Early clinical experience with sacubitril/valsartan from a large UK tertiary centre

Br J Cardiol 2019;26(suppl 1):S9-S14doi:10.5837/bjc.2019.s03 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 has been approved for use by the National Institute for Health and Care Excellence (NICE) as an alternative to angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) in adult patients with symptomatic chronic heart failure with reduced ejection fraction (HFrEF). We report our clinical experience of the use of sacubitril/valsartan in 140 patients with HFrEF in a retrospective analysis from a major UK centre. Up-titration to the target dose was achieved in 55% (n=77), and New York Heart Association class improved in 31% (n=43). A symptomatic fall in systolic blood pressure of >10 mmHg prevented up-titration in 31% (n=44). Heart failure (HF)-related admissions occurred in 6% of patients at both six months (n=8/140) and one year (n=4/68), with a mortality of 4% (n=5/140) and 7% (n=5/68), respectively. Renal function worsened in 10.7% (n=15/140). Sacubitril/valsartan was withdrawn for adverse events in 8% (n=11/140). Sacubitril/valsartan was well tolerated and improved HF outcomes and symptoms, but 45% (n=63/140) were unable to achieve the target dose.

clinical experience with sacubitril/valsartan from a large UK tertiary centre

Introduction

Much progress has been made over the last 30 years in the discovery of evidence-based pharmacological treatments that improve morbidity and mortality in people with heart failure with reduced left ventricular ejection fraction (HFrEF). Landmark trials first established angiotensin-converting enzyme (ACE) inhibitors as the mainstay therapy for heart failure (HF),1-3 with angiotensin II receptor blockers (ARB) subsequently demonstrating similar benefits for patients intolerant to ACE inhibitors.4 Further trials reported improved outcomes with mineralocorticoid receptor antagonists (MRA) used together with ACE inhibitors in HFrEF.5,6

Recently, the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated reduced overall mortality by 16% (absolute risk reduction [ARR] 2.85) and cardiovascular (CV) mortality by 20% (ARR 3.2%) with sacubitril/valsartan (SV) compared with enalapril alone.7 These benefits were likely due, in part, to inhibition by sacubitril of neutral endopeptidases (neprilysin), leading to increased levels of endogenous vasoactive peptides, including bradykinin, adrenomedullin and natriuretic peptides, which facilitate sodium excretion and vasodilation, and prevent adverse remodelling.8

The UK National Institute for Health and Care Excellence (NICE) approved the use of sacubitril/valsartan in adult patients with symptomatic chronic HFrEF as an alternative to ACE inhibitor/ARB therapy in 2016.9 We report the results of a retrospective evaluation of the clinical use of sacubitril/valsartan in our large CV care centre, in terms of morbidity and mortality, tolerability and up-titration to its guideline-mandated target dose (97/103 mg twice daily [bd]).

Methods

Study population

The HF service of University Hospitals Coventry & Warwickshire (UHCW) covers a total population of 496,000 with two HF consultants and eight HF nurse specialists. Patients eligible for analysis were seen in our HF clinics from April 2016 to July 2017, and were aged ≥18 years, with documented left ventricular ejection fraction (LVEF) ≤35%, New York Heart Association (NYHA) class II–IV, estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2, and had received at least four weeks of treatment with ACE inhibitor/ARB prior to initiation of sacubitril/valsartan.9 The ACE inhibitor or ARB was stopped at least 48 hours prior to starting sacubitril/valsartan due to a higher risk of angioedema if these drugs are combined. All patients prescribed sacubitril/valsartan were either identified by the HF team, or referred by other cardiologists. The eligibility of each patient for this treatment was discussed in the HF multi-disciplinary team (MDT) meetings before initiation of therapy in a nurse-led HF clinic, as described below.

Initiating sacubitril/valsartan in the nurse-led heart failure clinic

A HF nurse specialist reconfirmed each patient’s suitability for sacubitril/valsartan according to the NICE technology appraisal guidance prior to commencing treatment. Baseline characteristics were assessed, including weight, blood pressure (BP), NYHA class, fluid balance status, renal function, hospital admissions, and full medication history. Supine BP was checked after five minutes in the supine position and again after standing for one minute, and symptoms of dizziness, light-headedness or visual disturbance were documented. Once confirmed to be suitable for sacubitril/valsartan, patients were started on the 49/51 mg bd dose if systolic blood pressure (SBP) was ≥110 mmHg, or 24/26 mg bd if SBP was 100–110 mmHg.

