|Principal Investigator: Kevin Shah|
|Keywords: HFpEF , HFrEF , Heart Failure , Interatrial Shunt||Department: Cardiovascular Services|
|IRB Number: 00131417||Co Investigator: Stavros Drakos|
|Specialty: Cardiology, Cardiology, Cardiology|
|Sub Specialties: Interventional Cardiology, General Cardiology, Heart Failure|
|Recruitment Status: Recruiting|
The objective of this study is to provide reasonable assurance of safety and
effectiveness of the V-Wave Interatrial Shunt System to improve clinical
outcomes in a certain high-risk subset of symptomatic patients suffering
Primary Safety Endpoint: The percentage of Treatment Group patients experiencing device-related Major Adverse Cardiovascular and Neurological Events (MACNE) during the first 30-days after randomization, compared to a pre-specified Performance Goal.
Primary Effectiveness Endpoint: Comparison between Treatment and Control groups of the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device (LVAD) implantation, recurrent HF hospitalizations (including Emergency Room HF Visits with duration >6 hours), and change in 6-minute walk test (6MWT) distance. The analysis is based on the method of Finkelstein and Schoenfeld.
Hierarchically Tested Secondary Effectiveness Endpoints
- 6MWT changes from Baseline to 12 months
- KCCQ changes from Baseline to 12 months
- Heart failure hospitalizations adjusted for all cause mortality
- Time to all-cause death, LVAD/Transplant or heart failure hospitalization
- Time to all-cause death or first heart failure hospitalization
- Cumulative heart failure hospitalizations
- Time to first heart failure hospitalization
- Modified Primary Effectiveness Endpoint including all-cause death, LVAD/Transplant and HF Hospitalizations but without 6MWT
Additional Effectiveness Outcome Measurements
- NYHA Class
- Patient Global Assessment
- Combined all-cause death and all-cause hospitalizations
- All-cause death
- Time to all-cause death (KM analysis)
- Time to cardiovascular death (KM analysis)
- Time to all-cause death, transplant or LVAD (KM analysis)
- Time to cardiovascular death, transplant or LVAD (KM analysis)
- Days alive free from heart failure hospitalization
- Outpatient intensification of heart failure therapy
- Emergency room HF visits
- HF Clinical Composite Assessment (improved, unchanged, or worsened) as described by Packer comprised of all-cause mortality, HF hospitalization, and changes in NYHA functional class ranking and Patient Global Assessment
- Comparison of transthoracic echocardiographic parameters as listed in Echocardiography Core Laboratory Manual
- Incidence of loss of shunt flow as measured on TTE and/or TEE
- Changes in 6MWT
- Changes in KCCQ
- Death: All-cause; Cardiovascular cause (with breakdown by cause, e.g. sudden death, myocardial infarction, pump failure, stroke); Non-Cardiovascular cause; Undetermined cause; and relationship to device, study intervention or other cardiovascular procedure
- Hospitalization: All-cause; HF hospitalization, Non-HF
- hospitalization (with breakdown for cause including if associated
- with secondary worsening of HF)
- Change in renal function
- Medication utilization including type, dose, frequency and changes
- Cost and cost-effectiveness data
- Technical success defined as successful delivery and deployment of the shunt and removal of the delivery catheter
- Technical success
- Device success
- Procedural success
- For Roll-in patients, transesophageal or intracardiac echocardiography at 6 and 12 months to assess shunt patency and other parameters as listed in the Echocardiography Core Laboratory Manual
Additional Safety Data Collection
- Major Adverse Cardiovascular and Neurological Events (MACNE) and Bleeding Academic Research Consortium (BARC) types 3 and 5 bleeding at 30 days
- Percentage of Treatment Group patients with device-related MACNE at 12 months
- Incidence of all Serious Adverse Events by type at study duration
- Incidence of cerebrovascular events at study duration with subclassification of CNS infarction, CNS hemorrhage, and TIA and their relationship to device or study procedures (per NeuroARC)
- Incidence of MI events at study duration after implantation
- Incidence of systemic embolization events at study duration after
- Incidence of pulmonary embolism events at study duration after
- Incidence of shunt implant embolization at study duration
- Device-related MACNE annually through 5 years
- MACNE in Control and Shunt Treatment arm patients receiving LVADs annually through 5 years
1. Ischemic or non-ischemic cardiomyopathy with either reduced or preserved LV ejection fraction and documented heart failure for at least 6 months from Baseline Visit.
