ArticlesThe angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial
Introduction
Heart failure with preserved ejection fraction accounts for up to half of heart failure cases,1, 2 is associated with substantial morbidity and mortality,3, 4, 5 and to date no treatments have improved clinical outcomes.6 Pathophysiological mechanisms that have been implicated in the disorder include abnormal diastolic function with resultant increased ventricular filling pressures,7, 8 increased vascular stiffness, and subtle abnormalities of systolic function despite relatively preserved ejection fraction.9, 10, 11, 12 These individuals also have an impaired natriuretic and renal endocrine response to acute volume expansion early in the development of this syndrome.13 Several pharmacological treatments have been tested in clinical trials, including β blockers,14 calcium-channel blockers,15 angiotensin-converting enzyme (ACE) inhibitors,16 and angiotensin receptor blockers (ARBs),17, 18, 19 with none showing definitive benefit.
LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises the molecular moieties of the neprilysin (neutral endopeptidase 24.11) inhibitor prodrug AHU377 and the ARB valsartan in one compound.20 AHU377 is metabolised by enzymatic cleavage to LBQ657, the active inhibitor of neprilysin. Neprilysin degrades biologically active natriuretic peptides, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide, but not the biologically inert NT-proBNP, which is not a substrate for this enzyme.21 By augmenting the active natriuretic peptides, neprilysin inhibition increases generation of myocardial cyclic guanosine 3′5′ monophosphate, which improves myocardial relaxation and reduces hypertrophy. Natriuretic peptides also stimulate diuresis, natriuresis, and vasodilation, and might have additional antifibrotic and antisympathetic effects.22, 23 However, neprilysin also contributes to the breakdown of angiotensin,24 which is the rationale for dual-acting compounds that both inhibit this enzyme and block the action or generation of angiotensin. One such compound, omapatrilat, which inhibited both neprilysin and ACE,25 lowered blood pressure more than did ACE inhibition alone.26 However, the development of omapatrilat (and similar compounds) was discontinued because of an increased risk of angio-oedema likely caused by accumulation of bradykinin secondary to both neprilysin and ACE inhibition.25 Because LCZ696 blocks the angiotensin receptor without inhibiting ACE, it is expected to have a lower risk of angio-oedema than omapatrilat, has shown greater blood pressure reduction in patients with hypertension compared with valsartan with similar tolerability,27 and is currently being tested in a large outcomes trial in heart failure with reduced ejection fraction (NCT01035255).
LCZ696 might also have potential therapeutic value in heart failure with preserved ejection fraction. We therefore undertook a randomised trial comparing LCZ696 with valsartan to assess the safety and efficacy of LCZ696 in patients with this disorder.
Section snippets
Patients
PARAMOUNT was a randomised, double-blind, parallel-group, active controlled trial undertaken in 65 centres and 13 countries. Patients were recruited between Nov 2, 2009, and March 31, 2011, and the study ended on Jan 24, 2012. Men and women aged 40 years or older with a left ventricular ejection fraction (LVEF) of 45% or higher and a documented history of heart failure with associated signs or symptoms (dyspnoea on exertion, orthopnoea, paroxysmal dyspnoea, and peripheral oedema) were eligible.
Results
We screened 685 patients, of whom 308 were eligible for randomisation on the basis of inclusion and exclusion criteria (figure 1). Seven patients from one site were excluded before unmasking because of major data irregularities, leaving 301 valid study patients, of whom 149 were randomly assigned to LCZ696 and 152 to valsartan. Baseline characteristics were similar between treatment groups (table 1). Patients were elderly and most were female, overweight, and in NYHA functional class II. Atrial
Discussion
We found that in patients with heart failure with preserved ejection fraction, the angiotensin receptor neprilysin inhibitor LCZ696 reduced NT-proBNP to a greater extent than did valsartan after 12 weeks of treatment (panel). The reduction in NT-proBNP in patients receiving LCZ696 became evident at 4 weeks and appeared to be sustained to 36 weeks, although the between-group difference was no longer significant. Additionally, we noted a reduction in left atrial size, indicative of reverse left
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