As well as dealing with disease modifying therapies, heart failure specialists also manage the complications of heart failure. This module will familiarise the reader with the clinical significance and treatment of the more commonly encountered problems; electrolyte disturbances, renal dysfunction, anaemia and iron deficiency.
Electrolyte abnormalities in patients with heart failure
Table 1. Common electrolyte abnormalities in heart failure and their prevalence
|Acute HF: 19.5%10
Chronic HF: 8.2%8
|Acute HF: 4.9%4
Chronic HF: 1.7%5
|Acute HF: 4.4%4
Chronic HF: 2.6%4
|Acute HF: 13%6
Chronic HF: 13%7
Electrolyte disturbances are a common complication of heart failure, which affect treatment decisions and outcome (table 1).1–7 Hyponatraemia, both hypo- and hyper- kalaemia and, more recently, hypochloraemia are the best defined. However, abnormalities in calcium, phosphate, bicarbonate and magnesium may also be common in patients with heart failure,8 and can be life threatening if severe, requiring urgent treatment.9
Hyponatraemia is the most common electrolyte abnormality seen in patients admitted with acute heart failure. Hyponatraemia is strongly associated with an adverse outcome in acute and chronic heart failure and is a marker of severe heart failure that might prompt consideration for transplant.10 It arises through two mechanisms: dilution and depletion11
Decreased blood pressure due to a fall in cardiac output in heart failure stimulates baroreceptors in the atria, aorta and peripheral arteries thus increasing the activity of the renin-angiotensin-aldosterone (RAAS) 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 heart failure, there must be a non-osmolar stimulus to its release. The net result is water retention in excess of sodium retention (figure 1).12
Additionally, reduced renal blood flow reduces glomerular filtration rate thus limiting the rate at which the kidneys can excrete free water.13 Increased water retention leads to a relative sodium reduction; the serum is diluted although the body has an absolute excess of sodium.
The first-line treatment of venous congestion in heart failure is loop diuretics which act by inhibition of the sodium potassium chloride (Na2+-K+-2Cl–) symporter in the ascending limb of the loop Henle. The resulting increase in urine sodium, potassium and chloride causes increased free water excretion alongside electrolyte loss.14
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.15
Approximately 90% of patients admitted with acute HF are treated with loop diuretics and a similar proportion remains on them one year from discharge.16
Hyponatraemia is strongly associated with greater mortality in patients with acute or chronic heart failure.17,18 A patient whose hyponatraemia recovers to normal during an admission for heart failure has a better outcome than patients with persistent hyponatraemia at discharge.19
Salt restriction or salt supplementation?
Treatment of hyponatraemia in heart failure remains a controversial subject: in practice, many patients admitted with heart failure 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 of 1.5–2.0 L/day for treatment of congestion rather than hyponatraemia – again, in the absence of any supporting evidence that this is the correct approach.20 Similarly, sodium restriction is often used, but without supporting evidence. A low salt diet is unpalatable, and just induces thirst rather than normalising sodium.21
There is some evidence that high sodium diets22 or sodium supplementation23,24 is the correct approach. Compared to high dose intravenous (IV) loop diuretic alone, IV hypertonic saline in conjunction with diuretic in patients admitted with heart failure and severe fluid retention may:
- improve diuresis (measured by reduction in body weight)23
- increase serum sodium levels23
- cause a greater reduction in natriuretic peptide levels24
- reduce length of hospital stay24
- reduce readmission rate.24
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 diuretic. However, one small study (n=44, New York Heart Association [NYHA] class III-IV, median left ventricular ejection fraction [LVEF] 32%), found improvements in diuresis (measured by urine volume) and natriuretic peptide levels 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.25 More work, as ever, is required.
ADH receptor antagonists
ADH receptor antagonists can treat hyponatraemia in patients with syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Early trials of ADH receptor antagonists when added to standard diuretic treatment in patients with heart failure showed reductions in patient symptoms and signs of congestion,26 while also increasing serum sodium concentrations more effectively than fluid restriction alone.27 There have been three multicentre RCTs of ADH receptor antagonists in patients admitted with heart failure: EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan),28 TACTICS(Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study)29 and SECRET of CHF (Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure).30
The EVEREST trial investigators enrolled 4,133 patients admitted with heart failure (average age 66 years; average LVEF 27.5%). Patients were randomised to either tolvaptan 30 mg per day or placebo. The co-primary end points were all-cause mortality and cardiovascular mortality or heart failure hospitalisation. Treatment with tolvaptan conferred no survival benefit despite increasing serum sodium levels among those who were hyponatraemic.
