Cardiovascular Improvements With MV ASV Therapy in Heart Failure

Study Overview
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Brief Summary
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The aim of the study is to compare the effects of MV targeted ASV in addition to optimized medical therapy versus optimized medical therapy alone at 6 months in patients with acute decompensated HF. The study will also assess changes in functional parameters, biomarkers, quality of life (QOL), and sleep.

Detailed Description
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This study is a randomized, unblinded, multi-center trial with parallel group design, with subjects randomized to either control (optimized medical therapy for chronic heart failure) or active treatment (optimized medical therapy plus use of MV-targeted ASV) in a 1:1 ratio.

Official Title
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Cardiovascular Improvements With Minute Ventilation-targeted ASV Therapy in Heart Failure (CAT-HF)

Conditions
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Acute Decompensated Heart Failure, Sleep Disordered Breathing

Intervention / Treatment
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* Device: MV ASV
* Drug: Optimized Medical Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 21 years or older Patients with prior clinical diagnosis of heart failure (HFrEF or HFpEF), or de novo diagnosis of HFpEF indicated by a local BNP≥300 pg/mL or NT pro-BNP≥1200 pg/mL on admission without systolic blood pressure >180 mmHg or atrial fibrillation, or diagnosis of HFrEF indicated by documented evidence of prescribed beta-blockers and ACE-inhibitors or ARBs for at least 4 weeks prior to admission Hospital admission for acute decompensated HF as determined by: Dyspnea at rest or with minimal exertion AND At least two of the following signs and symptoms: Orthopnea Pulmonary rales beyond basilar Chest congestion on x-ray BNP≥300pg/mL or NT pro-BNP≥1200pg/mL Pulmonary capillary wedge pressure (PCWP) ≥25mmHg during current hospitalization Presented to hospital or clinic at least 24 hours prior to consent Patient stable enough to stop oxygen use for duration of polygraphy test or have access to dual lumen cannula for polygraphy test Sleep disordered breathing (SDB) documented by polygraphy with an AHI≥15 events/hour Patient is able to fully understand study information and sign a consent form Exclusion Criteria: Right-sided heart failure without left-sided heart failure Sustained systolic blood pressure <80 mmHg at baseline Acute coronary syndrome within 1 months of randomization Active myocarditis Complex congenital heart disease Constrictive pericarditis Non-cardiac pulmonary edema Clinical evidence of digoxin toxicity Need for mechanical hemodynamic support at time of randomization Oxygen saturation ≤85% at rest during the day or at start of nocturnal oximetry recording or regular use of oxygen therapy (day or night) COPD exacerbation as the primary reason for hospital admission Current use (within 4 weeks of study entry) of any PAP-therapy (eg, fixed, bi-level, or APAP) Life expectancy < 1 year for diseases unrelated to HF Transient ischemic attack (TIA) or Stroke within 3 months prior to randomization CABG procedure within 3 months prior to randomization, or planned to occur during study period CRT implant within 3 months prior to randomization , or planned to occur during study period VAD implant planned to occur during study period Heart transplant list Status 1a or 1b Status post-transplant or LVAD Prescribed inotrope therapy anticipated at discharge Chronic Dialysis Known amyloidosis, hypertrophic obstructive cardiomyopathy, arteriovenous fistulas Primary hemodynamically significant uncorrected valvular heart disease (obstructive or regurgitant) with planned intervention within 6 months of randomization Pregnant, or planning to become pregnant Cannot tolerate ASV treatment during run-in Cannot perform 6MWT at baseline Occupation as a commercial driver or pilot and plan to be performing these activities during the study period Inability to comply with planned study procedures Participation in pharmaceutical or treatment-related clinical study within 1 month of study enrollment

