The aetiology of anaemia in patients with chronic heart failure is multifactorial and therefore difficult to treat. Treatment depends upon the cause and severity of anaemia as determined by investigations.
Chronic heart failure (CHF) and anaemia frequently co-exist.1 One may cause the other, and anaemia in a patient with CHF is associated with more severe symptoms and poorer prognosis.2 3 4 As many as 50% of patients with the heart failure syndrome will have a normal ejection fraction (HeFNEF),5 6 and the prevalence and prognostic significance of anaemia is similar regardless of heart failure phenotype.7 8 9
Treatment depends upon the cause and severity of anaemia as determined by investigation. Blood transfusion is recommended for patients with acute coronary syndrome and haemoglobin levels <80 g/dL to target 80-100 g/dL,10 yet there is no specific guidance for patients with CHF and severe anaemia. For patients in whom an acute or dramatic decrease in haemoglobin concentration is thought to have caused worsening heart failure, a blood transfusion may be indicated, often given with diuretic,11 but such decisions are purely clinical and not supported by evidence.12 13 Infusion of as little as 200ml of blood may lead to pulmonary oedema in patients with CHF and extreme caution is required.14
The bulk of trial data in patients with heart failure has focussed on treatment in patients with iron deficiency and anaemia. Erythropoiesis-stimulating agents (ESAs),15 intravenous (IV) iron,16 or both17 have been studied. Early studies suggested that either strategy may improve functional capacity in patients with CHF and anaemia, and large scale randomised controlled trials (RCT) followed. However, interpretation of the studies is hampered by the failure to specify (and report) investigations for sinister causes of anaemia before enrolling patients into the trials.
Erythropoetin Stimulating Agents
In RED-HF, 2278 patients with anaemia (but no iron deficiency) and left ventricular systolic dysfunction (LVSD) were randomised to receive darbepoetin (an ESA) or placebo. Although darbepoetin caused a rapid and sustained increase in haemoglobin, it had no effect on the primary outcome of all-cause mortality and HF hospitalisation. Any potential benefit may have been offset by a higher rate of thromboembolic events with darbepoetin.18
Although vitamin B12 or folate deficiencies are uncommon in patients with heart failure, treatment of haematinic deficiencies is only sensible.19 Micronutrient supplementation in patients with CHF has been investigated in only a handful of small trials20 21 22 23 with few published results. Multiple “micronutrient” supplementation (including vitamin B12 and folate) may be associated with improved left ventricular function and quality of life, but whether this was due to correction of deficiency in either micronutrient is unknown.20
Three multi-centre RCTs have investigated the effect of IV iron on exercise variables, symptoms and functional capacity in patients with CHF and iron deficiency (ferritin <100ng/mL or ferritin 100-300ng/mL and transferrin saturations <20%): FAIR-HF, CONFIRM-HF and EFFECT-HF.24 25 26
In FAIR-HF, 459 patients with LVSD and iron deficiency, 51% of whom were anaemic (haemoglobin <12.0g/dL), were randomised to either IV iron (given weekly until the patient was no longer deficient – repletion phase; and monthly thereafter – maintenance phase) or a placebo and were followed up for 26 weeks. Patients with chronic inflammatory conditions or significant renal impairment were excluded. IV iron was associated with an improvement in patient-reported symptoms, physician-assessed NYHA class, 6-minute walk test (6MWT) distance and quality of life (QoL) scores.24
In CONFIRM-HF, 304 patients, 20% of whom were anaemic, were randomised in 1:1 ratio to IV iron (in a similar repletion and maintenance dosing schedule) or placebo and were followed up for 1 year. IV iron was associated with a 33m average increase in 6MWT, improved NYHA class, patient-reported symptoms and quality of life scores. All improvements were observed after 24 weeks of treatment and sustained to 1 year.25
In EFFECT-HF, 174 patients with mean haemoglobin of 13.0 g/dL were randomised in 1:1 ratio to IV iron or standard of care. Although investigators reported a small but significant difference in peak exercise oxygen consumption (pVO2) between patients treated with IV iron and placebo (+1.0 ml/kg/min; P=0.02) for all patients (including the last observation carried forward for patients who did not reach 24 weeks follow up), there was no difference in between the groups at 24 weeks.6
IV iron was well tolerated in all three trials: the drop-out rate was low and only a minority of patients (2% in FAIR-HF, 9% in CONFIRM-HF and none reported in EFFECT-HF) in the IV iron reported treatment-related adverse events.24-26
Regular IV iron infusions are expensive and regular attendance at a medical day unit can be logistically challenging for patients and health services alike. By comparison, oral iron is cheap and widely available. In the IRONOUT study, 225 patients with LVSD and iron deficiency were randomised in 1:1 ratio to either iron polysaccharide 150mg BD or placebo for 16 weeks.27
Oral iron had no effect on the primary outcome of change in pVO2 , or other secondary outcomes including natriuretic peptide levels, or QoL measures. The increments in iron indices in the treatment group were very small (+3% and +11 ng/mL for TSAT and ferritin levels respectively). Compared to changes reported with IV iron in the FAIR-HF study (+12% and +260 ng/mL for TSAT and ferritin respectively),24 such small improvements are unlikely to result in clinical benefit. Ultimately, patients in the oral iron group in remained iron deficient (median ferritin 95ng/L) after 16 weeks of treatment suggesting the duration, dose, route of administration, or all three may be insufficient to improve iron stores in patients with CHF.
