Elsevier

The Lancet

Volume 387, Issue 10025, 26 March–1 April 2016, Pages 1298-1304
The Lancet

Articles
A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial

https://doi.org/10.1016/S0140-6736(16)00704-2Get rights and content

Summary

Background

Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF.

Methods

The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01913613.

Findings

Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg [SD 8] at baseline vs 29 mm Hg [9] at 6 months, p=0·0124) and at peak exercise (34 mm Hg [8] vs 32 [8], p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min [SD 3·1] vs 8·2 min [3·4], p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 [SD 0·32] at baseline vs 1·27 [0·20] at 6 months, p=0·0004).

Interpretation

Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial.

Funding

Corvia Medical Inc.

Introduction

Many patients with symptoms of heart failure do not have evidence of reduced left ventricular systolic function—a syndrome that has been termed heart failure with preserved ejection fraction (HFPEF)1, 2 to distinguish it from those with heart failure and a reduced ejection fraction (HFREF). Epidemiological studies suggest that the incidence of HFPEF is rising worldwide,3, 4 although whether this increase is mainly attributable to improved recognition, an ageing population, or increases in the prevalence of comorbid diseases such as hypertension, chronic kidney disease, and diabetes, is unclear. Each of these factors probably contributes to the increase.

Although pharmacological treatment has improved symptoms and reduced morbidity and mortality for patients with HFREF, discovery of an effective treatment for patients with the disorder has proved elusive.5, 6, 7, 8, 9, 10 The hallmark of HFPEF is effort intolerance, which is associated with a profound and rapid increase in left atrial pressure during exercise indicating impaired left ventricular diastolic reserve,11, 12 with consequent pulmonary congestion. This disproportionate rise in left atrial pressure is thought to provoke symptoms and contribute to increased morbidity and mortality in HFPEF.13

In 1916, Lutembacher14 described the combination of mitral stenosis, which mimics some of the pathophysiology of HFPEF, and an atrial septal defect. Patients with Lutembacher's syndrome might have fewer symptoms and better outcomes than those with pure mitral stenosis, and closure of their atrial septal defect can trigger a rise in pulmonary artery pressure and pulmonary oedema in some patients. An iatrogenic left-to-right atrial shunt is therefore a potentially attractive intervention that might have therapeutic value. Haemodynamic modelling based on clinical measurements suggests that an appropriately sized iatrogenic atrial septal defect could attenuate exercise-induced increases in left atrial pressure in patients with HFPEF.15 We postulated that a novel device-based therapy targeting a common pathophysiological feature of HFPEF might succeed where pharmacological therapies have failed. The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was designed to assess the device performance and safety of a transcatheter, transvenous interatrial shunt device in symptomatic patients with HFPEF.

Research in context

Systematic review

We did a search of publicly available sources including PubMed, learned body guidelines (including those published by the American Heart Association, American College of Cardiology, and European Society of Cardiology), and the Cochrane Library using the search terms “diastolic heart failure”, “heart failure with preserved ejection fraction”, and “clinical trials” on Dec 22, 2015. We regarded multicentre, randomised controlled trials as clinically important. We identified a series of studies that focused on the role of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists in patients with heart failure with preserved ejection fraction (HFPEF). We also identified a large number of ongoing studies, which is consistent with the substantial unmet clinical need represented by HFPEF.

Added value of this study

The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was the first large-scale trial designed to systematically investigate the effect of placement of an interatrial shunt device (IASD) to decompress the left atrium in patients with HFPEF. Following placement of the shunt, patients had improved quality of life, did better on the 6-min walk test, and had a reduction in exercise pulmonary capillary wedge pressure.

Implications of all the available evidence

Previous evidence highlights the key role of raised left atrial pressure, especially during exertion, as a key pathophysiological feature in patients with HFPEF. This study reports the effect of a purpose-designed device (IASD) placed in the interatrial septum intended to reduce left atrial pressure. The demonstration of a beneficial effect of the IASD provides further support for the notion that increased left atrial pressure is the fundamental abnormality in patients with HFPEF and that a mechanical approach to reduce left atrial pressure is feasible.

Section snippets

Study design and participants

The REDUCE LAP-HF study was a multicentre, prospective, non-randomised, open-label, single-arm study designed to investigate the safety and performance of a transcatheter, transvenous interatrial shunt device (IASD system II, Corvia Medical Inc [Tewkesbury, MA, USA]; figure 1). The study design has been described in detail elsewhere.16

Patients with known HFPEF enrolled from hospital outpatient departments or via referring physicians were eligible for study inclusion if they were adults (aged

Results

Between Feb 8, 2014, and June 10, 2015, 102 patients were enrolled from 21 centres, of whom 68 met the inclusion and exclusion criteria. The most common reasons for exclusion were failure to meet the haemodynamic inclusion criteria (pulmonary capillary wedge pressure too low in 22 patients, and central venous pressure too high in three patients). One patient was excluded for each of the following reasons: left ventricular ejection fraction below 40%, cardiac index lower than 2·0 L per min/m2,

Discussion

In this open-label study of a novel transcatheter interatrial shunt device, which was developed for the management of patients with HFPEF, we recorded reductions in left atrial pressure during exercise with improvements in functional capacity and quality of life 6 months after implantation. The procedure was well tolerated, and echocardiographic and oximetric studies showed the presence of continuing device patency and left-to-right shunting at 6 months.

HFPEF is characterised by complex

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