The PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated that the angiotensin receptor/neprilysin inhibitor (ARNI), sacubitril/valsartan (formerly known as LCZ696), was superior to enalapril in reducing the occurrence of adverse cardiovascular (CV) outcomes in patients with heart failure with reduced ejection fraction (≤40%; HFrEF).1,2 The trial was terminated early, on the advice of the independent safety monitoring board, on the basis of clear benefits. These included:1
- a 20% relative risk reduction (4.7% absolute risk reduction [ARR]) in the primary composite end point of CV death or hospitalisation for HF (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.73 to 0.87; p<0.001)
- a 20% reduction in CV death (3.2% ARR) (HR 0.80; 95%CI 0.71 to 0.89; p<0.001)
- a 21% reduction in HF hospitalisation (2.8% ARR) (HR 0.79; 95%CI 0.71 to 0.89; p<0.001)
- a 16% reduction in all-cause death (2.8% ARR) (HR 0.84; 95%CI 0.76 to 0.93; p<0.001).
On the basis of these results, the treatment has been approved by regulatory authorities across the world, and international and national guidelines have now incorporated it into their treatment algorithms for patients with HFrEF (i.e. an ejection fraction of ≤40%).3–5 The guidelines are broadly similar in their recommendations, but each have some subtle differences in how they have interpreted the trial and, consequently, how they have incorporated the drug into treatment algorithms. Clinicians are, therefore, left to integrate the information on efficacy and safety from the PARADIGM-HF trial, and reconcile this, with the guidelines and clinical practice. This review will examine the guidelines and relevant secondary analyses of PARADIGM-HF, which may help in guiding the appropriate use of sacubitril/valsartan in clinical practice.
Sacubitril/valsartan in guidelines for the management of HFrEF
Although the broad indication for sacubitril/valsartan is for adult patients with symptomatic chronic HFrEF, the guidelines have differentially interpreted what constitutes a reduced ejection fraction for this particular drug (table 1). Although the major guidelines define HFrEF as an ejection fraction of ≤40%, some guidelines (including the National Institute for Health and Care Excellence [NICE] in the UK5) have suggested that only patients with an ejection fraction ≤35% should be prescribed an ARNI (table 1). This is because the PARADIGM-HF trial underwent a protocol amendment to reduce the ejection fraction inclusion criteria from ≤40% to ≤35% after approximately one year of the study commencing. This amendment was made because EMPHASIS-HF (The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)6 was published during the early phase of PARADIGM-HF and it reported an improvement in mortality with the mineralocorticoid receptor antagonist (MRA), eplerenone. The investigators anticipated that the use of these drugs would increase in participants in PARADIGM-HF and event rates would fall, therefore, the ejection fraction criterion was reduced to enrich the event rate of the trial to ensure it would remain adequately powered.7
A substantial proportion of patients with ejection fraction ≥35% and ≤40% were nevertheless included in PARADIGM-HF (n=2,056; 24%).7 An analysis showed that the clinical benefit of sacubitril/valsartan did not vary according to patients’ ejection fraction at baseline (figure 1)7. Similarly, the guideline from the European Society of Cardiology (ESC) suggested that sacubitril/valsartan should be prescribed to patients with elevated natriuretic peptides (table 1). Although natriuretic peptides were used to define a high-risk population for enrolment into PARADIGM-HF, there was no difference in the effect of sacubitril/valsartan on the primary end point by N-terminal pro B-type natriuretic peptide (NT-proBNP) levels at baseline (figure 1).8
