Anaemia in Chronic Heart Failure 2011 Update Piotr Ponikowski, MD, PhD, FESC Medical University, Centre for Heart Disease Clinical Military Hospital Wroclaw, Poland
DECLARATION OF CONFLICT OF INTEREST Consultancy fees and speaker s honoraria from: Vifor Pharma Ltd, Amgen
Heart Failure Patient Importance of co-morbidities HF pathophysiological mechanisms CV & non-cv co-morbidities Clinical picture (symptoms) Disease progression Outcome Management
Anaemia in Heart Failure 1. Prevalence 2. Contributing factors and mechanisms 3. Consequences: a. pathophysiology b. symptoms & QoL c. outcome 4. Therapy
US National Health & Nutrition Examination Survey; Guralnik JM, et al Blood 2004; Prevalence of anaemia in HF How to define anaemia in HF? Distribution of haemoglobin in persons > 65 years N = 4199 Anaemia at age > 65y M 11%; F 10% (age > 85y 20%+) Mostly mild 1/3 unexplained WHO definition
Lopez-Sendon J; ESC 2005 Prevalence of anaemia in HF 70 60 % Registries 55 70 60 Clinical Trials 50 40 30 33 30 40 25 47 28 50 40 30 26 20 10 15 17 20 10 10 17 12 16 15 0 0
Ambulatory pts: Prevalence of anaemia in HF Tang WH et al., JACC 2008;51:569-76 Cleveland Clinic; internal med and cardiology outpatient departments; year 2001-6 Anaemia: Hb<11g/dL (women) & < 12 g/dl (men) Prevalence (overall): 17% Dunlay SM et al., Am J Med 2008;121:726-32 Community study; Olmsted County; retrospective: 1979-2002 & prospective: 2003-6 Anaemia: Hb<12 g/dl (women) & < 13 g/dl (men) Prevalence (overall): retrospective 40%, prospective 53% (HFPEF 58%) Hospitalized pts: Young JB et al., Am J Cardiol 2008;101:223-30 Patients hospitalized with HF, OPTIMIZE-HF; Prevalence: 50% had Hb<12.1 g/dl, 25% had Hb 5-10.7 g/dl (Hb quartiles)
Prevalence of anaemia in HF How to define anaemia in HF? UK General Practice Research Database; N=20131 pts with stable angina & N=14741 pts with first MI; follow-up -3.2yrs Adjusted HR for mortality 11.9 g/dl 13.1 g/dl Shah AD et al., PLoS 2011;8:e1000439
Prevalence of anaemia in HF How to define anaemia in HF? Relationship Between Baseline Hemoglobin and Annual Mortality in HF Metaanalysis; 34 studies, 153180 HF patients; 37% anaemic Groenveld HF et al. JACC 2008;52:818-827
Anaemia in Heart Failure 1. Prevalence 2. Contributing factors and mechanisms 3. Consequences: a. pathophysiology b. symptoms & QoL c. outcome 4. Therapy
Clinical characteristics associated with increased risk of anaemia in HF Advanced age Female gender Chronic renal disease Severity of heart failure Acute settings (hemodilutions) Other co-morbidities (DM) Decreased BMI Use of ACE-I / ARBs / (BB?) Tang and Katz, Circulation 2006
Potential mechanisms underlying anaemia in HF LV dysfunction Kidney RAS&SNS activation EPO secretion Plasma volume expansion Haemodilution EPO resistance Bone Marrow Dysfunction RBC production Anemia Modified from Felker GM,JACC 2004;44:959; Tang Y, Circulation 2006;113:2454
Potential mechanisms underlying anaemia in HF LV dysfunction Kidney RAS&SNS activation EPO secretion Iron deficiency (absolute & functional) Plasma volume expansion Haemodilution Bone Marrow Dysfunction EPO resistance RBC production Anemia Modified from Felker GM,JACC 2004;44:959; Tang Y, Circulation 2006;113:2454
Anaemia of chronic disease the most frequent cause of anaemia in HF Other 57% 14% Anaemia of chronic disease N=148 anaemics 5% Opasich C et al.; Eur Heart J 2005 Iron deficiency 24% Renal disease Iron deficiency for erythropoiesis 64% Defective endogenous EPO production 76%
