ARNI in Asymptomatic Patients With Elevated Natriuretic Peptide and Elevated Left Atrial Volume Index eLEvation — PARABLE  

Diastolic Dysfunction Clinical Trial

Official title: Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvation (The PARABLE Study)

Status Recruiting

Clinical Trial Summary

The purpose of this study is to determine whether LCZ696 (valsartan/sacubitril) is safe and has beneficial effects on the heart and blood vessels in patients with high blood pressure and/or diabetes or other risk factors for developing heart failure (elevated levels of natriuretic peptide and elevated left atrial volume index). Patients will be randomized to receive LCZ696 or valsartan (and matching placebo) for 18 months to assess the impact on left ventricular diastolic function.

Clinical Trial Description

The STOP-HF prospective, randomized trial demonstrated that a biomarker driven strategy of natriuretic peptide (NP) based screening and collaborative care with general practice can help target cardiovascular prevention and improve outcome in an at-risk population of patients without heart failure.

However, while successful, the STOP-HF biomarker strategy lacks a specific pharmacological intervention linked to the screening biomarker, NP. The most appropriate therapy to build on STOP-HF is LCZ696 (sacubitril/valsartan), a first in class angiotensin receptor neprilysin inhibitor (ARNI). As neprilysin degrades biologically active NP, LCZ696 increases myocardial cyclic guanosine monophosphate (cGMP) while reducing myocardial stiffness and hypertrophy. 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.

Elevated NP in an at-risk population independently identifies cardiovascular risk, which can be specifically targeted by LCZ696. In a small number of patients (4%) with cardiovascular risk factors and elevated NP, significant asymptomatic LV systolic dysfunction will be present and for these RAAS modifying therapy is mandated.

However, there is a larger group of patients with elevated NP who have normal systolic function of the left ventricle but who have significant isolated diastolic dysfunction. These patients have asymptomatic left ventricular diastolic dysfunction (ALVDD) and are at heightened risk for heart failure and other cardiovascular events. The Investigators and others, have shown that cardiac inflammation, fibrosis and hypertrophy drive the pathophysiology. Importantly, there is currently no specific therapy for these patients, beyond conventional risk factor control.

Interrupting this pathophysiological process at an early stage before the development of ventricular dysfunction, may prevent/slow development to heart failure and also have an impact on the development of other cardiovascular events driven by this pathophysiological process. This represents a novel way to modify risks at an earlier stage in the natural course of cardiovascular disease, in a targeted and individualized manner. It is known that suppressing the RAAS will reduce the pro-fibrotic impact of angiotensin II. Addition of neprilysin inhibitor sacubitril in LCZ696, will reduce degradation of endogenous, cardio-protective, biologically active NPs and cGMP and will augment the beneficial impact on fibro-inflammation beyond conventional RAAS modifying therapy.

There are a number of emerging biochemical and imaging surrogates of left ventricular dysfunction, which can be evaluated in a relatively small population over a short time frame in a prospective, phase II study design. Of these, one of the most reliable, continuous markers of diastolic function in the heart is LAVI. There was a dramatic impact of LCZ696 on LAVI in comparison with valsartan in the PARAMOUNT study. Furthermore, this endpoint can be precisely defined using cardiac magnetic resonance imaging (cMRI) in a phase II design. In this study, doppler Echocardiographic images will be collected to correlate with cMRI images. Doppler Echocardiography will be more feasible in follow on studies with larger populations.

In summary, it has been demonstrated that asymptomatic patients with elevated NP levels are at higher risk of heart failure and other cardiovascular events. Elevated NP in this setting represents a protective, endogenous response to fibro-inflammation. The predominant cardiac abnormality in these patients is ALVDD, which can be tracked using LAVI. The hypothesis is that augmenting this protective fibro-inflammatory response with LCZ696 could demonstrate superiority over the current state of art therapy in patients with hypertension or diabetes and elevated NP in a phase II study design and, in doing so, PARABLE may deliver a major clinical innovation in the prevention of cardiovascular disease. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diastolic Dysfunction

• NCT number: NCT02682719
• Study type: Interventional
• Source: The Heartbeat Trust
• Contact: Kenneth McDonald, MD, FRCPI
• Phone: 0035312713071
• Email: kenneth.mcdonald@ucd.ie
• Status: Recruiting
• Phase: Phase 2
• Start date: December 2015
• Completion date: December 2018