Αντιμετώπιση αναιμίας σε ασθενή με καρδιακή ανεπάρκεια. Α. Καραβίδας Καρδιολογικό Τμήμα Γ.Ν.Α Γ. Γεννηματάς

Αντιμετώπιση αναιμίας σε ασθενή με καρδιακή ανεπάρκεια Α. Καραβίδας Καρδιολογικό Τμήμα Γ.Ν.Α Γ. Γεννηματάς

Επιπολασμός της αναιμίας στην καρδιακή ανεπάρκεια : 15-61% Ορισμό της αναιμίας Π.Ο.Υ Άνδρες Hb <13g/dl Γυναίκες Hb <12g/dl Anand I JACC 2008,Tsang YD et al Circulation 2006

Επιπολασμός της αναιμίας στην καρδιακή ανεπάρκεια: 15-61% Ορισμό της αναιμίας Πληθυσμό της μελέτης Γυναίκες Ηλικία Βαρύτητα του συνδρόμου-nyha Νεφρική ανεπάρκεια (συνυπάρχοντα νοσήματα) Xαμηλός δείκτης μάζας σώματος Anand I JACC 2008, Tsang YD et al Circulation 2006

Prevalence in HF ambulatory patients Prevalence in hospitalized HF patients 25-30% 50% Prevalence in HF pts in clinical trials 25% Yi-Da Tang et al. Heart Fail Rev 2008

Anemia as prognostic factor in CHF: a meta-analysis analysis of >150,000 patients Anemia is associated with an increased risk of mortality in both systolic and diastolic CHF Groenveld et al. JACC 2008

The Etiology of Anemia in Heart Failure is Likely Multifactorial Chronic Inflammation Anemia of Chronic Disease Pharmacotherapy Renal Dysfunction Decreased Cardiac Output Malnutrition Bone marrow dysfunction Abnormal iron homeostasis (uptake, release, utilization) Intravascular fluid imbalance (hemodilution) EPO deficiency or resistance

Αιτιολογία αναιμίας ΧΚΑ Χρόνια ανοσο-φλεγμονώδης διέγερση Χρόνια νεφρική ανεπάρκεια TNFα - παραγωγή EPO από τα νεφρά Σύνθεση EPO Απώλεια στα ούρα IL-6 - δραστικότητα EPO μυελό οστών - απελευθέρωση Fe δίκτυο - ενδοθηλιακό σύστημα Αιμοαραίωση Όγκου πλάσματος Έλλειψη αιμοποιητικών παραγόντων Σιδηροπενία Διαιτητική πρόσληψη σιδήρου Δυσαπορρόφηση των αιμοποιητικών παραγόντων Απώλεια αίματος ( χρήση αντιαιμοπεταλιακών και αντιπηκτικών) Καταστολή μυελού οστών Χαμηλή παροχή Αντίσταση EPO Φάρμακα (AMEA) Σύνθεση EP0 δράση EPO μυελό οστών

Possible Mechanisms Involved in the Genesis of Anemia in Heart Failure Anand IS JACC 2008

Αιτιολογία αναιμίας στη χρόνια καρδιακή ανεπάρκεια Αναιμία χρόνιας νόσου (ανεπαρκή παραγωγή ερυθροποιητίνης και μείωση της βιοδιαθεσιμότητας σιδήρου για την αιμοποίηση) 24% 5% 57% Opasish C et al. Eur Heart J 2005

Η αναιμία ως παθοφυσιολογικός μηχανισμός επιδείνωσης του συνδρόμου της καρδιακής ανεπάρκειας Tissue Hypoxia Anand IS JACC 2008

Treatment Options for Anaemia Optimal medical management Erythropoietic agents alone Erythropoietic agents in combination with IV iron Erythropoietic agents in combination with oral iron IV iron alone

Hemodilution Is Common in Patients With Advanced Heart Failure Androne et al. Circulation. 2003;107:226-229

- Prevalence of anemia 17% - Predictors of baseline anemia: Diabetes, BNP, LVEF, GFR - Documented evaluation of anemia 3% - At 6 month, new onset anemia 16% - Resolution of anemia 43% Tang et al. JACC 2008;51:569

Treatment Options for Anaemia Optimal medical management Erythropoietic agents alone Erythropoietic agents in combination with IV iron Erythropoietic agents in combination with oral iron IV iron alone

Διεγείρει τον πολλαπλασιασμό και τηv διαφοροποίση των ερυθροβλαστών Reduction of the physiological apoptosis

