Anaemia in heart failure

Prevalence,mechanism and treatment of Anemia in Heart Failure.

1. Anaemia in Heart Failure PRESENTER- DR ABHISHEK RATHORE SJIC&R ,Bangalore

2. Introduction Anemia – poor prognosis in HF Anemia itself can cause HF ( Hb < 5gm/dl)*, but uncommon to be the sole mechanism. Elderly, IHD, Renal dysfunction and even General population with anemia are at risk of HF. ESPs or iron therapy may have role in HF with anemia. *ACC/AHA 2005 Guideline update for diagnosis and management of CHF in adults.

3. Potential Therapeutic Targets

4. Definition of Anemia WHO- Hb < 13g/dl (Men) Hb < 12g/dl (Women) NKF criteria- Hb < 12g/dl (Men and Postmenopausal women) Hb < 11g/dl (Premenopausal women)

5. Prevalence Depend on population studied and definition of anemia used. ARIC ( Atherosclerosis Risk in Communities) study- A/c to WHO Age: 45-64 years N= 15,792 9% patients were found Anemic.

6. ANCHOR study N= 59,772 43% had anemia. N= 12,065 (New onset heart failure) Prevalence- 17% Ezekowitz JA et al, Circulation.2003;107:223–5 AS GO et al, Circulation.2006;113:2713-23

7. Anemia in patients with heart failure Hb = hemoglobin Hct = hematocrit HF = heart failure The prevalence of anemia in heart failure patients is approximately: 30% for Inpatients 20% for Outpatients

8. 4 – 61% (Median 18%) by Tang and Katz from 15 papers. Circulation.2006;113:2454-61

9. The prevalence of anemia and the severity of heart failure Source: STAMINA Registry – 45 General Cardiologist sites, n=673, 12 Academic sites (incl. HF Specialists), n=337 2% 2% 4% 6% 8% 29% 30% 40% 60% 12% 44% 11% 52% 19% 14% 13% 29% 21% 20% 56% 0% 10% 20% 30% 40% 50% 60% 70% I (n=158) II (n=467) III (n=340) IV (n=25) Patients Hb<10g/dL (n=32) Hb<=11g/dL (n=97) Hb <=11.5g/ dL (n=165) Hb<=12.0g/dL (n=244) Hb<=12.5g/dL (n=337) NYHA Class

10. Mechanism of Anemia in HF Concominant CKD (in 40-50% patients)—M.C. Inflammation and Cytokine activation ( TNF-alpha, IL-6 and CRP) Aspirin usage (GI loss) ACE inhibitor and ARBs Decrease Fe absorption (Bowel edema, Inc Hepecidin ) Hemodilution Nutritional

11. Type of Anemia M.C.- Normocytic normochromic Anand et al- Prevalence of Fe deficiency anemia- 5 to 21%# De Silva et al *. 43% pts had low serum iron or ferritin , but only 6% had Microcytic anemia. Nanas JN et al$. Found depleted bone marrow stores in 73% pts despite normal serum iron, ferritin and EPO levels. # Anand IS.JACC.2008;52:501-11 *Am J Cardiol.2006;98:391-8 $ JACC.2006;48:285-9

12. Prognostic significance of anemia in HF Poor prognosis Increase mortality and hospitalisations

13. Study Design N Anemia Risk Assessment Limitations Alexander 1 Retrospective cohort study of a population based HF database 90,316 Anemia was an independent risk factor of 1-year rehospitalization (RR 1.162; 95% CI: 1.134 to 1.191) no confirmation of the HF diagnosis; undercounts of minorities and biased results. Polanczyk 2 Prospective, single center, observational study 205 Anemia was an independent predictor of 3-month rehospitalization (p=0.002) Too small of a population to resolve a small difference in readmission rates; role of confounding variables due to lack of control OPTIME-CHF 3 Retrospective chart review 906 Anemia was an independent predictor of 60-day death or rehospitalization (odds ratio of 0.89 per 1 g/ dL increase in hemoglobin; 95% CI: 0.82 to 0.97) Anemia may have been caused by hemodilution in hospitalized patients Kosiborod 4 Retrospective chart review 2,281 Patients had 2% higher risk of 1-year rehospitalization for every 1% lower hematocrit (95% CI: 1.01 to 1.03; p=0.0002) Lack of data on transfusions or other treatments for anemia; study generalizability to non-study population COPERNICUS 5 Randomized, double blind, placebo controlled trial 2,286 Anemia was an independent risk factor for 1-year morbidity (HF hospitalization) and mortality outcomes - Anemia is associated with increased risk for hospitalization in heart failure patients 1 Alexander M, et al. Am Heart J. 1999;137:919-927 2 Polanczyk CA, et al. J Card Failure. 2001;7:289-298 3 Felker GM, et al. Am J Cardiol . 2003;92:625-628 4 Kosiborod M, et al. Am J Med . 2003;114:112-119 5 Anker SD, et al. J Am Coll Cardiol . 2004;43 ( suppl A): Abstract 842-2

14. Hemoglobin and mortality in heart failure patients

15. Groenveld HF et al*. Anemia and mortality in heart failure patients: a systematic review and metaanalysis . Meta-analysis of 34 studies, Includes 1,53,180patients JACC.2008;52:817-28

16. If Anemia as mediator of HF - T/t is beneficial If Anemia as marker of HF - Benefits limited Should we treat anemia in a patient with heart failure ?

