Heart failure: management

Chronic heart failure can broadly be separated into heart failure with reduced ejection fraction (HFREF; also referred to as left-ventricular systolic dysfunction) and heart failure with preserved ejection fraction (HFPEF). Whereas there is substantial evidence to support the use of interventions that improve prognosis for patients with HFREF, there is little evidence available to support interventions for HFPEF. This article will focus primarily on the management of patients with HFREF.

There are three aims of management for chronic heart failure. They are:

• To reduce mortality
• To delay disease progression
• To control symptoms and improve quality of life

From a patient’s perspective, the ability to carry out normal activities of daily living may be more important than longevity; therefore, symptom control is an essential component of care.

Lifestyle change

All patients with heart failure, regardless of cause, should be supported to make changes to their lifestyle that may improve their health. Key lifestyle interventions include:

• Stopping smoking
• Making dietary changes, such as moderating salt intake, increasing fruit and vegetable intake, reducing saturated fat
• Losing weight (if obese)
• Increasing physical activity, aiming for at least 30 minutes of exercise on most days of the week
• Moderating alcohol intake to below recommended limits (patients with alcoholic cardiomyopathy should be advised to abstain from alcohol entirely)

Symptom control

Many of the symptoms of heart failure (see accompanying article, p115) are driven by pulmonary congestion and peripheral oedema; therefore, the most effective intervention for symptom control is diuretic therapy. Loop diuretics, such as furosemide or bumetanide, provide substantial diuresis in most patients and can be titrated up and down as required.¹ Patients are advised to monitor their own fluid levels by weighing themselves daily — usually on waking and after voiding — and many can be taught to tailor the dose they take according to any fluctuations in their weight.

Some patients are more susceptible to sudden episodes of fluid overload that are resistant to oral loop diuretics, despite dose increases. Admission to hospital for intravenous diuretic therapy may be needed when this occurs; treatment should aim for a fluid loss of 500ml to 1L per day. Intermittent oral metolazone dosing (see below) and day case loop diuretic infusions are used by specialist community and hospital services to reduce the need for hospital admissions by patients with chronic resistant fluid overload. Frequent episodes of fluid overload are a particular problem for patients with HFPEF.

Adding a thiazide or thiazide-type diuretic, such as metolazone, can cause profound diuresis and therapy must be approached with caution. Most clinicians will prescribe a low dose (2.5–5mg) of metolazone every other day in addition to a daily loop diuretic. This prevents excessive fluid loss over a short period and reduces the risk of precipitating a decline in renal function.

Renal function must be monitored throughout diuretic therapy, paying particular attention to serum sodium, creatinine and potassium levels. Care should be taken to avoid over-diuresis, which may manifest as excessive thirst alongside raised serum creatinine and urea. For some patients, it is difficult to balance the benefits of diuresis (ie, enough to control symptoms) against the risks (ie, precipitating renal failure and hyponatraemia). Other complications that can occur during diuretic therapy include hypotension, tiredness and gout. Although diuretic therapy is the mainstay of symptom control for patients with chronic heart failure, there is little evidence that it improves prognosis.

Optimising outcomes

The prognosis for patients with HFREF has been revolutionised over the past two decades by the introduction of a series of medicine classes that target the two key pathways implicated in the progression of the disease: activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic over-activity. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers are used as first-line treatment.

ACE inhibitors

ACE inhibitors block the conversion of angiotensin I to angiotensin II, the latter being responsible for mediating many of the effects of RAAS stimulation, including vasoconstriction, stimulating aldosterone release and cross-activating the sympathetic nervous system.

ACE inhibitors have been shown to improve outcomes in a number of clinical studies, with one meta-analysis concluding that ACE inhibitors reduce mortality and cardiovascular-related hospital admissions by 35% for patients with heart failure due to left-ventricular systolic dysfunction^[2]
. There are real-world data to suggest reductions in mortality of up to 44% over two years^[3]
.

