Elsevier

The Lancet

Volume 399, Issue 10330, 19–25 March 2022, Pages 1130-1140
The Lancet

Articles
Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial

https://doi.org/10.1016/S0140-6736(22)00016-2Get rights and content

Summary

Background

Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients.

Methods

In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033.

Findings

Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8–1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11).

Interpretation

Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%.

Funding

Corvia Medical.

Introduction

Dyspnoea due to left atrial pressure overload during exercise is a hallmark of heart failure with preserved or mildly reduced ejection fraction.1 The potential therapeutic benefit of an iatrogenic interatrial shunt in heart failure is based on the observation that the presence of a congenital secundum atrial septal defect in patients with mitral stenosis (Lutembacher syndrome2) appeared to be beneficial due to the ability to decompress the pressure-overloaded left atrium by shunting blood to the lower pressure reservoir of the right atrium and systemic veins. Multiple devices and procedures to accomplish this are in various stages of development in patients with heart failure.3, 4, 5, 6, 7, 8, 9, 10

A multicentre, open-label study of the Corvia atrial shunt system (IASD System II; n=64) found that the device was safe and associated with improved invasive exercise haemodynamics, health status, exercise capacity, and outcomes in patients with heart failure, an ejection fraction of at least 40%, and elevated pulmonary capillary wedge pressure (PCWP) during exercise.6, 11 Patients were also required to have no evidence of significant pulmonary vascular disease at rest, right-sided heart failure, or moderate or greater tricuspid regurgitation, because each of these would be associated with the potential for inadequate left-to-right interatrial shunting or right-to-left shunting, both of which could worsen symptoms and outcomes.5, 8 Subsequently, a multicentre, phase 2 randomised, sham-controlled trial of the Corvia atrial shunt in patients with heart failure and an ejection fraction of at least 40% (REDUCE LAP-HF I; n=44) showed that the shunt reduced PCWP during exercise at 1 month (p=0·028)7 and led to a numerically lower rate of heart failure events at 1 year (0·22 vs 0·63 in the sham procedure group, p=0·06),12 but had no statistically significant effect on health status or exercise capacity.

Research in context

Evidence before this study

We searched PubMed for papers published between Jan 1, 2015, and Nov 20, 2021, using the search terms “heart failure”, “shunt device”, “randomised”, and “sham”, and various combinations of these words with no language restrictions. We aimed to identify randomised clinical trials of interatrial shunt devices and procedures to decompress the left atrium in patients with heart failure. We identified only one previous randomised trial of an interatrial shunt therapy (the Corvia Atrial Shunt Device) in 44 patients with heart failure (REDUCE LAP-HF I; all with ejection fraction ≥40%), which showed a reduction in exercise pulmonary capillary wedge pressure at 1 month (p=0·028) and numerically lower rate of heart failure-related admissions to hospital at 1 year (0·22 vs 0·63 in the sham procedure group, p=0·06), but no effect was seen on health status or exercise capacity.

Added value of this study

REDUCE LAP-HF II was an adequately powered, phase 3 pivotal trial of the Corvia Atrial Shunt in patients with heart failure and ejection fraction of at least 40%. It showed no difference between the active treatment and control groups for the hierarchical composite endpoint of cardiovascular death, non-fatal ischaemic stroke, first and recurrent heart failure events, and health status (Kansas City Cardiomyopathy Questionnaire). In prespecified subgroup analyses, individuals with the following had more frequent heart failure events when treated with the atrial shunt device: pulmonary artery systolic pressure greater than 70 mm Hg at 20W bicycle exercise, right atrial volume index greater than 29·7 mL/m2, and male sex.

Implications of all the available evidence

REDUCE LAP-HF II is the first phase 3, randomised clinical trial to evaluate an interatrial shunt device in patients with heart failure, with the goal of evaluating the efficacy of shunt-induced lowering of left atrial pressure on cardiovascular death, total heart failure events, and patient-reported outcomes. Despite the reduction of exercise pulmonary capillary wedge pressure in the previously completed REDUCE LAP-HF I trial, there was no improvement in clinical outcomes in this study after atrial shunt device placement compared with sham procedure. However, prespecified analyses showed divergent results in select subgroups.

Here, we report the primary efficacy and safety results of the Corvia atrial shunt in patients with heart failure and preserved or mildly reduced ejection fraction enrolled in a phase 3, randomised, double-blind, sham-controlled trial (REDUCE LAP-HF II), designed to determine whether an interatrial shunt would improve outcomes and quality of life.

Section snippets

Study design and participants

This randomised, international, multicentre, double-blind, sham-controlled REDUCE LAP-HF II trial was conducted in 89 centres in the USA, Canada, Europe, Australia, and Japan (appendix pp 4), and the protocol has been described previously.8 Eligible participants were aged at least 40 years with symptomatic heart failure and an ejection fraction of at least 40%, and evidence of PCWP during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Major exclusion

Results

Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, 626 of whom met eligibility criteria for random assignment and were assigned to receive the atrial shunt device (n=314) or sham procedure (n=312; figure 1).

Baseline characteristics of participants were similar between study groups (table 1; appendix pp 36–37), and were typical for patients with heart failure and preserved ejection fraction (HFpEF) or with heart failure and mildly reduced ejection fraction (HFmrEF). The

Discussion

Overall, among patients with heart failure, an ejection fraction of at least 40%, and documented invasive exercise PCWP of at least 25 mm Hg, we found no significant differences between atrial shunt device treatment and sham procedure in terms of cardiovascular death, nonfatal ischaemic stroke, total rate of worsening heart failure events, and health status. However, there were differential treatment effects in some of the prespecified subgroups. Men and patients with pulmonary artery systolic

Data sharing

Data requests can be submitted to Corvia Medical ([email protected]). Data will be shared with researchers who submit a detailed research proposal upon approval by the study steering committee. Data will not be made available until after approval of the product in the USA and Japan and not until reporting of the final results, anticipated in 2027. Individual patient data will be shared in datasets in a de-identified and anonymised format.

Declaration of interests

SJS reports research grants from the National Institutes of Health (NIH; U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and personal fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, Intellia, Ionis, Ironwood,

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    Investigators are listed in the appendix (pp 4–18)

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