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 cardiovascular death or hospitalisation (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.37 – 0.98, p=0.04).31
The TACTICS trial investigators enrolled 257 patients admitted with heart failure (average age 65 years, average LVEF 33%, average NTproBNP 10,246 ng/L, all of whom had serum sodium levels <140 mmol/L at randomisation). Patients were randomised to either tolvaptan 30 mg per day or matching placebo alongside fixed dose intravenous furosemide. The primary end point was a ‘moderate’ improvement in patient reported breathlessness at 8 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.
The very similar SECRET of CHF trial enrolled 250 patients admitted with heart failure (average age 70 years, average LVEF 35%, median BNP 577 ng/L in the treatment arm) who either had renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2), hyponatraemia (<134 mmol/L) or diuretic resistance. Patients were randomised to either tolvaptan 30 mg/day vs. matching placebo. The primary end point was an improvement in patient assessed breathlessness after 24 hours of treatment with weight and net fluid loss as amongst the pre-specified secondary end points. Again, treatment with tolvaptan had no effect on symptoms but was associated with greater weight loss compared to treatment with furosemide alone. In pre-specified subgroup analysis amongst patients with hyponatraemia similar effects were observed regardless of the presence of hyponatraemia.
Table 2. Diuretic effects of tolvaptan in addition to intravenous furosemide in the EVEREST, TACTICS and SECRET of CHF trials
|EVEREST28,31||4,133||235 mg||30 mg||Change in body weight from baseline|
|Tolvaptan -1.76 kg|
|Placebo -0.97 kg|
|TACTICS29||257||71 mg||30 mg||Change in body weight from baseline|
|After day 1 p=0.005||Tolvaptan -2.0 kg|
|Placebo -0.5 kg|
|After day 2 p=0.004||Tolvaptan -2.8 kg|
|Placebo -1.6 kg|
|After day 3 p=0.07||Tolvaptan -3.7 kg|
|Placebo -2.5 kg|
|Net fluid loss|
|On day 1
|Tolvaptan -2,182 ml|
|Placebo -1,541 ml|
|On day 2
|Tolvaptan -1,948 ml|
|Placebo -1,419 ml|
|On day 3
|Tolvaptan -1,757 ml|
|Placebo -1,401 ml|
|250||160 mg||30 mg||Change in body weight from baseline|
|After day 1 p<0.001||Tolvaptan -2.4 kg|
|Placebo -0.9 kg|
|After day 2 p<0.001||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 levels. At present, they are only ‘suggested’ for the treatment of resistant hyponatraemia in the context of congestion.20
Until recently, the importance of hypochloraemia in heart failure has been overlooked. It is common and associated with a higher risk of mortality in patients with acute or chronic heart failure, independent of serum sodium levels.6,7
It is likely to develop through the same broad mechanisms that cause hyponatraemia but, unlike hyponatraemia, hypochloraemia may have a pathological effect – diuretic resistance.32,33 Whether or not low serum chloride is a therapeutic target in heart failure remains to be seen.
Hypokalaemia in patients with heart failure is most often a consequence of diuretic therapy.34 Hypokalaemia prolongs ventricular repolarisation, slows conduction between myocytes and reduces intrinsic pacemaker activity all of which predispose to atrial and ventricular arrhythmia.35 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.36
Electrocardiogram (ECG) changes associated with hypokalaemia (figure 2) are:
- U waves
- T-wave flattening
- ST-segment changes
- ventricular tachycardia
- pulseless electrical activity (PEA) or asystole.
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 normal saline. Oral supplementation may be sufficient in mild cases.
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.
Of course, treatment with mineralocorticoid receptor antagonists (MRAs) is the most obvious long-term option for either treatment or prevention of mild hypokalaemia in patients with heart failure due to reduced ejection fraction (HeFREF) – 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 resorbed from the urine in the proximal convoluted tubule and loop of Henle. Excretion of excess serum potassium into the urine occurs via Na+/K+-ATPase pumps in the principal cells of the collecting duct which resorb sodium in exchange for potassium ions and are upregulated by aldosterone.37,38 Thus, a reduction in serum aldosterone levels or mineralocorticoid receptor antagonism reduces urinary excretion of potassium.
Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with higher serum potassium levels and increased risk of hyperkalaemia (figure 3).39,40 The rate of hyperkalaemia is higher with MRAs than with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (table 2).41–44 Combination therapy can thus be dangerous, making close monitoring of potassium mandatory in patients receiving both an ACE inhibitor/ARB and an MRA.