All patients with impaired left-ventricular systolic function, regardless of the presence or absence of symptoms, should be considered for treatment with an ACE inhibitor.¹ Therapy should be started at a low dose to avoid first-dose hypotension, which is less common when using longer-acting options such as ramipril and lisinopril. Hypotension is not a contraindication to using ACE inhibitors: initiation of therapy can be attempted in patients with systolic blood pressures as low as 85–90mmHg. Serum creatinine must be monitored to ensure renal perfusion has not been compromised.

ACE inhibitors should be avoided by patients with bilateral renal artery stenosis and those with a history of angioedema, a rare but serious adverse effect caused by the accumulation of bradykinin in susceptible patients during therapy. Patients with aortic stenosis should be referred for specialist review before starting ACE inhibitor therapy.

Although raised creatinine levels are not a contraindication to therapy, clinicians may be more comfortable referring patients with evidence of substantial renal dysfunction (serum creatinine >200µmol/L) to a specialist heart failure service or renal physician.¹

Once initiated, ACE inhibitor doses should be titrated upwards over a few weeks to reach therapeutic doses as determined by clinical studies.

Renal function should be monitored before starting therapy, within a month of starting therapy or after a change in dose, and at least six-monthly thereafter. Changes in creatinine levels are expected in the initial stages of therapy and when doses are increased (Box 1).

Although hyperkalaemia can be a problem, stopping therapy should only be considered if serum potassium rises to over 6mmol/L. Mildly raised potassium levels can often be managed with a change in diet; patients should be advised to avoid consumption of potassium-rich foods such as bananas, tomatoes and citrus fruits.

A dry, irritating cough, caused by accumulation of bradykinin, can be a troublesome side effect of ACE inhibitor therapy. This may fade over time or disappear when switched to an alternative ACE inhibitor, but it can often persist and cause substantial disruption to patients and their partners, particularly if it occurs at night. In this circumstance, clinicians should consider whether switching to an angiotensin receptor blocker (ARB) is warranted.

Other adverse effects include hypotension, which may limit how far the dose can be titrated, change in voice and rash.

Beta-blockers

Beta-adrenoceptor blockers are used to suppress sympathetic activity in the management of chronic heart failure. The effect of beta-blockers on patients with New York Heart Association (NYHA) functional class II to IV has been studied in a number of clinical trials. In CIBIS-II, the addition of bisoprolol to standard care (ACE inhibitor, with or without diuretics and digoxin) reduced mortality by 34%, with a similar reduction observed in admissions to hospital, and improved symptom control^[4]
. Overall, clinical trial evidence demonstrates that beta-blockers reduce mortality from heart failure by approximately one third, which includes a reduction in the risk of sudden cardiac death. Real-world data suggest that beta-blockers reduce mortality by as much as 58%.³

The National Institute for Health and Care Excellence recommends that all patients with heart failure due to left-ventricular systolic dysfunction (NYHA classes I–IV) are started on a beta-blocker, regardless of the presence or absence of ongoing symptoms.¹ Beta-blocker therapy for heart failure must be started at a very low dose, below the usual doses used for the treatment of angina or hypertension (ie, bisoprolol should be started at a dose of 1.25mg daily, carvedilol at a dose of 3.125mg twice daily and nebivolol at a dose of 1.25mg daily). Doses should be titrated slowly over a period of two to three months or longer until the patient’s heart rate is controlled between 50 and 60 beats/min.

Heart failure symptoms may be exacerbated during the initiation and dose titration phase while the body adjusts to a slower heart rate and reduced force of contraction. Patients should be informed that increased breathlessness or ankle swelling are not uncommon in the first few days after starting a beta-blocker and advised on what to do if symptoms become pronounced or troublesome. This may involve increasing the dose of their diuretic temporarily or seeking advice from their GP or local heart failure team. Patients with marked symptoms may need to remain on the same beta-blocker dose for a number of weeks to stabilise before therapy can be stepped up. Doses may occasionally need to be stepped down if a patient experiences a significant deterioration in symptom control after a dose increase.

Beta-blockers are not suitable for patients with severe bronchial asthma or severe chronic obstructive pulmonary disease, evidence of current significant fluid overload, sinus bradycardia (heart rate <50 beats/min) and symptomatic hypotension (or systolic blood pressure <90mmHg). Although mild-to-moderate reversible airway disease is not an absolute contraindication, patients should be referred to a specialist heart failure service to allow lung function to be assessed fully and, if appropriate, a cardioselective beta-blocker can be introduced cautiously.

Heart rate and blood pressure should be checked before and within one month of starting a beta-blocker. An electrocardiogram should be carried out to exclude heart block in patients who have a heart rate below 60 beats/min before starting therapy.

Further management

A number of second-line options can be considered for patient who remain symptomatic on ACE inhibitor and beta-blocker treatment (ie, they remain at NYHA class II–IV). NICE recommends that specialist advice should be sought at this stage.

Aldosterone antagonists

The aldosterone antagonists, spironolactone and eplerenone, are mineralocorticoid receptor antagonists that competitively inhibit the action of aldosterone. Aldosterone can cause magnesium depletion, increase sympathetic activity while reducing parasympathetic activity and stimulate myocardial fibrosis — all of which can cause arrhythmias. The benefits of spironolactone were first shown the in RALES study. In this placebo-controlled study of patients with severe heart failure (NYHA class IV or class III with a recent class IV exacerbation), low-dose spironolactone reduced all-cause mortality to 35% compared with 46% in the placebo arm (P=0.0001), and reduced admissions to hospital^[5]
.

Since then, findings from the EMPHASIS-HF study supported the use of eplerenone for patients with less severe heart failure (NYHA class II). A 37% reduction was found in the composite of death or admission to hospital compared with placebo (on top of standard therapy)^[6]
. Therefore, the available evidence supports the use of spironolactone for patients with severe heart failure and eplerenone for those with less severe symptoms, which is reflected in the product licences.

Both should be started at 25mg daily, increasing to 50mg daily after a few weeks if symptoms persist. Hyperkalaemia is a common problem with aldosterone antagonists and doses may need to be reduced to 25mg on alternate days (or 12.5mg daily). If serum potassium exceeds 6.0mmol/L, the medicine should be stopped. Patients should be advised to avoid foods that are high in potassium.

Renal function may also be affected and serum creatinine and electrolytes should be monitored within one week of starting therapy, at four, eight and 12 weeks, six, nine and 12 months, then at three- to six-month intervals thereafter.¹ Aldosterone antagonists should be stopped if serum creatinine rises to above 200µmol/L.

Gynaecomastia can occur during spironolactone treatment as a result of effects on the androgen and progestogen receptors and therapy may need to be stopped, or changed to eplerenone if this is troublesome for the patient. Other adverse effects include nausea, vomiting and diarrhoea.

Angiotensin receptor blockers

The evidence to support the use of ARBs in the treatment of patients with heart failure is less robust than for ACE inhibitors. The ValHeFT study investigated the effect of adding valsartan to standard therapy and demonstrated a reduction in heart failure admissions, but no overall mortality benefit^[7]
. The CHARM study investigated the use of candesartan as an alternative option for patients who are intolerant to ACE inhibitors and, in a separate arm, as an add-on to standard treatment^[8]
[9]
. CHARM reported benefits in mortality and morbidity in both arms. These effects were smaller for patients already taking an ACE inhibitor.

The weight of evidence from placebo-controlled studies supports the use of an ACE inhibitor wherever possible, but an ARB may be considered for any patient who is unable to tolerate an ACE inhibitor. In 2010, NICE recommended that ARBs should be considered in combination with an ACE inhibitor for patients with ongoing symptoms. However, the benefits of using aldosterone antagonists in combination with ACE inhibitors have since emerged and these should now be used in preference to ARBs.

