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In Partnership with: North East Hampshire and Farnham CCG, Windsor, Ascot and Maidenhead CCG Bracknell and Ascot CCG Chiltern CCG Slough CCG Shared Care Prescribing Guideline Sacubitril/valsartan for the treatment of LVSD Frimley Health Area Prescribing Committee classification: Amber Shared Care NOTES to the GP Amber Shared Care drugs: Prescribing to be initiated by a hospital specialist (or if appropriate by a GP with specialist interest) but with the potential to transfer to primary care when. . an individual GP has agreed to accept clinical responsibility for an individual patient. . agreed shared care arrangements have been established and the GP is willing to take over shared care. . the patient’s condition and/or treatment has been stabilised. . In one off situations, a specific GP can agree to enter into a ‘shared care arrangement’ without a formal shared care guideline providing a letter is sent to the GP giving appropriate advice and guidance. . The request is accompanied by a written proposal to request that the GP accepts ongoing prescribing and monitoring. The expectation is that these guidelines should provide sufficient information to enable GPs to be confident to take clinical and legal responsibility for prescribing these drugs. The questions below will help you confirm this: Is the patient’s condition predictable? Do you have the relevant knowledge, skills and access to equipment to allow you to monitor treatment as indicated in this shared care prescribing guideline? Have you been provided with relevant clinical details including monitoring data? If you can answer YES to all these questions (after reading this shared care guideline), then it is appropriate for you to accept prescribing responsibility. Sign and return a copy of page 4 to the requesting consultant at the Acute Trust. Until the requesting consultant at the Acute Trust has received a signed copy of page 4 indicating that shared care has been agreed all care (including prescribing) remains with the consultant at the Acute Trust. If the answer is NO to any of these questions, you should not accept prescribing responsibility. You should write to the consultant outlining your reasons for NOT prescribing. If you do not have the confidence to prescribe, we suggest you discuss this with your local Trust/specialist service, who will be willing to provide training and support. If you still lack the confidence to accept clinical responsibility, you still have the right to decline. Your CCG pharmacist will assist you in making decisions about shared care. Prescribing unlicensed medicines or medicines outside the recommendations of their marketing authorisation alters (and probably increases) the prescriber’s professional responsibility and potential liability. The prescriber should be able to justify and feel competent in using such medicines. The patient’s best interests are always paramount The GP has the right to refuse to agree to shared care, in such an event the total clinical responsibility will remain with the consultant Prepared by : Sarah Crotty & Ann Parker Valid from: December 2016 Review date: December 2017 Version: 1 Supersedes version: Approved by: Frimley Interface Prescribing Committee, December 2016 This guideline provides prescribing and monitoring guidance for sacubitril valsartan therapy. It should be read in conjunction with the Summary of Product Characteristics (SPC) available on www.medicines.org.uk/emc and the BNF. 1. BACKGROUND FOR USE Sacubitril valsartan is a neprilysin inhibitor (sacubitril) with an angiotensin II receptor blocker (ARB; valsartan). It is licensed for treatment of symptomatic chronic heart failure with reduced ejection fraction in adults. NICE TA 388 recommends sacubitril valsartan as an option for chronic heart failure patients who remain symptomatic despite optimal medical treatment. It is offered only in people: With New York Heart Association (NYHA) class II to IV symptoms AND With a left ventricular ejection fraction (LVEF) of 35% or less AND Who are already taking an optimised and stable dose of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor-blocker (ARB). NICE TA 388 states that sacubitril valsartan must be initiated by a heart failure specialist with access to a multidisciplinary heart failure team. An example checklist to support implementation of the drug can be found using the following link: https://www.nice.org.uk/guidance/ta388/resources/example-checklist-2551344448 The Frimley Health APC has approved the use of sacubitril/valsartan in patients who have LVEF <35% and who are tolerating optimal medical therapy (OMT) to include ACEI or ARB, Beta blocker and either spironolactone or eplerenone who: 1. Have had a recent unplanned heart failure admission without an obvious precipitating cause despite OMT 2. Are at risk of unplanned hospital admission or who have worsening symptoms despite OMT, but who have a predicted good/ stable prognosis. 