Controversies around endogenous EPO in HF Elevated levels of circulating EPO in HF Volpe M et al., AJC 1994 van der Meer P et al., JACC 2004 Elevated EPO levels poor prognosticator George J et al., Arch Intern Med. 2005 Belonje AMS, Circulation 2010 In anaemic HF pts impaired EPO responsiveness (level lower than expected) Belonje AMS, Circulation 2010 lower than expected EPO levels EPO levels as expected Belonje AMS et al. Circulation 2010;121:245-251 Higher than expected EPO levels (worse prognosticator)
Jankowska EA et al. Eur Heart J 2010 Iron deficiency in patients with HF Prospective observational study, 546 patients with stable systolic HF ID: ferritin <100 μg/dl, or 100-299 μg/dl with TSAT<20% % of HF pts 50% p<0.001 57±10 p=0.007 52±12 40% 37±4 p=0.004 43±6 p=0.03 p=0.02 41±6 41±6 30% 20% 37±4 32±4 34±4 31±5 32±6 32±6 10% 0% All patients
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, anticoagulants), inadequate intake (elderly, malnutrition, impaired absorption) 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%
Myocardial iron is depleted in HF Myocardial Iron Content Regulation of TfR Expression Myocardial TfR Expression Patients with advanced HF demonstrated evidence of iron deficiency in the blood and in the myocardium (generalised disorder?) Potential role of neurohormonal activation in disturbed iron metabolism Maeder MT et al. JACC 2011;58:474-80
Anaemia in Heart Failure 1. Prevalence 2. Contributing factors and mechanisms 3. Consequences: a. pathophysiology b. symptoms & QoL c. outcome 4. Therapy
Anaemia: cause or (and) consequence of HF Chicken or egg: Which comes first?
Anaemia: cause and consequence of HF HF worsening Remodelling LVH cell death LV diameter Plasma volume Oedema Anaemia HF Tissue Hypoxia Peripheral vasodilatation Blood pressure Activation of SNS Increased Salt & Water Retention Renal blood flow RAA, ADH
What affects exercise tolerance: anaemia or iron deficiency? 17 16 Iron deficiency (ID) F=12.72 p<0.001 Anemia F=2.13 p=0.15 Interactions F=0.01 p=0.94 Peak VO 2 (ml/min/kg) 15 14 13 12 ID (-) Anemia (-) ID (-) Anemia (+) ID (+) Anemia (-) ID (+) Anemia (+) Jankowska EA et al., JCF 2011 (in press)
Anaemia in HF adversely affects the outcome Meta-analysis, 34 studies, N=153180 HF patients; anaemics 37% Mortality: anaemics 46.8% vs non-anaemics 29.5%; OR=1.96 (1.74-2.21) Anaemia independent risk of mortality; adjusted HR 1.46 (1.26-1.69) Groenveld HF et al., JACC 2008;52:818 CHARM program 150 100 Per 1000 pt-years Death Anaemics Non-anaemics 400 300 200 Per 1000 pt-years Hospital admission 50 100 CV Non-CV Reduced LVEF CV Non-CV Preserved LVEF CV Non-CV Reduced LVEF CV Non-CV Preserved LVEF O Meara E et al., Circulation 2006;113:986
Laboratory Values and Outcome CHARM CV Death/HF Hospitalisation Model 952 events Variable 2 HR* Age (per 10 yrs over age 60) 41 1.32 NYHA Class III/IV 40 1.42/2.09 Cardiomegaly 28 1.56 Diabetes (insulin/other) 27 1.31/1.07 RDW (%) 25 1.17 Prior HF Hosp 21 1.53 Bilirubin (total) 21 1.14 Ejection fraction (per 5% <45%) 18 1.59 * per SD for continuous variables % lymphocytes, uric acid, glycosylated Hgb, Hgb, creatinine were also all independent predictors