Interventional studies with rhuepo in Patients with heart failure and Anemia

Effects of rhuepo Therapy on Exercise Duration and 6-Minute Walk in Anemic HF patients

Effects of rhuepo Therapy on Peak VO2 and Quality of Life in Anemic HF patients

Effects of β-erythropoietin treatment on LV remodeling, systolic function, and BNPB levels in patients with the cardiorenal anemia syndrome Pallazzuoli et al. Am Heart J, October 2007

Effects of darbepoetin-alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart N= 32 HF pts, EF < 40%, NYHA II-III, Hgb< 12,5g/dl were randomized (2:1) to receive a 3-month darbepoetin a regimen at 1.5μg/kg every 20 days plus oral iron (n=21) or placebo plus oral iron ( n=11). Parissis J et al. Am Heart J 2008

Effects of darbepoetin-a plus oral iron on proinflammatory cytokine activation and apoptosis mediators in CHF Kourea K, Parissis J, Farmakis D, et al. Atherosclerosis 2007

Effects of darbepoetin alpha on quality of life and emotional stress in anemic patients with chronic heart failure Mean percent changes in Kansas City Cardiomyopathy Questionnaire Summary (KCCQ-S) and in Zung Self-rated Depression Scale (Zung-SDS) in the two study groups (* p<0.05, ** p<0.001). Kourea K, Parissis J, Farmakis D, et al. Eur J Cardiovasc Prev Rehabil 2008

Darbepoetin reduces oxidative stress in anemic patients with CHF 7,00 p<0.05 Baseline Post treatment 4,00 p=0.006 Baseline Post treatment 6,00 5,00 3,00 MDA 4,00 3,00 Carbonyl protein 2,00 2,00 1,00 1,00 0,00 Placebo Darbepoetin-alpha Placebo Darbepoetin-alpha Parissis J, et al. Am J Cardiol 2009

Treatment of Anemia with Darbepoetin Alfa in Heart Failure

Hemoglobin concentration in Darbepoetin Alfa Heart Failure Study Subjects

Effects of Darbepoetin alfa on Exercise Tolerance Compared with Placebo

Effects of Darbepoetin alfa on NYHA Classification Compared with Placebo

Pre-Specified Pool Analysis for Time to Death or First HF Hospitalization

Hazard Ratios for Composite EndPoint and Its Individual Components

Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia (CREATE TRIAL) NEJM 2006;355:2071

Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease (CHOIR TRIAL) NEJM 2006;355:2085-98

NEJM 2009

NEJM 2010

Meta-analyses of ESA in CHF

Erythropoietin treatment is not associated with a higher mortality rate or more adverse events and that a beneficial effect on HF hospitalization may be apparent

Meta-analyses of ESA in CHF

Darbepoetin-alpha in CHF: RED-HF trial Swedberg et al, N Engl J Med 2013

Darbepoetin-alpha in CHF: RED-HF trial Similar design to earlier unsuccessful trials in CKD (CHOIR, CREATE, TREAT) Patients with mild anemia (9-12g/dL, median 11.2), expected by their renal dysfunction (72% CKD) Abrupt, even beyond-target Hb increase Potential benefits overweighed by drawbacks (blood viscosity, undesired tissue growth etc) * FDA suggestion: ESA in CKD when Hb<10g/dL Farmakis, Parissis & Filippatos, N Engl J Med 2013

ESA trials in CKD and HF Farmakis, Parissis, Filippatos. N Engl J Med 2013

Iron deficiency in HF Common, even in the absence of anemia More common in advanced CHF Associated with worse prognosis Opasich et al, Eur Heart Journal 2005 Nanas et al, J Am Coll Cardiol 2006 Jankowska et al, Eur Heart J 2010 Okonko et al, J Am Coll Cardiol 2010

Iron deficiency in HF 546 CHF pts Jankowska et al, Eur Heart J 2010

Etiology of anemia in advanced CHF Bone marrow aspiration 37 pts, advanced CHF, LVEF 25% Hgb < 12g/dl men,hgb < 11.5 g/dl women Iron deficiency: absence of iron stores in bone marrow Hemodilution: Normal RBC volume by Cr-51 labeled RBC Drug-induced: enalapril (restoration after discont.) Chronic disease anemia: no specific cause found Nanas et al, J Am Coll Cardiol 2006