3. Patients who remain heavily symptomatic and at risk from unplanned admission despite OMT i.e. NYHA III. Under a shared care arrangement, treatment must be initiated by a consultant Cardiologist. Dose titration, monitoring and prescribing for the first three months must be by the Heart Failure team. After the dose is stabilised the patient will be transferred to the GP. Evidence from PARADIGM-HF TRIAL (2014) demonstrated that patients with heart failure with reduced ejection fraction (LVEF<35%) and NYHA class II-IV treated with sacubitril/valsartan versus standard of care (ACEI- enalapril) had reduced mortality risk and reduced risk of heart failure hospitalisation. Contemporary BNP/ NT-BNP testing and echo are also recommended before initiation to ensure patient symptoms are consistent with left ventricular systolic dysfunction. Patients who have severe heart failure, but who remain NYHA IV despite OMT should have access to quality palliative care support recognising that there is limited clinical experience with sacubitril/valsartan in this group within the PARADIGM trial and therefore specialist referral is highly recommended before initiation. 2 SUPPORTING INFORMATION 2. Contraindications Contra-indications Cautions Bilateral renal artery stenosis, refer patients for advice Aortic or mitral valve stenosis or obstructive cardiomyopathy, refer patients for advice Known hypersensitivity to ARB, sacubitril or excipients History of angioedema of any cause Pregnancy Baseline potassium > 5.4 mmol/l Concomitant use with ACEI or ARB sacubitril valsartan must NOT be started for at least 36 hours after discontinuing ACEI. (This does not apply when stopping an ARB and starting sacubitril valsartan.) 3. Known history of angioedema to ACEI or ARB therapy Concomitant use with aliskiren containing products in patients with diabetes mellitus or in patients with eGFR<60ml/min Systolic BP<100mmHg Serum K+ > 5.4 mmol/l Patients with a documented intolerance of ACEI due to symptomatic hypotension - consider re-challenging with a longer acting ACEI (such as perindopril). Patients on high dose diuretics (i.e. furosemide > 80mg daily) – increased risk of hypotension and renal dysfunction Breast feeding- suggest avoid Dose reduction suggested for patients with moderate renal impairment, eGFR 30-60ml/min Limited clinical experience for eGFR<30ml/min Baseline potassium > 5 to 5.3mmol/l Concomitant aliskiren use not meeting contra indications Moderate hepatic impairment (ChildPugh B classification) or with AST/ALT values more than twice the upper limit of normal Concomitant use with aliskiren in patients with diabetes mellitus. Severe hepatic impairment, biliary cirrhosis, cholestasis (Child-Pugh C classification) Treatment should not be initiated unless SBP is ≥100 mmHg. End stage renal disease Dosage Initiation must be by specialist review only. Check baseline blood chemistry. (e.g. serum creatinine, urea, potassium, sodium and eGFR) and blood pressure (BP) 3 Discontinue potassium supplements/potassium sparing diuretics (except spironolactone or eplerenone) and review need for concomitant nephrotoxic drugs e.g. NSAIDs Review dose of diuretic therapy. Do not start for at least 36hours after discontinuing ACEI Dose Titration The recommended starting dose depends on the BP reserve: i. If BP is at the low end of usual for LVF or if on a low dose of an ACEI start on 50 mg (24mg/26mg) twice daily ii. Consider a higher starting dose of 100 mg (49mg/51mg) twice daily for patients on higher doses of ACEI or ARB (i.e. more than 50% of the maximum dose) or for patients with systolic BP ≥ 100mmHg iii. The dose should be doubled every 2 - 4 weeks to the target of 200 mg (97mg/103mg) twice daily, as tolerated by the patient. Patients will not be transferred to GP prescribing until stabilized on the maximum tolerated dose for them. Reduce dose/stop according to “worsening renal function” and “symptomatic hypotension” in “problem solving” below. If a dose is missed, the tablet should be taken at the next scheduled time. Tablets should be swallowed whole with water and can be taken with or without food. Dose in renal impairment Mild (eGFR 60-90 ml/min) Moderate (eGFR 30 to 60 ml/min) Severe (eGFR <30 ml/min) End-stage renal disease 4. No dose adjustment required. Consider starting dose of 24 mg/26 mg twice daily Limited clinical experience. Use with caution. Starting dose of 50mg (24 mg/26 mg) twice daily is recommended. No experience. Use of sacubitril valsartan is not recommended TIME TO RESPONSE 7 to 10 days for therapeutic effects, effects on BP happen within hours. 4 5. RESPONSIBILITIES and ROLES Specialist responsibilities (May be consultant or specialist LVF nurse or specialist pharmacist) 1. Assess the patient. Establish the diagnosis and assess the patient’s ability to adhere to treatment. 2. Initiate treatment, monitor and titrate to a stable dose (supply the first three months of treatment). 