Heart failure module 6: commonly encountered complications in HF

Released 24 May 2024     Expires: 24 May 2026      Programme:

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Table 1. Common electrolyte abnormalities in HF and their prevalence

Electrolyte abnormality Prevalence N
<135 mmol/L
Acute HF: 19.5%10
Chronic HF: 8.2%8
<3.5 mmol/L
Acute HF: 4.9%4
Chronic HF: 1.7%5
>5.5 mmol/L
Acute HF: 4.4%4
Chronic HF: 2.6%4
<96 mmol/L
Acute HF: 13%6
Chronic HF: 13%7
Key: HF = heart failure

As well as dealing with disease-modifying therapies, heart failure (HF) specialists also manage the complications of HF. This module will familiarise the reader with the clinical significance and treatment of the more commonly encountered problems: electrolyte disturbances, anaemia and iron deficiency and renal dysfunction.

Electrolyte abnormalities in patients with HF

Electrolyte disturbances are a common complication of HF, which affect treatment decisions and outcomes (table 1).1–7 Hyponatraemia, both hypo- and hyperkalaemia, and more recently, hypochloraemia, are the best-defined electrolyte abnormalities. However, abnormalities in calcium, phosphate, bicarbonate and magnesium may also be common in patients with HF,8 and can be life-threatening if severe, requiring urgent treatment.9


Hyponatraemia is the most common electrolyte abnormality seen in patients hospitalised with HF.

Hyponatraemia is strongly associated with an adverse outcome in acute and chronic HF and is a marker of severe HF that might prompt consideration for transplant.10 It arises through two mechanisms: dilution and/or depletion.11

Heart failure module 6 - Figure 1. Mechanisms for developing hyponatraemia in heart failure
Figure 1. Mechanisms for developing hyponatraemia in heart failure

Key: ADH = antidiuretic hormone; eGFR = estimated glomerular filtration rate
  • Dilution12
  • Decreased blood pressure due to HF stimulates baroreceptors in the atria, aorta and peripheral arteries leading to an increase in the activity of the renin-angiotensin-aldosterone and sympathetic nervous systems.

    It also causes increased secretion of anti-diuretic hormone (ADH; also known as arginine vasopressin). ADH is normally secreted in response to increasing plasma osmolality, and so in patients with HF, there must be a non-osmolar stimulus to its release.12 The net result is water retention in excess of sodium retention (figure 1).13

    Additionally, reduced renal blood flow reduces glomerular filtration rate, thus limiting the rate at which the kidneys can excrete free water.14 Increased water retention leads to dilution of the blood and a fall in sodium concentration, even though the body has an absolute excess of sodium.

  • Depletion
  • The first-line treatment of venous congestion in HF is loop diuretics which act by inhibition of the sodium-potassium-chloride (Na2+-K+-2Cl) symporter in the ascending limb of the loop of Henlé. The resulting increase in urine sodium, potassium and chloride causes increased free water excretion alongside electrolyte loss.15

    However, in the context of low renal perfusion, the ability of the kidneys to produce dilute urine is reduced; under such circumstances, loop diuretics cause urinary electrolyte loss without significant free water excretion.16

    Approximately 90% of patients admitted with acute HF are treated with loop diuretics and a similar proportion remains on them one year from discharge.17

Treatment of hyponatraemia

Hyponatraemia is strongly associated with greater mortality in patients with acute or chronic HF.18,19 A patient whose hyponatraemia recovers to normal during an admission for HF has a better outcome than patients with persistent hyponatraemia at discharge.20 However, it is unknown whether treatments which specifically aid to correct low sodium concentrations improve outcomes. Possible treatments include salt restriction, salt supplementation and ADH (arginine vasopressin) receptor antagonists.

  • Salt restriction or salt supplementation?
  • Treatment of hyponatraemia in HF remains a controversial subject: in practice, many patients admitted with HF are placed on a fluid restriction in the hope that limiting oral free water intake, in conjunction with loop diuretics, will treat haemodilution. However, evidence to support this is scant and current guidelines recommend fluid restriction to 1.5–2.0 L/day for the treatment of congestion rather than hyponatraemia – again, in the absence of any supporting evidence that this is the correct approach.21 Similarly, sodium restriction is often used, but without supporting evidence. A low-salt diet is unpalatable, and just induces thirst rather than normalising sodium.22

    There is some evidence that high-sodium diets23 or sodium supplementation24,25 is the correct approach. Compared to high-dose intravenous (IV) loop diuretic alone, IV hypertonic saline in conjunction with a diuretic in patients admitted with HF and severe fluid retention may:

    • improve diuresis (measured by reduction in body weight)24
    • increase serum sodium24
    • cause a greater reduction in natriuretic peptide (NP)25
    • reduce length of hospital stay25
    • reduce readmission rate.25

    The dose of diuretic used in these studies was far higher than recommended in guidelines (500–1,000 mg twice daily) and it is possible that the ‘beneficial’ effect of hypertonic saline is merely protective against such high doses of loop diuretics. However, one small study (n=44; New York Heart Association [NYHA] class III–IV; median left ventricular ejection fraction [LVEF], 32%) found greater diuresis (measured by urine volume) and fall in NPs with 40 mg of furosemide in 500 ml of 1.7% saline infused over 24 hours compared to the same dose of diuretic infused over the same time period in 5% glucose.26 More work, as ever, is required.

  • ADH receptor antagonists
  • ADH receptor antagonists can treat hyponatraemia in patients with syndrome of inappropriate secretion of ADH (SIADH). Early trials of ADH receptor antagonists, when added to standard diuretic treatment in patients with HF, showed reductions in patient symptoms and signs of congestion,27 while also increasing serum sodium concentrations more effectively than fluid restriction alone.28 There have been three multi-centre RCTs of ADH receptor antagonists in patients admitted with HF: EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan),27,29 TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure),30 and SECRET of CHF (Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure).31

    The EVEREST trial investigators enrolled 4,133 patients admitted with HF (average age, 66 years; average LVEF, 27.5%).29 Patients were randomised to either tolvaptan 30 mg per day or placebo. The co-primary end points were all-cause mortality and cardiovascular (CV) mortality or HF hospitalisation.29 Treatment with tolvaptan conferred no survival benefit, despite increasing serum sodium among those who were hyponatraemic.29

    Subsequent post-hoc analysis amongst patients with hyponatraemia (<135 mmol/L; n=475) found that treatment with tolvaptan was associated with greater weight loss and dyspnoea relief compared to placebo and, amongst patients with severe hyponatraemia (<130 mmol/L; n=92), treatment with tolvaptan was associated with reduction in CV death or hospitalisation (hazard ratio [HR] 0.60; 95% confidence interval [CI], 0.37–0.98; p=0.04).32