Patients were seen in the nurse-led HF clinic at four-weekly intervals for up-titration, where possible, and for assessment of tolerability and changes in biomarkers, until a stable dose of sacubitril/valsartan was achieved. Where SBP fell by >10 mmHg on standing, an attempt was made to withdraw or to reduce the dose of non-essential BP-lowering (typically antihypertensive or anti-anginal but sometimes loop diuretics) medications. The dose of beta blockers was not changed merely to improve BP for sacubitril/valsartan use. Other evidence-based medications were continued where possible unless, for example, complications of treatment, such as hyperkalaemia, necessitated dose reduction or withdrawal of MRA treatment. An outline of our model of the sacubitril/valsartan clinic is shown in figure 1.

2019 Supplement 1 Banerjee - Figure 1. The Coventry Model of nurse-led sacubitril/valsartan clinic
Figure 1. The Coventry Model of nurse-led sacubitril/valsartan clinic

A repeat evaluation of left ventricular (LV) systolic function was carried out at the end of the up-titration phase in a small proportion of the patients, e.g. where previously requested cardiac magnetic resonance imaging coincided with completion of sacubitril/valsartan therapy. In some cases, a follow-up transthoracic echocardiogram was requested to explore the reasons for a dramatic symptomatic improvement on sacubitril/valsartan.

Banerjee - Table 1. Baseline characteristics of 140 patients commenced on sacubitril/valsartan
Table 1. Baseline characteristics of 140 patients commenced on sacubitril/valsartan

Data collection and statistical analysis

Data were collected retrospectively using the electronic records of the Trust’s HF clinic. This consisted of baseline clinical characteristics, clinical data from each clinic visit, and clinical outcomes at six months and one year post-initiation of sacubitril/valsartan. HF admission was defined as development of signs and symptoms of HF requiring hospital admission for intravenous loop diuretics. Descriptive statistics (see results section) were generated using Microsoft® Excel; data shown are means ± standard deviation (SD) except where indicated.

Ethics

The study was approved by our Research and Development department and as the study involved previously collected, non-identifiable information within our hospital care, using previously collected data during the course of care, patient’s consent was not required.

Results

Patients

A total of 140 patients received sacubitril/valsartan and were included in the analysis (table 1). The mean age of the cohort was 67 ± 12 years and most were male (77%). About half had NYHA II HF (53%) and 38% had a prior history of ischaemic heart disease. About three-quarters were taking ACE inhibitors and a loop diuretic prior to sacubitril/valsartan, about 95% were taking a beta blocker, and about two-thirds were receiving MRA therapy. A minority (16%) had received cardiac resynchronisation therapy.

2019 Supplement 1 Banerjee - Table 2. Up-titration of sacubitril/valsartan in 140 patients initiated on this treatment
Table 2. Up-titration of sacubitril/valsartan in 140 patients initiated on this treatment

Effects of sacubitril/valsartan

Tolerability

A total of 77 patients (55%) achieved up-titration to the target dose with 30 (27%) patients reducing their loop diuretic dosage; 11 patients (8%) did not tolerate sacubitril/valsartan, mainly due to symptoms of postural hypotension (table 2). A significant proportion (31%) had postural hypotension with a SBP drop >10 mmHg at clinic follow-up, preventing up-titration to the target dose (table 2).

Renal function

Fifteen patients (10.7%) had deterioration of eGFR >10 ml/min/1.73 m². There was no progressive impairment of renal function and, subsequently, five of these patients achieved up-titration to the target dose.

Hyperkalaemia and angioedema

Only four patients (3%) developed hyperkalaemia (serum potassium >6.0 mmol/L), prompting dose reduction or discontinuation of spironolactone in three of them. Two of these patients were admitted to hospital, but there were no serious sequelae of hyperkalaemia or instances of angioedema.

Blood pressure

Mean SBP fell noticeably between the second and third study visits and remained stable thereafter (figure 2).

