Heart failure learning module 3: lifestyle modifications and pharmacological treatment of heart failure

Released 24 May 2024     Expires: 24 May 2026      Programme:

Sponsorship Statement: Novartis Pharmaceuticals UK Ltd has provided OmniaMed Communications Ltd with an arm’s length sponsorship towards the update of the BJC e-learning programme for heart failure.

Introduction

Elderly woman patient foreground. Nurse, daughter. Nursing home.

The aims of chronic heart failure (HF) management are:

  • to provide symptom relief
  • to prevent hospitalisation for HF
  • to improve survival.

Optimal pharmacological and non-pharmacological management (including device treatment) have had an enormous beneficial impact on the clinical course of HF. This module will focus on lifestyle modifications and pharmacological treatment.

There are national and international guidelines on the management of acute and chronic HF. The National Institute for Health and Care Excellence (NICE), European Society of Cardiology (ESC) and the Scottish Intercollegiate Guidelines Network (SIGN) have produced guidelines on the management of HF in primary and secondary care.1–4

Lifestyle modifications

The importance of non-pharmacological interventions, such as lifestyle modification, psychosocial support and empowering patients to manage the condition themselves, should not be overlooked.

The key components of lifestyle modification for patients with chronic HF are1–4:

  • exercise and cardiac rehabilitation
  • diet and weight control
  • limitation of alcohol intake
  • smoking cessation
  • patient education and self-care behaviours.

Exercise and cardiac rehabilitation

Most patients with HF have fatigue and exertional dyspnoea that make exercise unappealing. In addition, depression and anxiety are common in patients with HF, which may reduce the motivation to exercise.5

Guidance in older textbooks was that patients with chronic HF should be advised to rest as much as possible. However, starting from the mid-1990s, a large body of evidence has accumulated showing that exercise training can improve exercise tolerance and potentially reverse many of the abnormalities of skeletal muscle morphology and function seen in HF (see below – ‘Evidence’).

NICE guidelines recommend that patients with stable chronic HF should be offered a supervised, personalised, group exercise-based rehabilitation programme with a psychological and educational component.2 The ESC guidelines on HF recommend that patients with chronic HF are reassured about the benefits of exercise and are encouraged to exercise regularly.3

It is unclear if cardiac rehabilitation is appropriate for patients soon after discharge following a hospitalisation with HF, but it is safe and efficacious for ambulatory patients with chronic HF.

Evidence

The HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training) enrolled 2,331 patients with chronic HF (average age, 59 years; median left ventricular ejection fraction [LVEF], 25%; 37% with New York Heart Association [NYHA] III–IV symptoms the majority of whom were taking an angiotensin-converting-enzyme [ACE] inhibitor or angiotensin II receptor blocker [ARB], and a beta blocker) who were randomised to either ‘usual care’ with no formal exercise programme or a structured, supervised, group-based exercise programme of 36 sessions over a three-month period, which transitioned to home-based unsupervised exercise of five 40-minute sessions per week. Median follow up was 30 months and the primary outcome was a composite of all-cause mortality or all-cause hospitalisation. After adjustment for prognostic variables, exercise training was associated with an 11% reduction in the primary end point compared to usual care (p=0.03).6

A meta-analysis of cardiac rehabilitation in patients with chronic HF and NYHA II–IV symptoms found a reduction in hospitalisation rates and improvements in quality-of-life measures, regardless of the ‘dose’ or form of exercise involved.7

The timing of cardiac rehabilitation remains uncertain; no guideline recommends cardiac rehab immediately following hospitalisation for HF. However, the REHAB-HF trial (Rehabilitation Therapy in Older Acute Heart Failure Patients), which enrolled 349 patients during, or just after, hospitalisation with HF (average age, 73 years; 53% with an LVEF >45%; median N-terminal pro-B-type natriuretic peptide [NT-proBNP], 2,527 ng/L in the intervention arm, 80% NYHA class III/IV) found a greater improvement in a physical disability score in patients randomised to a cardiac rehab program lasting 36 sessions, compared to usual care alone. Approximately one in five patients in the intervention group dropped out of the trial and of those who remained, one in three were unable to complete the rehabilitation programme.8

Weight control

Obesity increases the risk of developing HF (5–7% for every body mass index [BMI] increase of 1 kg/m2).9 However, there are conflicting reports regarding the association between obesity and outcome in patients with HF; some have found a lower mortality rate in overweight or obese patients,10–12 others have found no association between BMI (and other measures of adiposity, such as waist-to-height ratio) and outcome.13 Thus, it is unclear whether the overweight patient with chronic HF should be counselled to lose weight.

Weight loss is associated with a fall in left ventricular (LV) mass, LV wall thickness and diastolic dimensions,14 and weight loss in obese patients with HF and reduced LVEF (HFrEF) may improve LV systolic function.15

Atrial fibrillation (AF) is a common complication of HF and may be the primary driver of symptoms in some patients with HF with preserved ejection fraction (HFpEF). Weight loss in patients with paroxysmal AF reduces the number and duration of AF episodes, and symptom burden.16 In a patient in whom AF is thought be a key driver of symptoms, weight loss should be a priority of management.

At the other end of the scale, cachexia (>5% weight loss in 12 months)17 and unintentional weight loss is associated with an adverse prognosis in chronic HF.10

The cause of cachexia in HF is not clear but may be due, in part, to neurohormonal activation18; treatment with ACE inhibitors is associated with a lower risk of weight loss,19 and treatment with a beta blocker may prevent weight loss and promote weight gain in patients with HF.20

Diet and alcohol

Salt and fluid restriction is advocated in most guidelines,2–4 but there is no strong evidence to support these recommendations.21 Salt restriction may even be harmful in patients with HF.22

Guidelines recommend tailoring alcohol-use advice to the aetiology of HF, for example, if a patient has alcoholic cardiomyopathy or deterioration due to paroxysmal AF secondary to excessive alcohol intake, then abstinence should be advised. Otherwise, normal alcohol-use guidelines should apply.2,3

Evidence

One small study (n=232, NYHA II–IV, LVEF ≤35% taking 250–500 mg of furosemide per day and restricted to ≤1,000 ml fluid per day) found higher levels of serum NT-proBNP, aldosterone and renin in patients on salt-restricted diets compared to those on a normal salt diet.23

The SODIUM-HF trial (Study of Dietary Intervention under 100 mmol in Heart Failure) enrolled 806 patients with chronic HF (median age, 67 years; median LVEF, 36%; 75% NYHA class II and median NT-proBNP, 763 ng/L in the intervention group).24 Patients were randomised to a salt-restricted diet of <1.5 g/day or usual care. The primary end point was cardiovascular hospitalisation or emergency department visit, or all-cause mortality assessed at 12 months. Salt restriction, while apparently safe, had no impact on the primary end point or any of its components.

Other lifestyle changes

Useful advice on resumption of sexual activity for patients with cardiovascular disease is available from the British Heart Foundation (BHF).25 Advice on driving is available from the Driver and Vehicle Licensing Agency (DVLA) and guidance on fitness to fly can be accessed from the British Cardiovascular Society (BCS).26

Self-management plans3

Self-management for patients with HF now has a class I level A recommendation in the ESC HF guidelines 2021 (figure 1), including specific goals of patient education and how this might be achieved.

The ESC guidelines recommend that patients with chronic HF are advised to monitor their weight regularly to detect rapid weight gain, which may be a sign of fluid retention. Diuretic dose may be altered accordingly:

  • increase dose if ≥2 kg weight gain in three days – a sign of developing congestion
  • reduce dose if ≥2 kg weight loss in three days – a sign of excessive diuresis.
Heart failure module 3 - Figure 1. Self-management advice for patients with HF
Figure 1. Self-management advice for patients with HF

Adapted with kind permission from JJ Cuthbert.
† – only seen with ACE inhibitor
Key: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; D&V = diarrhoea and vomiting; HF = heart failure; NSAIDs = non-steroidal anti-inflammatory drugs; OTC = over the counter

Treatment of HF in primary care

4761597-silver-haired-couple-enjoying-walk-in-park

HF care should be delivered by a multidisciplinary team across primary, secondary and tertiary care. On average, a general practitioner (GP) will look after 30 patients with HF and suspect a new diagnosis of HF in 10 patients per year.27

The role of primary care includes:

  • patient education
  • managing the psychosocial aspects of living with HF
  • monitoring adherence to guideline-recommended treatments
  • managing co-morbidities
  • referral to specialist services.

GPs are often the first port-of-call for a patient with increased breathlessness or ankle swelling and thus play a central role in establishing a diagnosis, initiating treatment and avoiding hospital admission. A 2018 study of ~36,000 community-based patients with HF found that ~40% patients presented to their GP with symptoms of HF in the five years before diagnosis, thus highlighting a common problem encountered in primary care. A high index of suspicion for possible cardiac dysfunction is required when assessing a patient with breathlessness; HF is but one of many causes of exertional breathlessness (module 2).28

The availability of support for patients with HF in the community, such as HF Specialist Nurses (HFSN) or rapid-access clinics, is highly variable.29,30 As a result, a large burden of the ongoing care for patients with HF falls to general practice.

Pharmacological treatment

The present module focuses on the current pharmacological treatment of chronic HF as recommended by the NICE1,2 and ESC3,31 guidelines (summary available at the end of the module – table 4). Pharmacological treatment has been hugely successful in reducing mortality and morbidity for patients with HF and systolic dysfunction. However, the prognosis for patients with HF remains poor (module 1).

