Iron deficiency – the invisible comorbidity in HF: prioritising QoL as a target for treatment

Br J Cardiol 2021;28(suppl 1):S15–S18doi:10.5837/bjc.2021.s04 Leave a comment
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This supplement was fully funded by an unrestricted grant from Vifor Pharma UK Limited. The content of the articles was independently developed by the authors and according to a brief agreed between Vifor Pharma UK and the BJC. Vifor Pharma reviewed the final version of each article for Code Compliance only. Prescribing information for Ferinject ▼ (ferric carboxymaltose) can be found here.

Job code: UK-FCM-2100010
Date of preparation: January 2021

This article explores the benefits of routine screening and treatment of iron deficiency in patients with heart failure, taking into account patient-centered outcome goals.

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Introduction

Despite significant advances in treatment, many patients with heart failure (HF) have poor outcomes, with one- and five-year mortality worse than most cancers.1 In view of this, improving quality of life (QoL) for patients with HF is considered a key target for treatment.2-4

Among patients with HF, iron deficiency (ID) is prevalent and affects up to 50% of patients.5 Like HF, ID is not only associated with increased morbidity and mortality, but it is also associated with reduced QoL.6,7 As the predominant symptoms of ID (fatigue, breathlessness and lethargy) particularly with anaemia, are often indistinguishable from those of HF, this treatable comorbidity needs to be identified and corrected promptly where present.

Quality of life matters to patients

Priorities for care, although commonly overlapping, often differ between patients and clinicians. Age, severity of symptoms, sociodemographic factors, perceived control, and QoL experienced may all impact on patient-selected healthcare priorities.8 When questioned about the most important treatment goal, many patients choose longevity, others indicate a preference to prioritise improved QoL, either alongside or ahead of increased longevity. Importantly, one of the unintended consequences of prolonging longevity is increased symptom burden, which may in turn lead to reduced QoL (figure 1a).9-12

Iron supplement - Figure 1a. A poll of over 500 patients surveyed by the Pumping Marvellous Foundation reported that the majority of patients prioritise quality of life over how long they live
Figure 1a. A poll of over 500 patients surveyed by the Pumping Marvellous Foundation reported that the majority of patients prioritise quality of life over how long they live

Clinicians, specialist nurses and the wider HF multi-disciplinary team may have additional priorities for care, but frequently, improving QoL is a key target for treatment (figure 1b). It is recognised that poor QoL is associated with high hospitalisation and mortality rates.13 Moreover, improving heath-related QoL (HRQoL) for patients with chronic long-term conditions like HF has been identified as a key priority by NHS England.14 However, a key problem is that clinical practice is often steered by clinical guidelines, and, currently, routine assessment of HRQoL is not advocated within the 2018 National Institute for Health and Care Excellence (NICE) chronic HF guidance.3 Therefore, although reduced QoL is an independent predictor of increased hospitalisation and mortality, and improving QoL is established as an important target for treatment in HF, it is seldom assessed objectively in clinical practice.15,16 Furthermore, there is no clear consensus on the best instrument to use when measuring HRQoL.

Iron supplement - Figure 1b. A pie chart showing responses from the audience at the British Society for Heart Failure Annual Conference 2018 (predominantly HF clinicians, specialist nurses and trainees), to the question “What do you want to achieve in your heart failure patients?”
Figure 1b. A pie chart showing responses from the audience at the British Society for Heart Failure Annual Conference 2018 (predominantly HF clinicians, specialist nurses and trainees), to the question “What do you want to achieve in your heart failure patients?”

Indicators of HF status assessed at clinical review – should we be measuring QoL?

Table 1. Do we really need to assess QoL in HF? Isn’t it related to NYHA functional class?

  • Although NYHA functional class has been shown to correlate with HRQoL, the two are not interchangeable and previous studies have highlighted the drawback to using NYHA class as a surrogate for HRQoL at an individual patient level
  • Good functional status is not a guarantee of good HRQoL at an individual patient level
Key: HRQoL = health-related quality of life; NYHA = New York Heart Association

When reviewing HF patients and monitoring the effects of therapies, there is a tendency for clinicians to place increased importance on assessing echocardiographic and biomarker responses to treatment, which are predominantly markers of prognosis. While New York Heart Association (NYHA) functional status is routinely evaluated at clinical review, formal assessment of HRQoL in HF patients is not commonplace, and the use of patient-assessed QoL questionnaires remains, for the most part, limited to clinical trials (table 1).16 Serial assessment of QoL is even less common and seldom performed in clinical practice.

Much of the data around the benefits of IV iron in HF are heavily weighted in favour of improved patient-reported outcomes measures and HRQoL.17-19 In failing to assess QoL in clinical practice we are perhaps inadvertently failing to acknowledge the impact of illness on the patient and identify potential therapeutic targets.20 Moreover, if we consider that for many patients, HF is an incurable condition with poor prognostic outlook, then, in many cases, improving QoL should be prioritised over the pursuit of improvements in left ventricular ejection fraction (EF) and longevity, especially if increased longevity is associated with poor QoL. Whereas, in patients with a favourable prognosis, failure to diagnose ID can impact on general well-being and the ability to undertake physical activity. More recently, ID has been identified as a predictor of non-response to cardiac resynchronisation therapy.21

Scientific basis and rationale for treating ID in HF

Several studies have explored the benefits of correcting ID in a HF population. To date, investigation of the benefits of treating ID in HF has focused on both improvements in circulating biomarkers, e.g. iron levels, haemoglobin, C-reactice protein (CRP) and brain natriuretic peptide (BNP) levels, as well as indicators of functional capacity, e.g. NYHA class and six-minute walk distance (6MWT), and, finally, QoL as assessed by standardised questionnaires (figure 2).17-19,22

Iron supplement - Figure 2. How to assess health-related quality of life (HRQoL) in patients with heart failure (HF). This figure summarises the advantages and disadvantages of commonly used questionnaires used to assess HRQoL in HF patients
Figure 2. How to assess health-related quality of life (HRQoL) in patients with heart failure (HF). This figure summarises the advantages and disadvantages of commonly used questionnaires used to assess HRQoL in HF patients

Previous studies in patients with reduced EF have used a combination of patient global assessment (PGA) tools and QoL questionnaires to assess the impact of ID and its treatment on patient-reported outcomes. As well as reporting improvements in functional class, the FAIR-HF study was the first study reporting that HF patients receiving IV iron were significantly more likely to report feeling much or moderately improved compared with those receiving placebo, as evaluated by PGA.17 The dosing of ferric carboxymaltose in FAIR-HF was still based on the Ganzoni formula and is not consistent with the current Summary of Product Characteristics.23 In the CONFIRM-HF trial, at just 12 weeks from randomisation, the treatment cohort had a significantly better self-reported PGA scores (p=0.03), whereas superior NYHA class scores became statistically significant in the treatment cohort at 24 weeks from randomisation (p=0.004). Similarly, in the same trial, treatment with ferric carboxymaltose (FCM) also significantly prolonged 6MWT distance at week 24 (difference FCM vs. placebo: 33 ± 11, p=0.002).18 In addition, the CONFIRM-HF study demonstrated reduced risk of HF hospitalisation (as a secondary trial end point), when HF patients with ID were treated with IV iron.18

However, mortality and cardiovascular hospitalisation have long since been considered the gold standard of clinical end points for cardiologists, with QoL often considered an end point of secondary importance. The fact that previous trials of iron have not been designed  to examine ‘hard’ end points has so far had the unintended consequence of diminishing the importance of correcting ID in HF, perhaps to the detriment of the patient who may benefit from treatments that improve QoL. Especially since, from a patient perspective, improvement of symptoms and QoL may be equally or even more important as an end point.25 Previous studies of ID in HF have also included symptomatic patients with lesser degrees of left ventricular systolic dysfunction (EF up to 45%) and, thereby, generated QoL data supporting extending ID correction to a group in whom there is a paucity of data to support traditional disease-modifying therapies. In view of these considerations, various international and national guidelines have incorporated management of ID as standard practice in HF patients.2,26,27 For example, European Society of Cardiology (ESC) guidelines advocate that HF patients should be screened for ID at initial evaluation and treatment be considered in symptomatic patients with HF with reduced ejection fraction (HFrEF) in order to alleviate symptoms, and improve  exercise capacity and patient QoL.2

Case study

A 67-year-old man with severe left ventricular systolic dysfunction (dilated cardiomyopathy) on guideline-directed medical therapy reported NYHA functional class III symptoms when reviewed in clinic in November 2017. He reported lethargy and tired easily when walking the dog, which he found upsetting and frustrating.

