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

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.