2019 Supplement 1 - Banerjee Figure 2. Trend of average blood pressure (BP) during the clinic visits
Figure 2. Trend of average blood pressure (BP) during the clinic visits
2019 Supplement 1 Banerjee - Table 3. Six-month and one-year mortality and heart failure (HF) hospitalisations
Table 3. Six-month and one-year mortality and heart failure (HF) hospitalisations

Clinical outcomes: mortality and HF hospitalisation

A total of 140 patients achieved six-months follow-up and 68 patients had one-year follow-up (table 3). At six months, eight [Author: changed to 8 for consistency with table 3] patients (6%) were admitted for HF, and five (4%) patients had died (two patients died due to end-stage HF). At one year, four (6%) HF admissions had occurred and five patients (7%) had died. The one-year mortality and admissions were calculated on the smaller cohort of 68 patients, which meant that some patients with events within six months may not have been counted in the one-year data if they had not reached the one-year follow-up stage.

HF symptoms and LVEF

Forty-three patients (31%) reported an improvement of at least one NYHA class. Only 34 patients underwent repeat LVEF evaluation post-sacubitril/valsartan therapy, with improvement seen in 23 (66%); mean LVEF in these patients increased from 19% to 27%. Seven patients (5%, all with non-ischaemic cardiomyopathy) showed a remarkable improvement of LVEF, from severe LV systolic impairment (LVEF ≤35%) to a normal LVEF of ≥55%; two of these patients had undergone successful cardioversion for atrial fibrillation. Table 4 summarises the characteristics of these patients before (and for some parameters, after) treatment.

2019 Supplement 1 Ali Table 4 Baseline characteristics of seven individual patients in whom left left ventricular ejection fraction improved to greater than 55% on sacubitiril/valsartan therapy
Table 4. Baseline characteristics of seven individual patients in whom left ventricular ejection fraction improved to >55% on sacubitril/valsartan therapy

Discussion

Our data on the initiation of sacubitril/valsartan, in a nurse-led clinic in a real-world setting, demonstrated high tolerability, significant symptomatic improvement and low all-cause mortality and HF-hospitalisation rates associated with this treatment. The substantial proportion of patients who reported symptomatic improvement is in line with the results of the PARADIGM-HF study. The study showed that, compared to baseline, the Kansas City Cardiomyopathy Questionnaire (KCCQ) score – a marker of symptoms and physical limitations associated with heart failure – deteriorated less at eight months with sacubitril/valsartan than with enalapril.7

HF mortality in our cohort was lower than documented in the CONSENSUS (Effects of Enalapril on Mortality in Severe Congestive Heart Failure) trial (where six-month and one-year mortality on enalapril was 26% and 36%, respectively),1 and in the PARADIGM-HF study, where 27-month all-cause mortality was 17.0% on sacubitril/valsartan and 19.8% on enalapril.7 The lower mortality in our cohort may be related to a higher use of MRAs and a slightly higher use of beta blockers compared with PARADIGM-HF,10 together with our smaller sample size and an earlier assessment of mortality post-initiation. Two patients presented as emergencies with syncopal episodes associated with postural hypotension. Both were aged >80 years, were initially started on 49/51 mg bd sacubitril/valsartan but later switched to, and tolerated, the lower dose of 24/26 mg bd. We suggest that low-dose sacubitril/valsartan is probably more suitable as a starting dose for elderly patients with severe LV dysfunction, multiple comorbidities and polypharmacy, with thorough evaluation of non-essential BP-lowering medication and diuretics. A reduction of eGFR in 10% of patients did not prevent up-titration, as loop diuretics could be reduced or discontinued to accommodate this.

Three of the four patients who developed hyperkalaemia were on a combination of sacubitril/valsartan and MRA; the MRA was down-titrated or withdrawn. A secondary analysis of the PARADIGM-HF trial showed that MRA-treated HFrEF patients on sacubitril/valsartan had lower rates of severe hyperkalaemia (potassium >6 mmol/L) than those on enalapril (3.1 vs. 2.2 per 100 patient-years; hazard ratio [HR] 1.37; p=0.02).11 Two patients in our study were also admitted with hyperkalaemia, needing dose reduction and then discontinuation of spironolactone. Our real-life experience with sacubitril/valsartan on renal function and electrolytes does not raise any undue concerns. It is important, however, to be vigilant with safety monitoring – as with all renin-angiotensin-aldosterone-system blockers and MRAs – in patients initiated on sacubitril/valsartan.