3. Send a letter to the GP requesting shared care for the patient, (there is a template below), including this shared care protocol 4. The Heart Failure Team will be available for verbal (or written) advice to the GP if the patient’s condition changes or deteriorates. Following this advice GP’s may refer patients back to the Heart Failure Team for assessment if this is required. 5. The Heart Failure Team will ensure the patient & carer(s) are given information regarding the treatment and a contact for the heart failure team if they have any concerns. General Practitioner responsibilities 1. Monitor patient’s overall health and wellbeing. 2. Prescribe the drug treatment as described 3. Report any adverse events to the hospital specialist, where appropriate 4. Monitor blood results in line with recommendations from 4 months onwards Patient counselling (conducted by Specialist & reinforced by the GP) 6. Explain the expected benefits to the patient –treatment can improve their symptoms, prevent their heart failure getting worse, increase survival and decrease hospital admissions. Symptoms may not improve immediately. It may take a few weeks or months to have a full effect. Advise patients to report adverse effects e.g. hypotension or dizziness Advise patients to take the first dose at night as they may experience a first dose hypotensive effect Advise patient that renal function monitoring is needed Advise patients to avoid OTC NSAIDs, soluble tablets and salt substitutes high in K+ Advise patients that if a dose is missed, the tablet should be taken at the next scheduled time. Hospital Pharmacy: Duration of Supply After initiation, a total of 3 months’ treatment will be provided by secondary care, or until the patient is on a stable dose if this is longer. 7. MONITORING PRE-TREATMENT ASSESSMENT (by the Specialist) In general patients will be established on ACEI or sartans prior to switching Echo demonstrating LVEF <35% within the last 12 months Medication review (including optimisation of heart failure medication. Blood U&E (serum creatinine, urea, potassium, sodium and eGFR). ECG and resting heart rate /pulse BP Weight 5 ONGOING MONITORING SCHEDULE The following parameters will be monitored 2 - 4 weeks after initiation and at each dose adjustment. Pulse BP Blood U&E (serum creatinine, urea, potassium, sodium and eGFR) The Specialist will undertake this monitoring from month 1 to 3 inclusive; the GP will undertake monitoring from month 4 onwards, including 6-12 monthly reviews. 8. SIDE EFFECTS AND ACTIONS TO BE TAKEN The GP may contact the specialist team for advice at any time if there are concerns. The most commonly reported adverse reactions during treatment with sacubitril valsartan were hypotension, hyperkalaemia and renal impairment. For other side effects see SPC Side-effect Angioedema hypersensitivity Action & If symptoms are severe this is a medical emergency and patients may require urgent hospital treatment. Stop sacubitril valsartan and monitor until complete and sustained resolution of signs and symptoms has occurred.* It must not be readministered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Stop concomitant medication that can increase serum potassium (e.g. potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), mineralocorticoid antagonists, potassium supplements). Consider reducing or stopping sacubitril valsartan.* Hyperkalaemia Serum K+ >5.4 mmol/L Asymptomatic low BP (Systolic BP <100mmHg) Does not usually warrant a change in therapy, but BP requires monitoring and watch for worsening renal function. Symptomatic hypotension (including dizziness, headache, syncope) (e.g. Systolic BP <100mmHg) Monitor BP, consider ambulatory monitoring if available Consider dose adjustment of concomitant diuretics or antihypertensives (stop nitrates or calcium channel blockers 1st then consider reducing betablocker) If dehydrated treat. hypovolaemia. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Giving fluids must be carefully weighed against the risk of volume overload. Consider temporary down-titration or discontinuation of sacubitril valsartan.* 6 Renal impairment Persistant Dry cough An increase in urea, creatinine and K+ is to be expected after initiation/titration. If the increase is small and asymptomatic, no action is necessary If eGFR <60 ml/min consider: Stopping concomitant nephrotoxic medication (e.g. NSAID’s, diuretics, calcium channel blockers or nitrates). If on a diuretic reduce the dose to increase fluid & perfusion of the kidneys Dose reduction of sacubitril valsartan. Stopping sacubitril valsartan* (rarely needed unless GFR<30). Anaemia, hypoglycaemia, vertigo, fatigue, asthenia, gastro-intestinal disorders (diarrhoea, nausea, gastritis) If affected this may limit the dose possible or longer intervals between dose adjustments may be needed. Review aetiology of cough e.g. due to smoking, worsening heart failure/pulmonary oedema, respiratory disease Review cough tolerability versus benefits of sacubitril/valsartan May require discontinuation of treatment. If discontinuation is required refer patient back to heart failure team for re-assessment If severe consider seeking specialist advice *Allow 48 hour wash out