In FERRIC-HF (an early small study of IV iron vs placebo in patients with LVSD and iron deficiency),16 peak VO2 increased in anaemic patients treated with iron but did not increase in those without anaemia. However, there was no correlation between changes in pVO2 and changes in haemoglobin, suggesting the mechanism of benefit may be independent haemoglobin levels.
The much larger CONFIRM-HF and FAIR-HF studies found no difference in treatment effect between anaemic and non-anaemic patients. It may be that it is treatment of iron deficiency and the consequences for cellular respiration and oxygen transport and storage, rather than anaemia, which is associated with functional benefit in patients with CHF. Indeed, the RED-HF trial found no difference in the rate of improvement in patient-reported symptoms despite an early and sustained correction of anaemia (>13g/dL) in 72% of patients in the ESA arm.
Post-hoc outcome analysis in the CONFIRM-HF trial found a significantly lower rate of death or hospitalisation for heart failure in patients receiving IV iron compared to placebo (hazard ratio = 0.53 (95% confidence interval (CI) = 0.30–0.95); P=0.03).25 Subsequent individual patient meta-analysis of data from 844 patients suggested that IV iron is associated with a reduced risk of the composite endpoint of recurrent hospitalisation with heart failure or all-cause mortality (risk ratio = 0.54 (95% CI = 0.34–0.87); P=0.01) compared to placebo.28
Although the outcome signal from CONFIRM-HF is promising, no published trial of IV iron in patients with CHF has been powered to detect a difference in hard outcomes. This is especially important to bear in mind considering that it is not reported in either FERRIC-HF, FAIR-HF, CONFIRM-HF or EFFECT-HF whether patients with either anaemia or iron deficiency were investigated for malignancy or bleeding lesions before enrolment.
The prevalence of malignancy in patients involved in all of these trials is unknown yet it is possible that, by treating iron deficiency without thorough investigation, the treatment merely disguised the symptoms of underlying cancer and thus delayed diagnosis. Similarly, IV iron supplementation in a patient with iron deficiency due to a non-malignant bleeding lesion in the GI tract treats only the secondary effect and not the root cause of the problem, and thus is unlikely to lead to longer-term benefit.
Large RCTs powered to detect differences in hard outcomes over several years follow up are essential before the use of IV iron can be considered safe practice in patients with CHF. The IRONMAN (NCT02642562), AFFIRM (NCT02937454), FAIR-HF 2 (NCT03036462) and HEART-FID (NCT03037931) trials are all powered for hard outcomes as their primary endpoint and are currently ongoing. Until then, IV iron may be a useful treatment for symptomatic patients with CHF and iron deficiency in whom more sinister pathology has been excluded.