Sacubitril/valsartan was well tolerated, despite about half of patients being unable to reach the target dose of 97/103 mg bd; all patients had already tolerated an ACE inhibitor or ARB prior to commencement of sacubitril/valsartan. No attempt was made to reach higher doses of these drugs before switching to sacubitril/valsartan, as we felt that the superior benefits of sacubitril/valsartan should be offered to the patient as early as possible rather than spending time in up-titrating the ACE inhibitor or ARB. Furthermore, the use of low-dose sacubitril/valsartan (24/26 mg bd) in patients with SBP <110 mmHg was associated with a low frequency of hypotension, which likely supported improved compliance with therapy.

Following the PARADIGM-HF study, another randomised, double-blind study (TITRATION) evaluated up-titration of low-dose sacubitril/valsartan using two different regimens: conservative (‘gradual up-titration’ over six weeks) versus ‘condensed’ titration (over three weeks).12 On the conservative regimen, the target dose was achieved in >80% of patients with SBP ≥100 mmHg. This is higher than the 55% in our cohort, despite our use of 12 weeks of follow-up. This may be explained by a more cautious approach from our nurses regarding measured or reported symptomatic hypotension, despite the changes to non-essential BP-lowering medications described above. Our baseline average SBP was lower compared with patients in the TITRATION study (124 vs. 130 mmHg). Also, our cohort may have contained patients with more comorbidities and/or more severe LV dysfunction, as indicated by the higher proportion with NYHA III HF symptoms (46% vs. approximately 29% in the conservative arm of TITRATION).

Our experience suggests that in clinical practice, conservative (six weeks) up-titration to target dose in patients with severe LV dysfunction and SBP ≥100 to 110 mmHg may often not be achievable. Nevertheless, our experience indicates that BP can be managed successfully in the majority of patients taking sacubitril/valsartan through judicious adjustments of the dose of sacubitril/valsartan and other BP-lowering medications (reduction or discontinuation of other commonly used drugs, such as amlodipine, isosorbide mononitrate, loop diuretics, when not needed). A post-hoc analysis of the PARADIGM-HF study found that benefit was still observed at lower doses of sacubitril/valsartan, and a lower than target dose of sacubitril/valsartan was still superior to lower doses of enalapril. However, it should be noted that any dose reduction did result in increased likelihood of the primary outcome of death from cardiovascular causes or hospitalisation for heart failure.13 Our practice is to continue patients on the 24/26 mg bd dose if we are unable to up-titrate to higher doses.

The subgroup of seven patients with >20% increase in LVEF on sacubitril/valsartan was of particular interest. All had non-ischaemic cardiomyopathy. Improvement in LVEF of ~10% has been observed previously, particularly with beta blocker therapy and particularly in patients with non-ischaemic cardiomyopathies.14,15 While we cannot account for the mechanism of this dramatic improvement in LVEF, enhanced vasodilation by sacubitril/valsartan may have contributed, either via reduced BP, or reduced cardiac remodelling.

Limitations to our evaluation include its single-centre, retrospective design and limited size. Mortality and HF hospitalisations may theoretically have been recorded at other centres without our knowledge; this is unlikely – these patients are well known to, and mostly still in telephone contact with, our HF service, which facilitated follow-up. In addition, we did not measure quality of life, and the recorded measure of symptomatic improvement by NYHA class was subjective. Finally, we did not follow changes in natriuretic peptides to confirm clinical improvements.

Conclusion

Our real-world early clinical experience with sacubitril/valsartan showed low six-month and one-year mortality and low admission rates for HF, with a significant proportion of patients demonstrating improved LVEF and/or symptomatic benefit. The tolerability of sacubitril/valsartan was generally good, although a significant number of patients could not be up-titrated to the target dose, mainly due to postural dizziness and hypotension. Deterioration of renal function in a small proportion of patients did not prevent up-titration to target dose.

