The aims of chronic heart failure (CHF) management are:
- symptomatic relief
- to prevent hospital admission
- improve survival.
Optimal pharmacological and non-pharmacological (including device-based treatment) management have both had an enormous beneficial impact on the clinical course of heart failure. This module will focus on lifestyle modifications and pharmacological treatment.
There are national and international guidelines on the management of heart failure with reduced ejection fraction (HeFREF). The National Institute for Health and Care Excellence (NICE), European Society of Cardiology (ESC) and the Scottish Intercollegiate Guidelines Network (SIGN) have produced guidelines on the management of heart failure in primary and secondary care.1,2,3
The importance of non-pharmacological interventions such as lifestyle modification, psychosocial support and empowering patients to manage the condition themselves cannot be overlooked.
The key components of lifestyle modification for patients with heart failure are:1-3
- diet and weight control
- alcohol intake
- smoking cessation
- patient education and self-care behaviours.
Most patients with heart failure have fatigue and exertional dyspnoea that make exercise unappealing. In addition, depression and anxiety are common in patients with heart failure, which may reduce the motivation to exercise.
Guidance in older textbooks is that patients with heart failure should be advised to rest as much as possible. However, starting from the mid-1990s, a large body of evidence has accumulated showing that exercise training can improve exercise tolerance and potentially reverse many of the abnormalities of skeletal muscle morphology and function seen in patients.
The HF-ACTION (Efficacy and Safety of Exercise Training in Patients with Chronic Heart Failure) trial enrolled 2,331 patients with chronic heart failure (average age 59 years, median left ventricular ejection fraction [LVEF] 25%, 37% with New York Heart Association [NYHA] III–IV symptoms the majority of whom were taking an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB] and a beta blocker) who were randomised to either ‘usual care’ with no formal exercise programme or a structured, supervised, group-based exercise programme of 36 sessions over a three-month period which transitioned to home-based unsupervised exercise of five 40-minute sessions per week. Median follow up was 30 months and the primary outcome was a composite of all-cause mortality or all-cause hospitalisation. After adjustment for prognostic variables exercise training was associated with an 11% reduction in the primary end point compared to usual care (p=0.03).4
A meta-analysis of cardiac rehabilitation in patients with heart failure and NYHA II–IV symptoms found a reduction in hospitalisation rates and improvements in quality of life measures regardless of the ‘dose’ or form exercise involved.5
NICE guidelines recommend that patients with stable chronic heart failure, should be offered a supervised, personalised, group exercise-based rehabilitation programme with a psychological and educational component.1 The ESC guidelines on heart failure recommend that patients with heart failure are reassured about the benefits of exercise and are encouraged to exercise regularly.2
While obesity increases the risk of developing heart failure (5-7% for every 1 kg/m2)6, overweight or obese patients with heart failure have a lower mortality rate than normal or underweight patients.7,8 It is thus not clear whether the overweight patient with heart failure should be counselled to lose weight.
Weight loss is associated with reduced left ventricular (LV) mass, LV thickness and diastolic dimensions,9 and weight loss in obese patients with heart failure and reduced LVEF may improve LV systolic function.10
At the other end of the scale, cachexia (>5% weight loss in 12 months)11 and unintentional weight loss is associated with an adverse prognosis in chronic heart failure.12
The cause of cachexia in heart failure is not clear but may be due, in part, to neuro-hormonal activation:13 treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower risk of weight loss,14 and treatment with a beta blocker may prevent weight loss and promote weight gain in patients with heart failure.15
The ESC guidelines recommend that patients with heart failure are advised to monitor their weight regularly to detect rapid weight gain which may be a sign of fluid retention.2,16 Diuretic dose may be altered accordingly:
- increase dose if ≥2 kg weight gain in three days – a sign of developing congestion
- reduce dose if ≥2 kg weight loss in three days – a sign of excessive diuresis.
Diet and alcohol
Salt and fluid restriction is advocated in most guidelines,1–3 but there is no strong evidence to support these recommendations.17 In fact, one small study (n=232, NYHA II-IV, LVEF ≤35% taking 250-500 mg of furosemide per day and restricted to ≤1000 ml fluid per day) found higher levels of serum N-terminal fragment of the prohormone B-type natriuretic peptide (NTproBNP), aldosterone and renin in patients on salt-restricted diets compared to those on a normal salt diet.18
Guidelines recommend tailoring alcohol advice to aetiology of heart failure: for example, if a patient has alcoholic cardiomyopathy or deterioration due to paroxysmal atrial fibrillation secondary to excessive alcohol intake, then abstinence should be advised. Otherwise, normal alcohol guidelines should apply.
Useful advice on resumption of sexual activity for patients with cardiovascular disease is available from the British Heart Foundation (BHF). Advice on driving is available from the DVLA and guidance on fitness to fly can be accessed from the British Cardiovascular Society (BCS).19
Treatment of heart failure in primary care
Heart failure care should be delivered by a multidisciplinary team across primary, secondary and tertiary care. On average, a general practitioner (GP) will look after 30 patients with heart failure, and suspect a new diagnosis of heart failure in perhaps 10 patients per year.1
GPs are financially incentivised by the Quality and Outcomes Framework (QoF) to maintain a register of patients with heart failure and manage them appropriately (see module 1).20
The role of primary care includes:
- patient education
- managing the psychosocial aspects of living with heart failure
- monitoring adherence to guideline-recommended treatments
- managing co-morbidities
- referral to specialist services.
GPs are often the first port-of-call for a patient with increased breathlessness and thus play a central role in establishing a diagnosis, initiating treatment and avoiding hospital admission. A recent study of around 36,000 community-based patients with heart failure found that circa 40% patients presented to their GP with symptoms of heart failure in the five years before diagnosis, thus highlighting a common problem encountered in primary care – a high index of suspicion for possible cardiac dysfunction is required when assessing a patient with breathlessness but heart failure is but one of many causes of exertional breathlessness.21
Pharmacological treatment has been hugely successful in reducing mortality and morbidity for patients with heart failure and systolic dysfunction. However, the prognosis for patients with heart failure remains poor (module 1) and no drug has yet shown convincing outcome benefit in clinical trials for patients with HeFNEF. Research continues to develop potential new therapies.
