Lessons and initiatives for driving success in heart failure

Transcription

1 Lessons and initiatives for driving success in heart failure Saturday 11 th November :50 10:35 East Midlands Conference Centre (EMCC) Nottingham This meeting is organised and funded by Novartis Pharmaceuticals UK Ltd. Prescribing Information is available at this meeting. Entresto (sacubitril/valsartan) is indicated in adult patients with symptomatic chronic heart failure with reduced ejection fraction. ENT17-C189i November 2017

2 Welcome and introduction Dr Iftikhar Fazal Consultant Cardiologist Sherwood Forest Hospitals NHS Foundation Trust Nottinghamshire ENT17-C189i November 2017

3 Disclosures I have received honoraria and/or payments for professional services from the following companies: Novartis Boehringer Ingelheim Servier ENT17-C189i November 2017

4 Before we get started Please turn off mobile phones Fire alarms and location of emergency exits Please complete your evaluation form at the end of the meeting ENT17-C189i November 2017

5 Questions Questions can be submitted using the questions cards. Please pass to a member of staff. ENT17-C189i November 2017

6 Your faculty Dr Iftikhar Fazal Dr Raj Thakkar Ms Ann Jones Ms Pauline Rouse ENT17-C189i November 2017

7 Agenda for today Time Content Speaker 09:50 09:55 Welcome and introduction Dr Iftikhar Fazal 09:55 10:05 Reassessing what we know about heart failure Dr Iftikhar Fazal 10:05 10:15 How can we do more for our heart failure patients? Dr Raj Thakkar 10:15 10:35 Through the keyhole: Coming together to improve heart failure patient outcomes Dr Iftikhar Fazal Dr Raj Thakkar Ms Ann Jones Ms Pauline Rouse 10:35 Summary and close Dr Iftikhar Fazal ENT17-C189i November 2017

8 Reassessing what we know about heart failure Dr Iftikhar Fazal Consultant Cardiologist Sherwood Forest Hospitals NHS Foundation Trust Nottinghamshire ENT17-C189k November 2017

9 HF outcomes remain poor ENT17-C189k November 2017

10 Heart failure is a leading cause of: Mortality HF mortality remains high despite treatment: 1 ~27% 1-year mortality Hospital occupancy One million inpatient bed-days 2 Hospital admissions Acute heart failure leading cause of hospital admission in patients 65 years 3 Poor QoL HF negatively affects patients QoL: % of patients have depression 4 HF, heart failure; QoL, quality of life. 1. National Heart Failure Audit Available at: 2. NICE. Chronic HF: management of chronic HF in adults in primary and secondary care (CG108) Available at: Last accessed November NICE. Acute heart failure guideline (CG187) Available at: Last accessed November Ponikowski et al. ESC Heart Fail 2014;1: Heo. Heart Lung. 2009;38(2): Jeon et al. BMC Health Serv Res. 2010;10:77. ENT17-C189k November 2017

11 The evolving standard of care for HF ENT17-C189k November 2017

12 Impact of therapeutics on mortality CONSENSUS year mortality (%) RALES Placebo ACEI ACEI MRA ACEI MRA COPERNICUS ACEI MRA BB CARE-HF ACEI MRA BB CRT-P PARADIGM-HF Entresto* MRA BB CRT-P * LCZ696 subsequently licensed as Entresto ACEI, angiotensin-converting enzyme inhibitor; BB, beta blocker; CRT-P, cardiac resynchronization therapy pacemaker; HF, heart failure; MRA, mineralocorticoid antagonist. 1. CONSENSUS Study Group. N Engl J Med. 1987; 316: Pitt et al. N Engl J Med. 1999;341: Packer et al. N Engl J Med. 2001; 344: Cleland et al. N Engl J Med. 2005;352: McMurray et al. N Engl J Med. 2014;371: ENT17-C189k November 2017