Hyperkalaemia (>6.0 mmol/L) is associated with higher mortality in patients with heart failure,5 and discontinuation of drugs with proven prognostic benefit (such as MRAs) to avoid iatrogenic hyperkalaemia is common.45
In clinical trials, however, hyperkalaemia is also seen in the placebo groups, and thus hyperkalaemia is not solely due to heart failure treatment. Diabetes and chronic kidney disease (CKD), are associated with hyperkalaemia (>5.5 mmol/L) independent of treatment with an MRA.46,47 Potentially as few as 54% of cases of hyperkalaemia among patients with heart failure who are taking an MRA are attributable to the drug itself.48
Hyperkalaemia and the ECG
Hyperkalaemia causes shortening of the action potential duration and slowed conduction velocity of the action potential across myocytes. The consequence is impaired 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. Hyperkalaemia also predisposes to VT/VF through an incompletely understood mechanism.35
ECG changes associated with hyperkalaemia (figure 4) are:9
- peaked T-waves (‘tall, tented T-waves’)
- broad, small or absent P waves
- broadened QRS
- varying degrees of heart block
- sine-wave pattern – T-waves fused with a broad QRS
- idioventricular rhythm
- ventricular tachycardia / fibrillation.
The goal of emergency treatment of hyperkalaemia is to treat/prevent the associated arrhythmic complications and is generally only required for patients with serum potassium greater than 6.0 mmol/L (figure 5).
Until recently the only potassium binder available was calcium resonium, a polymer derived from polystyrene which absorbs potassium ions in the gut. It is useful in the acute setting to increase potassium excretion. However, the polymer swells when in contact with water and gastrointestinal (GI) side effects are common, making it unsuitable for longer term use.49 Thus clinicians and patients had few options when presented with the problem of hyperkalaemia due to treatment with ACE inhibitors, ARBs or MRAs: 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 heart failure; patiromer and sodium zirconium cyclosilicate. Both have received technology appraisal guidance from the National Institute for Health and Care Excellence (NICE).50,51
In the PEARL-HF (Evaluation of Patiromer in Heart Failure Patients) trial, investigators enrolled 105 patients with heart failure (average age 68 years, average LVEF 40%), all of whom had previously had ACE inhibitors, ARBs or MRAs discontinued for hyperkalaemia or had chronic kidney disease (CKD). Patients were randomised to either the study drug RLY5016 30 g (equivalent to patiromer 25.2 g) per day or matching placebo. 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.52
Treatment with RLY5016 (patiromer) for four weeks was associated with a lower rate of hyperkalaemia (≥5.5 mmol/L) compared to placebo (7% vs. 25%, p=0.015). 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).
Adverse event rate was 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 spironolactone (50 mg once daily).53
Patiromer is recommended by NICE as an option for treating hyperkalaemia in adults only if used in emergency care for acute life-threatening hyperkalaemia alongside standard care or for people with persistent hyperkalaemia and stages 3b to 5 chronic kidney disease or heart failure, if they have: a confirmed serum potassium level of at least 6.0 mmol/L and are not taking, or are taking a reduced dosage of, a RAAS inhibitor because of hyperkalaemia and are not on dialysis. Patiromer should be stopped if RAAS inhibitors are no longer suitable.
Sodium zirconium cyclosilicate
In the HARMONIZE (Safety and Efficacy of Zirconium Silicate Dosed for 28 days in Hyperkalaema) trial, investigators enrolled 258 patients with potassium levels >5.1 mmol/L and randomised them to either 5 g, 10 g or 15 g of sodium zirconium cyclosilicate per day or matching placebo for 28 days. The proportion of patients with potassium levels <5.1 mmol/L was significantly greater in all sodium zirconium cyclosilicate groups compared to placebo (p<0.001).54 Time to effect with sodium zirconium cyclosilicate was quick; during the initial open-label phase (during which all patients received the drug) 98% of patients treated with sodium zirconium cyclosilicate had normal potassium levels with the median time to normalisation only circa two hours.
Subgroup analysis of patients with heart failure 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 leves with sodium zirconium cyclosilicate versus placebo.55
There were no serious adverse events or events that led to study drug discontinuation during the open-label phase and the adverse event rate was similar between the sodium zirconium cyclosilicate and placebo groups during the maintenance phase. The most common adverse event in the sodium zirconium cyclosilicate group was peripheral oedema in patients taking either 10 g per day (6%) and 15 g per day groups (14%), the clinical significance of which is not clear with such small numbers.