Treatment of chronic heart failure
The present module focusses on the current pharmacological treatment of chronic heart failure (CHF) as recommended by NICE1 and the ESC2 guidelines. Modern medical therapy for HeFREF can improve the chances of patient surviving two years by as much as 90% and reduce overall mortality by around 60%.22,23
NICE and ESC guidelines recommend ACE inhibitors and beta blockers as first-line treatment.
ARBs are often used as an alternative in patients who are unable to tolerate ACE inhibitors.1,2 However, ACE inhibitors and ARBs are not interchangeable.
Enalapril was the first drug proven to improve outcome for patients with HeFREF. Since then, pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) has been central to improving outcome for patients with chronic heart failure.
ACE inhibitors should be initiated and titrated upward, starting low and increasing the dose gradually depending on the responses of the individual patient, particularly blood pressure and renal function.
Potential adverse effects for ACE inhibitors include:
- reduced renal function
- dizziness and syncope (rare)
- angioedema (very rare – discontinue).
NICE recommends that heart failure patients who are taking an ACE inhibitor should have their serum urea, electrolytes, creatinine and estimated glomerular filtration rate (eGFR) monitored for signs of renal impairment or hyperkalaemia.1
Bradykinin is broken down by angiotensin-converting enzyme and inhibition of bradykinin breakdown causes side effects such as a dry cough, taste disturbance, skin rash and, rarely, angio-oedema. Angio-oedema is more common in black Afro-Caribbean patients.
Only enalapril amongst all the ACE inhibitors has been shown to improve survival in patients with chronic heart failure.
The efficacy and safety of enalapril was established by landmark trials: CONSENSUS (Co-operative North Scandinavian Enalapril Survival Study)24 and SOLVD (Studies of Left Ventricular Dysfunction) (figure 1).25
The CONSENSUS trial (n=253, average age 71 years, NYHA class IV, predominantly taking digoxin and loop diuretics which was the standard of care at the time) was stopped early because of the dramatically lower mortality rate in the enalapril group at 6 (26% vs. 44%) and 12 months (36% vs. 52%, p=0.002).21
The SOLVD treatment study (n=2,569, average age 61, average LVEF 25%, NYHA II-IV, the majority of whom were taking diuretics and digoxin) found that treatment with enalapril was associated with a lower all-cause mortality rate (35.2% vs. 39.7%, p<0.0036), lower heart failure mortality rate and lower hospitalisation rate (47.7% vs. 57.3%, p<0.0001) compared to placebo after average 41 month follow up.22
The SOLVD prevention study (n=4,228, average age 59 years, average LVEF 29%, NYHA I or II) found that enalapril reduced the risk of all-cause mortality or hospitalisation with heart failure in patients with HeFREF who were asymptomatic or had mild symptoms at worst (21% in enalapril group vs. 25% in placebo group, p<0.001).26
Angiotensin II receptor blockers (ARBs)
ARBs are recommended as an alternative to ACE inhibitors for patients with HeFREF, who have intolerable side effects with ACE inhibitors.1
Unlike ACE inhibitors, they do not cause cough, one of the most common reasons for stopping ACE inhibitor therapy, as they do not inhibit bradykinin breakdown. The impact on renal function and blood pressure is similar.
These are similar to those seen with ACE inhibitors – except for the dry cough and angio-oedema.
The Val-HeFT (Valsartan Heart Failure Trial) study included 5,010 patients with HeFREF and NYHA II or worse (average age 62 years, average LVEF 27%, 93% were taking ACE inhibitors and 35% were taking beta blocker in the treatment arm).
Patients were randomised to either valsartan or placebo in addition to standard therapy. There was no reduction in mortality with valsartan but there were fewer hospital admissions and a 13% relative risk reduction in the combined end point of all-cause mortality, heart failure hospitalisation, aborted cardiac arrest and treatment with intravenous inotrope or vasodilator for >4 hours (p=0.009).28
The CHARM-Added (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) study (n=2,548, average age 64 years, average LVEF 28%, 99.8-100% of patients were also taking an ACE inhibitor) showed a lower rate of a combined end point of cardiovascular death or heart failure hospitalisation in the candesartan group compared with placebo (38% vs. 42%) after median follow up of 41 months (p=0.01). However, candesartan had no effect on all-cause mortality (30% vs. 32%, p=0.086).29
The CHARM-Alternative trial (n=2,028, average age 67 years, average LVEF 30%, NYHA II or worse) found that candesartan in patients with HeFREF intolerant of ACE inhibitors was associated with lower rates of a combined end point of cardiovascular death or heart failure hospitalisation compared to placebo (adjusted hazard ratio 0.70, p <0.0001). However, again, candesartan had no effect on all-cause mortality (26% vs. 29%, p=0.11).30
The ELITE II (the Losartan Heart Failure Survival Study) and OPTIMAAL (Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan) studies found no difference in mortality or morbidity end points between losartan and captopril.31,32
No ARB has been shown convincingly to reduce mortality, only to reduce the risk of hospitalisation for heart failure. If a patient complains of cough, then explain that the choice facing them is:
- to continue the ACE inhibition, put up with the cough, and retain the survival advantage
- switch to an ARB, have less cough, but lose the survival advantage.
Remember, too, that if the reason for ACE inhibitor intolerance is a fall in blood pressure or renal dysfunction, an ARB will have much the same effect.
The morbidity and mortality reductions seen with mineralocorticoid receptor antagonists (MRAs) in RALES (Randomised Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalisation and Survival Study in Heart Failure) were greater than that seen in CHARM-Added or CHARM-Alternative. As a result, ARBs and ACE inhibitors are not recommended in combination for patients with HeFREF who are symptomatic despite optimal therapy – an MRA is the preferred third agent.
