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Heart failure 

Heart failure
Chapter:
Heart failure
Author(s):

Faiez Zannad

, João Pedro Ferreira

, and Theresa McDonagh

DOI:
10.1093/med/9780198759935.003.0009_update_001

Update:

Pharmacological management of chronic heart failure section updated

Table 3.1.4 updated

New section and table on dapagliflozin

Updated on 29 July 2020. The previous version of this content can be found here.
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date: 24 January 2022

Introduction

Heart failure (HF) is a complex condition that results from cardiac functional and/or structural abnormalities that affect the ability of the heart to pump blood, potentially leading to inadequate organ perfusion and/or systemic congestion. The commonest manifestations of HF are dyspnoea and fatigue.

The HF syndrome can result from both impaired systolic and/or diastolic function. Up to 50% of HF cases occur in the presence of a preserved systolic function (LVEF ≥45–50%), currently referred to as HF with preserved ejection fraction (HFpEF), in contrast to HF with reduced ejection fraction (HFrEF). This division is mainly made on the basis of trial results, since HF treatments only reduced mortality in HFrEF. More recently, an ‘intermediate’ class was created. This class refers to HF with mid-range ejection fraction (HFmEF) for patients with LVEF of 40–50%. However, this division is based on ‘expert opinion’ and does not reflect trial results. Hence, for the purposes of HF management, we will refer only to HFpEF or HfrEF, as just described.

HF can also be classified as acute or chronic, depending on how quickly symptoms and signs develop, and ‘right’ versus ‘left’ HF indicating whether symptoms predominantly suggest RV failure with peripheral oedema, raised jugular venous pressure (JVP), and hepatomegaly, or predominantly LV failure with pulmonary oedema and/or hypoperfusion. HF can also be classified has high- versus low-output, depending on conditions that may increase or decrease the CO.

Ejection fraction can be assessed objectively with echocardiography, cardiac magnetic resonance (CMR), or nuclear imaging. Independently of the used method, LVEF has been used systematically as a major inclusion criterion in HF trials, and, as stated earlier, it has become one of the most commonly used measurements for the assessment of the severity of LV dysfunction and for treatment indication. Although the severity of LV dysfunction does not necessarily correlate with HF severity and symptoms, useful grading systems exist in the clinical setting that are based on symptoms and cardiac function, i.e. the New York Heart Association (NHYA) classification for symptoms and the ACC/AHA classification for symptoms in the context of cardiac structure and function (see Table 3.1.1). Note that the ACC/AHA classification is much different to the NYHA functional classification system, in that there is no moving backwards to prior stages. Once symptoms develop, stage C overt HF is present and stage B will never again be achieved. In the NYHA classification, in contrast, patients can move between class I and class IV relatively quickly, as these are all designated on symptoms alone.

Table 3.1.1 New York Heart Association (NHYA) classification for symptoms and the American College of Cardiology/American Heart Association (ACC/AHA) classification for symptoms in the context of cardiac structure and function

NYHA classification I–IV

Class

Symptoms

I

No limitation to physical activity. Ordinary physical activity does not cause fatigue, breathlessness, or palpitations (asymptomatic HF)

II

Slight limitation to physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, breathlessness, or angina pectoris (mildly symptomatic HF)

III

Marked limitation of physical activity. Although patients are comfortable at rest, less than ordinary physical activity will lead to symptoms (symptomatically ‘moderate’ HF)

IV

Inability to carry out any physical activity without discomfort. Symptoms are even present at rest (symptomatically ‘severe’ HF)

ACC/AHA classification A–D

Stage

Cardiac structure and function

A

Patients at risk for HF who have not yet developed structural heart changes (i.e. those with diabetes, those with coronary disease without prior infarct)

B

Patients with structural heart disease (i.e. reduced ejection fraction, LVH, chamber enlargement) who have not yet developed HF symptoms

C

Patients who have developed clinical HF

D

Patients with refractory HF requiring advanced intervention (i.e. biventricular pacemakers, LVAD, transplantation)

Source data from http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp#.WxEoFDQvyUk

The present chapter discusses, separately, three subgroups of HF patients:

  • Chronic HF with reduced LVEF (HFrEF).

  • Chronic HF with preserved LVEF (HFpEF).

  • Acute HF.

Chronic heart failure with reduced LVEF (HFrEF)

Incidence and prognosis

HF is a common condition, with an increasing incidence with age. Due to demographic trends of an ageing population, its prevalence is also increasing.

Heart failure There are an estimated 934,000 people over the age of 45 years who have diagnosed or suspected HF in the United Kingdom, and nearly 30 million people worldwide (with increasing prevalence).

Mortality has been quoted as high as 30% at 1 year after diagnosis, but survival has improved with newer HF treatments.

Aetiology

The commonest HF causes are:

  • IHD—the commonest cause in developed countries (50–70% of cases).

  • Arterial hypertension, which often causes HF with preserved LVEF.

  • The cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, peripartum cardiomyopathy, and arrhythmogenic cardiomyopathy.

  • Other common causes include: alcohol consumption, treatments/drugs (i.e. chemotherapy), valvular heart disease (VHD), infiltrative disorders (amyloid and sarcoid), and rhythm disturbances such as chronic uncontrolled tachycardia.

  • High-output HF is a less common form of presentation and can be caused by thyrotoxicosis, beriberi, Paget’s disease, sepsis, anaemia, and some arrhythmias.

  • The commonest causes for an acute decompensation in a patient with chronic HF include myocardial ischaemia or infarction, arrhythmias, inappropriate or insufficient drug therapy, infection, anaemia, etc.

Symptoms and signs of heart failure

The cardinal symptoms of HF are dyspnoea at rest or on exertion, orthopnoea, paroxysmal nocturnal dyspnoea, and fatigue. Signs of HF include those attributable to LV failure, such as pulmonary oedema, cold extremities, hypotension, and a third heart sound, and those of right HF such as a raised JVP, peripheral oedema, hepatomegaly, and ascites.