Analysis of patients with severe hyperkalaemia (≥6.0 mmol/L, n=45) from all studies of sodium zirconium cyclosilicate has found that 80% of patients achieved potassium levels <6.0 mmol/L within four hours of starting treatment5 and thus sodium zirconium cyclosilicate may also be helpful for the emergency management of severe hyperkalaemia.56
The HARMONIZE-Global study (n=267, average age 67 years, ~20% with heart failure, 98% with risk factors of hyperkalaemia – CKD, diabetes, heart failure 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). In the initial 48 hour ‘correction phase’ of the study, all patients received 10 g sodium zirconium cyclosilicate three times per day, those who reached normal potassium levels (<5.1 mmol/L, n=248, 92%) were then entered into the 29 day ‘maintenance phase’ in which patients were randomised to either once-daily sodium zirconium cyclosilicate 5 g, sodium zirconium cyclosilicate 10 g or matching placebo in 2:2:1 ratio.57
The primary end point was average serum potassium level during days 8–29 of the maintenance phase of the trial. Potassium fell to within the study-defined normal range (<5.1 mmol/L) in both sodium zirconium cyclosilicate groups more frequently than in the placebo group (p<0.001). At the end of the study, 78% of patients taking sodium zirconium cyclosilicate 10 g per day and 59% of patients taking sodium zirconium cyclosilicate 5 g per day had normal potassium levels compared to only 24% of patients taking placebo (p<0.001). Interestingly, serum aldosterone levels were significantly lower in patients taking sodium zirconium cyclosilicate compared to placebo at the end of the study compared to baseline (p=0.001).
While the adverse event rate was high (44% in the sodium zirconium cyclosilicate 10 g/day group, 28% in the sodium zirconium cyclosilicate 5g /day, compared to 20% in the placebo group), the rate of discontinuation of the study drug was low and similar between the groups (7% vs. 7% vs. 6%). The most commonly reported adverse event associated with sodium zirconium cyclosilicate was new onset oedema occurring in 15% and 5% of patients taking 10 g and 5 g, respectively. While the exact mechanism by which sodium zirconium cyclosilicate 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.
NICE currently recommends sodium zirconium cyclosilicate as an option for treating hyperkalaemia in adults only if used: in emergency care for acute life-threatening hyperkalaemia alongside standard care or in outpatient care for people with persistent hyperkalaemia and chronic kidney disease stage 3b to 5 or heart failure, if they have a confirmed serum potassium level of at least 6.0 mmol/L,
are not taking an optimised dosage of RAAS inhibitor because of hyperkalaemia and are not on dialysis.In outpatient care, sodium zirconium cyclosilicate should be stopped if RAAS inhibitors are no longer suitable.
Hyperkalaemia is often cited as the reason for not achieving target dose of ACE inhibitor, ARB or MRA and the wording of the NICE appraisal suggests a significant proportion of patients with heart failure may be eligible for treatment with sodium zirconium cyclosilicate.45 This is problematic as it is not yet clear whether chronic use of potassium binders in order to allow the use of MRAs in patients with chronic heart failure is beneficial.
At least part of the benefit of MRAs can be attributed to prevention of hypokalaemia: for example, patients with heart failure who take potassium-sparing diuretics have lower risk of adverse outcome compared to those taking non-potassium sparing diuretics.58 Furthermore, potassium levels 5.0–5.5 mmol/L are associated with the lowest risk of adverse outcome in patients with chronic heart failure.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.
Renal dysfunction in patients with heart failure
Renal dysfunction is common in patients with heart failure:59,60 while one in five patients with heart failure have a label of CKD, as many as 50% of patients may have an eGFR of <60 ml/min/1.72m.2,61 Renal dysfunction may be a consequence of heart failure, its treatment, or both; and is invariably associated with a poor prognosis in trial and registry data regardless of heart failure phenotype.62–65
In clinical practice there is frequently a tension between the need to initiate and up-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 ACE inhibitors, ARBs or MRAs 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 heart failure
Haemodynamic and neurohormonal changes in heart failure
In normal physiology, glomerular filtration is maintained by the action of the RAAS across a wide range of systolic blood pressures. The low-flow state of heart failure causes increased dependency on activation of the RAAS to maintain glomerular filtration pressure. Introduction of ACE inhibitors, ARBs, MRAs and sacubitril/valsartan inevitably causes a reduction in glomerular filtration pressure on initiation and causes apparent deterioration in renal function tests.66
With reduced activity of the RAAS, glomerular filtration becomes more dependent on systolic blood pressure to perfuse the glomerulus adequately and blood pressure is, of course, further reduced by the systemic effects of ACE inhibitors, ARBs, MRAs or sacubitril/valsartan (alongside beta blockers).67
Increased sympathetic activation in patients with heart failure contributes to a fall in renal perfusion: vasoconstriction of the afferent arteriole in the glomerulus reduces glomerular blood flow but also reduces the surface area of the glomerulus available for filtration.