Beta blockers should be offered to all patients with HeFREF regardless of age, peripheral vascular disease, erectile dysfunction, diabetes, interstitial pulmonary disease or chronic obstructive pulmonary disease (all of which might otherwise be considered relative contraindications).1
They are first-line treatment, along with an ACE inhibitor in patients with stable heart failure. They should be started as early as possible in the course of the disease, alongside ACE inhibitors or ARBs, and require careful up-titration.
Potential adverse effects of beta blockers include:
- postural hypotension
- increased atrioventricular (AV) block
- bronchospasm in susceptible individuals
- peripheral vasoconstriction including Raynaud’s phenomenon, cold extremities
- central nervous system (CNS) effects (headache, dizziness)
- sleep disturbances
- gastrointestinal (GI) disturbances
Specialist opinion should be sought if considering beta blockers in patients with genuine asthma or in those with pronounced conduction system disease.
Cardio-selective beta blockers increase the risk of new onset diabetes, especially in combination with diuretics, while in patients with insulin-dependent diabetes, non-selective beta blockers may mask hypoglycaemia due to their effect on sympathetic nerve activation. In many patients with heart failure the huge benefits generally outweigh the small risks.33 Recent evidence suggests that beta blockers have no effect on sexual function despite common belief, and the excess of tiredness and fatigue is only around eight per 1,000 patients treated.
In CIBIS II (Cardiac Insufficiency Bisoprolol Study II), bisoprolol was associated with a reduction in all-cause mortality versus placebo (11.8% vs. 17.3%, p=0.0001, RRR 32%). There was also a significant reduction in sudden death (3.6% vs. 6.3%, p=0.001, RRR 42%).34
The MERIT (Metropolol CR/XL Randomised Intervention Trial in Heart Failure) study (n=3,991, average age 64 years, average LVEF 28%, NYHA II–IV) found improved survival (risk reduction of 34% for all-cause mortality, 38% for cardiovascular mortality, 41% for sudden death, and 49% for death due to worsening heart failure) with metoprolol (CR/XL) compared to placebo in patients with HeFREF after one-year average follow up.35
The CAPRICORN (Carvedilol Post-Infact Survival Control in Left Ventricular Dysfunction) study (n=1,959, average age 63 years, average LVEF 33%, also taking an ACE inhibitor)36 and COPERNICUS (Carvedilol Prospective Randomised Cumulative Survival) study (n=2,289, LVEF <25%, NYHA III or IV)37 found reduced mortality and hospitalisation rates with carvedilol compared to placebo in patients with heart failure. Carvedilol was also associated with a significant increase in LVEF and reduction in LV volume compared to placebo in subgroup analysis of patients recruited to COPERNICUS.38
SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure) (n=2,128, average age 76 years, 65% had LVEF ≤35%, 95% were NYHA II or III, ~88% were also taking an ACE inhibitor or an ARB) found a reduction in the primary composite endpoint of all-cause mortality or cardiovascular hospitalisation rate with nebivolol compared to placebo (HR 0.86, p=0.036). However, nebivolol had no impact on all-cause mortality (15% vs. 18%, p=0.21).39
Which beta blocker?
Interestingly, BEST (Beta Blocker Evaluation in Survival Trial) (n=2,708, average age 60 years, average LVEF 23%, NYHA III or IV, 91% also taking an ACE inhibitor) found no significant benefit of bucindolol over placebo in patients with heart failure.40 Bucindolol has partial sympathomimetic activity, as does an older agent, xamoterol, which was found to be harmful in heart failure.41 A beta blocker shown to be beneficial is thus essential, but which out of those available?
There has only been one trial directly comparing one beta blocker with another: COMET (Carvedilol Or Metoprolol European Trial).42 Patients (n=3,029, average age 62 years, average LVEF 26%, 98% were also taking an ACE inhibitor or ARB) were randomised to receive either the selective beta1 blocker, metoprolol, or the non-selective agent, carvedilol (which has alpha-blocking properties as well as being a non-selective beta blocker).
Carvedilol was unequivocally the better agent at the doses used in the trial, and thus many feel that it should be used in preference to bisoprolol. Although bisoprolol was not directly compared with carvedilol, it, like metoprolol, is a selective beta1-antagonist.
Beta blockers licensed for use in heart failure include:
- metoprolol CR/XL (a preparation not available in the UK).
Once a patient is established on initial treatment, the dose should then be increased in a step-wise fashion to reach the target dose – the target dose of all heart failure medications is the dose used to prove efficacy in randomized trials (table 2).
Table 2. Target doses of medications used to treat heart failure with reduced ejection fraction
|Starting dose||Target dose|
|Angiotensin-converting enzyme inhibitors|
|Enalapril||2.5 mg twice per day||10 mg twice per day|
|Ramipril||2.5 mg once per day||10 mg once per day|
|Lisinopril||2.5 mg once per day||35 mg once per day|
|Angiotensin receptor blockers|
|Candesartan||4 mg once per day||32 mg once per day|
|Valsartan||40 mg twice per day||160 mg twice per day|
|Losartan||50 mg once per day||150 mg once per day|
|Bisoprolol||1.25 mg once per day||10 mg once per day|
|Carvedilol||3.125 mg twice per day||25 mg twice per day†|
|Nebivolol||1.25 mg once per day||10 mg once per day|
|Mineralocorticoid receptor antagonists|
|Spironolactone||25 mg once per day||50 mg once per day|
|Eplerenone||25 mg once per day||50 mg once per day|
|Angiotensin receptor blocker / neprilysin inhibitors|
|Sacubitril/valsartan||49/51 mg twice per day‡||97/103 mg twice per day|
|Sinus node blockers|
|Ivabradine||2.5 mg twice per day||7.5 mg twice per day|
|Adapted from Ponikowski et al.2
† In patients over 85 kg the maximum dose of carvedilol is 50 mg twice per day
‡ In patients in whom there is concern regarding renal dysfunction or symptomatic hypotension, a starting dose of 24/26 mg twice per day can be considered
In practice, only 20-35% of patients taking an ACE inhibitor or ARB and 15-20% of patients taking beta blockers are taking target doses.43,44 This may have prognostic implications; higher doses of ACE inhibitors, ARBs and beta blockers are associated with lower rates of mortality and hospitalisation for heart failure than lower doses.45,46,47
Guidelines recommend a ‘start low, go slow’ approach to starting heart failure medications but this should not be interpreted as an instruction in favour of less frequent or less than therapeutic dosing. A common example of inadequate dosing is enalapril 2.5 mg once per day or spironolactone 12.5mg every other day – medications that require twice-daily dosing will only be effective if given twice per day at the recommended dose.
