Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial
Abstract
Background:
In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%.
Methods:
REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise.
Results:
A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0).
Conclusions:
In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation.
Clinical Trial Registration:
URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.
Introduction
Clinical Perspective
What Is New?
•
We report a novel therapy for patients with heart failure (HF) with preserved ejection fraction (EF >50%) or midrange EF (40% to 50%) utilizing an implanted device to create an atrial shunt (interatrial shunt device [IASD]).
•
The objective of the IASD is to dynamically (at rest and during exercise) decompress left atrial pressure overload associated with HF with preserved EF and HF with midrange EF.
•
We conducted a randomized sham-controlled trial to evaluate the mechanistic effect of the IASD on invasively measured pulmonary capillary wedge pressure. At 1 month after randomization, the IASD treatment group had a significantly greater reduction in pulmonary capillary wedge pressure during exercise compared with the control group. In addition, pulmonary capillary wedge pressure during passive leg raise and also during 20 W of exercise decreased to a greater degree in the patients randomized to IASD compared with the sham control.
What Are the Clinical Implications?
•
In patients with HF and EF ≥40%, the creation of an interatrial shunt with the IASD unloads the left atrium and reduces pulmonary capillary wedge pressure during exercise.
•
This hemodynamic study demonstrates the beneficial mechanistic effect of the IASD.
•
The IASD could have beneficial clinical effects in patients with HF with preserved EF and HF midrange EF. A larger trial to examine the effects of the IASD on symptoms, quality of life, exercise capacity, and clinical outcomes such as HF hospitalization is warranted.
Heart failure (HF) with preserved ejection fraction (HFpEF, EF>50%), which is increasing in prevalence and currently accounts for ≈50% of all HF cases, is associated with high morbidity and mortality and lacks effective therapies.1,2 HF with midrange EF (EF 40% to 50%) is also prevalent and lacks proven therapies, and it was recently highlighted in the European Society of Cardiology HF guidelines.3,4 Although HFpEF and HF with midrange EF are heterogeneous with respect to etiology and pathophysiology, elevated left atrial (LA) pressure at rest or during exertion represents a central underlying abnormality in all patients with these syndromes.5
Patients with HFpEF are known to have left ventricular (LV) diastolic dysfunction (impaired LV relaxation and reduced LV compliance).6,7 These abnormalities result in elevated LA pressure and volume overload with subsequent elevation in pulmonary venous pressures, particularly during exertion, resulting in symptoms of dyspnea and exercise intolerance.8 In addition, intrinsic LA mechanical dysfunction is increasingly recognized as potentially important in driving symptoms and poor outcomes in HFpEF.5,9–11 The inability of the LA to handle increased load during exercise is especially problematic in patients with HFpEF.5,12 Pulmonary capillary wedge pressure (PCWP) is an invasive hemodynamic parameter that reflects LA and pulmonary venous pressures. Higher peak PCWP during exercise, corrected for workload, has also been associated with reduced exercise capacity13 and worse outcomes14 in the HFpEF setting, further underscoring the importance of the LA in the pathogenesis of HFpEF.
Given the importance of LA overload in HF—particularly HFpEF—unloading the LA with the goal of reducing pulmonary venous pressure may lead to improved symptoms and outcomes in these patients.15 It has long been known that in the setting of mitral stenosis, a condition also associated with elevated LA pressure and LA dysfunction, the coexistence of a congenital atrial septal defect (Lutembacher syndrome) can be associated with fewer symptoms and a more favorable clinical course.16 It has been hypothesized that an interatrial septal communication can unload the LA in the setting of increased LA pressure (such as during exercise), transferring the excess LA blood volume to the larger reservoir of the right atrium (RA) and systemic veins, thereby limiting the increase in LA pressure and pulmonary venous pressures during exercise. The recognition of this concept led to the development of a novel interatrial shunt device (IASD, Corvia Medical) for the treatment of HF.17
Hemodynamic simulations of the IASD have shown LA unloading during exercise without right ventricular (RV) pressure or volume overload.15 In nonrandomized, open-label, single-arm studies, placement of the IASD has been associated with the lowering of PCWP (a surrogate for LA pressure) during exercise in patients with HF and EF ≥40%.18–20 In these prior studies, the IASD was also found to be safe and associated with fewer symptoms, better quality of life, and greater exercise capacity, without the development of right-sided HF or pulmonary hypertension. However, these open-label, nonrandomized studies are subject to potential bias and confounding and cannot prove effectiveness of the IASD. We therefore conducted a randomized, blinded, sham-controlled clinical trial to determine the effectiveness of the IASD in HF with EF ≥40%. We hypothesized that the IASD reduces PCWP during exercise in patients with HF and EF ≥40% by unloading the LA.
Methods
Study Design and Participants
The rationale and design of the REDUCE LAP-HF I trial (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) have been described previously.17 The primary objective of the REDUCE LAP-HF I clinical trial was to evaluate the mechanistic effect of implanting the IASD System II (Corvia Medical) in patients with HF with EF ≥40% and elevated LA pressure who remained symptomatic despite optimal guideline-directed medical therapy. This was a multicenter, prospective, randomized, blinded controlled trial with nonimplant (sham) control group and 1:1 randomization. Patients were recruited between February 3, 2016, and November 23, 2016, at 22 centers in the United States, Europe (Belgium, France, The Netherlands, and United Kingdom), and Australia (Table I in the online-only Data Supplement lists all of the participating sites, principal investigators, and study coordinators for the trial).
