Among Australia’s 39,449 GPs,³ these numbers equate to each GP on average having about two patients newly diagnosed each year and eight patients with heart failure under their care.

Even when perceived to be stable, patients with heart failure are at a high risk of illness and premature death.⁴ In Australia, heart failure hospitalisations are followed by increasing re-admissions and mortality.⁵ An ageing population with multimorbidity and polypharmacy contributes to increased decision-making complexity for doctors.^6-8

Quadruple drug therapy achieves best outcomes

The use of recommended medicines is a key factor in reducing hospital admissions and improving survival in people with HFrEF (Left Ventricular Ejection Fraction of 40% or less).^9,10 Current guidelines recommend the use of four first-line medicines, referred to as quadruple therapy.^9,11,12,13

There is strong evidence that all four medicine classes should be prescribed together in combination for all patients with HFrEF, unless contraindicated.^10,12,14,15 These four foundational classes of medicines are: ^9,15

• renin-angiotensin system (RAS) inhibitor
• beta-blocker
• mineralocorticoid receptor antagonist (MRA) and,
• sodium glucose co-transporter 2 inhibitor (SGLT2I)

Individually, these therapies are proven to reduce hospitalisation, prolong survival, improve symptoms and quality of life.^10,16 When all four therapies are combined, these medicines have a far greater cumulative benefit that includes increasing years of survival and years free from cardiovascular death or hospitalisations.^10,14,16

Renin-angiotensin system inhibitor 

Renin-angiotensin system (RAS) inhibitors improve symptoms and reduce cardiovascular mortality and hospitalisation for heart failure.⁹ All patients with HFrEF should be treated with a RAS inhibitor.

RAS inhibitors include:

• angiotensin receptor - neprilysin inhibitor (ARNI)
• angiotensin-converting enzyme inhibitors (ACEI)
• angiotensin receptor blockers (ARBs)

ARNI is more effective in reducing the risk of death and hospitalisation for heart failure compared to ACEI in patients with symptomatic HFrEF.¹⁷ Studies have also demonstrated the safety and tolerability of starting ARNI in patients with newly diagnosed HFrEF.¹⁸ However, ARNI is more likely to cause symptomatic hypotension. ACEIs are well established for improving prognosis in patients with HFrEF and may be preferred over ARNI in patients with hypotension.⁹

ARNI (sacubitril/valsartan) is a combination tablet comprising a neprilysin inhibitor (sacubitril) and ARB (valsartan). Sacubitril cannot be prescribed as monotherapy. According to the PBS criteria, the patient must be stabilised on ACEI or ARB at time of initiation unless contraindicated or not tolerated.¹⁹

While ARB therapy improves symptoms and reduces cardiovascular mortality and hospitalisation for heart failure, it does not confer a reduction in all-cause mortality seen with ARNI or ACEI. An ARB is used only if an ACEI or ARNI is not tolerated (e.g. cough caused by ACEI and hypotension caused by sacubitril and valsartan).⁹

Beta-Blocker

Treatment of heart failure with a HFrEF specific beta-blocker (in combination with a RAS inhibitor) has been shown to reduce the symptoms of heart failure, improve left ventricular ejection fraction, and reduce hospitalisation and mortality (including sudden death).⁹ Patients with HFrEF who are already taking a different beta-blocker for a comorbidity (e.g. angina, hypertension) should be switched to one of these heart failure specific beta-blockers. Treat all patients with HFrEF with a heart failure specific beta-blocker, including patient groups in whom beta-blockers are traditionally avoided (e.g. older patients and chronic obstructive pulmonary disease without reversibility).^9,20

Start with a low dose of beta-blocker and aim to double the dose every 2 to 4 weeks to the maximum tolerated dose. For patients with clinical signs of congestion (e.g. pulmonary crackles, peripheral oedema), defer starting the beta-blocker until the patient is euvolaemic.⁹ If an increase in dose is not tolerated (e.g. HR < 50), go back to the lower dose and consider trying to increase the dose again in a few weeks’ time.

Mineralocorticoid receptor antagonist

Mineralocorticoid receptor antagonists (MRA) are also known as aldosterone antagonists. Treatment with MRAs improves survival and reduces hospitalisation in patients with HFrEF.^21,22

MRA that improve clinical outcomes in HFrEF are spironolactone and eplerenone.

Note: Access to eplerenone via the PBS is currently restricted for patients with recent acute myocardial infarction.

SGLT2 inhibitors 

SGLT2 inhibitors reduce hospitalisation for heart failure and cardiovascular mortality, with or without type 2 diabetes.^17,23

Dapagliflozin and empagliflozin is listed in the PBS via Authority Required (STREAMLINED) for patients with HFrEF. See the PBS website for eligibility criteria.

