What more can I do for my heart failure patient?

What more can I do for my heart failure patient?

Supplied by Novartis New Zealand Limited
Entresto man

George had been on his beta-blocker, angiotensin converting-enzyme inhibitor (ACEi) and diuretic since being diagnosed with heart failure with reduced ejection fraction (HFrEF) and hadn’t been troubled by any apparent side effects. His left ventricular ejection fraction (LVEF) had been 33% upon initial diagnosis 18 months ago. However, at his last visit George complained of feeling a little fatigued and now 4 weeks later he is still fatigued and also not able to do as much at work without having to stop for a rest. (George is a hypothetical patient)

The availability of ENTRESTO® (sacubitril/valsartan) provides GPs with a first-in-class ARNI therapy that has been proven to definitively and significantly improve morbidity and mortality as well as physical and social activity limitations.1-3

ENTRESTO® is a replacement for either an ACEi or ARB in heart failure.1,2

In the PARADIGM-HF study patients on ENTRESTO® experienced:

  • A 20% RRR in cardiovascular death compared to those on ACEi therapy (p<0.001)
    ARR=3.2% / NNT=322,†
  • A 21% RRR in time to first HF hospitalisation compared to those on ACEi therapy (p<0.001)
    ARR=2.8% / NNT=362,†
  • An improvement in QOL equivalent to 9 years of aging compared to those on ACEi therapy3

= The primary endpoint of the PARADIGM-HF study was a composite of death from cardiovascular causes or a first hospitalisation for heart failure.2
NNT – Number Needed to Treat, ARR – Absolute Risk Reduction

But which HFrEF patients on an ACEi or ARB can be switched to ENTRESTO®?

The patient population in the PARADIGM-HF study were:2

  • HFrEF patients2
  • NYHA Class II - IV functional status2
  • On existing optimal HFrEF therapy i.e. ACEi or ARB + BetaBlocker + diuretic2
  • And had an ejection fraction of ≤35% (initially ≤ 40% at the start of the trial).2
Who is the right patient to switch to Entresto® (sacubitril/valsartan) with Dr Raewyn Fisher

The Special Authority Criteria for ENTRESTO® matches the PARADIGM-HF patient profile. However, in response to the COVID-19 situation there has been a temporary change effective from 01 April 2020 to the ENTRESTO® Special Authority - SA1905.4

Initiating ENTRESTO®

This is a simple one or two step titration in patients with HFrEF.1

  • Starting dose one tablet of 49 mg/51 mg twice daily, double every 2-4 weeks to the target dose. Target dose one tablet of 97 mg/103 mg twice daily.
  • A reduced starting dose of one tablet of 24 mg/26 mg taken twice daily recommended for:
    o ACEi/ARB naive patients,
    o those with severe renal impairment, moderate hepatic impairment,
    o those with low systolic blood pressure (SBP ≥100 to 110 mmHg),
    o those ≥ 75 years old.

What to do when replacing an ACEi with ENTRESTO®
For patients currently on an ACEi a 36-hour washout period is required to reduce this risk of angioedema. This is due to potential interaction between ACE inhibitors and Natriuretic Peptide System Inhibitor.1

What to do when replacing an ARB with ENTRESTO®
No washout period is required for patients on an ARB as valsartan. If the patient is on a low-dose of ARB then they should be started on the lowest dose of ENTRESTO®.1

Patients switched to ENTRESTO® must not be restarted on an ACEi or ARB.1

Monitoring patients switched to ENTRESTO®

ENTRESTO® has a safety and tolerability profile generally similar to that of an ACEi. It is however recommended that patients be reviewed two weeks after being switched to ENTRESTO®.1,2

Patients switched to ENTRESTO® should have their blood pressure, renal function, potassium levels and volume status monitored.1

Practical tips for GPs switching patients to Entresto® (sacubitril/valsartan) with Dr Raewyn Fisher


Symptomatic hypotension is more likely to occur if the patient has been volume-depleted e.g. by diuretic therapy, dietary salt restrictions, diarrhoea or vomiting. When initiating therapy with ENTRESTO® blood pressure should be monitored routinely. Dose adjustment of diuretics, concomitant antihypertensives and treatments of other caused of hypotension (e.g. hypovolaemia) should be considered. If hypotension does occur, temporary down-titration of ENTRESTO® is recommended or discontinuation.1,2


During the run-in period of the PARADIGM-HF trial, 12% of all patients withdrew because of adverse events (most frequently cough, hyperkalaemia, renal dysfunction or hypotension). After adjustment for the shorter duration of treatment, there was a lower withdrawal rate with ENTRESTO® that with the ACEi (enalapril).2