13 NICE pathway for treating LVSD 1 First-line treatment 1 Second-line treatment 1 ACEI Aldosterone antagonist Beta blockers ARB for ACEI intolerance ARB licensed for HF* Hydralazine in combination with nitrate Entresto NICE pathway recommends Entresto as a second-line option, in patients still symptomatic on ACEI and beta blocker in line with NICE TA388 1,2 *In addition to an ACEI. Entresto should be used as a replacement of ACEI or ARBs. ACEI, angiotensin-converting enzyme inhibitor, ARB, angiotensin II receptor antagonist; HF, heart failure; LVSD; left ventricular systolic dysfunction; NICE, National Institute for Health and Care Excellence; NYHA, New York Heart Association. 1. NICE pathway on treating chronic heart failure due to left ventricular systolic dysfunction. April Available at: 2. NICE guidance on sacubitril/valsartan TA388 April Available at: All URLs last accessed November ENT17-C189k November 2017

14 Entresto (sacubitril/valsartan) Entresto (sacubitril/valsartan) is a novel drug that delivers simultaneous neprilysin inhibition and AT 1 receptor blockade 1 3 Entresto is a salt complex that comprises the two active components: 2,3 Sacubitril (AHU377) a pro-drug; further metabolised to the neprilysin inhibitor LBQ657 Valsartan an AT 1 receptor blocker in a 1:1 molar ratio 1. Bloch MJ, Basile JN. J Clin Hypertens. 2010;12: Gu J, et al. J Clin Pharmacol. 2010;50: Langenickel TH, Dole WP. Drug Discov Today: Ther Strateg. 2012;9:e ENT17-C189k November 2017

15 Efficacy: Impact on outcomes 1,2 Entresto demonstrated significant clinical benefits vs. enalapril: 20% reduced risk of death from CV causes or first hospitalisation for HF (ARR=4.7%; p< ) 1 Mortality Hospitalisation QoL 20% reduced risk of CV mortality (ARR=3.2%, p<0.001) 1 20% reduced risk of sudden death (ARR=1.4%, p=0.008) 2 16% reduced risk of all-cause mortality (ARR=2.8%, p=0.0005) 1 21% reduced risk of first HF hospitalisation (ARR=2.8%) 1 23% fewer hospitalisations for worsening HF (p<0.001) 3 Better patient-reported QoL than enalapril* (p=0.001) 4 Improvement in NYHA class (p<0.001) 5 *As measured by the QoL subdomain in KCCQ. Patients reporting a 5-point deterioration in KCCQ summary score over 8 months of treatment. Post-hoc analysis at 8 months. ARR, absolute risk reduction; CV, cardiovascular; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVSD; left ventricular systolic dysfunction; NYHA, New York Heart Association; QoL, quality of life. 1. McMurray et al. N Engl J Med 2014;371: Desai et al. Eur Heart J 2015;36: Packer et al. Circulation 2015;131: Novartis Data on File (DoF-KCCQ-LCZ15-C ). 5. Novartis Data on File (LCZ15-C ). ENT17-C189k November 2017

16 The AE profile of Entresto was comparable to that of enalapril 1 Event Entresto, n=4187 n (%) Enalapril, n=4212 n (%) Hypotension Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic with SBP <90 mmhg 112 (2.7) 59 (1.4) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) mg/dl 63 (1.5) 83 (2.0) 0.10 Elevated serum potassium >5.5 mmol/l 674 (16.1) 727 (17.3) 0.15 >6.0 mmol/l 181 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) <0.001 Angioedema (adjudicated in a blinded fashion by an expert committee) No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19 Catecholamines or glucocorticoids without hospitalisation 6 (0.1) 4 (0.1) 0.52 Hospitalised without airway compromise 3 (0.1) 1 (<0.1) 0.31 Airway compromise Fewer patients in the Entresto group than in the enalapril group stopped their study medication because of an AE (10.7% vs. 12.3%, p=0.03) p value AE, adverse event; SBP, systolic blood pressure. 1. McMurray et al. N Engl J Med 2014;371: ENT17-C189k November 2017

17 Benefits of treating HF patients with Entresto vs. enalapril In the PARADIGM-HF trial, treating 1000 patients with Entresto, instead of enalapril, over a median treatment period of 27 months, avoided: 1,2 31 cardiovascular deaths* 111 hospitalisations for any reason* 53 HF hospitalisations* *Extrapolated estimates based on numbers needed to treat. HF, heart failure. 1. McMurray et al. N Engl J Med 2014;371: Packer et al. Circulation 2015;131: ENT17-C189k November 2017

