Initial experience of introducing sacubitril/valsartan in a UK heart failure service

Br J Cardiol 2019;26(suppl 1):S15-S19doi:10.5837/bjc.2019.s04 Leave a comment
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Sponsorship Statement:

This sponsored supplement was initiated and funded by Novartis Pharmaceuticals UK Ltd. Editorial control, however, was retained by the authors and editors but Novartis reviewed the supplement for technical accuracy and compliance with relevant regulatory requirements before publication.

Prescribing information for Entresto® (sacubitril/valsartan) in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction is available here.

Date of preparation: July 2019
Job bag number: ENT19-C029

Advances in the treatment of chronic heart failure in real-world settingsThis article will contribute to a ‘Learning with reflection’ CPD activity

Sacubitril/valsartan (formerly LCZ696) is recommended for adult patients with symptomatic chronic heart failure with reduced ejection fraction (HFrEF) already established on conventional heart failure therapy. Large numbers of patients are potentially eligible for this drug, but patient monitoring and lack of experience of drug tolerability may mean some are not considered. We describe our trainee-led service to deliver sacubitril/valsartan therapy in the setting of limited extra resources. This pathway was delivered successfully by working closely with primary care. Up-titration to the target dose level of sacubitril/valsartan (given alongside other standard-of-care treatments for HFrEF) was possible in two-thirds of patients. Tolerability was generally good, with the majority achieving successful dose optimisation of sacubitril/valsartan.

Introduction

Heart failure (HF) remains a significant problem globally.1 In the UK, the prevalence is estimated at over 500,000 individuals,2 with care representing 2% of National Health Service (NHS) resources (approximately £2.3 billion).3 A large proportion of the economic burden relates to lengthy and recurrent hospitalisations. Despite advancements, HF is still associated with a poor prognosis. The National Heart Failure Audit from England and Wales demonstrates an in-hospital mortality rate of around 9%, and a one-year mortality of just over 23%.4

Treatment for patients suffering from HF with reduced ejection fraction (HFrEF) is primarily based around the use of neurohormonal antagonists acting upon the renin–angiotensin–aldosterone system (RAAS), alongside sympathetic adrenoceptor antagonism. It is 30 years since initial trials demonstrated lower risk of death in patients taking the angiotensin-converting enzyme (ACE) inhibitor, enalapril.5,6 Since then, key studies have confirmed the incremental benefit of neurohormonal blockade, revolutionising the therapeutic options for patients with HFrEF.7-11 Current national and international guidelines suggest patients with HFrEF should be considered for such agents in a stepwise algorithm.12-15 Despite major improvements in outcomes, there remains a need for more efficacious treatments, and many patients still endure impaired quality of life, repeated hospitalisations and premature death.

Sacubitril/valsartan, formerly known as LCZ696, is a combination of sacubitril, a neprilysin inhibitor that prevents breakdown of vasoactive peptides, including B-type natriuretic peptide (BNP); and valsartan, an angiotensin II receptor blocker (ARB) acting on the RAAS. This first-in-class combination drug offers the potential to overcome the natriuretic peptide resistance seen in HFrEF, offering additional vasodilation.16 The PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial studied sacubitril/valsartan in comparison to enalapril, with a composite primary end point of cardiovascular (CV) death and first HF hospitalisation in patients with HFrEF.17 Significant reduction in the primary end point was observed in the sacubitril/valsartan group, leading to premature termination of the trial, fast-tracked National Institute for Health and Care Excellence (NICE)18 and regulatory approval for HFrEF patients. Both UK, and all major international guidance, has been amended to reflect the successful outcome of PARADIGM-HF.13,15,18

Little is known regarding real-world experience with this drug, particularly regarding tolerability and potential adverse effects outside a clinical trial setting. Many patients could potentially benefit from sacubitril/valsartan, but its initiation and early monitoring requirements may add additional burden to specialist HF teams in the first few weeks. This report describes our initial experience regarding the clinical application of sacubitril/valsartan in a large UK district general hospital serving a population of around 650,000 people.

