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Iron deficiency in heart failure: from evidence to practice

Mahendra Patel
27 May, 2014  
A Vifor Pharma-sponsored Satellite Symposium at the 2013 ESC Congress emphasised the burden of iron deficiency in patients diagnosed with chronic heart failure and the value of different treatment options
 
Mahendra Patel PhD FRPharmS 
FHEA Fellow of NICE
Senior Lecturer in Pharmacy Practice,
University of Huddersfield, UK;
Honorary Senior Lecturer,
Medical School, University of Sheffield, UK;
Adjunct Professor of Pharmacy,
Wilkes University,
Pennsylvania, USA 
 
Dr Dirk van Veldhuisen (Groningen, The Netherlands) opened the Symposium, defining the learning objectives:
To raise awareness of the impact of iron deficiency (ID) on chronic heart failure (CHF) patients’ outcomes, physical performance and quality of life (QoL) and the benefits of treatment with intravenous (IV) iron
  • Review recent European Society of Cardiology (ESC) Guidelines HF 2012 in the context of diagnosing and treating patients for ID in HF patients
  • Review available tests and thresholds for ID in HF
  • Discuss practical aspects of therapy.
HF is recognised internationally as a deadly disease with poor prognosis, despite advances in both pharmacotherapy and non-pharmacotherapy. It has a five-year survival rate of <50% irrespective of ejection fractions, and the impact HF has on a patient’s daily life is certainly of great concern. HF is commonly associated with worsening symptoms, decreased QoL,(1) impaired exercise capacity,(2) greater risk of hospitalisation and reduced survival. Patients with more severe symptoms are even willing to trade their length of life for a better QoL, as rated according to the “time to tread of” test which directly assesses the amount of time in perfect health that a patient perceives as equivalent to an amount of time in their current state of health.(3,4) Furthermore, HF represents still a considerable burden for the health care system.
 
ID is regarded as the main cause of anaemia and is found to be present in almost 50% of the total CHF patient population regardless of their anaemic status. It is noteworthy that up to 45% of the non-anaemic CHF patients have ID and over 60% of the anaemic are as well iron deficient.(5) 
 
Iron link and heart failure
Dr Piotr Ponikowski (Wroclaw, Poland) reiterated that patients with HF are often susceptible to ID as a result of depletion of iron stores (absolute ID), or more frequently by the impaired metabolism of iron caused by the inflammatory process characterising CHF (functional ID).(6) In HF, the activation of pro-inflammatory cytokines block intestinal absorption of iron and divert iron from the general circulation into the reticulo-endothelial system, causing reticulo-endothelial block. Hepcidin, which is produced in the liver in response to pro-inflammatory cytokines, is thought to be an important regulator in iron homeostasis, where elevation of protein serves to suppress iron absorption and utilisation. Decreased intestinal iron absorption (and hence the importance of IV iron therapy), together with its accumulation within the reticulo-endothelial stores, reduces iron availability to its target tissues and organs.
 
Iron plays a central role in the uptake, transport, storage and metabolism of oxygen, erythropoiesis, and cellular immune response. Therefore, the regulation of systemic iron balance, which is determined by the combination of dietary iron absorption, utilisation and excretion, is essential to maintain those fundamental cellular functions, in particular for cells that are characterised by high energy demand, such as skeletal and cardiac myocytes.
 
Clinical evidence show that iron deficiency is associated to reduced functional capacity,(2) decreased quality of life(1) and poor health outcomes(5) in CHF patients, independently of anaemia. Studies on an animal model confirm that iron plays an important role in maintaining functional capacity irrespectively of haemoglobin level.(7) 
 
Guidelines
Previous ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic HF (ESC Guidelines HF) failed to recognise the importance of ID in HF other than as a cause of anaemia; furthermore, neither had correcting anaemia as routine therapy in the treatment of HF ever been established. However, it was not until the ESC HF Guidelines 2012(8) that ID as a co-morbidity of HF in its own right, rather than only as a cause of anaemia, was clearly highlighted, and detection of ID recommended. These guidelines, not surprisingly therefore, emphasise the importance of identifying and managing ID in HF patients as a significant and independent predictor of morbidity in HF patients and not anaemia, in terms of reduced exercise capacity, reduced QoL and poor outcome.
 
