Correspondence: Sacubitril/valsartan: where should it sit in the heart failure pathway?

Br J Cardiol 2016;23:92 Leave a comment
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Dear Sirs,

Sacubitril/valsartan (Entresto™, Novartis), the first angiotensin receptor blocker (ARB) and neprilysin inhibitor (NEP) combination – known as an angiotensin-receptor-neprilysin inhibitor (ARNI) – has recently been approved by the National Institute for Health and Care Excellence (NICE) in the treatment of patients with chronic heart failure.1 The guidance, largely based on results from the landmark PARADIGM- HF study,2 recommends sacubitril/valsartan as an “option” for symptomatic patients (New York Heart Association [NYHA] class II– IV) who have an ejection fraction of 35% or less and are established on a “stable dose” of an angiotensin-converting enzyme (ACE) inhibitor or ARB (it is unclear in the guidance whether or not optimisation is implied). Although NICE do recommend that treatment should be initiated by a heart failure specialist, there are no other caveats to widespread prescription. The implication from the guidance is that the majority of patients with heart failure associated with reduced ejection fraction (HFREF) are potential candidates for treatment and sacubitril/valsartan has been widely acclaimed and indeed marketed as “a breakthrough in heart failure”.

The question now is whether the size of the breakthrough is sufficient to justify a wholescale change in clinical practice or whether a more cautious approach should be adopted initially. Widespread adoption of the new therapy would potentially lead to the abandonment of the current ACE inhibitor-based treatment pathway in which ARBs are generally considered second line to ACE inhibitors. Instead, it would be replaced by one with an ARB (valsartan) at its core.

The key to answering this question lies with the PARADIGM-HF data and specifically its extrapolation to the wider UK heart failure population. The headline results are undoubtedly impressive and widely publicised. As in any trial, however, there are caveats, most of which have been taken into consideration during the NICE appraisal process.1 For example, the mean age at study entry was just 64 years, over a decade younger than the UK National Heart Failure Audit (NHFA) population.3 Only 21% were female (versus 44% in NHFA). More importantly, the study population appears to have been relatively well and likely to have been in the early stages of heart failure (72% NYHA class II, median brain natriuretic peptide [BNP] 255 pg/ml, 7% receiving cardiac resynchronisation therapy) with a mortality of less than 10% at one-year post-randomisation. Moreover, just 80% were receiving diuretics at randomisation, which is a potentially important confounder given the likely natriuretic effect of sacubitril-induced BNP enhancement. It is plausible, for instance, that the diuretic effect of sacubitril contributed significantly to the observed reduction in hospitalisation for heart failure, and that this effect may be attenuated in a less diuretic naïve population.

Dose equivalence

There is also the issue of dose equivalence. Unusually, PARADIGM-HF tested sacubitril/valsartan directly against another active and proven treatment (the ACE inhibitor, enalapril). The usual format for heart failure trials has been to compare the study drug with placebo as an addition to standard optimised therapy. Use of a combination drug (sacubitril/valsartan) further adds to the complexity. The design rationale is presumably accounted for by the difficulties of combining sacubitril with an ACE inhibitor (high risk of angioedema) and the hitherto disappointing performance of BNP-enhancing therapies used as single agents.4 The doses of valsartan and enalapril chosen for each arm of the study were considered to be broadly equivalent. Any disparity, however, is likely to have impacted on outcome and it is difficult to exclude the possibility that the trial was essentially one between an ACE inhibitor and an ARB at non-equivalent dosage. Furthermore, in the UK at least, ramipril (up-titrated to 10 mg daily) is the usual ACE inhibitor of choice.

More fundamental is the apparent paradox of a pharmacotherapy (i.e. neprilysin inhibition) designed to enhance the levels of a peptide (BNP), which rises naturally with disease progression and is associated negatively with prognosis. In contrast, other heart failure therapies are essentially system inhibiting rather than system enhancing. The paradox is, of course, easily explained. Unlike sympathetic and renin-angiotensin activation, BNP promotes natriuresis and, alongside its related peptides, has a number of complex but ultimately beneficial actions. However, it does raise the question as to whether or not the benefit of neprilysin inhibition may be attenuated in the more advanced stages of heart failure where BNP levels are already raised through natural production (a subgroup analysis of the PARADIGM-HF data does lend some support to this notion with a trend towards greatest benefit in patients with lower pre-treatment levels of BNP).

Sacubitril/valsartan is an exciting and novel addition to the heart failure treatment arsenal which, with NICE approval, is now available for widespread prescription. Heart failure guidelines will require major revision to accommodate the new therapy but it remains to be seen where sacubitril/valsartan sits in the overall treatment pathway. There may be a rationale for its use in targeting younger patients in the relatively early stages of heart failure in the hope of slowing disease progression. Its effectiveness in older patients with more disordered physiology requiring high-dose diuretics may be more questionable. Finally, it would seem premature to totally abandon ACE inhibition.

Conflict of interest

None declared.

Robert Stevenson  
Consultant Cardiologist
Calderdale and Huddersfield NHS Trust, Huddersfield Royal Infirmary, Lindley, Huddersfield, HD3 3EA


1. National Institute for Health and Care Excellence (NICE). Technology appraisal guidance (TA388). Sacubitril valsartan for treating symptomatic chronic heart failure with reduced ejection fraction. London: NICE, 27 April 2016. Available from: (accessed 09 August 2016)

2. McMurray JJ, Packer M, Desai AS et al.; for the PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med 2014;371:993–1004. http://dx.doi. org/10.1056/NEJMoa1409077

3. National Institute for Cardiovascular Outcomes Research (NICOR) and British Society for Heart Failure. National Heart Failure Audit April 2013–March 2014 (published 20 October 2015).

4. O’Conner CM, Starling RC, Hernandez AF et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43. http://dx.doi. org/10.1056/NEJMoa1100171