Methods

Patient selection

A local pathway was designed ensuring initiation and up-titration of sacubitril/valsartan solely in secondary care and patients were identified by consultant cardiologists with HF expertise. Patients considered had a reduced left ventricular ejection fraction (LVEF ≤35%) with ongoing symptoms (New York Heart Association [NYHA] class II–IV), despite optimal dose of ACE inhibitor/ARB. Sacubitril/valsartan was used with caution in patients with significant renal dysfunction or a history of postural hypotension, while those with either end-stage renal disease or prior angioedema on ACE inhibitor/ARB were excluded in accordance with the Summary of Product Characteristics (SmPC)19 recommendations. Despite the SmPC recommending sacubitril/valsartan not be considered in patients with systolic blood pressure (SBP) <100mmHg, the NICE TA388 guidance18 on this is less clear and a number of patients were commenced on the drug with a lower starting SBP. Sacubitril/valsartan was commenced following informed discussion with patients, with written information provided.

Design and procedure

Sacubitril/valsartan was initiated in place of ACE inhibitor/ARB therapy during either outpatient or inpatient care (once stabilised). Most were commenced on 49/51 mg twice daily (bd), but reduced starting doses were considered if there was concern about blood pressure (BP), renal function or comorbidity. Patients stopping ACE inhibitors were instructed to adhere to a 48-hour washout period prior to starting sacubitril/valsartan. Clear documentation was provided to GPs reinforcing that concomitant prescription of sacubitril/valsartan with ACE inhibitor/ARB must not occur.

Patients were enrolled into a dedicated follow-up clinic led by a cardiology specialist registrar, run within the hospital and supervised by a consultant HF cardiologist. Patients were reviewed every two to six weeks, when a history of their current symptoms and perceived progress were documented. Observations, including BP, pulse and weight were recorded, and all recent laboratory results reviewed (our centre provides biochemistry services for all local GP practices). Patient outcomes included discontinuation of treatment or discharge from the service – where responsibility of sacubitril/valsartan prescribing transitioned to primary care.

Adverse events were identified, particularly drug side effects, deterioration in renal function and development of hyperkalaemia. The dose was up-titrated where patients tolerated their current sacubitril/valsartan dosage and maintained acceptable BP. When optimum dose was established, patients were discharged and primary care took over responsibility for administration of sacubitril/valsartan. If there were issues with drug tolerability, the therapy was down-titrated to a lower dose, and further review scheduled.

The majority of data were collected during the up-titration and monitoring process, prior to discharge from the service. Information regarding HF hospitalisations and deaths was obtained by thorough analysis of hospital notes and discharge summaries. After nine months, having successfully completed the set-up phase, additional funding was secured and the clinics transitioned to being run by HF specialist nurses.

Results

Patients

A total of 150 patients (table 1) were commenced on sacubitril/valsartan between 19 May 2016 and 14 August 2017. The drug titration and monitoring period for all patients was completed by mid-October 2017. One patient was initially lost to follow-up, and although data collection was completed using primary care records retrospectively, the patient was eventually reviewed in clinic. By the end of the evaluation, all patients had fully completed the drug titration process.

2019-Supplement-1-Initial-Experience-3 Crawley Table 1. Characteristics of patients at initiation of sacubitril/valsartan (including relevant data from PARADIGM-HF,17,20 for comparison)
Table 1. Characteristics of patients at initiation of sacubitril/valsartan (including relevant data from PARADIGM-HF,17,20 for comparison)
2019 Supplement 1 Crawley - Table 2. Reasons for discontinuation of sacubitril/valsartan
Table 2. Reasons for discontinuation of sacubitril/valsartan

Outcomes

Twenty-one (14.0%) patients discontinued sacubitril/valsartan treatment due to either side effects or patient choice during the up-titration period (table 2). The mean age of the 21 patients who discontinued sacubitril/valsartan treatment was higher than that of the whole cohort (66.9 ± 12.7 vs. 63.6 ± 11.8); eight (38.1%) fell under the median age of the population (65 years).