2. NYHA Class III or ambulatory Class IV HF (historical assessment documented at the Baseline Screening visit).
3. Receiving guideline directed medical therapy (GDMT) for heart failure which refers to those HF drugs carrying a Class I indication:
a) Patients with reduced LVEF (≤40%): An inhibitor of the reninangiotensin system (RAS inhibitor), including an angiotensinV-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) or angiotensin receptor- neprilysin inhibitor (ARNI) and a beta-blocker (BB), for at least 3 months prior to the Baseline Visit.
b) Patients with reduced LVEF (≤40%): Other medications recommended for selected populations, e.g., mineralocorticoid receptor antagonist (MRA) or nitrates/hydralazine should be used in appropriate patients, according to the published guidelines.
c) All patients: Patient has been 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.
d) All patients: Drug intolerance, contraindications, or lack of indications must be attested to by the investigator. Patients should be on appropriate doses of diuretics as required for volume control.
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. These criteria may be waived if a patient is clinically contraindicated for these therapies or refuses them and must be attested to by the investigator.
5. Has a minimum of:
a) 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.
i) If a CRT device was previously implanted, the heart failure hospitalization must be ≥ 1 month after CRT implantation.
ii) If a mitral valve repair device (e.g. MitraClip) was previously implanted, the heart failure hospitalization must be ≥ 1 month after mitral valve repair implantation.
b) Alternatively, if patients have not had a HF hospitalization or ER HF Visit within the prior 12 months, they 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 1,500 pg/ml, according to local measurement, within 3 months of the Baseline Visit during a clinically stable period and at least 1 month after implantation of a CRT or mitral valve repair devices. (Note: "corrected" refers to a 4% reduction in the BNP or NT-proBNP
cutoff for every increase of 1 kg/m2 in BMI above a reference BMI of 20 kg/m2). If patient is on ARNI, NT-proBNP should be used exclusively.
6. Able to perform the 6-minute walk test with a distance ≥100 meters and ≤450 meters. The test will be performed twice separated by a minimum of 60 minutes between tests. The second test may be performed up to 7 days after the first test, if needed. The higher reading shall be used as the baseline value.
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.
Preliminary Exclusion Criteria at Baseline
1. Age <18 years old.
2. BMI >45 or <18 kg/m2.
3. Females of childbearing age who are not on contraceptives or surgically sterile; pregnant or lactating mothers.
4. Resting systolic blood pressure <90 or >160 mmHg after repeated measurements.
5. Baseline echocardiographic evidence of unresolved, non-organized or mobile intracardiac thrombus.
6. Severe pulmonary hypertension defined as PA systolic pressure >70 mmHg by echo/Doppler (or PVR >4.0 Wood Units by PA catheter measurement that cannot be reduced to ≤4 Wood Units by vasodilator
7. RV dysfunction defined as TAPSE <12mm or RVFAC ≤25% as assessed on Baseline TTE.
8. Left Ventricular End-Diastolic Diameter (LVEDD) >8cm as assessed on Baseline TTE.
9. Atrial septal defect (congenital or iatrogenic), patent foramen ovale, or anomalous pulmonary venous return, with more than trace shunting on color Doppler or intravenous saline contrast (bubble study) or prior surgical or interventional correction of congenital heart disease involving the atrial septum(excluding closure by suture only but including placement of a PFO or ASD closure device).
10. Untreated moderate to severe aortic or mitral stenosis.
11. Untreated severe (3+ to 4+) regurgitant valve lesions, which are anticipated to require surgical or percutaneous intervention within 12 months.
12. Mitral valve repair device (e.g. MitraClip) implanted within 3 months prior to Baseline Visit.
13. Untreated coronary stenosis which requires surgical or percutaneous intervention.
14. Acute MI, acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), rhythm management system revision, lead extraction, or cardiac or other major surgery within 3 months of
15. Active valvular vegetations, atrial myxoma, hypertrophic cardiomyopathy with significant resting or provoked subaortic gradient, acute myocarditis, tamponade, or large pericardial effusion, constrictive pericarditis, infiltrative cardiomyopathy (including cardiac sarcoidosis, amyloidosis, and hemochromatosis), or congenital heart disease, as cause of HF.
16. Stroke, transient ischemic attack (TIA), systemic or pulmonary thromboembolism, or deep vein thrombosis (DVT) within 6 months of Baseline Visit. Any prior stroke with permanent neurologic deficit.
Existing IVC filter.
17. Transseptal procedure for another indication (e.g. AF ablation, left atrial appendage occlusion, mitral valve repair/replacement) anticipated within 6 months.
18. Bradycardia with heart rate <45 bpm (unless treated with a permanent pacemaker) or uncontrolled tachyarrhythmias. This includes defibrillation shocks reported by the patient within 30 days of Baseline
19. Intractable HF with:
a) Resting symptoms despite maximal medical therapy (ACC/AHA HF Stage D).
b) Treatment with IV vasoactive medications (e.g., IV inotropes, IV vasodilators) within the last 30 days.
c) Cardiac Index <1.5 L/min/m2.
d) Treated with a ventricular assist device (VAD).
e) Listed for cardiac transplantation.
