2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

3.2.1 Heart failure with preserved, mildly reduced, and reduced ejection fraction

The diagnosis of HFrEF, HFmrEF, and HFpEF is covered in more detail in their respective sections (sections 5, 7, and 8, respectively). These definitions are consistent with a recent report on the Universal Definition of Heart Failure.¹⁵

Patients with non-CV disease, e.g. anaemia, pulmonary, renal, thyroid, or hepatic disease may have symptoms and signs very similar to those of HF, but in the absence of cardiac dysfunction, they do not fulfil the criteria for HF. However, these pathologies can coexist with HF and exacerbate the HF syndrome.

3.2.2 Right ventricular dysfunction

Heart failure can also be a result of right ventricular (RV) dysfunction. RV mechanics and function are altered in the setting of either pressure or volume overload.¹⁶ Although the main aetiology of chronic RV failure is LV dysfunction-induced pulmonary hypertension, there are a number of other causes of RV dysfunction [e.g. MI, arrhythmogenic right ventricular cardiomyopathy (ARVC), or valve disease].¹⁷ The diagnosis is determined by a quantitative assessment of global RV function, most commonly by echocardiography, using at least one of the following measurements: fractional area change (FAC); tricuspid annular plane systolic excursion (TAPSE); and Doppler tissue imaging-derived systolic S′ velocity of the tricuspid annulus. The diagnosis and management of RV dysfunction is covered comprehensively in a recent Heart Failure Association (HFA) position paper.¹⁸

3.2.3 Other common terminology used in heart failure

Heart failure is usually divided into two presentations: chronic heart failure (CHF) and acute heart failure (AHF). CHF describes those who have had an established diagnosis of HF or who have a more gradual onset of symptoms. If CHF deteriorates, either suddenly or slowly, the episode may be described as ‘decompensated’ HF. This can result in a hospital admission or treatment with intravenous (i.v.) diuretic therapy in the outpatient setting. In addition, HF can present more acutely. Both of these are considered in the section on AHF (section 11).

Some individuals with HF may recover completely [e.g. those due to alcohol-induced cardiomyopathy (CMP), viral myocarditis, Takotsubo syndrome, peripartum cardiomyopathy (PPCM), or tachycardiomyopathy]. Other patients with LV systolic dysfunction may show a substantial or even complete recovery of LV systolic function after receiving drug and device therapy.

3.2.4 Terminology related to the symptomatic severity of heart failure

The simplest terminology used to describe the severity of HF is the New York Heart Association (NYHA) functional classification (Table 4). However, this relies solely on symptoms and there are many other better prognostic indicators in HF.¹⁹ Importantly, patients with mild symptoms may still have a high risk of hospitalization and death.²⁰ Predicting outcome is particularly important in advanced HF to guide selection of cardiac transplantation and device therapies. This will be covered in detail in the section on advanced HF (section 10).

3.3.1 Incidence and prevalence

In developed countries, the age-adjusted incidence of HF may be falling, presumably reflecting better management of CV disease, but due to ageing, the overall incidence is increasing.^21-24 Currently, the incidence of HF in Europe is about 3/1000 person-years (all age-groups) or about 5/1000 person-years in adults.^{25, 26} The prevalence of HF appears to be 1–2% of adults.^21,27-31 As studies only usually include recognized/diagnosed HF cases, the true prevalence is likely to be higher.³² The prevalence increases with age: from around 1% for those aged <55 years to >10% in those aged 70 years or over.^33-36 It is generally believed that, of those with HF, about 50% have HFrEF and 50% have HFpEF/HFmrEF, mainly based on studies in hospitalized patients.^{32, 35, 37, 38} The ESC Long-Term Registry, in the outpatient setting, reports that 60% have HFrEF, 24% have HFmrEF, and 16% have HFpEF.³⁹ Somewhat more than 50% of HF patients are female.^{21, 40, 41}

3.3.2 Aetiology of heart failure

The most common causes (as well as some key investigations) of HF are shown in Table 5. The aetiology of HF varies according to geography. In Western-type and developed countries, coronary artery disease (CAD) and hypertension are predominant factors.²⁷

With regard to ischaemic aetiology, HFmrEF resembles HFrEF, with a higher frequency of underlying CAD compared to those with HFpEF.^{38, 42, 43}

3.3.3 Natural history and prognosis

The prognosis of patients with HF has improved considerably since the publication of the first treatment trials a few decades ago. However, it remains poor, and quality of life (QOL) is also markedly reduced. The improvement in prognosis has been confined to those with HFrEF.

Mortality rates are higher in observational studies than in clinical trials.⁴⁴ In the Olmsted County cohort, 1-year and 5-year mortality rates after diagnosis, for all types of HF patients, were 20% and 53%, respectively, between 2000 and 2010.⁴⁵ A study combining the Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts reported a 67% mortality rate within 5 years following diagnosis.⁴⁶ Despite receiving less evidence-based treatment, women have a better survival than men.⁴⁷

Overall prognosis is better in HFmrEF compared to HFrEF.³⁹ Of note, transition in ejection fraction over time is common, and patients who progress from HFmrEF to HFrEF have a worse prognosis than those who remain stable or transition to a higher ejection fraction category.^48-52

HFpEF is generally considered to confer a better survival than HFrEF, but most observational studies show that this difference is negligible.^{45, 46} In contrast, the large MAGGIC meta-analysis concluded that the adjusted mortality risk for patients with HFpEF was considerably lower than in patients with HFrEF.⁵³

Studies from several countries have shown that between 1980 and 2000 survival in HF patients has improved markedly.^{41, 54-57} However, this positive trend may have levelled off since then.⁴⁵

After the initial diagnosis, HF patients are hospitalized once every year on average.⁵⁴ From 2000 to 2010, the mean rate of hospitalization in the Olmsted County cohort was 1.3 per person-year. Interestingly, the majority (63%) of hospitalizations were related to non-CV causes.⁴⁵ Studies from several European countries and the United States (US) have shown that HF hospitalization rates peaked in the 1990s, and then declined.^{54, 55, 58-60} However, in a recent study of incident HF conducted between 1998 and 2017 in the United Kingdom (UK), age-adjusted rates of first hospitalizations increased by 28% for both all-cause and HF admissions, and by 42% for non-CV admissions.⁶¹ These increases were higher in women, perhaps related to higher comorbidity rates. The risk of HF hospitalization is 1.5 times higher in patients with diabetes compared to controls. AF, a higher body mass index (BMI), and higher glycated haemoglobin (HbA1c), as well as a low estimated glomerular filtration rate (eGFR) are strong predictors of HF hospitalizations.²⁹

Due to population growth, ageing, and the increasing prevalence of comorbidities, the absolute number of hospital admissions for HF is expected to increase considerably in the future, perhaps by as much as 50% in the next 25 years.^{24, 62}

4.2.1 Use in the non-acute setting

The diagnostic value of NPs, in addition to signs and symptoms and other diagnostic tests, such as an ECG, has been assessed in several studies in the primary care setting.^68,76-80 The aim of these studies was to either exclude or establish a diagnosis of HF. The Task Force considered studies of adequate quality that included NP cut-off points in their diagnostic algorithms, below which the probability of having HF was extremely low. The upper limits of normal in the non-acute setting are 35 pg/mL for BNP, and 125 pg/mL for NT-proBNP. In these studies, the negative predictive values of NP concentrations below these thresholds range from 0.94 to 0.98.^76-78 Fewer data are available for MR-proANP in CHF than in AHF. A concentration of <40 pmol/L can be used to rule out HF.⁶⁸

5.2.1 Goals of pharmacotherapy for patients with heart failure with reduced ejection fraction

Pharmacotherapy is the cornerstone of treatment for HFrEF and should be implemented before considering device therapy, and alongside non-pharmacological interventions.

There are three major goals of treatment for patients with HFrEF: (i) reduction in mortality, (ii) prevention of recurrent hospitalizations due to worsening HF, and (iii) improvement in clinical status, functional capacity, and QOL.^100-102

The key evidence supporting the recommendations in this section for patients with symptomatic HFrEF is given in Supplementary Table 1.

Figure 2 depicts the algorithm for the treatment strategy, including drugs and devices in patients with HFrEF, for Class I indications for the reduction of mortality (either all-cause or CV). The recommendations for each treatment are summarized below.