    The TACTICS-HF trial investigators enrolled 257 patients admitted with HF (average age, 65 years; average LVEF, 33%; average N-terminal of the prohormone of B-type NP [NT-proBNP], 10,246 ng/L; all of whom had serum sodium ≤140 mmol/L at randomisation).30 Patients were randomised to either tolvaptan 30 mg per day or matching placebo alongside fixed-dose IV furosemide.30 The primary end point was a ‘moderate’ improvement in patient-reported breathlessness at eight and 24 hours after starting treatment. Secondary end points included weight and fluid loss at 48 and 72 hours. Treatment with tolvaptan had no impact on the primary end point compared to placebo but was associated with greater weight and fluid loss in the first 48 hours – although there was no significant difference between the two groups after 72 hours.30

    The very similar SECRET of CHF trial enrolled 250 patients admitted with HF (average age, 70 years; average LVEF, 35%; median B-type NP [BNP], 577 ng/L in the treatment arm) who either had renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2), hyponatraemia (≤134 mmol/L) or diuretic resistance.31 Patients were randomised to either tolvaptan 30 mg per day or matching placebo. The primary end point was an improvement in patient-assessed breathlessness after 24 hours of treatment with weight and net fluid loss amongst the pre-specified secondary end points.31 Again, treatment with tolvaptan had no effect on symptoms, but was associated with greater weight loss compared to treatment with furosemide alone.31 In a pre-specified sub-group analysis amongst patients with hyponatraemia, similar effects were observed, regardless of the presence of hyponatraemia.32

    Table 2. Diuretic effects of tolvaptan in addition to intravenous furosemide in the EVEREST, TACTICS-HF and SECRET of CHF trials

    Trial N Mean daily furosemide dose Daily tolvaptan dose Diuretic effect
    EVEREST29,32 4,133 235 mg 30 mg Change in body weight from baseline
    Day 1
    Tolvaptan −1.76 kg
    Placebo −0.97 kg
    TACTICS-HF30 257 71 mg 30 mg Change in body weight from baseline
    After day 1
    Tolvaptan −2.0 kg
    Placebo −0.5 kg
    After day 2
    Tolvaptan −2.8 kg
    Placebo −1.6 kg
    After day 3
    Tolvaptan −3.7 kg
    Placebo −2.5 kg
    Net fluid loss
    On day 1
    Tolvaptan −2182 ml
    Placebo −1541 ml
    On day 2
    Tolvaptan −1948 ml
    Placebo −1419 ml
    On day 3
    Tolvaptan −1757 ml
    Placebo −1401 ml
    SECRET of CHF31 250 160 mg 30 mg Change in body weight from baseline
    After day 1
    Tolvaptan −2.4 kg
    Placebo −0.9 kg
    After day 2
    Tolvaptan −3.1 kg
    Placebo −1.9 kg
    After day 3
    Tolvaptan −3.6 kg
    Placebo −2.4 kg
    Key: EVEREST = Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan; SECRET of CHF = Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure; TACTICS = Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure Study

    Taken together, the data suggest that vasopressin antagonists may be useful adjuncts to loop diuretics to stimulate a diuresis in cases of diuretic resistance, regardless of serum sodium. At present, they are only ‘suggested’ for the treatment of resistant hyponatraemia in the context of congestion.21


Box 1. Electrocardiogram changes associated with hypokalaemia

U waves
T-wave flattening
ST-segment changes
Ventricular tachycardia
Pulseless electrical activity or asystole

Hypokalaemia in patients with HF is most often a consequence of diuretic therapy.33 Hypokalaemia prolongs ventricular repolarisation, slows conduction between myocytes and reduces intrinsic pacemaker activity; all of which predispose to atrial and ventricular arrhythmias.34 In animal studies, even moderate hypokalaemia (2.5–3.0 mmol/L) can be highly arrhythmogenic; 50% of the rabbits tested had either ventricular tachycardia (VT) or ventricular fibrillation (VF) after reducing serum potassium to 2.7 mmol/L.35 Electrocardiogram (ECG) changes due to hypokalaemia indicate those at greatest risk of arrhythmia (box 1) (figure 2).

Heart failure module 6 - Figure 2. Electrocardiogram changes associated with hypokalaemia. Arrow indicates a U wave
Figure 2. Electrocardiogram changes associated with hypokalaemia. Arrow indicates a U wave

Reproduced with the kind permission of Han B Xiao ©Concise Clinical Consulting Ltd.
Treatment of hypokalaemia

Correction of hypokalaemia is indicated if ECG changes are present or if potassium is <2.5 mmol/L.9 Unless cardiac arrest is imminent, potassium replacement should be at a rate of 10–20 mmol/hr given intravenously with sodium chloride 0.9% solution. Oral supplementation may be sufficient in mild cases (3.0–3.4 mmol/L).

Hypomagnesaemia increases renal excretion of potassium and is often seen in conjunction with hypokalaemia; thus, correction of concurrent hypomagnesaemia is essential for effective potassium replacement.36

Of course, treatment with mineralocorticoid receptor antagonists (MRAs) is the most obvious long-term option for either treatment or prevention of hypokalaemia in patients with HF due to reduced ejection fraction (HFrEF) – which may be one mechanism by which the medication provides prognostic benefit.


Some 90% of potassium excretion is via the kidneys. Once filtered through the glomerulus, the majority is then reabsorbed from the urine in the proximal convoluted tubule and loop of Henlé.37 Excretion of excess serum potassium into the urine occurs via Na+/K+-ATPase pumps in the principal cells of the collecting duct which reabsorb sodium in exchange for potassium ions. The pumps are upregulated by aldosterone.38,39 Thus, a reduction in serum aldosterone (or mineralocorticoid receptor antagonism with spironolactone or eplerenone) reduces urinary excretion of potassium.40

Hyperkalaemia (>6.0 mmol/L) is associated with higher mortality in patients with HF5 and discontinuation of drugs with proven prognostic benefit (such as MRAs) to avoid iatrogenic hyperkalaemia is common.41

Causes of hyperkalaemia in patients with HF
  • Renin-angiotensin-aldosterone system (RAAS) inhibitors
  • RAAS inhibitors are associated with higher serum potassium and increased risk of hyperkalaemia (figure 3).42,43

    Heart failure module 6 - Figure 3. Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with higher serum potassium
    Figure 3. Renin-angiotensin-aldosterone system inhibitors are associated with higher serum potassium