Deciding when to prescribe sacubitril/valsartan provides a second dilemma for clinicians. The NICE guidance suggests the drug should be used in place of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) in those with ongoing symptomatic heart failure (after a washout period of ≥36 hours for those receiving an ACE inhibitor).5 The guidelines from the ESC and the Scottish Intercollegiate Guidelines Network (SIGN) suggested that sacubitril/valsartan should be used when the patient is symptomatic despite an ACE inhibitor or ARB, beta blocker and MRA.3,9 The US guideline suggests that it can be considered after an ACE inhibitor or ARB and beta blocker, either before or after the addition of an MRA.4 But which is correct? Should an MRA be started first, before switching to an ARNI? In PARADIGM-HF, patients gained benefit from sacubitril/valsartan irrespective of the concurrent use or not of MRA therapy (figure 1).10 The lower rates of severe hyperkalaemia with sacubitril/valsartan may mean that switching to an ARNI before starting a MRA may facilitate initiation of the MRA (see below).11
Whether to use the drug in patients who have not received an ACE inhibitor or ARB raises a more difficult issue. The guidelines would suggest they should not be considered eligible for an ARNI, but both the European Medicines Agency12 and the US Food and Drug Administration (FDA)13 do not restrict the license for sacubitril/valsartan for use in patients previously on an ACE inhibitor or an ARB. This question cannot be answered with a trial (it would be unethical to continue the ACE inhibitor-naïve group on an ACE inhibitor after four weeks, as the patients would then be a candidate for an ARNI), but we can gain some insight from other trials and analyses of PARADIGM-HF:
- A shorter duration of HF did not reduce the benefit from sacubitril/valsartan (figure 1).1
- In the Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients (TITRATION) study of dose escalation strategies of sacubitril/valsartan, approximately 7% of patients were ACE inhibitor- or ARB-naïve and rates of adverse events were similar to those reported in PARADIGM-HF.14
- The beneficial effect of sacubitril/valsartan in PARADIGM-HF to delay the time to first hospitalisation for heart failure, compared to enalapril, was evident at 30 days post-randomisation.15 Therefore, waiting four weeks to up-titrate an ACE inhibitor or ARB would deny the patient more effective therapy during this time period, and could be seen as unnecessarily exposing them to a period of greater risk.
There is little evidence regarding the initiation of sacubitril/valsartan in patients who have been hospitalised with decompensated heart failure. Results from the TRANSITION (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) study, are expected to help add to the evidence base.16 This multi-centre, randomised, open-label, parallel-group study, compared pre-discharge and post-discharge treatment initiation with sacubitril/valsartan following haemodynamic stabilisation in HFrEF patients hospitalised for an acute decompensation event.
Once a decision has been made about whether the evidence and guidelines support the use of a drug, the clinical team must decide if the drug is appropriate, based on their assessment of the patient and the balance of potential risks and benefits. This is often the hardest part of the decision-making process, but we describe below a number of secondary analyses that can assist the clinical team with their decision making.
Key subgroup analyses from PARADIGM-HF
The elderly patient with HF
Comorbidities are often the first aspects of a patient’s history that any clinical team has to consider when selecting appropriate therapies. Prescribers are often wary of elderly patients, who in general may not derive the same benefit in terms of life-expectancy gains, or may experience more adverse side effects, compared with younger patients.
In PARADIGM-HF, 18.6% (n=1,563) of patients were aged 75 years or over and 7% (n=587) were aged 80 years or over.17 Patients of all ages benefited similarly from sacubitril/valsartan compared with enalapril for all of the morbidity or mortality outcomes studied (figure 1 shows effects on the primary end point). Improving quality of life may be a more important aim than improving the ‘quantity of life’ for elderly patients. Fewer patients receiving sacubitril/valsartan experienced a decline in quality of life compared with those randomised to enalapril,18 and the effect of sacubitril/valsartan on quality of life was similar across all ages.17 Finally, and perhaps most importantly, the rate of adverse events (hypotension, renal impairment, hyperkalaemia, cough and angioedema) was no different in the older versus younger patients.17 Hypotension, however, was more common with sacubitril/valsartan compared to enalapril.