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MV ASV+OMT<br>Minute Ventilation-targeted adaptive servo-ventilation therapy plus optimized medical treatment | Device: MV ASV<br>* Minute ventilation-targeted servo-ventilation therapy.<br>* Other names: AutoSet CS;Drug: Optimized Medical Treatment<br>* Beta Blockers, ACE inhibitor or ARB, loop diuretics and/or spironolactone as appropriate, statin if indicated, aspirin and/or warfarin if indicated<br>|
| Active Comparator: OMT only<br>Optimized Medical Treatment for heart failure in accordance with applicable guidelines (ACCF/AHA Guideline for the Management of Heart Failure and HFSA Heart Failure Guidelines. | Drug: Optimized Medical Treatment<br>* Beta Blockers, ACE inhibitor or ARB, loop diuretics and/or spironolactone as appropriate, statin if indicated, aspirin and/or warfarin if indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global Rank Endpoint | A rank order response based on survival free from CV hospitalization and improvement in functional capacity measured by 6MWD. All participants were first ranked by time to death, then ranked by time to CV hospitalization, and then ranked by percentage change in 6MWD. For time to event measures (time to death and time to hospitalization), the shorter the amount of time, the lower the rank assigned to that participant. For percentage changes in 6MWD, the smaller the percentage change, the lower the rank assigned to that participant. Each component was then combined to create a rank value that ranged between 0 and 100. Overall, higher rank values are associated with better outcomes. | Baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute Walk Distance | Change in functional parameters as measured by 6-minute walk test (6MWT) | Change from Baseline to 6 months | 
| NT Pro-BNP | Change in neurohumoral activation as measured by N-terminal pro b-type natriuretic peptide. | Change from Baseline to 6 months | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | The KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | Change from Baseline to 6 months | 
| Biomarkers - Inflammation | Biomarkers of inflammation reported as troponin I ultra-sensitive | Change from Baseline to 6 months | 
| Biomarkers - Cardiovascular | Biomarkers of cardiovascular function reported as hs-CRP | Change from Baseline to 6 months | 
| Biomarkers - Renal Function | Biomarkers of renal function reported as creatinine | Change from Baseline to 6 months | 
| ECHO Parameters - LVEF | Echocardiographic parameters, including LVEF (left ventricular ejection fraction) and LVESVI (left ventricular end-systolic volume index) for patients with HFrEF (heart failure with reduced ejection fraction), and E/e' (ratio between early mitral inflow velocity and mitral annular early diastolic velocity) for patients with HFrEF or HFpEF (heart failure with preserved ejection fraction). | Change from Baseline to 6 months | 
| ECHO Parameters - LVESVI | Echocardiographic parameters, including LVEF (left ventricular ejection fraction) and LVESVI (left ventricular end-systolic volume index) for patients with HFrEF (heart failure with reduced ejection fraction), and E/e' (ratio between early mitral inflow velocity and mitral annular early diastolic velocity) for patients with HFrEF or HFpEF (heart failure with preserved ejection fraction). | Change from Baseline to 6 months | 
| ECHO Parameters - E/e' Ratio | Echocardiographic parameters, including LVEF (left ventricular ejection fraction) and LVESVI (left ventricular end-systolic volume index) for patients with HFrEF (heart failure with reduced ejection fraction), and E/e' (ratio between early mitral inflow velocity and mitral annular early diastolic velocity) for patients with HFpEF (heart failure with preserved ejection fraction). | Change from Baseline to 6 months | 
| Win Ratio | Patients in the new treatment and control groups are formed into matched pairs based on their risk profiles. For each matched pair, the new treatment patient is labeled a 'winner' or a 'loser' depending on who had a CV death first. If that is not known, they are labeled a 'winner' or 'loser' depending on who had a HF hospitalization first. Otherwise they are considered tied. The win ratio is the total number of winners divided by the total numbers of losers. | 6 months | 
| Sleep Parameters | Sleep and sleep disordered breathing parameters (AHI, nocturnal hypoxemia) | Change from Baseline to 6 months | 
| Number of Subjects With HF Hospitalization | Rates of hospitalization or urgent clinic visit for worsening of heart failure and for any reason | 2 days, 1 week, 1, 2, 3, and 6 months | 
| Death | Rate of Cardiovascular and all-cause death | 2 days, 1 week, 1, 2, 3, and 6 months | 
| Time Dead/Hospitalized | Total days dead or hospitalized at study end | 6 months | 
| DASI | The Duke Activity Status Index is a 12-item patient-reported outcome validated for the assessment of functional capacity based on the ability to perform everyday activities. With a total range of 0 to 58.20, a higher score indicates better quality of life. | Change from Baseline to 6 months | 
| EQ-5D-5L Index | The EQ-5D-5L is a standardized self-report questionnaire that is used as a measure of health outcome. The EQ-5D-5L questionnaire is comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses were indexed using the EQ-5D-5L US value set to scale the 5 dimensions. A score of -0.109 indicates extreme problems for all dimensions and a score of 1.000 indicates no problems for all dimensions. Therefore, a higher score indicates better general health. | Change from Baseline to 6 months | 
| PHQ-9 | The PHQ-9 is the nine item depression scale of the Patient Health Questionnaire. The PHQ-9 is a self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. The PHQ-9 incorporates DSM-IV depression diagnostic criteria with other leading major depressive symptoms into a brief self-report tool. The tool rates the frequency of the symptoms which factors into the following scoring severity index: 0 - Not at all, 1 - Several Days, 2 - More than Half the Days, 3 - Nearly Every Day. Total score can range from 0 to 27. A higher score indicates increased severity. | Change from Baseline to 6 months | 
| PSQI | The Pittsburgh Sleep Quality Index is a 19-item subjective measurement of sleep. It is an effective instrument used to measure the quality and patterns of sleep in the older adult. It differentiates poor from good sleep by measuring seven areas: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction over the last month. The subject self-rates each of these seven areas of sleep. The seven component scores are then added to yield a total score with a range of 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all areas. | Change from Baseline to 6 months | 
| ESS | The Epworth Sleepiness Scale is a simple, 8-item self-administered questionnaire which provides a measurement of the subject's general level of daytime sleepiness. The individual is asked on a scale of 0-3 to score the likelihood of falling asleep in eight various situations. With a total range of 0 to 24, a higher score indicates increased severity. | Change from Baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, congestive heart failure, acute decompensated heart failure, chronic heart failure, left-sided heart failure, heart failure decompensation, sleep apnea, sleep disordered breathing, central sleep apnea, obstructive sleep apnea, cheyne-stokes respiration