Rationale and Design of the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial

doi:10.1016/j.cardfail.2015.05.008

Journal of Cardiac Failure

Volume 21, Issue 7, July 2015, Pages 594-600

https://doi.org/10.1016/j.cardfail.2015.05.008 Get rights and content

Abstract

Objective

Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF.

Methods

The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction ≥40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest or ≥25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization.

Conclusion

Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF.

Section snippets

Study Objectives

The primary objectives of this clinical study are to evaluate the safety and performance of the IASD System II (Fig. 1) in the treatment of HFpEF and elevated left atrial pressure in patients who have remained symptomatic despite appropriate medical management.

End Points

To investigate the study objectives, the following primary end points were chosen:

Discussion

The Reduce LAP-HF trial is the 1st study to examine the effect of directly reducing left atrial pressure in patients with HFpEF with the use of a purpose-designed medical device. The trial is based on the hypothesis that a reduction in left atrial pressure will improve symptoms in patients with this syndrome. Moreover, the reduction of left atrial pressure may be relevant to morbidity/mortality in HFpEF. Reduction of left atrial pressure will be achieved with the use of the IASD System II.

Study Limitations

There are 3 limitations of the trial. First, it is nonrandomized, primarily owing to insufficient data to design a randomized trial. Second, it may be hard to compare results with other studies, because an EF cutoff of 40% was selected. Third, the trial allows enrollment of multiple HFpEF phenotypes.

Conclusion

Current therapeutic options in HFpEF are sparse and ineffective. The results of our IASD pilot study clearly supported further investigations of this device to improve symptoms and potentially even outcome in this underserved population. A positive result of this trial could lead to improved treatment options and may help to design future studies with the technology.

Disclosures

Dr Burkhoff is the director of the hemodynamic core laboratory; Ms Raymond is an employee of the Contract Research Organization, and Mr Komtebedde is an employee of DC Devices. Dr Shah has received consulting fees from DC Devices.

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Cited by (32)