The aetiology of anaemia in patients with CHF is multifactorial and therefore difficult to treat. The possibility of malignancy in a patient with CHF and anaemia and/or iron deficiency must be taken seriously and excluded by thorough investigation before any treatment is started. A large proportion of patients with CHF and anaemia will be iron deficient and data suggests that, in these patients, IV iron may provide symptomatic benefit. By contrast, oral iron is less effective for treating iron deficiency. Likewise, ESAs should not be used routinely for the treatment of anaemia in patients with CHF - although they continue to be used to treat anaemia in chronic kidney disease and the co-diagnosis of heart failure is not a contra-indication.29
However, caution is required when considering IV iron for patients with CHF. In the FAIR-HF study, the proportion of patients in the placebo group who reported any improvement in symptoms (either ‘a little improved’, ‘moderately improved’ or ‘much improved’) was 53% in the placebo arm vs. 74% in the IV iron arm. This was despite significant differences in ferritin (74μg/L vs 312μg/L; P<0.001) and transferrin saturations (19% vs 29%; P<0.001) between the groups: the possibility of a placebo effect cannot be ignored.24
Similarly, the absolute increase in average 6MWT distance for patients in the IV iron arm in CONFIRM-HF was only 18m, but was concurrent with an odds ratio for improvement in NYHA class of ~2.5 after 24 weeks. Such a small change in walking distance is not compatible with the improvement in NYHA class. Inter- and intra-observer NYHA class ascriptions are variable with low validity and reproducibility,30 31 32 and a small increase in 6MWT distance may be due to a learning effect intrinsic to the test rather than benefit conferred by treatment with IV iron.33 The majority of patients in CONFIRM-HF had only mild symptoms (NYHA II) at baseline making it difficult to interpret an improvement in NYHA class in the context of such a small mean increase in 6MWT distance.
IV iron is recommended by the European Society of Cardiology guidelines to alleviate symptoms and improve quality of life for patients with CHF and iron deficiency regardless of the presence of anaemia, with the caveat that there are no robust data on the prognostic effect of IV iron in patients with CHF.34 Until the results of the various mortality outcome studies are available and compiled, the question of what role IV iron has in the management of CHF remains unanswered.
Patients with CHF and anaemia present many diagnostic and management dilemmas –treatment must always be guided by the results of thorough investigation. Heart failure as the cause of anaemia, particularly IDA, must always be a diagnosis of exclusion. While treatments of iron deficiency in patients with CHF may offer symptomatic benefit, the impact on mortality is unknown. Further work is required.
Dr Joseph J Cuthbert, Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Kingston upon Hull
1. O’Meara E, Rouleau JL, White M et al. Heart failure with anemia: novel findings on the roles of renal disease, interleukins, and specific left ventricular remodeling processes. Circ Heart Fail 2014; 7: 773–81
4. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, van Veldhuisen DJ, van der Meer P. Anemia and mortality in heart failure patients a systematic review and meta-analysis. J Am Coll Cardiol 2008; 52(10): 818-27
6. Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Co. Cardiol 2007;50: 768–77
8. Steinberg BA, Zhao X, Heidenreich PA, et al; Get With the Guidelines Scientific Advisory Committee and Investigators. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation 2012; 126(1): 65-75
9. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012; 59(11): 998-1005
12. Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2013; 159(11): 770-779
15. van Veldhuisen DJ, Dickstein K, Cohen-Solal A,et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007;28(18): 2208-16
16 Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008; 51(2):103-12
17 Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol 2001; 37(7): 1775-80
20. Witte KK, Nikitin NP, Parker AC, et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur Heart J 2005;26(21):2238-44.
21. Schoenenberger AW, Schoenenberger-Berzins R, et al. Thiamine supplementation in symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled, cross-over pilot study. Clin Res Cardiol. 2012;101(3):159-64.
22. US National Institutes of Health. ClinicalTrials.gov. Feasibility and Effectiveness of Micronutrients as Palliative Care Therapy in Patients With Congestive Heart failure [Available from: https://clinicaltrials.gov/ct2/show/NCT01474486. Accessed 1/9/2018]
23. US National Institutes of Health. ClinicalTrials.gov. A Trial of Thiamin Supplementation in Patients With Heart Failure [Available from: https://clinicaltrials.gov/ct2/show/NCT00959075. Accessed 1/9/2018]
25. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36(11):657-68.
26. van Veldhuisen DJ, Ponikowski P, van der Meer P, Metra M, Böhm M, Doletsky A, Voors AA, Macdougall IC, Anker SD, Roubert B, Zakin L, Cohen-Solal A; EFFECT-HF Investigators. Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2017;136(15):1374-1383.
27. Lewis GD, Malhotra R, Hernandez A, et al; NHLBI Heart Failure Clinical Research Network. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317(19):1958-1966.
28. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail. 2018;20(1):125-133.
29. Kasiske BL, Wheeler DC. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012. [Available from http://kdigo.org/clinical_practice_guidelines/pdf/KDIGO-Anemia%20GL.pdf . Accessed 25 August 2018]
30. Raphael C, Briscoe C, Davies J, et al. Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart. 2007;93(4):476-82.
31. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation 1981; 64:1227e34.
34. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016; 18(8): 891-975