Relevant past medical history included a primary prevention implantable cardioverter defibrillator (ICD) and hypertension. His electrocardiogram (ECG) demonstrated sinus rhythm with a QRS duration of 116 ms.

Table 2. Case study: blood results, including iron studies, performed before and after treatment with intravenous iron

November 2017 Administered IV iron May 2018
Haemoglobin, g/L 147 149
Ferritin, ng/ml 68 314
TS, % 21 23
NT-proBNP, pg/ml 1,107 1,076
Key: IV = intravenous; NT-proBNP = N-terminal pro-brain naturietic peptide; TS = transferrin saturation

Physical examination identified the patient to be euvolaemic, with a heart rate of 66 beats per minute and blood pressure of 125/85 mmHg. The option to screen for ID was discussed with the patient. After identifying an iron-deficient picture, the patient was listed for IV iron on the day-case unit (table 2).

In May 2018 the patient was once again seen in the HF clinic. He reported more energy compared with previous and was less fatigued since the IV iron treatment. He was able to walk the dog around the park, albeit at a slow pace. Repeat bloods identified improved iron levels. This case exemplifies a small objective impact gained by simple ID treatment but one with significant downstream impact on QoL, allowing the patient to once again enjoy an activity that gives him great pleasure and arguably aids his chronic illness coping strategy.

Patient perspective: quality of life matters to me

ID has the ability to go entirely unnoticed and has been described as the invisible comorbidity in patients with HF.28 Renal profile is routinely monitored in patients with HF, in part due to the concomitant prescription of potentially nephrotoxic agents, and more frequently, the very common coexistence of renal impairment alongside HF. However, despite the knowledge that ID is prevalent in HF patients, it often goes undetected and untreated until such time that they develop the more extreme phenotype of anaemia. There is scope for ID indices to be bundled within the regular blood tests that are undertaken in patients with HF, both in an acute setting and primary care setting, to avoid missed opportunities for diagnosis and treatment.

People want to live better with HF. Irrespective of their clinical status, individuals want support in reducing the impact of the often-debilitating symptoms on everyday life. Even in relatively stable patients we should be aiming to maximise QoL and consider its inclusion as a metric when assessing the impact of HF on the individual.

Due to the reduced life-expectancy associated with HF, many patients who are currently experiencing reduced QoL on account of symptomatic status, functional capacity or fatigue, will not live long enough to benefit from future NICE endorsement of IV iron in HF. However, the absence of NICE recommendations on screening and treating ID in HF does not mean that there is absence of benefit. On the contrary, international guidelines acknowledge and endorse correction of ID in patients with HFrEF and this is supported by clinical trial data.

Conclusion

ID can either masquerade as or amplify HF symptoms, and this has a direct effect on QoL for patients. From suboptimal cardiac resynchronisation therapy (CRT) response to worsening symptoms and QoL, the impact of ID in HF is far-reaching.

On the other hand, testing for ID is inexpensive and treatment with IV iron is proven to improve several QoL indicators for patients with HF. In view of this, can we afford not to test and treat ID routinely in HF?

Key messages

  • Iron deficiency (ID) is a common cause of morbidity and reduced quality of life (QoL) in patients with heart failure (HF)
  • Screening for ID is inexpensive and easily performed
  • Assessment of health-related QoL is key to developing a patient-centric model of care, and assumptions that QoL is less important to clinicians are ill-founded

Conflicts of interest

FZA has received consultancy and educational grants from Pharmacosmos and Vifor. NHE has received education grants and honoraria from Vifor. CC has received consultancy fees and educational grants from Vifor. FZA and CC are investigators/subinvestigators for the Ironman study. The sponsor/funder and industry did not have any role in manuscript content.

Funding

None.

Jacquelyn Hooper
Specialist Trainee in Cardiology

Colin Cunnington
Consultant Cardiologist

Fozia Zahir Ahmed
Consultant Cardiologist
(fozia.ahmed@mft.nhs.uk)

Manchester Heart Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Oxford Road, Manchester, M13 9PL

Nick Hartshorne-Evans
CEO

Pumping Marvellous Foundation, Suite 111, Business First, Millenium City Park, Millenium City Road, Preston, PR2 5BL

Articles in this supplement

Prevalence, causes, diagnosis and guidelines for treatment

United Kingdom treatment of iron deficiency in heart failure: are we missing opportunities?

Intravenous iron therapies and their differences

Conclusions

References

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