Heart failure is a debilitating condition that contributes to more than 4,000 deaths each year. Approximately 300,000 Australians are affected by heart failure, with an additional 30,000 new cases diagnosed annually. Prevalence increases with age, reaching 50% in people aged over 85 years. Heart failure-related hospital admissions rose by 24% between 2002-2003 and 2011-2012, placing a major burden on the healthcare system.

Heart failure occurs when the heart is unable to pump enough blood to meet the demands of the body. Left ventricular failure causes shortness of breath and fatigue, while right ventricular failure typically causes peripheral and abdominal fluid accumulation. However, patients often present with symptoms of both left and right ventricular dysfunction.

Entresto® is a new medication recently approved by the Therapeutic Goods Administration (TGA). It is indicated for the treatment of chronic heart failure (NYHA class II-IV) in adult patients with reduced ejection fractions. Entresto® contains sacubitril, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI), and is presented in a fixed-dose combination with valsartan, an angiotensin II receptor type I inhibitor. Neprilysin is a neutral endopeptidase that breaks down vasoactive peptides, including natriuretic peptides, bradykinin and substance P. Inhibition of neprilysin increases the levels of these peptides, thereby producing vasodilation, natriuresis, and anti-proliferative effects. Valsartan inhibits the effects of angiotensin II by blocking the angiotensin receptor, resulting in vasodilation and inhibition of aldosterone secretion. Sacubitril is readily metabolised to LBQ657, the active metabolite, by esterases. This metabolite does not undergo significant further metabolism; metabolism of valsartan is also minimal. Therefore, Entresto® is not expected to be involved in clinically significant interactions via the CYP450 enzyme system.

The safety and efficacy of Entresto® was investigated in a randomised, double-blind, Phase III clinical trial (Paradigm-HF) using enalapril as the comparator. This trial involved 8,442 patients with class II-IV heart failure and reduced ejection fraction. Patients were randomised to Entresto® 200mg twice daily (sacubitril 97mg/valsartan 103mg) or enalapril 10mg twice daily. After a median duration follow-up of 27 months, a significant reduction in both the primary endpoint (cardiovascular death or hospitalisation, 21.8% versus 26.5%) and cardiovascular death (13.3% versus 16.5%) was observed. The trial was stopped early due to compelling evidence of reduced cardiovascular mortality.

Entresto® is contraindicated with concomitant use of angiotensin-converting enzyme inhibitors (ACEIs) due to the risk of serious angioedema. There should be a wash-out period of 36 hours between administrations of these two products. Co-administration of potassium-sparing diuretics or potassium supplements requires close monitoring due to the increased risk of hyperkalaemia . Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and Entresto® may result in worsening of renal function. Although the potential for an interaction with lithium has not been investigated, lithium toxicity has been reported in patients taking lithium with angiotensin receptor blockers (ARBs). Entresto® is contraindicated with concomitant use of aliskiren (not currently marketed in Australia) in patients with diabetes.

Hypotension, hyperkalaemia, and renal impairment were very common adverse effects reported in the trial. Hypotension is more common in patients taking Entresto® (18%) than patients taking enalapril (12%). Patients with an activated rennin-angiotensin system, such as those taking high doses of diuretics, are at greater risk of becoming hypotensive. Hyperkalaemia occurred in 12% of patients treated with Entresto® and 14% of patients treated with enalapril. Due to the nature of inhibition of the renin-angiotensin-aldosterone system, impaired renal function has been reported as one of the adverse effects. However, dose adjustment is not required in patients with mild (eGFR 60 to 90 mL/min/1.73m2) to moderate (eGFR 30 to 60 mL/min/1.73m2) renal failure.

Angioedema is an uncommon side effect, reported to occur in 0.5% of patients treated with Entresto® and 0.2% of patients treated with enalapril. However, the risk of angioedema may be higher in patients with a prior history of angioedema related to ACEI or ARB therapy, or hereditary or idiopathic angioedema.

Entresto® is not recommended to be used in women who are pregnant or planning to become pregnant. Medications that act on the renin-angiotensin-aldosterone system can reduce foetal renal function and increase foetal and neonatal morbidity and death. Like other medications containing ARBs, Entresto® belongs to Pregnancy Category D.

The recommended starting dose for Entresto® is 49/51mg twice daily. The dose should be doubled after two to four weeks, as tolerated by patients, to reach the target dose of Entresto® 97/103mg twice daily. ACEIs should be ceased for at least 36 hours before starting Entresto®. A lower starting dose of Entresto® 24/26mg twice a day is recommended for patients who were not taking an ACEI or ARB, or previously taking low doses of these agents. This lower starting dose should also be used for patients with severe renal impairment (eGFR <30mL/min/1.73m2), moderate hepatic impairment (Child-Pugh B classification), systolic blood pressure ≥ 100 to 110mmHg, and patients over 75 years of age. The dose may then be doubled every two to four weeks until the target dose of 97/103mg twice daily is reached, or as tolerated by patients. Entresto® is not recommended for patients with severe hepatic impairment.

Entresto® is a new class of medication available for heart failure management. More studies are required to justify its place in heart failure treatment. A submission for listing on the Pharmaceutical Benefits Scheme (PBS) was rejected by the Pharmaceutical Benefits Advisory Committee in March 2016 on the basis of uncertain cost-effectiveness. Entresto® is, therefore, not currently subsidised and may cost patients more than $200 a month.




  1. Australian Institute of Health and Welfare. Cardiovascular diseases: Australian facts 2011. Canberra: AIHW; 2011.
  2. Entresto® (sacubitril/valsartan) Australian approved product information. Macquarie Park: Novartis Pharmaceuticals Australia. Approved January 2016.
  3. National Heart Foundation of Australia. A systemic approach to chronic heart failure care: a consensus statement. Melbourne: National Heart Foundation of Australia, 2013.
  4. National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand. Guidelines for the prevention, detection and management of chronic heart failure in Australia. Updated October 2011.
  5. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014; 2(6): 663-70.

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