Iron, combination therapies and new drugs on horizon

Transcription

1 Anaemia and iron deficiency in HF Iron, combination therapies and new drugs on horizon Piotr Ponikowski, MD, PhD, FESC Wroclaw Medical University Military Hospital Wroclaw, Poland

2 Disclosure Consultancy fees and speaker s honoraria from: Vifor Pharma Ltd, Amgen, Servier, Sanofi-aventis, Corthera, Novartis, Bayer, Pfizer, Merck-Serono, Merck and Respicardia

3 Some Facts About Iron Most common element on Earth (approx. 37%) Oxidation levels : -2 to +6 Relevant for biological organisms: Fe 2+ and Fe 3+ There is no biological life (on Earth) without iron Iron content of humans: g (~ mg / kg body weight)

4 Importance of iron Essential for growth and survival CELLS TISSUES ORGANS BODY POPULATION Mitochondrial dysfunction Deranged enzyme activity Abnormal transport and structural proteins Apoptosis Iron is particularly important for cells of high mitogenic potential and high energy demand, e.g. skeletal myocytes and cardiomyocytes Andrews NC. N Engl J Med 1999;341: Cairo G, et al. Genes Nutr 2006;1: Zimmermann MB, Hurrell RF. Lancet 2007;370: Tissue remodelling Impaired organ efficacy Impaired exercise capacity Reduced work efficiency Impaired cognitive performance and behaviour Increased morbidity and mortality

5 Prevalence of iron deficiency in CHF patients (%) Prevalence of iron deficiency in patients with systolic heart failure Prospective observational study, 546 patients with stable systolic CHF Iron deficiency: serum ferritin <100 μg/l, or μg/l with TSAT <20% p< ± 10 p= % 52 ± 12 40% 37 ± 4 p= ± 6 p=0.03 p= ± 6 41 ± 6 30% 32 ± 4 34 ± 4 31 ± 5 32 ± 6 32 ± 6 20% 10% 0% All patients hs-crp=serum high-sensitivity C-reactive protein; TSAT=transferrin saturation Jankowska EA, et al. Eur Heart J 2010;31:

6 Definition of Iron Deficiency in HF Functional vs Absolute Absolute iron deficiency Anaemia (Hb <12 g/dl) depletion of body iron stores diagnosis: low serum ferritin level (<100μg/L) ID-Anaemia Iron Deficiency (no Anaemia) Functional iron deficiency inadequate iron supply to meet demand (impaired iron utilization; iron stores N / ) diagnosis: serum ferritin level ~ N (< 300μg/L) & TSAT<20% Wish JB. Clin J Am Soc Nephrol 2006;1(Suppl 1):S4-8.

7 Patients with CHF are prone to develop absolute iron deficiency REDUCED DIETARY INTAKE Poor diet Poor gastrointestinal absorption (impaired duodenal iron transport) Interactions with certain drugs (e.g. omeprazole) or food reducing absorption INCREASED LOSSES Gastrointestinal blood loss: impaired integrity of intestinal mucosa, occult gastrointestinal losses, peptic ulceration medications increasing bleeding risk (e.g. antiplatelets, anticoagulants) Andrews NC. N Engl J Med 1999;341: Macdougall IC. Curr Med Res Opin 2010;26:

8 Patients with CHF are prone to develop absolute iron deficiency REDUCED DIETARY INTAKE Poor diet* Poor gastrointestinal absorption (impaired duodenal iron transport)** Interactions with certain drugs (e.g. omeprazole) or food reducing absorption INCREASED LOSSES Gastrointestinal blood loss: impaired integrity of intestinal mucosa, occult gastrointestinal losses, peptic ulceration medications increasing bleeding risk (e.g. antiplatelets, anticoagulants) * Half of CHF patients consumed less iron than the dietary reference value ** Rats with HF and iron deficiencyderanged iron transportation systems in the enterocytes (abnormal response to regulating molecules) Andrews NC. N Engl J Med 1999;341: Macdougall IC. Curr Med Res Opin 2010;26: Naito Y, et al. J Hypertens 2011;29: Hughes CM, et al. Nutr Metab Cardiovasc Dis 2011

9 Why CHF patients may become prone to develop functional iron deficiency? Potential role of hepcidin central regulator of systemic iron homeostasis FPN=ferroportin; HFE=hemochromatosis; HJV=haemojuvelin; RBC=red blood cell; TFR=transferrin receptor Babitt JL, Lin HY. Am J Kidney Dis 2010;55:

10 Why CHF patients may become prone to develop functional iron deficiency? Potential role of hepcidin central regulator of systemic iron homeostasis Inflammation Reduced GFR Anaemia Tissue hypoxia (HIF) Hypothesis: dysregulation in hepcidin production may play an important role in iron deficiency in CHF GFR=glomerular filtration rate; HIF=hypoxia-inducible factor Ganz T. Blood : Babitt JL, Lin HY. Am J Kidney Dis 2010;55:

11 Why CHF patients may become prone to develop functional iron deficiency? Iron a critical element in erythropoiesis About 3 4 days Iron dependence Erythropoietin Iron About days About 21 days Erythropoietin dependence About 1 2 days Pluripotent stem cell Burst-forming unit-erythroid cells Colony-forming unit-erythroid cells Proerythroblasts Erythroblasts Reticulocytes Red blood cells Adapted from: Besarab A, et al. Oncologist 2009;14(Suppl 1):22 33.