    Key: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist;
  • MRAs
  • The rate of hyperkalaemia is higher with MRAs than with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (table 3).44–47 Perhaps as few as 54% of cases of hyperkalaemia among patients with HF who are taking an MRA are attributable to the drug itself.49

    Table 3. Rates of hyperkalaemia in clinical trials of RAAS inhibitors in patients with HF

    Trial Drug Follow-up duration Hyperkalaemia definition Rates of hyperkalaemia
    Treatment Control
    SOLVD44 (1991) Enalapril 41 months ≥5.5 mmol/L 7.8% 4.2%
    CHARM-Added45 Candesartan 41 months Hyperkalaemia associated with an adverse event 8.4% 2.9%
    RALES46 (1999) Spironolactone 24 months ≥5.5 mmol/L 19.0% 5.6%
    EMPHASIS-HF47 (2011) Eplerenone 21 months ≥5.5 mmol/L 5.4% 3.8%
    PARADIGM-HF48 (2014) Sacubitril/valsartan 27 months ≥5.5 mmol/L 16.1% 17.3%
    Death, dose reduction or drug discontinuation for any reason
    Key: CHARM-Added = Candesartan in Heart Failure – Assessment of Mortality and Morbidity; EMPHASIS-HF = Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms; PARADIGM-HF = Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure; RAAS = renin-angiotensin-aldosterone system; RALES = Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure; SOLVD = Studies of Left Ventricular Dysfunction
  • Concomitant conditions: Diabetes and chronic kidney disease (CKD) are associated with hyperkalaemia (>5.5 mmol/L), independent of treatment with an MRA.50,51

Combination therapy can thus be dangerous, making monitoring of potassium mandatory in patients receiving both an ACE inhibitors/ARBs and an MRA.21,52 In clinical trials, however, hyperkalaemia is also seen in the placebo groups, and thus hyperkalaemia is not solely due to HF treatment.

Box 2. Electrocardiogram changes associated with hyperkalaemia

Peaked T-waves (‘tall, tented T-waves’)
Broad, small or absent P-waves
Broad QRS complexes
Varying degrees of heart block
Sine-wave pattern – T-waves fused with a broad QRS complexes
Idioventricular rhythm
Ventricular tachycardia / fibrillation

As with hypokalaemia, hyperkalaemia is associated with an increased risk of tachy- and bradyarrhythmias. High intracellular potassium causes shortening of the action potential duration and slowed conduction velocity of the action potential across myocytes.34 The consequence is impaired atrioventricular (AV) node conduction and heart block which – in conjunction with suppression of infranodal pacemaking (the ability of ventricular myocardium to generate an ectopic beat) in hyperkalaemia – may cause asystole.34 Hyperkalaemia also predisposes to VT/VF through an incompletely understood mechanism.38

The appearance of ECG changes with hyperkalaemia (box 2, figure 4) is a medical emergency which requires urgent treatment (see below).9

Heart failure module 6 - Figure 4. Electrocardiographic (ECG) changes associated with hyperkalaemia
Figure 4. Electrocardiogram changes associated with hyperkalaemia

Reproduced from Mikael Häggström, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:ECG_in_hyperkalemia.svg
Treatment of hyperkalaemia
Moderate to severe hyperkalaemia

The goal of emergency treatment of hyperkalaemia is to treat/prevent the associated arrhythmias and is generally only required for patients with serum potassium levels >6.0 mmol/L (figure 5).34

Treatment options
  • Potassium binders
  • Patiromer calcium is recommended by the National Institute for Health and Care Excellence (NICE) as an option for treating patients with persistent hyperkalaemia (≥6.0 mmol/L) and HF, if they are not taking, or are taking a reduced dosage of a RAAS inhibitor because of hyperkalaemia and are not on dialysis.53

    NICE currently recommends sodium zirconium cyclosilicate (ZS-9) for the emergency treatment of life-threatening hyperkalaemia or in outpatients with either HF or CKD stage IIIb–V with persistently high serum potassium levels (≥6.0 mmol/L) who are not on dialysis and are not taking an ‘optimised dose’ of RAAS inhibitor due to hyperkalaemia.54

    The guidance is couched in very cautious terms, recognising the weakness of the available evidence for long-term use.

    Heart failure module 6 - Figure 5. Emergency management of hyperkalaemia
    Figure 5. Emergency management of hyperkalaemia

    Key: ECG = electrocardiogram; RAAS = renin-angiotensin-aldosterone system; OD = once daily; QDS = quater die sumendum (four times daily); TDS = ter die sumendum (three times daily); VT = ventricular tachycardia

    Prior to the advent of the newer potassium binders, the only treatment available (beyond emergency measures) was calcium resonium: a polymer derived from polystyrene which bound to potassium ions in the gastrointestinal (GI) tract, thus increasing excretion. However, the polymer swells when in contact with water and GI side effects are common, making it unsuitable for longer term use.55 Thus clinicians and patients had few options when presented with the problem of hyperkalaemia due to treatment with ACE inhibitor, ARB or MRA: reduce the dose or stop altogether.

    Newer potassium binders are non-absorbable compounds that bind potassium in the gut without such high rates of GI side effects. Two drugs have been investigated for the treatment and prevention of hyperkalaemia in patients with HF: patiromer and sodium zirconium cyclosilicate (ZS-9); both have received technology appraisal guidance from NICE,53,54 but it is unlikely either will be commonly used in routine practice.

    At least part of the benefit of MRAs can be attributed to prevention of hypokalaemia; for example, patients with HF who take potassium-sparing diuretics have a lower risk of adverse outcomes compared to those taking non-potassium-sparing diuretics.56 Furthermore, potassium concentration of 5.0–5.5 mmol/L are associated with the lowest risk of adverse outcomes in patients with chronic HF.5 In a patient who has to stop or reduce MRA for hyperkalaemia, there is no evidence that taking both an MRA and a potassium binder is better than taking neither.