5.2.2 General principles of pharmacotherapy for heart failure with reduced ejection fraction

Modulation of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems with angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) has been shown to improve survival, reduce the risk of HF hospitalizations, and reduce symptoms in patients with HFrEF. These drugs serve as the foundations of pharmacotherapy for patients with HFrEF. The triad of an ACE-I/ARNI, a beta-blocker, and an MRA is recommended as cornerstone therapies for these patients, unless the drugs are contraindicated or not tolerated.^103-105 They should be uptitrated to the doses used in the clinical trials (or to maximally tolerated doses if that is not possible). This guideline still recommends the use of ARNI as a replacement for ACE-I in suitable patients who remain symptomatic on ACE-I, beta-blocker, and MRA therapies; however, an ARNI may be considered as a first-line therapy instead of an ACE-I.^{106, 107} The recommended doses of these drugs are given in Table 8. Angiotensin-receptor blockers (ARBs) still have a role in those who are intolerant to ACE-I or ARNI.

The sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin added to therapy with ACE-I/ARNI/beta-blocker/MRA reduced the risk of CV death and worsening HF in patients with HFrEF.^{108, 109} Unless contraindicated or not tolerated, dapagliflozin or empagliflozin are recommended for all patients with HFrEF already treated with an ACE-I/ARNI, a beta-blocker, and an MRA, regardless of whether they have diabetes or not.

Other drugs may be used for selected patients with HFrEF. These are discussed in section 5.4.

5.3.1 Angiotensin-converting enzyme inhibitors

ACE-Is were the first class of drugs shown to reduce mortality and morbidity in patients with HFrEF.^110-113 They have also been shown to improve symptoms.¹¹¹ They are recommended in all patients unless contraindicated or not tolerated. They should be uptitrated to the maximum tolerated recommended doses.

Practical guidance on how to use ACE-Is is given in Supplementary Table 2.

5.3.2 Beta-blockers

Beta-blockers have been shown to reduce mortality and morbidity in patients with HFrEF, in addition to treatment with an ACE-I and diuretic.^114-120 They also improve symptoms.¹²³ There is consensus that ACE-I and beta-blockers can be commenced together as soon as the diagnosis of symptomatic HFrEF is established. There is no evidence favouring the initiation of a beta-blocker before an ACE-I and vice versa.¹²⁴ Beta-blockers should be initiated in clinically stable, euvolaemic, patients at a low dose and gradually uptitrated to the maximum tolerated dose. In patients admitted with AHF, beta-blockers should be cautiously initiated in hospital, once the patient is haemodynamically stabilized.

An individual patient data (IPD) meta-analysis of all major beta-blocker trials in HFrEF has shown no benefit on hospital admissions and mortality in the subgroup of patients with HFrEF with AF.¹²⁵ However, since this is a retrospective subgroup analysis, and because beta-blockers did not increase risk, the guideline committee decided not to make a separate recommendation according to heart rhythm.

Practical guidance on how to use beta-blockers is given in Supplementary Table 3.

5.3.3 Mineralocorticoid receptor antagonists

MRAs (spironolactone or eplerenone) are recommended, in addition to an ACE-I and a beta-blocker, in all patients with HFrEF to reduce mortality and the risk of HF hospitalization.^121,122 They also improve symptoms.¹²¹ MRAs block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormones (e.g. corticosteroid and androgen) receptors. Eplerenone is more specific for aldosterone blockade and, therefore, causes less gynaecomastia.

Caution should be exercised when MRAs are used in patients with impaired renal function and in those with serum potassium concentrations >5.0 mmol/L.

Practical guidance on how to use MRAs is given in Supplementary Table 4.

5.3.4 Angiotensin receptor-neprilysin inhibitor

In the PARADIGM-HF trial, sacubitril/valsartan, an ARNI, was shown to be superior to enalapril in reducing hospitalizations for worsening HF, CV mortality, and all-cause mortality in patients with ambulatory HFrEF with LVEF ≤40% (changed to ≤35% during the study). Patients in the trial had elevated plasma NP concentrations, an eGFR ≥30 mL/min/1.73 m² and were able to tolerate enalapril and then sacubitril/valsartan during the run-in period.¹⁰⁵ Additional benefits of sacubitril/valsartan included an improvement in symptoms and QOL,¹⁰⁵ a reduction in the incidence of diabetes requiring insulin treatment,¹²⁶ and a reduction in the decline in eGFR,¹²⁷ as well as a reduced rate of hyperkalaemia.¹²⁸ Additionally, the use of sacubitril/valsartan may allow a reduction in loop diuretic requirement.¹²⁹ Symptomatic hypotension was reported more commonly in patients treated with sacubitril/valsartan as compared to enalapril, but despite developing hypotension, these patients also gained clinical benefits from sacubitril/valsartan therapy.^{128, 130}

Therefore, it is recommended that an ACE-I or ARB is replaced by sacubitril/valsartan in ambulatory patients with HFrEF, who remain symptomatic despite optimal treatment outlined above. Two studies have examined the use of ARNI in hospitalized patients, some of whom had not been previously treated with ACE-I. Initiation in this setting appears safe and reduces subsequent CV death or HF hospitalizations by 42% compared to enalapril.^{106, 107, 131} As such, initiation of sacubitril/valsartan in ACE-I naive (i.e. de novo) patients with HFrEF may be considered (class of recommendation IIb, level of evidence B). Patients being commenced on sacubitril/valsartan should have an adequate blood pressure (BP), and an eGFR ≥30 mL/min/1.73 m². A washout period of at least 36 h after ACE-I therapy is required in order to minimize the risk of angioedema.

Practical guidance on how to use ARNI is given in Supplementary Table 5.

5.3.5 Sodium-glucose co-transporter 2 inhibitors

The DAPA-HF trial investigated the long-term effects of dapagliflozin (SGLT2 inhibitor) compared to placebo in addition to optimal medical therapy (OMT), on morbidity and mortality in patients with ambulatory HFrEF.¹⁰⁸ Patients participated in the trial if they were in NYHA class II–IV, and had an LVEF ≤40% despite OMT. Patients were also required to have an elevated plasma NT-proBNP and an eGFR ≥30 mL/min/1.73 m².¹⁰⁸

Therapy with dapagliflozin resulted in a 26% reduction in the primary endpoint: a composite of worsening HF (hospitalization or an urgent visit resulting in i.v. therapy for HF) or CV death. Both of these components were significantly reduced. Moreover, dapagliflozin reduced all-cause mortality,¹⁰⁸ alleviated HF symptoms, improved physical function and QOL in patients with symptomatic HFrEF.¹³² Benefits were seen early after the initiation of dapagliflozin, and the absolute risk reduction was large. Survival benefits were seen to the same extent in patients with HFrEF with and without diabetes, and across the whole spectrum of HbA1c values.¹⁰⁸

Subsequently, the EMPEROR-Reduced trial found that empagliflozin reduced the combined primary endpoint of CV death or HF hospitalization by 25% in patients with NYHA class II–IV symptoms, and an LVEF ≤40% despite OMT.¹⁰⁹ This trial included patients with an eGFR >20 mL/min/1.73 m² and there was also a reduction in the decline in eGFR in individuals receiving empagliflozin. It was also associated with an improvement in QOL.¹³³ Although there was not a significant reduction in CV mortality in the EMPEROR-Reduced trial, a recent meta-analysis of the DAPA-HF and EMPEROR-Reduced trials found no heterogeneity in CV mortality.¹³⁴

Therefore, dapagliflozin or empagliflozin are recommended, in addition to OMT with an ACE-I/ARNI, a beta-blocker and an MRA, for patients with HFrEF regardless of diabetes status. The diuretic/natriuretic properties of SGLT2 inhibitors may offer additional benefits in reducing congestion and may allow a reduction in loop diuretic requirement.¹³⁵

The combined SGLT-1 and 2 inhibitor, sotagliflozin, has also been studied in patients with diabetes who were hospitalized with HF. The drug reduced CV death and hospitalization for HF.¹³⁶ It is discussed further in the AHF and comorbidity sections.

Therapy with SGLT2 inhibitors may increase the risk of recurrent genital fungal infections. A small reduction in eGFR following initiation is expected and is reversible and should not lead to premature discontinuation of the drug.

