Sacubitril Valsartan Protocol to Support the Initiation and Up Titration, for Heart Failure (509)

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A guideline is intended to assist healthcare professionals in the choice of disease-specific treatments.

Clinical judgement should be exercised on the applicability of any guideline, influenced by individual patient characteristics. Clinicians should be mindful of the potential for harmful polypharmacy and increased susceptibility to adverse drug reactions in patients with multiple morbidities or frailty.

If, after discussion with the patient or carer, there are good reasons for not following a guideline, it is good practice to record these and communicate them to others involved in the care of the patient.

Introduction

Sacubitril/valsartan (Entresto®) is indicated for the treatment of symptomatic heart failure due to reduced ejection fraction.  The NHS Greater Glasgow and Clyde Formulary restricts use to initiation by the specialist heart failure multidisciplinary team in patients with:

  • heart failure New York Heart Association (NYHA) class II to IV AND
  • left ventricular ejection fraction (LVEF) ≤40% AND
  • ongoing symptoms despite optimally tolerated treatment (e.g. beta blocker, ACEI inhibitor (ACEI) or Angiotensin
    Receptor Blocker (ARB) and either spironolactone or eplenerone) AND
  • plasma B-type natriuretic peptide (BNP) level of at least 150 nanograms/L* or N-terminal pro-BNP level (NT-proBNP) of at least 600 nanograms/L* (or, if they have been hospitalised for heart failure within the previous 12 months, a BNP of at least 100 nanograms/L* or NT-proBNP of at least 400 nanograms/L*)...

* PLEASE NOTE: nanograms/L is equivalent to picograms/mL

Any use of sacubitril/valsartan not covered by this guidance (e.g. unlicensed uses) must be discussed with the multidisciplinary team and the justification explained to the GP on an individual case-by-case basis before initiation, to obtain agreement and ensure governance.

This guidance document is intended primarily for those clinicians and specialist teams involved in the initiation, baseline assessment and subsequent transfer of care to the patient’s GP for ongoing prescribing of sacubitril/valsartan.

Pre-initiation checks

Acute care specialist heart failure teams (not primary care) will:

  • Undertake essential baseline investigations and checks (i.e. echo, BNP (or NT-proBNP), symptom history, medication history, renal function tests, liver function tests, and blood pressure)
  • Optimise ACEI/ARB, beta-blocker and either spironolactone or eplenerone as tolerated before considering initiation

Contraindications

  • Concomitant use of ACEI
  • End-stage renal disease
  • Known history of angioedema related to previous ACEI or ARB
  • Hereditary or idiopathic angioedema
  • Concomitant use with aliskiren*
  • Severe hepatic impairment, biliary cirrhosis or cholestasis
  • Pregnancy

*Please note that aliskiren is not recommended by SMC for use in Scotland

See Summary of Product of Characteristics (available at www.medicines.org.uk) for full details.

Cautions

  • Renal artery stenosis
  • Hyperkalaemia (Treatment should not be initiated if the potassium level is >5.4 mmol/l)
  • New York Heart Association Class IV
  • Moderate hepatic impairment (Child-Pugh B classification or with AST/ALT values more than twice the upper limit of the normal range)

See Summary of Product of Characteristics (available at www.medicines.org.uk) for full details.

Clinically significant drug interactions

  • Lithium: this combination is not recommended; if it proves necessary, careful monitoring of serum lithium level is recommended
  • Atorvastatin: sacubitril/valsartan can increase peak serum concentrations of atorvastatin by up to two fold and total exposure by up to 1.3 fold. Close monitoring of liver function tests and for myalgia is recommended and doses of atorvastatin may need to be reduced if problems are encountered.
  • Potassium salts
  • Non-steroidal anti-inflammatory agents (NSAIDs)

Please note: This is not an exhaustive list of potential clinically significant drug interactions. See the BNF (www.medicinescomplete.com) or Summary of Product Characteristics (www.medicines.org.uk) for further detail.

Pharmaceutical aspects

  • Sacubitril/valsartan is assumed to be suitable for administration in a weekly compliance box (Novartis have advised that tablets were found to be stable for at least 3 months in stability studies in so called ‘open dish’ conditions without any packaging).
  • No data is available on whether tablets can be crushed or dispersed in water if needed. Therefore, this cannot be recommended and would be a clinical decision made on a case-by-case basis.

