Iron Deficiency in Heart Failure Peter van der Meer Hartfalendag - PowerPoint PPT Presentation

Iron deficiency in chronic heart failure Iron Deficiency in Heart Failure Peter van der Meer Hartfalendag Zeist – 27 sept 2019 Peter van der Meer, cardioloog University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Disclosures Research grants and/or consultancy fees: Astra Zeneca, Vifor Pharma, Novartis, Pfizer, Ionis, Servier University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Anaemia and mortality Study Al Ahmad (2001) Tanner (2002) McClellan (2002) Horwich (2002) 34 studies included Szachniewi (2003) Kerzner (2003) Kalra (2003) Mozaffarian (2003) Kosiborod (2003) - 150,000 patients Van der Meer (2004) Anand (2004) Sharma (2004) Ralli (2005) - 37.8% had anaemia Kosiborod (2005) Rosolova (2005) Gardner (2005) Maggioni-V (2005) Maggioni-I (2005) - Odds ratio: 1.96 [1.74 – 2.21, p <0.001] Ezekowitz (2005) Varadarajan (2006) Elabbassi (2006) Maraldi (2006) DeSilva (2006) - Adjusted HR: 1.46 [1.26 – 1.69, p <0.001] Berry (2006) Go (2006) Komajda (2006) Newton (2006) Formiga (2006) Terrovitis (2006) - Similar outcome in systolic/diastolic HF O’Meara (2006) Felker (2006) Shamagian (2006) Schou (2007) Overall (I- .4 .5 1 2 4 8 10 squared=92.4%,p=0.000) Lower risk of anaemia Higher risk of anaemia Groenveld HF. J Am Coll Cardiol 2008;52:818 – 27 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure PHASE 3 TRIAL (RED-HF) Inclusion Criteria • LVEF < 40% • Hb 9-12.0 g/dL • T-SAT: > 15% • Kreat: <265 umol/L University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Possible aetiologies of anaemia in heart failure Bone marrow failure Iron defiency Westenbrink EJHF 2010 Ruifrok J Mol Med 2011 Jankowska EHJ 2011 Renal failure Anaemia Blood loss EPO production Anticoagulation Westenbrink EHJ 2007 Belonje Circ 2010 Medication Fluid retention ACE-inhibitors Inflammation Hemodilution vd Meer Circ 2005 Kleijn Heart 2012 Westenbrink EHJ 2007 van der Meer P. Eur Heart J 2004;25:285 – 91 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure The “life cycle of iron ” University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure How to diagnose iron deficiency Ferritin = storage of iron Iron deficiency in HF <100 ug/L Transferrin Transferrin-saturation (T-sat) iron Fe --------------- X100 = T-SAT% Transferrin Ferritin < 100 OR Ferritin 100-300 AND T-SAT < 20% University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Welke lab-waarden zijn naast ferritine nodig om ijzer status te meten in patienten met hartfalen? Serum ijzer + transferrine 1) Transferrine + hemoglobine 2) Hemoglobine + MCV 3) Serum ijzer + zuurstof saturatie 4) Hemoglobine + hepcidine 5) University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Beenmergaspiratie • Prussian Blue-staining • Iron stores • Iron incorporation sideroblasts University Medical Center Groningen University of Groningen