Useful investigations

Blood tests

  • In addition to routine blood tests, including blood count, urea, creatinine, electrolytes, fasting glucose, lipids, liver function tests (LFTs), and thyroid function tests, the measurement of natriuretic peptides is relevant. Natriuretic peptides can help not only in the diagnosis and prognosis of patients with HF, but also in the assessment of response to treatment. A normal BNP concentration in an untreated patient makes the diagnosis of HF unlikely, whereas a high BNP level, despite maximal medical treatment, often indicates a poor prognosis. Conditions other than HF that can lead to a raised BNP level include: sepsis, renal dysfunction, LV hypertrophy (LVH), myocardial ischaemia, and advanced age.

  • The resting 12-lead ECG may show signs of IHD, such as an old infarction or LBBB, LVH, conduction disturbances [important to note that a QRS of >120ms is one of the criteria for cardiac resynchronization therapy (CRT)], or cardiac arrhythmias. Holter monitoring might be considered to look for VT in high-risk patients.

  • The chest X-ray provides evidence for cardiomegaly, pulmonary venous congestion, pulmonary oedema, pleural effusion, and lung disease.

  • Transthoracic echocardiography is essential in the assessment of patients with symptoms/signs of HF. LVEF is used to classify HF as diastolic or systolic, and the echocardiogram may establish the aetiology of HF in the individual patient, e.g. VHD, MI, LVH, or global LV dysfunction associated with dilated cardiomyopathy (DCM). Stress echocardiography can be used to detect reversible myocardial ischaemia and to assess for myocardial hibernation, valvular abnormalities, and the response to CRT.

  • Coronary angiography should be performed in patients presenting with HF who have angina or significant myocardial ischaemia on non-invasive testing. Controlled trials have not addressed the issue of whether coronary revascularization can improve clinical outcomes in patients with HF who do not have angina pectoris.

  • MRI is the gold standard for evaluating ventricular dimensions, as it has a high degree of reproducibility. It is also extremely useful for the assessment of ventricular function and wall motion abnormalities, myocardial viability, and scar tissue. It can also be useful for detecting RV dysplasia and identifying the presence of pericardial disease.

  • Maximal oxygen consumption (VO2max) exercise testing can give useful information in patients presenting with HF who may be candidates for cardiac transplantation or device implantation.

Pharmacological management of chronic heart failure

The recommendations that follow are based on NICE, ESC, and AHA guidelines. Of importance, the NICE guidelines apply only to patients who already have HF. AHA guidelines take into account patients without HF but who have risk factors for HF, including known CAD, hypertension, diabetes mellitus, and a family history of cardiomyopathy. These high-risk patients require treatment with disease-modifying agents. There is substantial trial evidence for the treatment of HF, but one should acknowledge that women, blacks, and the very elderly are not well represented in these trials.

Pharmacological treatment

Heart failure This can be divided into:

  • Treatments that prolong life in patients with HFrEF and should be prescribed to all patients with HfrEF, unless contraindicated, i.e. ACEIs, ARBs, angiotensin receptor–neprilysin inhibitor (ARNI) (i.e. sacubitril/valsartan), aldosterone antagonists (i.e. spironolactone and eplerenone), β‎-blockers, and the sodium–glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin (trials with other SGLT2i are under way).

  • Treatments that improve symptoms only (i.e. diuretics and digoxin).

  • Ivabradine which can be used to decrease hospitalizations in HFrEF patients with high heart rate (>70 bpm).

See the flow chart in Fig. 3.1.1 for a summary of the pharmacological management of chronic systolic HF.

Fig. 3.1.1 Summary of pharmacological treatment for HFrEF. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; HFrEF, heart failure with reduced ejection fraction; H-ISDN, hydralazine and isosorbide dinitrate; HR, heart rate; LVEF, left ventricular ejection fraction. Green boxes = mortality benefit. White boxes = no mortality benefit. * Device therapy or heart transplant are beyond the scope of this schema.

Fig. 3.1.1 Summary of pharmacological treatment for HFrEF. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; HFrEF, heart failure with reduced ejection fraction; H-ISDN, hydralazine and isosorbide dinitrate; HR, heart rate; LVEF, left ventricular ejection fraction. Green boxes = mortality benefit. White boxes = no mortality benefit. * Device therapy or heart transplant are beyond the scope of this schema.

ACE inhibitors or angiotensin receptor blockers (class I, level of evidence A)

ACE inhibitors

ACEIs are recommended as first-line therapy (unless contraindicated) in all patients with LVEF of <40%, irrespective of symptoms. Multiple trials have shown that ACEIs reduce mortality and morbidity in patients with HFrEF. However, many patients are excluded from these trials, such as those with hypotension, CKD (stage ≥4), normal ejection fraction, and the very elderly. ACEIs should be uptitrated to the maximum tolerated dose, in order to achieve adequate inhibition of the RAAS. However, there is evidence that, in clinical practice, the majority of patients receive suboptimal doses of ACEIs. Some patients improve within a few days of starting ACEI therapy, but most patients only get benefit after several weeks or months of treatment. Below we present some data from cornerstone trials with ACEIs in HFrEF.

  • The Survival and Ventricular Enlargement (SAVE) trial was the first large trial of ACEIs in LV dysfunction following MI. Over 2000 patients with an ejection fraction of <40% 3–16 days following MI were randomized to either placebo or captopril. All-cause mortality was 19% lower in the ACEI group. There was also a 37% reduction in the development of severe HF.

  • Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) and Studies of Left Ventricular Dysfunction (SOLVD) randomized patients with mild to severe HF to treatment with placebo or enalapril. There was a reduction in mortality of 27% in CONSENSUS and 16% in SOLVD.

  • The SOLVD-Prevention trial showed that patients with low ejection fraction, but no symptoms, benefited from ACEI with a 20% relative risk reduction (RRR) in death or hospitalization with HF. This emphasizes the importance of starting ACEI therapy in patients with HF, even before they become symptomatic.