17. What is the rationale for anemia correction? Potential Benefits Improved oxygen delivery Improved exercise tolerance Attenuate adverse remodeling Improved Quality of Life Antiapoptotic ? Decrease in hosp./death? Potential Risks Increased thrombosis Platelet activation Hypertension Endothelial activation Adapted from Felker and O ’ Connor J Am Coll Cardiol . 2004;44:959-966. Potential benefits and risks of treating anemia in HF:

18. Treatment options for anemia in HF Blood transfusion ESPs Iron therapy

19. Blood Transfusion in HF The clinical utility in CV disease is controversial. “Transfusion Threshold” Hematocrit < 30% in CV disease Based on expert opinion May be considered as an acute treatment for severe anemia . Not a strategy for the longterm management in CHF.

20. Saftey concern of ESP in variety of anemic patients. 1. In CKD

21. Pivotal Clinical Trials in CKD with Anemia NHCT(1998): National Hematocrit Cardiac Trial --- N-1200, high hemoglobin was conferred with high death and the trial was thereby prematurely stopped. Canadian Cardiac Trial(2005)--- similar trial with very similar observation. CREATE(2006): Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin beta CHOIR(2006): Correction of Hemoglobin and Outcomes in Renal Insufficiency TREAT(2009): Trial to Reduce Cardiovascular Events with Aranesp Therapy.

22. 2. In Cancer patients (N=1473 pts) Conclusion - DA not associated with significant reduction in transfusions and also patients had shorter survival time.

23. 3. In Ischemic Stroke Ehrenreich H et al*- Recombinant human erythropoietin in patients presenting in 6 hrs of ischemic stroke had higher death rates. *Stroke.2009;40:e647-e56

24. Erythropoietin Stimulating Proteins in HF

25. STAMINA HeFT trial Circulation. 2008;117:526-535

26. STAMINA HeFT trial Largest(319 pts) and longest (53 weeks) completed study of ESP in HF patients. Patients with EF ≤40% , Hb ≥ 9g/dl and ≤ 12.5 g/dl were randomised . Target Hb was 14.0 ± 1.0 g/dl Ghali JK et al.Circulation.2008;117:526-35

27. Conclusion: Darbepoetin alfa not associated with significant clinical benefits. DA was well tolerated and effectively raised Hb . A trend of lower risk of morbidity and mortality observed. 27 weeks 53 weeks Hb rise Exercise duration Hb rise Deaths Darbepoietin group(n = 162) 1.8g/dl +57.3 secs +2.1g/dl 11(7%) Placebo group(n = 157) 0.3g/dl +46.5 secs +0.5g/dl 18 (11%) Circulation. 2008;117:526-535

28. RED-HF trial (Reduction of Events by Darbepoetin Alfa in Heart Failure) March 28, 2013 N Engl J Med 2013;368:1210-19

29. Darbepoetin alfa group (target hemoglobin 13.0 to 14.5 g/dL) N = 1200 Placebo group N = 1200 Study Population Hemoglobin 9 to 12 g/dL LVEF ≤ 35% NYHA Class II to IV Approximately 620 global sites 1:1 randomization Timelines Event driven: ~1150 events Study End September 1 2012 Began enrolling June 2006 Site Evaluation & Selection Follow-up RED-HF trial

30. KCCQ primary analysis: Change from baseline to month 6 KCCQ Symptom Frequency Score Mean Change From Baseline to Month 6 6.20 3.91 2.46 95% CI: (0.90, 4.02) P = 0.011 Change from Baseline in KCCQ Symptom Frequency Score Darbepoetin alfa (n = 925) Placebo (n = 927) Mixed effects model estimating treatment effect adjusted for region, type of device, and baseline KCCQ score; scale scores range from 0 to 100, with higher scores indicating better functioning. KCCQ Overall Summary Score Mean Change From Baseline to Month 6 6.68 4.48 2.20 95% CI: (0.65, 3.75) P = 0.005 Change from Baseline in KCCQ Overall Summary Score Placebo (n = 929) Darbepoetin alfa (n = 928)

31. Primary outcome: All cause death or first hospitalization for worsening heart failure Years of Randomization Prop. of Subject With Event (%) Subjects at risk: 1136 1142 975 956 855 818 712 695 581 591 473 497 385 395 281 290 212 211 161 154 101 92 Stratified Log-rank, p = 0.87 Placebo Darbepoetin alfa 100 80 60 40 20 1 2 3 4 5

32. Selected adverse events of interest n (%) Darbepoetin alfa (N = 1133) Placebo (N = 1140) Risk difference (95% CI) p-value Ischaemic cerebrovascular conditions 51 (4.5) 32 (2.8) 1.7 (0.2, 3.2) 0.031 Embolic and thrombotic events 153 (13.5) 114 (10.0) 3.5 (0.9, 6.1) 0.009 Hypertension 81 (7.1) 69 (6.1) 1.1 (-0.9, 3.1) 0.292 Malignancies 69 (6.1) 68 (6.0) 0.1 (-1.8, 2.1) 0.900 Hypersensitivity reactions 99 (8.7) 96 (8.4) 0.3 (-2.0, 2.6) 0.787 Conclusion : Treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild to moderate anemia. Our findings do not support use of DA in HF.