Principles of management3,31 (pillars of therapy)

In UK practice, only 91%, 85%, 68%, 59% and 44% of eligible patients with HFrEF were prescribed a beta blocker, ACE inhibitor/ARB/ARNI, mineralocorticoid receptor antagonist (MRA), SGLT2 inhibitor, or all four classes of disease-modifying therapy, respectively.32

In the last few years, the introduction of two new therapies: a combination angiotensin receptor/neprilysin inhibitor (ARNI), such as sacubitril/valsartan, and sodium-glucose co-transporter-2 (SGLT2) inhibitors into the four pillars of therapy for HFrEF i.e. a LVEF of 40% or less, have led to two paradigm shifts in HF management.

Firstly, the well-known ‘triple therapy’ consisting of i) an ACE inhibitor, or an ARB for those intolerant of ACE inhibitors, ii) a beta blocker, and iii) a MRA has been replaced by the ‘four pillars’ of management or, more prosaically, ‘quadruple therapy’:
i) ACE inhibitor/ARB/ARNI, ii) beta blocker, iii) MRA, and iv) SGLT2 inhibitor.

In a meta-analysis, treatment with four pillars (ARNI, beta blocker, MRA and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor/ARB and beta blocker) was found to be associated with an extra three years of life free from HF hospitalisation or death for an 80-year-old, and an extra eight years for a 55-year-old with HFrEF.33 Each treatment has additive prognostic benefit independent of and incremental to the others,4 with a time to onset of benefit of less than 30 days.34,35

Relevant Quality and Outcomes Framework (QOF) indicators

HF003: 60–92% of patients with a current diagnosis of HF due to LV systolic dysfunction treated with an ACE inhibitor or ARB. (6 points)

HF006: 60–92% of patients with a current diagnosis of HF due to LV systolic dysfunction, who are currently treated with a beta blocker licensed for HF. (9 points)

Thus, the second paradigm shift is that the stepwise initiation of drugs only for patients with ongoing symptoms has been discarded. Guidelines now recommend that all classes of medications are offered to all patients with HFrEF with the aim of establishing patients on optimal doses (as close to target dose as tolerated) of all four treatments.1–4

Guidelines do not recommend a particular order or timing of initiation, but those caring for the patient must not lose sight of the ultimate goal of achieving quadruple therapy at maximal tolerated doses, despite apparent clinical stability.

Renin-angiotensin-aldosterone system inhibitors

These include ACE inhibitors, ARBs, MRAs, and ARNIs (specifically, sacubitril/valsartan). ACE inhibitors and ARBs are the most commonly used renin-angiotensin-aldosterone system (RAAS) inhibitors in patients with HF. Although ARBs are often used as an alternative in patients who are unable to tolerate ACE inhibitor,1–4 ACE inhibitors and ARBs are not interchangeable, and the ARNI sacubitril/valsartan may provide greater prognostic benefit than either ACE inhibitor or ARB.

ACE inhibitors

In practice

Drug Starting dose Target dose
Enalapril 2.5 mg BD 10–20 mg BD
Ramipril 2.5 mg BD 5 mg BD
Key: BD = twice daily

Enalapril was the first drug (and only ACE inhibitor) proven to improve outcome for patients with HFrEF (see below – ‘Evidence’). Since then, pharmacological inhibition of the RAAS has been central to improving outcomes for patients with chronic HF.

ACE inhibitors should be initiated and titrated upward, starting low and increasing the dose gradually, depending on the responses of the individual patient, particularly with regards to blood pressure and renal function.1–4

Mode of action

ACE inhibitors are competitive inhibitors of the ACE and thus prevent the conversion of angiotensin I (inert) to angiotensin II (vasoactive). Angiotensin II is a potent vasoconstrictor which also increases salt and water retention, aldosterone production and sympathetic activity. Neurohormonal activation is covered in more detail in module 1.

In HF, inhibition of ACE results in a fall in plasma angiotensin II and aldosterone levels, which causes lower systemic blood pressure, reduced peripheral vascular resistance, increased potassium, reduced left-sided cardiac pressure and reduced pulmonary artery pressure.

Adverse effects

Potential adverse effects for ACE inhibitors include:

  • hyperkalaemia
  • reduced renal function
  • hypotension
  • cough
  • anaemia
  • dizziness and syncope (rare)
  • angioedema (very rare – discontinue).

NICE recommends that patients with HF who are taking an ACE inhibitor should have their serum urea, electrolytes, creatinine and estimated glomerular filtration rate (eGFR) monitored for signs of renal impairment or hyperkalaemia.1,2

Bradykinin is broken down by ACE and inhibition of bradykinin breakdown causes side effects such as a dry cough, taste disturbance, skin rash and, rarely, angioedema. Angioedema is more common in black Afro-Caribbean patients.

Evidence

Only enalapril amongst all the ACE inhibitors has been shown to improve survival in all patients with chronic HF (trials of ramipril only included patients with clinical HF immediately post-myocardial infarction).36

The efficacy and safety of enalapril was established by the landmark trials CONSENSUS (Co-operative North Scandinavian Enalapril Survival Study)37 and SOLVD (Studies of Left Ventricular Dysfunction).38

The CONSENSUS trial (n=253; average age, 71 years; NYHA class IV; predominantly taking digoxin and loop diuretics, which was the standard of care at the time) was stopped early because of the dramatically lower mortality rate in the enalapril group at six (26% vs. 44%) and 12 months (36% vs. 52%, p=0.002).37

The SOLVD treatment study (n=2,569; average age, 61 years; average LVEF, 25%; NYHA II–IV, the majority of whom were taking diuretics and digoxin) found that treatment with enalapril was associated with a lower all-cause mortality rate (35.2% vs. 39.7%, p<0.0036), lower HF mortality rate and lower hospitalisation rate (47.7% vs. 57.3%, p<0.0001) compared to placebo after an average 41-month follow up.39

The SOLVD prevention study (n=4,228; average age, 59 years; average LVEF, 29%; NYHA I or II) found that enalapril reduced the risk of all-cause mortality or hospitalisation with HF in patients with HFrEF who were asymptomatic or had mild symptoms at worst (21% in enalapril group vs. 25% in placebo group, p<0.001).40

ARBs

In practice

Drug Starting dose Target dose
Candesartan 4 mg OD 32 mg OD
Losartan 50 mg OD 150 mg OD
Key: OD = once daily

ARBs are recommended as an alternative to ACE inhibitors for patients with HFrEF who have intolerable side effects with ACE inhibitors.1,2

Unlike ACE inhibitors, they do not cause cough – one of the most common reasons for stopping ACE inhibitor therapy – as they do not inhibit bradykinin breakdown. The impact on renal function and blood pressure is similar.

Mode of action

ARBs directly block angiotensin II receptor type 1 (AT-1) which, when activated by angiotensin II, mediates vasoconstriction, aldosterone release and sympathetic activation.40

Adverse effects

These are similar to those seen with ACE inhibitors – except for the dry cough and angioedema.

No ARB has been shown convincingly to reduce mortality, only to reduce the risk of hospitalisation for HF (see below – ‘Evidence’). If a patient complains of cough, then explain that the choice facing them is:

  • to continue the ACE inhibition, tolerate the cough and retain the survival advantage, or
  • switch to an ARB, have less cough, but lose the survival advantage.

Remember, too, that if the reason for ACE inhibition intolerance is a fall in blood pressure or renal dysfunction, an ARB will have much of the same effect.

Evidence

The Val-HeFT (Valsartan Heart Failure Trial) study included 5,010 patients with HFrEF and NYHA II or worse (average age, 62 years; average LVEF, 27%; 93% were taking ACE inhibitiors and 35% were taking a beta blocker in the treatment arm).41

Patients were randomised to either valsartan or placebo in addition to standard therapy. There was no reduction in mortality with valsartan but there were fewer hospital admissions and a 13% relative risk reduction (RRR) in the combined end point of all-cause mortality, HF hospitalisation, aborted cardiac arrest and treatment with intravenous (IV) inotrope or vasodilator for more than four hours (p=0.009).41

The CHARM-Added (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) study (n=2,548; average age, 64 years; average LVEF, 28%; 99.8–100% of patients were also taking an ACE inhibitor) showed a lower rate of a combined end point of cardiovascular death or HF hospitalisation in the candesartan group compared with placebo (38% vs. 42%) after median follow up of 41 months (p=0.01). However, candesartan had no effect on all-cause mortality (30% vs. 32%, p=0.086).42

The CHARM-Alternative trial (Effects of Candesartan in Patients with Chronic Heart Failure and Reduced Left Ventricular Systolic Function Intolerant to Angiotensin-Converting-Enzyme Inhibitors) (n=2,028; average age, 67 years; average LVEF, 30%; NYHA II or worse) found that candesartan in patients with HFrEF intolerant of ACE inhibitors was associated with lower rates of a combined end point of cardiovascular death or HF hospitalisation compared to placebo (adjusted hazard ratio 0.70, p<0.0001). However, again, candesartan had no effect on all-cause mortality (26% vs. 29%, p=0.11).43

The ELITE II (Evaluation of Losartan in the Elderly II) and OPTIMAAL (Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan) studies found no difference in mortality or morbidity end points between losartan and captopril.44,45

ARNI

In practice

Drug Starting dose Target dose
Sacubitril/valsartan 49/51 mg BD 97/103 mg BD
Key: BD = twice daily

Box 1. Physiological effects of natriuretic peptides

Natriuresis/diuresis
Vasodilatation
Inhibition of the sympathetic nervous system
Inhibition of the renin–angiotensin–aldosterone system (RAAS)

Natriuretic peptides (NPs) counteract some of the effects of RAAS activation in HF (module 2 – natriuretic peptides) and are degraded by the endopeptidase neprilysin.46 Neprilysin inhibitors increase circulating levels of NPs (box 1) and, when used in conjunction with ACE inhibitiors, improve survival in animal models of HF compared to ACE inhibitiors alone.47 However, neprilysin also plays a role in the degradation of angiotensin II; neprilysin inhibition alone would cause an increase in serum NPs and angiotensin II concentrations, potentially negating any beneficial effects.