Practical guidance on how to use the SGLT2 inhibitors dapagliflozin and empagliflozin are given in Supplementary Table 6.

5.4.1 Diuretics

Loop diuretics are recommended to reduce the signs and/or symptoms of congestion in patients with HFrEF. The quality of the evidence regarding diuretics is poor and their effects on morbidity and mortality have not been studied in RCTs. However, it should also be remembered that the major disease-modifying treatment trials for HFrEF were conducted with a high background use of loop diuretic therapy. One meta-analysis has shown that in patients with HFrEF, loop and thiazide diuretics appear to reduce the risk of death and worsening HF compared with a placebo, and compared with an active control, diuretics improve exercise capacity.¹³⁷

Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically (sequential nephron blockade) and the combination may be used to treat diuretic resistance. However, adverse effects are more likely, and these combinations should only be used with care. Of note, ARNI, MRAs, and SGLT2 inhibitors may also possess diuretic properties.^{129, 145}

The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest diuretic dose. In some euvolaemic/hypovolaemic patients, the use of a diuretic drug might be reduced or discontinued.¹⁴⁶ Patients should be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements.

Practical guidance on how to use diuretics is given in Supplementary Table 7.

5.4.2 Angiotensin II type 1 receptor blockers

The place of ARBs in the management of HFrEF has changed over the last few years. They are now recommended for patients who cannot tolerate ACE-I or ARNI because of serious side effects. Candesartan in the CHARM-Alternative study reduced CV deaths and HF hospitalizations in patients who were not receiving an ACE-I due to previous intolerance.¹³⁸ Valsartan, in addition to usual therapy, including ACE-I, reduced HF hospitalizations in the Val-HeFT trial.¹⁴⁷ However, no ARB has reduced all-cause mortality in any trial.

5.4.3 I_f-channel inhibitor

Ivabradine slows heart rate by inhibition of the I_f channel in the sinus node and is therefore only effective in patients in sinus rhythm (SR). Ivabradine reduced the combined endpoint of CV mortality and HF hospitalization in patients with symptomatic HFrEF with an LVEF ≤35%, with HF hospitalization in recent 12 months, in SR and with a heart rate ≥70 b.p.m. who were on evidence-based therapy including an ACE-I (or ARB), a beta-blocker, and an MRA.^139,140 Our recommendation is based on the heart rate of ≥70 b.p.m. used in the SHIFT trial. However, the European Medicines Agency (EMA) approved ivabradine for use in Europe in patients with HFrEF with LVEF ≤35% and in SR with a resting heart rate ≥75 b.p.m., because in this group ivabradine conferred a survival benefit¹⁴⁸ based on a retrospective subgroup analysis. Every effort should be made to commence and uptitrate beta-blocker therapy to guideline recommended/maximally tolerated doses prior to considering ivabradine.

Practical guidance on how to use ivabradine is given in Supplementary Table 8.

5.4.4 Combination of hydralazine and isosorbide dinitrate

There is no clear evidence to suggest the use of this fixed-dose combination therapy in all patients with HFrEF. A small RCT conducted in self-identified black patients showed that an addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy (an ACE-I, a beta-blocker, and an MRA) reduced mortality and HF hospitalizations in patients with HFrEF and NYHA classes III–IV.¹⁴² These results are difficult to translate to patients of other racial or ethnic origins.

Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who cannot tolerate any of an ACE-I, ARNI, or an ARB (or if they are contraindicated) to reduce mortality. However, this recommendation is based on the results of the relatively small Veterans Administration Cooperative Study, which included only male patients with symptomatic HFrEF who were treated with digoxin and diuretics.¹⁴³

5.4.5 Digoxin

Digoxin may be considered in patients with HFrEF in SR to reduce the risk of hospitalization,¹⁴⁴ although its effect on those routinely treated with beta-blockers has not been tested. In the DIG trial, the overall effect on mortality with digoxin was neutral.

The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs. Some studies have suggested a potentially higher risk of events in patients with AF receiving digoxin,^{149, 150} whereas another meta-analysis concluded, on the basis of non-RCTs, that digoxin has no deleterious effect on mortality in patients with AF and HF, most of whom had HFrEF.¹⁵¹ Therefore, in patients with symptomatic HF and AF, digoxin may be useful for the treatment of patients with HFrEF and AF with rapid ventricular rate, when other therapeutic options cannot be pursued.^{150, 152-155}

Digoxin has a narrow therapeutic window and so levels should be checked aiming for a serum digoxin concentration <1.2 ng/mL.^{156, 157} Caution should also be exercised when using it in females, the elderly, frail, hypokalaemic, and malnourished subjects. In patients with reduced renal function, digitoxin could be considered. Digitoxin use in HF and SR is currently being investigated.¹⁵⁸

5.4.6 Recently reported advances from trials in heart failure with reduced ejection fraction

Soluble guanylate cyclase stimulator

The VICTORIA study assessed the efficacy and safety of the oral soluble guanylate cyclase stimulator, vericiguat, in patients with a reduced EF and recently decompensated CHF. The incidence of the primary endpoint of death from CV causes or hospitalization for HF was lower among those who received vericiguat than among those who received placebo.¹⁴¹ There was no reduction in either all-cause or CV mortality. Thus, vericiguat may be considered, in addition to standard therapy for HFrEF, to reduce the risk of CV mortality and hospitalizations for HF.

Cardiac myosin activator

The GALACTIC-HF study assessed the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil, in HFrEF patients, enrolling patients in both the inpatient and outpatient settings. The primary endpoint of a first HF event or CV death was reduced by 8%. There was no significant reduction in CV mortality. Currently, this drug is not licensed for use in HF. However, in the future it may be able to be considered, in addition to standard therapy for HFrEF to reduce the risk of CV mortality and hospitalization for HF.¹⁵⁹

6.1.1 Secondary prevention of sudden cardiac death

Compared with amiodarone treatment, ICDs reduce mortality in survivors of cardiac arrest and in patients who have experienced sustained symptomatic ventricular arrhythmias. An ICD is recommended in such patients when the intent is to increase survival; the decision to implant should take into account the patient’s view and their QOL, the LVEF (survival benefit is uncertain when LVEF >35%) and the absence of other diseases likely to cause death within the following year.^162-164,184

6.1.2 Primary prevention of sudden cardiac death

In an analysis of over 40 000 patients from 12 pivotal HF trials, rates of sudden cardiac death decreased by 44% over the 20-year period (from the mid-1990s to 2015).¹⁶⁰ This is almost certainly due to advances in HF treatment, as many key guideline-recommended therapies, including beta-blockers, MRAs, sacubitril/valsartan, and CRT pacemakers (CRT-P), reduce the risk of sudden death. While the afore-mentioned HF therapies have been shown to reduce mortality in patients with HFrEF, amiodarone has not.¹⁶¹ However, if it is to be used, it should be with caution due to its significant side-effect profile. Conversely, dronedarone¹⁸⁵ and the class I antiarrhythmic agents disopyramide, encainide, and flecainide¹⁸⁶ should not be used for prevention of arrhythmias due to the increase in mortality seen in clinical studies.

Although an ICD reduces the rate of sudden arrhythmic death in patients with HFrEF,¹⁸⁷ it would be expected that, in well-managed patients, the additional benefit afforded by an ICD would be lower. In the DANISH trial, rates of sudden death were low in patients with non-ischaemic cardiomyopathy (NICM); only 70 patients out of 1116 followed up over 5 years had sudden death.¹⁶⁶ Whilst there was a modest absolute reduction in sudden death with a defibrillator-containing device, this did not significantly improve the overall risk of mortality. However, subgroup analysis suggested there was a benefit in those ≤70 years.¹⁸⁸ In a recent meta-analysis of studies that examined the effect of ICDs in NICM a survival benefit was still seen, although the effect was significantly weakened by the inclusion of the DANISH trial.¹⁶⁷

On average, patients with IHD are at greater risk of sudden death than patients with NICM and therefore, although the relative benefits are similar, the absolute benefit is greater in patients with IHD.¹⁸⁷ Two RCTs showed no benefit in patients who had an ICD implanted within 40 days after a MI.^{177, 178} Although sudden arrhythmic deaths were reduced, this was balanced by an increase in non-arrhythmic deaths. Accordingly, an ICD for primary prevention is contraindicated in this time period. Furthermore, ICD implantation is recommended only if a minimum of 3 months of OMT has failed to increase the LVEF to >35%. OMT ideally includes the use of Class I recommended drugs for HFrEF. However, the ICD trials we cite predate the use of ARNI and SGLT2 inhibitors. Whether implantation of ICDs reduces mortality in those with an LVEF >35% is unknown. There is an ongoing trial of ICD therapy in such patients with the presence of scar on CMR imaging.¹⁸⁹

6.1.3 Patient selection for implantable cardioverter-defibrillator therapy

Patients with HFrEF and a QRS duration ≥130 ms can be considered for CRT with a defibrillator (CRT-D) rather than ICD. See the section on CRT for further details (section 6.2).

