The role of the interatrial shunt device in the treatment of patients with heart failure with preserved ejection fraction: experience from the REDUCE LAP-HF studies

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Kosin Med J. 2025;40(2):88-95

Publication date (electronic) : 2025 February 17

doi : https://doi.org/10.7180/kmj.24.150

Bong-Joon Kim

Division of Cardiology, Department of Medicine, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Corresponding Author: Bong-Joon Kim, MD, PhD Division of Cardiology, Department of Medicine, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 633 North Saint Clair Street 19th FL, Chicago, IL 60611, USA Tel: +1-312-409-1153 Fax: +1-312-695-0063 E-mail: kbj1315450@gmail.com

Received 2024 October 12; Revised 2024 December 5; Accepted 2024 December 11.

Abstract

Introduction

The difference between heart failure (HF) with preserved ejection fraction (HFpEF) and HF with reduced left ventricular systolic function (HFrEF) is a lack of significant impairment of left ventricular (LV) systolic function. The global prevalence of HFpEF has been increasing, possibly due to heightened awareness, increasingly older population, and a higher prevalence of comorbidities [1-3]. Effective treatment for HFpEF remains a challenge due to the heterogeneity of the condition and lack of diagnostic criteria [4]. Symptoms of HFpEF may not manifest at rest, leading to underdiagnosis. Although biomarkers aid in HFpEF diagnosis, limitations exist due to variable sensitivity, specificity, and the influence of other factors [5]. Recent medications have shown promise in improving HFpEF prognosis but do not produce the significant improvements observed in HFrEF patients.

Therefore, the interatrial shunt device (IASD) has been developed to lower left atrial (LA) pressure [6]. This device represents an innovative treatment for HFpEF and currently is in various stages of clinical trials. This review will discuss IASDs as a potential interventional option for HFpEF, highlighting findings from the REDUCE LAP-HF (Reduce Left Atrial Pressure in Patients with Heart Failure) studies and exploring appropriate patient selection criteria.

Key pathophysiology of HFpEF

HFpEF is characterized by the presence of HF signs and symptoms, coupled with structural and/or functional cardiac abnormalities with elevated natriuretic peptides and an LV ejection fraction (LVEF) ≥50% [7]. Various cardiovascular (CV) risk factors contribute to HFpEF, particularly LA dysfunction caused by elevated LV filling pressures, resulting in LA myopathy and remodeling [8]. Standard diagnostic tests include measures of LA size (LA volume index), which indicates LV diastolic dysfunction, and E/e′, which reflects elevated LV filling pressure. Thus, reducing LA pressure by unloading is a primary therapeutic target in HFpEF [9]. When LA myopathy progresses beyond a certain level, pulmonary hypertension (PH) occurs, commonly called HFpEF complicated by PH (PH-HFpEF). This corresponds to group 2 in the World Health Organization (WHO) PH classification and is the most prevalent subtype [10]. The typical pathophysiology of PH-HFpEF involves secondary PH arising from left HF or valvular disease. As the disease progresses, pulmonary vascular resistance (PVR) increases, leading to irreversible changes and possibly culminating in right HF and death [11].

Trends in medical treatment for HFpEF

In the 2021 European Society of Cardiology guidelines, no medications were conclusively recommended to improve outcomes in HFpEF patients [7]. However, subsequent studies have highlighted the efficacy of certain drugs. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (empagliflozin and dapagliflozin) have shown improved outcomes in the EMPEROR-preserved HF and DELIVER trials [12,13]. In addition, angiotensin receptor-neprilysin inhibitors (ARNIs) have shown benefits for specific patient subsets, with expectations that recommendation levels for these drugs will be changed in future HFpEF guidelines. Recent HF guidelines in Europe, the United States, and Korea are being updated to reflect these latest research results (Table 1) [7,14-16]. In particular, the Korean Heart Failure Society actively reflects recent key trials and actively recommends the use of SGLT2-inhibitors and ARNI in HFpEF patients. Emerging evidence indicates that glucagon-like peptide-1 agonists may also offer benefits for HFpEF patients [17,18]. Furthermore, ongoing research is examining the role of mineralocorticoid receptor antagonist agents in HFpEF [19]. Uses of these drugs are expected to be reflected in future HF guidelines.

