAs may help a little but will need the synergy of IV iron for optimal clinical response. Oral iron will be unable to bypass the iron restriction caused by elevated hepcidin levels in the presence of metastatic disease In this case any of the IV formulations are prudent because of the frequent visits. Ferric gluconate or iron sucrose can be given over multiple visits with the ESA or one or two infusions of LMW iron dextran, ferumoxytol, FCM or (in Europe) iron isomaltoside are equally efficacious and likely less expensive and more convenient. 18

19 Case Presentation #2: Inflammatory Bowel Disease A 38 year old man with a two year history of well controlled Crohn s colitis presented with fatigue, a Hb of 12.3 g/dl, MCV 79, and restless legs syndrome interfering with sleep on a nightly basis. Ice was craved and chewed on daily. RFTs, LFTs, B12, reticulocytes were normal. A serum ferritin was 11 ng/ml and a TSAT 14%. No visible bleeding has been present for months. You should recommend: A. Oral ferrous sulfate 325 mg every other day B. Oral ferrous sulfate 325 mg every other day plus an ESA C. Intravenous iron alone D. Intravenous iron plus an ESA E. Probiotics 0% 0% 0% 0% 0% A. B. C. D. E. Inflammatory Bowel Disease (IBD) In patients with IBD, oral iron therapy is associated with severe side effects, results in low iron absorption, has limited efficacy, and has been associated with worsening of the bowel symptoms de Silva AD, et al. Aliment Pharmacol Ther. 2005;22:

20 Oral versus intravenous iron distinctly alters gut microbiota in IBD Oral iron is standard but GI side effects and potential to exacerbate intestinal inflammation support implementation of IV iron Oral and IV iron differentially affect bacterial communities and the metabolic landscape in IBD IV iron might specifically benefit anemic patients with IBD with an unstable microbiota Lee et al, GUT 2015 Ferric Carboxymaltose in IBD Patients DOSING Significantly Faster Hb Response vs. Oral Iron (Kaplan-Meier Analysis: Increase in Hb 2 g/dl at Weeks 2 and 4) Responders (%) FCM (n=136) Ferrous sulphate (n=60) 2 * 4 ** 8 12 Study Week Ferric carboxymaltose: The median calculated iron deficit was mg (range mg), requiring 1 3 administrations on an individual basis at one week intervals. Ferrous sulfate: 2x100 mg/day for 12 weeks (total 16,800 mg). Non-inferiority of ferric carboxymaltose confirmed in primary endpoint. Treatment comparison log-rank test *P=0.0051; **P= Kulnigg S, et al. Am J Gastroenterol. 2008;103:

21 Answer: (C) Intravenous iron alone This man has absolute iron deficiency. While oral may be beneficial in a small minority of patients who can tolerate it, high quality literature suggests that oral iron is toxic to the intestinal epithelium and worsens symptoms independent of anemia. Further the data from Lee et al points to a disadvantageous growth of bacteria negatively altering the microbiome. In this case one of the formulations in which a total dose infusion of intravenous iron should be used. There is no reason to subject an outpatient with inflammatory bowel disease to multiple doses of ferric gluconate or iron sucrose when a single infusion of LMW ID, ferumoxytol, FCM or iron isomaltoside can be utilized with equal efficacy and safety. Case Presentation #3: Bariatric Surgery A 42 year old woman with a former BMI of 46 presented 18 months after a rouxen Y procedure for weight loss. 146 pounds were shed. Fatigue and restless legs syndrome were the major complaints. Oral iron daily was recommended. Fatigue increased. The Hb was 12.0 g/dl, MCV 81, reticulocytes 71,000, LFTs and RFTs were normal. A B12 level was 980 pg/ml, serum ferritin 96 ng/ml, and TSAT 4%. 21

22 Case Presentation #3: Bariatric Surgery You recommend: A. Discontinue the oral iron B. Increase iron to 325 mg bid C. Increase iron containing foods D. Intravenous iron E. Revise the roux en Y 0% 0% 0% 0% 0% A. B. C. D. E. Bariatric Surgery: Iron Absorption With permission from Dr. Jerry Spivak, Johns Hopkins University School of Medicine 22

23 Predicted Probability of Ferritin Deficiency Over Time (with Indication of 95 % Confidence Interval) Gesquiere et al, Obesity Surgery 2014;24:56-61 Better Response with IV iron in Bariatric Surgery Malone et al, Ann Pharmacother 2008;42:

24 Answer: (D) Intravenous Iron This individual has absolute iron deficiency with a TSAT of 4 and a condition known to be associated with elevated hepcidin level which causes concomitant iron restricted erythropoiesis and elevated ferritin due to its acute phase reactivity. Ferrous sulfate is largely unabsorbed due to its inability to be conjugated to vitamin C, amino acids and sugars in the stomach in the presence of gastric acid The current guidelines of the American Bariatric Association still recommend oral iron as frontline therapy for iron deficiency. The preponderance of published evidence suggests these guidelines are in need of revisiting Once again, one of the formulations (LMWID, FCM, ferumoxytol, isomaltoside) able to be administered as a single infusion should be offered. There is no reason that a non anemic, bariatric patient with iron deficiency should wait for anemia to occur as iron deficiency independent of anemia causes symptoms as evidenced in this case. Further high quality prospective, double blind, placebo controlled evidence supports treating non anemic, iron deficient patients with iron Case Presentation #4: Pregnancy A 24 year old G2P1 presented to her obstetrician at week six of the 2 nd pregnancy. An iron panel was prudently ordered even in the absence of anemia. an iron panel was ordered. The Hb was 11.9 g/dl, TSAT 7% and the ferritin 38 ng/ml. The menses were normal in the inter-partum period. You should now recommend: A. Ignore the TSAT and repeat in eight weeks B. One ferrous sulfate every other day with repeat labs at week 14 C. Ferrous sulfate twice daily D. Intravenous iron with follow up at week E. Large amounts of organ meat 0% 0% 0% 0% 0% A. B. C. D. E. 24

25 Guidelines Differ USPSTF: There is insufficient evidence that routine screening and supplementation for iron deficiency anemia improves maternal or infant clinical health outcomes 2008 ACOG Practice Bulletin: Intravenous iron is recommended in the rare patient who cannot tolerate or will not take modest doses of oral iron with the caveat that patients with severe malabsorption may benefit from parenteral iron 2012 UK guidelines: Parenteral iron should be considered from the 2 nd trimester onwards and during the postpartum period for women with confirmed ID who fail to respond to, or are intolerant of, oral iron Blood 2017 Achebe and Gafter Gvili: IV iron for any oral intolerant 2 nd or 3 rd trimester patient, for 2 nd trimester gravidas with [Hb]<10.5 g/dl and all in the 3 rd with ID No guidelines for non anemic ID pregnant women Daily Iron Requirement in Pregnancy 0.8mg/day 1st 4-mg/day 2nd ~6mg/day 3rd Bothwell. Am J Clin Nutr 2000;72(suppl):257S-64S 25

26 Pregnancy Maternal iron deficiency potentially affects fetal, neonatal, and childhood brain growth and development with adverse effects on myelination, neurotransmitters, and brain programming 1 Children born to iron-deficient mothers demonstrate lower cognitive function, memory, and motor development recognizable up to 19 years after iron repletion 2-4 Iron deficiency anemia (IDA) in pregnancy has been associated with increased risk of adverse perinatal outcomes, including preterm birth, low birth weight, and small-for-gestational age infants Roncagliolo M, Walter T, Peirano P, et al. Am J Clin Nutr 1998;68: Congdon E, Westerlunjd B, Algarin C, et al. J Pediatr 2012;160: Chang S, Zeng L, Brouwer I, et al. Pediatrics 2013; 131:e755 e Tran T, Tran T, Simpson J, et al. BMC Pregnancy Childbirth 2014;14: Scholl T, Hediger M, Fischer R, et al. Am J Clin Nutr 1992;55: Ren A, Wang J, Ye R, et al. Int J Gynecol Obstet 2007;98: Radlowski E, Johnson R. Front Human Neurosci 2013;7: Scholl T. Iron status during pregnancy: Am J Clin Nutr 2005;81:1218S 1222S. [PMID: ] Fetal Iron Status with Maternal Iron Deficiency Reduction in fetal iron status when maternal ferritin is <15 (Shao et al, J Nutrition 2012) Prenatal iron supplementation reduces maternal anemia, iron deficiency, iron deficiency anemia but iron deficiency is common in neonates even with iron supplementation (Zhou et al, J Nutrition 2015) 26

27 Pregnancy: Treatment options Oral iron Up to 70% to whom oral iron is prescribed report gastrointestinal distress 1,2 A study of adherence and side effects of three ferrous sulfate regimens in anemic pregnant women in clinical trials concluded the incidence of gastrointestinal side effects was unacceptably high 3,4 Intravenous iron - Numerous publications report the safety and efficacy of IV iron during pregnancy but its use is sporadic 5 - No IV formulation had been assigned Pregnancy Category A by the Food and Drug Administration - Excessive fears of anaphylactic reactions - Misperception among clinicians that the incidence and severity of infusion reactions is unacceptably high 6 1. Souza A, Batista F, Bresani C. Cad Saude Publica 2009;6: Tolkien Z, Stecher L, Mander A, et al. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: A systematic review and meta-analysis. PLoS One 2015;10:e DOI: /journal.pone Van Wyck D, Martens M, Seid M, et al. Obstet Gynecol 2007;110: Dhanani J, Ganguly B, Chauhan L. J Pharmacol Pharmcother 2012;3: American College of Obstetricians and Gynecologists. ACO Practice Bulletin No. 95: Anemia in pregnancy. Obstets Gynecol 2008;112: Auerbach M, Ballard H, Glaspy J. Lancet 2007;369: Results 73 of 74 enrolled subjects were treated Paired follow-up data were available on 60/73 mothers (4 weeks post infusion) Auerbach et al, AJM 2017; 130:

28 Answer: (B) Ferrous sulfate every other day and repeat Fe studies at 14 weeks This woman has iron deficiency without ACOG criteria for anemia and would not have been diagnosed without the proactive, well considered decision of the obstetrician to screen for ID. There is no safety data (or toxicity data) with IV iron in the first trimester The recent data on elevations of hepcidin with oral iron ingestion suggests that alternate day therapy is preferred and results in improved absorption and efficiency At 14 weeks, if the Hb is below 10 g/dl in the second trimester or any time in the third, or if there is no improvement in the iron parameters, or if symptomatic ID is present, intravenous iron is appropriate Relation Between Peripheral Iron Status and Restless Leg Syndrome (RLS) Low serum ferritin associated with worse RLS symptoms 1 Oral iron reduces RLS symptoms when serum ferritin <75 mcg/l 2 RLS with iron deficiency anemia (IDA) Prevalence high? (only 2 small studies) Recovers when anemia corrected? (never previously studied) 1. Akyol A, et al. Clin Neurol Neurosurg. 2003;106: Rangarajan S, D Souza G. Sleep Med. 2007;8:

29 RLS in Patients with Anemia Is Generally Severe When RLS present level of distress Not at all 7% A little bit 11% Moderate 50% Extreme 32% (82% moderate to extreme distress) Frequency of RLS symptoms (days/week) 6-7 days/week 46% 4-5 days/week 22% 2-3 days/week 26% (94% 2-7 days/week) 1 day/week 2% <1 day/week 4% RLS sufferer (moderate to extreme distress) 2 days/week 78.2% of all RLS with anemia 37.3% of all RLS 1 in the general population 1. Allen R, et al. Arch Intern Med. 2005;165: IV Iron Response in Patients with RLS Response to IV iron (LMW ID 1000 mg TDI) Responses measured at 6-20 weeks RLS change after IV iron Complete remission 50% Very much improved 4% Much improved 16% No change 30% No change may respond to further IV iron infusions based on our experience Allen RP, et al. Am J Hematol. 2013;88:

30 Protective Effect of Intravenous Iron in Preventing Acute Mountain sickness Legend: Increase in Lake Louise score - a marker of severity of mountain sickness after rapid ascent to 4340 meters. Prior to ascent the iron group received 200mg iron sucrose and placebo normal saline. Difference between groups significant (p < 0.05) With permission from: Talbot NP, Smith TG, Privat C, Nickol AH, Rivera-Ch M, León-Velarde F, Dorrington KL, Robbins PA. Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial. High Alt Med Biol Fall;12(3): PASP Responses to Hypoxia Frise et al, J Clin Invest 2016;126:

31 Discussion The results support the convenience, safety, and efficacy of a single infusion of a gram of intravenous iron as therapy for iron deficiency We believe IV iron should be administered as soon as oral iron intolerance occurs or as front line therapy to those in whom oral iron is known to be ineffective or harmful such as after bariatric surgery or IBD. IV, and not oral iron, should be administered for IDA of pregnancy if Hb<10 g/dl in the second trimester and to all after week 30. If oral iron is indicated, one tablet QOD is the preferred schedule. Oral iron should be proscribed in the 3 rd trimester All pregnant women should be screened for ID at presentation to their obstetricians and again at the beginning of the third trimester (week 30) All at risk newborns (diabetic, anemic or iron deficient mother, preterm, infants of smokers) should be screened for ID at birth and treated if deficient Compared to oral iron, intravenous iron has fewer side effects and nearly always effective. Our data and that of others call for large prospective studies of IV vs. oral iron for therapy of maternal iron deficiency anemia Auerbach et al, AJM 2017; 130: Key Points Oral iron is frontline therapy for uncomplicated iron deficiency in those who tolerate it High quality published evidence suggests alternate day oral iron is preferable For heavy uterine bleeding, late pregnancy, IBD, CIA and other comorbid conditions associated with iron lack, GB, OWR and oral iron intolerance the intravenous route is preferred and should be moved to the frontline The preponderance of published evidence suggests the USPSTF recommendations for screening for iron deficiency in pregnancy should be revisited Four formulations are able to be administered in a single total dose infusion obviating multiple visits and decreasing infusion reactions and increasing adherence: LMWID, FCM, isomaltoside (Europe only) and ferumoxytol Intravenous iron is likely safer than most physicians believe and should be moved forward in the treatment paradigm for iron deficient anemia 31