  • Patiromer calcium
  • In the PEARL-HF trial (Prevention of Hyperkalemia in Patients with Heart Failure Using a Novel Polymeric Potassium Binder, RLY5016), investigators enrolled 105 patients with HF (average age, 68 years; average LVEF, 40%), all of whom had previously had an ACE inhibitor, ARB or MRA discontinued for hyperkalaemia or had CKD.57 Patients were randomised to either patiromer 30 g per day or matching placebo.57 All patients (except two in the placebo arm) were taking an ACE inhibitor or an ARB and all patients started spironolactone 25 mg on the same day as the study drug.57

    Treatment with patiromer (30 g per day for four weeks) was associated with a lower rate of hyperkalaemia (≥5.5 mmol/L) compared to placebo (7% vs. 25%; p=0.015).57 This allowed the dose of spironolactone to be increased (from 25 mg to 50 mg once daily) in a higher proportion of patients taking patiromer compared with placebo (91% vs. 74%; p=0.019).57

    Adverse event rates were low; GI disturbances such as flatulence, diarrhoea and constipation were the most commonly reported in the patiromer group, but only 7% of patients required discontinuation of the study drug. A subsequent smaller trial (n=63) found that treatment with patiromer enabled patients who would otherwise be classed as high risk of developing hyperkalaemia (CKD and serum potassium 4.3–5.1 mmol/L) to achieve target dose of spironolactone (50 mg once daily).58

    The largest trial of patiromer to date – the DIAMOND trial (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAAS Inhibitor Medications for the Treatment of Heart Failure) – enrolled 1,195 patients with HFrEF and a history of hyperkalaemia with RAAS inhibitor treatment (average age, 66 years; 25% women; 50% NYHA class II; about 45% of whom had an eGFR <60 ml/min/1.73 m2, and about 40% of whom had serum potassium concentrations >5.0 mmol/L at screening).59 DIAMOND was originally designed to assess the effect of long-term patiromer on CV hospitalisation or death, but due to slow recruitment, the end point was altered to change in serum potassium from baseline.

    Patiromer was associated with a 0.1 mmol/L reduction in serum potassium. Hyperkalaemia (>5.5 mmol/L) occurred in 13.9% of patients in the patiromer group and 19.4% of patients in the control arm (p=0.006).59 Hypokalaemia was just as common as hyperkalaemia and more likely to occur in the patiromer arm (15% vs. 10.7%). Rates of MRA discontinuation were low in both arms with no difference between the groups.59

    The primary findings of the DIAMOND trial are that 1) hyperkalaemia is an uncommon side effect in patients with HFrEF taking RAAS inhibitor medications, even in patients with a history of hyperkalaemia on RAAS inhibitors; and 2) patiromer has a statistically significant but clinically unimportant effect on serum potassium concentrations.59

  • ZS-9
  • In the HARMONIZE trial (Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients with Hyperkalemia) of ZS-9 in patients with hyperkalaemia regardless of aetiology, investigators enrolled 258 patients with potassium ≥5.1 mmol/L and randomised them to either 5 g, 10 g or 15 g of ZS-9 per day or matching placebo for 28 days.60 The proportion of patients with potassium <5.1 mmol/L was significantly greater in all ZS-9 groups compared to placebo (p<0.001).60 The effect of ZS-9 was rapid; during the initial open-label phase (during which all patients received the drug), 98% of patients treated with ZS-9 had normal potassium with the median time to normalisation of only about two hours.60

    Subgroup analysis of patients with HF in the HARMONIZE study (n=94; 70% had CKD or diabetes; 69% taking ACE inhibitors, ARBs or MRAs) found similar rapid and beneficial improvements in serum potassium with ZS-9 versus placebo.61

    There were no serious adverse events or events that led to study drug discontinuation during the open-label phase. The adverse event rate was similar between the ZS-9 and placebo groups during the maintenance phase. The most common adverse event in the ZS-9 group was peripheral oedema in patients taking either 10 g per day (6%) or 15 g per day (14%), the clinical significance of which is not clear with such small numbers.60

    In a combined analysis of patients with severe hyperkalaemia (≥6.0 mmol/L, n=45) from two studies of ZS-9, investigators found that 80% of patients achieved potassium levels <6.0 mmol/L within four hours of starting treatment5 and thus ZS-9 may also be helpful for the emergency management of severe hyperkalaemia.62

    The HARMONIZE-global study (n=267; average age, 67 years; ~20% with HF; 98% with risk factors of hyperkalaemia – CKD, diabetes, HF or RAAS inhibitor use) aimed to replicate the results of the HARMONIZE trial in a more ethnically diverse group of patients with hyperkalaemia (≥5.1 mmol/L).63 In the initial 48-hour ‘correction phase’ of the study, all patients received 10 g ZS-9 three times per day. Those who reached normal potassium levels (<5.1 mmol/L, n=248, 92.9%) were then entered into the 29-day ‘maintenance phase’ in which patients were randomised to either once-daily ZS-9 5 g, ZS-9 10 g or matching placebo in a 2:2:1 ratio.63

    The primary end point was average serum potassium during days 8–29 of the maintenance phase of the trial.63 Potassium fell to within the study-defined normal range (<5.1 mmol/L) in both ZS-9 groups more frequently than in the placebo group (p<0.001).63 At the end of the study, 77.3% of patients taking ZS-9 10 g per day and 58.6% of patients taking ZS-9 5 g per day had normal potassium compared to only 24.0% of patients taking placebo (p<0.001).63 Interestingly, serum aldosterone levels were significantly lower in patients taking ZS-9 compared to placebo at the end of the study compared to baseline (p=0.001).63

    While the adverse event rate was high (44.4% in the ZS-9 10 g/day group and 28.3% in the ZS-9 5 g/day compared to 20.0% in the placebo group), the rate of discontinuation of the study drug was low and similar between the groups (7% vs. 7% vs. 6%).63 The most commonly reported adverse event associated with ZS-9 was new-onset oedema occurring in 15% and 5% of patients taking 10 g and 5 g, respectively.63 While the exact mechanism by which ZS-9 may cause oedema is unknown, by the end of the study, oedema had resolved or was resolving in most patients (80%) either without specific treatment or with loop diuretic without requiring discontinuation of the study drug.63

Renal dysfunction in patients with HF

Renal dysfunction is common in patients with HF;64,65 while one in five patients with HF have a label of CKD, as many as 50% of patients may have an eGFR <60 ml/min/1.73 m2.66

Renal dysfunction may be a consequence of HF, its treatment, or both, and is invariably associated with a poor prognosis in trial and registry data, regardless of HF phenotype.67–70

In clinical practice, there is frequently a tension between the need to initiate and titrate drugs that inhibit the RAAS on the one hand, and the avoidance of further detriment to renal function on the other.

The inclusion of ACE inhibitors, ARBs and MRAs in lists of ‘nephrotoxic’ drugs, combined with unclear, and occasionally, conflicting clinical guidelines have resulted in the sometimes ‘hair-trigger’ response of stopping an ACE inhibitor, ARB or MRA in response to any deterioration in renal function without any attempt to consider an alternative cause or reintroduce the medications in the future.

The situation is compounded by the frequently conflicting recommendations given to GPs by nephrologists, cardiologists and other hospital specialists.