Trials of neprilysin inhibitors and ACE inhibitors in humans found a high risk of serious angioedema due to the combined inhibitory effect of the two drugs on bradykinin degradation.48,49

Consequently, sacubitril/valsartan was developed. The combination of valsartan (an ARB, which does not inhibit the degradation of bradykinin by ACE) and sacubitril (a neprilysin inhibitor), reduces the action of angiotensin II and neprilysin without increasing the risk of angioedema.

In the UK, sacubitril/valsartan should only be initiated by a HF specialist. Dose titration and monitoring must be in the community.1 Currently, it is indicated in adult patients with NYHA class II to IV symptoms and HFrEF who are already on a stable dose of an ACE inhibitor/ARB.2

Mode of action

Box 2. Effects of AT-1 receptor activation

Vasoconstriction
Increased aldosterone synthesis and secretion
Increased vasopressin secretion
Increased renin secretion
Increased renal sodium reabsorption
Increased sympathetic nervous system activity.

Sacubitril is a neprilysin inhibitor. Neprilysin is the enzyme responsible for the breakdown of NPs into inactive metabolites.

Valsartan, an ARB, blocks angiotensin II AT-1 receptors and inhibits the effects of receptor stimulation.

The combination of the two drugs causes vasodilation, promotes diuresis and has inhibitory effects on neurohormonal activation (figure 2).

Heart failure module 3 - Figure 2. Mechanism of action of sacubitril/valsartan
Figure 2. Mechanism of action of sacubitril/valsartan

Key: BNP = brain natriuretic peptide; RAAS = renin-angiotensin-aldosterone system
Adverse effects

These are similar to those seen with ACE inhibitors or ARBs. Sacubitril/valsartan is not associated with a cough. Symptomatic hypotension is common in clinical trials of sacubitril/valsartan and caution should be taken, particularly with older patients.

Evidence

In the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), investigators randomised 8,442 patients with chronic HF who had NYHA II symptoms or worse (average age, 63 years; average LVEF, 29%; median NT-proBNP, 1,631 pg/ml in the treatment arm) to either sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. Ninety-three per cent were taking a beta blocker, and 54% were taking a MRA. The trial was stopped early after 27 months as it demonstrated significant survival benefit with sacubitril/valsartan over enalapril 10 mg twice daily (table 1).50 The trial was so overwhelmingly positive that guidelines all over the world have changed to accommodate sacubitril/valsartan.

Table 1. Primary outcome data from PARADIGM-HF after median follow up of 27 months

Outcome LCZ696 N=4,187 Enalapril N=4,212 p
Cardiovascular death 13.3% 16.5% <0.001
First heart failure hospitalisation 12.8% 15.6 <0.001
Composite outcome (cardiovascular death or first heart failure hospitalisation) 21.8% 26.5% <0.001

There is some uncertainty as to the details of exactly which patients are eligible for sacubitril/valsartan, but some estimate that as many as 84% of patients with HFrEF might be switched.51 Others, taking account of exclusion criteria (such as systolic blood pressure <100 mmHg or an eGFR <30 ml/min/1.73 m2) and strict application of the entry criteria for PARADIGM-HF (on which the ESC recommendations are based) suggest that only 21% of patients may be suitable for sacubitril/valsartan.52

Not all patients who are started on the drug will be able to tolerate it. Approximately half of those recruited to the run-in period of the PARADIGM-HF trial, which aimed to establish patients on target dose of enalapril or sacubitril/valsartan before randomisation, were unable to continue into the main trial. Of those who were successfully randomised, there was a high incidence of symptomatic hypotension compared to those taking enalapril (14% vs. 9.2%, p<0.001).50 The rate of dose reduction for any reason was high during the trial but similar between the groups (42% with sacubitril/valsartan vs. 43% with enalapril).53

The more recent PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-Terminal pro-B type Natriuretic Peptide] in Patients Stabilized from an Acute HF Episode) (n=881, average age 62 years; median LVEF, 26%; median NT-proBNP, 2,883 ng/L in the treatment arm)54 and TRANSITION (Comparing Pre-Discharge and Post‐Discharge Treatment Initiation with Sacubitril/Valsartan in Heart Failure Patients with Reduced Ejection Fraction Hospitalised for an Acute Decompensation Event) (n=991; average age, 67 years; median LVEF, 29%; median NT-proBNP, 1,902 ng/L)55 trials have demonstrated the safety, feasibility and possible outcome benefit of starting sacubitril/valsartan soon after completing treatment for acute HF, either while the patient is in hospital or immediately after discharge.

About 50% of patients in PIONEER-HF and 25% of patients in TRANSITION were not taking an ACE inhibitor or ARB before starting sacubitril/valsartan. Although current NICE guidelines recommend switching to sacubitril/valsartan only in patients who are taking a ‘stable’ dose of ACE inhibitor or ARB in patients with LVEF <35%,56 sacubitril/valsartan has been recommended as a first-line treatment in the 2021 ESC HF treatment guidelines.3

There has been much debate about the comparator (enalapril 10 mg twice daily) when ramipril is so commonly used, but as noted above, enalapril is the only ACE inhibitor shown to confer a mortality advantage to patients with chronic HF. The dose of enalapril achieved in PARADIGM-HF exceeded that in CONSENSUS, so there can be little doubt the correct comparator was chosen.

In practice

Drug Starting dose Target dose
Spironolactone 25 mg OD 50 mg OD
Eplerenone 25 mg OD 50 mg OD
Key: OD = once daily

MRAs

The MRAs, spironolactone or eplerenone, should be added for patients with ongoing symptoms despite maximum-tolerated dose of beta blocker and ACE inhibitor, and LVEF <35%.4

Mode of action57

MRAs compete to block the effect of aldosterone at distal tubular sites in the nephron. Important physiological effects of aldosterone in HF include:

  • activation of basolateral Na+/K+ pumps in the principle cells of the distal tubule resulting in Na+ and water reabsorption from the urine and K+ secretion
  • increase in collagen synthesis in the heart, blood vessels and kidneys, promoting fibrosis and scarring.

Thus, MRAs promote natriuresis and promote K+ retention. However, because myocardial fibrosis is mediated by aldosterone, MRAs should not be seen simply as ‘potassium-sparing diuretics’; they have disease-modifying properties as well.

Compared with spironolactone, the selective MRA eplerenone has a lower risk of progesterone-like and anti-androgenic side effects, such as gynaecomastia.

Adverse effects

Potential adverse effects of MRAs include:

  • hyperkalaemia
  • hyponatraemia
  • renal impairment
  • hypotension and postural hypotension
  • pre-syncope and syncope
  • gastrointestinal symptoms; dyspepsia, abdominal pain
  • rash, pruritus and photosensitivity
  • ataxia and confusion.

Potential adverse effects of spironolactone due to progesterone-like and anti-androgen effects include:

  • gynaecomastia and breast pain
  • menstrual disturbances
  • loss of libido.

Careful monitoring of renal function and potassium levels is essential with MRAs, particularly when used with ACE inhibitors. Treatment should be tailored to the individual patient. Dietary advice should be given if potassium increases moderately, and a repeat sample taken.

If potassium remains significantly elevated, then dose reduction may be required. Recent work on potassium binders may prove a possible solution to hyperkalaemia due to MRAs in patients with HFrEF and may widen their use (see module 6).

Evidence

In the RALES study (Randomized Aldactone Evaluation Study) (n=1,663; average age, 65 years; average LVEF, 25%; 94–95% taking ACE inhibitors; 99% were NYHA III or IV), spironolactone was associated with improved symptoms (measured by NYHA class), a 30% RRR in cardiovascular mortality and hospitalisations, and a 30% RRR in all-cause mortality compared to placebo in patients with HF.58

In the EPHESUS trial (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) (n=6,632; average age, 64 years; average LVEF, 33%; most taking ACE inhibitors and beta blockers; 90% with ‘symptoms of HF’), eplerenone was associated with 15% RRR in all-cause mortality and 13% RRR in a composite end point of cardiovascular death or hospitalisation compared with placebo in patients with HF following myocardial infarction.59

The EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) (n=2,737; average age, 69 years; average LVEF, 26%; NYHA II; most taking ACE inhibitors or ARBs and beta blockers) found that eplerenone was associated with a reduction in all-cause mortality (12.5% vs. 15.5%), cardiovascular mortality (10.8% vs. 13.5%) and HF hospitalisation (12.0% vs. 18.4%) compared to placebo.60 Note the patients in EMPHASIS-HF were only mildly symptomatic.