Angiotensin receptor blockers

ACEIs are generally preferred to ARBs, because there is more clinical experience and weight of trials behind their use, compared to ARBs. It is reasonable to use an ARB when a patient is intolerant to ACEIs (e.g. develops significant ACEI-induced cough). The combination of an ACEI plus an ARB is not generally recommended due to increased adverse events (e.g. symptomatic hypotension and worsening renal function) without mortality benefit. In the context of adding another RAAS blocker, an MRA should be preferred. Below we present some data from cornerstone trials with ARBs in HFrEF.

  • Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Alternative was a placebo-controlled trial with candesartan in patients with LVEF of <40%, who were intolerant to ACEIs. Candesartan resulted in an RRR of death from a CV cause or hospital admission for worsening HF of 23%.

  • Despite some evidence [CHARM–Added and Valsartan Heart Failure Trial (Val-HeFT)] that HFrEF patients in NYHA class III or IV, despite ACEI and β‎-blocker therapy, do benefit from the addition of candesartan or valsartan for reducing hospitalizations, this guidance is complicated by the fact that, in the VALsartan In Acute myocardial iNfarcTion (VALIANT) study (captopril versus valsartan versus a combination of both), the combination of both drugs did not reduce mortality and was associated with an increase in adverse events.

Initiation of treatment and uptitration

Prior to initiation of ACEI/ARB treatment, renal function and electrolytes should be assessed and then rechecked 1–2 weeks after starting treatment (see Table 3.1.2).

Table 3.1.2 Doses of ACEIs and ARBs with the largest evidence in HF trials

Starting dose

Target dose

ACEI

Captopril

6.25mg tds

50–100mg tds

Enalapril

2.5mg od

10–20mg bd

Lisinopril

2.5mg od

20–35mg od

Ramipril

1.25–2.5mg od

10mg od

ARB

Candesartan

4–8mg od

32mg od

Valsartan

40mg bd

160mg bd

ACEIs/ARBs should be commenced at a low dose and titrated up at 2-weekly intervals, with the aim of reaching target doses. Uptitration is dependent on BP and renal function. Hypotension is acceptable if SBP is >90mmHg and asymptomatic, and worsening renal function is acceptable if the estimated glomerular filtration rate (eGFR) does not drop >30% from baseline or it does not drop below 30mL/min/1.73m2. Symptomatic hypotension can be minimized by nocturnal dosing. In hospitalized patients, ACEIs should be started prior to discharge.

ACEIs and β‎-blockers should always be titrated up to the maximum tolerated dose.

Contraindications

History of angio-oedema, bilateral renal artery stenosis, serum potassium >5mmol/L, eGFR <30mL/min/1.73m2, severe aortic stenosis.

Side effects

  • Cough: a dry cough related to the use of ACEIs is the commonest reason for the withdrawal of long-term treatment. It occurs in 5–10% of white patients and up to 50% of Chinese patients. It usually appears within the first month of treatment and disappears within 1–2 weeks of discontinuing treatment. Given the known benefits of ACEIs, it is important to try and persist with treatment, unless the cough is severe, particularly since the cough may be coincidental, as found in many studies. If a significant and persistent cough does develop on an ACEI, then an ARB should be used instead.

  • Hypotension: if a patient develops symptomatic hypotension, reduce the dose of any other antihypertensives before reducing the dose of the ACEI.

  • Hyperkalaemia: may be managed by stopping potassium supplements or potassium-sparing diuretics. If the potassium level still rises above 5.5mmol/L, halve the dose of the ACEI. If the potassium level rises above 6.0mmol/L, then stop the ACEI.

  • Deterioration in renal function: some increase in urea and creatinine levels can be expected after starting an ACEI. A decrease of up to 30% in the eGFR may be acceptable but must be carefully monitored.

  • Angio-oedema is a very serious side effect, and if this occurs, then the ACEI must be stopped immediately.

Beta-blockers (class I, level of evidence A)

β‎-blockers should be used (unless contraindicated) in all patients with LVEF of <40%, irrespective of symptoms. Like ACEIs, they have been shown to reduce mortality and morbidity. Evidence to support the use of β‎-blockers derives from the following trials.

  • Cardiac Insufficiency Bisoprolol Study II (CIBIS II) (bisoprolol), Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) (carvedilol), and Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) (sustained-release metoprolol). These trials randomized nearly 9000 patients with HF to either placebo or β‎-blocker therapy; 90% of these patients were on an ACEI or ARB. Each of these trials showed that β‎-blockers reduced mortality (RRR of about 34% in each trial) and hospital admissions for worsening HF (RRR 28–36%).

  • There are very few trials in HF that included elderly patients. The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial was an RCT in elderly (>70 years old) patients with HF. Treatment with nebivolol resulted in an RRR of 14% in the primary composite endpoint of death or hospital admissions for a CV reason.

Of note, not all β‎-blockers have the same effect. Metoprolol tartrate (as opposed to sustained-release metoprolol succinate) does not confer as much benefit as carvedilol [Carvedilol Or Metoprolol European Trial (COMET)]. There is no evidence of benefit for bucindolol (increases death in African Americans), and xamoterol has been found to be harmful. As such, the only recommended β‎-blockers for management of HF patients are bisoprolol, carvedilol, nebivolol, and sustained-release metoprolol (not available in the United Kingdom).

Commencing therapy and uptitration

β‎-blockers should be commenced at a low dose and titrated up to target doses at 2- to 4-weekly intervals (see Table 3.1.3). They should usually be initiated in stable patients and only with caution in recently decompensated patients. Do not increase the dose if signs of worsening HF or symptomatic hypotension appear, or if the heart rate is <50bpm.

Table 3.1.3 Doses of β‎-blockers with the largest evidence in HF trials

β‎-blockers

Starting dose

Target dose

Bisoprolol

1.25mg od

10mg od

Carvedilol

3.125mg bd

25–50mg bd

Metoprolol succinate

12.5mg od

200mg od

Nebivolol

1.25mg od

10mg od

In patients admitted with a decompensation of HF and hypotension, β‎-blockers may need to be discontinued temporarily. However, a recent study has shown increased mortality in HF patients who have their β‎-blockers stopped during hospital stay.