A full list of inclusion and exclusion criteria is listed in the online-only Data Supplement. The inclusion and exclusion criteria were designed to ensure that patients had symptomatic HF (New York Heart Association class III or ambulatory class IV), an elevated LA pressure with a pressure gradient between the LA and RA, and no evidence of right-sided HF. Key inclusion criteria included documented chronic symptomatic HF and (1) prior hospitalization for HF (or acute care facility/emergency room intensification of diuretic therapy) within the prior 12 months, or (2) elevated B-type natriuretic peptide (BNP) or N-terminal pro-BNP within the past 6 months (BNP >70 pg/mL in normal sinus rhythm, >200 pg/mL in atrial fibrillation, or N-terminal pro-BNP >200 pg/mL in normal sinus rhythm, >600 pg/mL in atrial fibrillation); EF ≥40%; ≥40 years of age; elevated LA pressure documented invasively by end-expiratory PCWP during supine bike exercise ≥25 mm Hg, and PCWP-RA pressure gradient ≥5 mm Hg. Key exclusion criteria included stage D HF; cardiac index <2.0 L/min/m2; history of stroke, transient ischemic attack, deep vein thrombosis, or pulmonary embolism within the past 6 months; hemodynamically significant valvular disease; hypertrophic or infiltrative cardiomyopathy; RV dysfunction (>mild RV dysfunction, tricuspid annular plane systolic excursion <1.4 cm, RV size >LV size, or RV fractional area change <35%); resting RA pressure > 14 mm Hg; or pulmonary vascular resistance >4 wood units.
The study protocol was approved by the institutional review board or ethics committee at each of the 22 enrolling sites, and all enrolled patients provided written informed consent. A data safety monitoring committee oversaw the program and reviewed trial data for patient safety at regular intervals. Because of the proprietary nature of the study data, it will not be made publically available at this time. All statistical analyses were performed independently by the Baim Clinical Research Institute.
Randomization and Blinding
Eligible patients were randomized if they met all of the inclusion and exclusion criteria after undergoing the study-related qualification procedures (Figure I in the online-only Data Supplement), including noninvasive screening with echocardiography and supine bicycle exercise right heart catheterization. Immediately after qualification, eligible patients were randomized in a 1:1 ratio to the treatment or control group. Patient randomization was performed via the Interactive Web Response System. Patient blinding included sedation, earphones with music to preclude the patient from hearing the procedural discussions, and blindfolding (or the use of opaque screens) to prevent the participant from viewing the imaging screens. Participants and nonprocedural research staff were blinded to treatment assignment for 1 year after randomization. Each site was assigned blinded and unblinded staff to facilitate unbiased patient assessments through follow-up. The physicians managing the randomized patients clinically (including the treating cardiologist) and research staff involved in conducting selected evaluations after randomization, including the hemodynamic core laboratory, were blinded to the study arm. Treating physicians were also blinded to all right heart catheterization measurements. Research staff members were given explicit instructions to maintain patient blinding throughout the trial (online-only Data Supplement).
Study Procedures
Before enrolling patients into the study, all interventional cardiology investigators and associated investigative staff at each site underwent training to optimize and standardize invasive hemodynamic testing and recording of hemodynamic data, and to ensure proper deployment of the IASD System II device.
Once enrolled into the study, all patients underwent noninvasive screening, including comprehensive echocardiography to ensure EF ≥40%, diastolic dysfunction, and the absence of significant RV dysfunction or valvular disease. Participants meeting echocardiographic criteria underwent further screening with invasive hemodynamic testing. Right heart and pulmonary arterial catheterization was performed from the right internal jugular vein approach using the standard Seldinger technique under fluoroscopic guidance. Using a fluid-filled pulmonary artery catheter, all participants underwent recording of hemodynamics (RA pressure, pulmonary artery pressure, and PCWP) with a properly zeroed and calibrated pressure transducer. Hemodynamic measurements were recorded at rest, with legs up in the exercise bike pedals (equivalent to a passive leg raise procedure, a preload challenge), and during supine bike exercise. All pressure recordings were performed at a 50 mm/second paper speed with adjustment of pressure (mm Hg) scale as needed, and the recordings were saved for blinded measurement by the hemodynamic core laboratory. Cardiac output was measured with the thermodilution method, and pulmonary vascular resistance was calculated as the transpulmonary gradient (mean pulmonary artery pressure—PCWP) divided by cardiac output.
After the baseline right heart catheterization and exercise protocol, all patients who remained eligible by invasive hemodynamic criteria were sedated, blinded using the methods described above, and randomized to IASD treatment or sham control. Patients in both the treatment and control arm underwent femoral venous access after randomization. Patients randomized to the control arm underwent intracardiac or transesophageal echocardiographic examination of the atrial septum and LA appendage (but no transseptal puncture). Patients randomized to the treatment arm underwent a transseptal puncture and IASD System II implantation guided by fluoroscopy and intracardiac or transesophageal echocardiography. The IASD System II consists of a 1-piece, self-expanding metal cage that has a double-disc design with an opening (barrel) in the center (Figure 1A through 1C). The implant is radiopaque and echogenic to allow for imaging during the implantation procedure. The LA side of the implant is flat so the legs rest flush against the LA side of the interatrial septum, thereby minimizing the LA profile of the deployed implant. The RA side is curved to accommodate variable interatrial septal wall thicknesses, with only the leg ends contacting the RA side of the interatrial septum. The expanded external diameter of each disc is 19.4 mm. The inner diameter of the barrel in the center of the fully expanded implant is 8 mm, which corresponds to the optimal interatrial communication size (ie, maximizing the ability to reduce PCWP during exercise while keeping the ratio of pulmonary to systemic blood flow at 1.2–1.3) (Figure 1D).15 Details regarding medication administration related to the procedure and device are listed in Table II in the online-only Data Supplement. Patients randomized to the IASD who were not previously on an anticoagulant (eg, warfarin, direct oral anticoagulant) were treated with clopidogrel after the procedure. All patients who were on clopidogrel at baseline were kept on clopidogrel after the procedure. All patients in both treatment arms received aspirin after the procedure. The baseline use of these medications (before randomization) is listed in Table III in the online-only Data Supplement.