Mineralocorticoid receptor antagonists (MRAs)
The MRAs, spironolactone or eplerenone, should be added for patients with ongoing symptoms despite maximum tolerated dose of beta blocker and ACE inhibitor and LVEF <35%.3
Careful monitoring of renal function and potassium levels is essential with MRAs, particularly when used with ACE inhibition. Treatment should be tailored to the individual patient. Dietary advice should be given if potassium increases moderately, and a repeat sample taken.
If potassium remains significantly elevated, then dose reduction may be required. Recent work on potassium binders may prove a possible solution to hyperkalaemia due to MRAs in patients with HeFREF and may widen their use (see module 5 – special cases).
Potential adverse effects of MRAs include:
- renal impairment
- hypotension and postural hypotension
- pre-syncope and syncope
- gastrointestinal symptoms; dyspepsia, abdominal pain
- rash, pruritus and photosensitivity
- ataxia and confusion.
Potential adverse effects of spironolactone due to progesterone-like and anti-androgen effects include:
- gynaecomastia and breast pain
- menstrual disturbances
- loss of libido.
In the RALES study (n=1,663, average age 65 years, average LVEF 25%, 94-95% taking ACE inhibition, 99% were NYHA III or IV), spironolactone was associated with improved symptoms (measured by NYHA class), a 30% relative risk reduction (RRR) in cardiovascular mortality and hospitalisations and a 30% RRR in all-cause mortality compared to placebo in patients with heart failure.48
In the EPHESUS (Eplerenone in Heart Failure after Myocardial Infarction) trial (n=6,632, average age 64 years, average LVEF 33%, most taking ACE inhibitors and beta blockers, and 90% with ‘symptoms of heart failure’), eplerenone was associated with 15% relative risk reduction (RRR) in all-cause mortality and 13% RRR in a composite end point of cardiovascular death or hospitalisation compared with placebo in patients with heart failure following myocardial infarction.49
The EMPHASIS-HF trial (n=2,737, average age 69 years, average LVEF 26%, NYHA II, most taking ACE inhibitors or ARBs and beta blockers) found that eplerenone was associated with a reduction in all-cause mortality (12.5% vs. 15.5%), cardiovascular mortality (10.8% vs. 13.5%) and heart failure hospitalisation (12.0% vs. 18.4%) compared to placebo.50 Note the patients in EMPHASIS-HF were only mildly symptomatic.
Heart failure with a normal ejection fraction (HeFNEF)
A recent post-hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (n=3,445, average age 68 years, median LVEF 56%, median NTproBNP in spironolactone group 887 ng/L, 96% of whom were NYHA II or III) suggested that spironolactone was associated with lower mortality or heart failure hospitalisation compared to placebo in the sub-group of patients recruited in North and South America.51 However, the results of the main trial were neutral (the primary composite end point of cardiovascular death, aborted cardiac arrest or heart failure hospitalisation was 18.6% in the spironolactone group vs. 20.4% in the placebo group).52 Although spironolactone may be beneficial in patients with HeFNEF, there is no convincing evidence to support its use; work is ongoing (NCT02901184).53
Third line treatment
For patients who remain symptomatic despite maximum tolerated ‘triple therapy’, there are two further pharmacological options: ivabradine and angiotensin receptor neprilysin inhibitors (ARNIs).
Ivabradine acts to reduce the rate of sinus node node firing, reducing heart rate in people in sinus rhythm. It has no effect on sinus rhythm, and is not negatively inotropic.
A high resting heart rate is a marker of adverse outcome in patients with heart failure. Even with maximum dose beta blockers, some patients with heart failure have high resting heart rates. Ivabradine reduces the rate of sinus node firing, reducing heart rate in people in sinus rhythm without reducing blood pressure (the most common limiting factor for beta blocker titration). It is not negatively inotropic, but has no effect in patients in atrial filbrillation.7
Potential adverse effects of ivabradine include:
- phosphenes (bright illuminations in the periphery of the visual field exacerbated by sudden changes in ambient brightness)
- blurred vision
- bradycardia (discontinue treatment if heart rate <50 beats per minute [bpm] dose reduction)
- first degree AV block
- atrial fibrillation
- ventricular extrasystole
- blood pressure changes
In the SHIFT (Ivabradine and Outcomes in Chronic Heart Failure) study (n=6,558, average age 62 years, average LVEF 29%, average heart rate 80 bpm, all in sinus rhythm, NYHA II–IV, 89-90% taking beta blockers, 92-93% taking ACE inhibitors or ARBs and 59-61% of whom were taking an MRA), ivabradine was associated with a reduction in heart failure mortality (3% vs. 5%, p=0.014) and heart failure hospitalisations (16% vs. 21%, p=<0.0001) compared to placebo in patients with heart failure.55
There is also some evidence that ivabradine has beneficial effects on clinical status, functional capacity and quality of life in patients with heart failure.56,57
Subsequently, ESC and NICE guidelines recommend ivabradine for patients with symptomatic heart failure despite triple therapy, with an LVEF <35%, who are in sinus rhythm with a resting heart rate above 70 (≥75 bpm in NICE guidance) despite maximally tolerated treatment with an appropriate betablocker.1,2,58
Heart failure with normal ejection fraction (HeFNEF)
In the EDIFY (Effect of ivabradine in patients with heart failure with preserved ejection fraction) trial, investigators randomised 174 patients (average age 72 years, median LVEF 60%, median NTproBNP 385 ng/L, average heart rate 75 bpm, all in sinus rhythm, 66% of whom were taking beta blockers, NYHA II-III) to ivabradine or placebo. Despite significant reductions in heart rate, ivabradine had no effect on symptom severity, NTproBNP or echocardiographic variables in patients with HeFNEF.59 It is therefore unlikely that future trials will be conducted using ivabradine in patients with HeFNEF.