Renal interstitial oedema increases pressure within 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.68 Additionally, patients with severe congestion can develop ascites, which may cause functional ureteric obstruction due to increased intra-abdominal pressure.69
Coronary artery disease is common amongst patients with heart failure and is often associated with other arteriopathies such as peripheral vascular disease or renal artery stenosis. The prevalence of renal artery stenosis in patients with heart failure varies between 15–54% depending on the definition used and the population studied.70 Reduced renal blood flow due to a stenotic renal artery increases RAAS activation in order 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.71
Patients with heart failure 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 heart failure who is taking RAAS inhibitors and who had previously stable renal function.
The clinical significance of changes in renal function with drug therapy
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:
- In the CONSENSUS (Effects of Enalapril on Mortality in Severe Congestive Heart Failure) trial, the average increase in serum creatinine in patients treated with enalapril was 44 µmol/L. Creatinine decreased in ~25% of patients in the treatment group.72,73
- In SOLVD (Studies of Left Ventricular Dysfunction)-Prevention, the proportion of patients with serum creatinine increase >44 µmol/L was 16% in the enalapril arm compared to 12% in the placebo arm.74
- In RALES (Randomised Aldactone Evaluation Study), the median increase in creatinine in the spironolactone group was 4–9 µmol/L.75
- In the PARADIGM-HF (Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure) study, the proportion of patients who developed creatinine levels >221 µmol/L was 3% in the sacubitril/valsartan group and 5% in the enalapril group.
In post-hoc analsyis of both the SOLVD and RALES trials, worsening renal failure on starting treatment was associated with poorer prognosis amongst patients in the placebo group but not the treatment group.76,77
Similarly, meta-analysis of data from the SOLVD (enalapril), RALES (spironolactone), SAVE (captopril), Val-HeFT (valsartan) and EPHESUS (eplerenone) trials found that, while worsening renal function is associated with higher mortality compared to patients with stable renal function, the overall reduction in all-cause mortality associated with RAAS inhibitors is greater amongst patients with worsening renal function compared to those with stable renal function.78
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,79 it does not demonstrate causality. Post-hoc analysis of the DOSE (Diuretic Strategies in Patients with Acute Decompensated Heart Failure) trial (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.80
In a study of approximately 600 consecutive patients admitted with acute heart failure, the presence of worsening renal failure on discharge (>26.5 µmol/L increase in serum creatinine from admission) was not associated with adverse outcome whereas the presence of residual congestion was.81 Ultimately, it is treatment of congestion not maintenance of stable renal function that is the goal of treatment during diuresis, and the two rarely go hand-in-hand.
Thresholds for changing medication
The decision to reduce the dose of, or withdraw 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 heart failure 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.82 The European Society of Cardiology Heart Failure guidelines permit a creatinine increase of <50% from baseline before recommending dose reduction or withdrawal.
What action is taken depends very much on the clinical context and the indication for which the medication is prescribed. For example, there is no evidence that treatment with RAAS inhibitors improves outcome for patients with heart failure and a normal left ventricular ejection fraction and thus the threshold to reduce the dose or withdraw treatment altogether is much lower than for patients with HeFREF in whom the RAAS inhibitors are providing undoubted prognostic benefit.
Recently, the British Society for Heart Failure and the Renal Association released guidelines on how to manage deteriorating renal function and hyperkalaemia in patients with heart failure. Firstly, a clinical assessment should involve:
- assessment of previous renal function
- assessment of fluid status and cautious intravenous replacement if deplete
- assessment of systolic blood pressure and previous readings – the presence of symptomatic hypotension should override any decision based on serum creatinine levels
- assessment of the consequences of worsening renal function such as hyperkalaemia – levels >6.0 mmol/L should override any decision based on serum creatinine levels
- plan ahead for repeat assessment of renal function and re-introduction of medication at a later date, involving specialists where appropriate.
Table 4. Recommendations from the Renal Association and British Society for Heart Failure regarding changes in medication in response to changes in renal function
|Increase in serum creatinine from baseline||HeFNEF||HeFREF|
|<30%||Consider stopping RAAS inhibitor||Continue|
|30-50%||Stop RAAS inhibitor||Consider reduced dose or temporary withdrawal|
|>50%||Stop RAAS inhibitor||Temporary withdrawal|
|eGFR <l20 ml/min||Stop RAAS inhibitor||Stop RAAS inhibitor|
|Key: eGFR = estimated glomerular filtration rate; HeFNEF = heart failure with normal ejection fraction; HeFREF = heart failure with reduced ejection fraction; RAAS = renin-angiotensin-aldosterone system|
The recommendations mean that, in a patient with HeFREF, 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. However, such an increase in a patient with heart failure with normal ejection fraction (HeFNEF) should prompt dose reduction or withdrawal.
There is a danger that concern regarding renal function may lead to underuse of potentially life prolonging medications in patients with heart failure. 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 many factors other than serum creatinine.