At 1 month after randomization, all study patients underwent repeat right heart catheterization with hemodynamic measurements at rest, with legs up, and during exercise using the exact same protocol as the exercise study performed at baseline. The primary effectiveness end point was change in PCWP during exercise from baseline to 1 month. All hemodynamic pressure measurements for the trial were made at end expiration using a standardized measurement protocol by the hemodynamic core laboratory, which was blinded to treatment allocation, baseline versus follow-up procedure, and all other clinical data. After initial review, for patients with hemodynamic values that were outside the expected range (eg, PCWP >mean pulmonary artery pressure), a systematic reascertainment of hemodynamic tracings for those patients was conducted by the hemodynamic core laboratory in a blinded fashion as part of their quality assurance process. Secondary effectiveness end points included change in peak exercise PCWP from baseline at 1 month, change in exercise duration at 1 month, and change in peak exercise workload at 1 month. Additional end points included change in New York Heart Association class and change in diuretic use from baseline.
The primary safety end point was periprocedural events and major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. MACCRE included cardiovascular death, embolic stroke, device- or procedure-related adverse cardiac events, and new-onset or worsening of kidney dysfunction (defined as a decrease in estimated glomerular filtration rate >20 mL/min/1.73 m2) through 1-month after implant. Additional safety-related end points included the need for implant removal or occlusion of the implant and HF hospitalization. All end points were adjudicated centrally by a blinded, independent clinical events committee.
Statistical Analysis
The statistical analyses for the primary efficacy and safety outcomes (including power calculations and the use of a mixed-effects model repeated measures, described below) were prespecified a priori and documented in the trial protocol and in our prior publication on the rationale and design of the REDUCE LAP-HF I trial.17 We assumed a mean change in exercise PCWP of −6.0 mm Hg in the treatment group and 0.0 mm Hg in the control group at each of 20 W, 40 W, 60 W, and 80 W stages, and we assumed a standard deviation in PCWP change of 7.2 mm Hg in each treatment group at each of the exercise stages. Based on these assumptions, a sample size of 20 evaluable participants per treatment arm yielded 82% power at a 2-sided 0.05 level of significance to detect a significant beneficial effect of IASD System II over control when comparing treatment means using a mixed-effects model repeated measures 21 analysis of covariance that included data from all available stages of exercise, assuming the compound symmetry correlation structure where the pairwise correlations among 20 W, 40 W, 60 W, and 80 W stages of exercise are ≤0.8.
The key safety outcome analysis on the end point of MACCRE at 1 month is descriptive (percentage of patients with MACCRE and 2-sided exact confidence interval of the percentage based on the binomial distribution for each treatment group). It was anticipated that the true MACCRE rate in the population would be ≈5%. Under this assumption, there was a 92% chance in a sample of size of 20 that the observed rate would be ≤10%. Sample size calculations were performed using PASS 14 software (NCSS, LLC).
The primary statistical analysis was based on an intention-to-treat (ITT) analysis that included all randomized patients with available data (n=44; n=22 in each treatment arm). Femoral venous access was attempted on all ITT patients; thus, the safety population (n=44) was identical to the ITT population. The per-protocol population consisted of 42 patients (2 of the patient randomized to the treatment arm were excluded from the per-protocol population because they did not receive the IASD implant). All statistical tests were carried out at a 2-sided 0.05 level of significance, and all P values were presented as 2-sided. There was no imputation for missing data. For the primary mechanistic end point (change in PCWP during exercise from baseline at 1 month), the 2 treatment groups were compared using the aforementioned prespecified mixed-effects model repeated measures analysis of covariance, which included data from all available stages of exercise. For the primary safety end point (peri-procedural and 1-month MACCRE), the 2 treatment groups were compared using a 2-sided exact confidence interval of the percentage of patients who experienced events in the 2 groups based on the binomial distribution for each treatment arm. Given the sample size and low MACCRE rates that were expected, there was no anticipation of a treatment difference on 1-month MACCRE. Mean values of continuous secondary effectiveness outcomes were compared between treatment groups using analysis of covariance with adjustment for the baseline value of the variable of interest. The rate of HF hospitalization was compared between treatments using the Fisher exact test. Mean differences between baseline and 1-month PCWP at rest (legs down), legs up, 20 W, and peak exercise were calculated using paired t tests within each treatment group. Analyses were carried out using SAS version 9.4 (SAS Institute).
This trial is registered at ClinicalTrials.gov, NCT02600234.
Results
A total of 94 patients with HF and EF ≥40% underwent screening procedures. Of the 94 enrolled patients, 44 met inclusion/exclusion criteria and were randomized 1:1 to the IASD and control (sham) groups (Figure 2). Baseline demographic, clinical, and invasive hemodynamic characteristics were similar between treatment groups except for more black patients in the control arm (Table 1). Echocardiographic indices of diastolic function were similar between the treatment groups (Table IV in the online-only Data Supplement).