Angiotensin receptor neprilysin inhibitors (ARNIs)
Natriuretic peptides can counteract the effects of neurohormonal over-activation in heart failure (module 2 – natriuretic peptides) and are degraded by the endopeptidase neprilysin.60
The physiological effects of natriuretic peptides are:
- inhibition of the sympathetic nervous system
- inhibition of the renin–angiotensin–aldosterone system (RAAS).
Neprilysin inhibitors increase circulating levels of natriuretic peptides and, when used in conjunction with ACE inhibitors, improve survival in animal models of heart failure compared to ACE inhibitors alone.61
However, trials of neprilysin inhibitors and ACE inhibitors in humans found increased risk of serious angio-oedema, due to the combined inhibitory effect of the two drugs on bradykinin degradation.62,63
Consequently, LCZ696 was developed. The combination of valsartan (an ARB, which does not inhibit the degradation of bradykinin by angiotensin converting enzyme) and sacubitril (a neprilysin inhibitor), reduces the action of angiotensin II and neprilysin without increasing the risk of angio-oedema.
In the PARADIGM-HF (Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure) trial, investigators randomised 8,442 patients with chronic heart failure who had NYHA II symptoms or worse (average age 63 years, average LVEF 29%, median NTproBNP 1,631 pg/mL in the treatment arm) to either sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. Some 93% were taking a beta blocker, and 54% were taking a MRA. The trial was stopped early after 27 months having demonstrated significant survival benefit with sacubitril/valsartan over enalapril 10 mg twice daily (table 3).64 The trial was so overwhelmingly positive that guidelines the world over have changed to accommodate sacubitril/valsartan.
There is some uncertainty as to the details of which patients exactly are eligible for sacubitril/valsartan, but some estimate that as many as 84% of patients with HeFREF might be switched.65 Others, taking account of contraindications (such as systolic blood pressure <100 mmHg or an estimated glomerular filtration rate <30 ml/min/1.73m2) and strict application of the entry criteria for PARADIGM-HF (on which the ESC recommendations are based) suggest that only 21% of patients may be suitable for sacubitril/valsartan.66
The more recent PIONEER-HF (Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure) trial (n=881, average age 62 years, median LVEF 26%, median NTproBNP 2,883 ng/L in the treatment arm)67 and TRANSITION (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) study (n=991, average age 67 years, median LVEF 29%, median NTproBNP 1,902 ng/L)68 trials have demonstrated the safety, feasibility and possible outcome benefit of starting sacubitril/valsartan soon after completing treatment for acute heart failure either while an in-patient or immediately after discharge.
Around 50% of patients in PIONEER-HF and 25% of patients in TRANSITION were not taking an ACE inhibitor or an ARB before starting sacubitril/valsartan. Although current guidelines recommend a switch from an ACE inhibitor or ARB in patients with LVEF <35% and persistent symptoms despite optimal triple therapy,1,2,3 it may be that sacubitril/valsartan becomes first-line treatment in the future.
Neprilysin is responsible, in part, for the breakdown of amyloid-beta peptides, the accumulation of which in the brain is associated with Alzheimer’s dementia. Although there was no significant difference in dementia-related adverse events between the two treatment groups in PARADIGM-HF,69 a further trial of sacubitril/valsartan in patients with heart failure and normal ejection fraction involving more detailed cognitive assessment and PET-CT brain scans is underway (NCT02884206).70
Other concerns regarding the widespread use of sacubitril/valsartan include the high incidence of symptomatic hypotension in the treatment arm of the PARADIGM-HF study (14% vs. 9.2%, p<0.001).56
There has been much debate about the comparator (enalapril 10 mg twice daily) when ramipril is so commonly used, but as noted above, enalapril is the only ACE inhibitor shown to confer a mortality advantage. The dose of enalapril achieved in PARADIGM-HF exceeded that in CONSENSUS, so there can be little doubt the correct comparator was chosen.
Heart failure with normal ejection fraction (HeFNEF)
In the PARAGON-HF trial, investigators randomised 4,822 patients (average age 72 years, LVEF ≥45%, median NTproBNP 904 ng/L in the treatment group, NYHA class II–IV) to either sacubitril/valsartan 200 mg twice daily or valsartan 160 mg twice daily. After follow up of a minimum 26 months, sacubitril/valsartan was not associated with significant morbidity or mortality benefit (37% of patients in the sacubitril/valsartan group met the primary composite end point of cardiovascular death or heart failure hospitalisation vs. 42% in the valsartan group; p=0.06).71 As with the PARADIGM-HF study, the rate of hypotension was greater with sacubitril/valsartan (15.8% vs. 10.8%; p<0001).
Pre-specified subgroup analysis suggested possible outcome benefit for patients with LVEF less than the median (57%), indicating that treatment with sacubitril/valsartan may have benefit for patients with subtle LV dysfunction but no benefit for those with obviously normal LV function.
This highlights a central problem with the current definition of HeFNEF in that it includes patients with subtle LV dysfunction or at risk of LV dysfunction for whom inhibition of the renin-angiotensin-aldosterone system may be beneficial, but also includes patients with functionally normal hearts, in whom the breathlessness may be due to a different pathology.