Anaemia in patients with heart failure
Anaemia is common in patients with heart failure. It is most often seen in women, the elderly and patients with renal dysfunction.83 It is associated with more severe symptoms, worse functional status and higher risk of morbidity and mortality.84,85 The aetiology is multifactorial (figure 6).
The prevalence of anaemia varies between 7–50% in study populations and heart failure 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 <13 g/dL for men; <12 g/dL for women), the prevalence of anaemia was 37% amongst 153,000 patients with heart failure.
Chronic kidney disease
CKD is common among patients with chronic heart failure (18%).59,60 The primary cause of anaemia in patients with CKD is reduced erythropoietin (EPO) production but other factors, such as nutrient deficiency associated with renal dysfunction, also play a role.
The prevalence of anaemia among patients with CKD is inversely proportional to eGFR (table 5).86
Suppression of angiotensin II activity
ACE inhibitors may also contribute to anaemia in patients with heart failure.87
- Reduced angiotensin II activity causes dilation of the afferent 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 cells.88
- ACE inhibitors inhibit the breakdown of N-acetyl-seryl-aspartyl-lysyl-proline which suppresses haematopoetic stem cell proliferation.89
Effect of pro-inflammatory cytokines
Heart failure is a pro-inflammatory state associated with raised levels of tumour necrosis factor and interleukin-6 among other cytokines.90 Levels of these cytokines are inversely proportional to haemoglobin.91 Pro-inflammatory states reduce EPO secretion,92 and reduce GI absorption and the bioavailability of iron for haem production.93
Neurohormonal activation in heart failure leads to increased salt and water retention which increases plasma volume. Increased plasma volume, in turn, can dilute serum components, including haemoglobin. Haemodilution may account for as many as half the cases of anaemia in patients with chronic heart failure,94 and is associated with low haemoglobin in patients with heart failure regardless of eGFR and EPO levels.95
Malnutrition and frailty are increasingly recognised as complications of heart failure, possibly due to impaired gut absorption secondary to bowel oedema.96,97 However, while malnutrition is a common cause of anaemia worldwide,98 vitamin B12 and folate deficiencies are uncommon in patients with heart failure.99–102 Iron deficiency is far more common (figure 8); in one international cohort of patients with chronic heart failure (n=610), 58% had iron deficiency whereas only 5% and 4% had vitamin B12 folate deficiencies, respectively.103
While the true cause is unclear, it is likely that iron deficiency in patients with heart failure stems from a combination of reduced iron stores, poor absorption and sub-acute blood loss (due to oral antiplatelets and anticoagulants).104,105
Antiplatelet agents, such as aspirin, are almost ubiquitous in the treatment of ischaemic heart disease,106 which is the leading cause of chronic heart failure.59,60 Atrial fibrillation is another common co-morbidity in patients with heart failure, treatment of which in a patient with heart failure should involve anticoagulation with either warfarin or direct-acting oral anticoagulants in the absence of a contraindication.
As a result, approximately three in four patients with heart failure will be prescribed either an antiplatelet or anticoagulant – potentially increasing the risk of GI blood loss. For example, treatment with aspirin (and other non-steroidal anti-inflammatory drugs) is the second most common cause of iron deficiency anaemia in the western world after menstrual blood loss.107
In the general population iron deficiency is approximately three times more common that iron deficiency anaemia. Anaemia should thus be considered the end point of iron depletion which, in itself, may be detrimental.
Iron has multiple physiological roles that may be negatively affected by low serum levels. Physiological roles of iron include:108,109
- forming the oxygen-binding component in both haemoglobin 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 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 within cells and mitochondria.
Patients with heart failure and iron deficiency have lower six-minute walk test (6MWT) distances and peak exercise oxygen consumption, and worse outcome than those with normal iron stores regardless of the presence of anaemia.110-112
Investigating anaemia in patients with heart failure
All patients with anaemia (regardless of the presence of heart failure) will require further investigation, initially with haematinics and a blood film. As most patients with heart failure are elderly with multiple co-morbidities and risk factors for malignancy, most ought to go on for gastrointestinal (GI) evaluation.107
However, a large proportion of patients with iron deficiency anaemia may be suboptimally investigated.113,114 Current British Society of Gastroenterology guidelines recommend urgent referral for investigation of possible GI malignancy in all patients aged over 60 with iron deficiency anaemia (Hb <13 g/dL for men, <12 g/dL for women; ferritin levels <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.107
Whether patients with iron deficiency but normal haemoglobin levels 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 at ‘high risk’ of malignancy, for example those over 50 – which, of course, includes most patients with heart failure!107
Treating anaemia in patients with heart failure
Blood transfusions are the most simple and obvious treatment for anaemia yet very few data exist that suggest benefit. A blood transfusion, given with a diuretic, may be indicated for patients in whom severe anaemia or a sudden drop in haemoglobin is thought to have caused worsening heart failure symptoms.