In the PARADIGM-HF trial, the incidence of angioedema with ENTRESTO® was higher compared to enalapril (0.45% vs 0.24%). However, ENTRESTO® was not associated with an increased risk of serious angioedema.2


  1. ENTRESTO New Zealand Data Sheet.
  2. McMurray JJ et al. N Eng J Med 2014; 371(11): 993-1004.
  3. Chandra A et al. JAMA Cardiol. 2018 Jun; 3(6): 498–505.
  4. Pharmaceutical Schedule – Pharmac www.pharmac.govt.nz

ACE – Angiotension Converting Enzyme, ACEi – Angiotension Converting Enzyme inhibitor, ARB – Angiotension Receptor Blocker, MRA – Mineralocorticoid Receptor Antagonist, RRR – Relative Risk Reduction, ARR – Absolute Risk Reduction, ARNI - Angiotensin Receptor Neprilysin Inhibitor NNT – Number Needed to Treat, QOL – Quality Of Life, NYHA – New York Heart Association, LVEF – Left Ventricular Ejection Fraction.

Minimum Prescribing Information

PRESCRIPTION MEDICINE. Entresto® 24mg/26mg, 49mg/51mg, 97mg/103mg (sacubitril/valsartan) film coated tablets. Consult full Data Sheet before prescribing, available from www.medsafe.govt.nz. Entresto is fully funded under Special Authority Criteria, please refer to www.pharmac.health.nz

Indication: Treatment of chronic heart failure (NYHA Class II-IV) with reduced ejection fraction.
Contraindications: Hypersensitivity to sacubitril, valsartan, or excipients. ACE inhibitors (ACEi). Do not administer within 36 hours of switching from or to an ACEi. Angioedema related to previous ACEi or ARB therapy. Use with aliskiren in Type 2 diabetes (T2D). Severe hepatic impairment, biliary cirrhosis and cholestasis. Pregnancy.
Precautions: Caution switching from ACEi or while co-administering with aliskiren in T2D (see Contraindications). Should not be co-administered with an ARB. May cause symptomatic hypotension, especially in those ≥75 years old, renal disease and systolic BP <112 mmHg or patients with an activated RAAS. Initiation not recommended in systolic BP <100 mmHg. Monitor BP when initiating therapy or during dose titration. If hypotension occurs, dose adjustment of diuretics, antihypertensives, and consider treatment of other causes of hypotension. If hypotension persists, consider dose reduction or temporary interruption. Correct sodium and/or volume depletion before starting treatment. May be associated with decreased renal function; assess renal function before initiation and during treatment. Monitor serum creatinine, and down-titrate or interrupt if a clinically significant decrease in renal function develops. May increase urea and creatinine levels in patients with renal artery stenosis. Not recommended with end-stage renal disease. Should not be initiated and consider discontinuation if the serum potassium level is >5.4 mmol/L. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors, dosage reduction or interruption may be required. Caution with medications known to raise potassium levels. If clinically significant hyperkalaemia occurs, consider adjusting the dose of concomitant medications. If angioedema occurs, immediately discontinue, and provide appropriate therapy and monitoring until complete and sustained resolution; black patients or patients with a prior history of angioedema may be at higher risk. Caution in NYHA Class IV or in moderate hepatic impairment or with AST/ALT >2X ULN. Use in lactation not recommended. Use contraception during treatment and for 1 week after last dose.
Interactions: Aliskiren in T2D, ACEi/ARB. Caution with statins, sildenafil, lithium, potassium-sparing diuretics including mineralocorticoid antagonists, potassium supplements, or salt substitutes containing potassium, NSAIDs including selective COX-2 Inhibitors, frusemide, inhibitors of OATP1B1/B3, OAT3 or MPR2 and metformin.
Dosage: Target dose one tablet of 97 mg/103 mg twice daily. Starting dose one tablet of 49 mg/51 mg twice daily. Starting dose one tablet of 24 mg/26 mg taken twice daily recommended for ACEi/ARB naive patients, those with severe renal impairment, moderate hepatic impairment, and in those ≥ 75 years old. Double every 2-4 weeks to the target dose.
Adverse effects: Very common (≥ 10%): Hyperkalaemia, hypotension, renal impairment. Common (1 to 10%): Cough, dizziness, renal failure, diarrhoea, hypokalaemia, fatigue, headache, syncope, nausea, asthenia, orthostatic hypotension, vertigo. Uncommon (0.1 to 1%): Angioedema, dizziness postural. Unknown: Hypersensitivity (including rash, pruritus, and anaphylaxis).

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NZ-00696 May 2020 TAPS NA11919 BGA200406