Update on Atrial Shunt Therapy for Treatment of Heart Failure
2022, Structural Heart
Heart failure with preserved ejection fraction is associated with elevated left atrial pressure during exercise. Sodium-glucose cotransporter-2 inhibitors have demonstrated the evidence of benefit in heart failure with preserved ejection fraction, but even with this treatment, heart failure hospitalizations remain high, and improvements in quality of life scores are modest. Thus, there is growing interest in nonpharmacological methods of limiting the rise in left atrial pressure during exertion. Creation of an interatrial shunt (IAS) may unload the left heart during exercise. Multiple implant or nonimplant IAS procedures are under investigation. Implantation of the most studied device results in 3 to 5 mm Hg decreases in pulmonary capillary wedge pressure during exercise, no increase in incidence of stroke, stable increases in Qp/Qs (1.2-1.3), and mild right heart enlargement without change in function out to at least a year after treatment. The findings from the first large randomized controlled trial of an atrial shunt have recently been published. For the population as a whole, implantation of the atrial shunt device appeared to be safe but did not provide clinical benefit. However, prespecified and post-hoc analyses have demonstrated that men, patients with larger right atrial volumes, and those with pulmonary artery systolic pressure >70 mm Hg at 20 W exercise had worse outcomes with IAS therapy, whereas those with peak exercise pulmonary vascular resistance <1.74 Wood units and absence of a pacemaker represented a potential responder group. Here, we summarize the results of the published data and the current IAS therapies under investigation. We also highlight unanswered questions in this field of inquiry.
Feasibility of a No-Implant Approach to Interatrial Shunts: Preclinical and Early Clinical Studies
2022, Structural Heart
Citation Excerpt :
These therapies are being studied for their potential to reduce heart failure symptoms, improve quality of life, and reduce heart failure hospitalizations. Thus far, IASs have demonstrated positive safety signals and positive reported outcomes, including significant reduction in left ventricular filling pressures and improvements in 6-minute walk test, quality of life, and New York Heart Association classification.6,8,12,13,15 The REDUCE LAP-HF II trial (Corvia Medical, Tewksbury, Massachusetts) was a randomized, double-blinded, sham-controlled study comparing IAS therapy to placebo in 626 patients.3
Heart failure with preserved ejection fraction represents a major unmet clinical need with limited treatment options. Recent device therapies under investigation have focused on decompression of the left atrium through an implantable interatrial shunt. Although these devices have shown favorable safety and efficacy signals, an implant is required to maintain shunt patency, which may increase the patient risk profile and complicate subsequent interventions requiring transseptal access.
The Alleviant System is a no-implant approach to creating an interatrial shunt using radiofrequency energy to securely capture, excise, and extract a precise disk of tissue from the interatrial septum. Acute preclinical studies in healthy swine (n = 5) demonstrated the feasibility of the Alleviant System to repeatably create a 7 mm interatrial orifice with minimal collateral thermal effect and minimal platelet and fibrin deposition observed histologically.
Chronic animal studies (n = 9) were carried out to 30- and 60-day time points and exhibited sustained shunt patency with histology demonstrating completely healed margins, endothelialization, and no trauma to adjacent atrial tissue. Preliminary clinical safety and feasibility were validated in a first-in-human study in patients with heart failure with preserved ejection fraction (n = 15). All patients demonstrated shunt patency by transesophageal echocardiographic imaging at 1, 3, and 6 months, as well as cardiac computed tomography imaging at 6-month follow-up timepoints.
Combined, these data support the safety and feasibility of a novel no-implant approach to creating an interatrial shunt using the Alleviant System. Continued follow-up and subsequent clinical studies are currently ongoing.
Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial
2022, The Lancet
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.
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.
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 (p_interaction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (p_interaction=0·012 [≥29·7 mL/m², worse outcomes]), and sex (p_interaction=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).
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%.
Corvia Medical.
Transcatheter InterAtrial Shunt Device for the treatment of heart failure: Rationale and design of the pivotal randomized trial to REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP-HF II): Rationale and design of REDUCE LAP-HF II
2020, American Heart Journal
A randomized, sham-controlled trial in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% demonstrated reductions in pulmonary capillary wedge pressure (PCWP) with a novel transcatheter InterAtrial Shunt Device (IASD). Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study.
REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) is a multicenter, prospective, randomized, sham-controlled, blinded trial designed to evaluate the clinical efficacy of the IASD in symptomatic HF and elevated left atrial pressures. Up to 608 HF patients age ≥ 40 years with LVEF ≥40%, PCWP ≥25 mm Hg during supine ergometer exercise, and PCWP ≥5 mm Hg higher than right atrial pressure will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes (1) cardiovascular mortality or first nonfatal ischemic stroke through 12 months; (2) total (first plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; and (3) change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure.
REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated left atrial pressure and LVEF ≥40%.
Effects of Interatrial Shunt on Pulmonary Vascular Function in Heart Failure With Preserved Ejection Fraction
2019, Journal of the American College of Cardiology
Citation Excerpt :
Collectively, these data indicate that on average, up to 6 months following IASD implantation, the lungs are able to accommodate the increase in blood flow associated with the IASD in HF patients with EF ≥40% (and without significant pulmonary vascular disease or RV dysfunction at baseline), and that these increases in blood flow and O2 content are associated with favorable effects on pulmonary vascular function, potentially mitigating risk for progression in pulmonary vascular disease, without compromising systemic perfusion, which could worsen peripheral O2 delivery during stress. This analysis confirms and expands upon the previously published findings, showing a significant reduction in left-sided filling pressure during exercise after IASD implantation (7–13). However, recent studies have shown that left atrial hypertension is not the only important pathophysiological target in HFpEF, as pulmonary vascular disease is also common.
Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion.
The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs).
This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded.
Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise.
Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF]; NCT01913613; and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I]; NCT02600234)
20th Annual Feigenbaum Lecture: Echocardiography for Precision Medicine—Digital Biopsy to Deconstruct Biology
2019, Journal of the American Society of Echocardiography
Heart failure with preserved ejection fraction (HFpEF) is a complex, heterogeneous syndrome in need of improved classification given its high morbidity and mortality and few effective treatment options. HFpEF represents an ideal setting to examine the utility and feasibility of a precision medicine approach. This article (based on the 20th annual Feigenbaum Lecture, presented at the 2019 American Society of Echocardiography Scientific Sessions) describes the utility of echocardiography as a “digital biopsy” and how deep quantitative echocardiographic phenotyping, coupled with machine learning, can be used to identify novel HFpEF phenotypes. The cellular and ultrastructural basis of abnormal speckle-tracking echocardiography– (STE-) based measurements of cardiac mechanics can provide a window into cardiomyocyte calcium homeostasis. STE-based measurements of longitudinal strain can thus inform the extent of myocardial involvement in patients with HFpEF, which may help to determine responsiveness to cardiac-specific HF medications. However, classifying the complex, systemic, multiorgan nature of HFpEF appropriately likely requires more advanced methods. Using unsupervised machine learning, HFpEF can be classified into three distinct phenogroups with differing clinical and echocardiographic characteristics and outcomes: (1) natriuretic peptide deficiency syndrome; (2) extreme cardiometabolic syndrome; and (3) right ventricle-cardio-abdomino-renal syndrome. Each can be probed to determine their biological basis. The goal of improved classification of HFpEF is to match the right patient with the right treatment, with the hope of improving the track record of HFpEF clinical trials. This article emphasizes the central role of echocardiography in advancing precision medicine and illustrates the integration of basic, translational, clinical, and population research in echocardiography with the goal of better understanding the pathobiology of a complex cardiovascular syndrome.

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Clinical Trials: Methods and DesignRationale and Design of the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial

Abstract

Objective

Methods

Conclusion

Section snippets

Study Objectives

End Points

Discussion

Study Limitations

Conclusion

Disclosures

J Am Coll Cardiol

J Am Coll Cardiol

Ann Thorac Surg

J Am Soc Echocardiogr

J Card Fail

ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

Eur Heart J

Trends in prevalence and outcome of heart failure with preserved ejection fraction

N Engl J Med

Outcome of heart failure with preserved ejection fraction in a population-based study

N Engl J Med

The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis

Eur Heart J

Clinical Trials: Methods and Design
Rationale and Design of the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial