Iron deficiency in heart failure

Transcription

1 Iron deficiency in heart failure Piotr Ponikowski, MD, PhD, FESC Department of Heart Diseases, Wroclaw Medical University Centre for Heart Diseases, Military Hospital, Wroclaw, Poland

2 Objectives Importance of iron Iron deficiency in heart failure: Prevalence Potential causes Association with symptoms and outcome Benefits of iron repletion

3 Iron distribution and turnover * mg / kg b.w. Duodenum Reticuloendothelial macrophages ~600 mg Liver parenchyma ~1000 mg Storage Iron Iron sloughed with senescent enterocytes (and skin cells) * * no physiological pathway for iron excretion 1 2 mg/day Menstruation in women at childbearing age Transferrin iron 3 mg Utilization Erythroid bone marrow ~300 mg 8 Muscles ~300 mg Other tissues ~100 mg Iron atom Ferritin Adapted from Andrews NC. N Eng J Med 1999;341:

4 Importance of iron Required for: transport of electrons transport (Hb) and storage (myoglobin) of oxygen cell respiration oxidative phosphorylation catalytic enzymes and proteins crucial for DNA synthesis Important for cells of high mitogenic potential and energy demand (e.g. skeletal myocytes and cardiomyocytes). Essential for growth and survival CELLS TISSUES ORGANS BODY POPULATION

5 Objectives Importance of iron Iron deficiency in heart failure: Prevalence Potential causes Association with symptoms and outcome Benefits of iron repletion

6 Iron deficiency common cause of anaemia in HF Other 14% 57% Iron deficiency 5% Anaemia of chronic disease (ACD) 24% Renal disease Iron deficiency for erythropoiesis N=148 anaemics Defective endogenous EPO production Opasich C et al.; Eur Heart J 2005

7 Iron deficiency common cause of anaemia in HF 37 anaemic patients with advanced CHF, NYHA IV, LVEF 22% Bone marrow biopsy confirmed ID in 27/37 pts ID pts: MCV, MCHb, ferritin, Na + ; ~ BNP, fru, creat, CRP 73.0% Iron deficient anemia Anemia of chronic disease Hemodilution Drug induced 18.9% 5.4% 2.7% Nanas JN et al.; JACC 2006

8 Jankowska EA et al. Eur Heart J 2010 Prevalence of iron deficiency in patients with systolic HF Prospective observational study, 546 patients with stable systolic CHF ID (definition): ferritin <100 g/dl, or g/dl with TSAT<20% 50% p< ±10 p= ±12 40% 37±4 p= ±6 p=0.03 p= ±6 41±6 30% 32±6 32±4 34±4 31±5 32±6 32±6 20% 10% 0% All patients

9 Definition of Iron Deficiency in HF Functional vs Absolute Anaemia (Hb <12 g/dl) ID-Anaemia Iron Deficiency (no Anaemia) 1. absolute ID (depletion of iron stores) causes: chronic blood loss (ASA), inadequate intake (elderly, malnutrition, malabsorption) diagnosis: low ferritin level (<30? <100?) 2. functional ID (impaired iron utilization; iron stores =/ ) causes: chronic inflammation & renal dysfunction diagnosis: ferritin ~ N (< 300) & TSAT<20%

10 Hepcidin is a central regulator of systemic iron homeostasis Babitt JL, Lin HY. Am J Kidney Dis 2010 (in press)

11 Hepcidin is a central regulator of systemic iron homeostasis Hepcidin in Heart Failure: 33 HF pts with anaemia and renal dysfunction elevated HEP level HEP correlated with ferritin and TSAT but not hscrp/il-6 EPO therapy - HEP Baseline HEP predicted BM-response to EPO Conclusion: HEP seems to reflect iron load and response to EPO rather than inflammation and EPO resistance van der Putten K et al., Eur J Heart Fail 2010

12 Objectives Importance of iron Iron deficiency in heart failure: Prevalence Potential causes Association with symptoms and outcome Benefits of iron repletion

13 HAEMATOPOIETIC TISSUES ERYTROPOIESIS (IMMUNE CELLS, PLATELETS) Anaemia Oxygen carrying capacity ( Hb) Symptoms O 2 -transportation-dependent (Maximal performance) Importance of iron Adapted from Haas JD & Brownlie T. J Nutr 2001;131:676S 690S IRON DEFICIENCY (ID) EXTRA-HAEMATOPOIETIC TISSUES SKELETAL MUSCLES (MYOCARDIUM, ADIPOSE TISSUE, LIVER, KIDNEYS, BRAIN) Oxygen storage (myoglobin) Tissue oxidative capacity Energetic efficiency Anaerobic metabolism ID = Mitochondrial Dysfunction Symptoms Tissue ID-dependent (Endurance) EXERCISE INTOLERANCE

14 Iron deficiency independent determinant of exercise intolerance 443 CHF pts with CPX, LVEF 26%, peak VO ±4.4 ml/kg/min Determinants Peak VO 2, ml/min VE-VCO 2 slope Standardized β coefficient Partial correlatory coefficient Standardized β coefficient Partial correlatory coefficient Age, years ** ** Sex, males vs females 0.17 ** 0.22 ** BMI, kg/m ** 0.36 ** ** ** CHF aetiology, isch vs non-isch * 0.15 * NYHA class, I/II/III/IV ** ** 0.23 ** 0.25 ** LVEF, % 0.12 * 0.15 * ** ** NT-proBNP, pg/ml (ln) ** ** 0.22 ** egfr, ml/min/1.73m Haemoglobin, g/dl Iron deficiency, yes vs no * * 0.13 * 0.15 * Adjusted R 2 for a set of variables 51% *** 36% *** * p<0.01, ** p< Jankowska EA et al. submitted 2010