Contraindications

  • Second- or third-degree heart block.

  • Sinus bradycardia (<50bpm).

  • Symptomatic hypotension.

  • Peripheral vascular disease: relative contraindication as benefits may outweigh a potential deterioration in symptoms of peripheral vascular disease.

  • Obstructive airways disease (not COPD per se): relative contraindication as benefits may outweigh risks, and respiratory symptoms should be assessed during β‎-blocker uptitration.

Side effects

Symptomatic hypotension is relatively common but often improves over time. If hypotension appears, it may require β‎-blocker dose reduction. Asymptomatic hypotension does not require intervention.

Symptomatic bradycardia (<50bpm) may also require β‎-blocker dose adaptation.

Mineralocorticoid receptor antagonists (class I, level of evidence A)

MRAs should be used (unless contraindicated) in all HFrEF patients (with mild or severe symptoms) with an LVEF of <35%, in combination with ACEIs, β‎-blockers, and diuretics. MRAs have demonstrated to reduce mortality and morbidity in these patients and also in post-MI patients with systolic dysfunction (eplerenone).

MRA therapy has been evaluated in three large RCTs:

  • Randomized Aldactone Evaluation Study (RALES).

  • Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms (EMPHASIS).

  • Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).

These trials showed that MRAs reduce the mortality and morbidity rate from 15% (EPHESUS) to 35% (RALES and EMPHASIS), compared to placebo (see Table 3.1.4).

Heart failure Table 3.1.4 Doses of MRAs with the largest evidence in HF trials

β‎-blockers

Starting dose

Target dose

Spironolactone

12.5mg od

50mg od

Eplerenone

12.5mg od

50mg od if eGFR >50 ml/min

25mg od if eGFR =50 ml/min

eGFR, estimated glomerular filtration rate in mL/min/1.73m2.

Cautions/contraindications

Cautions for starting treatment include hyperkalaemia and renal impairment. Check renal function prior to starting therapy and again at 1 and 4 weeks after starting treatment. Increase the dose after 4–8 weeks. Recheck renal function and potassium levels at 1 and 4 weeks after each dose increase and 3-monthly thereafter.

MRAs should not be prescribed if a patient is receiving combined treatment with an ACEI plus an ARB.

In the case of intolerance (e.g. gynaecomastia, hyperkalaemia, worsening renal function, or sexual dysfunction), clinicians should assess all possible causes, including medication interactions, and consider other agents of the MRA class before stopping treatment.

Side effects

  • Hyperkalaemia: if the potassium level rises to >5.5mmol/L, the dose of the MRA should be halved and potassium levels monitored. If the potassium level rises to 6.0mmol/L, stop spironolactone or eplerenone and monitor carefully.

  • Worsening renal function: if the eGFR drops below 50mL/min/1.73m2, halve the MRA dose. If the eGFR drops below 50mL/min/1.73m2 or deteriorates >30% relative to the baseline value, then stop spironolactone or eplerenone and resume carefully after renal function recovery.

  • Gynaecomastia: occurs in about 10% of patients given spironolactone. These patients should be switched to eplerenone.

Angiotensin receptor–neprilysin inhibitor (class I, level of evidence B)

A therapeutic class of agents acting on the RAAS and the neutral endopeptidase system (ARNI). LCZ696 is a molecule that combines the moieties of valsartan and sacubitril (the neprilysin inhibitor) in a single substance (sacubitril/valsartan). By inhibiting neprilysin, the degradation of natriuretic peptides, bradykinin, and other peptides is slowed. Hence, high circulating levels of natriuretic peptides enhance diuresis, natriuresis, myocardial relaxation, and anti-remodelling, on top of the ARB effects of valsartan.

Sacubitril/valsartan reduced mortality and morbidity by 20%, compared to enalapril, in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial that included symptomatic HFrEF patients with an LVEF of <40% (changed to <35% during the study), elevated plasma natriuretic peptide levels, and eGFR of >30mL/min/1.73m2, who were able to tolerate separate treatments periods with enalapril (10mg bd) and sacubitril/valsartan (97/103mg bd) during a run-in period. Sacubitril/valsartan is therefore recommended in patients with HFrEF who fit this profile.

Cautions/contraindications

In the PARADIGM-HF trial, symptomatic hypotension was more often present in the sacubitril/valsartan group.

The risk of angio-oedema in the trial was reduced by recruiting only those who tolerated therapy with enalapril and sacubitril/valsartan during an active run-in phase. Moreover, the number of African American patients, who are at a higher risk of angio-oedema, was relatively small in this study. To minimize the risk of angio-oedema caused by overlapping ACE and neprilysin inhibition, the ACEI should be withheld for at least 36h before initiating sacubitril/valsartan.

Combined treatment with an ACEI (or ARB) and sacubitril/valsartan is contraindicated.

There are additional concerns about its effects on the degradation of β‎-amyloid peptide in the brain, which could theoretically accelerate amyloid deposition, but this is yet to be proven in humans and long-term safety needs to be addressed.

Side effects

The side effects for this combined agent are the same as those reported earlier for ACEIs/ARBs. However, symptomatic hypotension is more frequent with sacubitril/valsartan (see Table 3.1.5).