While much emphasis is placed on initiation at low doses and titration to target doses with disease-modifying therapy, such considerations may not apply to MRAs. Half doses of 12.5 mg per day or 25 mg every other day have never been tested in clinical trials, and the mean dose of spironolactone in the RALES trial was 26 mg per day, suggesting that titration to 50 mg per day may not be necessary to obtain the outcome benefit.58

In practice

Drug Starting dose Target dose
Carvedilol 3.125 mg BD 25 mg BD
Bisoprolol 1.25 mg OD 10 mg OD
Nebivolol 1.25 mg OD 10 mg OD
Metoprolol XR 23.75 mg OD 190 mg OD
Key: BD = twice daily; OD = once daily

Beta blockers

Beta blockers should be offered to all patients with HFrEF regardless of age, peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease (all of which might otherwise be considered relative contraindications).1,2

They should be started as early as possible in the course of the disease, alongside an ACE inhibitor or ARB, and require careful up-titration.

Mode of action61

Beta blockers are competitive antagonists of the adrenergic beta receptors. There are three kinds of beta receptors:

  • beta-1 receptors are found predominantly in the heart and kidneys
  • beta-2 receptors are found in the heart, lungs, liver, uterus, vascular smooth muscle and skeletal muscle
  • beta-3 receptors are found in adipose tissue.

Beta blockers reduce heart rate (negative chronotropic effect), cardiac output (negative inotropic effects) and counteract other adverse effects of sympathetic activation, such as renin production, predominantly through their effect on beta-1 receptors. They also block other adverse effects of sympathetic activation (see mode of action video).

Non-cardioselective beta blockers such as carvedilol may cause bronchoconstriction via blockade of beta-2 receptors in the lungs. Cardioselective beta blockers such as bisoprolol or nebivolol, which are more selective beta-1 antagonists, might thus be more appropriate for patients with reversible airways obstruction.

Adverse effects61

Potential adverse effects of beta blockers include:

  • bradycardia
  • postural hypotension
  • increased atrioventricular block
  • bronchospasm in susceptible individuals
  • dyspnoea
  • peripheral vasoconstriction, including Raynaud’s phenomenon, cold extremities
  • central nervous system effects (headache, dizziness)
  • sleep disturbances
  • gastrointestinal disturbances
  • hyperglycaemia.

Specialist opinion should be sought if considering beta blockers in patients with genuine asthma or in those with pronounced conduction system disease.

Cardioselective beta blockers increase the risk of new-onset diabetes, especially in combination with diuretics, while in patients with insulin-dependent diabetes, non-cardioselective beta blockers may mask hypoglycaemia due to their effect on sympathetic nerve activation. In many patients with HF, the huge benefits generally outweigh the small risks.62 Despite the common belief, there is no evidence that beta blockers impair sexual function, and the excess of tiredness and fatigue is only around 18 per 1,000 patients treated.63

The presence of renal dysfunction often prevents prescription or titration of disease-modifying therapy for patients with HFrEF. However, this does not apply to beta blockers; outcome benefit with non-cardioselective beta blockers, like carvedilol, has been demonstrated even in patients with end-stage renal failure receiving haemodialysis.64

Evidence

In CIBIS II (Cardiac Insufficiency Bisoprolol Study II), bisoprolol was associated with a reduction in all-cause mortality versus placebo (11.8% vs. 17.3%; p=0.0001; RRR 32%). There was also a significant reduction in sudden death (3.6% vs. 6.3%; p=0.001; RRR 42%).65

MERIT (Metoprolol CR/XL Randomised Intervention Trial in Heart Failure) (n=3,991; average age, 64 years; average LVEF, 28%; NYHA II–IV) found better survival (risk reduction of 34% for all-cause mortality; 38% for cardiovascular mortality; 41% for sudden death and 49% for death due to worsening HF) with metoprolol (CR/XL) compared to placebo in patients with HFrEF after one-year average follow up.66

CAPRICORN (Carvedilol Post-Infarct Survival Controlled Evaluation) (n=1,959; average age, 63 years; average LVEF, 33%; also taking an ACE inhibitor)67 and COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) (n=2,289; LVEF, <25%; NYHA III or IV)68 found reduced mortality and hospitalisation rates with carvedilol compared to placebo in patients with HF. Carvedilol was also associated with a significant increase in LVEF and reduction in LV volume compared to placebo in the subgroup analysis of patients recruited to COPERNICUS.68

SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) (n=2,128; average age 76 years; 65% had LVEF ≤35%; 95% were NYHA II or III; ~88% were also taking an ACE inhibitor or ARB) found a reduction in the primary composite end point of all-cause mortality or cardiovascular hospitalisation rate with nebivolol compared to placebo (hazard ratio [HR] 0.86; p=0.036). However, nebivolol had no impact on all-cause mortality (15% vs. 18%; p=0.21).69

Which beta blocker?

BEST (Beta Blocker Evaluation of Survival Trial) (n=2,708; average age, 60 years; average LVEF, 23%; NYHA III or IV; 91% also taking an ACE inhibitor) found no significant benefit of bucindolol over placebo in patients with HF.70 Bucindolol has partial sympathomimetic activity, as does an older agent, xamoterol, which was found to be harmful in HF.71 Some, but not all, beta blockers are beneficial for patients with HF; but which out of those available?

There has only been one trial directly comparing one beta blocker with another: COMET (Carvedilol or Metoprolol European Trial).72 Patients (n=3,029; average age, 62 years; average LVEF, 26%; 98% were also taking an ACE inhibitor or ARB) were randomised to receive either the selective beta1 blocker, metoprolol, or the non-selective agent, carvedilol (which has alpha-blocking properties as well as being a non-selective beta blocker).72

Carvedilol was unequivocally the better agent at the doses used in the trial, and thus many feel that it should be used in preference to bisoprolol. Although bisoprolol was not directly compared with carvedilol, it – like metoprolol – is a selective beta1-receptor antagonist.

Beta blockers licensed for use in HF include:

  • carvedilol
  • bisoprolol
  • nebivolol
  • metoprolol CR/XL (a preparation not available in the UK).

In practice

Drug Starting dose Target dose
Dapagliflozin 5–10 mg OD 10 mg OD
Empagliflozin 10 mg OD 10 mg OD
Key: OD = once daily

SGLT2 inhibitors

SGLT2 inhibitors were initially conceived as an anti-hyperglycaemic medication for type 2 diabetes mellitus (T2DM). Results of phase III clinical trials suggested that they might have benefit for patients with HF, and so trials in patients with HF have followed.

Mode of action

The mechanism of benefit is unclear and is the subject of much debate. The SGLT2 proteins re-absorb filtered glucose from the urine in the proximal convoluted tubule. Inhibition of these proteins increases the amount of glucose excreted in the urine, resulting in a loss of body glucose (and a fall in blood glucose) and an osmotic diuresis.73

The SGLT2 inhibitors may also inhibit the Na+/H+ exchanger, which is responsible for the majority of sodium reabsorption in the proximal tubule, causing natriuresis alongside the osmotic diuretic effect.74

Inhibition of the Na+/H+ exchanger in the heart may reduce myocardial injury, fibrosis and remodelling.75 Other proposed mechanisms of benefit are wide-ranging and include a reduction in arterial stiffness,76 improved mitochondrial function,77 beneficial changes in renal blood flow,78 and a reduction in blood pressure.79 It is likely that the mechanism of benefit is multi-faceted.

Adverse effects

Potential adverse effects of SGLT2 inhibitors are largely due to the increased risk of infection due to increased glucose along the urinary tract and include:

  • balanoposthitis – infection or inflammation of the foreskin or glans
  • urinary tract infections
  • urosepsis
  • Fournier’s gangrene – necrotizing fasciitis affecting the external genitalia or perineum
  • hypoglycaemia – only when used in conjunction with insulins or sulphonlyureas
  • thirst or symptoms of hypovolaemia – side effects of the diuretic effect
  • diabetic ketoacidosis – rare, but presentation in diabetic ketoacidosis while on SGLT2 inhibitors may be atypical with only moderately raised blood glucose levels, thus a high index of suspicion is required.

Box 3. Euglycaemic ketoacidosis and SGLT2 inhibitors80

Mechanism Multifactorial. SGLT2 inhibitors:

  • increase renal ketone retention
  • promote pancreatic glucagon secretion increasing ketogenesis
  • reduce plasma glucose, which increases fatty acid release from adipose tissue
  • reduce plasma volume, which increases serum catecholamine, cortisol and growth hormone secretion which, in turn, increases fatty acid release from adipose tissue
Incidence
  • 1.3–8.8 per 1,000 patient years in patients with T2DM
  • three per 1,000 patient years in clinical trials of SGLT2 inhibitors in patients with T2DM
Clinical features Symptoms are common amongst patients presenting acutely unwell and a high index of suspicion is needed. Symptoms include:

  • thirst
  • increased urinary frequency
  • increased respiratory rate
  • sweet-smelling breath
  • abdominal pain, nausea and vomiting
  • confusion and drowsiness
Diagnosis Ketosis, defined as ketone concentration >3 mmol/L or urinary ketones ++ or greater on dipstick
Acidosis, defined as serum bicarbonate <15 mmol/L or pH <7.3
Treatment Most patients will require admission to hospital, particularly if symptoms are severe. Treatment includes IV administration of insulin, glucose and potassium to restore normal glucose metabolism and avoid severe hypokalaemia (a common side effect of IV insulin)
Referral to endocrinology and stopping the SGLT2 inhibitors are mandatory
Advice to patients Inform of the rare but potentially serious side effect and what symptoms to look out for
Encourage patients to check blood ketones regularly in the first few weeks of treatment, regardless of symptoms
Encourage patients to check blood ketones and stop the SGLT2 inhibitors in the event of any symptoms developing
Stop SGLT2 inhibitors during severe acute illness and three days prior to elective surgery
Key: IV = intravenous; SGLT2 = sodium-glucose co-transporter-2; T2DM = type 2 diabetes mellitus
Evidence

The EMPA-REG OUTCOMES trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) of empagliflozin (2015) was the first trial of an anti-hyperglycaemic agent to show a beneficial effect on hard outcomes in patients with T2DM.81 Treatment with empagliflozin was associated with a reduction in the risk of the composite end point of cardiovascular death and non-fatal myocardial infarction or stroke versus placebo (37.4% vs. 43.0%; p=0.04).81

There was a striking reduction in the rate of hospitalisation with HF or cardiovascular death in the main trial, even in patients without a diagnosis of HF at baseline.82 The findings prompted further investigation of SGLT2 inhibitors in patients with HF without diabetes.

