Διαχείριση ασθενούς με καρδιακή ανεπάρκεια και αναιμία. Βασιλική Μπιστόλα Καρδιολόγος Β Πανεπιστημιακή Καρδιολογική Κλινική Νοσοκομείο Αττικό

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1 Διαχείριση ασθενούς με καρδιακή ανεπάρκεια και αναιμία Βασιλική Μπιστόλα Καρδιολόγος Β Πανεπιστημιακή Καρδιολογική Κλινική Νοσοκομείο Αττικό

2 Based on WHO Definition, 9% of Adults Have Anemia: ARIC Study* ARIC Study1 Population: Ages 45 to 64; N = 15,792 Men 95% 5% Anemia definition:2 Men = Hgb <13 g/dl Women = Hgb <12 g/dl All Anemic 9% Women 91% 87% 13% *The Atherosclerosis Risk in Communities (ARIC) study enrolled subjects in 4 US communities: Forsyth County, NC; Jackson, Miss; Minneapolis, Minn; and Washington County, Md. 1. Sarnak et al. J Am Coll Cardiol. 2002;40: World Health Organization. Geneva, Switzerland; 2001.

3 Anemia and CV Death in ACS OR & 95% CI for CV Death by 30 d Hgb (g/dl) n Unadjusted OR (95% CI) Adjusted for Baseline Characteristics OR (95% CI) P value > ( ) 1.79 ( ) ( ) 1.08 ( ) ( ) 1.08 ( ) reference 1.0 reference ( ) 1.17 ( ) ( ) 1.40 ( ) ( ) 1.63 ( ) ( ) 1.98 ( ) < ( ) 2.50 ( ) Sabatine et al. Circulation 2005

4 % Mortality at 1 year Acute MI: Higher Hematocrit is Associated with Lower Risk of Death 45.00% 40.00% % Odds Ratio 30.00% % 20.00% 15.00% % 5.00% 0.00% > 40% 36-39% 30-35% < 30% Hematocrit Langston, Kid Int 2003, 64: Retrospective cohort of 709 Medicare patients admitted to community hospitals for acute MI Odds Ratio Adjusted for age, sex, race, kidney function and cardiovascular co-morbidities 4% decrease in one year risk of death per 1% increase in hematocrit

5 Hazard Ratio for 3-yr Mortality < < > 39 >75 Hematocrit (%) Gurm et al. Am J Cardiol 2004;94:30-4.

6 Dual Antiplatelet Agents Increase Risk of GI Bleeding in Cardiac Patients Risk ratio (95% CI) % Weight MATCH 2.92 (1.96,4.36) 40.5 CURE 1.78 (1.25,2.54) 59.5 Overall (95% CI) 2.24 (1.72,2.92) Study In VALIANT, dual antiplatelet agent use was associated with an 85% increased adjusted risk of GI bleeding (each 10 points of reduced egfr increased 1 GI bleeding risk by 20%)

7 Prevalence of Anaemia in Large-scale CHF Studies Study Gender Definition (g/dl) Prevalence (%) M+F < ELITE II F M <12 < IN CHF F <11 <12 Val-HeFT F M <11 <12 HTx F M <12 <13 COPERNICUS } } }

8 Prevalence of Anaemia in a CHF Outpatient Clinic (Hgb <12 g/dl) Male 82% Female 18% Prevalence (%) 40 N = % % 7% 9% 0 Class I Class II Class III Class IV NYHA Class Tanner H et al. Int J Cardiol 2002

9 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

10 Relation of Low Hemoglobin and Anemia to Morbidity and Mortality in Patients Hospitalized With Heart Failure (OPTIMIZE-HF Registry) Figure 2. Estimated relation between admission hemoglobin and in-hospital mortality. Restrictive cubic spline transformation plot with 95% confidence intervals is shown. Young et al. Am J Cardiol 2008

11 Treatment Options for Anemia in HF Optimal medical management Erythropoietic agents in combination with iv or oral iron IV iron alone

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

13 - 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% - 5 year mortality: Persistent 58%, Incident 45%, No anemia 31% Tang et al. JACC 2008;51:569

14 Treatment Options for Anemia in HF Optimal medical management Erythropoietic agents in combination with IV or oral iron IV iron alone