In patients with moderate or severe HF, a reduction in sudden death may be partially or wholly offset by an increase in death due to worsening HF.¹⁶¹ As such, ICD therapy is not recommended in patients in NYHA class IV, with severe symptoms refractory to pharmacological therapy, who are not candidates for a ventricular assist device (VAD) or cardiac transplantation. Such patients have a very limited life expectancy and are likely to die from pump failure. Similarly, patients with serious comorbidities who are unlikely to survive substantially more than 1 year with good QOL are unlikely to obtain substantial benefit from an ICD.^179-183

Although the DANISH trial did not show a significant benefit from ICD therapy in patients with NICM, it should be remembered that NICM is a heterogeneous condition, and certain subgroups (e.g. laminopathies, sarcoidosis) are at higher risk of sudden death and therefore merit careful consideration of ICD implantation. Tools to help risk stratification (e.g. scar burden on magnetic resonance imaging) can be helpful in that regard.^190-192

Patients should be counselled as to the purpose of an ICD and involved in the decision-making process. They should also be aware of the potential complications related to implantation, any additional implications for driving, and the risk of inappropriate shocks. Furthermore, patients should be informed about the circumstances where the defibrillator (or defibrillator component of a CRT-D) might be deactivated (e.g. terminal disease) or explanted (e.g. infection or recovery of LV function).¹⁹³ Subsequent timely conversations regarding defibrillator deactivation should be held with the patient and caregiver(s).

When an ICD generator reaches its end of life or requires explantation, it should not be replaced automatically. Rather, shared decision making should be undertaken.^168-172 Patients should be carefully evaluated by an experienced cardiologist as treatment goals may have changed since implantation (the risk of fatal arrhythmia may be lower, or the risk of non-arrhythmic death may be higher). It is a matter of some controversy whether patients whose LVEF has greatly improved and who have not required device therapy during the lifetime of the ICD should have another device implanted.^168-172

6.1.4 Implantable cardioverter-defibrillator programming

Routine defibrillation threshold testing is no longer performed following implantation of an ICD or CRT-D as it does not improve shock efficacy or reduce arrhythmic death.¹⁹⁴ Conservative programming with long delays¹⁹⁵ between detection and the ICD delivering therapy dramatically reduces the risk of both inappropriate and appropriate but unnecessary shocks.^{194, 196, 197} Generally, for primary prevention, defibrillators are programmed to minimize pacing (e.g. ventricular demand pacing VVI at 40/min), and with a tachycardia treatment zone >200/min.^{194, 198} Ultimately—and particularly for secondary prevention—programming should be adapted according to the patient’s specific needs.

6.1.5 Subcutaneous and wearable implantable cardioverter-defibrillators

Subcutaneous ICDs (S-ICDs) appear to be as effective as conventional transvenous ICDs with a similar complication rate. Although the risk of inappropriate shocks appeared to be higher initially, improved patient selection has shown S-ICDs are non-inferior to transvenous ICDs in this regard.^199-202 They may be the preferred option for patients with difficult venous access or those who require ICD explantation due to infection. Patients must be carefully selected, as S-ICDs cannot treat bradyarrhythmia (except post-shock pacing) and cannot deliver either anti-tachycardia pacing or CRT. Substantial RCTs with these devices and more long-term data on safety and efficacy are awaited.

A wearable cardioverter-defibrillator that is able to recognize and treat ventricular arrhythmias may be considered for a limited period of time in selected patients with HF who are at high risk for sudden death but otherwise are not suitable for ICD implantation.^{162, 175, 176, 203} However, the large VEST trial failed to show that the wearable cardioverter-defibrillator reduced arrhythmic death in patients with an LVEF ≤35% following a recent acute MI.²⁰⁴

For more detailed recommendations on the use/indications of ICD we refer the reader to the ESC/European Heart Rhythm Association (EHRA) Guidelines on ventricular tachyarrhythmias and sudden cardiac death.²⁰¹

7.3.1 Angiotensin-converting enzyme inhibitors

There are no specific trials of ACE-I in patients with HFmrEF. Although, the PEP-CHF trial was conducted in patients with HFpEF and included patients with an LVEF >40%, it did not report outcomes according to LVEF.¹¹

However, in patients with HFmrEF, many will also have CAD, hypertension, or post-MI LV systolic dysfunction and will, therefore, already be treated with ACE-I.

Therefore, ACE-I use may be considered in patients with HFmrEF.

7.3.2 Angiotensin receptor II type 1 receptor blockers

There are no specific trials of ARBs in HFmrEF. The CHARM-Preserved trial missed its primary endpoint of CV death or HF hospitalizations.²⁴⁶ However, a retrospective analysis showed that candesartan reduced the number of patients hospitalized for HF among those with HFmrEF (with similar trends for CV and all-cause mortality).⁸ Moreover, a recurrent-event analysis suggested a reduction in hospitalizations for HF among the entire CHARM-Preserved cohort, including those with HFmrEF.²⁴⁹

As for ACE-I, many with HFmrEF will already be on an ARB for other CV indications. Therefore, treatment with ARBs may be considered in patients with HFmrEF.

7.3.3 Beta-blockers

There is no specific trial of beta-blockade in HFmrEF. An IPD meta-analysis of landmark trials of beta-blockers suggested similar reductions in CV and all-cause mortality (of 50%) for patients in SR with HFrEF and HFmrEF.¹² This IPD meta-analysis included the SENIORS trial where nebivolol reduced the composite primary endpoint of all-cause mortality or CV hospital admissions in the overall population. No interaction between LVEF (35% of patients had an LVEF of 35–50%) and the effect of nebivolol on the primary outcome was observed.^119,250 Many patients with HFmrEF may have another CV indication, such as AF or angina, for a beta-blocker. Therefore, treatment with beta-blockers may be considered in patients with HFmrEF.

7.3.4 Mineralocorticoid receptor antagonists

There is no specific trial of MRAs in HFmrEF. In a retrospective analysis of the TOPCAT trial in patients with an LVEF ≥45%,⁹ spironolactone reduced hospitalizations for HF in those with an LVEF <55%. There was a similar trend for CV but not all-cause mortality.

Treatment with an MRA may be considered in patients with HFmrEF.

7.3.5 Angiotensin receptor-neprilysin inhibitor

There is no specific trial of ARNI in HFmrEF. In the PARAGON-HF trial, which included patients with EF ≥45%, although the trial missed its primary endpoint overall, a significant EF-by-treatment interaction was observed. Sacubitril/valsartan, compared with valsartan, reduced the likelihood of the primary composite outcome of CV death and total HF hospitalizations by 22% in those with an EF below or equal to the median of 57%.¹³ Further data are available from a combined analysis of the PARADIGM-HF and PARAGON-HF trials showing that sacubitril/valsartan, compared to other forms of RAAS blockade, has a beneficial effect, especially on hospitalizations for HF in those with HFmrEF.²⁴⁸

Treatment with an ARNI may be considered in patients with HFmrEF.

7.3.6 Other drugs

In the DIG trial,¹⁰ for those with HFmrEF in SR, there was a trend to fewer hospitalizations for HF in those assigned to digoxin, but no reduction in mortality and a trend to an excess of CV deaths. Therefore, there are insufficient data to recommend its use.

There are also insufficient data on ivabradine in HFmrEF to draw any conclusions.

7.3.7 Devices

While post hoc analyses of landmark CRT trials suggest that CRT may benefit patients with LVEF >35%, trials of CRT for HFmrEF were abandoned due to poor recruitment.²⁵¹ There are no substantial trials of ICDs for primary prevention of ventricular arrhythmias for HFmrEF; trials conducted more than 20 years ago suggested no benefit from ICD implantation for secondary prevention of ventricular arrhythmias for HFmrEF.