Jankowska EA et al. Eur Heart J 2010 Iron deficiency: an ominous sign in patients with systolic HF Prospective observational study, 546 patients with stable systolic CHF ID: ferritin <100 μg/dl, or 100-299 μg/dl with TSAT<20% Cumulative event-free survival 1.0 0.9 0.8 0.7 0.6 Patients without ID: Survival: 67% 95% CI: 61-72% p=0.0002 0.5 0.4 0.3 0.2 0.1 Patients with ID: Survival: 53% 95% CI: 46-61% ID (but not anaemia) related to an increased risk of death or HTX: HR (adjusted) = 1.6 (95% CI 1.1-2.2, p<0.01) Follow-up (months) 0 0 6 12 18 24 30 36
Anaemia in Heart Failure 1. Prevalence 2. Contributing factors and mechanisms 3. Consequences: a. pathophysiology b. symptoms & QoL c. outcome 4. Therapy
Anaemia in heart failure: how (and whether) to treat? Rationale (already very strong) Treatment options: Blood transfusions Demetri GD et al. Br J Cancer 2001 Erythropoietin or ESPs (in combination with iron and vit B 12 /folate) Silverberg D et al. J Am Coll Cardiol 2000 & 2001 Mancini DM et al. Circulation 2003; Palazzuoli et al. AHJ 2006 & 2007 AMGEN programme Iron (oral or iv) Bolger AP et al., JACC 2006; Toblii JE et al. JACC 2007; Okonko DO, JACC 2008; FAIR-HF Anker SD et al., NEJM 2009
Anaemia therapeutic target in CHF? Pooled risk ratio for mortality in randomized, placebo-controlled trials of erythropoiesis-stimulating agent treatment in patients with heart failure and anaemia. Desai A et al. Eur J Heart Fail 2010;12:936-942
Poor initial hematopoietic response to ESA may be associated with poor outcome Solomon SD et al., NEJM 2010;363:1146 Death, Myocardial Infarction, Stroke, Heart Failure, or Hospitalization for Myocardial Ischemia poor initial response DA the lowest quartile of % change in Hb level (<2%) after the first 2 standardized doses of the drug
Results Patient Global Assessment NYHA functional class 6-minute walk test KCCQ overall score EQ-5D VAS score EQ-5D, European Quality of Life 5-Dimensions; KCCQ; Kansas City Cardiomyopathy Questionnaire; VAS; visual analog scale. Anker SD et al. New Engl J Med 2009;361:2436 48
Anaemia in Heart Failure Conclusions 1. Prevalence common, affecting 20-40% pts several contributing factors (age, severity, renal dysfunction, co-morbidities) 2. Complex pathophysiology hemodilution, impaired EPO production/signalling, iron deficiency, ACD 3. Clinical consequences: associated with exercise intolerance, poor quality of life, high M&M 4. Therapy not yet established whether it can become therapeutic target
100% Lab test performed by cardiologist to diagnose/confirm and explore cause of anaemia in HF patients 90% 80% 70% 80% 77% 85% 71% 86% 84% 68% 63% 60% 50% 51% 51% 47% 40% 35% 30% 20% 10% 8% 8% 6% 8% 5% 18% 11% 13% 10% 9% 10% 4% 0% Hb Ferritin TSAT None Total (1155) France (268) Germany (258) Spain (254) Switzerland (125) UK (250) Hb assessment undertaken ~ 80% of patient, ferritin measured in ~ 40% In 10% of HF patients none of these tests (Hb, ferritin or TSAT) is performed Mori C et al., ESC 2011 presentation
I.V. Iron Performs Better than Placebo in all Patient Subgroups Anker SD et al. N Engl J Med 2009;36:2436 2448 Self-reported PGA score NYHA functional class
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 ± 1.5 3.0 ± 1.5 4.0 ± 1.7 * LSM mean ± SE
Importance of iron Essential for growth and survival CELLS TISSUES ORGANS BODY POPULATION Iron is particularly important for cells of high mitogenic potential and high energy demand, e.g. skeletal myocytes and cardiomyocytes.
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