12 Heart Failure: Targeting Iron Deficiency Iron therapy Oral Intravenous

13 Heart Failure: Targeting Iron Deficiency Limitations of oral iron: Frequent dose-related gastrointestinal adverse events, particularly with ferrous sulphate affecting up to 20% e.g. constipation, dyspepsia, bloating, nausea, diarrhoea heartburn can adversely affect nutritional intake Tolerance can be improved by taking iron tablets with, but it decreases iron absorption Absorption also limited by hepcidin upregulation Long-term therapy needed (months) to replete iron deficiency Courtesy IC Macdougall

14 History of parenteral iron Value of iron in chlorosis Sydenham 1681 First FeSO 4 pills Blaud 1832 IV iron for anaemia Heath 1932 Use of IV iron saccharate Nissim 1947 IM iron dextran (Imferon, Fisons) Baird & Podmore 1954 Anaphylactoid AEs to Fe dextran serious and unpredictable: Hamstra 1980 Non-dextran irons (US): gluconate, sucrose Resulted in black box and test dose 1600s 1800s Severe toxic reactions: preclude use for therapeutics IV colloidal Fe(OH) 3 for anaemia Goetsch 1946 Meningism case: Shuttleworth 1983 Recall world s Imferon supply Ferric carboxymaltose *, Ferumoxytol * Bailie GR, HFA 2009 *Currently available only in EU Adapted from Auerbach M. Am J Hematology 2008;83:

15 Hypersensitivity reactions and deaths associated with intravenous iron preparations Bailie G, Nephrol Dial Transplant (2005) 20:

16 The Structure of iv Iron IV Iron Formulations are Spherical Nanoparticles Consisting of an Iron Core and a Carbohydrate Shell Iron oxy hydroxidecore Carbohydrate shell

17 Different Types of iv Iron Ferric carboxymaltose Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd in-hospital therapy ambulatory therapy

18 Different Types of iv Iron Ferric carboxymaltose LMW Iron dextran (CosmoFer, Pharmacosmos) kd - 50 mg iron (III) / ml - 2 / 5 / 10 ml ampules - dose: typical mg (2-4 ml) diluted in 0.9%NaCL or 5%Glc ml test dose needed - application time min Molecular weight 165 kd 37.5 kd 43.3 kd 150 kd Feromoxytol (Feraheme, AMAG Pharmaceuticals) - approved only in USA, based on 1726 CKD patients with ID - 17 ml ampules - a 510 mg undiluted dose can be delivered at a rate up to 1 ml/sec in-hospital therapy ambulatory therapy

19 IV iron preparations Past Iron complex Product* Iron dextran Imferon High MW iron dextran Dexferrum Development Present Low MW iron dextran INFed /CosmoFer Iron dextrin/polymaltose Maltofer Sodium ferric gluconate Ferrlecit Iron sucrose Venofer Ferric carboxymaltose** Ferinject Ferumoxytol*** *EU or US nomenclature; **only available in EU; ***currently awaiting approval by FDA Adapted from Macdougall IC & Ashenden M. Adv Chronic Kidney Dis 2009;16:

20 Oxidative stress potential Potential toxicity of IV iron Balancing complex robustness with potential toxicity from bioactive iron further complicated by risks of dextran allergy Ferric gluconate Iron sucrose Ferric Carboxymaltose?, Ferumoxytol? Iron dextrans Risk of dextran allergy Bailie GR, HFA 2009 Chertow GM et al. Nephrol Dial Transplant 2006;21: Toblli JE et al. Port J Nephrol Hypert 2009;23(Suppl 1):53 63

21 Potential toxicity of IV iron IV iron potential toxicity Acute/ short term Intermediate? Chronic/ long term Allergic hypersensitivity Nonimmunological Oxidative stress Infection? Mortality? Immediate effects on surrogate biomarkers but long-term outcomes unclear Bailie GR, HFA 2009

22 Cumulative 6 month iron dose (mg) Iron dose is not linked to increased mortality in haemodialysis patients Probability of mortality (Adjusted hazard ratio ± 95% CI) >1800 From unlagged time-dependent model (p=0.78) Feldman HI et al. J Am Soc Nephrol 2004;15:

23 Heart Failure: Targeting Iron Deficiency Where is the evidence?

24 Heart Failure: Targeting Iron Deficiency Where is the evidence?

25 FAIR-HF study design Main inclusion criteria: NYHA class II/III, LVEF 40% (NYHA II) or 45% (NYHA III) Hb: g/dl Iron deficiency: serum ferritin <100 µg/l or <300 µg/l, if TSAT <20% Treatment adjustment algorithm: Interruption: Hb >16 g/dl or serum ferritin >800 µg/l or serum ferritin >500 µg/l, if TSAT >50% Restart: Hb <16 g/dl and serum ferritin <400 µg/l and TSAT<45% Blinding: Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections * Total dose required for repletion calculated using the Ganzoni formula Anker SD, et al. N Engl J Med 2009;361: FAIR-HF= Ferric carboxymaltose Assessment in patients with IRon deficiency and chronic Heart Failure; PGA=Patient Global Assessment

26 FAIR-HF results Patient Global Assessment NYHA functional class p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p< minute walk test KCCQ overall score EQ-5D VAS score p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p< p< p<0.001 Anker SD, et al. N Engl J Med 2009;361: EQ-5D=European Quality of Life 5-Dimensions; FCM=ferric carboxymaltose; KCCQ=Kansas City Cardiomyopathy Questionnaire; VAS=visual analogue scale

27 FAIR-HF results: intravenous iron performed better than placebo in all patient subgroups Patient Global Assessment NYHA functional class Haemoglobin (g/dl) 12 >12 Median serum ferritin (μg/l) 39 >39 egfr (ml/min/1.73 m 2 ) 60 >60 Median age (years) Gender Male Female NYHA Class II Class III Median ejection fraction (%) 33 >33 CHF Non-ischaemic Ischaemic Diabetes No Yes Median BMI (kg/m 2 ) >27.37 Anker SD, et al. N Engl J Med 2009;361: BMI=body mass index; egfr=estimated glomerular filtration rate

28 Safety endpoints in FAIR-HF Patients with events (Incidence per 100-patient years at risk) Ferric carboxymaltose (N=305) Placebo (N=154) Death 5 (3.4) 4 (5.5) 0.47 CV death 4 (2.7) 4 (5.5) 0.31 Death due to worsening HF 0 (0.0) 3 (4.1) First hospitalization 25 (17.7) 17 (24.8) 0.30 Hospitalization for any CV reason 15 (10.4) 14 (20.0) 0.08 First hospitalization for worsening HF 6 (4.1) 7 (9.7) 0.11 Any hospitalization or death 30 (21.2) 19 (27.7) 0.38 Hospitalization for any CV reason or death 20 (13.9) 16 (22.9) 0.14 First hospitalization for worsening HF or death 11 (7.5) 10 (13.9) 0.15 p Anker SD, et al. N Engl J Med 2009;361: CV=cardiovasuclar; HF=heart failure

29 Reported adverse events in FAIR-HF Patients with events (Incidence per 100-patient years at risk) Ferric carboxymaltose (N=305) Placebo (N=154) Cardiac disorder 38 (27.6) 33 (50.2) 0.01 Gastrointestinal disorder 24 (16.9) 5 (6.9) 0.06 General disorder or administration site condition 23 (16.2) 6 (8.3) 0.14 Injection-site pain or discoloration 6 (4.1) 0 (0.0) Infection or infestation 50 (37.0) 24 (35.8) 0.97 Abnormal laboratory test, vital sign or physical finding 32 (23.0) 10 (14.0) 0.17 Nervous system disorder 22 (15.6) 14 (20.3) 0.44 Respiratory, thoracic or mediastinal disorder 9 (6.2) 10 (14.2) 0.06 Vascular disorder 20 (14.0) 11 (15.7) 0.80 p There were no severe or serious hypersensitive reactions Anker SD, et al. N Engl J Med 2009;361:

30 FAIR-HF results: impact of intravenous iron on renal function p=0.054 p=0.049 p=0.017 Treatment effect (ml/min/1.73m 2 )*: 2.8 ± ± ± 1.7 *LSM mean ± SE Ponikowski P, et al. Heart Failure Association Congress 2010; abstract 114 and late-breaking trial oral presentation. LSM=least squared mean; SE=standard error

31 FAIR-HF: beneficial effect of intravenous iron on 6-minute walk test is independent of baseline anaemia status FCM, non-anaemic FCM, anaemic Placebo, non-anaemic Placebo, anaemic Treatment effect: Anaemic Week 4 p<0.001 Week 12 p<0.001 Week 24 p=0.01 Non-anaemic Week 4 p=0.04 Week 12 p=0.002 Week 24 p<0.001 Filippatos G, et al. American Heart Association Scientific Sessions 2010; abstract and oral presentation.

32 Anaemia and iron deficiency in HF: new drugs / studies on the horizon? ESAs EPO Normal dose (very) Low dose Long-acting EPOs Darbepoietin alpha (Aranesp) Continuous EPO Receptor Activator (Cera) Peptide-based erythropoietin receptor agonist (Hematide, Affymax) SEP, Fc-EPO, CTNO CEPO TPMs (Araim) Iron New formulas long-acting, less side-effects doses (optimal repletion dose) Hepcidin agonists and antagonists

33 Anaemia and iron deficiency in HF: new drugs / studies on the horizon?