15

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

17 Low-dose erythropoietin improves cardiac function in experimental CHF without increasing haematocrit Lipsic E et al. Eur J Heart Fail 2008:10: 22 29

18 RED-HF Trial: efficacy n=2278 HFREF plus Anemia (Hb 9-12g/dl) Darbepoetin vs placebo Swedberg K, et al. NEJM 2013

19 RED-HF trial: safety Swedberg K, et al. NEJM 2013

20 Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure: RED-HF NEJM 2013 March

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

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

23 Iron deficiency in anaemic patients with HF 37 anaemic patients with advanced CHF, NYHA IV, LVEF 22% Bone marrow biopsy confirmed iron deficiency in 27/37 pts ID pts: MCV, MCHb, ferritin, Na+; ~ BNP, creat, CRP 73.0% Iron deficient anaemia Anaemia of chronic disease Haemodilution-related anaemia Drug-induced anaemia 18.9% 5.4% 2.7% Nanas JN et al. J Am Coll Cardiol 2006

24 Can iron repletion have an impact in patients with heart failure? Iron deficiency: an ominous sign in patients with systolic heart failure Cumulative event-free survival Patients without ID: Survival: 67% 95% CI: 61 72% p= ID (but not anaemia) related to an increased risk of death or HTX: Hazard ratio (adjusted) = 1.6 (95% CI , p<0.01) Patients with ID: Survival: 54% 95% CI: 46 61% Follow-up (months) CHF=chronic heart failure; CI=confidence interval; HTX=heart transplantation; ID=iron deficiency; TSAT=transferrin saturation Jankowska EA, et al. Eur Heart J 2010;31:

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

26 Iron Deficiency can Affect Oxygen Consumption Iron deficiency Hb Aerobic enzymes Mitochondrion Oxidative phosphorylation O2 O2 delivery ATP O2 utilization pvo2 Haas JD & Brownlie T. J Nutr 2001;131(2 suppl 2):676S 690S; Dallman PR. J Intern Med 1989;226: ; Willis WT & Dallman PR. Am J Physiol 1989;257:C

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

28 Markers of iron deficiency in peripheral blood Eur Heart J 2013; 34,

29 60 R=0.76 P= R=0.56 P= MLWHF Score 33 ± ± 14 (p=0.02) 6MWT Prospective, uncontrolled study with iron sucrose N=16 Left ventricular ejection fraction (LVEF) 26±13% Hb 12 g/dl Ferritin 400 ng/ml 200 Change in 6MWT (m) Change in MLWHF questionnaire score IV Iron Sucrose Improves Functional Capacity and Quality of Life in Patients with CHF and Anemia 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:

30 * 0.28 * * 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% Creatinine clearance (ml/min) * * Months 5 6 * * 20 Hospitalizations: I.v. iron: 0/20 Control: 5/20* *P< Months * * I.v. iron (n=20) Placebo (n=20) LVEF (%) TSAT (%) 0.24 * NT-proBNP (pg/ml) I.v. Iron Sucrose Improves Kidney Function in Patients with CHF and Iron Deficiency Months 5 * 6 7 * Treatment: 200 mg i.v. iron sucrose per week Weekly for 5 weeks then monthly Duration: 6 months Months Toblli JE et al. J Am Coll Cardiol 2007;50:

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

32 Clinical trials (except FAIR-HF) concerning iv iron use in CHF

33 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%

34 What is Ferric Carboxymaltose? Stable polynuclear iron complex Essentially no release of ionic iron in the circulation Dextran-free carbohydrate shell (low immunogenic potential) No test dose Physiological ph and osmolarity Rapid administration of up to 1000 mg iron Ferric hydroxide Ribbon-like molecules carboxymaltose Macdougall IC and Ashenden M. Adv Chron Kid Dis 2009;16:

35 FAIR-HF study design Anker SD, Colet C, Filippatos G, et al. Eur J Heart Fail 2009;11: 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 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

36 Primary and secondary endpoints in FAIR-HF Primary: Self-reported Patient Global Assessment score at week 24 NYHA class at week 24 (adjusted for baseline NYHA class) Key secondary PGA score 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:

37 FAIR-HF: Primary endpoints Patient Global Assessment at Week vs 27% NYHA Functional Class at Week vs 30% N=459 NYHA class II/III, HFREF Hb: g/dl Iron deficiency FU: 24W, (Safety 26W) FCM FCM Placebo Placebo At Week 24, intravenous ferric carboxymaltose 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:

38 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 m2) 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/m2) >27.37 Anker SD, et al. N Engl J Med 2009;361: BMI=body mass index; CHF=chronic heart failure; egfr=estimated glomerular filtration rate

39 FAIR-HF results: Main secondary endpoints Patient Global Assessment p<0.001 p< minute walk test p<0.001 p<0.001 NYHA functional class p<0.001 p<0.001 KCCQ overall score p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 EQ-5D VAS score p<0.001 p<0.001 p<0.001 p<0.001 Anker SD, Colet C, Filippatos G, et al. N Engl J Med 2009;361: VAS=visual analogue scale

40 Safety endpoints in FAIR-HF Patients with events (Incidence per 100-patient years at risk) FCM (N=305) Placebo (N=154) p 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) 25 (17.7) 17 (24.8) (10.4) 14 (20.0) (4.1) 7 (9.7) (21.2) 19 (27.7) (13.9) 16 (22.9) (7.5) 10 (13.9) 0.15 Death First hospitalisation Hospitalisation for any CV reason First hospitalisation for worsening HF Any hospitalisation or death Hospitalisation for any CV reason or death First hospitalisation for worsening HF or death CV=cardiovascular; HF=heart failure Anker SD, et al. N Engl J Med 2009;361:

41 Reported adverse events in FAIR-HF Patients with events (Incidence per 100-patient years at risk) FCM (N=305) Placebo (N=154) p 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) (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) (6.2) 10 (14.2) (14.0) 11 (15.7) 0.80 Injection-site pain or discoloration Respiratory, thoracic or mediastinal disorder Vascular disorder There were no severe or serious hypersensitive reactions Anker SD, et al. N Engl J Med 2009;361: Adverse events were classified by the Medical Dictionary for Regulatory Activities and were reported by system organ class when they occurred for more than 4% of patients in total

42 FAIR-HF: additional analyses FCM in anaemic and non-anaemic patients FCM and renal function

43 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 without anaemia Placebo Patients (%) Patients (%) Patients with anaemia FCM Odds ratio for better rank at Week 24: 2.48 (95% CI 1.49, 4.14), p<0.001 Filippatos G, Farmakis D,, Parissis J, et al. Eur J Heart Fail Odds ratio for better rank at Week 24: 2.60 (95% CI 1.55, 4.35), p<0.001

44 FAIR-HF results: NYHA at Week 24 by baseline anaemia status FCM Patients without anaemia Placebo Patients (%) Patients (%) Patients with anaemia Odds ratio for improvement by 1 class at Week 24: 1.90 (95% CI 1.06, 3.40), p=0.030 Filippatos G, Farmakis D,, Parissis J, et al. Eur J Heart Fail 2013 Odds ratio for improvement by 1 class at Week 24: 3.39 (95% CI 1.70, 6.75), p<0.001

45 FAIR-HF results: changes in patient global and NYHA class by baseline anaemia status Patients with anaemia p<0.001 p<0.001 Patients without anaemia p<0.001 p<0.001 p<0.001 p<0.001 Patient Global Assessment Patients with anaemia p=0.002 p<0.001 NYHA functional class Filippatos G, Farmakis D,, Parissis J, et al. Eur J Heart Fail 2013 Patients without anaemia p=0.03 p=0.02 p=0.004 p<0.001

46 FAIR-HF: Anemic vs non-anemic pts 232 of 459 patients had anaemia at baseline (51%) Patients with anemia % Patients without anemia % Patients with anemia % Patients without anemia % Filippatos, G et al. Eur J Heart Fail 2013

47 FAIR-HF results: beneficial effect of intravenous iron on 6-minute walk test is independent of baseline anemia status FCM, non-anaemic FCM, anaemic Placebo, non-anaemic Placebo, anaemic SE=standard error Filippatos G, Farmakis D,, Parissis J, et al. Eur J Heart Fail 2013 p treatment effect Anaemic Week 4 Week 12 Week 24 Non-anaemic Week 4 Week 12 Week 24 p <0.001 < <0.001