18 What is the NICE recommendation for Entresto? NICE Technology Appraisal Guidance (TA388): 1 Entresto is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people: 1 With NYHA class II to IV symptoms and With a left ventricular ejection fraction of 35% or less and Who are already taking a stable dose of ACEIs or ARBs ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; NICE, National Institute for Health and Care Excellence; NYHA, New York Heart Association. 1. NICE. Technology Appraisal Guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. April Last accessed November ENT17-C189k November 2017

19 How can we incorporate national guidelines and recommendations locally? ENT17-C189k November 2017

20 NICE quality statements 1 NICE quality standards aim to help improve patient safety, patient experience and clinical effectiveness Adults with suspected chronic HF Those referred for diagnosis should have an echocardiogram and specialist assessment Those with a previous MI or very high levels of serum natriuretic peptides should have an echocardiogram and specialist assessment within 2 weeks Adults with chronic HF Those with LVSD should be started on low-dose ACEI and BBs that are gradually increased until the target or optimal tolerated doses are reached Should have a review within 2 weeks of any change in the dose or type of their HF medication Adults with stable chronic HF Should have a review of their condition at least every 6 months Should be offered an exercisebased programme of cardiac rehabilitation* *Those referred to a programme of cardiac rehabilitation should be offered sessions during and outside working hours, and the choice of undertaking the programme at home, in the community or in a hospital setting. ACEI; angiotensin-converting enzyme inhibitor, BB, beta blocker; HF, heart failure; LVSD; left ventricular systolic dysfunction; MI, myocardial infarction; NICE, National Institute for Health and Care Excellence. 1. NICE Chronic heart failure quality standard Available at: www. guidance.nice.org.uk/qs9. Last accessed November ENT17-C189k November 2017

21 What are the barriers to improving HF patient outcomes and how do we overcome them? ENT17-C189k November 2017

22 What are the barriers to effective HF management? Uncertainty about clinical practice 1 Tensions between individual and organisational practice 1 The value of clinical guidelines 1 Many patients do not have access to specialist multidisciplinary HF teams 2 1. Hancock HC, et al. BMJ Open 2014 (April 1); 4(3): e Department of Health (DH). Cardiovascular Disease Outcomes Strategy. DH London March ENT17-C189k November 2017

23 What is the role of integrated care for improving HF patient outcomes? NICE recommend an integrated approach to HF across the healthcare community for a positive effect on patients life expectancy and QoL 1,2 Effective multidisciplinary specialist services, which include primary care, can help to reduce recurrent hospital stays by: % HF, heart failure; NICE, National Institute for Health and Care Excellence; QOL, quality of life. 1. NICE Chronic heart failure: management of chronic heart failure in adults in primary and secondary care. NICE Clinical Guideline 108 [online] Available at: 2. Department of Health (DH). Cardiovascular Disease Outcomes Strategy. DH London March NICE. Chronic heart failure quality Standard Available at: All URLs last accessed: November 2017 ENT17-C189k November 2017

24 Need to modify natural history of heart failure 1 Chronic decline Cardiac function Hospitalisation for acute decompensation episodes Disease progression Patients with HF with reduced ejection fraction are at high risk of sudden death 2 HF, heart failure. 1. Gheorghiade et al. Am J Cardiol 2005;96(Suppl):11G 17G. 2. Shen et al. Eur J Heart Fail 2015;17(S1)5 441F:266. ENT17-C189k November 2017

25 Summary: Driving success in heart failure Heart failure remains an urgent, evolving system-wide challenge; more can be done to reduce mortality and hospitalisation Across the UK, increased integration between primary and secondary care with successful multidisciplinary local care models are creating capacity benefits and improved outcomes Entresto is recommended in selected HFrEF in patients who remain symptomatic despite optimal treatment with an ACEI, beta-blocker and an MRA 1 In PARADIGM-HF, Entresto was superior to enalapril in reducing CV death or first HF hospitalisation 2 ACEI, angiotensin-converting enzyme inhibitor; CV, cardiovascular; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid antagonist. 1. NICE. Technology Appraisal Guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. April Last accessed November McMurray et al. N Engl J Med 2014;371: ENT17-C189k November 2017