Therefore, there is insufficient evidence to advise CRT or ICD therapy in patients with HFmrEF.

In HF patients with an LVEF ≥40%, the implantation of an interatrial shunt device was found to be safe, and this device is subject to investigation in a larger study before any recommendation on their use in HFpEF or HFmrEF can be given.²⁵²

10.2.1 Pharmacological therapy and renal replacement

Inotropes may improve haemodynamic parameters, reducing congestion, augmenting cardiac output, and aiding peripheral perfusion. Although not proven, this may help to prevent worsening end-organ function. Conversely, traditional inotropes may favor myocardial ischaemia and/or tachyarrhythmias and worsen the clinical course.^388,389 They can be used as palliative therapy for the relief of symptoms in patients without other treatment options. Intermittent long-term use of inotropes may be considered in outpatients to improve functional class and QOL.^390,391

Kidney dysfunction and loop diuretic resistance often characterize the clinical course of patients with advanced HF. Doubling of the loop diuretic dose is proposed, in the first instance, followed by concomitant administration of thiazides or metolazone (see section 11.3.3).¹⁴⁵ In patients who fail to respond to diuretic-based strategies, renal replacement therapies should be considered. Ultrafiltration is one of the most common approaches. It may be considered in those with diuretic resistance even if data about its effects on outcomes are unsettled.^392,393

10.2.2 Mechanical circulatory support

MCS can improve survival and symptoms of patients with advanced HF.^377,394 The use of MCS should be considered for the different scenarios listed in Table 15. Indications for short- and long-term MCS should be based on the INTERMACS profiles (Table 14, Figure 4).

Short-term mechanical circulatory support

Short-term MCS devices are indicated to reverse critical end-organ hypoperfusion and hypoxia in the setting of cardiogenic shock. They can be used for a short, limited, period of time, from a few days up to several weeks. The aim is to support the central nervous system and organ perfusion, to reverse acidosis and multi-organ failure until the patient’s outcome becomes clearer be that of cardiac recovery, transition to durable MCS or heart transplantation, or, in some cases, towards a more palliative approach. The care of patients on short-term MCS is complex and requires dedicated expertise including having specific plans for stopping support when neither cardiac nor brain injury recovers. Short-term MCS should be used in patients with INTERMACS profiles 1 or 2 as a bridge to decision (BTD), bridge to recovery (BTR), bridge to bridge (BTB) for either long-term MCS or urgent heart transplantation (Figure 4).³⁹⁵ Further details about short-term MCS are reported in the Supplementary text 11.4.

Long-term mechanical circulatory support

Long-term MCS is indicated in selected patients when MT is insufficient or when short-term MCS has not led to cardiac recovery or clinical improvement, to prolong life and improve QOL, or to keep the patient alive until transplantation (bridge to transplantation, BTT) or to reverse contraindications to heart transplantation (bridge to candidacy, BTC), or as destination therapy (DT) (Table 15).

Long-term MCS should be considered in patients with INTERMACS profiles 2 to 4 and also in patients with INTERMACS profile 5–6, when they have high-risk characteristics. Patients with no irreversible end-organ failure other than cardiac, recovering from INTERMACS level 1 while on short-term MCS, may also qualify for long-term MCS (Figure 4).^{377,379,384,396-403} The characteristics of patients potentially eligible for implantation of an LVAD are reported in Table 16.

The details of the devices and studies on long-term MCS are summarized in Supplementary Table 15.

Current 2-year survival rates in patients receiving the latest continuous-flow LVADs are comparable to those after heart transplantation, although adverse events negatively affect QOL. Among patients with continuous flow LVADs, actuarial survival was reported of 80% at 1 year and 70% at 2 years.^404,405 Two-year survival was 84.5% and survival free of disabling stroke or need of reoperation for LVAD malfunction was 76.9% with a centrifugal-flow LVAD in MOMENTUM 3.⁴⁰⁶ The fully magnetically levitated centrifugal-flow LVAD has significantly reduced pump thrombosis. In MOMENTUM 3, the need for reoperation to replace a malfunctioning device was 2.3% per 24 months, with only 0.6% per 24 months risk of pump replacement because of pump thrombosis. Stroke (namely, disabling stroke), major bleeding, and gastrointestinal haemorrhage were also lower in the centrifugal-flow pump group than in the axial-flow pump group. However, the incidence of all bleeding events, thromboembolism and driveline infection remained similar to that with older devices.⁴⁰³

Data on fully magnetically centrifugal-flow LVAD use in real-world studies with the 2-year outcomes from the ELEVATE registry showed an overall survival of 74.5%, with gastrointestinal bleeding in 9.7%, stroke in 10.2%, and pump thrombosis in 1.5% of patients.⁴⁰⁷ According to the IMACS Registry, a new composite endpoint including QOL and adverse events beyond survival was proposed to help in guiding decision making. In this sense ‘living well at one year’ defined as freedom from death, stroke, bleeding requiring operation, RV assist device, pump replacement, or device-related infection within the first year, was 56.8% after isolated, centrifugal flow-LVAD.³⁸⁴

Although now outdated, REMATCH was the only RCT comparing an LVAD as DT with OMT in patients with advanced HF, NYHA class IV and a contraindication to transplantation. REMATCH showed lower all-cause mortality with LVAD therapy when compared with medical treatment (primary endpoint). However, there were high mortality rates at 2 years in both arms.³⁷⁹ Other studies were not randomized (INTrEPID, ROADMAP)^397,408,409 or compared different devices (ADVANCE, ENDURANCE, MOMENTUM 3).^400,403,410 The two strategies of early LVAD implantation vs. medical treatment with LVAD implantation only after serious deterioration of the patient's condition are currently being compared in a prospective trial, Early-VAD (ClinicalTrials.gov Identifier: NCT02387112). Also, the Swedish evaluation of LVAD (SweVAD) study is comparing the survival of patients with advanced HF ineligible for heart transplantation prospectively randomized to LVAD as DT vs. MT (ClinicalTrials.gov Identifier: NCT02592499).⁴¹¹

10.2.3 Heart transplantation

Heart transplantation remains the gold standard for the treatment of advanced HF in the absence of contraindications. Post-transplant 1-year survival is around 90% with a median survival of 12.5 years.^386,412,413 Transplantation significantly improves QOL and functional status, although, for unclear reasons, the percentage of patients returning to work is lower than expected.⁴¹³ Apart from primary graft dysfunction, the main challenges after heart transplantation relate to either the efficacy or side effects of immunosuppression (e.g. rejection, infection, cardiac allograft vasculopathy, late graft dysfunction, malignancy, renal failure, hypertension, diabetes mellitus).

Organ donor shortage remains the main limitation to heart transplantation. Thus, the donor heart criteria have now been extended to allow an increased upper limit of the donor age, particularly in Europe. Moreover, careful recipient selection is needed, based on pre-transplant and post-transplant life expectancy (both are influenced by pre-operative status and comorbidities).

The main indications and contraindications for heart transplantation are listed in Table 17.^377,386

Active infection is a relative contraindication to transplant but in some cases of infected LVADs it may actually be an indication. Elderly age is not an absolute contraindication. Although patients aged <65 years might be more appropriate candidates due to their overall life expectancy, most programmes accept patients up to 70 years of age, and biological age as well as chronological age must be taken into account. Surgical complexity [previous sternotomies, mediastinal radiation, adult congenital heart disease (ACHD)] should also be considered.

The decision pathway to transplantation or LVAD is never straightforward and is unique to each patient. Eligibility for each option may change according to the particular conditions of each patient, which may also change over time. Other factors, not related to the patient, such as time on the heart transplant waiting list, the centre’s surgical experience, and resources, can also influence decision making.⁴¹⁴

10.2.4 Symptom control and end-of-life care

While the disease trajectory of each patient with HF is unique, there is a generalizable pattern of gradual decline, punctuated by episodes of acute deterioration leading either to sudden death or death due to progressive HF. Communication about the disease trajectory and anticipatory planning should start when a patient is diagnosed with advanced HF. Indications for and key components of a palliative care service are reported in Tables 18 and 19.^313,419

A team-based approach to palliative and end-of-life care for patients with HF has been proposed.⁴²⁰ Specific models of palliative care for patients with advanced HF have been also reported. They reduce hospitalizations, without a clear effect on survival, and have some effects on QOL and symptom burden.^421,422

Symptom assessment should be performed on a regular basis. In addition to clinical assessment, symptoms can be assessed using the Numeric Rating Scale, the Edmonton Symptom Assessment Scale (ESAS) or ESAS-HF, or the Integrated Palliative care Outcome Scale.

Proactive decisions and advanced planning with regard to palliative and end-of-life care discussions should be documented, regularly reviewed, and routinely communicated to all those involved in the patient’s care. Healthcare providers should make sure that patients’ and carer preferences are followed, wherever possible. They should also take into account that patients may choose not to, or may not be in a position to, express preferences (e.g. due to symptoms of depression or cognitive impairment).

11.2.1 Acute decompensated heart failure

Acute decompensated heart failure (ADHF) is the most common form of AHF, accounting for 50–70% of presentations.^427,428,433 It usually occurs in patients with history of HF and previous cardiac dysfunction across the spectrum of LVEF and may include RV dysfunction. Distinct from the acute pulmonary oedema phenotype, it has a more gradual onset, and the main alteration is progressive fluid retention responsible for systemic congestion. Sometimes, congestion is associated with hypoperfusion.⁴²⁷ The objectives of treatment are identification of precipitants, decongestion, and in rare instances, correction of hypoperfusion (Figure 7).

11.2.2 Acute pulmonary oedema

Acute pulmonary oedema is related to lung congestion. Clinical criteria for acute pulmonary oedema diagnosis include dyspnoea with orthopnoea, respiratory failure (hypoxaemia-hypercapnia), tachypnoea, >25 breaths/min, and increased work of breathing.⁴⁴⁹

Three therapies should be commenced, if indicated. First, oxygen, given as continuous positive airway pressure, non-invasive positive-pressure-ventilation and/or high-flow nasal cannula, should be started. Second, i.v. diuretics should be administered, and third, i.v. vasodilators may be given if systolic BP (SBP) is high, to reduce LV afterload (Figure 8). In a few cases of advanced HF, acute pulmonary oedema may be associated with low cardiac output and, in this case, inotropes, vasopressors, and/or MCS are indicated to restore organ perfusion.

11.2.3 Isolated right ventricular failure

RV failure is associated with increased RV and atrial pressure and systemic congestion. RV failure may also impair LV filling, and ultimately reduce systemic cardiac output, through ventricular interdependence.⁴⁵⁰

Diuretics are often the first option of therapy for venous congestion. Noradrenaline and/or inotropes are indicated for low cardiac output and haemodynamic instability. Inotropes reducing cardiac filling pressures may be preferred (i.e. levosimendan, phosphodiesterase type III inhibitors). Since inotropic agents may aggravate arterial hypotension, they may be combined with norepinephrine if needed (Figure 9).⁴⁵⁰

11.2.4 Cardiogenic shock

Cardiogenic shock is a syndrome due to primary cardiac dysfunction resulting in an inadequate cardiac output, comprising a life-threatening state of tissue hypoperfusion, which can result in multi-organ failure and death.^451-453 Cardiac insult causing severe impairment of cardiac performance may be acute, as a result of the acute loss of myocardial tissue (acute MI, myocarditis) or may be progressive as seen in patients with chronic decompensated HF who may experience a decline in disease stability as a result of the natural progression of advanced HF and/or specific precipitants.⁴²⁷

Diagnosis of cardiogenic shock mandates the presence of clinical signs of hypoperfusion, such as cold sweated extremities, oliguria, mental confusion, dizziness, narrow pulse pressure. In addition, biochemical manifestations of hypoperfusion, elevated serum creatinine, metabolic acidosis and elevated serum lactate are present and reflect tissue hypoxia and alterations of cellular metabolism leading to organ dysfunction.^438,454 Of note, hypoperfusion is not always accompanied by hypotension, as BP may be preserved by compensatory vasoconstriction (with/without pressor agents), albeit at the cost of impaired tissue perfusion and oxygenation.^{427,428,451,455}

Management of cardiogenic shock should start as early as possible. Early identification and treatment of the underlying cause, concomitant with haemodynamic stabilization and management of organ dysfunction, are key components of its management (Figure 10, Supplementary text 11.1; Supplementary Figure 2).

11.3.1 General aspects

Management can be subdivided in three stages (pre-hospital, in-hospital, and pre-discharge), having different goals and requiring different approaches (Figure 11).

Pre-hospital phase

In the pre-hospital setting, AHF patients should benefit from non-invasive monitoring, including pulse oximetry, BP, heart rate respiratory rate, and a continuous ECG, instituted within minutes of patient contact and in the ambulance if possible.³⁰⁶ Oxygen therapy may be given based on clinical judgment unless oxygen saturation is <90% in which case it should be administered. In patients with respiratory distress, respiratory rate >25 breaths/min, oxygen saturation <90%, non-invasive ventilation should be initiated.^445,449 Although therapeutic tools may be available in the prehospital setting, whether more effective pre-hospital care would alter the clinical outcome remains to be proven in randomized clinical trials.⁴⁵⁶ Furthermore, pre-hospital management should not delay the rapid transfer of AHF patients to the most appropriate medical setting.^456,457

In-hospital management

Diagnostic workup and appropriate pharmacological and non-pharmacological treatment must be started promptly and in parallel (Figure 12). AHF patients are triaged to the appropriate level of care according to the degree of haemodynamic instability and severity of the critical illness. Disposition decisions are important components of the initial phase of management (see Supplementary text 11.2 and Supplementary Tables 17–19).

The type and intensity of in-hospital monitoring depends on clinical severity, settings of care and in-hospital course (see Supplementary text 11.3). As AHF is a heterogeneous condition, management may differ according to the main clinical presentation. Management starts with the search for specific causes of AHF.^1,306,431 These include ACS, a hypertensive emergency, rapid arrhythmias or severe bradycardia/conduction disturbance, acute mechanical causes such as acute valve regurgitation or acute pulmonary embolism, infection, including myocarditis, and tamponade (CHAMPIT) (Figure 12). After exclusion of these conditions, which need to be treated/corrected urgently, management of AHF differs according to the clinical presentations (Figures 7–10).

Pre-discharge phase

Details on this phase are shown in section 11.3.11.

11.3.2 Oxygen therapy and/or ventilatory support

In AHF, oxygen should not be used routinely in non-hypoxaemic patients, as it causes vasoconstriction and a reduction in cardiac output.⁴⁵⁸ Oxygen therapy is recommended in patients with AHF and SpO₂ <90% or PaO₂ <60 mmHg to correct hypoxaemia. In chronic obstructive pulmonary disease (COPD), hyper-oxygenation may increase ventilation–perfusion mismatch, suppress ventilation and lead to hypercapnia. During oxygen therapy, acid-base balance and SpO₂ should be monitored.

Non-invasive positive pressure ventilation, either continuous positive airway pressure and pressure support, improves respiratory failure, increases oxygenation and pH, and decreases the partial pressure of carbon dioxide (pCO₂) and work of breathing. Although a large randomized trial had neutral results, meta-analyses suggest it may improve dyspnoea and reduce the need for intubation and mortality, compared with traditional oxygen therapy.^1,459,460 Non-invasive positive pressure ventilation should be started as soon as possible in patients with respiratory distress (respiratory rate >25 breaths/min, SpO₂ <90%) to improve gas exchange and reduce the rate of endotracheal intubation.^449,460 The fraction of inspired oxygen (FiO₂) should be increased up to 100%, if necessary, according to oxygen saturation level.

Blood pressure should be monitored regularly during non-invasive positive pressure ventilation. The increase in intrathoracic pressure with non-invasive positive pressure ventilation decreases venous return and right and left ventricular preload. It may also decrease cardiac output and BP and should therefore be used with caution in patients with reduced preload reserve and hypotension. The increase in pulmonary vascular resistance and RV afterload may also be detrimental in RV dysfunction.⁴⁴⁹

Intubation is recommended for progressive respiratory failure in spite of oxygen administration or non-invasive ventilation (Supplementary Table 20).⁴⁴⁹

11.3.3 Diuretics

Intravenous diuretics are the cornerstone of AHF treatment. They increase renal excretion of salt and water and are indicated for the treatment of fluid overload and congestion in the vast majority of AHF patients.

Loop diuretics are commonly used due to their rapid onset of action and efficacy. Data defining their optimal dosing, timing, and method of administration are limited. No difference in the primary efficacy outcome of patients’ symptoms global assessment was shown with a high-dose regimen, compared with a low-dose regimen, in the DOSE trial. However, there was a greater relief of dyspnoea, change in weight and net fluid loss (with no prognostic role for increases in serum creatinine) in the higher-dose regimen.^461-463 High diuretic doses may cause greater neurohormonal activation and electrolyte abnormalities and are often associated with poorer outcomes, although a cause and effect relation cannot be proven by these retrospective analyses.^464-467 Based on these observations, it may be appropriate, when starting i.v. diuretic treatment, to use low doses, to assess the diuretic response and increase the dose when that is insufficient.

Diuretic treatment should be started with an initial i.v. dose of furosemide, or equivalent dose of bumetanide or torasemide, corresponding to 1–2 times the daily oral dose taken by the patient before admission. If the patient was not on oral diuretics, a starting dose of 20–40 mg of furosemide, or a bolus of 10–20 mg i.v. torasemide, can be used.^145,468 Furosemide can be given as 2–3 daily boluses or as a continuous infusion. Daily single bolus administrations are discouraged because of the possibility of post-dosing sodium retention.^145,462 With continuous infusion, a loading dose may be used to achieve steady state earlier. Diuretic response should be evaluated shortly after start of diuretic therapy and may be assessed by performing a spot urine sodium content measurement after 2 or 6 h and/or by measuring the hourly urine output. A satisfactory diuretic response can be defined as a urine sodium content >50–70 mEq/L at 2 h and/or by a urine output >100–150 mL/h during the first 6 h.^145,469 If there is an insufficient diuretic response, the loop diuretic i.v. dose can be doubled, with a further assessment of diuretic response.¹⁴⁵ If the diuretic response remains inadequate, e.g. <100 mL hourly diuresis despite doubling loop diuretic dose, concomitant administration of other diuretics acting at different sites, namely thiazides or metolazone or acetazolamide, may be considered. However, this combination requires careful monitoring of serum electrolytes and renal function (Figure 13).^145,470,471 This strategy, based on early and frequent assessment of diuretic response, allows starting treatment with relatively low doses of loop diuretics, with frequent dose adjustments that may be less likely to cause dehydration and increase in serum creatinine. The loop diuretic dose should be progressively decreased when a significant negative fluid balance has been obtained. However, it should be pointed out that this algorithm is entirely based on expert opinion, to date.^145,462

Transition to oral treatment should be commenced when the patient’s clinical condition is stable. It is recommended that, after achievement of congestion relief, oral loop diuretics are continued at the lowest dose possible to avoid congestion.^464,472 Care must also be taken to avoid patients being discharged from hospital with persistent congestion, as this is a major predictor of increased deaths and rehospitalizations.^463,473 Hence, care should be taken to achieve adequate decongestion and establish an appropriate long-term diuretic dose before discharge.^428,474

11.3.4 Vasodilators

Intravenous vasodilators, namely nitrates or nitroprusside (Supplementary Table 21), dilate venous and arterial vessels leading to a reduction in venous return to the heart, less congestion, lower afterload, increased stroke volume and consequent relief of symptoms. Nitrates act mainly on peripheral veins whereas nitroprusside is more a balanced arterial and venous dilator.^475,476 Because of their mechanisms of action, i.v. vasodilators may be more effective than diuretics in those patients whose acute pulmonary oedema is caused by increased afterload and fluid redistribution to the lungs in the absence or with minimal fluid accumulation.^428,477-479 However, two recent randomized trials comparing usual care with early intensive and sustained vasodilation failed to show a beneficial effect of i.v. vasodilators vs. high-dose diuretics.^480,481 No recommendation favouring a regimen based on vasodilator treatment vs. usual care can thus be given, to date.

Intravenous vasodilators may be considered to relieve AHF symptoms when SBP is >110 mmHg. They may be started at low doses and uptitrated to achieve clinical improvement and BP control. Nitrates are generally administered with an initial bolus followed by continuous infusion. However, they may also be given as repeated boluses. Nitroglycerine can be given as 1–2 mg boluses in severely hypertensive patients with acute pulmonary oedema.⁴⁷⁸ Care should be taken to avoid hypotension due to an excessive decrease in preload and afterload. For this reason, they should be used with extreme caution in patients with LVH and/or severe aortic stenosis. However, favorable effects were described in patients with LV systolic dysfunction and aortic stenosis when vasodilators were given with careful monitoring of haemodynamic parameters.⁴⁸²

11.3.5 Inotropes

Inotropes are still needed for treatment of patients with low cardiac output and hypotension (Table 22). They should be reserved for patients with LV systolic dysfunction, low cardiac output and low SBP (e.g. <90 mmHg) resulting in poor vital organ perfusion. However, they must be used with caution starting at low doses and uptitrating them with close monitoring.^388,389

Inotropes, especially those with adrenergic mechanisms, can cause sinus tachycardia, increase ventricular rate in patients with AF, may induce myocardial ischaemia and arrhythmias, and increase mortality.^{388,389,431,479} Levosimendan or type-3-phosphodiesterase inhibitors may be preferred over dobutamine for patients on beta-blockers as they act through independent mechanisms.^483,484 Excessive peripheral vasodilation and hypotension can be major limitations of type-3-phosphodiestaerase inhibitors or levosimendan, especially when administered at high doses and/or when commenced with a bolus dose.^483,485

11.3.6 Vasopressors

Vasopressors used for the treatment of AHF are reported in Table 22.

Among drugs with a prominent peripheral arterial vasoconstrictor action, norepinephrine may be preferred in patients with severe hypotension. The aim is to increase perfusion to the vital organs. However, this is at the expense of an increase in LV afterload. Therefore, a combination of norepinephrine and inotropic agents may be considered, especially in patients with advanced HF and cardiogenic shock.

Some studies, though with limitations, support the use of norepinephrine as first choice, compared with dopamine or epinephrine. Dopamine was compared with norepinephrine as a first-line vasopressor therapy in patients with shock and was associated with more arrhythmic events and with a greater mortality in patients with cardiogenic shock but not in those with hypovolaemic or septic shock. Although the trial included 1679 patients, significance was seen only in a subgroup analysis of the 280 patients with cardiogenic shock and <10% of the patients had MI. As there were no data regarding revascularization, this limits the generalizability of the results.⁴⁸⁶ In another prospective randomized trial epinephrine was compared with norepinephrine in patients with cardiogenic shock due to acute MI.⁴⁸⁷ The trial was stopped prematurely due to a higher incidence of refractory shock with epinephrine. Epinephrine was also associated with higher heart rate and lactic acidosis. Despite limitations related to its relatively small sample size, short time of follow-up and lack of data regarding the maximum reached dose, the study suggests superior efficacy and safety with norepinephrine. These data are consistent with a meta-analysis including 2583 patients with cardiogenic shock showing a three-fold increase in the risk of death with epinephrine, compared with norepinephrine, in patients with cardiogenic shock.⁴⁸⁸ However, the lack of information about dose, duration of treatment, and aetiology, makes these results partially explorative.

11.3.7 Opiates

Opiates relieve dyspnoea and anxiety. They may be used as sedative agents during non-invasive positive pressure ventilation to improve patient adaptation. Dose-dependent side effects include nausea, hypotension, bradycardia, and respiratory depression. Retrospective analyses suggest that morphine administration is associated with a greater frequency of mechanical ventilation, prolonged hospitalization, more intensive care unit admissions, and increased mortality.^489-492 Thus, routine use of opiates in AHF is not recommended although they may be considered in selected patients, particularly in case of severe/intractable pain or anxiety or in the setting of palliation.