Blood transfusions are recommended for patients with acute coronary syndrome and Hb <8 g/dL to a target Hb of 8–10 g/dL and, in practice, such targets also seem reasonable for patients with heart failure. However, such decisions are purely clinical and have no evidence base to support them.
Of the various aetiologies of anaemia in patients with heart failure explored above, two mechanisms have been targeted in therapeutic trials to varying degrees of success: iron depletion and reduced EPO levels.
Early studies suggested that treatment with erythropoiesis-stimulating agents,115 intravenous iron,116 or both,117 may improve functional capacity in patients with heart failure and anaemia; large scale randomised controlled trials (RCTs) followed.
Erythropoesis-stimulating agents (ESA)
In the RED-HF (Reduction of Events by Darbepoetin Alfa in Heart Failure) trial, investigators enrolled 2,278 patients (median age 72 years, median LVEF 31%, median Hb 11.15 g/dL, median transferrin saturations 24%).118 Patients were randomised to two-weekly subcutaneous injections of either darbepoetin (dose adjusted to baseline haemoglobin) or placebo until they reached normal haemoglobin levels (≥13 g/dL). Injections were given monthly thereafter to maintain haemoglobin in the normal range. Despite a quick and sustained increase in haemoglobin in the treatment group, darbepoetin had no effect on the primary outcome of death or hospitalisation with heart failure. 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.118
Similar neutral results for cardiovascular outcomes and increased risk of thrombotic events have been observed with ESAs in other patient populations.119 Consequently, ESAs are not used to treat anaemia in patients with heart failure. However, they continue to be used to treat anaemia in patients with CKD and the co-diagnosis of heart failure is not a contraindication.120
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 heart failure and iron deficiency (ferritin <100 μg/L or <300 μg/L and transferrin saturations <20%).116,121,122,123
In the FERRIC-HF study, investigators enrolled 35 patients (average age 64 years, LVEF <45%, NYHA II-III) who 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. Despite a significant increase in ferritin and transferrin saturations in the iron group, there was no difference in the primary end point of a change in peak exercise oxygen consumption (VO2) from baseline to 18 weeks compared to placebo.116
In the EFFECT-HF trial, investigators enrolled 174 patients (average age 63 years, average LVEF 33%, median NTproBNP 1576 ng/L in the treatment group) who 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 haemoglobin. 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.121
In the FAIR-HF trial, investigators enrolled 459 patients (average age 67 years, average LVEF 31%, approximately 80% of whom were NYHA class III) who were randomised in a 2:1 ratio to either IV iron or placebo. 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: 50% of 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 pre-planned subgroup analysis, IV iron was as effective for patients without anaemia (Hb ≥12 g/dL) as it was for patients with low haemoglobin levels.122
In CONFIRM-HF, investigators enrolled 301 patients (average age 69 years, average LVEF 37%, NYHA class II or III, average NTproBNP 2,511 pg/mL in the iron group) who were randomised to either IV iron or placebo. 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 six-minute walk test (6MWT) distance after 24 weeks of treatment, secondary outcomes included change in NYHA class, patient reported symptoms and quality of life scores. Follow up continued to one year.
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). 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.
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 reduced risk of all-cause mortality or heart failure hospitalisation compared with placebo (HR 0.53, p=0.03).123
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 reduction in the rate of recurrent hospitalisation with heart failure (risk ratio [RR] 0.41, p=0.003) and rate of hospitalisation with heart failure or all-cause mortality (RR 0.54, p=0.011).124
However, to date, no published trial of IV iron in patients with heart failure has been powered to detect outcome benefit. Four such studies are ongoing (IRONMAN – NCT02642562; AFFIRM-AHF – NCT02937454; FAIR-HF 2 – NCT03036462; HEART-FID – NCT03037931) the results of which are essential to determine exactly how IV iron will fit into the management of patients with heart failure due to reduced ejection fraction.
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 heart failure until 2016.
In the IRONOUT study, investigators enrolled 225 patients (ferritin <100 μg/L or <300 μg/L and transferrin saturations <20%, average age 63 years, NYHA II-III, median LVEF 25%, median NTproBNP 1,111 pg/mL, median Hb 12.6 g/dL) who were randomised to either iron polysaccharide 150 mg twice daily or placebo for 16 weeks. The primary outcome was the change in peak VO2, secondary outcome measures included other exercise variables, 6MWT distance, NTproBNP levels and quality of life (QoL) measures. The study was neutral for all primary and secondary outcomes.125
While transferrin saturations 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 investigator’s definition) after 16 weeks of treatment (median ferritin 95 ng/L).125 Such small improvements were unlikely to translate into a clinically detectable difference suggesting that the duration, the dose, the route of administration of iron, or all three were insufficient to improve iron stores in patients with heart failure.