| Patient Characteristics | IASD Patients (N=22) | Control Patients (N=22) | P Value |
|---|---|---|---|
| Demographics | |||
| Age, y | 69.6±8.3 (22) | 70.0±9.2 (22) | 0.86 |
| Male | 63.6% (14/22) | 36.4% (8/22) | 0.13 |
| Race | 0.03 | ||
| Black | 0.0% (0/22) | 18.2% (4/22) | |
| White | 86.4% (19/22) | 81.8% (18/22) | |
| Other | 13.6% (3/22) | 0.0% (0/22) | |
| Body mass index, kg/m2 | 35.2±6.4 (22) | 35.1±9.1 (22) | 0.98 |
| Comorbidities/risk factors | |||
| Hypertension | 81.8% (18/22) | 90.9% (20/22) | 0.66 |
| Hyperlipidemia | 72.7% (16/22) | 72.7% (16/22) | 1.00 |
| Diabetes | 54.5% (12/22) | 54.5% (12/22) | 1.00 |
| Chronic obstructive pulmonary disease | 13.6% (3/22) | 31.8% (7/22) | 0.28 |
| Ischemic heart disease | 22.7% (5/22) | 23.8% (5/21) | 1.00 |
| Prior myocardial infarction | 22.7% (5/22) | 19.0% (4/21) | 1.00 |
| Prior coronary revascularization | 47.6% (10/21) | 45.5% (10/22) | 1.00 |
| Atrial fibrillation | 54.5% (12/22) | 45.5% (10/22) | 0.76 |
| Atrial flutter | 4.5% (1/22) | 9.1% (2/22) | 1.00 |
| Stroke | 9.1% (2/22) | 14.3% (3/21) | 0.66 |
| Transient ischemic attack | 13.6% (3/22) | 9.1% (2/22) | 1.00 |
| Peripheral arterial disease | 13.6% (3/22) | 9.1% (2/22) | 1.00 |
| Pulmonary embolism | 4.5% (1/22) | 4.5% (1/22) | 1.00 |
| Deep vein thrombosis | 13.6% (3/22) | 0.0% (0/21) | 0.23 |
| Cardiac status | |||
| Left ventricular ejection fraction, site-reported (%) | 59.9±9.0 (22) | 58.5±6.9 (22) | 0.59 |
| NYHA classification | 0.32 | ||
| III | 100.0% (22/22) | 95.5% (21/22) | |
| IV | 0.0% (0/22) | 4.5% (1/22) | |
| Loop diuretic dose, mg furosemide equivalents | 92.7±99.4 (22) | 113.2±90.3 (22) | 0.48 |
| Hospitalization/emergency room visit/acute care facility visit for heart failure in the past 12 mo | 54.5% (12/22) | 72.7% (16/22) | 0.35 |
| Systolic blood pressure, mm Hg | 131±17 (22) | 128±22 (22) | 0.72 |
| Diastolic blood pressure, mm Hg | 68±9 (22) | 71±14 (22) | 0.53 |
| Mean arterial pressure, mm Hg | 89±11 (22) | 90±15 (22) | 0.84 |
| Heart rate at rest, bpm | 65±7 (22) | 72±13 (22) | 0.05 |
| Heart rate at peak exercise, bpm | 102±20 (22) | 104±21 (22) | 0.78 |
| Increase in heart rate during exercise, bpm | 37±21 (22) | 32±25 (22) | 0.47 |
| Right atrial pressure, mm Hg | 10.1±2.3 (22) | 9.1±3.7 (22) | 0.27 |
| Mean pulmonary artery pressure, mm Hg | 30.2±9.5 (22) | 28.4±8.6 (22) | 0.52 |
| Cardiac output, L/min/m | 5.4±1.6 (22) | 5.7±2.7 (22) | 0.66 |
| Pulmonary vascular resistance, WU | 2.19±1.52 (22) | 1.74±1.45 (21) | 0.32 |
| PCWP, legs down, mm Hg | 20.9±7.9 (21) | 19.9±7.5 (22) | 0.67 |
| PCWP, legs up, mm Hg | 26.6±7.1 (21) | 24.0±9.3 (22) | 0.32 |
| PCWP, peak exercise, mm Hg | 37.3±6.5 (19) | 37.3±6.7 (19) | 1.00 |
| PCWP, right atrial pressure gradient at rest, mm Hg | 10.8±5.6 (21) | 10.9±7.3 (22) | 0.95 |
| Workload-corrected PCWP, mm Hg/W/kg | 95.0±49.8 (18) | 94.1±45.3 (19) | 0.74 |
| Exercise duration, min | 7.4±3.1 (22) | 8.9±4.0 (22) | 0.18 |
| Peak exercise workload, W | 42.3±19.5 (22) | 41.8±16.2 (22) | 0.93 |
IASD indicates interatrial shunt device; NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; W, watts; and WU, wood units. Values represent mean±SD (N) or % (n/N).
The study participants ranged from 48 to 84 years of age (mean age 70 years), were 50% women, and had multiple comorbidities (including a 50% prevalence of atrial fibrillation). At the time of screening, all but 1 participant were New York Heart Association class III. The vast majority (42/44, 95%) of the participants were on a diuretic at baseline, and 28/44 (64%) had ≥1 hospitalization or emergency department/acute care facility visit for HF within the 12 months before enrollment. All study participants had an EF ≥40% at baseline, and the majority (39/44, 89%) had a baseline EF ≥50%.
