RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF

RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF

This study will evaluate the V-Wave Ventura Interatrial shunt. The Shunt is a small, hourglass-shaped device implanted in the dividing wall (septum) between the right and left atria (top chambers) of the heart placed during a minimally invasive cardiac catheterization procedure. The hourglass shape of the device holds the Shunt in place. The small opening in the center allows a small amount of blood to flow (to be shunted) from the top left chamber to the top right chamber of the heart. By "shunting" this small amount of blood, the increased pressure in the left side of the heart is reduced, which is expected to reduce congestion in the lungs and improve your symptoms of heart failure.

A previous study, the REducing Lung congestIon symptoms using the v-wavE shunt in adVancEd Heart Failure (RELIEVE-HF) trial showed that implantation of an interatrial shunt device was safe. In that study, patients whose heart pumping function (left ventricular ejection fraction, or LVEF) was >40% did not have better HF outcomes, such as hospitalization or even death after getting the device. However, the study looked separately at the LVEF ≤40% group and found that patients with an LVEF ≤40% showed improvements in these HF outcomes, as well as fewer episodes of worsening HF requiring an artificial heart pump. This suggests the shunt may help people whose heart pump is reduced, but more information is needed. The purpose of this study is to add to the data on the safety and whether the shunt works in preventing worsening heart failure for patients with reduced pumping strength or LVEF ≤40% .

This study is a multi-center, randomized, patient and observer blinded trial, with three (3) patients randomized to received the shunt (Treatment arm) for every two (2) non-implant Placebo-Procedure (Control patients). A total of approximately 250 patients will be randomized. Patients and research staff managing patients after randomization will be blinded during follow-up for a minimum of 12 months to a maximum of 24 months. All patients (Randomized to Treatment and Control) will be followed for a total of 3 years from the time of the randomization for comparison. Follow-up visits will be performed for the study will be conducted in clinic with the research doctors and staff and will include some telephone/remote visits. Patients randomized to the Control group who still meet inclusion/without exclusion criteria and consent will have an opportunity to receive the shunt if the effectiveness endpoint is met at primary study results.

The Study Device, the V-Wave Interatrial Shunt System, includes a permanent implant-the Shunt, placed during a minimally invasive cardiac catheterization procedure using its dedicated Delivery Catheter. By transferring blood from the left to the right atrium, the Shunt is intended to reduce excessive left-sided cardiac filling pressures in patients with advanced Heart Failure with reduced Ejection Fraction (HFrEF). The anticipated outcome is a reduction in heart failure events (all-cause mortality, cardiac transplantation or LVAD implantation (HT/LV), and all heart failure hospitalizations).

The study is a prospective, multi-center, 3:2 randomized, patient and observer blinded trial, with three (3) patients randomized to the Shunt Treatment arm for every two (2) non-implant Placebo-Procedure Control patients. The primary analysis will be performed when the last enrolled patient has been followed for a minimum of 12 months from randomization. The duration of follow-up evaluated by the primary effectiveness endpoint will range from a minimum of 12 to a maximum of 24 months. All patients (Randomized to Treatment and Control) will be followed for a total of 3 years from the time of the randomization. Patients randomized to the Control group who still meet inclusion/without exclusion criteria will have an opportunity to crossover and receive the shunt if the primary effectiveness endpoint is met at primary study analysis.

The REducing Lung congestIon symptoms using the v-wavE shunt in adVancEd Heart Failure (RELIEVE-HF) trial demonstrated that transcatheter implantation of an interatrial shunt device was safe but did not improve outcomes in HF patients across the full range of left ventricular ejection fraction (LVEF). However, results from a prespecified exploratory analysis in stratified randomized LVEF subgroups (LVEF ≤40% versus >40%) suggests that shunt implantation was beneficial in patients with reduced LVEF ≤40%. The RELIEVE- HFrEF trial is designed to provide additional data supporting this finding from the RELIEVE-HF trial.

Inclusion Criteria:

1. Heart failure with a reduced LV ejection fraction (≤40%) and documented heart failure for at least 6 months from Baseline Visit.

2. NYHA Class III symptoms

3. Receiving guideline directed medical therapy (GDMT) for heart failure which refers to those HF drugs carrying a Class I indication:

   1. An inhibitor of the renin-angiotensin system (RAS inhibitor), including an angiotensin receptor-neprilysin inhibitor (ARNI), angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and an evidence-based beta-blocker (BB) for at least 3 months prior to the Baseline Visit
   2. An SGLT2I Inhibitor for at least 1 month prior to the Baseline Visit
   3. Other medications recommended for selected populations, e.g., on diuretics as required for volume control. Mineralocorticoid receptor antagonist (MRA) or nitrates/hydralazine should be used in appropriate patients, according to the published guidelines.
   4. All patients are on stable HF medications as determined by the investigator, for at least 1 month, with the exception of diuretic therapy. Stable is defined as no more than a 100% increase or 50% decrease in dose within these periods.

4. Receiving Class I recommended cardiac rhythm management device therapy. Specifically: if indicated by class I guidelines, cardiac resynchronization therapy (CRT), implanted cardioverter-defibrillator (ICD) or a pacemaker should be implanted at least 3 months prior to Baseline Visit.

5. Must meet 5a OR 5b.

   1. One (1) prior Heart Failure Hospitalization with duration >24 hours or Emergency Room Heart Failure Visit with duration ≥6 hours, or Heart Failure Clinic ADHF Visit with duration ≥6 hours, within 12 months from Baseline Visit.
   2. Alternatively, if patients have not had a HF hospitalization or ER HF Visit within the prior 12 months, they must have a BMI corrected elevated Brain Natriuretic Peptide (BNP) level of at least 300 pg/ml or an N-terminal pro-BNP (NT-proBNP) level of at least 1,500 pg/ml, according to local measurement, within 3 months of the Baseline Visit.

6. Able to perform the 6-minute walk test with a distance ≥100 meters and ≤450 meters.

7. Provide written informed consent for study participation and be willing and able to comply with the required tests, treatment instructions and follow-up visits.

Main Exclusion Criteria:

• Resting systolic blood pressure <90 or >160 mmHg
• Baseline echocardiographic evidence of intracardiac blood clot, significant right ventricular dysfunction or severe left sided dilation.
• Diagnosis of severe pulmonary hypertension.
• Congenital Atrial septal defect, patent foramen ovale, with known shunting on echo
• Untreated moderately severe or severe aortic or mitral stenosis.
• Mitral valve repair device (e.g. MitraClip) implanted within 3 months prior to Baseline Visit.
• Acute MI, acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), rhythm management system revision (not including generator change), lead extraction, or cardiac or other major surgery within 3 months of Baseline Visit.
• Stroke, transient ischemic attack (TIA), systemic or pulmonary thromboembolism, or deep vein thrombosis (DVT) within 6 months.
• Intractable HF with any of the following:

Treatment with IV vasoactive medications (e.g., IV inotropes, IV vasodilators) within the last 30 days.

Treated with a ventricular assist device (VAD). Listed for cardiac transplantation.

• Prior cardiac transplantation.
• Life expectancy <1 year due to non-cardiovascular illness.
• Kidney failure or is receiving dialysis.
• Active infection requiring parenteral or oral antibiotics.
• Known allergy to nickel.
• Hemodynamic, heart rhythm or respiratory instability at the time of Final Exclusion Criteria.