The future of iron therapy for patients with heart failure
IV iron is currently recommended by the European Society of Cardiology (ESC) guidelines to alleviate symptoms and improve QoL for patients with heart failure and iron deficiency (ferritin <100 μg/L or <300 μg/L and transferrin saturations <20%).20
Table 6 summarises the recent and ongoing trials of iron in outpatients with heart failure.
Table 6. Recent and ongoing trials of iron in outpatients with heart failure
|Trial (year)||Treatment||N||Study duration||Changes in iron stores
Iron vs. placebo
IV iron vs. placebo
|IV Iron sucrose||35||16 weeks||Ferritin +273 ng/mL
|No change in peak VO2
Increased peak VO2 adjusted for body weight +2.2 ml/kg/min (p=0.01)
|No AE or SAE related to study drug|
|IV Ferric carboxy-maltose||459||24 weeks||Ferritin +238 nmg/mL (p<0.001)
TSAT +12% (p<0.001)
|Improvement in patient reported symptoms OR 2.51, p<0.001
Improvement by one NYHA class OR 2.40 p<0.001
|Discontinuation of study drug: IV iron (5.3%) vs. placebo (9.0%)
IV iron injection site AEs n=6
|IV Ferric carboxy-maltose||301||52 weeks||Ferritin +265 ng/mL (p<0.001)
TSAT +9% (p<0.001)
|Change in 6MWT distance
|Discontinuation of study drug IV iron (9.2%) vs. placebo (12.5%)
IV iron injection site AEs n=10
|IV Ferric carboxy-maltose||174||24 weeks||Ferritin +204 ng/mL (p<0.05)
TSAT +7% (p<0.05)
|Difference in peak VO2 +1.0 ml/kg/min; P=0.02
Improvement in NYHA class and patient global assessment score (p<0.05)
|PO Iron poly-saccharide||225||16 weeks||Ferritin +11 ng/mL (p=0.056)
TSAT +3% (p=0.003)
|No change in peak VO2||No difference in any AE or SAE between groups.|
|IV Iron (III) Isomalt-oside 1000||~1,300||Minimum 2.5 years follow up||Primary end point: CV mortality or hospitalisation for worsening HF|
|IV Ferric carboxy-maltose||~1,200||Minimum 12 months follow up||Primary end point: CV mortality or heart failure hospitalisation|
|IV Ferric carboxy-maltose||~3,000||Minimum 12 months follow up||All-cause mortality or heart failure hospitalisation|
|IV Ferric carboxy-maltose||~1,100||Minimum 12 months follow up||CV mortality or heart failure hospitalisation|
|Key: AE = adverse event; AFFIRM-AHF = Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency; CONFIRM-HF = Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure; CV = cardiovascular; EFFECT = 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; FAIR HF2 = Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity & Mortality; FERRIC-HF = Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure; IV = Intravenous; HEART-FID = Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency; HF = Heart failure; IRONMAN = Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency; IRONOUT = Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure; NYHA = New York Heart Association; PO = Oral; SAE = safety adverse effect; TSAT = transferrin saturation; VO2 = oxygen uptake|
However, caution is required when considering IV iron for patients with heart failure. 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. This improvement was despite significant differences in ferritin (312 μg/L vs. 74 μg/L, p<0.001) and transferrin saturations (29% vs. 19%, P<0.001) between the groups after 24 weeks of treatment. The possibility of a placebo effect cannot be ignored.
Similarly, the absolute improvement in 6MWT distance for patients treated with IV iron in CONFIRM-HF after 24 weeks was 18 metres. The 6MWT is prone to a ‘learning effect’ and such a small change in distance may not be purely due to treatment.
Peak VO2 is the gold-standard measure of exercise capacity in patients with heart failure but was unchanged after 16 weeks of treatment with oral iron in the IRONOUT study with only small and (likely) clinically insignificant changes reported in the FERRIC-HF and EFFECT-HF trials. 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 heart failure as measured by peak VO2 will remain unsettled. Meanwhile, IV iron is given for symptomatic relief and the effects on morbidity and mortality remain unclear.
Electrolyte abnormalities, anaemia and iron deficiency are common complications of heart failure and its treatment. All have negative effects on prognosis and are potential therapeutic targets. However, whether or not correction of the abnormality translates into improved outcomes is unproven.
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