Etiology of Anemia in Patients With Advanced Heart Failure N=37 pts hospitalized advanced CHF, Hgb < 12g/dl men,hgb < 11.5 g/dl women Bone marrow aspiration Nanas J et al. J Am Coll Cardiol 2006

Iron deficiency in HF: etiology Increased loss: Antiplatelets, anticoagulants (GI bleeding) Reduced intake: Intestinal edema or ischemia (malabsorption) Malnutrition Impaired metabolism: Inflammation (IL-6 induces hepcidin release) Silverberg, Heart Fail Rev 2010 Pagourelias et al, Angiology 2009 Krack et al, Eur Heart J 2005 Detivaud L et al, Blood 2005

Definition of iron deficiency TSAT <20% Absolute: low ferritin (<100 μgl/) Functional: TSAT <20% plus high ferritin (100-300μg/L ) * TSAT = (Serum Iron / TIBC) x 100%

The concept of absolute and functional iron deficiency in CHF Eur Heart J 2013; 34, 816 826

The role of hepcidin Pietrangelo, N Engl J Med 2004

Consequences of iron deficiency: Eryhtropoiesis Besarab et al, The Oncologist 2009

Consequences of iron deficiency: Oxygen uptake, transportation and storage Hemoglobin Myoglobin

Consequences of iron deficiency: Oxygen metabolism Respiratory chain Complexes I-IV

Anker et al, Eur J Heart Fail 2009

van Veldhuisen et al, Nature Rev Cardiol 2011

Consequences of iron deficiency: Defensive mechanisms Haber-Weiss & Fenton reaction ROS production ROS degradation

Iron deficiency in HF: additional evidence Cardiac tissue iron content is low in CHF Iron deficiency is followed by structural cardiomyocyte changes Iron deficiency reduces exercise capacity regardless of anemia Iron repletion improves functional status regardless of anemia Dong et al, Clin Science 2005 Brownlie et al, Am J Clin Nutr 2004 Haas et al, J Nutr 2001 Zhu et al, J Appl Physiol 1998 Ohira et al, Br J Haematol 1979

Clinical importance of iron in CHF Eur Heart J 2013; 34, 816 826

Treatment of anemia using iron alone Bolger 16 HF pts Hgb <12g/dl iv iron sucrose FU 92days Hgb NYHA MLHFQ 6MWD et al 2006 serum ferritin<400ng/ml 12-17days Tobbli 20 pts Hgb <12.5 i.v iron sucrose FU 6 m Hgb et al 2007 200mg/week (5 weeks) 20 control iv saline EF Crcl NTproBNP CRP Ferric-HF 18 anemic Hgb <12.5 VO2< 18ml/kg/min =Hgb ferritin NYHA peak VO2 2008 iv iron sucrose (200mg/week for 4 weeks then 200mg/month up to 16 weeks) 17 nonanemic placebo

I.v. Iron Sucrose Improves Functional Capacity and Quality of Life in Patients with CHF and Anemia Change in MLWHF questionnaire score 60 50 40 30 20 10 0-10 R=0.76 P=0.002-20 -1 0 1 2 3 Change in 6MWT (m) 200 175 150 125 100 75 50 25 0-25 -50 R=0.56 P=0.03-75 -1 0 1 2 3 Prospective, uncontrolled study with iron sucrose N=16 Left ventricular ejection fraction (LVEF) 26±13% Hb 12 g/dl Ferritin 400 ng/ml MLWHF Score 33 ± 19 19 ± 14 (p=0.02) 6MWT 242 ±78 286 ±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;48:1225 1227

I.v. Iron Sucrose Improves Kidney Function in Patients with CHF and Iron Deficiency TSAT (%) 0.28 0.24 0.20 0.16 0.12 0.08 0.04 0.00 * * * * Inclusion criteria: 40 CHF outpatients, GFR 90 ml/min LVEF 35%, Hb <12.5 (m)/<11.5 g/dl(f) Ferritin <100 ng/ml and/or TSAT 20% NT-proBNP (pg/ml) 800 700 600 500 400 300 200 100 0 * I.v. iron (n=20) Placebo (n=20) * Creatinine clearance (ml/min) 0 1 2 3 4 5 6 7 Months 60 * * * * 50 40 30 20 10 0 Hospitalizations: I.v. iron: 0/20 Control: 5/20* LVEF (%) 45 40 35 30 25 20 15 10 5 0 0 1 2 3 4 5 6 7 Months * * Treatment: 200 mg i.v. iron sucrose per week Weekly for 5 weeks then monthly Duration: 6 months *P<0.01 0 1 2 3 4 5 6 7 Months 0 1 2 3 4 5 6 7 Months Toblli JE et al. J Am Coll Cardiol 2007;50:1657 1665