Diabetes mellitus is a common comorbidity in HF and is associated with poorer outcomes, and diabetes may itself cause renal dysfunction. The efficacy of sacubitril/valsartan was no different in those with and without diabetes (figure 1).1 In a further analysis, those patients with diabetes at baseline, over time HbA1c fell more in the group randomised to sacubitril/valsartan (average reduction of 0.26%; standard deviation [SD] 1.25) than in the enalapril group (0.16%; SD 1.40).19 In addition, fewer patients in the sacubitril/valsartan group required initiation of insulin versus the enalapril group (HR 0.71; 95%CI 0.56 to 0.90; p=0.0052).19 Whether this is a consequence of greater glucagon-like peptide 1 (GLP-1) levels (neprilysin also breaks down GLP-1) or simply reflects a greater improvement in the severity of HF is unknown.
As noted above, renal function is of particular concern in those with diabetes, but is also an issue in those without diabetes. In general, patients with HF have poorer renal function, and this is exacerbated by age and comorbidities such as diabetes.
Renal function and potassium
The effect of sacubitril/valsartan on cardiovascular outcomes did not vary according to estimated glomerular filtration rate (eGFR) at baseline (figure 1); patients with pre-existing chronic kidney disease (CKD) (eGFR <60 ml/min/1.73 m2) derived the same relative risk reduction as patients with normal renal function, with a greater reduction in absolute risk.20 Moreover, renal function was better preserved in those who received sacubitril/valsartan versus enalapril. The decline in eGFR between screening and the end of follow-up was 7.8 ml/min/1.73 m2 (95%CI 9.6 to 6.0) in those receiving sacubitril/valsartan and 10.2 ml/min/1.73 m2 (95%CI 12.1 to 8.3) in those randomised to enalapril.20 There was a similar preservation of renal function over time, even in patients with CKD.20
Often co-existing with renal dysfunction, hyperkalaemia is a common issue in patients with HF who are prescribed drugs acting on the renin–angiotensin–aldosterone system. This is often a limiting factor in initiating such drugs and their up-titration. Treatment discontinuation for hyperkalaemia was less common with sacubitril/valsartan than enalapril in patients in PARADIGM-HF, although this result was not significant (p=0.56).11 Not only were absolute levels of serum potassium lower in those randomised to sacubitril/valsartan, but rates of severe hyperkalaemia (potassium >6.0 mEq/L) were also lower in the patients receiving sacubitril/valsartan and a MRA at baseline than in those receiving enalapril and a MRA.11 Rates of severe hyperkalaemia were lower in the patients randomised to sacubitril/valsartan versus enalapril, even after accounting for: patients taking a MRA at baseline; or in those in whom a MRA was initiated during PARADIGM-HF (HR 1.43; 95%CI 1.13 to 1.81; p=0.003).11
What are the implications for the patient and the HF team? Lower serum potassium and less hyperkalaemia may mean that patients will be more likely to tolerate MRA therapy with regards to hyperkalaemia, and that those who have not tolerated a MRA due to hyperkalaemia in the past may be able to do so once sacubitril/valsartan is introduced. Renal function and potassium often go hand in hand when treating patients, and are linked to blood pressure, which we discuss next.
The benefit of sacubitril/valsartan was consistent regardless of starting blood pressure (figure 1), although blood pressure is reduced more with sacubitril/valsartan than with enalapril.21 The incidence of permanent discontinuation of therapy due to hypotension during the study for sacubitril/valsartan was 0.9% compared to 0.7%, for enalapril (p=0.38).1 There was also more symptomatic hypotension in the sacubitril/valsartan group (14%) versus the enalapril group (9%, p<0.001).1 Although this side effect can be managed (in much the same way as when it occurs with ACE inhibitors or ARBs3), the clinical team faced with a patient whose blood pressure has fallen (without symptoms of hypotension) must make the decision on whether to continue the drug. Falling blood pressure is a marker of poor prognosis in patients with HFrEF and the Summary of Product Characteristics states that sacubitril/valsartan should not be initiated in patients unless systolic blood pressure is ≥100 mmHg.12
Two further analyses from PARADIGM-HF explored this potentially important side effect and reported findings that may assist decision-making. Patients were examined according to whether they had higher or lower systolic blood pressure (cut-off 100 mmHg) at baseline and at four months after randomisation to enalapril or sacubitril/valsartan. Compared to enalapril, the benefit of sacubitril/valsartan was consistent across all baseline systolic blood pressure categories for all clinical outcomes (although patients with a lower sytolic blood pressure at randomisation were still at higher risk than those with a higher systolic blood pressure).21 A second analysis examined survival following the report of an adverse event for hypotension in PARADIGM-HF.22 The incidence of death was lower in those patients with an episode of hypotension who were receiving sacubitril/valsartan compared with those who received enalapril (p=0.011).
