New therapies modifying the renin angiotensin aldosterone system, the natriuretic peptide system and the sympathetic nervous system have led to considerable improvement in heart failure outcomes in recent years. The long term prognosis of heart failure remains poor, however. Anaemia and iron deficiency are two important comorbidities common in patients with heart failure and are associated with worse outcomes. Correcting both should, in theory, improve outcomes. This article discusses the available evidence for this and the recommendations for treatment.

Some 30% of stable heart failure patients and 50% of patients with acute heart failure are anaemic (< 13g/dl men, < 12g/dl women). Iron deficiency can occur in the presence or absence of anaemia and 50% of patients with heart failure with or without anaemia have low levels of available iron. Iron deficiency can be absolute, when total body iron is decreased, or functional, when total body iron is normal or increased but inadequate to meet the needs of the body because of maldistribution.

Iron deficiency is defined as serum ferritin < 100µg/L – absolute iron deficiency – or serum ferritin <100-300µg/L in combination with a TSAT of < 20%, which is considered functional iron deficiency.

Causes of anaemia or iron deficiency in heart failure

In the general elderly population, anaemia is caused by nutritional deficiency of primarily iron, chronic inflammation or unexplained causes. In heart failure, the same may apply in addition to structural kidney problems/dysfunction causing reduced/abnormal erythropoietin production. There is also a suggestion that ACE inhibitors and ARBs may cause a modest reduction in haemoglobin level via renin angiotensin system inhibition. Chronic inflammation in heart failure is related to haemoglobin level, as is malabsorption of iron at gut level. Finally, anaemia may be related to haemodilution due to increased intravascular volumes.

Anaemia/iron deficiency and outcomes

Anaemia and iron deficiency are both independently associated with poor outcomes in heart failure. Anaemia is independently associated with increased mortality and hospitalisations in patients with both HFrEF (reduced ejection fraction) and HFpEF (preserved ejection fraction).¹

In a meta-analysis of 33 studies involving > 150,000 patients with heart failure, anaemia doubled the relative risk of death.² Multiple mechanisms appear to contribute to these poor outcomes including reduced oxygen delivery to tissue, leading to increased myocardial workload and causing left ventricular hypertrophy and remodelling.

In heart failure patients with iron deficiency alone with normal haemoglobin, there is impaired aerobic performance and poor prognosis independent of anaemia and LV ejection fraction. Several studies have shown a significant association with mortality, also independent of anaemia. Iron deficiency is also associated with decreased health-related quality of life, as assessed by the Minnesota Living with Heart Failure Questionnaire.³ These effects are seen in both HFrEF and HFpEF. 

Treatment options

Few options are available to increase haemoglobin or iron stores. Anaemic patients can be transfused;however this provides temporary benefit only and is not without associated transfusion risks. There is a suggestion that RBC transfusion in anaemic patients with heart failure may increase mortality. Routine blood transfusions are therefore not recommended.

Treatment of heart failure-associated anaemia with erythropoiesis-stimulating agents (ESAs) is inconclusive. Studies have failed to show that treating mild to moderate anaemia in HfrEF improved clinical outcomes. There is a suggestion that some ESAs (darbepoetin) may increase thromboembolic events in heart failure patients. Therefore, treatment of mild to moderate anaemia in heart failure patients in the absence of chronic kidney disease in not recommended and the heart failure societies recommend that, in patients with HF and anaemia, ESAs should not be used to improve morbidity and mortality. Investigators have been testing the safety and efficacy of iron replacement in heart failure for more than ten years now.

Oral iron supplementation is considered insufficient in heart failure patients with iron deficiency with or without concomitant anaemia. This is because the response to treatment is frequently suboptimal. Oral iron is not absorbed well, particularly in patients with heart failure because of effects of heart failure on the gastrointestinal tract. Oral iron is also associated with adverse effects, particularly gastrointestinal intolerance and constipation, which limit compliance. The superiority of IV iron over oral iron as a faster and more efficient source of iron replacement has been clearly demonstrated. Compliance issues are also improved as the gastrointestinal side-effects do not occur.

The most common IV iron formulation being used currently is ferric carboxymaltose, or Ferinject. This brings rapid and high-dose replenishment of iron stores after administration of a single dose of IV ferric carboxymaltose equivalent to 500-1000mg of iron.

There are two major clinical trials looking at IV iron replacement in heart failure patients and in both trials IV ferric carboxymaltose was used. Other IV iron preparations available include iron sucrose, iron dextran and iron isomaltose, however outcome studies are limited.