Table 1.

Comparison of recommendation levels of GDMT in HFmrEF/HFpEF guidelines

Unmet needs for device therapy in HFpEF

Despite the availability of medical therapies, not all HFpEF patients experience significant improvement with guideline-directed medical therapy. Because the etiology of HFpEF is diverse, there is no certainty that the effects of medical treatment will be consistent for all HFpEF patients. In addition, it is unclear whether SGLT2 inhibitors, a class I recommendation in HFpEF, will be effective in HFpEF patients whose symptoms persist even after fluid overload has resolved. Furthermore, as the global population ages, HFpEF patients often present with multiple comorbidities, leading to polypharmacy and increased risk of adverse effects such as renal dysfunction, electrolyte imbalances, and hypotension [20,21]. In particular, patients with HF need to undergo up-titration, which involves gradually increasing the doses of various drugs; however, many HF patients are unable to undergo active up-titration due to concerns regarding side effects. Therefore, a demand remains for procedural or device-based therapies in HFpEF management.

Interatrial shunt device

Over the past decade, transcatheter atrial shunt therapy has been developed as a treatment to dynamically unload the LA by creating a passage from the LA to the right atrium (RA). The atrial septum is anatomically thin and can be traversed through septal puncture. In theory, this shunt allows blood in the LA, which has relatively high pressure, to pass into the RA, which has relatively low pressure, reducing LA pressure at rest and during exercise, benefiting HFpEF patients [22]. Among the various IASDs, the Corvia atrial shunt device has shown promising efficacy and safety in clinical trials [23-25]. The Corvia IASD System II, an 8-mm double-disc nitinol-based device, has the most evidence supporting its use. Fig. 1 depicts the device.

Fig. 1.

Interatrial shunt device (IASD; courtesy of Sanjiv Shah). (A) Corvia IASD System II. (B) En face view of the IASD System II (single size). (C) The device creates an interatrial shunt that unloads the LA by shunting blood from the higher-pressure LA to the lower-pressure RA. LA, left atrium; RA, right atrium.

REDUCE LAP-HF trials

The REDUCE LAP-HF studies have provided valuable data on the efficacy and safety of IASD therapy (Table 2) [23-29]. The first REDUCE LAP-HF study, a multicenter, open-label trial, included 64 HF patients with LVEF >40% and pulmonary capillary wedge pressure (PCWP) ≥25 mmHg during exercise. The results showed that IASD implantation reduced PCWP during exercise by approximately 2–3 mmHg without procedural complications [23].

Table 2.

Summary of the REDUCE LAP-HF trials

The REDUCE LAP-HF I trial, a randomized controlled trial published in 2018, involved 44 HFpEF patients. The results showed a significant reduction in PCWP during exercise in the IASD group compared with the placebo group after 1 month [24].

In the REDUCE LAP-HF II trial, published in 2022, 626 patients were enrolled, and subjects who received IASD were compared with sham controls. Although the IASD group did not demonstrate superior efficacy on the primary endpoint, post hoc analysis results indicated that certain subgroups based on PVR might benefit more from the treatment [25,27]. Another study has shown the positive effects of IASD on cardiac structure and function, such as reducing LA minimal volume and improving LV systolic tissue Doppler velocity [29].