Table 3.1.5 Sacubitril/valsartan doses

Sacubitril/valsartan

Starting dose

Target dose

Sacubitril/valsartan

49/51mg bd

97/103mg bd

Dapagliflozin (class I, level of evidence B)

Heart failure In patients with type 2 diabetes (T2D), inhibitors of sodium–glucose cotransporter 2 (SGLT2i) reduce glucose and glycated haemoglobin levels by decreasing renal glucose reabsorption, thereby increasing urinary glucose excretion. SGLT2i decrease body weight and reduce blood pressure without increasing heart rate. SGLT2i also have favourable effects on arterial stiffness and vascular resistance, visceral adiposity, albuminuria, and plasma urate. The most common side effects of SGLT2i are urinary tract infections. In patients with T2D, SGLT2i reduce the risk of incident heart failure, possibly through mechanisms that are independent of glucose regulation. The SGLT2i dapagliflozin was tested in HFrEF in 4744 patients with and without diabetes in the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial. In DAPA-HF, compared with placebo, dapagliflozin reduced mortality and morbidity by 26% in symptomatic HFrEF patients with an LVEF of ≤40%, elevated plasma natriuretic peptide levels, and eGFR of ≥30mL/min/1.73m2. Dapagliflozin is therefore recommended in patients with HFrEF who fit this profile (see Table 3.1.6).

Table 3.1.6 Dapagliflozin dose

SGLT2i

Starting dose

Target dose

Dapagliflozin

10mg od

10mg od

Cautions/contraindications

Heart failure In the DAPA-HF trial, no notable excess of any event was observed in the dapagliflozin group, as compared with the placebo group.

Side effects

Heart failure The side effects of SGLT2i may be related to volume depletion and urinary tract infections; however, no notable excess risk of adverse events was observed in the DAPA-HF trial.

Ivabradine (class IIa, level of evidence B)

Ivabradine slows the heart rate through inhibition of the If channel in the sinus node and therefore should only be used for patients in sinus rhythm.

Ivabradine reduced by 18% the combined endpoint of mortality or hospitalization for HF in patients with symptomatic HFrEF in sinus rhythm and with a heart rate of >70bpm who had been hospitalized for HF within the previous 12 months in the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Hence, it can be used in patients with these characteristics.

Cautions/contraindications/side effects

Patients taking ivabradine (see Table 3.1.7) may experience symptomatic bradycardia in nearly 5% of cases. Visual side effects (phosphenes) can also occur in <3% of cases.

Heart failure Table 3.1.7 Ivabradine doses

Ivabradine

Starting dose

Target dose

Ivabradine

5mg od

7.5mg od

Digoxin (class IIa, level of evidence B for reducing hospital admissions)

Digoxin is of particular benefit in patients with AF and HF. It slows down the ventricular rate, leading to increased filling time, and has a positive inotropic effect. If a patient is in sinus rhythm, digoxin can still be beneficial if symptoms persist despite maximum treatment, by reducing hospital admissions, although there is no effect on mortality.

Loading doses are not generally required in stable patients. A daily dose of 125–250mcg is appropriate in the context of normal renal function. In the elderly and those with renal failure, a smaller dose may be required.

Contraindications

Digoxin is contraindicated in second- or third-degree heart block and pre-excitation syndromes. Caution is required in patients with renal dysfunction.

Diuretics (symptomatic improvement only)

Diuretics are used in HF to alleviate symptoms by reducing fluid overload but have not been shown to improve mortality (see Table 3.1.8). Diuretics reduce hospital admissions for worsening HF and improve exercise capacity. Commonly used diuretics include loop diuretics and thiazides. Thiazide diuretics may be preferred in hypertensive patients with HF.

Table 3.1.8 Diuretic doses

Diuretics

Usual dose (mg)

Up to (mg)

Loop diuretics

Furosemide

20–40

240

Bumetanide

0.5–1

5

Thiazide diuretics

Metolazone

2.5

10

Bendroflumethiazide

2.5

10

Patients who are in decompensated HF can develop resistance to oral diuretics due to reduced drug absorption. These patients often require admission to hospital for IV diuretics.

Side effects

  • Hypokalaemia, hyponatraemia, hypocalcaemia, hypomagnesaemia.

  • Hypotension.

  • Ototoxicity.

  • Hyperuricaemia.

Combination of hydralazine and isosorbide dinitrate (H-ISDN) (class IIa, level of evidence A)

Recommendations for the use of a combination of nitrates and hydralazine (H-ISDN) differ between NICE and AHA/ESC. NICE guidelines recommend, under specialist supervision, that this combination may be used in patients intolerant of ACEIs or ARBs but do not suggest using it in combination with ACEIs/ARBs.

There is some evidence that patients who still have moderate to severe symptoms, despite ACEIs or ARBs and β‎-blockers, may benefit from the addition of hydralazine and a nitrate, and this is recommended in the AHA/ESC guidelines. Evidence is strongest in those of African American background.

  • Veterans Administration Cooperative Vasodilator—Heart Failure Trial (V-HeFT I) trial: 642 men were randomized to placebo, prazosin, or H-ISDN. No patients were on β‎-blockers or ACEIs. With H-ISDN, there was a trend to a reduction in all-cause mortality (RRR 22%). H-ISDN increased exercise capacity and LVEF, compared with placebo.

  • African-American Heart Failure Trial (A-HeFT): 1050 African American men and women in NYHA class III or IV were randomized to either placebo or H-ISDN. Patients were already on ACEIs (70%), ARBs (17%), or β‎-blockers (74%). The trial was terminated prematurely at 10 months because of a significant reduction in mortality (RRR 43%).

Contraindications

Symptomatic hypotension, ‘lupus syndrome’ (in V-HeFT I and II, there was a sustained increase in antinuclear antibody in 2–3% of patients, but lupus-like syndrome was rare), and severe renal failure.

Side effects

The commonest side effects are headache, dizziness, hypotension, and nausea.

Anticoagulation in heart failure

RCTs have shown a reduction in the risk of stroke in patients on warfarin who have HF and AF. The non-vitamin K anticoagulants may also be effective in patients with HF and AF.

There is no good evidence for warfarin in HF patients with intra-cardiac thrombus or an LV aneurysm, but the consensus is that this group of patients probably benefits from anticoagulation.

There is no evidence to support the use of oral anticoagulants in HF patients in sinus rhythm.

Calcium channel blockers in heart failure

Amlodipine can be used to treat hypertension and angina in patients with HF. The use of verapamil, diltiazem, or short-acting dihydropyridines can cause clinical deterioration and should be avoided.