Initiation procedures

WASH-OUT PERIOD: If the patient is already prescribed an ACEI, the ACEI MUST be stopped 36 hours prior to initiation of sacubitril/valsartan to minimise the risk of angioedema. The importance of this wash-out period must ALWAYS be communicated directly to the patient, to the GP (in writing) and, if the person receives a weekly adherence aid, the community pharmacy (verbally, at the point the prescription is issued).

FIRST PRESCRIPTION: Specialist heart failure teams (not primary care) will initiate treatment and issue the first prescription for the medication and the first prescription for any medication dose changes in the majority of cases. Where initiation or up-titration is directly requested following a Consultant Cardiologist outpatient clinic GPs may be asked to issue a first prescription. However, in such cases Consultant Cardiologists will ensure appropriate patient education, wash-out period, and follow up/monitoring with the heart failure team/nurses rather than asking the GP to deliver this.

Recommended starting doses

Previous therapy Additional considerations regarding blood pressure and renal function Recommended Sacubitril/Valsartan starting dose

Patients tolerating medium to high dose ACEI or ARB before switch

ACEI or ARB prior to initiation ≥50% ESC target dose BP >110mmHg AND eGFR>60mL/min/1.73m2 49/51mg twice daily*
ACEI or ARB prior to initiation ≥50% ESC target dose BP ≥100-110mmHg AND/OR eGFR ≥30-60mL/min/1.73m2 49/51mg twice daily* OR 24/26mg twice daily
at clinician discretion
ACEI or ARB prior to initiation ≥50% ESC target dose eGFR <30mL/min/1.73m2 No safety data in this population, so extreme caution needed. If local HF MDT meeting agrees that benefits outweigh the risks then start 24/26mg twice daily. Renal function and serum potassium should be monitored more frequently in this group.
ACEI or ARB prior to initiation ≥50% ESC target dose SBP <100mmHg Not routinely recommended (unlicensed use) and not covered by this guidance, although may be considered at the discretion of the heart failure team.

Patients tolerating low dose ACEI or ARB before switch

ACEI or ARB prior to initiation <50% ESC
target dose
BP ≥100mmHg AND eGFR ≥30mL/min/1.73m2 24/26mg twice daily
ACEI or ARB prior to initiation <50% ESC target dose eGFR <30mL/min/1.73m2 No safety data in this population, so extreme caution needed. If local HF MDT meeting agrees that benefits outweigh the risks then start 24/26mg twice daily. Renal function and serum potassium should be monitored more frequently in this group.
ACEI or ARB prior to initiation <50% ESC
target dose
BP <100mmHg Not routinely recommended (unlicensed use) and not covered by this guidance, although may be considered at the discretion of the heart failure team.
Patients not taking ACEI or ARB prior to sacubitril/valsartan
Not prescribed ACEI or ARB Any SBPs and eGFR Not approved for use

*Patients with AST/ALT more than twice the normal reference range should be started on 24/26mg twice daily.

Recommended titration schedule

Patients Starting on Lowest Dose of Sacubitril/Valsartan

STEP 1. 24/26mg twice daily for four weeks* STEP 2. 49/51mg twice daily for four weeks* STEP 3. 97/103mg twice daily indefinitely

Patients Starting on Middle Dose of Sacubitril/Valsartan

  STEP 1. 49/51mg twice daily for four weeks* STEP 2. 97/103mg twice daily indefinitely

*Prescribe in four weekly cycles to reduce wastage, unless pressing clinical reasons dictate otherwise. When uptitrating the dose DO NOT routinely tell patients to take two of the previous strength, as this introduces added risk and will be less cost effective if continued long-term. Use professional discretion where needed

Post initiation / uptitration checks

All patients started on sacubitril/valsartan should have blood pressure and renal function rechecked 7 to 14 days after initiation and 7 to 14 days after any up-titration. These checks are the responsibility of the acute care/specialist heart failure teams and not primary care (i.e. the GP). The acute care/specialist heart failure teams will deliver follow-up monitoring (i.e. renal function, blood pressure and tolerance) in all patients for a minimum of three months post-initiation.

Communication with the patient, their GP, and Community Pharmacy

Acute care/specialist heart failure teams will provide the GP with a clinic letter which includes diagnosis, relevant clinical information, baseline results, treatment to date, treatment plan and plan for follow-up review.

Acute care/specialist heart failure teams will also provide the community pharmacy with verbal communication in all patients receiving a weekly compliance aid (Pluspak), to ensure the safety of initiation (including ACE inhibitor wash-out procedures).

Acute care/specialist heart failure teams will provide the patient with relevant drug information to enable understanding of benefits and risks of the medication, the potential side effects and any appropriate action.