11.3.8 Digoxin

Digoxin should be considered in patients with AF with a rapid ventricular rate (>110 b.p.m.) despite beta-blockers (see also section 12.1.1).^151,493,494 It can be given in boluses of 0.25–0.5 mg i.v., if not used previously. However, in patients with comorbidities (i.e. CKD) or other factors affecting digoxin metabolism (including other drugs) and/or the elderly, the maintenance dose may be difficult to estimate theoretically and measurements of serum digoxin concentrations should be performed. Digitoxin is a potential alternative to digoxin and is currently being evaluated in a randomized placebo-controlled trial (ClinicalTrials.gov Identifier: NCT03783429).¹⁵⁸

11.3.9 Thromboembolism prophylaxis

Thromboembolism prophylaxis with heparin (e.g. low-molecular-weight heparin) or another anticoagulant is recommended, unless contraindicated or unnecessary (because of existing treatment with oral anticoagulants).^495,496

11.3.10 Short-term mechanical circulatory support

In patients presenting with cardiogenic shock, short-term MCS may be necessary to augment cardiac output and support end-organ perfusion. Short-term MCS can be used as a BTR, BTD or BTB.⁴⁵¹-⁴⁵³ The initial improvements in cardiac output, BP and arterial lactate may be counterbalanced by significant complications. High-quality evidence regarding outcomes remains scarce. Hence, the unselected use of MCS in patients with cardiogenic shock is not supported and they require specialist multidisciplinary expertise for implantation and management, similar to that outlined for advanced HF centres (Supplementary text 11.4; Supplementary Table 22, see also section 10.2.2).^377,497 Recent studies show that a ‘standardized team-based approach’ using predefined algorithms for early MCS implant coupled with close monitoring (invasive haemodynamics, lactate, markers of end-organ damage) may potentially translate into improved survival.^498-500

The Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK-II) trial showed no difference in 30-day, as well as in long-term, mortality between intra-aortic balloon pump (IABP) and OMT in patients with cardiogenic shock following acute MI who underwent early revascularization.^501-503 According to these results, IABP is not routinely recommended in cardiogenic shock post-MI. However, it may still be considered in cardiogenic shock, especially if not due to ACS, and refractory to drug therapy, as a BTD, BTR, or BTB.

Other short-term MCS were compared with IABP in small, randomized trials and propensity-matched analyses with inconclusive results.^504-508 Similarly, RCTs comparing extracorporeal membrane oxygenation (ECMO) with IABP or MT are lacking. A meta-analysis including only observational studies showed favourable outcomes in patients with cardiogenic shock or cardiac arrest treated with veno-arterial (VA)-ECMO compared to controls.⁵⁰⁹ VA-ECMO may also be considered in fulminant myocarditis and other conditions causing severe cardiogenic shock.⁵¹⁰ Depending on the severity of myocardial dysfunction and/or concomitant mitral or aortic regurgitation, VA-ECMO may increase LV afterload with an increase in LV end-diastolic pressure and pulmonary congestion. In these cases, LV unloading is mandatory and can be achieved by means of transeptal/ventricular apex vent or adding an unloading device such as the Impella device.^511,512

11.3.11 Pre-discharge assessment and post-discharge management planning

A significant proportion of patients with AHF are discharged with minimal or no weight loss and, more importantly, persistent congestion.^428,473 Persistent congestion before discharge is associated with a higher risk of readmission and mortality.^427,473 Treatment, including diuretic dose, should therefore be optimized in order to keep the patient free of congestion.

In those admitted with ADHF, oral OMT should be continued, except for possible dose reduction or withdrawal if there is haemodynamic instability (symptomatic hypotension), severely impaired renal function or hyperkalaemia. Once haemodynamic stabilization is achieved with i.v. therapy, treatment should be optimized before discharge.⁴⁶⁸ Treatment optimization has three major aims. First, to relieve congestion. Second, to treat comorbidities, such as iron deficiency, that have an impact on post-discharge outcome.⁵¹³ Third, to initiate, or restart oral, OMT with beneficial effects on outcome. Doses may be uptitrated before discharge and/or in the early post-discharge phase.

Studies have shown that such optimization of medical treatment is associated with a lower risk of 30-day readmission, although prospective randomized trials have not been performed, to date.^103,468,514 Retrospective analyses show that discontinuation or dose reduction of beta-blocker therapy during an AHF hospitalization is associated with worse outcomes.⁵¹⁵ Initiation of ARNI in recently hospitalized stable patients with HFrEF, including those who are ACE-I/ARB naïve, is safe and may be considered in this setting.^106,107 Safety and better outcome have also been recently shown in a prospective randomized trial with sotagliflozin in diabetic patients hospitalized for HF, irrespective of their LVEF.¹³⁶

It is recommended to have one follow-up visit within 1 to 2 weeks after discharge.^516,517 Components of this follow-up visit should include monitoring of signs and symptoms of HF, assessment of volume status, BP, heart rate, and laboratory measurements including renal function, electrolytes, and possibly NPs. Iron status and hepatic function should also be assessed when not done before discharge. Based on clinical evaluation and laboratory exams, further optimization and/or initiation of disease-modifying treatment for HFrEF should occur. Retrospective studies show that such an approach is associated with lower 30-day readmission rates although prospective randomized trials have not been performed, to date.^514,517-519

12.1.1 Atrial fibrillation

AF and HF frequently coexist.^520,521 They can cause or exacerbate each other through mechanisms such as structural cardiac remodelling, activation of neurohormonal systems, and rate-related LV impairment.^520-524 The proportion of patients with HF who develop AF increases with age and HF severity. When AF causes HF the clinical course seems more favourable than with other causes of HF (so called tachycardiomyopathy).⁵²⁵ In contrast, development of AF in patients with chronic HF is associated with worse prognosis, including stroke and increased mortality.^526,527

Identification of triggers and management of heart failure

Potential causes or precipitating factors such as hyperthyroidism, electrolyte disorders, uncontrolled hypertension, mitral valve disease, and infection should be identified and corrected.

Worsening congestion due to AF should be managed with diuretics. Congestion relief may reduce sympathetic drive and ventricular rate and increase the chance of spontaneous return to SR. The presence of AF may reduce or abolish the prognostic benefits of beta-blockers and renders ivabradine ineffective.^12,125 Some treatments for HF decrease the risk of developing AF, including ACE-I, slightly, and CRT, probably.^7,528

Prevention of embolic events

Unless contraindicated, an oral, long-term anticoagulant is recommended in all patients with HF and paroxysmal, persistent, or permanent AF. Direct-acting oral anticoagulants (DOACs) are preferred for the prevention of thromboembolic events in patients with AF and without severe mitral stenosis and/or mechanical valve prosthesis, as they have similar efficacy to vitamin K antagonists (VKAs) but a lower risk of intracranial haemorrhage.⁵²⁹

LA appendage closure can be considered in patients with HF and AF who have a contraindication to oral anticoagulation though data from randomized trials have not included patients with contraindications to oral anticoagulants.^530,531

Rate control

Data regarding rate control are not conclusive for the patients with AF and HF. A strategy of lenient rate control, defined by a resting heart rate <110 b.p.m., was compared to a strategy of strict rate control, defined by a heart rate <80 b.p.m. at rest and <110 b.p.m. during moderate exercise, in RACE II and in a pooled analysis of RACE and AFFIRM.^152,532 The studies showed no differences in outcome between the two strategies. However, only 10% of the patients in RACE II and 17% of those in the pooled analysis had a history of HF hospitalization or NYHA class II–III, respectively.^152,532 Higher heart rates are associated with worse outcomes in observational studies.^533,534 Thus, a lenient rate control is an acceptable initial approach with, however, treatment targeting a lower heart rate in case of persistent symptoms or cardiac dysfunction likely related to tachycardia (e.g. tachycardia-induced cardiomyopathy).^7,535

Beta-blockers can be used for rate control in patients with HFrEF or HFmrEF because of their established safety in these patients (see section 5.3.2).^7,535,536 Digoxin or digitoxin can be considered when the ventricular rate remains high, despite beta-blockers, or when beta-blockers are contraindicated or not tolerated.^151,494,537 It may therefore be considered also an alternative to beta-blockers. For patients with NYHA class IV and/or haemodynamic instability, i.v. amiodarone can be considered to reduce ventricular rate.⁵³⁸ For HFpEF, there is a paucity of evidence to demonstrate efficacy of any agent. The RATE-AF trial compared digoxin with bisoprolol in patients with persistent AF and NYHA class II–IV symptoms. Compared with bisoprolol, digoxin had the same effect on QOL at 6 months (primary endpoint) and a better effect on EHRA and NYHA functional class.⁵³⁷ Only 19% of the patients had LVEF <50% so that most of the patients can be considered as having HFmrEF or HFpEF.⁵³⁷