Does sacubitril/valsartan represent value for money?
While the above data can reassure the HF team that the drug has a favourable risk/benefit profile, in a cost-constrained healthcare system, such as the UK National Health Service (NHS), we have a duty to ensure that the treatments we use are also good value for money. A cost-effectiveness analysis of sacubitril/valsartan, based on the risk of CV mortality in the UK, reported that the cost per quality-adjusted life-year (QaLY) gained with sacubitril/valsartan versus enalapril was £17,100, which is below the usual threshold of £20,000 per QaLY for defining a cost-effective treatment.23 Similar findings have been reported from the perspective of multiple other healthcare systems and countries.
Sacubitril/valsartan reduces morbidity and mortality in patients with symptomatic chronic HFrEF and improves quality of life at acceptable levels of cost. The findings of the PARADIGM-HF trial apply to a wide range of patients with HFrEF24. While there are some side effects with the drug, these tend to be less prevalent than with enalapril, with the exception of hypotension, and can be managed in the same way. Guidelines differ slightly in their interpretation of the clinical evidence base for sacubitril/valsartan, but they are uniform in recommending the use of this effective therapy within the management of patients with HFrEF.
- Sacubitril/valsartan reduces morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF)
- It improves quality of life at acceptable levels of cost
- Guidelines may differ in interpretation of the evidence but they are uniform in recommending this evidence-based therapy for patients with HFrEF
Conflicts of interest and funding
PSJ and JJVM are employees of the University of Glasgow, and the University of Glasgow has been funded by Novartis for their participation in a number of trials (including PARADIGM-HF), lectures, advisory boards, and other meetings related to sacubitril/valsartan.
Pardeep S Jhund
Clinical Senior Lecturer
John J V McMurray
Professor of Medical Cardiology
British Heart Foundation Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, G12 8TA
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2. McMurray JJV, Packer M, Desai AS et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact. Eur J Heart Fail 2013;15:1062–73. https://doi.org/10.1093/eurjhf/hft052
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17. Jhund PS, Fu M, Bayram E et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576–84. https://doi.org/10.1093/eurheartj/ehv330
18. Chandra A, Lewis EF, Claggett BL et al. Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2018;3:498–505. https://doi.org/10.1001/jamacardio.2018.0398
19. Seferovic JP, Claggett B, Seidelmann SB et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5:333–40. https://doi.org/10.1016/S2213-8587(17)30087-6
20. Damman K, Gori M, Claggett B et al. Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail 2018;6:489–98. https://doi.org/10.1016/j.jchf.2018.02.004
21. Böhm M, Young R, Jhund PS et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 2017;38:1132–43. https://doi.org/10.1093/eurheartj/ehw570
22. Vardeny O, Claggett B, Kachadourian J et al. Incidence, predictors, and outcomes associated with hypotensive episodes among heart failure patients receiving sacubitril/valsartan or enalapril: the PARADIGM-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circ Heart Fail 2018;11:e004745. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004745
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Articles in this supplement
2. Early clinical experience with sacubitril/valsartan from a large UK tertiary centre
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
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.