The most common adverse event reported was postural dizziness. One patient developed acute arthropathy upon treatment initiation, while another reported exacerbation of Parkinson’s disease symptoms. All adverse events were reported via the UK Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card website.

2019 Supplement 1 Crawley - Table 3. Outcomes and adverse events observed during sacubitril/valsartan treatment
Table 3. Outcomes and adverse events observed during sacubitril/valsartan treatment

The outcomes of all patients following discharge/discontinuation were reviewed (table 3). Six (4.0%) patients died; three (2.0%) deaths were attributed to a CV cause. In total, eight (5.3%) patients were admitted to hospital due to decompensated HF after starting sacubitril/valsartan.

2019 Supplement 1 Crawley - Figure 1. Total number of patients on each dose of sacubitril/valsartan discharged from clinic (n=129)
Figure 1. Total number of patients on each dose of sacubitril/valsartan discharged from clinic (n=129)

Successful discharges

One hundred and twenty-nine patients (86.0%) were successfully discharged from clinic taking a stable dose of sacubitril/valsartan (figure 1). Of those, 86 (66.7%) were taking the target dose (97/103 mg bd). The mean number of follow-up appointments was 2.2 ± 1.1, with median follow-up duration of 48 days (interquartile range [IQR] 37). Of those discharged on sacubitril/valsartan, 41 patients (31.8%) went on to have routine transthoracic echocardiography at >3 months following discharge. Thirteen (31.7%) of the follow-up scans demonstrated a ≥10% improvement in LVEF (reported by physiologist).

Tolerability

Mean SBP was 116 ± 18 mmHg at commencement of treatment. Twenty (13.3%) patients had a SBP of <100 mmHg prior to starting sacubitril/valsartan, and of those, four patients stopped the treatment. Others were maintained at the lowest dose, but eight of those with starting SBP <100 mmHg were discharged at the highest dose of sacubitril/valsartan. In total, 21 (14.0%) reported postural decreases in BP, usually from home monitoring, with cessation of treatment in just less than half (9/21).

Chronic kidney disease (CKD) stage 3a or worse was present in 65 patients (43.3%) at initiation of sacubitril/valsartan. Of this specific population, 14 (21.5%) discontinued sacubitril/valsartan treatment, while 31 (47.7%) patients were discharged on the highest dose. Among patients with CKD stage 3b or worse (n=30; 20% of the total cohort), more discontinued treatment (26.7%) and fewer were discharged on the highest dose (43.3%). It is important to note that there is very limited clinical experience in patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2) and sacubitril/valsartan is not recommended in end-stage renal disease.19

Effects on serum potassium and renal function

A total of 578 blood tests were carried out and documented during the up-titration phase (initiation to discharge/discontinuation), with a mean of 3.85 ± 3.19 tests/patient. During that time, absolute serum potassium ranged from 3.2–6.9 mmol/L. Increases of ≥1.0 mmol/L were only observed in five patients (3.3%), of whom three stopped treatment, while one patient (0.7%) had an observed decrease of ≥1.0 mmol/L. The highest serum potassium level (6.9 mmol/L) was seen during an inpatient cardiac arrest – the patient remained on the lowest dose of sacubitril/valsartan (24/26 mg bd) with normokalaemia at discharge. All nine patients who had serum potassium measurements ≥5.5 mmol/L were taking a mineralocorticoid receptor antagonist (MRA) before initiating sacubitril/valsartan, of whom seven reported significant symptomatic hypotension on up-titration. Treatment with sacubitril/valsartan should not be initiated if the serum potassium level is > 5.4 mmol/L. If patients experience clinically significant hyperkalaemia, it is recommended that concomitant medicinal products are adjusted, or sacubitril/valsartan is temporarily down-titrated or discontinued. Consider the latter if the serum potassium is >5.4 mmol/L.19

Absolute serum creatinine ranged from 58–234 µmol/L, and estimated glomerular filtration rate (eGFR) values as low as 19 ml/min/1.73 m² were observed. Nine patients had a ≥30% increase in serum creatinine after commencing sacubitril/valsartan (two had a ≥50% increase). Only one patient who had a ≥30% increase in creatinine discontinued sacubitril/valsartan, while renal function in the other patients returned to baseline within one month of up-titration being completed. The SmPC19 recommends that down-titration should be considered in patients who develop a clinically significant decrease in renal function.

