ACE inhibitors (ACEIs), ARBs, beta-blockers, MRAs and diuretics form the basis of first-line pharmacological management of left ventricular systolic heart failure (HFrEF). Treatment doses should be increased to those shown to be of benefit in the major trials or to the highest tolerated doses.  Greater benefits in morbidity are achieved with the recommended target doses.

Target doses of HF medications.

ACE inhibitors

• All patients with HFrEF (ejection fraction <50%) should be started on a low-dose ACE inhibitor, unless this is not tolerated or is contraindicated. (Some international guidelines make a distinction between moderate to severe reduction in EF (≤ 40%) and a mild reduction in EF (41-49%)).   Doses should be uptitrated to the target dose or to the highest tolerated dose. (See Titrating Medications in Heart Failure).
• ACEIs prolong survival in patients with New York Heart Association Class II-IV HF; improve patient symptoms and exercise tolerance; and reduce hospitalisations for worsening HF.

ARBs

• ARBs are recommended as an alternative for patients who experience ACE inhibitor-mediated adverse effects such as a cough. ARBs are generally better tolerated than ACE inhibitors due to the absence of kinin-mediated side effects.
• ARBs provide mortality and morbidity benefits in patients with HFrEF.  The body of evidence for ACEI is greater than for ARBs.  ARBs are generally chosen for patients who cannot tolerate ACEI.

Beta-blockers

• HF specific beta-blockers (carvedilol, bisoprolol, metoprolol extended-release, nebivolol) should be initiated in all patients with left ventricular HFrEF, unless contraindicated or not tolerated. Other beta-blockers including short-acting metoprolol are not registered for use in HFrEF and have not shown mortality and morbidity benefits.
• Beta-blockers should only be initiated after a patient’s condition has stabilised to avoid precipitating HF decompensation. They are often commenced in hospital with a plan for up-titration every 2-4 weeks until the target dose is reached. (See Titrating Medications in Heart Failure).
• Carvedilol (beta1, beta2 and alpha1 antagonist), bisoprolol, metoprolol controlled release (CR) (both beta1-selective antagonist) and nebivolol (beta1-selective antagonist with nitric oxide-vasodilatation activity) prolong survival and improve symptoms in patients with HF already receiving background ACEI therapy.
• The decision regarding which HF-specific beta-blocker should be prescribed is influenced by the patient’s co-morbidities and prescriber familiarity.

MRAs

• MRAs should be initiated in all patients with HFrEF associated with moderate or severe reduction in LVEF (≤40%) unless contraindicated or not tolerated, to decrease mortality and decrease hospitalisation for heart failure.
• Spironolactone reduces mortality and symptoms in patients with advanced HF.
• Eplerenone reduces mortality in HFrEF patients who still have mild symptoms despite receiving ACEI and beta-blocker therapy, or in the immediate post-MI period when left ventricular systolic dysfunction is identified.
• The choice of MRA is influenced by the severity of LV systolic dysfunction, the presence of recent myocardial infarction, the presence or likelihood of MRA-related adverse effects such as gynaecomastia and eligibility for a healthcare subsidy.

Diuretics are used to control symptoms of fluid retention and maintain euvolaemia. They should never be used as sole therapy for HFrEF as they do not improve survival in HF. Diuretics may be used in a flexible manner. Daily weight monitoring is an essential component in the assessment of fluid status and is useful in guiding diuretic dosing. Tools such as the Weight and symptom diary may assist patients to monitor changes in their weight.

Loop diuretics, such as furosemide (frusemide), are potent diuretics and are often used in patients with HF. Bumetanide is another loop diuretic that may be beneficial in patients with reduced gut absorption due to HF as it has better oral bioavailability than furosemide (frusemide).

Thiazide diuretics (hydrochlorothiazide and metolazone) and potassium-sparing diuretics (amiloride) are rarely used in clinical practice for HFrEF patients except in the presence of 'resistant fluid overload'. In these circumstances they may be combined with a loop diuretic such as furosemide (frusemide) cautiously and temporarily as prolonged use increases the risk of hypokalaemia and dehydration. Thiazides may also increase serum urate and hence contribute to gout, which is frequently experienced by patients with HFrEF.

Thiazide diuretics are sometimes used in HFpEF where they may have the advantage of treating mild fluid retention and hypertension, a common cause of HFpEF.

Angiotensin Receptor Neprilysin Inhibitors (ARNI)

Angiotensin Receptor Neprilysin Inhibitor (ARNI) combines the neprilysin inhibitor (sacubitril) with the angiotensin receptor blockade (valsartan).  Sacubitril/valsartan (trade name Entresto) has been shown to be superior to the ACE inhibitor (enalapril) in reducing cardiovascular mortality and hospitalisation due to HFrEF. 

