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).
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%)
- 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.
- 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.
- 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.