A Randomised, Controlled, Double-blind, Double-dummy, Clinical Trial Comparing Sacubitril-Valsartan Versus Valsartan in Asymptomatic, Stage A/B HFpEF Patients With Elevated Natriuretic Peptide and Abnormal LAVI. (Previously NCT02682719)

Background.

An effective prevention strategy is critical if the established epidemic of heart failure and cardiovascular disease is to be curbed. This is particularly important in the context of increasing community prevalence of stage B HFpEF and left ventricular diastolic abnormalities associated with hypertension and diabetes and requires community diagnostics and targeted preventative therapies. Individualising risk beyond the presence of established risk factors can be achieved with NP assessment. Elevated NP in a population with established cardiovascular disease defines a group more prone to cardiac dysfunction, heart failure and other cardiovascular events. This can be used to risk stratify asymptomatic populations, targeting those most likely to need intensive intervention and follow-up.

In the prospective, randomised, pragmatic St Vincent's Screening TO Prevent Heart Failure (STOP-HF) trial [Ledwidge 2013], NP-based screening and collaborative care with general practice provided a multi-faceted intervention for patients with risk factors for heart failure. This involved community NP screening, improved use of RAAS modifying therapy, collaborative care with general practice as well as cardiovascular coaching for patients with mild elevations of BNP (>50 pg/mL).The intervention reduced stage B and C heart failure, most of which was preserved ejection fraction, as well as major adverse cardiovascular events requiring hospitalisation. This first of type study, along with a second study in diabetes [Huelsmann 2013], indicates that a biomarker driven strategy based on NP screening amongst stage AB heart failure patients is feasible and has an impact on heart failure and other cardiovascular diseases. These studies have been incorporated into 2017 American Heart Association/American College of Cardiology guidelines as well as other international guideline recommendations in heart failure.

However, while successful, the STOP-HF biomarker strategy lacks a specific pharmacological intervention linked to the screening biomarker, NP. An analysis of the STOP-HF follow-up study, supports other work showing that the minor C allele of genetic variant rs198389 of the NPPB gene (in the promoter region) is associated with sustained, elevated circulating levels of BNP and reduced incidence of left ventricular dysfunction over a five-year follow up period. These data support the hypothesis that use of LCZ696 to pharmacologically raise NP could provide cardioprotection in stage A/B heart failure patients. As neprilysin degrades biologically active NP, LCZ696 increases myocardial cyclic guanosine monophosphate (cGMP) which reduces vascular and myocardial stiffness as well as hypertrophy. This could improve cardiac structure and performance. NPs also stimulate natriuresis, diuresis, vasodilation and have been shown to have anti-fibrotic and anti-sympathetic benefits, which could augment the STOP-HF preventative strategy with a specific pharmacological intervention. [Ledwidge 2103, Phelan 2012, Potter 2006, Gardiner 2007]. Atrial tissue gene expression of BNP in patients with stage B HFpEF is associated with atrial fibrosis, procollagen expression and presence of M2 monocyte-derived-macrophage marker CD163 [Watson 2020]. Further analyses of the STOP-HF follow-up study shows that BNP strongly associates with the presence of atrial cardiomyopathy, an independent predictor of new onset major adverse cardiovascular events.

Taken together, these data could support a role for sacubitril-valsartan versus valsartan alone in favourably modulating vascular compliance, cardiac structure, cardiac function as well as progression of left atrial structural and functional abnormalities amongst patients with stage B HFpEF. If left atrial structure and function is also associated with new onset major adverse cardiovascular events, the intervention could also modulate cardiovascular events. Finally, new CMRI imaging measures of cardiac function, such as CMR e' have been developed and will allow full characterisation of the cardiovascular impact of the intervention, including in subsets of patients with established atrial cardiomyopathy.