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

  • STATUS
    Recruiting
  • participants needed
    250
  • sponsor
    The Heartbeat Trust
Updated on 8 November 2020
diabetes
hypertension
heart failure
natriuretic peptide
sacubitril
valsartan

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.

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.

Details
Condition Diastolic Dysfunction
Treatment Valsartan, LCZ696, Placebo to LCZ696, Placebo to Valsartan
Clinical Study IdentifierNCT02682719
SponsorThe Heartbeat Trust
Last Modified on8 November 2020

Eligibility

Yes No Not Sure

Inclusion Criteria

Age > 40yrs
Cardiovascular risk factor(s) including at least one of
History of hypertension (medicated for greater than one month)
History of diabetes
Elevated NP: BNP>50pg/ml or NT-proBNP >250 pg/ml
LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening
Subjects must give written informed consent to participate in the study and before any study related assessments are performed

Exclusion Criteria

A history of heart failure
A history of asymptomatic left ventricular systolic dysfunction defined as LVEF reading <50%, at any time
Systolic blood pressure <100mmHg
Persistent atrial fibrillation
History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin therapy or to any of the excipients or other contraindication to their use
Previous history of intolerance to recommended target doses for ARBs
Subjects who require treatment with both an ACE inhibitor and an ARB
Presence of haemodynamically significant mitral and /or aortic valve disease
Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis
Conditions that are expected to compromise survival over the study period
Serum potassium level > 5.2 mmol/L at screening
Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2)
Hepatic dysfunction (Any LFT > 3 times the upper limit of normal (ULN))
Concomitant use of aliskiren
History of angioedema
History or evidence of drug or alcohol abuse within the last 12 months
Malignancy
Women who are pregnant, breast-feeding, or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. (Contraception must be continued for one week following discontinuation of study drug)
Concomitant participation in other intervention trials
Participation in any investigational drug trial within one month of visit 1
Refusal to provide informed consent
Subjects with contraindications to MRI
Hypersensitivity to gadolinium containing contrast agents
Brain aneurysm clip
Implanted neural stimulator
Implanted cardiac pacemaker or defibrillator
Cochlear implant
Ocular foreign body (e.g. metal shavings)
Other implanted medical devices: (e.g. Swan-Ganz catheter)
Insulin pump
Metal shrapnel or bullet
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following
History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection
Inflammatory bowel disease during the 12 months prior to Visit 1
Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase
Evidence of hepatic disease as determined by any one of the following: SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of oesophageal varices, or a history of portocaval shunt
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