In the EMPEROR-Reduced study (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) (2020), investigators randomised 3,730 patients (average age, 67 years; 99% NYHA II–III; median NT-proBNP in the treatment group, 1,887 ng/L; average LVEF, 28%) to either empagliflozin 10 mg once daily or placebo.83 After a median follow up of 16 months, empagliflozin was associated with a 5.3% absolute risk reduction (ARR) and 26% RRR (p<0.001) in the primary end point of HF hospitalisation or cardiovascular death.83 The benefit was driven by a reduction in HF hospitalisation; there was no difference in cardiovascular or all-cause mortality.83

In the DAPA-HF study (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) (2019), investigators randomised 4,744 patients (average age, 66 years; 98% NYHA II–III; median NT-proBNP in the treatment group, 1,428 ng/L; average LVEF, 31%) to either dapagliflozin 10 mg once daily or placebo.84 After a median follow up of 18 months, dapagliflozin was associated with a lower risk of worsening HF or cardiovascular death compared to placebo (16% vs. 21%; p<0.001).84 Dapagliflozin also reduced the risk of all-cause mortality by 17% (11.6% vs. 13.9%; p<0.001).84

SGLT2 inhibitors were well tolerated in both EMPEROR-Reduced and DAPA-HF; adverse events such as hypovolaemia, hypoglycaemia, keto-acidosis or renal dysfunction were rare (1–3%).83,84

The EMPAG-HF trial (Empagliflozin in Acute Decompensated Heart Failure) (n=60; average age, 73 years; 89% NYHA III–IV; median NT-proBNP, 4726 ng/L) found a 25% increase in diuresis with empagliflozin 25 mg once daily compared to placebo in patients admitted to hospital with HF.85 The EMPULSE trial (Empagliflozin in Patients Hospitalized for Acute Heart Failure) (n=530; average age, 71 years; 62% NYHA III–IV; median NT-proBNP, 3,299 ng/L; 69% of whom had HFrEF) found that patients treated with empagliflozin 10 mg once daily, started on or soon after admission to hospital with HF, were more likely to have an improvement in symptoms and better outcomes at 90 days after discharge than those treated with placebo.86 Neither trial found a difference in safety profile between empagliflozin or placebo. So, while current guidelines recommend the use of SGLT2 inhibitors only for stable out-patients with HFrEF, it may be that initiation during a decompensation episode leads to outcome benefit.

One advantage of SGLT2 inhibitors over other disease-modifying therapies for HF is the minimal effect on systolic blood pressure and renal function, which often limit initiation or uptitration.82,83,87 Trials of both medications in patients with chronic kidney disease have also established their prognostic benefit and safety in patients with poor renal function (the eGFR exclusion criteria for the DAPA-CKD trial [Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease] of dapagliflozin and the EMPA-KIDNEY trial [Empagliflozin in Patients with Chronic Kidney Disease] of empagliflozin were <15 ml/min/1.73 m2 and <20 ml/min/1.73 m2, respectively).88,89 Furthermore, SGLT2 inhibitors require no titration or monitoring.

After initiation of ‘quadruple therapy’

Priority should be given to initiating small doses of each class of medication rather than increasing the doses of individual drug classes. However, not all patients will be able to tolerate all four classes of medications.

Once a patient is established on initial treatment, the dose should then be increased in a stepwise fashion to reach the target dose, which refers to the dose of all HF medications which proved efficacious in randomised trials.

Although guidelines recommend a “start low, go slow” approach to starting each individual HF medications, this does not mean less frequent or less-than-therapeutic dosing, nor does it mean delaying the introduction of each of the four pillars of therapy.

In practice, only 20–35% of patients taking an ACE inhibitor or ARB and 15–20% of patients taking beta blockers are taking target doses.90,91 This may have prognostic implications; higher doses of ACE inhibitors, ARBs and beta blockers are associated with lower rates of mortality and hospitalisation for HF than lower doses.92–94

Other therapies

Some patients may be intolerant of one or more classes of quadruple therapy medications. Such patients may benefit from hydralazine plus isosorbide dinitrate, ivabradine or digoxin, all of which may also improve prognosis. However, the evidence base supporting their use is far less robust than that for ACE inhibitors, ARBs, ARNIs, beta blockers, MRAs or SGLT2 inhibitors.

The treatment of concomitant conditions is discussed in further detail in module 6.

In practice*

Drug Starting dose Target dose
Ivabradine 2.5 mg BD 7.5 mg BD
* Heart rate at rest should not be allowed to fall below 50 beats per minute
Key: BD = twice daily

Ivabradine

Ivabradine reduces heart rate in people in sinus rhythm. A high resting heart rate is a marker of adverse outcome in patients with HF.95 Even with maximum-dose beta blockers, some patients with HF have a high resting heart rate for whom ivabradine may be an option.

Mode of action

Ivabradine is a heart rate-lowering agent that acts by selective inhibition of the funny (If) channel. If channels are (at least in part) responsible for the spontaneous diastolic depolarisation in the sinus node that determines heart rate. It has no effect on intra-atrial, AV or intraventricular conduction times, and so ivabradine has no role in patients with permanent AF. Ivabradine has no effect on or on myocardial contractility or ventricular repolarisation.96

Adverse effects

Potential adverse effects of ivabradine include:

  • phosphenes (bright illuminations in the periphery of the visual field exacerbated by sudden changes in ambient brightness)
  • blurred vision
  • bradycardia (discontinue treatment if heart rate <50 beats per minute [bpm], dose reduction)
  • first-degree AV block
  • AF
  • ventricular extrasystole
  • headache
  • dizziness.
Evidence

In the SHIFT study (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine) (n=6,558, average age, 62 years; average LVEF, 29%; average heart rate, 80 bpm; all in sinus rhythm; NYHA II–IV, 89–90% taking beta blockers; 92–93% taking ACE inhibitors or ARBs; and 59–61% of whom were taking an MRA), ivabradine was associated with lower HF mortality (3% vs. 5%, p=0.014) and HF hospitalisations (16% vs. 21%, p<0.0001) compared to placebo in patients with HF.97

There is also some evidence that ivabradine has beneficial effects on clinical status, functional capacity and quality of life in patients with HF.98,99

Subsequently, ESC and NICE guidelines recommend ivabradine should be considered for patients with symptomatic HFrEF, despite therapy with a beta blocker, ACE inhibitor, MRA or SGLT2 inhibitor, with an LVEF <35% who are in sinus rhythm with a resting heart rate above 70 bpm (≥75 bpm in NICE guidance); or who are unable to tolerate or have a contraindication for a beta blocker, but continue to take an ACE inhibitor, MRA and SGLT2 inhibitor.1,3,31,99

In practice

Drug Starting dose Target dose
Hydralazine/isosorbide dinitrate 2.5 mg BD 7.5 mg BD
Seek specialist advice before initiating
Key: BD = twice daily

Vasodilators – hydralazine/isosorbide dinitrate combination2

The role of hydralazine/isosorbide dinitrate (H-ISDN) in the era of ‘quadruple therapy’ is unclear. It may be considered in patients who remain symptomatic despite optimal medical treatment or in those intolerant of one or more components of ‘quadruple therapy.’ Seek specialist advice and consider offering hydralazine in combination with a nitrate (especially if the person is of African or Caribbean family origin and has moderate to severe [NYHA class III/IV] HFrEF).

Mode of action

Hydralazine is a smooth muscle relaxant reducing arterial blood pressure. Isosorbide dinitrate is a nitric oxide donor which stimulates soluble guanylate cyclase-mediated smooth muscle relaxation and vasodilation. H-ISDN reduces both preload and afterload.100

Adverse effects

The potential adverse effects of hydralazine include:

  • hypotension
  • tachycardia
  • angina
  • flushes
  • headache
  • gastrointestinal upset
  • arthralgia
  • myalgia
  • joint swelling
  • systemic lupus erythematosus-like syndrome (high doses).
Evidence

Hydralazine/isosorbide dinitrate for the treatment of HF has been studied in three clinical trials (V-HeFT I [Vasodilator Heart Failure Trial I], V-HeFT II [Vasodilator Heart Failure Trial II] and A-HeFT [African-American Heart Failure Trial]), all of which found a RRR with H-ISDN compared to placebo in patients with HF.101–103

Sub-analysis of V-HeFT I and V-HeFT II reported that African-American patients with moderate-to-severe HF taking H-ISDN had a 47% RRR in mortality compared to non-African-American patients.104

In the subsequent A-HeFT trial of African-American patients (n=1,050; average age, 57 years; average LVEF, 24%; NYHA II–IV), only H-ISDN was associated with a reduction in all-cause mortality rates (6.2% vs. 10.2%; p=0.02) and first HF hospitalisation rates (16.4% vs. 22.4%) compared with placebo.103

The benefit of H-ISDN in patients who are not African-American is not clear: V-HeFT I and V-HeFT II were published before widespread use of ACE inhibitors, ARBs, beta blockers or MRAs.101,102 Furthermore, V-HeFT II found H-ISDN to be inferior to enalapril (18% two-year mortality rate in enalapril group vs. 25% in the H-ISDN group, p=0.016).102 However, the majority of patients in A-HeFT were taking ACE inhibitors/ARBs (86%) and beta blockers (74%).103

In practice105

Drug Loading dose Maintenance dose
Digoxin In hospital/rapid response: 750–1500 mcg in divided doses over 24 hours
Community: 250–750 mcg for 7 days
62.5–125 mcg BD
Seek specialist advice before initiating
Key: BD = twice daily

Digoxin (cardiac glycosides)

Digoxin is indicated in patients with HFrEF with resistant symptoms and for rate control in AF.