Causes of renal dysfunction in HF12

The cause of renal dysfunction in patients with HF is multifactorial. Additionally, patients with HF are vulnerable to acute intercurrent illnesses, which are a common cause of a decline in renal function. Intercurrent illness must always be considered in a patient with HF who is taking RAAS inhibitors and who had previously stable renal function. The commonest factors are:

  • Haemodynamic and neurohormonal changes12
  • Glomerular filtration is normally maintained by the action of the RAAS across a wide range of systolic blood pressures. The low-flow state of HF causes increased dependency on activation of the RAAS to maintain glomerular filtration pressure.

    Angiotensin II causes vasoconstriction of the afferent (in) and efferent (out) arterioles of the glomerulus. Vasoconstriction is more pronounced in the efferent arteriole, causing increased flow into the glomerulus via the afferent arteriole (less vasoconstriction – larger relative vessel diameter) and decreased flow out via the efferent arteriole (more vasoconstriction – smaller relative vessel diameter). The net effect is increased pressure within the glomerulus, which drives filtration from the glomerulus to the Bowman’s capsule and into the urinary space.

    Therefore, introduction of ACE inhibitors, ARBs, MRAs and sacubitril/valsartan inevitably cause a reduction in glomerular filtration pressure on initiation and cause apparent deterioration in renal function tests.71 With inhibition of the RAAS, glomerular filtration becomes more dependent on systolic blood pressure to perfuse the glomerulus adequately. Blood pressure is, of course, reduced by the systemic effects of ACE inhibitors, ARBs, MRAs or sacubitril/valsartan (alongside beta blockers).72 Thus, a degree of renal impairment after initiation of inhibitors of the RAAS is almost ubiquitous.

  • Venous congestion
  • Renal interstitial oedema increases pressure in the Bowman’s capsule, thus reducing the filtration pressure from glomerulus to Bowman’s capsule and reducing the filtration rate. Similarly, high pressure in the renal vein lowers eGFR and increases sodium retention, although the mechanism is unclear.73 Additionally, patients with severe congestion can develop ascites, which may cause functional ureteric obstruction due to increased intra-abdominal pressure.74

  • Atherosclerosis
  • Coronary artery disease is common amongst patients with HF and is often associated with other arteriopathies, such as peripheral vascular disease or renal artery stenosis.12 The prevalence of renal artery stenosis in patients with HF varies from 15–54%, depending on the definition used and the population studied.75,76 A stenosed renal artery reduces renal blood flow, in turn leading to renin production as a mechanism to maintain glomerular perfusion. Inhibition of the RAAS in such patients can lead to a profound drop in renal function, which is not always reversible and may lead to life-threatening pulmonary oedema.77

  • Effect of treatments

    RAAS inhibitors – Trial data suggests that while a large proportion of patients will experience a decline in renal function on starting RAAS inhibitors, the change is modest

  • RAAS inhibitor trials
    • In the CONSENSUS trial (Effects of Enalapril on Mortality in Severe Congestive Heart Failure), the average increase in serum creatinine in patients treated with enalapril was 44 µmol/L. Creatinine decreased in about 25% of patients in the treatment group78,79
    • In the SOLVD Prevention trial (Studies of Left Ventricular Dysfunction), the proportion of patients with serum creatinine increase >44 µmol/L was 16% in the enalapril arm compared to 12% in the placebo arm80
    • In RALES (Randomized Aldactone Evaluation Study), the median increase in creatinine in the spironolactone group was 4–9 µmol/L46
    • In the PARADIGM-HF study (Prospective Comparison of ARNI With ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure), the proportion of patients who developed creatinine ≥221 µmol/L was 3% in the sacubitril/valsartan group and 5% in the enalapril group.48

    In a post-hoc analysis of both SOLVD and RALES, worsening renal failure upon starting treatment was associated with poorer prognosis amongst patients in the placebo group but not the treatment group.81,82

    Similarly, a meta-analysis of data from the SOLVD (enalapril), RALES (spironolactone), SAVE (Survival and Ventricular Enlargement — captopril), Val-HeFT (Valsartan Heart Failure Trial — valsartan) and EPHESUS (Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction After Myocardial Infarction — eplerenone) trials found that while worsening renal function was associated with higher mortality compared to patients with stable renal function.83 Additionally, the overall reduction in all-cause mortality associated with RAAS inhibitors was greater amongst patients with worsening renal function compared to those with stable renal function.83

    Diuretics – Diuretics are the cornerstone of treatment for venous congestion but are often associated with worsening renal function. Although worsening renal function is often associated with worse outcome,84 it does not demonstrate causality.

  • Diuretics
  • Post-hoc analysis of the DOSE trial (Diuretic Strategies in Patients with Acute Decompensated Heart Failure) (module 3) suggests that worsening renal function during diuresis may actually be associated with better post-discharge outcomes compared to patients whose renal function is stable or improves.85

    In a study of approximately 600 consecutive patients admitted with acute HF, the presence of worsening renal failure on discharge (≥ 26.5 µmol/L increase in serum creatinine from admission) was not associated with adverse outcomes, whereas the presence of residual congestion was.86 Ultimately, treatment of congestion – not maintenance of stable renal function – is the goal of treatment during diuresis, and the two rarely go hand-in-hand.

Thresholds for changing medication

The European Society of Cardiology (ESC) HF guidelines permit a creatinine increase of ≤50% from baseline before recommending dose reduction or withdrawal.

The decision to reduce the dose or withdraw the treatment with a RAAS inhibitor is based on a risk–benefit calculation, for which there is very little evidence on which to base a decision. Current NICE HF guidelines refer to NICE CKD guidelines, which recommend either dose reduction or withdrawal of ACE inhibitors, ARBs or MRAs if serum creatinine rises >30% from baseline.87

What action is taken depends very much on the clinical context and the indication for which the medication was prescribed. For example, there is no evidence that treatment with RAAS inhibitors improves outcomes for patients with HF and a preserved left ventricular ejection fraction (HFpEF) and thus the threshold to reduce the dose or withdraw treatment altogether is much lower than for patients with HFrEF in whom the RAAS inhibitors unequivocally confer prognostic benefit.88

The British Society for Heart Failure and the Renal Association released guidelines on how to manage deteriorating renal function and hyperkalaemia in patients with HF (table 4).88

Table 4. Recommendations from the RA and BSH regarding changes in medication in response to changes in renal function

Increase in serum creatinine from baseline HFpEF HFrEF
≤30% Consider stopping RAAS inhibitor Continue
30–50% Stop RAAS inhibitor Consider reduced dose or temporary withdrawal
>50% Temporary withdrawal
eGFR <20 ml/min/1.73 m2 Stop RAAS inhibitor
Key: BSH = British Society for Heart Failure; eGFR = estimated glomerular filtration rate; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; RA = Renal Association; RAAS = renin-angiotensin-aldosterone system

The recommendations mean that in a patient with HFrEF, an increase in creatinine from 150 µmol/L at baseline to 190 µmol/L is tolerable, as long as it is not accompanied by another reason for dose adjustment, such as hyperkalaemia ≥6.0 mmol/L or symptomatic hypotension.88 However, such an increase in a patient with HFpEF should prompt dose reduction or withdrawal.88

There is a danger that anxiety about renal function may lead to underuse of potentially life-prolonging medications in patients with HF.89 However, real-life clinical scenarios are rarely as simple as the arbitrary cut-offs described above may imply and ultimately, the decision to reduce the dose of or stop treatment with RAAS inhibitors will be based on other factors as well as serum creatinine.