33. IV Iron Therapy for anemia in HF Table 1 Randomized, controlled studies with intravenous iron in patients with heart failure

34. FAIR-HF trial Anker SD et al. N Engl J Med 2009;361:2436–48

35. FAIR HF Trial Aim To determine whether treatment with IV iron (ferric carboxymaltose ) would improve symptoms in patients who had HF, reduced LV function, and iron deficiency either with or without anemia. Anker SD et al. N Engl J Med 2009;361:2436–48

36. Method Study design: A randomized, double-blind, multicenter study. Study population: N= 459 patients. NYHA class II or III, a LVEF of 40–45% or less, a Hb from 9.5 to 13.5 g/ dL and iron deficiency .. Treatment regimen: 4 ml Ferric carboxymaltose or saline was administered. Weekly injections were continued until Fe was repleted ( usually within 8 weeks) and then at 4 weekly intervals upto 24 weeks. End point: The primary end point was a self-reported Patient Global Assessment (PGA) form and NYHA functional class in the 24th week. Safety end points were serious and non-serious adverse effects, hospitalization and death up to the 26th week of study. The FAIR-HF trial Anker SD et al. N Engl J Med 2009;361:2436–48

37. Result The evaluation of PGA forms showed much or moderate i.e., around 50% improvement in the ferric carboxymaltose group as compared to the 28% in the placebo group. 47% in the ferric carboxymaltose group had NYHA functional class I or II as compared to 30% in the placebo group. Anker SD et al. N Engl J Med 2009;361:2436–48

38. Anker SD et al. N Engl J Med 2009;361:2436–48

39. Anker SD et al. N Engl J Med 2009;361:2436–48

40. Anker SD et al. N Engl J Med 2009;361:2436–48

41. Anker SD et al. N Engl J Med 2009;361:2436–48

42. The administration of ferric carboxymaltose in patients with chronic heart failure and iron deficiency with or without anemia was beneficial. Anker SD et al. N Engl J Med 2009;361:2436–48

43. FAIR HF Trial Conclusion Ferric carboxymaltose for a period of 24 weeks in patients with chronic heart failure and Fe deficiency with or without anemia showed improvement in the symptoms, functional capacity and the QoL . No additional side-effects were observed during this time-span. This treatment was beneficial to both patients with and without anemia. Anker SD et al. N Engl J Med 2009;361:2436–48

44. CONFIRM HF Trial

45. A multi-centre, double-blind, placebo-controlled trial. N= 304 patients with LVEF ≤ 45%, elevated natriuretic peptides, and Fe deficiency ( ferritin <100 ng / mL or 100–300 ng / mL if transferrin saturation ,20%). FCM, n = 152 or placebo (saline, n =152) for 52 weeks given. FCM significantly prolonged 6MWT distance, improvement in NYHA class, PGA, QoL , and Fatigue Score at Week 24 and was sustained to Week 52. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [ P = 0.009]. The number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of adverse events were comparable between both groups.

46. CONFIRM HF Trial Conclusion: Treatment of symptomatic, Fe-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF.

47. RECOMMENDATIONS

48.    Practical Tip: Symptomatic patients with low transferrin and/or ferritin levels should be considered for supplementary iron therapy principally with a goal of improving symptoms Anemia recommendations We suggest that for patients with documented iron deficiency, oral or intravenous iron supplement be initiated to improve functional capacity (Weak Recommendation, Low-Quality Evidence). Values and Preferences: The iron supplement recommendation was derived mostly from the experience of clinicians, small clinical trials, and 2 large randomized controlled trials (RCTs). Recommendation

49. EPO recommendation Values and Preferences: The recommendations against the use of erythropoiesis -stimulating agents (ESAs) were derived from robust data from RCTs. Recommendation We recommend erythropoiesis stimulating agents not be routinely used to treat anemia in HF (Strong Recommendation, High-Quality Evidence).

50. Take Home Message Anemia is a independent predictor of morbidity and mortality of HF. Anemia has emerged as a possible treatment target in HF. ESPs is a major concern for safety in HF patients. ESPs should not be used routinely in HF. For patients with documented Fe deficiency, oral or intravenous iron supplement may be initiated to improve functional capacity. Larger controlled clinical trials are needed for further information and therapy guidelines.