Flow Regulation by Opening the SepTum in Patients With Heart Failure; a Prospective, Randomized, Sham-controlled, Double-blind, Global Multicenter Study

Flow Regulation by Opening the SepTum in Patients With Heart Failure; a Prospective, Randomized, Sham-controlled, Double-blind, Global Multicenter Study

The purpose of this clinical study is to assess the safety and effectiveness of the Atrial Flow Regulator in the treatment of subjects, 18 years of age or older, who have symptomatic heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF) while on stable guideline directed medical therapy (GDMT) as outlined in the Guidelines for the Management of Heart Failure.

General Inclusion Criteria:

• Aged ≥18 years

• Presence of chronic symptomatic HF (NYHA ≥class 2) and at least one of the following:

  1. Previous heart failure hospitalization within 6 months of informed consent or

  2. Elevated NT-proBNP (or BNP):

     1. If in Sinus Rhythm, must have a 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 900 pg/mL, according to local measurement, within 2 months of the Screening Visit during a clinically stable period*.
     2. If in Atrial Fibrillation or Atrial Flutter, must have a corrected elevated BNP level of at least 400 pg/mL or an NT-proBNP level of at least 1200 pg/mL within 2 months of the Screening Visit during a clinically stable period*.

• If LVEF documented at screening is >55%, then must have one of either:

  1. Left atrial enlargement (LA diameter >2.3 cm/m2 or LA volume index >28 mL/m2), or
  2. PCWP ≥ 15 mmHg at rest within previous 12 months, or
  3. LVEDP ≥15 mmHg at rest within previous 12 months

• 6 MWT distance 100-450 meters

• Treated with maximally tolerated doses of class I GDMT and class electrical therapies (CRT and ICD) according to latest applicable guidelines (e.g., AHA or ESC) for at least 2 months prior to informed consent, and a stable dose diuretic for at least 1 month prior to informed consent.

General Exclusion Criteria:

• Myocardial infarction and/or revascularization with percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) within 3 months prior to informed consent

• Surgical or transcatheter valve (aortic, mitral, or tricuspid) repair or replacement within 2 months prior to informed consent

• Automated implantable cardioverter defibrillator (AICD) placement within 2 months prior to informed consent

• Resynchronization therapy started within 3 months prior to informed consent

• Major surgery within 3 months prior to informed consent

• History of stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT), or pulmonary emboli within 6 months prior to informed consent, or any prior stroke with persistent neurologic deficit, or any prior intracranial bleed, or known intracerebral aneurysm, AV malformation or other intracranial pathology increasing the risk of bleeding

• Uncontrolled atrial fibrillation with resting heart rate >110 beats per minute despite medical therapy

• Documented history of non-dilated cardiomyopathy (obstructive hypertrophic, restrictive, infiltrative) or pericardial disease

• Clinically significant valvular heart disease:

  1. regurgitation grade ≥3+ or
  2. severe stenosis of mitral or tricuspid valves, or
  3. moderate or greater stenosis of aortic valves

• Prior diagnosis of pulmonary hypertension with current treatment with one or more pulmonary hypertension specific drugs (e.g. endothelin receptor antagonists (ERAs), phosphodiesterase inhibitors (PDE 5 Inhibitors) or prostacyclin analogues)

• Uncontrolled hypertension, Systolic Blood Pressure (SBP) ≥160 or Diastolic Blood Pressure (DBP) ≥100 mmHg despite medical therapy at the time of screening visit

• Previous interventional or surgical atrial septal defect (ASD) or patent foramen ovale (PFO) closure

• Inadequate vascular access for implantation of shunt, e.g., suboptimal femoral venous access for transseptal catheterization or inferior vena cava (IVC) is not patent

• Chronic kidney disease currently requiring dialysis

• Allergy or contraindication to aspirin, or clopidogrel and prasugrel and ticagrelor, or heparin and bivalirudin

• Bleeding disorders (international normalized ratio [INR] >2.0, platelet count <100,000 x 109/L, hemoglobin <10.0 g/dL)

• Known clinically significant untreated carotid artery stenosis likely to require intervention, at discretion of investigator

• Current untreated coronary artery disease with indication for revascularization

• Significant Right Ventricular dysfunction demonstrated by:

  1. Tricuspid Annular Plane Systolic Excursion (TAPSE) <16mm or
  2. Right Ventricular Fractional Area Change (RVFAC) ≤30%

• Right Atrial Volume Index (RAVI) > 31ml/m2

• Left Ventricular End-Diastolic Diameter (LVEDD) > 8.0 cm as assessed by echocardiography

• Severe COPD requiring oral steroid therapy or daytime oxygen

• Echocardiographic evidence of intra-cardiac mass, thrombus, or vegetation

• On current immunosuppression or systemic oral steroid treatment

• Any condition that limits exercise tolerance other than heart failure (e.g., peripheral vascular disease, orthopedic issues, angina, other), at the discretion of the Investigator