Discussion

This observational patient cohort evaluation is an early description of the initiation of sacubitril/valsartan in real-world patients following NICE TA388 guidance18 in the setting of England and Wales. By substituting this therapy into the regimen of an established HFrEF population, it provided a unique experience for training in HF management. Overall, sacubitril/valsartan was well tolerated, and about two-thirds of patients were titrated to the target dose (97/103 mg bd) over a relatively short period of time. Only 14% discontinued sacubitril/valsartan, mostly secondary to postural hypotension. Hyperkalaemia and marked deterioration in renal function were uncommon and did not necessarily result in cessation of treatment, despite the fact that 92% of patients were taking a MRA.

Patients in clinical trials are carefully selected, with fewer comorbidities than in routine care. It is reassuring that in ‘real-world’ practice, a majority achieved the target sacubitril/valsartan dose. Notably, tolerability in our population were favourable compared with the recent PARADIGM-HF study.17 Although the follow-up period is not equivalent, in the context of this carefully selected population, our model allowed the optimisation of sacubitril/valsartan therapy to ensure a favourable benefit/risk profile.

The successful incorporation of sacubitril/valsartan into local clinical care may depend on several factors. All of our patients were selected by consultant cardiologists experienced in managing HFrEF, with candidates of uncertain eligibility discussed at a HF multi-disciplinary team meeting. As a result, 149 (99.3%) patients conformed to the criteria of NICE TA388.18 The majority of patients were optimally treated, following our local protocol, with beta blockers and MRAs; and the proportion with an indwelling complex cardiac device (cardiac resynchronisation therapy and/or implantable cardioverter-defibrillator) prior to sacubitril/valsartan was higher than in previous studies.17,21 Overall, the drug appears to be well tolerated following optimisation of HFrEF treatment.

This population has comparable clinical characteristics to previous trials,17,21 although the mean age of UK patients with HFrEF is higher.4 In this evaluation, almost three quarters of those discontinuing the therapy (n=21/150, 14%) were older than the mean age for the whole cohort (n=15/21, 71.4%), resulting in a higher mean age in this sub-population (66.9 vs. 63.6 years). Sacubitril/valsartan may induce severe hyperkalaemia; hence, in our early experience, it is likely that some patients with multiple comorbidities or HFrEF associated with hypotension and renal dysfunction were not considered. Concern regarding orthostatic hypotension may also have led to some patients not being titrated to the target dose, and those that discontinued sacubitril/valsartan were more likely to have significant CKD of stage 3a or worse (n=14/21, 66.7%). (The SmPC19 has more information on blood pressure and renal function safety considerations.)

The most common adverse effect was symptomatic orthostatic hypotension (n=21/150, 14.0%), with complete cessation of treatment in just under half of these patients (n=9/21, 42.9%). The rates of observed renal dysfunction (n=2/150, 1.3%) and hyperkalaemia (≥5.5 mmol/L) were low (n=13/150, 8.7%) and no patients were specifically hospitalised for these adverse effects, despite a high rate of background MRA usage. Indeed, a further sub-analysis study of PARADIGM-HF observed lower rates of severe hyperkalaemia (>6.0 mmol/L) in those taking MRAs and sacubitril/valsartan together as compared with MRAs and enalapril.22 It is possible some abnormalities in renal function and potassium could have been missed due to the observational nature of this evaluation, despite rigorous assessment of all follow-up serum biochemistry results. However, the laboratory at our centre is the sole provider to all local GP practices, minimising the risk of missing relevant results.