For now, sacubitril/valsartan in the UK should be initiated under specialist supervision in patients with LVEF <35% and ongoing symptoms despite triple therapy who are taking a ‘stable dose’ of an ACE inhibitor or ARB. Sacubitril/valsartan joins the long list of medications with unequivocal outcome benefit in patients with HeFREF that have no proven benefit in patients with HeFNEF.
Loop diuretics are the cornerstone of treatment of symptomatic venous congestion in heart failure. Their effect on outcome is not certain and has not been properly studied in randomised controlled trials.
Guidelines recommend the use of loop diuretics (furosemide, bumetanide) in the first instance with a thiazide diuretic (e.g. bendroflumethiazide) used as add-on therapy in patient with resistant oedema although the efficacy of thiazide diuretics reduces with worsening renal impairment.1,2,3
The goal of diuretic therapy is symptomatic relief and the maintenance of clinical euvolaemia with the lowest possible dose. In carefully selected patients, complete withdrawal of diuretics may be possible.1,2,3
Adverse effects (table 4)
Table 4. Potential adverse effects of diuretics (click to enlarge)
|Adverse effects of thiazide diuretics|
|Electrolyte depletion (K+, Mg) resulting in cardiac arrhythmias if also on digoxin|
|Hyperuricaemia (interference with the renal clearance of uric acid); diuretics increase the risk of acute gout|
|Hyperglycaemia with an increased risk of new onset diabetes|
|Impaired renal function|
|Impaired exercise tolerance|
|Erectile dysfunction (unknown mechanism)|
|Adverse effects of loop diuretics|
|Fluid and electrolyte imbalance|
|Raised serum creatinine|
|Adverse effects of potassium-sparing diuretics|
There are few randomised controlled trials involving diuretics in the modern age of triple therapy for heart failure. DOSE (Diuretic Studies in Patients with Acute Decompensated Heart Failure) studied continuous versus bolus and low (the patients’ ‘usual’ daily loop diuretic dose) versus high (2.5 times the patients’ ‘usual’ daily dose of diuretic) dose intravenous loop diuretic in patients admitted to hospital with fluid retention due to heart failure (n=308, average age 66 years, average LVEF 35%, mean NTproBNP 7,439 pg/mL, average daily dose of loop diuretic 127–134 mg).72
There was no significant difference between patient-assessed symptoms or change in renal function compared to low versus high dose or continuous versus bolus administration. However, there are some findings of note:
- patients in the low-dose group were more likely to require a 50% increase in total daily diuretic dose after 48 hours
- patients in the low-dose group were less likely to be switched to oral diuretic after 48 hours
- there was a trend to greater improvement in patient-reported symptoms in the high-dose group compared to the low-dose group (p=0.06)
- high-dose diuretic was associated with greater weight loss (p=0.01), net fluid loss (p=0.001) and relief from dyspnoea (p=0.04) after 72 hours compared to low dose
- It is important to note that weight loss during the first 72 hours of treatment in the high-dose group was modest (~3.9kg) raising concerns about the heterogeneity of the population studied and the efficacy of the treatment given.
- there was no significant difference in the primary safety end point of a change in serum creatinine between high- and low-dose diuretic. But high-dose diuretic was associated with transient deterioration in renal function compared to low dose
- there was no significant difference in the average change in creatinine between continuous infusion and bolus infusion groups.
Some retrospective analyses suggest there is an inverse relation between diuretic dose and survival in patients with chronic heart failure.73,74 The association may be due to diuretic-induced electrolyte abnormalities,75 such as hyponatraemia and hypochloraemia that are themselves associated with worse outcomes76,77 or may be purely because patients who require diuretic have more severe disease.
Other drug therapies
Not all patients are able to tolerate triple therapy, ivabradine or sacubitril/valsartan; for example, chronic kidney disease affects around 18% of patients with chronic heart failure and may limit initiation or up-titration of ACE inhibitors, ARBs or MRAs.78,79
Such patients may benefit from hydralazine plus isosorbide dinitrate and/or digoxin. However, the evidence base supporting their use is far less robust than that for ACE inhibitors, ARBs, beta blockers, MRAs, ivabradine or sacubitril/valsartan.
Anaemia and electrolyte abnormalities are common complications of heart failure, the management of which will be addressed in module 5.
Vasodilators – hydralazine/isosorbide dinitrate combination (H-ISDN)
H-ISDN is indicated in patients with HeFREF as an adjunct to triple therapy if the patient remains symptomatic or as an alternative first-line treatment if ACE inhibitors or ARBs are not tolerated.1
The potential adverse effects of hydralazine include:
- gastrointestinal upset
- joint swelling
- systemic lupus erythematosus (SLE)-like syndrome (high doses).
H-ISDN for the treatment of heart failure has been studied in three clinical trials (V-HeFT I, V-HeFT II and A-HeFT), all of which found a relative risk reduction with H-ISDN compared to placebo in patients with heart failure.81,82,83
Sub-analysis of VHeFT I and V-HeFT II reported that African American patients with moderate-to-severe heart failure taking H-ISDN had a 47% relative risk reduction in mortality compared to non-African American patients.84
In the subsequent A-HeFT trial (n=1,050, average age 57 years, average LVEF 24%, NYHA II-IV) H-ISDN was associated with a reduction in all-cause mortality rates (6.2% vs. 10.2%, p=0.02) and first heart failure hospitalisation rates (16.4% vs. 22.4%) compared with placebo.71
The benefit of H-ISDN in patients who are not African-Americans is not clear: V-HeFT I and V-HeFT II were published before widespread use of ACE inhibitors, ARBs, beta blockers or MRAs.
Furthermore, V-HeFT II found H-ISDN to be inferior to enalapril (18% two-year mortality rate in enalapril group vs. 25% in the H-ISDN group, p=0.016).69 However, the majority of patients in A-HeFT were taking ACE inhibitors/ARBs (86%) and beta blockers (74%).
