Treatment for heart failure - sacubitril/valsartan (Entresto)

Entresto is an angiotensin receptor neprilysin inhibitor combination (an “ARNI”) medication for patients with heart failure with reduced ejection fraction (HFrEF)¹.

• Valsartan is an angiotensin receptor blocker (ARB) that blocks the activity of angiotensin II at the receptor level. These drugs are well established for use in patients with heart failure.
• Sacubitril is a prodrug that ultimately causes vasodilation. It is converted to the active metabolite, LBQ657, which inhibits neprilysin, an enzyme that breaks down vasodilating natriuretic peptides such as brain natriuretic peptide [BNP].

Sacubitril/valsartan is available under special authority for patients who meet the following criteria:

• Heart failure with NYHA functional class II, III or IV symptoms; AND
• Documented left ventricular ejection fraction of ≤35%, or an ECHO is not reasonably practical, and in the opinion of the treating practitioner the patient would benefit from treatment; AND
• Receiving concomitant optimal standard chronic heart failure treatments.

Contra-indications include:

• Patients with systolic blood pressure (SBP) ≤100mmHg as hypotension can be a side effect - Entresto should only be started when SBP >100.
• Patients with potassium >5.4mmol/L - wait until corrected or resolved to start Entresto, as hyperkalaemia can be a side effect.
• Patients with a history of angioedema related to previous angiotensin converting enzyme inhibitor (ACEi) or ARB therapy.
• Patients with severe hepatic impairment, biliary cirrhosis, or cholestasis.
• Concomitant use of an ACE inhibitor (increased risk of angioedema with sacubitril) or ARB:
  • If stopping an ACEi and starting Entresto, wait at least 36hrs after the last ACEi dose before the first dose of Entresto.
  • If stopping an ARB and starting Entresto, the first dose of Entresto can be taken when the next ARB dose would be due.

Caution is advised when prescribing in:

• Older patients, children, and women of childbearing age. Sacubitril/valsartan is Category D in pregnancy.
• Patients with NYHA class IV symptoms.
• Renal impairment - reduce starting dose to 24 mg/26 mg twice daily if eGFR less than 30 mL/min/1.73 m2; avoid in end-stage renal disease.
• Hepatic impairment - reduce starting dose to 24 mg/26 mg twice daily in moderate impairment; avoid in severe impairment.

The additive effects of combination therapy with sacubitril/valsartan provide better clinical outcomes for patients with heart failure than can be achieved with current treatment.

The PARADIGM-HF trial² evaluated patients with reduced ejection fraction heart failure and NYHA class II, III or IV symptoms who received either sacubitril/valsartan 200mg twice daily or enalapril 10mg twice daily.

• Sacubitril/valsartan significantly reduced death from cardiovascular causes and hospitalisation for heart failure compared with enalapril (see figure below).
• The NNT to achieve a reduction in cardiovascular deaths or hospitalisation for heart failure was 21 over 27 months.

Figure 1: Primary endpoint (composite of death from cardiovascular causes or first hospitalisation for heart failure) in the PARADIGM-HF study²

Sacubitril/valsartan is recommended by European (ESC)³ and American⁴ heart associations as a replacement for an ACEi or ARB to reduce heart failure death or hospitalisation in patients who remain symptomatic despite treatment with an ACEi or ARB, beta-blocker and mineralocorticoid receptor antagonist.

In New Zealand, the Cardiovascular Disease Risk Assessment and Management for Primary Care consensus statement identifies patients with congestive heart failure as a high-risk group who require intensive management. New therapies for this patient population must be considered.  

It is recommended that you consider starting this drug in close consultation with your local heart failure service. (At any stage: consult your local Heart Failure Service for advice).

• symptomatic hypotension, especially in older patients;
  • In patients aged >75 years, hypotension occurred more often with sacubitril/valsartan than with enalapril in the PARADIGM-HF trial (18% vs 12%)

• angioedema (0.4% vs 0.2%)
• diarrhoea
• headache
• gastritis
• worsening renal function.

There are several interactions to be aware of, and full information can be found on NZ Formulary. Some key drug classes to consider are:

• Statins: sacubitril/valsartan may increase the effect of statins.
• Drugs that may increase potassium and thereby increase the risk of hyperkalaemia: potassium-sparing diuretics, mineralocorticoids, potassium supplements.
• NSAIDs: risk of worsening renal function with coadministration, especially in elderly and volume-depleted patients (think: Triple Whammy).
• Sildenafil: risk of hypotension even with a single dose of sildenafil.