These observational data represent initial experience at a large UK district general hospital. Initial caution regarding patient safety may have resulted in a degree of selection bias in prescribing sacubitril/valsartan, resulting in the selected cohort being younger, with fewer comorbidities than the wider HF population.4 Increasing familiarity with sacubitril/valsartan may lead, in future, to greater use for elderly patients and those with comorbidities.

Conclusion

We have established a successful pathway implementing the delivery of sacubitril/valsartan, to the local population of a large district general hospital in the UK. Up-titration to the target dose of sacubitril/valsartan was possible in two-thirds of patients, used alongside other optimal HF therapies. Tolerability of sacubitril/valsartan in our population was good, with biochemical stability and low levels of adverse events, even in patients considered to be at higher risk.

Key messages

  • Initial experience with sacubitril/valsartan for patients with HFrEF in a major UK hospital setting showed that successful optimisation of sacubitril/valsartan therapy is possible in a majority of patients
  • Up-titration to the target dose level of sacubitril/valsartan, alongside complementary guideline-directed therapies, was possible in two-thirds of patients
  • Tolerability of sacubitril/valsartan was good, with biochemical stability and low levels of adverse events, even in higher-risk patients

Conflicts of interest and funding

Novartis provided funding for running the clinics only after the transition to a nurse-led service in May 2017. However, Novartis had no involvement with the registrar-led clinics, and have had no input into data gathering, analysis or the authorship of this manuscript.

PRK has received funding from Novartis for talks, advisory boards and support for attendance at meetings. KG has received funding from Novartis for talks, presentations and support for attendance at meetings. RJC, GM and NK: none declared.

Acknowledgements

The authors thank some key team members: Dawn Lambert (Senior Heart Failure Nurse Specialist), Mark Green (Heart Failure Nurse Specialist), Karen Darroch (Community Heart Failure Nurse Specialist), and Lisa Male (Community Heart Failure Nurse Specialist).

Study approval and consent

This work was designed as a service improvement project, registered with the Trust’s Clinical Effectiveness Department: formal ethical approval was not required, but guidance laid out in the World Medical Association’s Declaration of Helsinki was followed throughout.

Dr Richard J Crawley
Cardiology Specialist Registrar
Email: richjcrawley@gmail.com

Dr Geraint Morton
Consultant Cardiologist

Dr Navneet Kalsi
Cardiology Research Fellow

Dr Paul R Kalra
Consultant Cardiologist

Dr Kaushik Guha
Consultant Cardiologist

Department of Cardiology, Queen Alexandra Hospital, Southwick Hill Road, Cosham, Portsmouth, PO6 3LY

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Articles in this supplement

Introduction
1. Applying PARADIGM-HF to the use of sacubitril/valsartan in clinical practice
2. Early clinical experience with sacubitril/valsartan from a large UK tertiary centre
4. Sacubitril/valsartan prescribing and community experience in Medway
5. Real-world experience and clinical data with sacubitril/valsartan: a Northern Ireland perspective

Advances in the treatment of chronic heart failure in real-world settingsOnce you have read all these articles, you can take the ‘Learning with reflection’ CPD activity on this supplement.

Dosing of sacubitril/valsartan: Throughout this supplement, the dosing of sacubitril/ valsartan (Entresto™, Novartis Pharmaceuticals) has been split to show the constituent doses. 

In clinical trials, sacubitril/ valsartan – initially known as the investigational agent LCZ696 – was used in 100 mg and 200 mg doses. These translate to the licensed doses of 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg of valsartan, respectively.

A smaller 50 mg dose, which equates to 24 mg sacubitril/26 mg valsartan, is also available.

Disclaimer: Medinews Cardiology Limited advises healthcare professionals to consult up-to-date Prescribing Information and the full Summary of Product Characteristics available from the manufacturers before prescribing any product. Medinews Cardiology Limited cannot accept responsibility for any errors in prescribing which may occur.
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