FAIR-HF and CONFIRM-HF

FAIR-HF (Ferinject assessment in patients with iron deficiency and chronic heart failure) is the largest randomsied study of IV iron in heart failure.⁴ Patients had heart failure and iron deficiency, with or without anaemia; 459 patients with heart failure and iron deficiency, with or without anaemia were studied. IV ferric carboxymaltose increased ferritin levels in all patients with an increase in haemoglobin in the anaemia patients.

There was a beneficial effect of IV iron in outcome terms in all patients  whether anaemic or not; however, there were no significant effects on all-cause mortality. Significant improvements were seen in NYHA class and the self-reported patient global assessment tool. IV iron was well tolerated generally and adverse events were similar in treatment and placebo arms.

CONFIRM-HF (a study to compare the use  of ferric carboxymaltose with placebo in patients with chronic heart failure and iron deficiency) was very similar to FAIR-HF except for higher doses of ferric carboxymaltose given for a longer duration.⁵ The primary endpoint was six minute walk distance and this was significantly better in the ferric carboxymaltose group compared with placebo. The benefit was sustained at one year. Secondary endpoints including NYHA class, patient global assessment tool and fatigue score were all improved in the treatment group. Similar to FAIR-HF, there was no mortality benefit from IV iron. CONFIRM-HF did, however, show a reduction in the risk of hospitalisation for worsening heart failure with IV iron treatment.

A meta-analysis of the available studies on IV iron replacement with ferric carboxymaltose has concluded that treatment with IV ferric carboxymaltose is associated with lower rates of recurrent cardiovascular hospitalisations, recurrent heart failure hospitalisations and possibly lower cardiovascular mortality, though this was not demonstrated in the studies described above.⁶

The weight of evidence, in particular from the FAIR-HF and CONFIRM-HF studies, has led the European Society of Cardiology to recommend measuring both ferritin and TSAT (transferrin saturation) in any patient with a diagnosis of heart failure, either HFrEF or HFpEF.⁷  Treatment with IV iron is recommended when ferritin is < 100µg/L, or if ferritin is between 100 and 299µg/L and TSAT < 20%. In patients with heart failure with preserved ejection fraction or HfpEF, the data is less clear. There is some evidence of symptomatic benefit but evidence for hospitalisation with acute heart failure and mortality data are inconclusive. The ongoing FAIR-HFpEF study may help  to clarify this.

IV iron in heart failure patients: practical considerations

In Ireland and elsewhere, IV iron is generally administered in an acute hospital setting, due to limited availability of specialised heart failure services and the requirement for monitoring during the intravenous infusion. Availability of day ward space is important as this is generally the optimal setting for IV administration and monitoring.

IV ferric carboxymaltose is generally given as 500mg as an infusion over 15 minutes. Hypersensitivity or allergy to iron is well known, and common side-effects of administration occur in approximately 10% of patients. These  include headache, dizziness and rash, and are generally self-limiting. Most patients require two doses of IV ferric carboxymaltose separated by at least one week and given the chronic nature of heart failure, repeated infusions over years may be required. This requires specialist nursing input and appropriate administrative support, which is generally available in an acute hospital setting rather than in the community/primary care setting. In a better resourced world however, primary care administration and follow-up of IV iron supplementation in heart failure patients would seem highly appropriate.

Conclusion

Iron deficiency is extremely common in heart failure in Ireland and elsewhere and appears to significantly impact on quality of life. Iron deficiency and anaemia are probably underdiagnosed in clinical practice. While the evidence of benefit of iron supplementation in terms of soft endpoints such as life quality seems clear, benefit to harder endpoints is more opaque, as is benefit in heart failure with preserved ejection fraction. Nevertheless, there appears to be sufficient evidence that IV iron supplementation in a large cohort of Ireland’s heart failure population with iron deficiency with or without anaemia produces significant benefit for patients and needs to be an active and essential part of our management of this growing population. 

References

1. Anaemia and chronic heart failure implications and treatment options J Am Coll Cardiol 2008;52:501-511
2. Anaemia and mortality in heart failure patients a systematic review and meta-analysis. J AM Coll Cardiol 2008;52:818-827
3. http://license.umn.edu/technologies/94019_minnesota-living-with-heart-failure-questionnaire-mlhfq
4. FAIR HF: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361:2436–2448
5. CONFIRM HF: Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36:657–668. doi: 10.1093/eurheartj/ehu385
6. 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; 20:125
7. ESC recommendations on IV Iron. EHJ (2016) 37 (27):2129-2200. https://doi.org/10.1093/eurheartj/ehw128