Effect of Intravenous Iron on Exercise Tolerance in CHF patients (FERRIC-HF) Okonko et al. J Am Coll Cardiol 2008;51:103 12

Anemia in chronic Heart Failure

FAIR-HF study design Anker SD, et al. Eur J Heart Fail 2009;11:1084 91. Main inclusion criteria: NYHA class II/III, LVEF 40% (NYHA II) or 45% (NYHA III) Hb: 9.5 13.5 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 FAIR-HF=Ferric carboxymaltose Assessment in patients with IRon deficiency and chronic Heart Failure; Hb=haemoglobin; i.v.=intravenous; LVEF=left ventricular ejection volume; NYHA=New York Heart Association; PGA=patient global assessment; TSAT=transferrin saturation

Primary: Primary and secondary endpoints in FAIR-HF Self-reported Patient Global Assessment score at week 24 NYHA class at week 24 (adjusted for baseline NYHA class) Key secondary PGA and NYHA class* at Weeks 4 and 12 Six-minute walk test distance** KCCQ score** EQ-5D questionnaire score** Safety endpoints * adjusted for baseline **at weeks 4, 12 and 24 and adjusted for baseline EQ-5D=European Quality of Life-5; KCCQ=Kansas City Cardiomyopathy Questionnaire Anker SD, et al. Eur J Heart Fail 2009;11:1084 91.

FAIR-HF results: Primary endpoints Patient Global Assessment at Week 24 50 vs 27% NYHA Functional Class at Week 24 47 vs 30% FCM Placebo FCM Placebo At Week 24, intravenous iron improved: Self-reported patient global assessment scores (odds ratio for better rank: 2.51 [95% CI 1.75, 3.61], p<0.001) NYHA functional class (odds ratio for improvement by 1 class: 2.40 [95% CI 1.55, 3.71], p<0.001)* Anker SD, Colet C, Filippatos G, et al. N Engl J Med 2009;361:2436 48.

FAIR-HF results: Main secondary endpoints 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<0.001 6-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<0.001 p<0.001 p<0.001 Anker SD, et al. N Engl J Med 2009;361:2436 48. VAS=visual analogue scale

FAIR-HF results: self-reported patient global assessment at Week 24 by baseline anaemia status 232 of 459 patients had anaemia at baseline (51%) Patients with anaemia Patients without anaemia FCM Placebo Patients (%) Patients (%) Odds ratio for better rank at Week 24: 2.48 (95% CI 1.49, 4.14), p<0.001 Odds ratio for better rank at Week 24: 2.60 (95% CI 1.55, 4.35), p<0.001 Filippatos G, et al. Eur J Heart Fail 2013.

FAIR-HF results Impact of intravenous iron on renal function

FAIR-HF PGA Patients with Anemia Patients without Anemia NYHA class Filippatos, et al, Eur J Heart Fail 2013

Iron preparations Iron sucrose iv (Venofer) Ferric carboxymaltose iv (Ferinject) Ferrous sulfate (FeSO 4 ) per os

Iron repletion therapy in HF: some unanswered questions Large-scale trials? Prognosis? Long-term safety? Who really benefits? Hb target in anemia? Hb restoration rate? No specific recommendations in ESC 2012 HF guidelines

Η αναιμία αυξάνει την θνητότητα και την νοσηρότητα στους ασθενείς με καρδιακή ανεπάρκεια και: 1. Μειωμένο ΚΕ 2. Διατηρημένο ΚΕ 3. 1 και 2 4. σε κανένα από τα δύο

Η θεραπεία με παράγωγα της ερυθροποιητίνης στην καρδιακή ανεπάρκεια με μειωμένο ΚΕ 1. Μειώνει την ολική θνητότητα 2. Μειώνει την καρδιαγγειακή θνητότητα 3. Μειώνει την νοσηρότητα 4. Όλα τα παραπάνω 5. Κανένα από τα παραπάνω

Η θεραπεία με σίδηρο στην καρδιακή ανεπάρκεια 1. Μειώνει την ολική θνητότητα 2. Μειώνει την καρδιαγγειακή θνητότητα 3. Μειώνει την νοσηρότητα 4. Όλα τα παραπάνω 5. Κανένα από τα παραπάνω