Anaemia in patients with HF

Anaemia is common in patients with HF. It is most often seen in women, the elderly and patients with renal dysfunction.90 It is associated with more severe symptoms, worse functional status, and greater morbidity and mortality.91,92 The aetiology is multifactorial.

The prevalence of anaemia varies from 7–50% in study populations and HF registries due to varying definitions and patient selection for studies (figure 6). In a systematic review of 34 studies, most of which used the World Health Organisation definition of anaemia (haemoglobin [Hb] <13 g/dL for men; <12 g/dL for women), the prevalence of anaemia was 37% amongst 153,000 patients with HF.93

Heart failure module 6 - Figure 6. Prevalence of anaemia in heart failure studies
Figure 6. Prevalence of anaemia in heart failure studies

Key: CHARM = Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; COMET = Carvedilol Or Metoprolol European Trial; ELITE = Evaluation of Losartan in the Elderly; IN-CHF = Italian Network on Congestive Heart Failure; OPTIMAAL = Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan; PRAISE = Prospective Randomized Amlodipine Survival Evaluation; SOLVD = Studies of Left Ventricular Dysfunction; Val-HeFT = Valsartan Heart Failure Trial

The most studied and best understood cause of anaemia in patients with HF is iron deficiency. While the true cause is unclear, it is likely that iron deficiency in patients with HF stems from a combination of reduced iron stores, inability to use intracellular iron stores, poor absorption and sub-acute blood loss (due to oral antiplatelets and anticoagulants).94,95

Antiplatelet agents, such as aspirin, are almost ubiquitous in the treatment of ischaemic heart disease,96 which is the leading cause of chronic HF.65,66 Atrial fibrillation is another common co-morbidity in patients with HF, treatment of which in a patient with HF should involve anticoagulation with either warfarin or direct-acting oral anticoagulants in the absence of a contraindication.12

In the general population, iron deficiency is approximately three times more common than iron-deficiency anaemia. Anaemia should be considered the end point of iron deficiency.

Iron has many physiological roles that may be negatively affected by low serum levels. Physiological roles of iron include99,100:

  • forming the oxygen-binding component in both Hb and myoglobin; the latter allows oxygen release in skeletal muscle in hypoxic conditions
  • a role in maturation of haematopoetic stem cells
  • a role in the cellular response to erythropoietin (EPO)
  • the electron emitted by the conversion of Fe2+ to Fe3+ is used as a catalyst for various biochemical reactions and in the electron transport chain in mitochondria.

Patients with HF and iron deficiency have lower six-minute walk test (6MWT) distances and peak exercise oxygen consumption (VO2), and worse outcomes than those with normal iron stores, regardless of the presence or absence of anaemia.91,101,102 While iron deficiency is common in patients with HF, other causes should also be considered.

Heart failure module 6 - Figure 7. Pathophysiology of anaemia in heart failure
Figure 7. Pathophysiology of anaemia in heart failure

Key: ACE = angiotensin-converting enzyme; AT-II = angiotensin II receptor type 2; CKD = chronic kidney disease; EPO = erythropoietin; GI = gastrointestinal; OAC = oral anticoagulant; RAAS = renin-angiotensin-aldosterone system; RBC = red blood cell

Causes of anaemia in HF

  • CKD
  • CKD is common among patients with chronic HF (see above).65,66 The primary cause of anaemia in patients with CKD is reduced EPO production but other factors, such as those described above, may also play a role.

    The prevalence of anaemia among patients with CKD is inversely proportional to eGFR (table 5).103

    Table 5. Prevalence of anaemia by glomerular filtration rate in outpatients with chronic kidney disease (n=18,474)66

    (ml/min/1.73 m2
    % Anaemia
    (≤13 g/dL for men; ≤12 g/dL for women)
    <30 75%
    30–49 50%
    50–59 35%
    60–69 25%
    70–79 20%
    Data obtained from Isakov E et al. Ann Clin Lab Sci 2014;44:419–24. https://doi.org/10.1002/uog.13313
    Key: eGFR = estimated glomerular filtration rate
  • Suppression of angiotensin II activity
  • ACE inhibitors may contribute to anaemia in patients with HF as follows:104

    • Reduced angiotensin II activity causes dilation of the efferent arteriole of the glomerulus and increased renal blood flow which, in turn, reduces EPO secretion
    • Angiotensin II stimulates production of red blood cell precursor cells via activation of angiotensin II receptor type 1 on blast cells105
    • ACE inhibitors inhibit the breakdown of N-acetyl-seryl-aspartyl-lysyl-proline, which suppresses haemopoetic stem cell proliferation.106
  • Effect of pro-inflammatory cytokines
  • HF is a pro-inflammatory state associated with raised tumour necrosis factor and interleukin-6, among other cytokines.107 Levels of these cytokines are inversely proportional to Hb.108 Pro-inflammatory states reduce EPO secretion,109 and reduce GI absorption and the bioavailability of iron for haem production.110

  • Venous congestion
  • Neurohormonal activation in HF leads to increased salt and water retention, which increases plasma volume. Increased plasma volume in turn can dilute serum components, including Hb. Haemodilution may account for as many as half the cases of anaemia in patients with chronic HF111 and is associated with low Hb in patients with HF, regardless of eGFR and EPO.112

  • Other haematinic deficiencies
  • Malnutrition is increasingly recognised as a complication of HF, possibly due to impaired gut absorption secondary to bowel oedema.113,114 However, while malnutrition is a common cause of anaemia worldwide,115 vitamin B12 and folate deficiencies are uncommon in patients with HF.91,116–118 Iron deficiency is far more common: in one international cohort of patients with chronic HF (n=610), 58% had iron deficiency, whereas only 5% and 4% had vitamin B12 and folate deficiencies, respectively.117

Investigating anaemia in patients with HF

Most patients with HF are elderly and have multiple co-morbidities and risk factors for malignancy, so those with iron deficiency ought to be offered GI evaluation.114

All patients with anaemia (regardless of the presence of HF) will initially require further investigation with haematinics and a blood film.

