Treatment for heart failure - sacubitril/valsartan (Entresto)

Adding sacubitril/valsartan to optimal chronic heart failure therapy provides better clinical outcomes for patients than can be achieved with current treatment.

This case study looks at the use of sacubitril/valsartan (brand name: Entresto), which is recommended as replacement for ACEi or ARB in patients with reduced ejection fracture heart failure who remain symptomatic on current best therapy.

 

Mr H, a 62-year-old Māori man, is at your clinic for a repeat of his usual medications for hypertension and heart failure.

You are reviewing your notes ahead of the appointment. Mr H was seen last month by Cardiology for follow-up of his longstanding heart failure, and the clinic letter mentions that he may be a candidate for a new medication, Entresto.

Mr H also has mildly impaired renal function and type II diabetes for which he takes metformin 500mg BD. He is an ex-smoker and he drinks 1-2 cans of beer per night. His father died at age 58 from a heart attack, and his mother died in her 70s from emphysema. His younger brother is also hypertensive.

Mr H is compliant with his medicines. He currently takes frusemide 40mg, cilazapril 5mg, bisoprolol 10mg, and spironolactone 25mg daily.

What is Entresto

Entresto is a new 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].

Who should use it?

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%; AND
  • Receiving concomitant optimal standard chronic heart failure treatments.

 

Mr H tells you he becomes tired and short of breath doing the supermarket shopping, and on his daily walks.

  • He can walk approximately 100 metres on the flat before needing to stop. He is not breathless doing his usual daily tasks such as showering or doing laundry.
  • He does not have chest pain.
  • You assess him as having NYHA class III symptoms.

So, it seems he may benefit from this medication…but are there any contraindications?

 

Who should not use it?

Sacubitril/Valsartan must not be given to:

  • Patients also taking ACE inhibitors. A washout period of 48 hours since the last ACEi dose is required.
  • Patients with systolic blood pressure (SBP) ≤100mmHg.
  • Patients with potassium >5.4mmol/L.
  • Patients with a history of angioedema related to previous angiotensin converting enzyme inhibitor (ACEi) or ARB therapy.
  • Patients with severe hepatic impairment.

Caution is advised when prescribing in:

  • Older patients, children, and women of childbearing age. Sacubitril/valsartan is Class D in pregnancy.
  • Patients with NYHA class IV symptoms.
  • Severe renal failure. Seek advice about dose adjustment for patients with eGFR <30ml/min.
  • Moderate hepatic impairment; these patients require a dose reduction.

 

Mr H’s blood pressure today is 134/76, and a quick search of MedTech shows his systolic blood pressure (SBP) usually ranges 120-140mmHg.

  • His blood tests from two weeks earlier show eGFR 55ml/min and potassium 4.8mmol/L.
  • His liver function tests are normal.
  • He has tolerated cilazapril for the past six years with no angioedema.
  • You assess him as appropriate for sacubitril/valsartan.

But, he has been stable on his current regimen for some time… is it worth changing?

 

How effective is Sacubitril/Valsartan?

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 2018 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.  

 

You consider the evidence and decide to start Mr H on sacubitril/valsartan.

How will you start this medication, and what monitoring is required?

 

How to start Sacubitril/Valsartan

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).

  1. Firstly, patients must stop their ACEi two days before starting the new medication. (Patients switching from an ARB can take their last ARB dose then start sacubitril/valsartan when the next dose is due).
  2. Determine the appropriate start dose:
    •  Patients on maximum ACEi/ARB dose start sacubitril/valsartan at 49/51mg BD
    •  Patients on less than maximum ACEi/ARB dose start sacubitril/valsartan at the lower dose of 24/26mg BD
    •  Patients at high risk of hypotension, including those aged ≥75 years and those with SBP 100-110mmHg, start sacubitril/valsartan at 24/26mg BD
  3. Titrate up to the target dose of 97/103mg BD with clinical review at each dose titration step. Sacubitril/valsartan causes both hypotension and vasodilation, so symptoms, blood pressure (including standing), renal function and electrolytes should be assessed at each visit.
  4. Once at a stable dose, regularly review patients’ symptoms and monitor for symptomatic hypotension and worsening renal function.

 

What will you warn Mr H about when starting the new medication?

 

Potential side effects

  • 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.

Important interactions

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.
  • Frusemide: theoretical risk of reduced effect of frusemide (though not observed clinically in the PARADIGM-HF trial).
  • Metformin: theoretical risk of reduced effect of metformin but clinical significance uncertain in the trials.

 

In summary: Practice points for Monday morning

  • Sacubitril/valsartan (brand name: Entresto) is recommended as replacement for ACEi or ARB in patients with reduced ejection fracture heart failure who remain symptomatic on current best therapy.

  • When used appropriately along with optimal chronic heart failure therapy, it provides better prevention of cardiovascular death or hospitalisation for heart failure than ACEi or ARB alone.

  • The most suitable patients are those with reduced ejection fracture heart failure, systolic blood pressure >100mm Hg, and eGFR >/= 30ml/min.

  • Stop ACEi two days before starting.

  • Start at low dose and titrate to target 97/103mg BD.

  • Monitor symptoms, blood pressure, renal function and potassium regularly.

  • Liaise with your local heart failure service for advice.

 

References
  1. Medsafe: New Zealand data sheet for Entrestro
  2. McMurray JJV et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med 2014;371:993
  3. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200
  4. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.

  

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