The European Medicines Agency has issued a warning to avoid the combined use of ACE inhibitors and ARBs in most circumstances. However, use of this combination for patients with chronic heart failure who are under specialist supervision has been listed as an exception to this guidance.

Hydralazine plus nitrate

According to NICE, hydralazine and a nitrate should be considered for patients with NYHA class III–IV heart failure, especially those who are of black African or Caribbean origin. The use of this combination as an adjunct to first-line therapies is based on a single trial. In the African American heart failure trial (A-HeFT), African American patients with NYHA class III–IV symptoms and evidence of left-ventricular systolic dysfunction were randomised to receive hydralazine 37.5mg and isosorbide dinitrate 20mg, taken as a single tablet three times a day, and titrated to 75mg/40mg three times a day, or placebo — both in addition to standard therapy.

The trial was terminated early because there was a 43% relative mortality benefit with the combination compared with placebo (10.2% versus 6.2%; P=0.01). In addition, there was a 33% reduction in the rate of first admission to hospital in the treatment group compared with the placebo group, as well as a reduced rate of severe heart failure exacerbations. This benefit was somewhat offset by a significant rate of adverse effects — 47% of patients reported headache and 29% reported dizziness during therapy^[10]
.

Ivabradine

Ivabradine is a lowering medicine that slows heart rate without affecting blood pressure or myocardial contractility. Heart rate is a strong predictor of cardiovascular mortality and morbidity in heart failure and national and international guidance recommends that patients with heart failure should be treated to achieve a heart rate of approximately 60 beats/min.^1[11]

Not all patients with chronic heart failure can be prescribed beta-blockers; they may have contraindications to therapy (eg, severe reversible airways disease) or be intolerant (eg, extreme fatigue). When beta-blockers are prescribed, the dose is often limited by hypotension or adverse effects. As a result of this, beta-blockers are often used at sub-optimal doses that fail to provide adequate heart rate control.

The SHIFT study was designed to investigate the benefits of ivabradine in patients with HFREF (ejection fraction ≤35%) and heart rates ≥70 beats/min, in addition to standard therapy, including a beta-blocker (more than 90% were treated with a beta-blocker). The primary composite endpoint of cardiovascular death or admission to hospital for worsening heart failure was reduced by treatment with ivabradine (reduced to 24% in the ivabradine group compared with 29% in the placebo group; relative risk reduction 18%; P<0.0001), with the main driver of the composite endpoint being a substantial reduction in hospital admissions from worsening heart failure. Sub-group analysis identified that the benefits of ivabradine were seen only in patients who had a baseline heart rate of over 77 beats/min^[12]
.

NICE has endorsed the use of ivabradine for patients with NYHA class II–IV heart failure due to left-ventricular systolic dysfunction who are in sinus rhythm and have a resting heart rate of 75 beats/min or higher^[13]
. Before ivabradine is considered, patients should be fully optimised on ACE inhibitors and beta-blockers (provided there are no contraindications to these medicines). Ivabradine is generally well tolerated. Patients should be monitored for the development of bradycardia and may experience visual adverse effects.

Other issues

Depending on the underlying cause of heart failure, certain patients may be suitable for non-pharmacological interventions (see Box 2).

Atrial fibrillation can exacerbate the symptoms of heart failure. Patients who are in atrial fibrillation may be considered for treatment with digoxin. Direct current cardioversion may be used to achieve sinus rhythm. Amiodarone may be added to therapy to improve success rates for patients who fail to respond to cardioversion. Digoxin may also be used to improve symptom control and reduce hospital admissions for patients who are in sinus rhythm but who continue to experience symptoms despite optimum treatment. However, the data to support this pre-date the routine use of beta-blockers.

Intensive control of blood pressure for hypertensive patients, anti-anginal therapies for patients with angina, and blood glucose control for patients with diabetes are all required alongside treatment for heart failure. Other primary and secondary prevention strategies, such as lipid management and antiplatelet therapy, are also important.

Finally, heart failure is associated with poor long-term outcomes and issues around palliative care and management of the dying patient should also be addressed.