Ongoing prescribing and monitoring

The patient’s GP practice is able to continue to repeat prescribe in collaboration with the specialist according to this protocol (i.e. the specialist heart failure teams will write any initiation prescription or first prescription for dose changes but the GP practice is able to continue prescribing thereafter). The GP practice will also undertake long-term follow-up monitoring (as per core annual GP practice care) once the patient is stabilised in accordance with HF nurse guidelines.

Undesirable effects and pharmacovigilance

See Summary of Product of Characteristics (available at www.medicines.org.uk) for full details.

Problem General Advice

Hyperkalaemia

Serum potassium ≤5.5mmol/L
  • No action needed
Serum potassium >5.5 and <6.0 mmol/L
  • Confirm potassium concentration in a non-haemolysed sample
  • Reinforce low potassium diet and restriction of food/drinks with high potassium content (e.g. orange juice, melon, bananas, low-salt substitutes etc)
  • Review other medical regimen (including dietary supplements, salt substitutes and over-the-counter medications) for agents known to cause hyperkalaemia and consider reduction in dose or discontinuation of these agents
  • Consider down-titration (e.g. halving dose) or temporarily discontinue sacubitril/valsartan according to clinician judgment
  • Repeat serum potassium measurement after 2-3 days
  • If serum potassium <5.5 mmol/L, consider resumption of sacubitril/valsartan at lower dose with repeat potassium within 5 days
Serum potassium ≥6.0 mmol/L
  • Immediately discontinue sacubitril/valsartan
  • Confirm potassium concentration in a non-haemolysed sample
  • Urgently evaluate patient and treat hyperkalaemia as clinically indicated
  • Apply all measures outlined for serum potassium >5.5 and <6.0 mmol/L above
  • Eventually if serum potassium <5.5 mmol/L, resumption of sacubitril/valsartan may only be considered after individual case review by local HF MDT.

Worsening Renal Function

eGFR decreases by <25% from baseline AND eGFR ≥30 mL/min/1.73m2
  • No action needed
eGFR decreases by ≥ 25-40% from baseline OR eGFR decreases to <30mL/min/1.73m2
  • Check for potentially reversible cases of renal dysfunction such as, NSAIDs (or other medications known to affect renal function), volume decrease or urinary infection
  • Consider down-titration (e.g. halving dose) or temporarily discontinue sacubitril/valsartan according to clinician judgment
  • Repeat eGFR measurement after 5-7 days
  • When eGFR is only decreased by <25% from baseline AND eGFR ≥30 mL/min/1.73m2, consider restarting sacubitril/valsartan at lower dose with repeat eGFR within 5-7 days
eGFR decreases by ≥ 40% from baseline
  • If a patient eGFR decreases by ≥40% from baseline, clinicians will check for potentially reversible causes of renal dysfunction (see above)
  • If no other obvious potentially reversible causes of renal dysfunction are identified or according to clinician
  • judgment then sacubitril/valsartan should be stopped
  • Repeat eGFR measurement after 5-7 days
  • Repeat eGFR at least weekly until levels return to acceptable values
  • Every effort should be made to restart sacubitril/valsartan but discuss all re-challenges with consultant before restarting

Symptomatic Hypotension

Symptomatic Hypotension
  • Correct any treatable cause (e.g. hypovolemia)
  • If hypotension persists, any antihypertensive drug and non-disease-modifying drugs, such as diuretics, calcium channel blockers (e.g. amlodipine), nitrates, and α-blockers, should be down-titrated or stopped first before down-titration of sacubitril/valsartan
  • If hypotension persists, sacubitril/valsartan should be down-titrated or even temporarily withdrawn according to clinician judgment
Angioedema-like Events (e.g. swelling around mouth, lips or eyes)
Angioedema-like Events
  • Immediately and permanently discontinue sacubitril/valsartan
  • Discuss immediately with consultant medic to agree if treatments for angioedema-like event is needed
  • A Yellow Card Report must be completed (www.mhra.gov.uk/yellowcard)

All significant suspected reactions to sacubitril/valsartan should be reported to the Yellow Card Scheme so that any new emerging information can be analysed. To report a Yellow Card please visit www.mhra.gov.uk/yellowcard

Last reviewed: 22 December 2021

Next review: 30 November 2022

Author(s): Paul Forsyth

Version: 3.9

Author Email(s): [email protected]

Approved By: Medicines Utilisation Subcommittee of ADTC

Document Id: 509