Implantation of the IASD System II was attempted in 21 of 22 of the participants randomized to the treatment arm. In 1 participant, RA access could not be established for insertion of the procedure catheters (an occluded inferior vena cava filter was noted); therefore, the procedure was aborted. No subsequent MACCRE events were reported in this participant. Of the 21 remaining participants in whom implantation was attempted, there was 1 participant in whom the device was inadvertently fully deployed in the LA instead of at the interatrial septum. The device was percutaneously retrieved over the guide wire, and the implantation of a second device was not attempted (see Table V in the online-only Data Supplement for further details). The 20 remaining participants randomized to the IASD treatment arm were successfully implanted; 19 participants had 1 implantation attempt, and 1 participant had 2 implantation attempts. Table 2 lists the differences in procedure characteristics between study groups. Total procedure duration, total fluoroscopy duration, and total contrast administered were greater in the treatment group compared to the control group. See Table V in the online-only Data Supplement for further details about the procedural and device characteristics. Of the 20 participants who underwent successful device implantation, 1 refused repeat right heart catheterization at 1 month but remained in the trial and underwent all other follow-up assessments. All 22 patients in the control arm underwent repeat right heart catheterization with invasive hemodynamic testing at 1 month.
| Procedure/Device Characteristic | IASD Patients (N=22) | Control Patients (N=22) | P Value |
|---|---|---|---|
| Device implantation attempted | 95.5 (21/22) | N/A | — |
| Total procedure duration, min | 58.1±25.8 | 12.9±9.0 | <0.001 |
| Total fluoroscopy time, min | 23.3±13.0 | 5.3±3.6 | <0.001 |
| Total contrast agent administered, mL | 19.2±17.4 | 19.0±15.6 | 0.986 |
| Femoral venous access* | <0.001 | ||
| Left only | 0.0 (0/22) | 4.8 (1/21) | |
| Right only | 18.2 (4/22) | 81.0 (17/21) | |
| Both | 81.8 (18/22) | 14.3 (3/21) | |
| Echocardiographic guidance tool used* | 0.317 | ||
| Intracardiac echocardiography | 95.2 (20/21) | 100.0 (21/21) | |
| Transesophageal echocardiography | 4.8 (1/21) | 0.0 (0/21) | |
| Device deficiency† | 4.5 (1/22) | N/A | — |
| Device malfunction‡ | 4.5 (1/22) | N/A | — |
| Device failure | 0.0 (0/22) | N/A | — |
| Device maldeployment without embolization§ | 4.5 (1/22) | N/A | — |
| L→R flow observed through device barrel | 100.0 (20/20) | N/A | — |
| R→L flow observed through device barrel | 15.0 (3/20) | N/A | — |
IASD indicates interatrial shunt device; N/A, not applicable; L, left; and R, right. Values represent mean±SD (N) or % (n/N).
*
In 1 patient in the control arm, femoral venous access was attempted but could not be established. Thus, the denominator is 21 for the control arm for both femoral venous access and echocardiographic guidance tool.
†
The device did not deploy properly in 1 patient enrolled in the treatment arm (the left atrium legs of the device did not deploy so the device was removed without incident and another device was successfully deployed).
‡
In 1 patient enrolled in the treatment arm, a small thrombus was observed on the tip of the device delivery system in the right atrium. The delivery system was removed and exchanged. A new system was then reinserted, and the IASD device was successfully implanted.
§
In 1 patient enrolled in the treatment arm, the device was inadvertently maldeployed in the left atrium. The device remained on the guide wire and was percutaneously removed, and the procedure was subsequently aborted.
The ITT analysis of the key effectiveness end point (PCWP during exercise) was performed on all participants who had PCWP results for ≥1 exercise level (at 20 W, 40 W, 60 W, or 80 W) at both baseline and 1 month (all participants achieved an exercise level of ≥20 W at 1 month). These results are shown in Table 3. Overall, the IASD treatment group had a greater reduction in PCWP during exercise after 1 month compared with the control group (P=0.028 by mixed-effects model repeated measures analysis of covariance). Thus, the trial met its key effectiveness end point measure. On secondary outcome analysis, the change in peak PCWP at 1 month was −3.5±6.4 mm Hg in the treatment group compared with −0.5±5.0 mm Hg in the control group (P=0.14). As shown in Figure 3, patients randomized to the IASD arm had a reduction in 1-month PCWP at legs up, 20 W, and peak exercise (P<0.05 for all comparisons), whereas the control group did not. From baseline to 1 month, the exercise time increased by a mean of 1.2±3.7 minutes in the treatment group compared with 0.4±3.5 minutes in the control group (P=0.60), and peak supine bike workload increased by a mean of 1.5±14.6 W in the treatment group compared with −1.9±10.8 W in the control group (P=0.35). On exploratory analyses, legs up PCWP and 20 W PCWP decreased to a greater amount in the IASD treatment group compared with the control group (P<0.05 for both comparisons) (Table 3). Results of the per-protocol analyses were similar to the results of the ITT analysis described earlier.