Effects on RV and RA After IASD insertion

Flow from the LA to the RA through the IASD could theoretically increase right-side volume, raising concerns about potential right ventricular (RV) dysfunction. However, current data do not show significant RV dysfunction following IASD implantation. Regarding volume overload, RA and RV adapt through various compensatory mechanisms, and remodeling progresses accordingly [11]. There are two mechanisms that may explain why increasing RA volume did not significantly affect RV dynamics. First, lowering LA pressure and PCWP may reduce reflected pressure waves, decreasing pulmonary artery (PA) pressure and RV strain [30]. Second, oxygenated blood entering the RA through the shunt may induce PA vasodilation, ultimately reducing RV pressure overload. In a recent post hoc analysis of the REDUCE LAP-HF II study, results indicated no significant effect on PA pressure, RA pressure, or RV systolic function compared with sham controls although RV and RA volumes increased after treatment [29]. If future analyses using RV strain are conducted, it is expected to be helpful in understanding the pathophysiology of RV mechanics following shunt.

Side effects or complications of the procedure

The safety outcomes from the REDUCE LAP-HF study series showed that adverse events were rare (Table 3) [23-25]. In the REDUCE LAP-HF II, the IASD group exhibited slightly higher rates in some safety indicators; however, significant difference was not observed in the composite safety endpoint. Recently, the long-term safety outcomes of REDUCE LAP-HF I (5 years) and REDUCE LAP-HF II (3 years) were published [31]. At 5 years in REDUCE LAP-HF I, there were no differences between the groups in CV mortality, HF events, embolic stroke, or new-onset A-fib. Similarly, after 3 years in REDUCE LAP-HF II, there was no difference in the primary outcome (a hierarchical composite of CV mortality, stroke, HF events, and Kansas City Cardiomyopathy Questionnaire score) between the shunt and sham groups in the overall trial. However, while the stroke rate showed no difference between groups among non-responders, among responders, shunt-treated patients had a higher rate of any ischemic stroke compared to sham control patients at 3 years (3.2% vs. 0.0%, p=0.032). The higher stroke frequency observed in some shunt-treated patients is a noteworthy finding and may indicate a potential risk associated with atrial shunts. Nonetheless, caution is needed when interpreting these findings. The study population had an average age of 72 years, with numerous underlying diseases and CV risk factors that could contribute to HF. Additionally, some patients who experienced strokes had pre-existing A-fib. Therefore, it is important to avoid over-attributing these strokes solely to the shunt.

Table 3.

Safety outcomes of the REDUCE LAP-HF trials

Responders versus non-responders to IASD

Although the overall results of the REDUCE LAP-HF II were not positive, the clinical benefit of IASD is evident in certain patient subgroups. A subgroup analysis based on PVR revealed that patients with a peak PVR <1.74 Wood units (WU) during exercise appeared to benefit from the shunt; however, subjects with a peak PVR ≥1.74 WU during exercise experienced worse outcomes from the device. These findings are clinically significant because the concept of a responder group for IASD was introduced, and specific PVR values were identified to classify patients.

Borlaug et al. [27] expanded on this concept, categorizing the REDUCE LAP-HF II population into subjects with and without latent pulmonary vascular disease (PVD) and evaluated the effects of IASD. In their analysis, latent PVD was defined as peak PVR ≥1.74 WU (upper tertile) during exercise. Patients with latent PVD had poorer outcomes of IASD, and subjects without PVD experienced positive effects. PVD plays a crucial role in the complexity of HFpEF pathophysiology and management [32].

In HFpEF patients, functional class deterioration and adverse outcomes are frequently associated with RV dysfunction, characterized by an inability to cope with increased afterload demands caused by PVD and elevated LA pressure [33]. Therefore, careful patient selection, particularly with exercise catheterization to assess for PVD, is essential when considering IASD.

Conclusions

Results of recent key trials have shown that medical treatments for HFpEF can improve prognosis. However, many challenges remain, including low quality of life, persistent symptom burden, adverse effects, and polypharmacy. IASD represents a novel therapeutic approach that may be appropriate for select HF patients. In particular, the Corvia shunt device was shown to have favorable safety and feasibility, with positive clinical outcomes in the REDUCE LAP-HF series. Although IASD may not benefit all HFpEF patients and potentially can be harmful in subjects with high PVR, with appropriate patient selection, IASD could be a valuable treatment option for HFpEF in the future.

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