48 FAIR-HF: beneficial effect of intravenous iron on QoL is independent of baseline anaemia status 70 EQ-5D score Anaemic placebo 50 Anaemic FCM Non-anaemic placebo Non-anaemic FCM Week SE=standard error Filippatos G, Farmakis D,, Parissis J, et al. Eur J Heart Fail FCM=ferric carboxymaltose

49 FAIR-HF: additional analyses FCM in anaemic and non-anaemic patients FCM and renal function

50 In FAIR-HF, what effect did intravenous iron treatment have on renal function, compared with placebo? A: No effect B: Significantly decreased egfr C: Significantly increased egfr

51 Assessment of renal function egfr was assessed by the Modification of Diet in Renal Disease formula:1 egfr = 170 x [Pcr] x [age] x [0.762 if patient is female] x [1.180 if patient is black] x [BUN] x [Alb] Alb=serum albumin concentration (g/dl); Pcr=serum creatinine concentration (mg/dl); BUN=blood urea nitrogen concentration (mg/dl) Baseline renal function:2 FCM: Placebo: 64 ± 21 ml/min/1.73 m2 65 ± 25 ml/min/1.73 m2 1. Levey AS, et al. Ann Intern Med 1999;130: Anker SD, et al. New Engl J Med 2009;361:

52 FAIR-HF results: impact of FCM on renal function Ponikowski P, et al. Eur J Heart Fail 2015

53 FAIR-HF results: primary endpoints by baseline egfr NYHA functional class Patient Global Assessment <60 ml/min/1.73 m2 60 ml/min/1.73 m2 PInteraction PInteraction Ponikowski P, et al. Heart Failure Association Congress 2010; abstract 114 and late-breaking trial oral presentation. 0.46

54 FAIR-HF: additional analyses FCM in anaemic and non-anaemic patients FCM and renal function Quality of life: detailed analysis

55 Baseline QoL: impaired in FAIR-HF patients QoL=quality of life Adapted from: Calvert MJ, et al. Eur J Heart Fail 2005;7: Comin Colet J, et al. American Heart Association Scientific Sessions 2010; abstract and oral presentation.

56 FAIR-HF results: effects of intravenous iron on QoL EQ-5D VAS * * * n (FCM) 295 n (placebo) Mean ± SE *p<0.001 vs placebo Comin Colet J, et al. American Heart Association Scientific Sessions 2010; abstract and oral presentation.

57 Effect of ferric carboxymaltose on functional capacity in patients with heart failure and iron deficiency (CONFIRM-HF) N= 304, HFREF, NYHA II/III, FU 1year Primary endpoint: change in 6-minutes walking test distance at Week 24 FCM vs placebo: 33 ± 11 m (least squares mean ± SE) LSM change in 6MWT distance from baseline (m) 30 P= FCM (N=150) Placebo (N=151) Week 24 Ponikowski P, et al. Eur Heart J 2014

58 Hospitalizations in CONFIRM-HF Secondary endpoint: First hospitalization due to worsening HF Hospitalization rate (per 100 subjects) No. of subjects at risk Placebo FCM Log rank test P=0.009 Placebo 20 FCM Time (days) FCM reduced the risk of recurrent hospitalisations due to worsening HF (post hoc): Hazard Ratio (95% CI) 0.30 ( ), p=0.0019

59 CONFIRM-HF: subgroup analysis

60 Iron Iron deficiency is common in patients with CHF, and is usually associated with anaemia. A recent study has demonstrated reduced symptoms and improved submaximal exercise tolerance and quality of life with use of intravenous ferric carboxymaltose (in addition to standard therapies) in iron-deficient patients with CHF. Iron deficiency should be looked for and treated in patients with CHF to reduce symptoms and improve exercise tolerance and quality of life (Grade B recommendation)

61 Unsolved issues Mortality data? Duration of treatment? Cost-effective studies?

62 What kind of treatment for anemic CHF patients? For all: optimization of conventional medical treatment For those with iron deficiency: IV iron For those with severe renal dysfunction: EPO plus iron (target Hb g/dl)