Current British Society of Gastroenterology guidelines recommend urgent referral for investigation of possible GI malignancy in all patients aged over 60 years with iron-deficiency anaemia (Hb <13 g/dL for men, <12 g/dL for women; ferritin <15 ng/ml) and specialist referral for all patients with iron deficiency and significant anaemia (Hb <12 g/dL for men, <10 g/dL for women), regardless of age.114 However, a large proportion of patients with iron-deficiency anaemia may be sub-optimally investigated.119,120

Whether patients with iron deficiency but normal Hb should be investigated is not clear. Current guidelines recommend coeliac screening in all patients with non-anaemic iron deficiency and consideration of GI evaluation in all patients thought to be ‘high risk’ of malignancy, for example those over 50 years, which of course, includes most patients with HF!114

Treating anaemia in patients with HF

Blood transfusions are the most simple and obvious treatment for anaemia, yet very few data exist that suggests benefit. A blood transfusion, given with a diuretic, may be indicated for patients in whom severe anaemia or a sudden drop in Hb is thought to have caused worsening HF symptoms.

Blood transfusions are recommended for patients with acute coronary syndrome and an Hb ≤8 g/dL to target an Hb 8–10 g/dL; in practice, such targets also seem reasonable for patients hospitalised with HF if anaemia is thought to contribute to worsening symptoms. However, such decisions are purely clinical and have no evidence base to support them.

Of the various aetiologies of anaemia in patients with HF explored above, two mechanisms have been targeted in therapeutic trials to varying degrees of success: iron depletion and low EPO.

Early studies suggested that treatment with erythropoiesis-stimulating agents (ESAs),121 IV iron,122 or both,123 may improve functional capacity in patients with HF and anaemia; large-scale randomised controlled trials (RCT) have followed.

There is no evidence that oral iron or ESAs are beneficial and, despite the adverse safety signals in RED-HF (Reduction of Events by Darbepoetin Alfa in HF),124 the latter is often given to patients with HF and end-stage renal failure. IV iron is recommended by the ESC HF guidelines for the treatment of iron deficiency defined as serum ferritin concentrations <100 μmol/L or ferritin 100–299 and transferrin saturation <20% to improve symptoms and reduce the risk of hospitalisation with HF.21 Screening for iron deficiency at regular intervals is also recommended.

  • ESAs
  • In the RED-HF trial (Reduction of Events with Darbepoetin Alfa in Systolic Heart Failure) 2,278 patients (median age, 72 years; median LVEF, 31%; median Hb, 11.2 g/dL; median transferrin saturation, 24%)124 were randomised to subcutaneous injections of either darbepoetin (dose adjusted to baseline Hb) or placebo every two weeks until they reached normal Hb levels (≥13 g/dL). Injections were given monthly thereafter to maintain Hb in the normal range. Despite a quick and sustained increase in Hb in the treatment group, darbepoetin had no effect on the primary outcome of death or hospitalisation with HF. There was a significantly higher rate of embolic and thrombotic events with darbepoetin compared to placebo (13.5% vs. 10%, p=0.009), which may have offset any potential benefit from darbepoetin.124

    Similar neutral results for CV outcomes and increased risk of thrombotic events have been observed with ESAs in other patient populations.125 Consequently, ESAs are not used to treat anaemia in patients with HF. However, they continue to be used to treat anaemia in patients with CKD and the co-diagnosis of HF is not a contraindication.126

  • IV iron
  • The FERRIC-HF (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure), EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency), FAIR-HF (Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency), and CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure) trials investigated the safety and efficacy of IV iron in patients with HF and iron deficiency (ferritin <100 μg/L or <300 μg/L and transferrin saturation <20%).122,127–129

    In the FERRIC-HF study, 35 patients (average age, 64; LVEF, ≤45%; NYHA II–III) were randomised in a 2:1 ratio to either placebo or IV iron, which was given weekly for four weeks and then at four-weekly intervals for 16 weeks.122 Despite a significant increase in ferritin and transferrin saturation in the iron group, there was no difference in the primary end point of change in peak exercise VO2 from baseline to 18 weeks compared to placebo.122

    In the EFFECT-HF trial, 174 patients (average age, 63; average LVEF, 33%; median NT-proBNP, 1,576 ng/L in the treatment group) were randomised to either standard of care (no placebo) or IV iron, which was given to all patients at baseline and then at six-weekly intervals, depending on serum Hb.127 The primary end point was the difference in peak VO2 measured at baseline and 24 weeks. Peak VO2 decreased in the control group but was stable in the IV iron group and so, there was a small, but statistically significant difference in peak VO2 (+1.0 ml/kg/min; p=0.02) at the end of the study.127

    In the FAIR-HF trial, 459 patients (average age, 67 years; average LVEF, 31%; approximately 80% of whom were NYHA class III) were randomised in a 2:1 ratio to either IV iron or placebo.128 Iron was given weekly until iron stores were normal and then every four weeks for a total of 24 weeks. The primary end point was a change in patient-reported symptoms or NYHA class. Half the patients in the iron group reported that their symptoms were ‘moderately’ or ‘much’ improved compared to 28% of patients in the placebo group (p<0.001). In a pre-planned subgroup analysis, IV iron was as effective for patients without anaemia (Hb ≥12 g/dL) as it was for patients with low Hb.130

    Caution is required when considering IV iron for patients with HF. For example, in FAIR-HF, 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% compared to 74% in the IV iron group.128 This improvement was despite significant differences in ferritin (312 μg/L vs. 74 μg/L; p<0.001) and transferrin saturation (29% vs. 19%; p<0.001) between the groups after 24 weeks of treatment.127

    In CONFIRM-HF, 301 patients (average age, 69 years; average LVEF, 37%; NYHA class II or III; average NT-proBNP, 2,511 pg/ml in the iron group) were randomised to either IV iron or placebo.129 Iron stores were replaced in an initial six-week treatment phase followed by further iron infusions every 12 weeks, only if the patient was still iron deficient. The primary outcome was change in 6MWT distance after 24 weeks of treatment; secondary outcomes included change in NYHA class, patient-reported symptoms and quality-of-life (QoL) scores. Follow up continued to one year.129

    6MWT distance increased on average by 18 metres in the iron group and reduced by 16 metres in the placebo group, giving a difference in the change in 6MWT distance of 33 metres (p=0.002).129 Secondary end points were significantly improved in the treatment group compared to placebo. As with the results of FAIR-HF, IV iron was beneficial, regardless of whether or not the patients were anaemic.129