Sacubitril/valsartan is recommended as a replacement for an ACE inhibitor or an ARB.  Indications include:

• Symptomatic with NYHA class II-IV
• Left ventricular EF ≤ 40%
• Be on concomitant optimal standard heart failure treatment that includes maximum tolerated dose of beta blocker (unless contraindicated)
• Be stabilised on an ACE inhibitor or ARB (unless contraindicated)

Commencing Sacubitril-Valsartan

• Do not co-administer with an ACEI or ARB
• Switching from an ACEI: Wait at least 36 hours after last dose of ACEI prior to commencement
• Switching from an ARB: No washout period is required and commence Sacubitril-Valsartan when next dose would have been due
• Local restrictions and healthcare system subsidies should be considered when initiating ARNI

Ivabradine

Ivabradine may be considered for patients with HFrEF, with a recent hospital admission and who are in sinus rhythm with a heart rate >70 bpm despite receiving optimal beta-blocker therapy. Ivabradine decreases heart rate by inhibiting the sinus node.

Ivabradine reduces cardiovascular mortality and HF hospitalisations in patients with symptomatic HFrEF, who have had a recent hospital admission and who are in sinus rhythm with a heart rate >70 bpm.

Digoxin

Digoxin may be considered in patients with ongoing symptoms of HF despite optimised pharmacotherapy (i.e., ACE inhibitor, beta-blocker and MRA diuretic therapy) to reduce the risk of hospitalisation. Digoxin is often prescribed to control ventricular rate in patients with co-existing AF.

Hydralazine-isosorbide dinitrate

Hydralazine-isosorbide dinitrate combination should be considered in patients who are actually intolerant of ACE inhibitors and ARBs or for whom these agents are contraindicated.

Fish oil (n-3 polyunsaturated fatty acids)

A small beneficial effect of fish oil supplementation on cardiovascular death and hospitalisation has been demonstrated in one large randomised trial of chronic HF patients. Noting the variation in proprietary fish oil supplements, and given this trial used high dose n-PUFA (EPA and DHA > 850mg/1g fish oil once daily), supplementation using this dose may be considered as an adjunct to optimised recommended pharmacotherapy (i.e., ACE inhibitor, beta-blocker and MRA therapy) in HFrEF patients.

Iron infusions

Iron supplementation for iron deficiency

Management of acute decompensated HF aims to treat signs and symptoms associated with fluid overload, abnormal gaseous exchange and reduced tissue perfusion. Treatment must be individualised to the patient, depending on their haemodynamic and volume status.

Initial pharmacological treatment may include:

• Furosemide: A potent diuretic in patients with evidence of fluid overload. It may be given IV to facilitate rapid drug delivery. Available evidence indicates that IV infusion of loop diuretics has a similar efficacy to IV bolus dosing
• Nitrate therapy: For rapid relief of symptoms of congestion in normotensive or hypertensive patients, acting via smooth muscle vasodilation
• Morphine therapy: For its haemodynamic and sedative properties, particularly in patients with restlessness, dyspnoea, anxiety or chest pain. Morphine should be used judiciously in acute decompensated HF as it has been associated with higher rates of mechanical ventilation and intensive care unit admissions, longer hospitalisations and increased mortality.[#peacock-wf-hollander-je-diercks-db-et-al.-2008]

Inotropes may be trialled in selected patients with signs of hypoperfusion, where symptoms include cold, clammy skin, renal or liver dysfunction, or for shock, in order to increase cardiac muscle contractility. Potential adverse effects of inotropes include arrhythmias and myocardial ischaemia.

Some medications can contribute to an acute exacerbation of HF. Patients should be regularly reviewed in order to avoid potential precipitants. These include non-steroidal anti-inflammatory drugs (NSAIDs), cyclo-oxygenase 2 (COX-2) inhibitors, non-dihydropyridine calcium channel blockers, thiazolidinediones (e.g., rosiglitazone) and corticosteroids.

For more detailed information refer to Potentially harmful drugs to avoid in heart failure.

Whilst there is limited evidence to support pharmacotherapy for HFpEF, therapy can assist in managing symptoms and underlying comorbidities. Symptoms often occur as a result of fluid retention and are controlled with diuretic therapy. ACE inhibitors/ARBs may be used in the treatment of the underlying hypertension rather than as treatment for HF. Similarly, beta-blockers are prescribed for pre-existing ischaemic heart disease, hypertension or atrial fibrillation.