Digoxin (cardiac glycosides)
Digoxin is indicated in patients with HeFREF with resistant symptoms and for rate control in atrial fibrillation.
The potential adverse effects of digoxin include:
- visual disturbances
- conduction system disturbance
- sinus bradycardia
- supraventricular arrhythmias
- psychological problems
- skin rashes
- thrombocytopaenia (very rarely).
In the DIG (Digitalis Investigation Group) study (n=6,800, all in sinus rhythm, average age 63 years, average LVEF 28%),85 digoxin was associated with reduced rates of heart failure hospitalisation (26.8% vs. 34.7%) but had no long-term mortality benefit.
Recent post hoc analysis of the DIG study found that digoxin at low doses (≤0.500 mg/day) is associated with reduced one-year all-cause mortality, cardiovascular mortality and heart failure mortality compared to placebo in patients with heart failure who are concurrently treated with ACE inhibitors and diuretics (figure 6). There was also a significant reduction in hospitalisation.86 Combination of digoxin and ACE inhibitor may be appropriate in patients who are intolerant of beta blockers or MRAs. However, DIG was conducted before beta blockers became widely used and the effect of digoxin on patients taking triple therapy is unknown.
A recent post-hoc analysis of the DIG trial found that pre-trial treatment with digoxin was associated with worse outcome after adjustment for prognostic variables (HR = 1.22 (95% CI 1.12–1.34, p<0.001 for mortality, HR = 1.47 (95% CI 1.33–1.61, p<0.001 for heart failure hospitalisation) regardless of whether patients were randomised to placebo or digoxin during the trial.87 The prescription bias of pre-treatment with digoxin was so great that the direction of treatment effect with randomised data (reduced risk of heart failure hospitalisation with digoxin) was the opposite of that with observational data in the same population (increased risk of hospitalisation with digoxin). Extreme caution must be exercised when using observational data to inform clinical practice; doing so may lead to underuse of medications that are potentially beneficial.
The introduction of ivabradine means the use of digoxin in patients with heart failure and sinus rhythm is mainly limited to those with advanced disease. Digoxin may have a role for rate control in patients with heart failure and atrial fibrillation but this should not be at the expense of beta-blocker use.
Sodium-glucose transport protein 2 inhibitors
Sodium-glucose transport protein 2 (SGLT2) inhibitors were initially conceived as an anti-hyperglycaemic medication for type 2 diabetes. Interesting results of phase III trials indicate they may have potential outcome benefit for patients with heart failure.
Potential adverse effects of SGLT2 inhibitors are largely due to the increased risk of infection due to increased glucose along the urinary tract and include:
- balanoposthitis – infection or inflammation of the foreskin or glans
- urinary tract infections
- Fournier’s gangrene – necrotising fasciitis affecting the external genitalia or perineum
- hypoglycaemia – only when used in conjunction with insulins or sulphonlyureas
- thirst or symptoms hypovolaemia – side effects of the diuretic effect
- diabetic keto-acidosis (DKA) – rare, but presentation with DKA on SGLT2 inhibitors may be atypical with only moderately raised blood glucose levels thus a high index of suspicion is required.
The EMPA-REG OUTCOMES (Empagliflozin, Outcomes, and Mortality in Type 2 Diabetes) trial of empagliflozin (published in 2015) was the first trial of an anti-hyperglycaemic agent to show a beneficial effect on hard outcomes in patients with type 2 diabetes.89 Treatment with empagliflozin was associated with a reduction in the risk of the composite end point of cardiovascular death and nonfatal myocardial infarction or stroke versus placebo (37.4% vs. 43.0%; p=0.04).
There was a striking reduction in the rate of hospitalisation with heart failure or cardiovascular death in the main trial, even in patients without a diagnosis of heart failure at baseline.90 The findings prompted further investigation of SGLT2 inhibitors in patients with heart failure without diabetes.
In the DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) study (published in 2019), investigators randomised 4,744 patients (average age 66 years, 98% NYHA II–III, median NTproBNP in the treatment group 1,428 ng/L, 42% of whom had diabetes) to either dapgliflozin 10 mg once-daily or placebo.91 After a median follow up of 18 months, dapagliflozin was associated with a reduced risk of worsening heart failure or cardiovascular death compared to placebo (16% vs. 21%; P%lt;0.001). The drug was well tolerated: adverse events such as hypovolaemia or renal dysfunction were rare (1-3%).
The mechanism of benefit is unclear and is the subject of much debate. For example, SGLT2 inhibitors may also have an inhibitory effect on the sodium-hydrogen exchanger, which is responsible for the majority of sodium reabsorption in the proximal tubule. Thus, SGLT2 inhibitors may have a natriuretic effect alongside the osmotic diuretic effect.92 Additionally, inhibition of the Na+/H+ exchanger in the heart may reduce myocardial injury, fibrosis and remodelling.93 Other proposed mechanisms of benefit are wide ranging and include a reduction in arterial stiffness,93 beneficial changes in renal blood flow,95 and a reduction in blood pressure.89 It is possible the mechanism of benefit is multi-faceted.
Quite how SGLT2 inhibitors will fit into future heart failure guidelines is unclear: only 10% of patients in the dapagliflozin arm of DAPA-HF were taking sacubitril/valsartan. Whether the benefit conferred by dapagliflozin is greater than, less than or incremental to that of sacubitril/valsartan in patients otherwise taking a beta blocker, MRA and ACE inhibitor or ARB is unknown. However, as the mechanisms of action of SGLT2 inhibitors and neprilysin inhibitors are separate, SGLT2 inhibitors may find a role as alternative therapies for patients intolerant of sacubitril/valsartan or as add-on therapy for patients with difficult to control symptoms. Studies are ongoing in patients with HeFREF (NCT03057977) HeFNEF (NCT03057951 and NCT03030235) and acute heart failure (NCT04049045) among others.