26 How can we do more for our heart failure patients? Dr Raj Thakkar GP partner, Wooburn Green, Buckinghamshire Clinical Commissioning Director, Chiltern and Aylesbury Vale CCGs Primary Care Cardiology Lead, Thames Valley AHSN, NHS England ENT17-C189j November 2017

27 Disclosures I have received honoraria and/or payments for professional services from the following companies: Novartis, Bayer, AbbVie Optum, MIMS, Open Access Consulting ENT17-C189j November 2017

28 Understanding the challenges ENT17-C189j November 2017

29 System wide challenges: Emergency admissions Heart Failure in Thames Valley Emergency Admissions 1 The number of emergency admissions directly related to heart failure within Thames Valley is rising Number of emergency admissions ,694 emergency admissions in 2013/ /12 M /13 M /14 M /15 M01 Data source: SUSPAC data 2011/ /15. With permission from Optum Consulting. 24% increase in admissions over the last 4 years 2 1 in 4 patients with chronic heart failure will be readmitted within three months of a hospital stay 3 Effective management after an acute admission can reduce re-admission into secondary care by 30 50% 2,4 1. NHS Commissioning guidance: Thames Valley & Milton Keynes Strategic Clinical Networks. August Optum Commissioning Annual Review 2015/16. Optum Chiltern CCG Operational plan 2015/ Holland R, et al. Systematic review of multidisciplinary interventions in heart failure. Heart 2005; 91: Image courtesy of the speaker ENT17-C189j November 2017

30 System wide challenges in HF management Clinical Patient Contractual Organisational Population Primary care Variation in secondary care performance Variation in understanding Early warning systems Activity based contracts No outcome based contracts Culture Learning organisation failure Competing priorities Fragmented, poorly integrated approach Prevention Variation Education Hospital at home Risk averse systems No golden thread Ageing population QOF Identification Admission avoidance systems Commissionerprovider mentality Information sharing Undiagnosed disease Education TEP Inequality gap Confidence LOS Quality Adherence to guidelines Author s own data ENT17-C189j November 2017

31 System wide challenges: Inequality gap 1 1. Buckinghamshire Director of Public Health s Annual Report Buckinghamshire Public Health ENT17-C189j November 2017

32 Leading change ENT17-C189j November 2017

33 What do we want to achieve? Population priorities Plan to prevent Prevalence to target Reduced inequality gap System integration Standardised care Learning organisation IT Patient ownership Streamlined pathways Community HF lounge EOL EOL, end of life; HF, heart failure. Author s own data ENT17-C189j November 2017

34 A systematic way of approaching LTCs 1 Patient education Moving care upstream Prevention: Public health messages Obesity Screening uptake Blood pressure Falls Early diagnosis: COPD HF Diabetes etc Symptom-based clinics Optimal primary care: Optimal medical care Managing referrals Community hubs: procedures, stable disease, specialists in community Admission avoidance: Patient education Early intervention Day units Hospital at home EOL Effective and efficient acute care: Rapid discharge Follow-up to avoid readmission Reducing inequality gap Learning organisation COPD, chronic obstructive pulmonary disease; EOL, end of life; HF, heart failure; LTC, long term condition. 1. Thakkar R. Draft STP Vision for planned care. Unpublished data. ENT17-C189j November 2017

35 Buckinghamshire strategy Create urgency for change across the system HF rehab Education and data Optimising care EMIS template Integrated record System delivery vehicles QIS HF day unit HF, heart failure; QIPP, Quality, Innovation, Productivity and Prevention; QIS, Quality Improvement System. Author s own data ENT17-C189j November 2017

36 Buckinghamshire strategy: Phase II Primary care development scheme HF HTN Accountable Care Organisation CVD inequality analysis GP clustering Excellence in HF project Whole pathway review MDT with primary care Code cleansing Primary care clinics, HF care support with quality improvement HF nurse spec review CVD, cardiovascular disease; HF, heart failure; HTN, hypertension; GP, general practitioner; MDT, multidisciplinary. Author s own data ENT17-C189j November 2017

37 Key outcomes from our strategy System urgency and priority HF day unit commissioned Scrapped QOF, developed PCDS 2016/17 675k savings on admissions Excellence in HF project initiated Cardiac champions programme HF, heart failure; PCDS, primary care development scheme; QOF, Quality and Outcomes Framework. Author s own data ENT17-C189j November 2017

38 Doing more for patients: Summary Doing nothing is not an option Key requirements Leadership System approach Golden thread Data Use of enablers Incentives New drugs Robust pathway Author s own data ENT17-C189j November 2017

39 Through the keyhole: Coming together to improve heart failure patient outcomes Dr Iftikhar Fazal Dr Raj Thakkar Ms Ann Jones Ms Pauline Rouse ENT17-C189i November 2017

40 Your panel Dr Iftikhar Fazal Dr Raj Thakkar Ms Ann Jones Ms Pauline Rouse ENT17-C189i November 2017

41 Real-world experience: Ipswich Hospital NHS Trust Ms Ann Jones Heart Failure Nurse Specialist Ipswich Hospital NHS Trust Suffolk ENT17-C189i November 2017

42 Disclosures I have received honoraria and/or payments for professional services from the following companies: Novartis ENT17-C189i November 2017

43 My centre Ipswich Hospital NHS Trust District Hospital serving a population of 360,000 Hospital and community clinics, telephone clinics, home visits, inpatient reviews MDT consists of HF lead, Consultant Cardiologist, two hospital-based HFNS and community HFNS Weekly MDT meetings and working closely with nephrology, care of the elderly, cardiac rehabilitation, hospice Centre has treated >100 patients with Entresto 1 since June 2016 HF, heart failure; HFNS, Heart Failure Nurse Specialist; MDT, multidisciplinary team. 1. Entresto Summary of Product Characteristics. March Available at: Last accessed: November ENT17-C189i November 2017

44 Real-world experience: Medway Community Healthcare Ms Pauline Rouse Cardiology Lead Nurse and Manager Medway Community Healthcare Rochester, Kent ENT17-C189i November 2017

45 Disclosures I have received honoraria and/or payments for professional services from the following companies: Novartis ENT17-C189i November 2017

46 My centre Community provider community interest company patients on the caseload MDT consists of Consultant Cardiologist, Cardiology lead nurse and three HFNSs referrals / month added to the caseload Centre has treated 59 patients with Entresto 1 since August 2016 HF, heart failure; HFNS, Heart Failure Nurse Specialist; MDT, multidisciplinary team. 1. Entresto Summary of Product Characteristics. March Available at: Last accessed: November ENT17-C189i November 2017

47 Panel discussion ENT17-C189i November 2017

48 Summary and close Dr Iftikhar Fazal ENT17-C189i November 2017

49 Evaluation forms Please remember to fill in your evaluation forms and hand them in before you leave. Thank you! ENT17-C189i November 2017

50 Thank you ENT17-C189i November 2017

51 Prescribing Information ENTRESTO (sacubitril/valsartan) Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Film-coated tablets of 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg of sacubitril and valsartan respectively (assacubitril valsartansodiumsalt complex). Indications: In adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Dosage & administration: The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient. In patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these medicinal products, a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3-4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP 100 to 110 mmhg, moderate or severe renal impairment (use with caution in severe renal impairment) and moderate hepatic impairment. Do not co-administer with an ACE inhibitor or an ARB. Do not start treatment for at least 36 hours after discontinuing ACE inhibitor therapy. Entresto may be administered with or without food. The tablets must be swallowed with a glass of water. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Concomitant use with ACE inhibitors. Do not administer until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema related to previous ACE inhibitor or ARB therapy. Hereditary or idiopathic angioedema. Concomitant use with aliskirencontaining medicinal products in patients with diabetes mellitus or in patients with renal impairment (egfr <60 ml/min/1.73 m 2 ). Severe hepatic impairment, biliary cirrhosis and cholestasis. Second and third trimester of pregnancy. Warnings/Precautions: Dual blockade of the renin angiotensin-aldosterone system (RAAS): Combination with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto. Combination of Entresto with direct renin inhibitors such as aliskiren is not recommended. Entresto should not be co administered with another ARB containing product. Hypotension: Treatment should not be initiated unless SBP is 100 mmhg. Patients with SBP <100 mmhg were not studied. Cases of symptomatic hypotension have been reported in patients treated with Entresto during clinical studies, especially in patients 65 years old, patients with renal disease and patients with low SBP (<112 mmhg). Blood pressure should be monitored routinely when initiating or during dose titration with Entresto. If hypotension occurs, temporary downtitration or discontinuation of Entresto is recommended. Impaired or worsening renal function: Limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m 2 ). There is no experience in patients with end-stage renal disease and use of Entresto is not recommended. Use of Entresto may be associated with decreased renal function, and down-titration should be considered in these patients. Hyperkalaemia: Entresto should not be initiated if the serum potassium level is >5.4 mmol/l. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If clinically significant hyperkalaemia occurs, consider adjustment of concomitant medicinal products or temporary down-titration or discontinuation of Entresto. If serum potassium level is >5.4 mmol/l discontinuation should be considered. Angioedema: Angioedema has been reported with Entresto. If angioedema occurs, discontinue Entresto immediately and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms has occurred. Entresto must not be re administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Entresto is used in these patients. Black patients have an increased susceptibility to develop angioedema. Patients with renal artery stenosis: Caution is required and monitoring of renal function is recommended. Patients with NYHA functional classification IV: Caution should be exercised due to limited clinical experience in this population. Patients with hepatic impairment: There is limited clinical experience in patients with moderate hepatic impairment (Child Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. Caution is therefore recommended in these patients. B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with Entresto because it is a neprilysin substrate. Interactions: Contraindicated with ACE inhibitors, 36 hours washout is required. Use with aliskiren contraindicated in patients with diabetes mellitus or in patients with renal impairment (egfr <60 ml/min/1.73 m 2 ). Should not be co-administered with another ARB. Use with caution when co-administering Entresto with statins or PDE5 inhibitors. Monitoring serum potassium is recommended if Entresto is co-administered with potassium-sparing diuretics or substances containing potassium (such as heparin). Monitoring renal function is recommended when initiating or modifying treatment in patients on Entresto who are taking NSAIDs concomitantly. Interactions between Entresto and lithium have not been investigated. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Co-administration of Entresto and furosemide reduced Cmax and AUC of furosemide by 50% and 28%, respectively, with reduced urinary excretion of sodium. Co-administration of nitroglycerin and Entresto was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone, no dose adjustment is required. Co administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised. Co-administration of Entresto with metformin reduced both Cmax and AUC of metformin by 23%. When initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be evaluated. Fertility, pregnancy and lactation: The use of Entresto is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. It is not known whether Entresto is excreted in human milk, but components were excreted in the milk of rats. Entresto is not recommended during breastfeeding. A decision should be made whether to abstain from breast feeding or to discontinue Entresto while breast feeding, taking into account the importance of Entresto to the mother. Undesirable effects: Very common ( 1/10): Hyperkalaemia, hypotension, renal impairment. Common ( 1/100 to <1/10): Anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure, acute renal failure, fatigue, asthenia. Uncommon ( 1/1,000 to <1/100): Hypersensitivity, postural dizziness, pruritis, rash, angioedema. Packs and price: Entresto 24 mg/26 mg per 28 tablet pack; Entresto 49 mg/51 mg per 28 tablet pack, per 56 tablet pack; Entresto 97 mg/103 mg 91.56per 56tablet pack. Legal classification: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Frimley Business Park, Camberley, GU167SR. Marketing Authorisation Numbers: Entresto 24 mg/26 mg film coated tablets EU/1/15/1058/001; Entresto 49 mg/51 mg film coated tablets EU/1/15/1058/ ; Entresto 97 mg/103 mg film coated tablets EU/1/15/1058/006. Date of last revision of prescribing information: September Full Prescribing Information available from: Novartis Pharmaceuticals UK Ltd, Frimley Business Park, Frimley, Surrey, GU16 7SR. Tel: Fax: Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Novartis via uk.patientsafety@novartis.com or online through the Patient Safety Information (PSI) tool at If you have a question about the product, please contact Medical Information on or by at medinfo.uk@novartis.com Date of prep: September 2017 ENT17-C189i November 2017