Mode of action7

Digoxin has a positively inotropic and negatively chronotropic effect; it increases the strength of myocardial contraction and slows the heart rate. Digoxin binds to and inhibits the Na+/K+-ATPase pump in cardiac myocytes, increasing intracellular Na+ and Ca2+ concentrations leading to positive inotropy. It has inhibitory effects on the sympathetic nervous system, but also increases activity of the vagus nerve – both of which act to reduce heart rate (figure 3).

Heart failure module 1 - Figure 3. Starling’s law of the heart. In the normal heart (blue), ventricular work increases as a function of preload. The horizontal lines show the ventricular work required at rest, then for mild and finally severe exertion. With increasing severity of HF (brown lines), a greater preload is needed for a given level of activity. Note the ‘descending limb’ of the Starling curve for patients with severe HF: the implication is that a reduction in preload might (paradoxically) increase ventricular work
Figure 3. Starling’s law of the heart. In the normal heart (blue), ventricular work increases as a function of preload. The horizontal lines show the ventricular work required at rest, then for mild and finally severe exertion. With increasing severity of HF (red lines), a greater preload is needed for a given level of activity. Note the ‘descending limb’ of the Starling curve for patients with severe HF: the implication is that a reduction in preload might (paradoxically) increase ventricular work

Adapted McDonagh et al. OUP 2011.
Adverse effects (see Digoxin module for more information)

The potential adverse effects of digoxin include:

  • nausea
  • visual disturbances
  • conduction system disturbance
  • sinus bradycardia
  • supraventricular arrhythmias
  • gynaecomastia
  • psychological problems
  • skin rashes
  • thrombocytopaenia (very rarely).
Evidence

In the DIG (Digitalis Investigation Group) study (n=6,800; all in sinus rhythm; average age, 63 years; average LVEF, 28%),106 digoxin was associated with a lower rate of HF hospitalisation (26.8% vs. 34.7%) but had no long-term mortality benefit.

Post hoc analysis of the DIG study found that digoxin at low doses (≤0.500 mg/day) is associated with lower one-year all-cause mortality, cardiovascular mortality and HF mortality compared to placebo in patients who were concurrently treated with ACE inhibitors and diuretics.107 There was also a significant reduction in hospitalisation.107 The combination of digoxin and an ACE inhibitor may be appropriate in patients who are intolerant of beta blockers or MRAs. However, DIG was conducted before beta blockers became widely used and the effect of digoxin on patients taking ‘triple therapy’ is unknown.

Another post hoc analysis of the DIG trial found that treatment with digoxin before being enrolled in the DIG trial was associated with worse outcome after adjustment for prognostic variables, regardless of whether patients were randomised to placebo or digoxin during the trial (HR 1.22 [95% confidence interval (CI), 1.12–1.34; p<0.001] for mortality; and HR 1.47 [95% CI, 1.33–1.61; p<0.001 for HF hospitalisation]).108

Perhaps due to concerns regarding toxicity, digoxin is usually only used in the sickest patients with HF in who the treating clinician is trying what they can to help. This ‘prescription bias’ of pre-treatment with digoxin and identifying the sicker patients was so great that the direction of treatment effect with the observational data (increased risk of hospitalisation with digoxin before randomisation) was the opposite of that with the randomised data (reduced risk of HF hospitalisation with digoxin) in the same population.109 Extreme caution must be exercised when using observational data to inform clinical practice; doing so may lead to underuse of medications that are beneficial.

The introduction of ivabradine means the use of digoxin in patients with HF and sinus rhythm is mainly limited to those with advanced disease. Digoxin may have a role for rate control in patients with HF and AF, but this should not be at the expense of beta blocker use.

Diuretics

In practice

Drug Starting dose Target dose
Loop diuretics
Furosemide 20–40 mg OD Adjusted to symptom control
Bumetanide 500 mcg OD
Torasemide 5 mg OD
Thiazide diuretics*
Bendroflumethiazide 5 mg OD on alternate days 10 mg OD
Hydrochlorthiazide Only available in the UK in combination. Consult individual prescribing information
Metolazone 5 mg OD 80 mg OD
Non-thiazide diuretic
Amiloride 10 mg OD 20 mg OD
* may only be of benefit in patients with mild fluid retention and an eGFR greater than 30 ml/minute/1.73 m2.
Key: OD = once daily

Loop diuretics are the cornerstone of treatment of symptomatic venous congestion in HF. Their effect on outcome is not certain and has not been properly studied in randomised controlled trials.

Guidelines recommend the use of loop diuretics (furosemide, bumetanide) in the first instance with a thiazide diuretic (e.g., bendroflumethiazide) used as add-on therapy in patients with resistant oedema – although the efficacy of diuretics reduces with worsening renal impairment.1,3,4

The goal of diuretic therapy is symptomatic relief and the maintenance of clinical euvolaemia with the lowest possible dose. In carefully selected patients, complete withdrawal of diuretics may be possible.1,3,4

Mode of action109

Diuretics act on the nephron in different segments (figure 4):

Figure 4. Simple diagram of a kidney nephron
Figure 4. Simple diagram of a kidney nephron (click to enlarge)
Loop diuretics

Loop diuretics, such as furosemide or bumetanide, act in the thick ascending limb of the loop of Henlé. They inhibit the Na+/K+/2Cl co-transporter. This increases Na+, K+ and Cl excretion and prevents high electrolyte concentrations from being generated in the renal medulla. Less water is thus re-absorbed throughout the remaining nephron.

Thiazide diuretics

Thiazides and thiazide-like diuretics, such as bendroflumethiazide or metolazone, act on the proximal part of the distal convoluted tubule. They inhibit the Na+/Cl co-transporter. This increases Na+ excretion and urine volume.

Amiloride hydrochloride

Amiloride hydrochloride acts on the distal convoluted tubule. It inhibits epithelial Na+ channels which prevents Na+ re-absorption without depleting K+; hence, a ‘potassium-sparing diuretic.’

Steroidal MRAs

While spironolactone and eplerenone have a mild diuretic effect, it is generally seen at much higher doses than those recommended for HF.

Acetazolamide110

Acetazolamide is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors act on the proximal tubule by reducing the inter-conversion of HCO3 and H+ to H2O and CO2. The net effect is a reduction in the intracellular H+ content in the cells of the proximal tubule; the fall in intracellular pH reduces the activity of the Na+/H+ antiporter on the apical membrane. As a result, Na+ reabsorption in the proximal tubule decreases and natriuresis increases.

Adverse effects

Table 2. Potential adverse effects of diuretics

Adverse effects of thiazide diuretics
Electrolyte depletion (K+, Mg2+) resulting in cardiac arrhythmia if also on digoxin
Postural hypotension
Hyperuricaemia (interference with the renal clearance of uric acid); diuretics increase the risk of acute gout
Hyperglycaemia with an increased risk of new-onset diabetes
Impaired renal function
Impaired exercise tolerance
Erectile dysfunction (unknown mechanism)
Skin rashes (rare)
Thrombocytopaenia (rare)
Adverse effects of loop diuretics
Fluid and electrolyte imbalance
Gastrointestinal upset
Hypotension
Rash
Hyperuricaemia
Hyperglycaemia
Raised serum creatinine
Gynecomastia (bumetanide)
Blood dyscrasias
Headaches
Dizziness
Tinnitus
Deafness
Adverse effects of potassium-sparing diuretics
Hyperkalaemia
Hyponatremia
Gastrointestinal disturbance
Hypotension
Dry mouth
Confused state
Rash
Evidence

There are few randomised controlled trials involving diuretics in the modern age of ‘triple and quadruple therapy’ for HF.

DOSE – High dose vs. low dose111

The DOSE trial (Diuretic Optimization Strategies Evaluation) studied continuous vs. bolus and low-dose (patients’ ‘usual’ daily loop diuretic dose) vs. high-dose (2.5× patients’ ‘usual’ daily dose of diuretic) IV loop diuretic in patients admitted to hospital with fluid retention due to HF (n=308; average age, 66 years; average LVEF, 35%; mean NT-proBNP, 7,439 pg/ml; average daily dose of loop diuretic, 127–134 mg).

There was no significant difference between patient-assessed symptoms or change in renal function compared to low- vs. high-dose or continuous vs. bolus administration. However, there are some findings of note:

  • patients in the low-dose group were more likely to require a 50% increase in total daily diuretic dose after 48 hours
  • patients in the low-dose group were less likely to be switched to an oral diuretic after 48 hours
  • there was a trend to greater improvement in patient-reported symptoms in the high-dose group compared to the low-dose group (p=0.06)
  • high-dose diuretic was associated with greater weight loss (p=0.01), net fluid loss (p=0.001) and relief from dyspnoea (p=0.04) after 72 hours compared to low dose
  • it is important to note that weight loss during the first 72 hours of treatment in the high-dose group was modest (~3.9 kg) raising concerns about the heterogeneity of the population studied and the efficacy of the treatment given
  • there was no significant difference in the primary safety end point of a change in serum creatinine between the high- and low-dose diuretic groups. However, high-dose diuretic use was associated with transient deterioration in renal function compared to low-dose diuretic use
  • there was no significant difference in the average change in creatinine between continuous infusion and bolus infusion groups.