Renin inhibitors

Aliskiren (a direct renin inhibitor) failed to improve outcomes in HF and is not recommended as an alternative to ACEIs or ARBs.

Management of atrial fibrillation in heart failure

AF is common in patients with HF. Some people may benefit from restoration of sinus rhythm, but this decision should be made on an individual basis, with specialist input. There are no RCTs demonstrating that restoration of sinus rhythm in patients with AF and HF improves mortality.

A review of large RCTs of β‎-blockers in HF showed that the benefits of these agents are the same whether the patient is in sinus rhythm or AF.

Non-pharmacological management of chronic heart failure

Description of the non-pharmacological management of HF is beyond the scope of this book, and the following section therefore represents just a brief summary.

Weight monitoring

Patients should weigh themselves regularly, and if they have sudden weight gain (approximately 2kg in 3 days), they should know how to increase their diuretic therapy. They should also be aware of the risk of volume depletion if their weight falls rapidly.

Fluid restriction

Restricting the volume intake to 1.5–2L of fluid in patients with severe HF may be considered but does not seem to help patients with mild to moderate HF.

Sodium restriction

Reducing salt intake may help to reduce fluid retention.

Alcohol

Patients suffering from alcohol-induced cardiomyopathy should completely abstain from alcohol. All other patients should not drink excessively, as alcohol has a negative inotropic effect, may increase BP, and can be cytotoxic.

Smoking

Smoking cessation should be strongly recommended, as it is associated with dismal prognosis.

Vaccination

Vaccination against influenza (annual) and Pneumococcus (once) should be considered.

Myocardial reperfusion

Reperfusion should be performed if there is evidence of myocardial ischaemia. Routine coronary angiography in all patients with HF is not recommended. Conduct angiography in patients with angina, and perform viability studies in selected patients.

Cardiac resynchronization therapy/implantable cardioverter–defibrillator

CRT is recommended if QRS is ≥130ms in the presence of LBBB (in sinus rhythm). CRT should/may be considered if QRS is ≥130ms with non-LBBB (in sinus rhythm) or in patients with AF, provided a strategy to ensure biventricular capture is in place (individualized decision).

An implantable cardioverter–defibrillator (ICD) is recommended to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA classes II–III) and an LVEF of ≤35%, despite ≥3 months of optimal medical therapy, provided they are expected to survive substantially longer than 1 year, with good functional status, and they have:

  • IHD (unless they had an MI in the previous 40 days).

  • DCM.

An ICD should be used for secondary prevention in patients who have recovered from a ventricular arrhythmia causing haemodynamic instability and who are expected to survive for >1 year with good functional status.

Transplantation

Specialist assessment for transplantation should be considered for patients with severe refractory symptoms or refractory cardiogenic shock.

Indications

Objective evidence of cardiopulmonary limitation, e.g. peak VO2max of <10mL/min/kg and patient dependent on inotropes.

Cautions/contraindications

Alcohol or drug abuse, severe renal failure (eGFR <30mL/min). Fixed high pulmonary vascular resistance [pulmonary artery pressure (PAP) >60mmHg], significant liver impairment.

Left ventricular assist devices

This needs specialist assessment. LVADs may provide an alternative to transplantation in advanced HF.

Chronic heart failure with preserved LVEF (HFpEF)

HF is most simply defined as the presence of symptoms and/or signs in the presence of cardiac dysfunction. Those with an LVEF of ≤40% are now more usually referred to as having HFrEF. Patients with an LVEF of >50% (in the normal range) are classified, according to the ESC 2016 guideline, as having HFpEF.1 The latter body has created a new category for those with an intermediate LVEF of 41–49% (HFmEF). In practice, this makes little difference to management, as no specific disease-modifying therapy exists for both categories.

The diagnosis of HFpEF or HFmEF by echocardiography is less clear-cut, with many abnormalities having been described in diagnostic algorithms. However, criteria for relevant structural heart disease such as LVH (LV mass index >115g/m2 for men and >95g/m2 for women) or an increased left atrial volume (left atrial volume index >34mL/m2) make the diagnosis more likely. Many of these patients have ‘diastolic dysfunction’. Tissue Doppler measures of raised filling pressures have emerged as useful predictors of diastolic abnormalities. Useful cut points to indicate ‘diastolic dysfunction’ are: an E/e′ average of ≥13 or an e′ average (lateral–septal) of <9cm/s.

The main echocardiographic abnormalities used for confirming the diagnosis of the HF syndrome and categorizing it into HFrEF, HFpEF, and HFmEF, according to the ESC 2016 guideline, are summarized in Table 3.1.9. For those with HFpEF or HFmEF, in addition to symptoms and/or signs of HF, raised natriuretic peptide levels are also required and at least one other criterion reflecting structural heart disease or ‘diastolic dysfunction’.

Table 3.1.9 Classification of heart failure according to the ESC 2016 Heart Failure Guideline

HFrEF

HFpEF

HFmEF

Symptoms/signs

Symptoms/signs

Symptoms/signs

LVEF ≤40%

LVEF ≥50%

LVEF = 41–49%

  1. 1. Increased NP

  2. 2. At least one additional criteria of: relevant structural heart disease, e.g LAE, LVH, or diastolic dysfunction

  1. 1. Increased NP

  2. 2. At least one additional criteria of: relevant structural heart disease, e.g LAE, LVH, or diastolic dysfunction

HFpEF: heart failure with preserved ejection fraction; HFmEF, heart failure with mid-range ejection fraction; HFrEF, heart failure with reduced ejection fraction; LAE, left atrial enlargement; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; NP, natriuretic peptide.

Prevalence and prognosis

HFpEF is present in up to 50% of patients presenting with HF. It is commoner in elderly people and those with hypertension or diabetes. Ageing is associated with decreases in the elastic properties of the heart and great vessels. The prognosis has been shown to be similar to that of systolic HF. The proportion of HFpEF patients dying from non-CV causes is higher than in HFrEF.

Aetiology

The commonest causes of HFpEF are:

  • Hypertension.

  • CAS.

  • VHD.