Current parameters for the measurement and diagnosis of ID include possible direct assessment of iron in bone marrow biopsies. However, due to its invasiveness, this method would not be ethically feasible in clinical practice. Therefore the use of a biomarker, such as ferritin, which characterises impaired iron storage in the body and correlates well with body iron stores in healthy individuals, is more useful. However, it does several have limitations, for example, it is an acute phase reactant, therefore high levels of ferritin could be due to concomitant inflammatory conditions. Other biomarkers include those for iron being utilised in the body on a daily basis, and the most common of these is transferrin saturation (TSAT), measuring the amount of iron available for erythropoiesis.
 
It is advantageous in that absence, or near absence, of sustainable iron in bone marrow correlates with TSAT <20%, although it does not account for diurnal variations. It is common that the two parameters are often combined for greater reliability, in which case the serum ferritin levels would be <100µg/l or between 100 and 299µg/l when TSAT is <20% to confirm diagnosis of ID in HF.
 
In the future, however, the traditional measures for ID assessment might soon be superseded by soluble transferrin receptor (STfR), for which early evidence suggests greater usefulness.
 
Treatment options
Considering the different treatment options available for ID and anaemia in HF, blood transfusion may appear an obvious choice; however, owing to the increased risk of mortality and longer duration of hospital stay associated with it, this would be a rare choice and used only for a subgroup of patients.
 
In the Phase III RED-HF trial,(9) treatment with a erythropoietin stimulating agent (ESA), darbepoetin-a  failed in demonstrating reduced mortality or improving QoL in anaemic CHF patients. Instead, the study showed a significant increase of thromboembolic and ischaemic events associated to ESA treatment. Moreover, ID was defined with TSAT <15%, whereas ferritin was not taken in consideration and only about 4% of the patients included were treated with IV iron when ID was identified. Therefore, there was a subpopulation of patients included in RED-HF with underlying not treated iron deficiency, which might be one of the causes of the treatment failure with ESA. These findings do not support the use of ESA in these patients.
 
In terms of oral iron treatment, to date, there is no evidence of any clinical benefits. ID correction in HF patients could take several months due to limited absorption to potentially show any improvement in health outcomes, and this would always be countered by the poor compliance rates often resulting from adverse and unpleasant side effects, for example, gastrointestinal problems, bad taste, pill burden and poor adherence due to lifestyle.
 
The ESC HF Guidelines 2012, on the back of a wave of evidence regarding the clinical benefits of using IV iron therapy in HF patients, was supported by findings from the FAIR-HF study.(10) The study aimed to evaluate the use of IV iron therapy (ferric carboxymaltose) in 459 iron-deficient patients with CHF in the presence or absence of anaemia. Compared with placebo, IV iron therapy showed significant improvements in symptoms, physical performance and QoL starting from four weeks post-randomisation, and it was maintained for the whole study period, 24 weeks (p<0.001 in all cases). The benefits have been seen in all pre-specified sub-groups and interestingly independent of haemoglobin level, anaemic and non-anaemic patients showed the same significant improvement compared with placebo. The median dose for the correction as well as for the maintenance phase was, in both periods, 1000mg iron as ferric carboxymaltose. The drug was well tolerated and showed a good safety profile. 
 
The inclusion of ferric carboxymaltose as a treatment option within the ESC Guidelines HF 2012 for the diagnosis and therapy of HF is quite clearly a significant development towards ensuring optimum management of ID in HF. As a consequence, the assessment and monitoring of iron status has now been recommended for the first time as a standard haematological test in patients with suspected HF. 
 
New therapeutic targets
The ESC Guidelines HF 2012 now indicate the measurement of iron parameters as standard, with the inclusion of ferritin and TSAT as part of the haematological tests for the diagnosis in ambulatory patients suspected of having HF. From a diagnostic perspective, ID is commonly deemed to be present when serum ferritin levels are found to be below 100µg/l or if serum ferritin levels are between 100 and 299µg/l when TSAT is <20%. It can therefore easily be detected by measuring ferritin and TSAT “and its recommended 1C”. In addition, the Guidelines further state that treatment with ferric carboxymaltose may be considered to improve symptoms, exercise capacity and QoL. Prof Dr Stefan Anker (Berlin, Germany) highlighted that this represents a novel diagnostic and therapeutic target in the management of ID as comorbidity in HF patients irrespective of anaemia. Correcting ID should be carried out as soon, and as safely, as possible in view of the evidence in supporting improved health outcomes and better QoL.
 
In view of ID being recognised as a new therapeutic target in HF and the benefits of IV iron therapy, major studies (EFFECT-HF, CONFIRM-HF)(11,12) currently underway to confirm and properly elucidate the efficacy and safety profile of available iron therapies and, in particular, ferric carboxymaltose in HF patients with ID. These studies will build upon the follow-up period and capture greater data on safety along with the evaluation of higher, single doses of up to 1000mg and different primary endpoints such as peak VO2 and six-minute walk test.
 
Conclusions
Dr John McMurray (Glasgow, UK) led the final panel discussion. The symposium provided a very valuable insight into the need for identifying and managing ID in patients with HF.
ID is the main cause of anaemia and it is observed in about 50% of HF patients. ID, but not anaemia, is associated with:
  • Reduced exercise capacity 
  • Reduced QoL
  • Poor outcomes.
Treatment with ferric carboxymaltose improved symptoms, exercise capacity and QoL in CHF with ID patients independently of anaemia (FAIR-HF). 
The ESC Guidelines 2012 (based on FAIR-HF) recommend measurement of iron parameters as standard for the diagnosis in ambulatory patients suspected of having HF.
 
Key messages
  • ID is the main cause of anaemia and it is observed in almost 50% of HF patients. 
  • ID, but not anaemia, is associated with:

–  Reduced exercise capacity

–  Reduced QoL

–  Poor outcomes

  • Treatment with ferric carboxymaltose in iron deficient CHF patients independently of anaemia (FAIR-HF) improves:

–  Symptoms

–  Exercise capacity

–  QoL

  • ESC Guidelines HF 2012 (based on FAIR-HF):

–   ID can easily be detected by measuring ferritin and TSAT ‘and its recommended 1C.’ 

 
Webcast
The entire Vifor Pharma-sponsored Satellite Symposium has been filmed and can be accessed as a webcast on the ESC 365 website (please follow http://congress365.escardio.org and enter ‘Vifor’ in the search function). 
 
References
  1. Comin-Colet J et al. Iron deficiency is a key determinant of health-related quality of life in patients with chronic heart failure regardless of anaemia status. Eur J Heart Fail 2013;15(10):1164–72.
  2. Jankowski EA et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail 2011;17:899–906.
  3. Lewis EF et al. Preferences for quality of life or survival expressed by patients with heart failure. J Heart Lung Transplant 2001;20(9):1016–24.
  4. Kraai IH et al. Preferences of heart failure patients in daily clinical practice: quality of life or longevity?
  5. Klip IT et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165(4):57–82.
  6. Jankowska EA et al. Iron status in patients with chronic heart failure. Eur Heart J 2013;34(11):827–34.
  7. Willis WT et al. Iron deficiency: improved exercise performance within 15 hours of iron treatment in rats. J Nutr 1990;120(8):909–16.
  8. McMurray J et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787–847.
  9. Swedberg K et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med 2013;368:1210–19.
  10. Anker SD et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.
  11. http://clinicaltrials.gov/show/NCT01394562.
  12. http://clinicaltrials.gov/show/NCT01453608.