Some retrospective analyses suggest an inverse relationship between diuretic dose and survival in patients with chronic HF.112,113 The association may be due to diuretic-induced electrolyte abnormalities,114 such as hyponatraemia and hypochloraemia that are themselves associated with worse outcomes,115,116 or may be purely because patients who require diuretics have more severe disease.

ADVOR – Acetazolamide

In the ADVOR study (Acetazolamide in Decompensated Heart Failure with Volume Overload), 519 patients admitted to hospital with HF (mean age, 78 years; mean LVEF, 43%; median NT-proBNP, 6,173 ng/L; median eGFR, 39 ml/min/1.73 m2; all of whom were taking loop diuretic on admission) were randomised to 500 mg IV acetazolamide or placebo, alongside IV furosemide given at twice the usual oral daily dose.117

The median dose of IV furosemide given in the study was only 120 mg per day. This is less than half the mean dose used in the high-dose arm of the DOSE trial,111 and only a fraction of what was permitted in the pharmacological treatment arm of the CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure).118

Although patients randomised to acetazolamide were 46% more likely to meet the primary end point of successful decongestion by day three of treatment (42% vs. 31%; HR 1.47 [95% CI, 1.17–1.82]; p<0.001), this was driven mostly by the effect of acetazolamide in patients receiving ≤120 mg of IV furosemide per day (HR 1.78 [95% CI, 1.33–2.36]).117 In patients receiving >120 mg IV furosemide per day, acetazolamide had very little effect on the primary end point (HR 1.08 [95% CI, 0.76–1.55]).117 Overall, the difference in diuresis by day two of treatment was only 500 ml.

Despite nearly half of patients in the acetazolamide arm achieving successful decongestion by day three, the median time to discharge was three times longer – nine days (95% CI, 8–10 days), compared to ten (95% CI, 9–11 days) in the placebo arm (p<0.001).118 Furthermore, only a third of patients had oedema above the knee. In the UK, over half of patients admitted to hospital have at least moderate oedema (above the level of the knees).119 Most patients with mild oedema are managed as an out-patient, particularly if the oral dose of loop diuretic is low – as was the case in ADVOR (median 60 mg per day on admission).117

Acetazolamide was well tolerated and there was no statistical difference in the safety profile compared to placebo.117 However, there was a trend towards higher rates of renal dysfunction, hypokalaemia, hypotension, and all-cause mortality at three months in the acetazolamide arm.117

CLOROTIC – Hydrochlorothiazide120

In the CLOROTIC study (Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure), 230 patients admitted to hospital with HF (mean age, 82 years; median LVEF, 55%; median NT-proBNP, 4,720 ng/L; median eGFR, 43 ml/min/1.73 m2; all of whom were taking a loop diuretic on admission) were randomised to varying doses of oral hydrochlorothiazide or matching placebo based on baseline eGFR (25 mg per day if eGFR >50 ml/min/1.73 m2; 50 mg per day if eGFR 20–50 ml/min/1.73 m2; 100 mg per day if eGFR <20 ml/min/1.73 m2; equivalent to 2.5 mg, 5 mg and 10 mg per day of bendroflumethiazide or metolazone, respectively) alongside IV furosemide given at the usual oral daily dose. The mean dose of IV furosemide given in the study was 80 mg per day.

The co-primary end points were change in body weight and patient-reported symptoms from baseline to three days. Hydrochlorothiazide was associated with greater weight loss (−2.3 kg vs. −1.5 kg; p=0.002) but had no effect on symptoms. Unlike acetazolamide, hydrochlorothiazide had an additional diuretic effect compared to placebo, regardless of IV furosemide dose. Although not a pre-specified end point, patients randomised to hydrochlorothiazide had fewer symptoms of congestion after three days of treatment. Median length of stay was seven days and was the same, regardless of treatment allocation.

The difference in urine output after 24 hours was 375 ml greater in the hydrochlorothiazide group (1,775 ml vs. 1,400 ml; p=0.05). The difference was statistically significant but might be considered clinically insignificant unless it can be demonstrated to persist throughout hospital admission (~2.5 L extra diuresis across a seven-day treatment period). However, this data was not collected.

While nearly half of patients experienced a mild increase in serum creatinine in the hydrochlorothiazide arm, there was no difference in the proportion of patients with a >50% decrease in the eGFR from baseline and there were more serious adverse renal events in the placebo arm than the hydrochlorothiazide arm. There was no difference in the rate of hyponatraemia between hydrochlorothiazide and placebo, but mild hypokalaemia (≤3.5 mmol/L) was approximately twice as likely with hydrochlorothiazide. There was a trend towards higher rates of all-cause hospitalization and all-cause mortality at three months in the hydrochlorothiazide arm.

The main flaw of both ADVOR and CLOROTIC is the low dose of furosemide used as a comparator. What diuretic effect acetazolamide or hydrochlorothiazide has in patients treated with high-dose furosemide is unanswered by either of these trials.

Calcium-channel blockers

Calcium-channel blockers are not indicated for the treatment of HF, although are commonly used. The PRAISE (Prospective Randomized Amlodipine Survival Evaluation) I and II studies found that amlodipine is safe in patients with HF but had no impact on outcomes.121,122 Verapamil and diltiazem are contraindicated in HF, as are short-acting dihydropyridine agents.1

Statins

There is no convincing evidence that statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] inhibitors) affect outcome for patients with HF. Two large studies (>10,000 patients) found that rosuvastatin conferred no benefit in HF.123,124

Anticoagulants and aspirin

Anticoagulants, such as warfarin or direct-acting oral anticoagulants (DOACs), are indicated for thrombo-embolic prophylaxis in patients with HF and AF.125 There is no evidence that aspirin alone improves the outcome of patients with chronic HF. It counteracts the pharmacological effects of ACE inhibitors and is associated with impaired renal function. It should be used in patients with a recent ischaemic event or percutaneous coronary intervention.

HF is a hypercoagulable state with a higher incidence of stroke than in the general population, regardless of underlying cardiac rhythm,126,127 but there is only limited evidence to support the use of oral anticoagulants in patients with HF in sinus rhythm, without a history of thromboembolism, LV aneurysm or intracardiac thrombus.2,128–130

Evidence

The COMMANDER-HF trial (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) enrolled 5,022 patients (average age, 66 years; median LVEF, 34%; 93% of whom were NYHA class II–III; median NT-proBNP 2,840 ng/L in the rivaroxaban arm) who were randomised to either rivaroxaban 2.5 mg twice daily or matching placebo. The primary outcome was a composite of death, stroke or myocardial infarction. Secondary outcomes included a composite of cardiovascular death or hospitalisation with HF. After median follow up of 21 months, there were no difference between the rivaroxaban or placebo groups in the primary or secondary outcomes. Safety outcomes were comparable, although more patients in the rivaroxaban group had a bleeding event requiring hospital admission than in the placebo group.131

The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) enrolled 27,395 patients with coronary artery disease, peripheral vascular disease or both (~20% of whom had HF) who were randomised to receive either rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone or aspirin 100 mg once daily alone. The primary outcome was a composite of cardiovascular death, stroke or myocardial infarction. The study was discontinued after an average follow up of 23 months with a clear outcome advantage associated with rivaroxaban-plus-aspirin compared to aspirin alone (4.1% vs. 5.4%; p<0.001). There was no difference in outcomes for patients treated with rivaroxaban alone compared to aspirin alone.133

Patients under the age of 65 years had to have additional risk factors, including evidence of atherosclerosis in two different vascular beds or two of either HF, current smoking, diabetes mellitus, eGFR <60 ml/min/1.73 m2 or stroke to be included.132 Coronary artery disease, diabetes mellitus and renal dysfunction are all common co-morbidities in patients with HF and it is conceivable the use of rivaroxaban plus aspirin in patients with HF may become more widespread in the wake of the COMPASS study. However, it should be noted that patients with HF and LVEF <30% or NYHA III-IV were excluded from the COMPASS study and thus the results cannot be applied to all patients with HF and atherosclerotic vascular disease, only those with mild disease.

The COMMANDER-HF results are perhaps the best guide to the use of anticoagulants in patients with HF although the results of the COMPASS study suggest outcome benefit with low-dose rivaroxaban-plus-aspirin for a subset of patients with HF.131,132

Omega-3 polysaturated fatty acids

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In GISSI-HF (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico-Heart Failure) (n=3,481; average age, 67 years; average LVEF, 33%, NYHA II–IV), supplementation with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with standard therapy (93% taking ACE inhibitors/ARBs, 65% taking beta blockers and 39% taking MRAs in the treatment arm) was associated with reduced all-cause mortality (27% vs. 29%; p=0.041) and cardiovascular hospitalisation (57% vs. 59%; p=0.009) compared to placebo in patients with HF.124 However, the small outcome benefit means they are rarely used in practice.

Pharmacological treatment of HF with preserved and mildly reduced ejection fraction

There is much disagreement in the HF community about what constitutes a diagnosis of HFpEF and how it and HF with mildly reduced ejection fraction (HFmrEF) should be treated. This is enormously unhelpful to generalists and patients.

The latest 2023 focused update to the 2021 ESC guidelines for HF now recommend (class I) the use of an SGLT2 inhibitor in patients with symptomatic HFmrEF and HFpEF.31 NICE has followed suit and updated their guidance to include the use of an SGLT2 inhibitor to optimise standard care in patients with HFmrEF and HFpEF on the advice of a HF specialist.1,133 However, the evidence is far from convincing.

Evidence

We include a brief summary of the data below (table 3), but long articles could be written on the merits (or otherwise) of each medication for patients with HFpEF.

The CHARM-Preserved trial of candesartan,134 the PEP-CHF trial (Perindopril for Elderly People with Chronic Heart Failure) of perindopril,135 the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) of spironolactone,136 the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF with Preserved Ejection Fraction) of sacubitril/valsartan,137 the EMPEROR-Preserved trial of empagliflozin,138 and the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) of dapagliflozin139 in patients with HF and a LVEF >40% have all demonstrated a reduction in HF hospitalisation with treatment versus placebo. However, none have shown a reduction in cardiovascular or all-cause mortality.

Table 3. Randomised trials studying various drugs for use in patients with HF which have been incorporated into the 2021 ESC guidelines and the 2023 ESC focused update

Class of drug Trial Number of participants Primary outcome (hazard ratio, p-value)* Secondary outcome(s) (hazard ratio, p-value)*
ACE inhibitor/ARB CONSENSUS37 (1987)
Enalapril vs. placebo
253 All-cause mortality – 40% reduction at six months compared with placebo
SOLVD-treatment39 (1991)
Enalapril vs. placebo
2,569 All-cause mortality reduced with enalapril (0.84, p=0.004) All-cause mortality/hospitalisation for HF (0.74, p<0.0001)
SOLVD-prevention38 (1992)
Enalapril vs. placebo
4,228 All-cause mortality reduced in participants with HF who received enalapril vs. placebo (RR 29%; p<0.001)
ATLAS92 (1999)
High- vs. low-dose lisinopril
3,164 All-cause mortality (0.92, p=0.13, non-significant reduction) CV death (0.90, p=0.07, non-significant).
All-cause mortality/CV hospitalisation
CV death/CV hospitalisation (0.85, p<0.001)
CHARM-added42 (2003)
Candesartan and ACE inhibitor vs. placebo and ACE inhibitor
2,548 CV death or hospitalisation for HF (0.85, p=0.01)
CHARM-alternative43 (2003)
Candesartan vs. placebo (no ACE inhibitor)
2,028 CV death or hospitalisation for HF (0.77, p<0.001)
Beta blocker CIBIS-II65 (1999)
Bisoprolol vs. placebo
2,647 All-cause mortality (0.66, p<0.001) Reduction in sudden death (0.56, p=0.0011)
COPERNICUS140 (2001)
Carvedilol vs. placebo
2,289 All-cause mortality (0.65, p<0.001) All-cause mortality/hospitalisation (0.76, p<0.001)
SENIORS69 (2005)
Nebivolol vs. placebo in patients >70 years
2,128 All-cause mortality or CV hospitalisation (0.86, p=0.04)
MRA RALES58 (1999)
Spironolactone vs. placebo
822 All-cause mortality (0.70, p<0.001)
EMPHASIS-HF60 (2011)
Eplerenone vs. placebo
2,737 CV death or hospitalisation for HF (0.63, p<0.001)
ARNI PARADIGM-HF50 (2014)
Enalapril vs. sacubitril/ valsartan
8,442 CV death or hospitalisation for HF (0.80, p<0.001)
SGLT2 inhibitor DAPA-HF84 (2019)
Dapagliflozin vs. placebo
4,744 Worsening HF or CV death, with or without diabetes (0.74, p<0.001)
DAPA-CKD88 (2020) 4,094 ≥50% ↓ in eGFR or ESRD or death from renal/CV cause (0.61, p<0.001) ≥50% ↓ in eGFR or ESRD or renal death (0.56, p<0.001).
HF hospitalisations or CV death (0.71, p=0.009)
Death any cause (0.69, p=0.004)
EMPEROR-Reduced83 (2020)
Empagliflozin vs. placebo
3,730 Worsening HF or CV death, with or without diabetes (0.75, p<0.001) Hospitalisation for HF (0.70, p<0.001). Composite renal outcome (0.50)
EMPEROR-Preserved138 (2021)
Empagliflozin vs. placebo
5,988 CV death or hospitalisation for HF in patients with or without diabetes (0.79, p<0.001)
DELIVER139 (2022) Dapagliflozin vs. placebo 6,263 Overall worsening HF or CV death (0.82, p<0.001) Total number of worsening HF events and CV deaths (0.77, p<0.001)
* Unless stated otherwise
Adapted from Kalra and Hardy, 2022142
Key: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; ATLAS = Assessment of Lisinopril and Survival Trial; CHARM = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; CIBIS II = Cardiac Insufficiency Bisoprolol Study II; CONSENSUS = Cooperative North Scandinavian Enalapril Survival Study; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival; CV = cardiovascular; DAPA-CKD = Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF = Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER = Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure; eGFR = estimated glomerular filtration rate; EMPEROR-Preserved = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; EMPEROR-Reduced = Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction; EMPHASIS-HF = Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; ESC = European Society of Cardiology; ESRD = end-stage renal disease; HF = heart failure; MRA = mineralocorticoid receptor antagonist; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; RALES = Randomized Aldactone Evaluation Study; RR = risk reduction; SENIORS = Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure; SGLT2 = sodium-glucose co-transporter-2; SOLVD = Studies of Left Ventricular Dysfunction

Of all the trials listed above, only EMPEROR-Preserved and DELIVER reported all-cause hospitalisations (alongside all-cause mortality).138,139 Empagliflozin had no effect on total all-cause hospitalisation, whereas dapagliflozin was associated with a modest reduction (3.8% ARR, 11% RRR) in all-cause hospitalisation.138,139

It is likely that the label of HFpEF represents a heterogenous group of diagnoses contributing, to a varying extent, to the overall clinical picture. Patients with HFpEF are generally older with more co-morbidities, and thus have greater competing risks for morbidity and mortality than do patients with HFrEF. As a result, treatments for HFpEF have only modest effects on rates of HF hospitalisation and, with the exception of dapagliflozin, no effect on all-cause morbidity and mortality. The cost-effectiveness of each treatment is therefore difficult to ascertain.

Guidelines in America and Europe differ and there is little consensus on how to implement the trial results described above. The vast majority of patients with a diagnosis of HFpEF may end up on many of these treatments anyway: treatment with ACE inhibitor, ARB, or MRA may be indicated for hypertension; and treatment with an SGLT2 inhibitor may be indicated for diabetes, CKD or both.

Monitoring1,2

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Relevant QOF indicators

HF005: 50–90% of patients with a diagnosis of HF (diagnosed on or after 1 April 2006) confirmed by an echocardiogram or by specialist assessment three months before or six months after entering on to the register. If newly registered in the preceding 12 months, with no record of the diagnosis originally being confirmed by echocardiogram or specialist assessment, a record of an echocardiogram or a specialist assessment within six months of the date of registration. (6 points)

HF007: 50–90% of patients with a diagnosis of HF on the register, who have had a review in the preceding 12 months, including an assessment of functional capacity and a review of medication to ensure medicines optimisation at maximal tolerated doses. (7 points)

NICE recommends that all patients with chronic HF are monitored at least every six months, and at shorter intervals if the patient’s clinical condition or drug treatment changes. Patients should be offered information and support if they wish to be involved in monitoring their condition and advised what to do if their condition deteriorates.

Patients admitted to hospital with HF should receive specialist advice for their management plan. The minimum checks required when monitoring HF patients are:

  • a clinical review to include:
    • clinical assessment of functional capacity, fluid status, cardiac rhythm, cognitive status and nutritional status
  • medication review (including the need for changes and possible side effects)
  • serum urea, electrolytes, creatinine and eGFR. Monitoring serum potassium is particularly important if a patient is taking digoxin or an MRA
  • ECG – new left bundle branch block appears in around 10% of patients per annum141
  • Monitoring of serum NPs should be considered in some patients (e.g. in those being considered for transplantation).

Conclusion

The pharmacological and non-pharmacological management of HF requires the input of a multidisciplinary team, as well as patient involvement, to deliver positive outcomes, reduce hospital admissions and improve survival.

Lifestyle changes, including exercise and diet as part of a self-management programme that promotes adherence to pharmacological treatment, should be actively promoted. Clinicians should be informed by the current NICE, ESC or SIGN guidelines in order to achieve optimal treatment and outcomes.

Table 4. Overview of recommended pharmacological treatments

Level of recommendation HFrEF HFmrEF HFpEF
Class I Diuretics
SGLT2 inhibitor (dapagliflozin/empagliflozin)
ACE inhibitor/ARNI Treat any underlying causes, CV and non-CV co-morbidities
MRA
Beta blocker
ARB (if unable to tolerate ACE inhibitor/ARNI – losartan, candesartan, valsartan)
Class IIa Ivabradine (in select patients)
Hydralazine/isosorbide dinitrate (in select black patients)
Class IIb Hydralazine/isosorbide dinitrate (in select patients) ACE inhibitor/ARNI
ARB
Digoxin MRA
Vericiguat Beta blocker
Recommendations based on the latest ESC guidelines, but have been amended to be compatible with NICE guidance1–3,31,133,143–146
Key: ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor/neprilysin inhibitor; CV = cardiovascular; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose co-transporter-2

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