Key messages

  • A real-world, retrospective evaluation of the effects of sacubitril/valsartan in 140 patients with heart failure with reduced left ventricular ejection fraction (HFrEF) initiated in a nurse-led, multi-disciplinary team (MDT)-backed heart failure (HF) clinic is presented
  • 55% achieved up-titration to the target (maximum) dosage (97/103 mg twice daily)
  • Postural hypotension was the main factor limiting up-titration in the remaining patients, and the treatment was otherwise well tolerated
  • A significant proportion of patients demonstrated improved HF symptoms and/or improved ejection fraction
  • The six-month and one-year mortality and readmissions rates were low
  • Successful initiation of sacubitril/valsartan is feasible in a nurse-led, MDT supported HF clinic

Conflicts of interest

No funding has been received by any of the authors in preparation for this manuscript. DA, JH, SK, FR, have received honoraria from Novartis. PB has received a speaker’s fee and honoraria for educational work by Novartis and has been on their advisory board, outside the submitted work.

Funding

None.

Study approval

The study was approved by our Research and Development department.

Consent

As the study involved previously collected, non-identifiable information within our hospital care, using previously collected data during the course of care, patient’s consent was not required.

Danish Ali
Research Fellow (and Warwick Medical School)

Jacqui Hyland
Heart Failure Specialist Nurse

Fiona Riley
Heart Failure Specialist Nurse

Stephanie Kirkland
Heart Failure Specialist Nurse

Lisa Hinnit
Heart Failure Specialist Nurse

Catherine Watson
Heart Failure Specialist Nurse

Hayley Nicholson
Heart Failure Specialist Nurse

Johanna McCann
Heart Failure Specialist Nurse

Victoria Allport
Heart Failure Specialist Nurse

Fraz Umar
Locum Consultant Cardiologist

Prithwish Banerjee
Consultant Cardiologist and Honorary Professor of Cardiology (Warwick Medical School and Coventry University) Email: Prithwish.Banerjee@uhcw.nhs.uk

Department of Cardiology, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX

Sarah Albarad
Medical Student

Warwick Medical School, Coventry, CV4 7AJ

Rajen Parekh
A Level Student

Gold Crest Award Research, Bablake School, Coventry, CV1 4AU

References

1. Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429–35. https://doi.org/10.1056/NEJM198706043162301

2. Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine–isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–10. https://doi.org/10.1056/NEJM199108013250502

3. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685–91. https://doi.org/10.1056/NEJM199209033271003

4. Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75. https://doi.org/10.1056/NEJMoa010713

5. Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. https://doi.org/10.1056/NEJM199909023411001

6. EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. https://doi.org/10.1056/NEJMoa1009492

7. McMurray JJV, Packer M, Desai AS et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. https://doi.org/10.1056/NEJMoa1409077

8. Menendez JT. The mechanism of action of LCZ696. Card Fail Rev 2016;2:40–6. https://doi.org/10.15420/cfr.2016:1:1

9. National Institute for Health and Care Excellence. Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. TA388. London: NICE, 2016. Available from: http://www.nice.org.uk/guidance/ta388

10. McMurray JJV, Packer M, Desai AS et al. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial. Eur J Heart Fail 2014;16;817-25. https://doi.org/10.1002/ejhf.115

11. Desai AS, Vardeny O, Claggett B et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril. A secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol 2017;2:79–85. https://doi.org/10.1001/jamacardio.2016.4733

12. Senni M, McMurray JJV, Wachter R et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 2016;18:1193–202. https://doi.org/10.1002/ejhf.548

13. PARADIGM investigators. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail 2016;18:1228–34. https://doi.org/10.1002/ejhf.580

14. de Groote P, Delour P, Mouquet F et al. The effects of beta-blockers in patients with stable chronic heart failure. Predictors of left ventricular ejection fraction improvement and impact on prognosis. Am Heart J 2007;154:589–95. https://doi.org/10.1016/j.ahj.2007.05.013

15. Metra M, Nodari S, Parrinello G et al. Marked improvement in left ventricular ejection fraction during long-term beta-blockade in patients with chronic heart failure: clinical correlates and prognostic significance. Am Heart J 2003;145:292–9. https://doi.org/10.1067/mhj.2003.105

Articles in this supplement

Introduction
1. Applying PARADIGM-HF to the use of sacubitril/valsartan in clinical practice
3. Initial experience of introducing sacubitril/valsartan in a UK heart failure service
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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