ALT-FLOW II Trial of the Edwards APTURE Transcatheter Shunt System

A Randomized, Sham-controlled Clinical Trial for Evaluation of the Edwards APTURE Transcatheter Shunt System (ALT-FLOW II)

This is a prospective, multi-center, randomized, sham-controlled, double-blinded (participant and outcomes assessor) clinical trial.

The objectives of this trial are to assess the safety, performance, and effectiveness of the Edwards APTURE transcatheter shunt system when used for the treatment of patients with heart failure with preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction (LVEF >40%) who remain symptomatic despite guideline-directed medical therapy (GDMT)

Key Inclusion Criteria:

• Symptomatic heart failure

1. A primary diagnosis of HFmrEF or HFpEF (LVEF > 40%), and
2. NYHA class II to ambulatory NYHA class IV (IVa), and
3. Documentation of at least one of the following from the date of initial informed consent or date of enrollment:

i. Within the prior 12 months, EITHER:

• HF hospital admission (with HF as the primary or secondary diagnosis)
• Treatment with intravenous (IV) or intensification of oral diuretics for HF

ii. Within the prior 6 months, EITHER:

• BNP value > 35 pg/ml in normal sinus rhythm (NSR) or paroxysmal atrial fibrillation (AF)
• BNP > 125 pg/ml for permanent or long-term persistent AF
• NT-proBNP > 125 pg/ml in NSR or paroxysmal AF
• NT-proBNP > 375 pg/ml for permanent or long-term persistent AF d. There is objective evidence of cardiogenic pulmonary congestion based on hemodynamic criteria obtained by right heart catheterization (RHC) at exercise, and confirmed by hemodynamics core lab as: As measured at end-expiration, pulmonary capillary wedge pressure (PCWP) at ≥ 20 Watts exercise (PCWP ≥ 20W) is elevated to ≥ 25 mmHg and exceeds [the corresponding] right atrial pressure (RAP) by ≥ 8 mmHg • In the judgment of the treating physician and the Central Screening Committee the patient is on GDMT for HFpEF/HFmrEF for >30 days prior to screening and baseline assessments, that is expected to be maintained without change for 6 months.

Key Exclusion Criteria:

• Severe heart failure defined as one or more of the below:

  1. ACC/AHA/ESC Stage D HF, non-ambulatory NYHA Class IV HF
  2. If Body Mass Index (BMI) < 30, cardiac index < 2.0 L/min/m2
  3. If BMI ≥ 30, cardiac index < 1.8 L/min/m2
  4. Inotropic infusion (continuous or intermittent) within the past 6 months
  5. Patient is on the cardiac transplant waiting list
  6. Prior diagnosis of HF with reduced ejection fraction (HFrEF), including patients with improvement in LVEF to > 40%

• Valve disease:

  1. Degenerative mitral regurgitation > moderate
  2. Functional or secondary mitral valve regurgitation defined as grade > moderate
  3. Mitral stenosis > mild
  4. Primary or secondary tricuspid valve regurgitation defined as grade > moderate
  5. Aortic valve disease defined as aortic regurgitation grade > moderate or aortic stenosis > moderate

• More than mild right ventricular (RV) dysfunction as determined by the echo core lab, taking into account the following available parameters:

  1. Tricuspid annular plane systolic excursion (TAPSE) <1.4 cm, or
  2. RV size ≥ LV size
  3. Right ventricular ejection fraction (RVEF) < 35%; or
  4. Imaging or clinical evidence of congestive hepatopathy

• Mean right atrial pressure (mRAP) > 15 mmHg at rest

• Pulmonary vascular resistance (PVR) ≥ 5.0 WU

• BMI ≥ 45

• Myocardial infarction (MI) and/or any therapeutic invasive, non-valvular cardiovascular procedure within past 3 months or current indication for coronary revascularization

• Stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT) or pulmonary embolus within the past 6 months

• Renal insufficiency as determined by creatinine (sCr) level > 2.5 mg/dL or estimated glomerular filtration rate (eGFR) < 25ml/min/1.73 m2 by CKD-Epi equation; or currently requiring dialysis

• Performance of the six-minute walk test (6MWT) with a distance < 50m OR > 450m

• Active endocarditis or infection requiring intravenous antibiotics within 3 months