Baseline Iron deficiency in chronic heart failure Variable Total N 42 68.0 ± 9.5 Age, y Female gender 10 (24%) Variable Total 28.6 ± 3.8 BMI, kg/m2 131.5 ± 16.5 SBP (mmHg) Laboratory values NYHA class NT-proBNP, ng/l 914 (454, 1755) 1 8 (19%) 2 21 (50%) 77.9 ± 18.8 eGFR, ml/min/1.73m2 3 12 (29%) 4 1 (2%) CRP, mg/l 2.0 (0.9, 4.5) 37.8 ± 7.0 LVEF, % Comorbidities Hematology Previous MI 20 (48%) 14.0 ± 1.3 Diabetes mellitus 22 (52%) Hemoglobin, g/dl Atrial fibrillation 12 (29%) 90.1 ± 5.3 MCV, fl. Hypertension 32 (76%) Hypercholesterolemia 39 (93%) Ferritin, μg /dl 144 (85, 263) ID (FAIR-HF) 21 (50%) Anemia 7 (17%) TSAT, % 20.9 (14.7, 27.8) Medication Anti-platelets 33 (79%) Diuretics 22 (52%) B-Blocker 32 (76%) ACEi or ARB 38 (90%) Grote Beverborg, … Van der Meer Circ HF 2018 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure FAIR-HF vs. bonemarrow Sensitivity = 82.4% Specificity = 72.0% University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Receiver operating characteristics (ROC) AUC ± SE Variables for prediction of ID Cut-off value Sensitivity Specificity ≤14.2 0.820 ± 0.064 Hemoglobin, g/dl 94.1% 48.0% 0.716 ± 0.081 ≤0.41 Hematocrit, % 70.6% 58.3% 0.586 ± 0.095 ≥13.1 Reticulocytes, x10 9 /l 64.7% 58.3% 0.618 ± 0.091 ≤60.2 RPI 82.4% 50.0% ≤90.1 0.645 ± 0.090 MCV, fl 76.5% 62.5% ≤1879 0.719 ± 0.084 MCH, fmol 75.0% 66.7% 0.773 ± 0.080 ≤20.9 MCHC, g/dl 75.0% 66.7% 0.733 ± 0.083 ≥13.5 RDW, % 58.8% 75.0% 0.687 ± 0.091 ≥0.2 HYPO, % 64.7% 78.3% ≤32.2 0.821 ± 0.066 RET-He, pg 76.5% 73.9% ≤30.0 0.706 ± 0.086 RBC-He, pg 82.4% 69.6% 0.776 ± 0.076 ≤1.8 Delta-He, pg 58.8% 91.3% Ferritin, μ g/l 0.666 ± 0.089 ≤145 70.6% 60.0% 0.932 ± 0.036 ≤19.8 TSAT, % 94.1% 84.0% ≤250 0.515 ± 0.096 Transferrin, mg/l 58.8% 68.0% Iron, μg/dl ≤13 0.922 ± 0.044 94.1% 88.0% ≥1.06 0.679 ± 0.089 sTfR, mg/l 70.6% 56.0% 0.706 ± 0.090 ≥0.19 sTfR-index 58.8% 92.0% 0.541 ± 0.111 ≤6.1 Hepcidin, nM 52.9% 84.0% University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure T-SAT < 20% goede voorspeller van ijzer deficientie Sensitivity = 82.4% Specificity = 72.0% University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Prevalence of iron deficiency in large cohort University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Why are patients with heart failure iron deficient? • N = 2352 patients with worsening HF • Mean age 69 years and 26% women • Median NTproBNP: 4300 ng/L • 62% of the patients are iron deficient 1 University Medical Center Groningen University of Groningen 5

Iron deficiency in chronic heart failure Predictors of iron deficiency Van der Wal, … Van der Meer Eur Heart J in press University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Iron deficiency leads to impaired exercise tolerance. 1 Iron deficiency p<0.001 7 • 443 patients with stable systolic CHF Anaemia p=0.15 Interactions p=0.94 • age 54 ± 10 years, 1 Peak VO 2 (mL/min/kg) 6 • males 90%, • LV ejection fraction 26 ± 7%, 1 5 • NYHA: I/II/III/IV 49/188/180/26) 1 4 1 3 1 ( – ) anaemia ( – ) anaemia (+) anaemia (+) anaemia 2 ( – ) ID ( – ) ID (+) ID (+) ID • Iron deficiency defined as serum ferritin <100 μ g/L, or serum ferritin 100 – 300 μ g/L with TSAT <20% • Anaemia defined as haemoglobin level <12g/dL in women and <13g/dL in men Jankowska EA, et al. J Cardiac Fail 2011;17:899 – 906 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Iron deficiency associated with lower QoL and higher mortality HR 1.44; 95% CI 1.16 - 1.81; p = 0.001) Klip J. Am Heart J 2013 accepted University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Heeft het zin om ijzerdeficientie in hartfalen te behandelen? University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure hypothesis Anker, .. Ponikowksi. NEJM 2009 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure CONFIRM-HF Design: Multicentre, randomised (1:1), double-blind, placebo-controlled • Main inclusion criteria: • NYHA class II / III, LVEF ≤45% • BNP > 100 pg/mL or NT-proBNP > 400 pg/mL • Iron deficiency: serum ferritin <100 ng/mL or 100-300 ng/mL if TSAT <20% • Hb < 15 g/dL • Correction phase Maintenance phase FCM treatment continues FCM up to 2000mg if ID is not corrected (2 x 500-1000mg i.v.) (500mg i.v.) FCM 1 ° EP: Screening R 6MWT Placebo W6 W12 W24 W36 W52 D0 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Primary endpoint: 6-minutes walking distance at week 24 • FCM improved 6MWT at week 24: • FCM vs placebo: 33 ± 11 m (least squares mean ± standard error ) 30 FCM (n=150) Placebo (n=151) P=0.002 20 LSM change in 6MWT distance 10 from baseline (m) 0 -10 -20 -30 Week 24 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure EFFECT-HF • Open label (Ferinject vs. OMT) • N=161 • Iron deficiency • HFrEF • Change peak VO2 at 24wk Circulation 2017 University Medical Center Groningen University of Groningen

Iron deficiency in chronic heart failure Werkt oraal ijzer net zo goed? University Medical Center Groningen University of Groningen