Calcium-channel blockers (CCBs) are not indicated for the treatment of heart failure. Verapamil and diltiazem are contraindicated in heart failure together with short-acting dihydropyridine agents.1
The PRAISE (Prospective Randomized Amlodipine Survival Evaluation) I and II studies found that amlodipine is safe in patients with heart failure.96,97
NICE therefore recommends the use of amlodipine for hypertension and/or angina in patients with heart failure uncontrolled by other therapy.1
There is no convincing evidence that statins (HMG-CoA inhibitors) affect outcome for patients with heart failure. Two large studies (>10,000 patients) found that rosuvastatin conferred no benefit to patients with heart failure.98,99
Anticoagulants and aspirin
Anticoagulants, such as warfarin or direct acting oral anticoagulants (DOACs), are indicated for thrombo-embolic prophylaxis in patients with heart failure and atrial fibrillation.100 There is no evidence that aspirin alone improves the outcome of patients with chronic heart failure. It counter-acts the pharmacological effects of ACE inhibitors and is associated with impaired renal function. It should be used in patients with a recent ischaemic event or percutaneous coronary intervention.
Heart failure is a hypercoagulable state with a higher incidence of stroke than in the general population, regardless of underlying cardiac rhythm,101,102 but there is only limited evidence to support the use of oral anticoagulants in patients with heart failure in sinus rhythm.103,104,105 There are two recent studies of interest – the COMMANDER-HF (Rivaroxaban in Patients with Heart Failure, Sinus Rhythm and Coronary Disease) and COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trials.
The COMMANDER-HF trial enrolled 5,022 patients (average age 66 years, median LVEF 34%, 93% of whom were NYHA class II–III, median NTproBNP 2,840 ng/L in the rivaroxaban arm) who were randomised to either rivaroxaban 2.5 mg twice daily or matching placebo. The primary outcome was a composite of death, stroke or myocardial infarction. Secondary outcomes included a composite of cardiovascular death or hospitalisation with heart failure. After median follow up of 21 months, there was no difference between the rivaroxaban or placebo groups in the primary or secondary outcomes. Safety outcomes were comparable although more patients in the rivaroxaban group had a bleeding event requiring hospital admission than in the placebo group.106
The COMPASS trial enrolled 27,395 patients with coronary artery disease, peripheral vascular disease or both (~20% of whom had heart failure) who were randomised to receive either rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone or aspirin 100 mg once daily alone. The primary outcome was a composite of cardiovascular death, stroke or myocardial infarction. The study was discontinued after average follow up of 23 months with a clear outcome advantage associated with rivaroxaban-plus-aspirin compared to aspirin alone (4.1% vs. 5.4%; p<0.001). There was no difference in outcomes for patients treated with rivaroxaban alone compared to aspirin alone.107
Patients under the age of 65 had to have additional risk factors including evidence of atherosclerosis in two different vascular beds or two of either heart failure, current smoking, diabetes mellitus, eGFR <60 ml/min or stroke to be included. Coronary artery disease, diabetes and renal dysfunction are all common co-morbidities in patients with heart failure and it is conceivable the use of rivaroxaban plus aspirin in patients with heart failure may become more widespread in the wake of the COMPASS study. However, it should be noted that patients with heart failure and LVEF <30% or NYHA III–IV were excluded from the COMPASS study and thus the results cannot be applied to all patients with heart failure and atherosclerotic vascular disease, only those with mild disease.
The COMMANDER-HF results are perhaps the best guide to the use of anticoagulants in patients with heart failure although the results of the COMPASS study suggest outcome benefit with low-dose rivaroxaban-plus-aspirin for a subset of patients with heart failure.
Omega-3 polysaturated fatty acids
In the GISSI-HF (Effects of n-3 PUFA and Rosuvastatin on Mortality-Morbidity of Patients With Symptomatic CHF) study (n=3,481, average age 67 years, average LVEF 33%, NYHA II-IV), supplementation with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with standard therapy (93% taking ACE inhibitors/ARBs, 65% taking beta blockers and 39% taking MRAs in the treatment arm) was associated with reduced all-cause mortality (27% vs. 29%, p=0.041) and cardiovascular hospitalisation (57% vs. 59%, p=0.009) compared to placebo in patients with heart failure.108 However, the small outcome benefit means they are rarely used in practice.
NICE recommends that all patients with chronic heart failure are monitored1 at least every six months and at shorter intervals if the patient’s clinical condition or drug treatment changes. Patients should be offered information and support if they wish to be involved in monitoring their condition and advised what to do if their condition deteriorates.
Patients admitted to hospital with heart failure should receive specialist advice for their management plan.
The minimum checks required when monitoring heart failure patients are:1
- a clinical review to include:
- clinical assessment of functional capacity, fluid status, cardiac rhythm, cognitive status and nutritional status
- medication review (including the need for changes and possible side effects)
- serum urea, electrolytes, creatinine and eGFR. Monitoring serum potassium is particularly important if a patient is taking digoxin or an MRA
- ECG – new left bundle branch block appears in around 10% of patients per annum
- Monitoring of serum natriutetic peptides should be considered in some patients (e.g. in those being considered for transplantation)
- Serum digoxin does not need to be routinely monitored but consider a measurement within 8-12 hours of the last dose if toxicity or non-adherence is suspected. Take care to interpret within the clinical context as toxicity can occur in the “therapeutic range”
- Pulmonary artery pressure monitors can be used in chronic heart failure – see NICE interventional procedure guidance 463 for more detail.109
In conclusion, the pharmacological and non-pharmacological management of heart failure require the input of a multidisciplinary team, as well as patient involvement to deliver positive outcomes, reduce hospital admissions and improve survival.
Lifestyle changes including exercise and diet as part of a self-management programme that promotes adherence to pharmacological treatment should be actively promoted. Clinicians should follow the current national NICE, ESC or SIGN guidelines in order to achieve optimal treatment and outcomes.
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