HFpEF is the predominant type of HF found in hypertrophic cardiomyopathy. Comorbidities are very common in HFpEF, particularly AF, diabetes, obesity, and CKD.

Treatment

No disease-modifying therapies are available, to date, for HFpEF. Results of large outcome trials with ACEIs/ARBs and MRAs have been disappointing. Treatment is therefore directed towards two goals:

  1. 1. Management of symptoms and signs of fluid retention.

  2. 2. Treatment of the underlying cardiac disease.

In practice, this means that many HFpEF patients end up on much the same therapy as HFrEF patients.

Heart failure Results of major trials in HFpEF

  • Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial: among patients aged ≥70 years with clinical HF and preserved LV systolic function, treatment with perindopril did not differ from placebo in the primary endpoint of death or unplanned hospitalizations for HF.2

  • Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction (CHARM-Preserved) trial: candesartan in patients with preserved LVEF did not show a significant reduction in the composite endpoint of death from CV causes or admissions with HF but did show a significant reduction in the risk of investigator-reported admissions for HF.3

  • Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE): investigated patients who were mostly NYHA class III (77%) with normal LVEF. The trial confirmed that angiotensin receptor blockade with irbesartan is not associated with a reduction in CV mortality and morbidity in patients with HF and a normal ejection fraction. In fact, there was an increase in the incidence of observed adverse effects, including hyperkalaemia.4

  • SENIORS trial: this trial of nebivolol in older patients with HF also included patients with an LVEF of >40%. All-cause mortality was reduced overall in the trial with nebivolol. There was no indication that patients treated with nebivolol who had HFpEF behaved differently from those with HFrEF, although the trial was not powered sufficiently to definitively comment on a reduction in outcomes for HFpEF.5 It does show that β‎-blockers are not harmful in HFpEF.

  • Digitalis Investigation Group (DIG) trial: the outcome trial with digoxin for those with HF and in sinus rhythm, also included patients with HFpEF. There was a neutral effect on mortality overall.6

  • Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial: this trial investigated the use of spironolactone in 3445 patients with HFpEF, compared to placebo. There was no significant reduction in the primary composite endpoint of CV death, HF hospitalization, or resuscitated cardiac arrest. A reduction in hospitalization for HF was seen.7 There was significant regional variation in outcomes between patients recruited in the Americas who did seem to benefit, compared to those recruited in Russia and Georgia.

  • Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trial: this trial investigated the use the ARNi sacubitril/valsartan in 4822 patients with HFpEF, compared to valsartan. There was no significant reduction in the primary composite endpoint of total hospitalizations for heart failure and death from cardiovascular causes, but the effect was ‘neutral’ by a narrow margin [rate ratio, 0.87; 95% confidence interval (CI), 0.75 to 1.01; p =0.06].

Heart failure Useful points for treating HFpEF

  1. 1. Give loop diuretics to relieve symptoms and signs of congestion, i.e. peripheral and pulmonary oedema. Use the minimum dose necessary to achieve euvolaemia. Spironolactone and sacubitril/valsartan may be considered for certain patients with HFpEF. Spironolactone has a IIb indication for the treatment of HFpEF in the updated ACC/AHA/HFSA heart failure guidelines. Sacubitril/valsartan may be useful for treating HFpEF patients in the ‘HFmrEF’ range.

  2. 2. Treat the underlying cause of HFpEF:

    1. a) For CAD: statin, ACEIs/ARBs, and β‎-blockers are useful. Revascularize, as appropriate.

    2. b) Hypertension: aim for a BP of <130/80mmHg—use thiazides, ACEIs/ARBs, and CCBs. Spironolactone and eplerenone are useful in resistant hypertension.

    3. c) Control the ventricular rate in patients with AF with β‎-blockers (and rate-limiting CCBs, as necessary).

Acute heart failure

Acute HF is characterized by a rapid onset of signs and symptoms of HF, requiring urgent treatment. Acute HF may present as a first occurrence (de novo) or, more frequently, as a consequence of acute decompensation of chronic HF and may be caused by primary cardiac dysfunction or precipitated by extrinsic factors, often in patients with chronic HF. In most cases, patients with acute HF present with either ‘normal’ (90–140mmHg) or ‘high’ (>140mmHg; hypertensive acute HF) SBP. Only 5–8% of all patients present with low BP (i.e. <90mmHg; hypotensive acute HF), which is associated with poor prognosis, particularly when hypoperfusion is also present. Therefore, there are several possible presentations, and an overlap of these presentations can occur:

  • Acute pulmonary oedema with severe respiratory distress.

  • Cardiogenic shock, defined as tissue hypoperfusion—associated with high in-hospital mortality, i.e. 40–60%.

  • Hypertensive HF, with evidence of vasoconstriction and tachycardia—there is often a relatively normal LVEF in these patients, and in-hospital mortality is relatively low.

  • Progressive worsening of chronic HF, with a gradual increase in systemic and pulmonary congestion.

  • Isolated right HF characterized by raised venous pressure, absence of pulmonary congestion, and a low output state due to low LV filling pressures.

Aetiology

The commonest aetiologies for acute HF are:

  • Ischaemia/MI.

  • Arrhythmias.

  • Infection/sepsis.

  • Hypertensive crisis.

  • Anaemia.

  • Lack of adherence to treatment.

  • Renal dysfunction.

  • Thyrotoxicosis.

  • Valve dysfunction.

  • Endocarditis.

  • Aortic dissection.

  • Pericardial disease.

  • PE.

  • Asthma and COPD.

  • Alcohol and drug abuse.

Diagnosis

The diagnosis of acute HF should be both rapid and accurate, in order to initiate treatment/interventions as soon as possible. A possible workup algorithm is depicted in Fig. 3.1.2. The diagnosis of acute HF in patients presenting with acute dyspnoea should be performed, including a clinical history, physical examination, 12-lead ECG, and natriuretic peptide levels. An echocardiography can be useful in ‘de novo’ HF (e.g. for excluding cardiac tamponade). After acute HF confirmation, the appropriate treatment should be initiated and adapted to each patient’s presentation and comorbidities.