15 Jankowska EA et al. submitted 2010 Iron deficiency independent determinant of exercise intolerance p< p< p< p< [ ml/min/kg] PeakVO slope VE-VCO A(-) ID(-) A(-) ID(+) A(+) ID(-) A(+) ID(+) 40 A(-) ID(-) A(-) ID(+) A(+) ID(-) A(+) ID(+)

16 IRON DEFICIENCY AND QUADRICEPS STRENGTH IN PATIENTS WITH SYSTOLIC HF 129 patients with systolic HF, age: 58±11 yrs, NYHA class III-IV: 36%, ID (ferritin <100 g/dl, or g/dl with TSAT <20%) 34% Independent determinants of quadriceps strength: BSA, NYHA class, loop diuretic dose, DM and iron status (ID or serum stfr) r=-0.48 (p<0.001) Quadriceps stre STfR (mg/l) Quadriceps stre Body iron amount (mg/kg) r=0.37 (p<0.001) Jankowska EA et al. submitted 2010

17 IRON DEFICIENCY AND DEPRESSIVE SYMPTOMS IN PATIENTS WITH SYSTOLIC HF Prevalence of BDI score categories 100% 80% 60% 23% 26% 50% 2 =13.94 (p<0.001) MODERATE DEPRESSION BDI score: 16 points 40% 51% 42% 20% 8% 0% ID (-) ID (+) BDI score: points NO DEPRESSIVE SYMPTOMS BDI score: 0-9 points Independent determinants of BDI: HF severity, hscrp, Hb level and ID

18 Iron deficiency: an ominous sign in patients with systolic HF prospective observational study, 546 patients with stable systolic CHF ID: ferritin <100 g/dl, or g/dl with TSat <20% Cumulative event-free survival ID (but not anaemia) related to an increased risk of death or HTX: HR (adjusted) = 1.6 (95% CI , p<0.01) Patients without ID: Survival: 67% 95% CI: 61-72% p= Patients with ID: Survival: 53% 95% CI: 46-61% Follow-up (months) Jankowska EA et al. EHJ 2010

19 Objectives Importance of iron Iron deficiency in heart failure: Prevalence Potential causes Association with symptoms and outcome Benefits of iron repletion

20 Change in MLWHF questionnaire score Change in 6MWT (m) I.v. Iron Sucrose Improves Functional Capacity and Quality of Life in Patients with CHF and Anaemia R=0.76 P= R=0.56 P=0.03 Prospective, uncontrolled study with iron sucrose N= Left ventricular ejection fraction (LVEF) 26±13% Hb 12 g/dl Ferritin 400 ng/ml MLWHF Score 33 ± ± 14 (p=0.02) 6MWT 242 ± ±72 m (p=0.01) Change in Hb (g/dl) Change in Hb (g/dl) MLWHF, Minnesota Living With Heart Failure; 6MWT, 6-minute walk test Bolger AP et al. J Am Coll Cardiol 2006;48:

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22 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>16.0g/dL or ferritin>800µg/l or ferritin>500µg/l, if TSAT>50% Restart: Hb <16.0g/dL and serum ferritin <400µg/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 et al, Eur J Heart Failure 2009;11:

23 Primary Endpoint: Patient Global Assessment at Week 24 FCM improved self-reported PGA scores at week 24 Odds ratio for better rank: 2.51 (95% CI 1.75,3.61), P< % vs 27% FCM Placebo Anker SD et al N Engl J Med 2009;36:

24 Primary Endpoint: NYHA Functional Class at Week 24 FCM improved NYHA functional class at week 24 Odds ratio for improvement by 1 class: 2.40 (95% CI 1.55,3.71), P<0.0001* 47% vs 30% FCM Placebo *adjusted for baseline Anker SD et al N Engl J Med 2009;36:

25 PGA & NYHA in Predefined Subgroups Self-reported PGA score NYHA functional class

26 Secondary Endpoint: Six-Minute Walk Test at Week 4, 12 & 24 FCM No. of patients Distance (mean±se) 274±6 294±7 312±6 313±7 Placebo No. of patients Distance (mean±se) 269±9 269±10 272±10 277±10 Treatment effect (mean±se) 21±6 37±7 35±8

27 Impact of i.v. FCM 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

28 Conclusions 1. Iron deficiency is common finding in CHF, affecting ~ 40% of symptomatic patients, irrespectively of anaemia 2. Iron deficiency is associated with exercise intolerance, poor QoL and predicts poor outcome 3. Cardiologists should become aware of the importance of iron deficiency in CHF patients, and be able to evaluate iron status with simple biomarkers 4. Correcting iron deficiency in CHF patients with i.v. FCM improved self-reported health status, NYHA functional class, exercise tolerance and QoL measures 5. Further studies are needed to evaluate whether iron deficiency should be considered therapeutic target in CHF

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