    Although the trial was not powered to detect a difference, the CONFIRM-HF study was the first to suggest possible outcome benefit with IV iron; post-hoc analysis found that treatment with IV iron was associated with a lower risk of all-cause mortality or HF hospitalisation compared with placebo (HR 0.53; p=0.03).129

    A subsequent individual patient data meta-analysis of 844 patients from four RCTs of IV iron (the majority from FAIR-HF and CONFIRM-HF) found that treatment with IV iron was associated with a lower rate of recurrent hospitalisation with HF (risk ratio [RR] 0.41; p=0.003) and lower rate of hospitalisation with HF or all-cause mortality (RR 0.54; p=0.011).130

    More recently, two trials have suggested that there might be a benefit of IV iron on HF hospitalisations, but no effect on mortality. In the AFFIRM-AHF trial (Association Between Hemoglobin Levels and Efficacy of Intravenous Ferric Carboxymaltose in Patients with Acute Heart Failure and Iron Deficiency), 1,108 patients recruited soon after recovery from an episode of decompensated HF (average age, 71 years; 44% female; 50% NYHA class III; average LVEF, 33%; median NT-proBNP, 4,743 ng/L) were randomised to receive either IV ferric carboxymaltose or placebo.131 The primary end point was total HF hospitalisations or CV death after 12 months. There were fewer total HF hospitalisations in the IV iron group compared to placebo (RR 0.74; 95% CI, 0.58–0.94; p=0.035), but there was no impact on CV mortality (HR 0.96; 95% CI, 0.70–1.32; p=0.81) and the study was neutral for the primary end point (RR 0.79; 95% CI, 0.62–1.01; p=0.06).131

    In the IRONMAN trial (Intravenous Ferric Derisomaltose in Patients with Heart Failure and Iron Deficiency in the UK), 1,137 patients with HF (average age 73 years; 25% female; 58% NYHA class II; median LVEF, 32%) were randomised to receive IV ferric derisomaltose or standard care.132 The trial was open label with masked adjudication of end points. The primary end point was recurrent hospital admissions for HF and CV death. After a median follow up of 2.7 years, IV iron was associated with a non-significant 5% absolute risk reduction (18% relative risk reduction) in the primary end point (p=0.07). In a COVID-19 (coronavirus disease 2019) sensitivity analysis during which all end points recorded after the onset of the COVID-19 pandemic were discarded, IV iron was associated with an 18% relative risk reduction in the primary end point (p=0.047). The benefit was driven by a reduction in HF hospitalisation; the rates of CV and all-cause mortality were not affected by IV iron.132

    However, in the largest trial of IV iron in patients with HFrEF and iron deficiency by the ESC guideline definition – the HEART FID trial (Ferric Carboxymaltose in Heart Failure with Iron Deficiency) (n=1,532) – there was no difference in the rate of HF hospitalisation or mortality between the two treatment groups (mortality 8.6% vs. 10.3%; total HF hospitalisations 297 vs. 332 for IV iron and placebo, respectively; p=non-significant for both).133 It is likely that if IV iron has any effect on morbidity or mortality, the effect is small.

    In IRONMAN, although patients were not blinded to treatment, QoL data was collected.132 IV iron was associated with a significant improvement in the Minnesota Living with Heart Failure symptom questionnaire score at four months after the first iron infusion (3.3 point difference; p=0.05) but by 20 months, the difference had disappeared.132 The IRONMAN investigators also assessed 6MWT distance in a subset of patients (n=193) at four and 20 months. In patients receiving standard of care, there was no change between the two time points (288 m at four months vs. 289 m at 20 months) but in patients receiving IV iron, the 6MWT distance fell by 33 metres (286 m at four months vs. 253 m at 20 months) with a p-value similar to that of the primary end point (p=0.068).132 IV iron clearly has a placebo effect, how much this contributes to the symptomatic benefit associated with IV iron is unknown.

    Peak VO2 is the gold-standard measure of exercise capacity in patients with HF but was unchanged after 16 weeks of treatment with oral iron in the IRONOUT HF study (Iron Repletion Effects on Oxygen Uptake in Heart Failure) with only small and (likely) clinically insignificant changes reported in the FERRIC-HF (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure) and EFFECT-HF (Effect of Ferric Carboxymaltose on Exercise Capacity in Patients with Chronic Heart Failure and Iron Deficiency) trials.122,127,134 It is not defined as a primary or secondary outcome for the ongoing studies of IV iron and so whether or not IV iron improves exercise capacity in patients with HF as measured by peak VO2 will remain unsettled.

    There is one more ongoing trial of IV iron in patients with HF and iron deficiency yet to complete: FAIR-HF 2 (Intravenous Iron in Patients with Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality 2).135

  • Oral iron
  • Regular IV iron infusions are expensive and logistically challenging. By comparison, iron tablets are cheap and widely available, yet were not investigated for the treatment of iron deficiency in patients with HF until 2016.

    In the IRONOUT study, 225 patients (ferritin <100 μg/L or <300 μg/L and transferrin saturation <20%; average age, 63 years; NYHA II–III; median LVEF, 25%; median NT-proBNP, 1,111 pg/mL; median Hb, 12.6 g/dL) were randomised to either iron polysaccharide 150 mg twice daily or placebo for 16 weeks.134 The primary outcome was the change in peak exercise VO2. Secondary outcome measures included other exercise variables, 6MWT distance, NT-proBNP and QoL measures. The study was neutral for all primary and secondary outcomes.134

    While transferrin saturation significantly improved (p=0.003), the median increment from baseline at 16 weeks for patients treated with oral iron versus placebo was very small (3%) and most patients in the oral iron group remained iron deficient (by the investigators’ definition) after 16 weeks of treatment (median ferritin, 95 ng/L).134 Such small improvements are unlikely to translate into a clinically detectable difference, suggesting that the duration, dose, route of administration of iron, or all three were insufficient to improve iron stores in patients with HF.134


Managing a patient with HF is as much about managing the complications of the disease and its treatment as it is the condition itself. Electrolyte abnormalities, hypotension, and renal dysfunction are common and may impair the efficacy of treatment, worsen quality of life, and lead to adverse outcomes. There are few strategies to combat each complication and more research is needed but that does not mean solutions cannot be found in some cases. Finally, although iron deficiency is common and treatment with IV iron common practice, there is no robust data demonstrating meaningful improvements in quality of life, morbidity, or mortality despite many thousands of patients randomised in multiple clinical trials.

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