| Outcome at 1 Mo | IASD Patients (N=22) | Control Patients (N=22) | P Value |
|---|---|---|---|
| Primary effectiveness outcome, change from baseline to 1 mo | 0.028* | ||
| PCWP at a workload of 20 W, mm Hg† | −3.2±5.2 (n=14) | 0.9±5.1 (n=18) | |
| PCWP at a workload of 40 W, mm Hg† | −1.0±4.5 (n=10) | −1.9±4.3 (n=10) | |
| PCWP at a workload of 60 W, mm Hg† | −2.3±4.9 (n=6) | −1.3±4.9 (n=6) | |
| Primary safety outcome (MACCRE) | 1.000 | ||
| Frequency, n/N (%) | 0/22 (0%) | 1/22 (4.5%) | |
| 95% confidence interval | (0.0−16.1) | (0.1−22.8) | |
| Secondary outcomes (change from baseline to 1 mo)‡ | |||
| Hemodynamic measures | |||
| PCWP, legs down at rest, mm Hg | −2.2±6.6 (n=18) | −0.5±5.0 (n=21) | 0.441 |
| PCWP, legs up at rest, mm Hg | −5.0±5.7 (n=19) | 0.0±6.4 (n=21) | 0.024 |
| PCWP, peak, mm Hg | −3.5±6.4 (n=17) | −0.5±5.0 (n=17) | 0.144 |
| PCWP, workload-corrected, mm Hg/W/kg | −5.7±27.3 (n=16) | 10.3±45.9 (n=17) | 0.231 |
| Right atrial pressure at rest, mm Hg | 0.5±4.0 (n=20) | 0.5±3.3 (n=20) | 0.673 |
| Mean pulmonary artery pressure at rest, mm Hg | −2.7±5.4 (n=20) | −0.7±4.6 (n=21) | 0.111 |
| Cardiac output at rest, L/min§ | 1.6±1.3 (n=20) | −0.5±1.4 (n=22) | <0.001 |
| Pulmonary vascular resistance at rest, WU | −0.76±1.59 (n=20) | 0.17±1.57 (n=21) | 0.102 |
| Pulmonary vascular resistance during exercise, WU | −0.29±1.22 (n=19) | 0.31±1.64 (n=21) | 0.051 |
| Systolic blood pressure at rest, mm Hg | 3.8±22.2 (n=20) | 6.2±31.6 (n=22) | 0.901 |
| Diastolic blood pressure at rest, mm Hg | 1.2±11.4 (n=20) | 1.6±21.7 (n=22) | 0.592 |
| Mean arterial pressure at rest, mm Hg | 2.0±14.0 (n=20) | 3.2±23.5 (n=22) | 0.725 |
| Heart rate at rest, bpm | 3.2±10.1 (n=19) | 0.6±12.3 (n=22) | 0.972 |
| Heart rate at peak exercise, bpm | −2.1±17.6 (n=19) | −3.5±24.0 (n=21) | 0.956 |
| Heart rate increase with exercise, bpm | −5.3±19.4 (n=19) | −3.3±24.0 (n=21) | 0.880 |
| Functional capacity | |||
| NYHA class | −0.5±0.7 (n=21) | −0.4±0.7 (n=21) | 0.538 |
| Exercise duration, min | 1.2±3.7 (n=20) | 0.4±3.5 (n=20) | 0.603 |
| Peak exercise workload, W | 1.5±14.6 (n=20) | −1.9±10.8 (n=21) | 0.348 |
| Weight, kg | −0.56±3.20 (n=21) | −0.25±2.33 (n=22) | 0.710 |
ANCOVA indicates analysis of covariance; CI, confidence interval; IASD, interatrial shunt device; MACCRE, major adverse cardiac, cerebrovascular embolic, or renal events; MMRM, mixed effects model repeated measures; NYHA, New York Heart Association; PCWP, pulmonary capillary wedge pressure; W, watts; and WU, wood units. Values represent mean±SD for continuous variables and n/N (%) for categorical variables.
*
The P value for change in supine exercise PCWP from baseline to 1 mo was computed using MMRM ANCOVA adjusting for the corresponding baseline values of supine exercise PCWP.
†
P=0.019 at 20 W, P=0.990 at 40 W, and P=0.822 at 60 W. P values were calculated using ANCOVA with adjustment for baseline value.
‡
P values in this section were calculated using ANCOVA with adjustment for baseline value.
§
Right-sided cardiac output, calculated by the thermodilution method.
Overall, few periprocedural, MACCRE, or other serious adverse events occurred in either the treatment or control groups at 1 month of follow-up (Table 4). At 1 month, 0/21 (0%) of the participants in the IASD treatment group experienced a MACCRE event, and 1/22 (4.5%) of the participants in the sham control group experienced a MACCRE event (new onset/worsening kidney function event) (P=1.0). At 1 month of follow-up, no deaths, myocardial infarctions, IASD occlusions or removals after the procedure, or strokes or transient ischemic attacks were reported in either of the study arms. Furthermore, during the 1-month follow-up period, none of the study participants in normal sinus rhythm at baseline developed new-onset atrial fibrillation or flutter, and no systemic embolic events or cardiac perforation, cardiac tamponade, or emergency cardiac surgery were reported in either of the study arms.
| Adverse Event | IASD Patient (N=22) | Control Patients (N=22) | P Value |
|---|---|---|---|
| MACCRE | 0.00 (0/21) | 4.55 (1/22) | 1.000 |
| Cardiovascular death | 0.00 (0/21) | 0.00 (0/22) | — |
| Embolic stroke | 0.00 (0/21) | 0.00 (0/22) | — |
| Device-/procedure-related MACE* | 0.00 (0/21) | 0.00 (0/22) | — |
| New onset or worsening renal dysfunction | 0.00 (0/21) | 4.55 (1/22) | 1.000 |
| MACE | 0.00 (0/21) | 0.00 (0/22) | — |
| Cardiac death | 0.00 (0/21) | 0.00 (0/22) | — |
| Myocardial infarction | 0.00 (0/21) | 0.00 (0/22) | — |
| Emergency cardiac surgery | 0.00 (0/21) | 0.00 (0/22) | — |
| Cardiac tamponade | 0.00 (0/21) | 0.00 (0/22) | — |
| Death | 0.00 (0/21) | 0.00 (0/22) | — |
| Myocardial infarction | 0.00 (0/21) | 0.00 (0/22) | — |
| Stroke or transient ischemic attack | 0.00 (0/21) | 0.00 (0/22) | — |
| Systemic embolization | 0.00 (0/21) | 0.00 (0/22) | — |
| Cardiac perforation | 0.00 (0/21) | 0.00 (0/22) | — |
| Newly acquired atrial fibrillation/flutter | 0.00 (0/21) | 0.00 (0/22) | — |
| Major vascular complications | 0.00 (0/21) | 0.00 (0/22) | — |
| Device embolization | 0.00 (0/21) | 0.00 (0/22) | — |
| Device occlusion | 0.00 (0/21) | 0.00 (0/22) | — |
| Device-related repeat procedure | 0.00 (0/21) | 0.00 (0/22) | — |
| Heart failure event | 4.76 (1/21) | 13.64 (3/22) | 0.607 |
| Heart failure event requiring intravenous treatment | 0.00 (0/21) | 9.09 (2/22) | 0.488 |
| Cardiogenic shock | 0.00 (0/21) | 0.00 (0/22) | — |
IASD indicates interatrial shunt device; MACCRE, major adverse cardiac, cerebrovascular and renal events; and MACE, major adverse cardiac event. Values represent % (n/N). Events in this table have been adjudicated by the independent, blinded Clinical Events Committee. Denominators indicate the number of patients with at least 23 days of follow-up or an out-of-hospital event through 1 mo.
*
Includes MACE events that were determined by the Clinical Events Committee to be definitely, probably, or possibly related to the procedure or device.
At 1 month of follow-up, the rate of HF-related hospitalizations or emergency department/acute care facility visits requiring intravenous treatment was 0/21 (0.0%) in the treatment arm compared with 2/22 (9.1%) in the control arm (P=0.49). There were no significant differences in loop diuretic dose (furosemide equivalents, in mg) at baseline or at 1 month of follow-up between the 2 treatment groups (mean change from baseline of −0.9±9.7 mg in the IASD treatment group versus 0.9±20.0 mg in the sham control group) (P=0.70).
Discussion
The REDUCE LAP-HF I randomized, blinded, sham-controlled trial was designed to test the hypothesis that the implantation of the IASD System II device in the interatrial septum in patients with symptomatic HF and midrange or preserved EF (≥40%) results in the lowering of PCWP during exercise. The trial met its primary effectiveness end point, with statistically significant lowering of PCWP during exercise at 1 month of follow-up (P=0.028). The 3.5 mm Hg reduction in peak exercise PCWP in the IASD arm at 1 month is similar to the reduction seen in the prior observational study (n=64, all of whom received the IASD) at 6 months.18,19 Although the decrease in peak exercise PCWP is modest, it was associated with clinically important improvements in exercise duration and quality of life in the prior observational study, which were observed at both 6 and 12 months after IASD implantation.18,19
The REDUCE LAP-HF I trial also showed that the IASD device was safe at 1 month. In 1 patient the IASD was mal-deployed in the left atrium; however, because the device remains on the guide wire after deployment and is fully retrievable, it was safely removed. The key safety outcome measure for the trial was MACCRE at 1 month, defined as the composite of cardiovascular death, embolic stroke, device- or procedure-related adverse cardiac events, and new-onset or worsening kidney dysfunction. Implantation of the IASD appeared to be safe at 1 month, with no MACCRE events reported in the IASD treatment arm compared with a 1-month MACCRE rate of 4.5% in the control arm. In addition, no patients in the treatment arm developed persistent or permanent atrial fibrillation/flutter or complications such as cardiac perforation, cardiac tamponade, emergency cardiac surgery, systemic embolization, or major vascular complications after the procedure. Finally, consistent with prior observational trials of the IASD, none of the patients in the treatment arm experienced device embolization, device occlusion, or device migration, and none of them required a repeat procedure for removal or occlusion of the device.
As shown in Table 1, the patients enrolled in the trial were similar to those in prior studies of patients with HFpEF.22 Participants were elderly, 50% female, were obese, and had multiple comorbidities. Left ventricular EF was preserved (>50%) in the majority, and most of the participants were on a relatively high dose of diuretics and had a prior HF hospitalization or acute care visit within the last 12 months. On invasive hemodynamic testing, baseline resting PCWP was elevated (mean 20 mm Hg) despite being on a mean dose of diuretics of 103 mg furosemide equivalents per day. Thus, the enrolled patients were symptomatic and had significant HF. Patients enrolled in REDUCE LAP-HF I were generally similar to those enrolled in HFpEF epidemiological studies23 and contemporary HFpEF clinical trials.22 However, unlike these prior studies, patients enrolled in the present trial had objective evidence of elevated LV filling pressure (ie, PCWP) at rest and during exercise at baseline, which confirmed the HF diagnosis. Together these findings show that patients enrolled in REDUCE LAP-HF I represent contemporary patients with HFpEF encountered in routine clinical practice.
The findings from the REDUCE LAP-HF I trial are important because they are the first randomized data for this device. In the prior observational, open-label studies of the Corvia IASD in patients with HFpEF, including 75 patients with the IASD implanted,18–20 were associated with lower PCWP during exercise, greater exercise capacity, and an excellent safety profile, but none of these prior studies were conclusive because they were nonrandomized and therefore subject to potential bias and confounding. In the present trial, randomized evaluation of the IASD confirmed the lowering of PCWP during exercise and demonstrated improvements in workload-corrected PCWP, exercise duration, and peak exercise workload compared with sham control. However, although these latter secondary outcomes were numerically better in the treatment group, the differences did not achieve statistical significance because the trial was not powered to demonstrate effectiveness in these end points.
Despite the fact that patients with HFpEF have evidence of pulmonary vascular stiffening, in open-label-treated patients with HFpEF enrolled in prior IASD studies,19 left-to-right shunting through the IASD (which increases flow through the pulmonary vasculature) was not associated with increased pulmonary artery pressure or pulmonary vascular resistance, both of which could be deleterious in HFpEF because of increased RV load, with subsequent right-sided HF. The present randomized trial findings were similar to the prior open-label studies; there was a greater reduction in mean pulmonary artery pressure and pulmonary vascular resistance in the IASD treatment arm compared with the control arm, although these differences did not achieve statistical significance (Table 3). Possible explanations for the seemingly paradoxical trend toward lower PA pressures after IASD placement are 2-fold. First, elevated PCWP can result in augmentation of the reflected pressure wave in the pulmonary artery, which would raise pulmonary artery pressures and can lead to increased pulmonary vascular resistance.24 Lowering of LA pressure and PCWP would therefore tend to reduce the reflected pressure wave, thereby lowering pulmonary artery pressure. Second, the LA blood that is shunted across the IASD is oxygenated and thus increases pulmonary artery saturation. The higher oxygen content in the pulmonary arterial vasculature, which was also seen in response to the IASD in prior nonrandomized studies, could have a vasodilatory effect that allows for the ability of the pulmonary vasculature to handle increased flow from the IASD-induced left-to-right shunting. This may be especially evident during exercise, as was seen in the present study (Table 3).
Elevated LV filling pressure (ie, increased PCWP) at rest or during exercise is an important determinant of both symptoms and outcomes in patients with HF.25 Borlaug and colleagues26 showed that elevated PCWP during exercise can distinguish patients with HFpEF from those with noncardiac dyspnea, and the rise in PCWP during exercise is an important pathophysiologic determinant of HFpEF early in the course of the clinical syndrome. PCWP during exercise also correlates with 6-minute walk test distance and is an important determinant of mortality in patients with HFpEF.13,14 In addition, implantable hemodynamic sensor-guided lowering of pulmonary artery diastolic pressure (a surrogate for PCWP in left heart failure) has been shown to reduce HF hospitalizations in patients with HF and EF >40%.27 On this background and in view of the hemodynamic effect of reduced exercise PCWP with the IASD,18,19 it is expected that treatment with the IASD will result in improved clinical outcomes in patients with HFpEF. However, this hypothesis must be tested in a larger, adequately powered randomized controlled trial.
The importance of testing cardiovascular device therapies against sham control procedures cannot be underestimated. The mere act of having an invasive procedure alone may result in improved symptoms in patients with HF. Although studies of invasive treatments can be difficult to study in a blinded fashion, lack of blinding may overestimate the effectiveness of treatments.28,29 Thus, the present trial, which evaluated a hemodynamic primary end point in a blinded fashion, is an important step in the development of the IASD as a potential treatment for patients with HF. The finding that the IASD does indeed lower exercise PCWP provides a mechanistic rationale for further randomized evaluation of the device in a larger pivotal trial that has clinical end points.
Certain limitations should be considered. Although an a priori power calculation was conducted showing adequate statistical power with a sample size of 20 in each treatment group, the overall size of the trial is small. Thus, although the treatment groups were well balanced overall, some demographic and clinical differences occurred between the groups, although only the difference in race/ethnicity was statistically significant. Furthermore, the primary effectiveness end point (PCWP during exercise) can be challenging to measure, even with training of sites and the use of a central hemodynamic core laboratory, as was done in the present study. However, the passive preload increase maneuver (which was done in this trial with legs up in the supine exercise bicycle pedals) does not suffer from the motion artifact of exercise but still provides information on how the LA handles an increased load. In the present trial, PCWP during the legs up maneuver decreased significantly at 1 month in the IASD treatment group but not in the control group (Table 3 and Figure 3), supporting the mechanistic effect of the IASD. Uniform measurement of either BNP or N-terminal pro-BNP at baseline and 1 month in all randomized patients (which was not available in the present study) could have provided additional information on the correlation of changes in natriuretic peptide biomarkers with IASD-induced reduction in exercise PCWP. An additional limitation relates to the use of anticoagulants (ie, clopidogrel) in the IASD-treated patients not previously on a nonaspirin anticoagulant but not in sham-control patients. Although we had specific instructions to maintain blinding throughout the trial (online-only Data Supplement), we did not administer a questionnaire to evaluate the success of blinding at 1 month (the trial does include a questionnaire at the 1-year follow-up visit that will evaluate blinding). A final limitation relates to the relatively short time frame of the study (1-month follow-up). However, the open-label studies show prolonged hemodynamic and symptomatic benefits of the IASD at 1 year.19
In summary, we found that in patients with HF and EF ≥40%, implantation of an IASD reduced PCWP during exercise to a greater extent than a sham control procedure, demonstrating that in patients with HF with elevated LA pressure during exercise, the creation of an 8-mm interatrial communication unloads the LA. We also found that the IASD is safe compared with the sham control procedure at 1 month, and it showed favorable but nonsignificant trends in several additional secondary hemodynamic and functional end points. These findings suggest that the IASD could have beneficial effects in patients with HFpEF and HF with midrange EF, setting the stage for a larger scale randomized clinical trial powered to examine the effects of the IASD on symptoms, quality of life, exercise capacity, and clinical outcomes.
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© 2017 American Heart Association, Inc.
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History
Received: 6 October 2017
Accepted: 25 October 2017
Published online: 15 November 2017
Published in print: 23 January 2018
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Disclosures
Dr Feldman has received consulting fees from Abbott, BSC, Edwards, and Gore. Dr Mauri has received research support from Corvia Medical, Inc. Dr Petrie has received speaker fees or consulting honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Maquet, Novartis, Novo Nordisk, Pfizer, Servier, and Takeda; and has served on clinical events committees for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, GlaxoSmithKline, Reservlogix, Roche, and Stealth Biotherapeutics. Dr Basuray received financial support from Corvia Medical to run the hemodynamic core laboratory and has received consulting fees from Abbott, BackBeat Medical, Boston Scientific, Impulse Dynamics, Medtronic, and Sensible Medical. Dr Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, and United Therapeutics.
Sources of Funding
REDUCE LAP-HF I was designed jointly by the academic steering committee and the sponsor. The study was funded by Corvia Medical Inc. Data collection and analyses were done by the Baim Clinical Research Institute. The sponsor had no role in the collection, analysis, or interpretation of data, or the decision to submit for publication.
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Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.