20. Prior cardiac transplantation.
21. Patients with HFrEF (LVEF ≤40%) who are intolerant to a RAS inhibitor including all of ACEI, ARB or ARNI, and intolerant to beta-blocker medical therapy.
22. Not eligible for emergency cardiothoracic or vascular surgery in the event of cardiac perforation or other serious complication during study intervention procedure.
23. Life expectancy <1 year due to non-cardiovascular illness.
24. Coagulopathy or is taking anticoagulation therapy which cannot be interrupted for the study intervention procedure, or has contraindications for all of the study mandated post implantation
anticoagulation / antiplatelet regimens or known hypersensitivity, or contraindication to procedural medications which cannot be adequately managed medically.
25. Estimated glomerular filtration rate (eGFR) <25 ml/min/1.73 m2 by the MDRD method, or not responsive to diuretics, or is receiving dialysis.
26. Hepatic impairment with at least one liver function test (transaminases, total bilirubin, or alkaline phosphatase) ≥ 3 times upper limit of normal.
27. Severe chronic pulmonary disease requiring daytime home oxygen or chronic oral steroid therapy (Note: nighttime oxygen therapy and inhaled steroid therapy are acceptable).
28. Active infection requiring parenteral or oral antibiotics.
29. Known allergy to nickel.
30. Any condition that may interfere with compliance of all protocol procedures, such as active drug addiction, active alcohol abuse, or psychiatric hospital admission for psychosis within the prior year.
31. Currently participating in a clinical trial of any investigational drug or device that has not reached its primary endpoint, or any study that may interfere with the procedures or endpoints of this trial.
Participation in an observational study or registry with market approved drugs or devices would not exclude a patient from participation in this trial.
32. Patient is otherwise not appropriate for the study as determined by the investigator or the Eligibility Committee, for which the reasons must be documented.
33. Patient belongs to a vulnerable population per investigator’s judgment or patient has any kind of disorder that compromises his/her ability to give written informed consent and/or to comply with study
Final Exclusion Criteria (FEC): Assessed during cardiac catheterization, at Study Intervention Visit, just prior to Randomization
1. Change in clinical status between baseline screening and Study Intervention visit such that the patient is not stable to undergo the Intervention Procedure.
2. Females with a positive pregnancy test on laboratory testing for FEC.
3. Unable to undergo TEE or ICE.
4. Unable to tolerate or cooperate with general anesthesia or conscious sedation.
5. Anatomical anomaly on TEE or ICE that precludes implantation of Shunt across fossa ovalis (FO) of the interatrial septum including:
a) Minimal FO Thickness >6mm.
b) Minimal FO Length <10mm.
c) ASD or PFO with more than a trace amount of shunting.
d) Intracardiac thrombus felt to be acute and not present on prior exams.
e) Atrial Septal Aneurysm defined as ≥ 10 mm of phasic septal excursion into either atrium or a sum total excursion of ≥ 15 mm during the cardiorespiratory cycle, with a base of ≥ 15 mm.
6. Inadequate vascular access for implantation of Shunt. Femoral venous or inferior vena cava (IVC) access for transseptal catheterization are not patent as demonstrated by failure to pass Swan-Ganz or ICE catheter from the right or left femoral vein to the right atrium.
7. Hemodynamic, heart rhythm, or respiratory instability at time of cardiac catheterization including:
a) Mean PCWP <7 mmHg, not correctable by IV volume infusion (maximum 1,000 ml normal saline or equivalent).
b) Mean PCWP >35 mmHg, not correctable by medical therapy (e.g. IV Furosemide, IV or sublingual nitroglycerin).
c) Right Atrial Pressure (RAP) ≥ Left Atrial Pressure (LAP or PCWP) when LAP (PCWP) ≥7 mmHg.
d) Cardiac Index (CI) <1.5 liters/min/m2 after correction of volume depletion with IV fluids (maximum 1,000 ml normal saline or equivalent).
e) Severe pulmonary hypertension defined as PASP >70 mmHg associated with PVR >4.0 Wood Units, that cannot be reduced to PVR ≤4 Wood Units by acute vasodilator therapy.
f) Resting systolic Blood Pressure <90 or >160 mmHg, not corrected with IV fluid administration or vasodilators, respectively.
g) Need for IV infusions of vasopressor or inotropic medication.
Transient hypotension or bradycardia during anesthesia or catheterization, manifest as a vagal or similar acute episode or dehydration, responding promptly to IV fluid boluses or IV push vasopressors or chronotropic agents is not an exclusion criterion.
h) Malignant arrhythmias such as ventricular fibrillation, ventricular tachycardia, atrial fibrillation/flutter with rapid ventricular response associated with hypotension and requiring cardioversion.
i) Acute respiratory distress or hypoxemia.
8. Patient is otherwise not appropriate for study as determined by the Investigator.