period before restarting an ACE inhibitor 7 9. NOTABLE DRUG INTERACTIONS (refer to BNF AND SPC also) The following drugs are contraindicated with sacubitril valsartan: ACEI Aliskiren ARB NSAIDs The risk of worsening renal function and heart failure is increased with use of NSAIDs and sacubitril valsartan. Statins The manufacturers state that caution is needed in patients taking statins as use of sacubitril/valsartan may increase the systemic exposure to metabolites. No formal recommendations exist on management of the combination however sensible precautions would include patients being reminded to report symptoms such as muscle pains and jaundice. Lithium and sacubitril/valsartan has not been tested and is therefore not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased further. Potassium supplements & potassium sparing diuretics may increase the risk of hyperkalaemia and potassium should be monitored. Sacubitril/valsartan taken with sildenafil is associated with significantly greater hypotension compared to administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan. Co-administration of sacubitril/valsartan with rifampicin, ciclosporin, tenofovir, cidofovir, ritonavir may increase sacubitril/valsartan levels. Metformin Co-administration of sacubitril valsartan with metformin reduces the bioavailability of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with sacubitril/valsartan in patients receiving metformin, the control of the patient’s diabetes may need to be re-evaluated. Furosemide- may reduce effectiveness of furosemide 10. BACK-UP INFORMATION/ADVICE BHT: Contact Details Wycombe and Amersham Stoke Mandeville Bucks Heart Failure Specialist Team Medicines Information BHT 01494 426919 (8am – 4pm) On-call Cardiologist Registrar via switchboard (out-of-hours) 01494 425355 Switchboard BHT 01494 526161 (WH) 8 01296 315000 (SMH) FRIMLEY HEALTH BACK-UP ADVICE AND SUPPORT Contact Details Frimley Park Community heart failure nurse Cardiology Pharmacist Annabel Sturgess, 01276 526969 Ann Parker 01276 604604 bleep 400 Heart Failure Clinical Nurse Specialist Heart Failure Consultant Medicines Information 11. 1. 2. 3. Dr Lydia Sturridge Via switchboard 01276 604604 01276 606744 Wexham Park Preya Fakira 01753 633000 bleep 2215 Mark Stephens 07785996702 Stephanie Murray 07775404609 or 01753 634791 Dr Sofia Metaxa Via switchboard 01753 63300 REFERENCES NICE TA388 ‘Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction’ available at : https://www.nice.org.uk/guidance/TA388/chapter/1-recommendations accessed 12/8/16 Summary of product characteristics for sacubitril valsartan (Entresto®®) tablets available at http://www.medicines.org.uk/emc/medicine/31244 <accessed 18/10/16> Entresto dosing and titration guide. Novartis Pharmaceuticals UK Ltd. Published 11/2015 With thanks to St Thomas Hospital London for sharing their sacubitril/valsartan documentation. 9 Appendix 1 SHARED CARE PRESCRIBING GUIDELINE Sacubitril valsartan for the treatment of LVSD Agreement for transfer of prescribing to GP Patient details / addressograph: Name…………………………………….. Address………………………………….. ………………………………….. ………………………………….. DOB………………. Hospital No………………………………. NHS No………………………………. Drug name and dose: Date initiated:…………………………………. Date care transferred………………………….. The patients has now been stabilised on a dose of: ………………………………………….. Consultant/Specialist: Agreement to shared care, to be signed by GP and Consultant/Specialist. Address: Consultant Signature: Contact Number ……………………………………………….. Date: GP: Address: GP Signature: Contact Number ………………………………………………… Date: 10 Appendix 2 Patient name Hospital number NHS number Dear Dr…………. This patient has been initiated on sacubitril valsartan in accordance with Frimley Health guideline for treatment of chronic heart failure with reduced ejection fraction. Details of treatment plan Date initiated Dose on transfer Date of next review Sacubitril Valsartan (ENTRESTO® ) This patient is on maximum tolerated dose and I am writing to transfer the prescribing responsibility for this patient’s ongoing treatment from ….. /…../…… This transfer of care document should be reviewed in conjunction with the sacubitril valsartan guidelines (appendix 1) All patients receiving sacubitril valsartan therapy should be reviewed at least six monthly throughout their treatment. Please refer to the guidelines for more details. Monitoring Test Result Date of test Please repeat test in: Serum Creatinine ………….………..months Estimated GFR Potassium ………….………..months Blood pressure ………….………..months ALT Liver Function Tests 12 months ALP Other relevant information: …………………………………………………………………………………………………………… …………………………………………………………………………………………………………………………………………… I confirm that I have prescribed in accordance with the local heart failure guidelines I confirm that the patient has been made aware of the benefits and risks of sacubitril valsartan and that they know how to seek medical help I confirm the patient has consented to treatment Signed:……………………………………. Name of Clinician:…………………………… Date: ……………. 11