Approach to medicines management of HFrEF

All four medicine classes should be started as soon as possible after HFrEF diagnosis,¹⁴ unless contraindicated or not tolerated.⁹ Delaying the initiation and up-titration of therapy for HFrEF is associated with unnecessary deaths, hospitalisations and progression of the underlying disease.²⁴ Quadruple therapy improves prognosis and controls signs and symptoms of HFrEF, with benefits seen within 30 days of starting treatment.⁹ Other recommendations include starting with two medications initially, followed by the introduction of the remaining medications.¹² Once all four medications have been started, the doses can be titrated as needed (Figure 1).

Achieving target doses of quadruple therapy may be challenging or not possible for some patients, particularly those who are older and have multimorbidity, frailty, worsening renal impairment or baseline hypotension.^16,25 If target doses cannot be achieved, titrate the dose to the highest-tolerated dose still provides benefit. ^26,27

Note: Diuretics should be used to manage congestion and down-titrated as appropriate.¹³

Undertake ongoing monitoring and review of prescribed medicines

Starting quadruple therapy or increasing the dose of drug therapy can result in:

• fall in blood pressure
• rise in serum creatinine (up to 30%)
• rise in serum potassium (within the normal range).

These changes are often transient and do not necessarily require dose reduction or cessation of treatment.⁹

If a patient taking combination therapy has symptomatic hypotension, consider:⁹

• Reviewing the patient’s volume status and down-titrate or cease diuretics if appropriate.
• Changing the timing of doses (e.g. split into morning and night).
• Refer patients for a Home Medicines Review (HMR) or a Residential Medication Management Review (RMMR) for advice about reducing adverse medicine-related effects.

If kidney function continues to deteriorate:⁹

• Review the patient’s volume status and medical therapy.
• If there are no clinical symptoms or signs of congestion, initially reduce or withhold the loop diuretic.
• If the patient is taking a nonsteroidal anti-inflammatory drug, this should be stopped.
• Consider decreasing the dose of the renin-angiotensin system inhibitor or mineralocorticoid receptor antagonist.
• Rule out other causes of renal impairment, such as obstruction.

If the patient has hyperkalaemia:⁹

• Ensure they are not taking a potassium supplement and review their diet.
• Consider decreasing the dose of the RAS inhibitor or MRA.
• For MRA if potassium is:
• between 5.5 to 5.9 mmol/L, reduce the dose (e.g. by half)
• higher than 6.0 mmol/L, stop immediately and reintroduce at a lower dose when potassium is less than 5.0 mmol/L.28

Intravenous iron 

Patients with heart failure are also at increased risk of developing iron deficiency. Intravenous iron therapy in patients with HFrEF and iron deficiency (with or without anaemia) improves symptoms, exercise tolerance and quality of life, and HF hospitalisation.^9,29

Early follow-up after discharge from hospital

Heart failure patients are most vulnerable to being re-admitted and poor outcomes after being discharged home from hospital. This is often because of new treatments, alterations in their HF medications, fluid balance issues (e.g starting, stopping or reducing of diuretics), ongoing symptoms, poor sleep and nutrition, stress, and inactivity.^5,7

Home Medicines Review (HMR) and GP Management Plan (GPMP) have proven benefits for heart failure patients.^30,31 HMR can reduce hospitalisation rate by 45% and GPMP have been associated with a 17% reduction in rates of hospitalisation for heart failure patients.^30,31 It is also important to conduct regular assessment for depression, especially as depression is a common comorbidity in patients with heart failure.¹⁷

Ensure all patients have a HF action plan and that vaccinations including, influenza, pneumonia and COVID are up-to-date.  For eligible patients, Team Care Arrangement should also be considered.

Educate and empower your patients

If your patient is diagnosed with HFrEF:

• Explain the benefits of quadruple therapy (at highest tolerated dose) and also explore side effects.
• Advise patients to be familiar with their HF action plan and understand what to do when symptoms worsen.
• Guide your patients towards credible sources of consumer information:
• The Medicines Advice Initiative Australia (MAIA)’s Patient Information
• Heart Foundation Living Well with Heart Failure booklet.
• Their community pharmacist.
• Emphasise the benefits of regular physical activity and consider referring to a physiotherapist or exercise physiologist to develop a tailored exercise program.
• Consider referral to a dietitian for further dietary advice.

Take Home Messages

• All four therapies should be considered for patients with HFrEF unless contra-indicated.
• Monitor blood pressure and postural symptoms, heart rate, kidney function, electrolytes, following initiation and each dose escalation at 1–2 weeks and six-monthly in the long term.
• Provide early follow-up after discharge from hospital, to review medicines and consider appropriate action (e.g. up-titrate medications and review the need for diuretics).
• Refer patients for a HMR, create a GPMP and for eligible patients also a Team Care arrangement.
• Promote and support patient self-care, emphasising a HF action plan, the benefits of regular physical activity, immunisation, smoking cessation and provide dietary advice.