Fig. 3.1.2 Heart failure algorithm. IVC, inferior vena cava; MRA, mineralocorticoid receptor antagonist; TTx, treatment; WRF, worsening renal function; W-U, workup.

Fig. 3.1.2 Heart failure algorithm. IVC, inferior vena cava; MRA, mineralocorticoid receptor antagonist; TTx, treatment; WRF, worsening renal function; W-U, workup.

Treatment

In the published trials of acute HF, most agents have been shown to improve CV haemodynamics, but no agent has been shown to reduce mortality. The following recommendations are from expert consensus, and therefore, the level of evidence is C, unless otherwise stated.

Diuretics (class I, level of evidence B)

IV loop diuretics have never been evaluated in an RCT but are universally accepted to be beneficial and are recommended for all patients with acute HF admitted with signs/symptoms of fluid overload, to improve symptoms. It is recommended to regularly monitor symptoms, urine output, renal function, and electrolytes during use of IV diuretics.

  • An initial dose of 20–40mg of furosemide (or equivalent, e.g. bumetanide 0.5–1mg) can be tried and adjusted afterwards, according to patients` response (higher initial doses may be needed if the patient has renal failure or is receiving chronic diuretic therapy).

  • The highest dose of a diuretic that should really be used is as an infusion of 240mg in 24h (in exceptional circumstances, 480mg in 24h).

  • A combination of a loop diuretic with either a thiazide-type diuretic or spironolactone may be considered in patients with resistant oedema or persistent signs and symptoms. If diuresis cannot be restored, patients may need renal specialist treatment.

Oxygen

Administer to maintain oxygen saturation of 94–98% (88–92% in COPD if evidence of carbon dioxide retention has been obtained).

Non-invasive ventilation

Early non-invasive ventilation (NIV) with positive end-expiratory pressure (PEEP) improves LV function by reducing LV afterload. NIV should be used with caution in cardiogenic shock and RV failure. Intubation should not be delayed for a trial of NIV. Three recent meta-analyses found that early application of NIV reduces the need for intubation and reduces short-term mortality. However, in the Three Interventions in Cardiogenic Pulmonary Oedema (3CPO) trial, a large RCT, NIV improved clinical parameters, but not mortality. Start with a PEEP of 5–7.5cmH2O, and titrate up to 10cmH2O. Use a fraction of inspired oxygen (FiO2) of >40%.

Morphine

Morphine is good for treating restlessness, dyspnoea, anxiety, and chest pain. It also acts as a vasodilator. Use boluses of 2.5–5mg IV.

Use with great caution in patients with carbon dioxide retention due to reduced consciousness level, in sedated patients, and in hypotension.

Vasodilators (class I, level of evidence B)

IV nitrates decrease left and right filling pressures and SVR, i.e. GTN continuous infusion of 1–10mg/h. They are recommended early in acute HF if SBP is >110mmHg and may be used with caution if SBP is between 90 and 110mmHg. They are particularly useful in hypertensive HF. It is important to monitor BP levels and to avoid acute drops in BP. Use with caution in patients with aortic stenosis, as they may lead to marked hypotension. Patients develop tolerance to vasodilators with continuous use (see Table 3.1.10).

Table 3.1.10 Intravenous vasodilators used to treat acute heart failure

Vasodilator

Dosing

Glyceryl trinitrate

Start with 10–20mcg/min, increase up to 200mcg/min

Isosorbide dinitrate

Start with 1mg/h, increase up to 10mg/h

Nitroprusside

Start with 0.3mcg/kg/min, increase up to 5mcg/kg/min

Nesiritide

Bolus of 2mcg/kg + infusion of 0.01mcg/kg/min

Side effects

  • Headache, hypotension.

Inotropic agents

  • They may acutely improve haemodynamics, but they increase oxygen consumption and may worsen myocardial ischaemia/necrosis. No evidence for improved mortality. Initiated as early as required, but stopped as soon as no longer needed.

  • Continuous ECG monitoring is advised. BP should be monitored closely.

  • Dose should be titrated according to BP, organ perfusion, clinical condition, and diuresis. When weaning off inotropes, do this gradually.

  • Indications: low SBP in the presence of hypoperfusion if the patient has not responded to correction of preload with fluids or when there is a poor response to diuretics/nitrates due to hypotension.

(See Table 3.1.11.)

Table 3.1.11 Inotropic treatment in acute heart failure

Inotrope

Bolus

Infusion rate

Dobutamine

No

2–20mcg/kg/min

Dopamine

No

3–5mcg/kg/min: inotropic

>5mcg/kg/min: vasopressor

Milrinone

25–75mcg/kg over 10–20min

0.375–0.75mcg/kg/min

Enoximone

0.5–1.0mg/kg over 5–10min

5–20mcg/kg/min

Levosimendan

12mcg/kg over 10min (optional)

0.1mcg/kg/min, which can be decreased to 0.05mcg/kg/min or increased up to 0.2mcg/kg/min

Noradrenaline

No

0.2–1.0mcg/kg/min

Adrenaline

Bolus: 1mg can be given IV during resuscitation, repeated every 3–5min

0.05–0.5mcg/kg/min

Side effects

Increased risk of ventricular and atrial arrhythmias. Caution is needed in patients with a resting heart rate of over 100bpm.

Additional interventions

If the measures listed earlier fail to treat cardiogenic shock, the following mechanical interventions can be considered: IABP, intubation, and LVADs as a bridge to transplantation. If ACS is the underlying cause of acute HF, then coronary reperfusion with PCI or surgery may improve prognosis. Urgent surgery can be indicated in patients with mechanical complications after MI.

References

1 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891–975.Find this resource:

2 Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338–45.Find this resource:

3 Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777–81.Find this resource:

4 Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456–67.Find this resource:

5 van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009;53:2150–8.Find this resource:

6 The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525–33.Find this resource:

7 Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2017;370:1383–9.Find this resource: