Aquapheresis Efficacy in Outpatients With Decompensated Heart Failure

Study Overview
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Brief Summary
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With this research the Investigators hope to learn if early aquapheresis in an outpatient setting will improve congestive heart failure symptoms in outpatients with decompensated heart failure who have been refractory to high dose diuretics. In previous trials in inpatient settings, aquapheresis has been demonstrated to improve quality of life and reduce hospital visits for those who have undergone the treatment. This study is one of the first to evaluate the effectiveness of aquapheresis in veterans with congestive heart failure in an outpatient setting. The aquapheresis device, Aquadex FlexFlow® System, manufactured by CHF Solutions™, Minneapolis, MN, has been approved by the Food and Drug Administration (FDA) for removing excess sodium and fluid from patients suffering from volume overload, like in congestive heart failure.

Detailed Description
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Congestive heart failure (CHF) affects nearly 2% of the U.S. population, with almost 1 million hospital admissions for acute decompensated CHF annually. Congestive heart failure is the most frequent cause of hospitalization in patients over the age of 65. Patients admitted for acute decompensated heart failure (ADHF) have a high 6-month readmission rate for acute CHF, ranging from 23% to 40% in different studies. It is estimated that 25 to 30% of these patients are diuretic resistant with 50% of patients losing less than 5 lbs. from admission weight and 20% actually gaining weight during the hospitalization. Although loop diuretics have not been shown to improve survival in patients with CHF, they effectively alleviate symptoms of congestion. Diuretics have been part of standard CHF therapy in all recent survival trials of β-blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers. Loop diuretics have been shown to be the most effective diuretics as single agents in moderate to severe heart failure. However, loop diuretics may be associated with increased morbidity and mortality attributable to deleterious effects on neurohormonal activation, electrolyte balance, and cardiac and renal function. Removal of excessive fluid in patients with CHF is usually achieved by a combination of fluid and salt restriction and loop diuretics, but in some cases volume overload persists. Diuretic resistance is common, especially after chronic exposure to loop diuretics; patients require escalating doses (PO or IV to bypass delayed absorption in gut due to bowel edema), addition of another diuretic that works on different part of renal tubules (i.e. Thiazides) +/- diuretic drip and, if still refractory, ultimately Aquapheresis (a form of ultrafiltration). Aquapheresis (AQ) compared to IV diuretics in the UNLOAD Trial (10), AQ safely produced greater weight loss, fluid removal, and reduction in 90-day readmission rate compared to IV diuretic. A meta-analysis of 10 randomized control trials (RCTs) showed AQ not only to be effective but safe. These observations suggest that a strategy of early ultrafiltration may improve responsiveness to diuretics, quicker weight loss, decrease hospitalization, readmission to hospital, ER or doctor visits with minimal risks. As result of these trials, American Hospital Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of American (HFSA) guidelines state it is reasonable to start Aquapheresis in patients with obvious volume overload or patients who are refractory to high dose diuretics (IIa, LOE B). Moreover, while this therapy is part of standard of care in an inpatient setting, many hospitals as a result of Affordable Care Act (ACA), have taken to AQ on an outpatient setting to further decrease the burden and attended cost associated with management of CHF. But the Investigators are unaware of any other prospective outpatient studies that have looked at the outcomes and cost effectiveness of aquapheresis.

Official Title
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Efficacy of Aquapheresis in Patients Treated as Outpatients With Decompensated Heart Failure at a Veterans Hospital

Conditions
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Heart Failure, Congestive Heart Failure, Decompensated Heart Failure

Intervention / Treatment
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* Device: Aquapheresis
* Drug: IV Diuretics


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be 18 years of age or older already on standard of care therapy including Angiotensin Converting Enzyme Inhibitors (ACE-I), Angiotensin Receptor Blockers (ARBs), Sacubitril/Valsartan, beta-blocker, oral diuretic (80 mg Lasix/2 mg Bumex/40 mg Torsemide+/-Thiazide diuretic), and meet the following inclusion criteria to be enrolled: Inclusion Criteria: CHF refractory to oral diuretic (80mg Lasix, 2mg Bumex, or 40mg Torsemide) Volume overload secondary to systolic or diastolic HF, evidenced by at least 2 of the following: Elevated BNP (>100) Paroxysmal nocturnal dyspnea or orthopnea Elevated jugular venous distention (>/ 7 cm) X-ray findings consisted with CHF Presence of ascites or LE edema . - Exclusion Criteria: Acute Coronary Syndrome Hypertensive urgency or emergency Rapid atrial fibrillation difficult to control Contraindication to anticoagulation Pregnancy Requires hemodialysis (> CR > 3.0 mg/dl) Symptomatic hypotension Poor venous access Pressor dependent. -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a Controlled Trial with two arms (aquapheresis and IV diuretics/Control), but there is the potential for cross-over to aquapheresis if a patient receiving diuretics is refractory to maximum doses of IV diuretics.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aquapheresis<br>Per protocol, if randomized to Aquapheresis arm (AQ), all diuretics are discontinued and AQ will be administered as per established protocol. BMP and CBC will be checked prior to initiation and as needed, 7-10 days, 30, 60 and 90 days post discharge. Note, aquapheresis rate is to be decreased by 100 cc/hr if Hgb increases by 1gm/dL, and stopped if rate is decreased to 50 cc/hr or reaches euvolemia, whichever comes first. | Device: Aquapheresis<br>* The Aquadex FlexFlow® Fluid Removal System (from CHF Solutions™, Minneapolis, MN) is an FDA approved device that provides mechanical isosmotic fluid removal in volume-overloaded CHF patients via veno-venous ultrafiltration, and has been used in patients with congestive heart failure refractory to diuretics, it should be considered standard of care also. This study is using it in a randomized, controlled study in the Outpatient setting. The Aquadex FlexFlow® Fluid Removal System is a dual rotary pump device used with a sterile, single-use UF 500 Blood Circuit Set. Blood withdrawal is usually from a peripheral arm vein (such as the antecubital vein), using a 16 or 18- gauge, 3.5 cm catheter (similar to a standard IV catheter). A similar IV catheter is used for blood return via a second peripheral vein (typically in the forearm).<br>* Other names: Hemodialysis;|
| Active Comparator: IV Diuretics<br>Per protocol (Fig 2), if randomized to IV diuretic therapy arm (IV), the patient will receive initial dose of IV diuretic based on base line renal function; then the dose will be doubled every 2 hrs if refractory, to a maximum of 8mg IV Bumex (or 320mg IV Lasix). Metolazone may be added at 2.5mg PO 30 minutes before loop diuretic if CR< 2.0, or 5mg PO if Cr > 2.0, if refractory to high dose loop diuretic. If a patient in IV arm is refractory to maximum 320 mg IV Lasix or 8 mg IV Bumex plus Metolazone then the patient may cross over to AQ arm. | Drug: IV Diuretics<br>* Active Comparator: Intravenous Diuretics Per protocol (Fig 2), if randomized to IV diuretic therapy arm (IV), the patient will receive initial dose of IV diuretic based on base line renal function; then the dose will be doubled every 2 hrs if refractory, to a maximum of 8mg IV Bumex (or 320mg IV Lasix). Metolazone may be added at 2.5mg PO 30 minutes before loop diuretic if CR< 2.0, or 5mg PO if Cr > 2.0, if refractory to high dose loop diuretic. If the patient in IV arm is refractory to max 320 mg IV Lasix or 8 mg IV Bumex plus Metolazone then the patient may cross over to AQ arm.<br>* Other names: Intravenous Diuretics;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Hospitalizations by 7 days post-treatment | Compare number of hospitalization readmissions for CHF between Intervention (Aquaphersis arm) & Control groups | Between outpatient treatment and 7-days after outpatient treatment | 
| Number of Hospitalizations by 30 days post-treatment | Compare number of hospitalization readmissions for CHF between Intervention (Aquaphersis arm) & Control groups | Between outpatient treatment and 30 days after outpatient treatment | 
| Number of Hospitalizations by 60 days post-treatment | Compare number of hospitalization readmissions for CHF between Intervention (Aquaphersis arm) & Control groups | Between outpatient treatment and 60 days after outpatient treatment | 
| Number of Hospitalizations by 90 days post-treatment | Compare number of hospitalization readmissions for CHF between Intervention (Aquaphersis arm) & Control groups | Between outpatient treatment and 90 days after outpatient treatment | 
| Weight change by 7 days post-treatment | Compare weight change (pounds) in patients between Intervention & Control groups | Outpatient treatment to 7 days after outpatient treatment | 
| Weight change by 30 days post-treatment | Compare weight change (pounds) in patients between Intervention & Control groups | Outpatient treatment to 30 days after outpatient treatment | 
| Weight change by 60 days post-treatment | Compare weight change (pounds) in patients between Intervention & Control groups | Outpatient treatment to 60 days after outpatient treatment | 
| Weight change by 90 days post-treatment | Compare weight change (pounds) in patients between Intervention & Control groups | Outpatient treatment to 90 days after outpatient treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total fluid removal | Compare total fluid removal (ml) in patients between Intervention & Control groups | Baseline (Randomization) to outpatient discharge | 
| Blood urea nitrogen at Baseline | Compare Blood urea nitrogen (BUN; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | Baseline (Randomization) | 
| Blood urea nitrogen at 7 days post-treatment | Compare Blood urea nitrogen (BUN; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| Blood urea nitrogen at 30 days post-treatment | Compare Blood urea nitrogen (BUN; mg/dl) (higher than normal range is worse)) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| Blood urea nitrogen at 60 days post-treatment | Compare Blood urea nitrogen (BUN; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| Blood urea nitrogen at 90 days post-treatment | Compare Blood urea nitrogen (BUN; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| Creatinine at Baseline | Compare Creatinine (Cr; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | Baseline (Randomization) | 
| Creatinine at 7 days post-treatment | Compare Creatinine (Cr; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| Creatinine at 30 days post-treatment | Compare Creatinine (Cr; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| Creatinine at 60 days post-treatment | Compare Creatinine (Cr; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| Creatinine at 90 days post-treatment | Compare Creatinine (Cr; mg/dl) (higher than normal range is worse) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| Glomerular filtration rate at Baseline | Compare Glomerular filtration rate (GFR; ml/min/1.73 meters squared) (lower than normal range is worse) in patients between Intervention & Control groups | Baseline (Randomization) | 
| Glomerular filtration rate at 7 days post-treatment | Compare Glomerular filtration rate (GFR; ml/min/1.73 meters squared) (lower than normal range is worse) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| Glomerular filtration rate at 30 days post-treatment | Compare Glomerular filtration rate (GFR; ml/min/1.73 meters squared) (lower than normal range is worse) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| Glomerular filtration rate at 60 days post-treatment | Compare Glomerular filtration rate (GFR; ml/min/1.73 meters squared) (lower than normal range is worse) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| Glomerular filtration rate at 90 days post-treatment | Compare Glomerular filtration rate (GFR; ml/min/1.73 meters squared) (lower than normal range is worse) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| Brain natriuretic peptide (BNP) test at Baseline | Compare BNP (pg/ml of blood) (higher than normal range is worse) in patients between Intervention & Control groups | Baseline (Randomization) | 
| Brain natriuretic peptide (BNP) test at 7 days post-treatment | Compare BNP (pg/ml of blood) (higher than normal range is worse) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| Brain natriuretic peptide (BNP) test at 30 days post-treatment | Compare BNP (pg/ml of blood) (higher than normal range is worse) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| Brain natriuretic peptide (BNP) test at 60 days post-treatment | Compare BNP (pg/ml of blood) (higher than normal range is worse) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| Brain natriuretic peptide (BNP) test at 90 days post-treatment | Compare BNP (pg/ml of blood) (higher than normal range is worse) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| 6-minute Walk Test at Baseline | Compare 6-minute Walk Test (meters/6 minutes; less distance means more disability) in patients between Intervention & Control groups | Baseline (Randomization) | 
| 6-minute Walk Test at 7 days post-treatment | Compare 6-minute Walk Test (meters/6 minutes; less distance means more disability) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| 6-minute Walk Test at 30 days post-treatment | Compare 6-minute Walk Test (meters/6 minutes; less distance means more disability) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| 6-minute Walk Test at 60 days post-treatment | Compare 6-minute Walk Test (meters/6 minutes; less distance means more disability) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| 6-minute Walk Test at 90 days post-treatment | Compare 6-minute Walk Test (meters/6 minutes; less distance means more disability) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| Minnesota Living with Heart Failure Questionnaire (MLWHFQ) | Compare Minnesota Living with Heart Failure Questionnaire (MLWHFQ) (total score; higher score means more impairment) in patients between Intervention & Control groups | Baseline (Randomization) | 
| Minnesota Living with Heart Failure Questionnaire (MLWHFQ) | Compare Minnesota Living with Heart Failure Questionnaire (MLWHFQ) (total score; higher score means more impairment) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| Minnesota Living with Heart Failure Questionnaire (MLWHFQ) | Compare Minnesota Living with Heart Failure Questionnaire (MLWHFQ) (total score; higher score means more impairment) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| Minnesota Living with Heart Failure Questionnaire (MLWHFQ) | Compare Minnesota Living with Heart Failure Questionnaire (MLWHFQ) (total score; higher score means more impairment) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| Minnesota Living with Heart Failure Questionnaire (MLWHFQ) | Compare Minnesota Living with Heart Failure Questionnaire (MLWHFQ) (total score; higher score means more impairment) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| SF-36 at Baseline | Compare SF-36 weighted sums (0-100 scale; lower score means more disability) in patients between Intervention & Control groups | Baseline (Randomization) | 
| SF-36 at 7 days post-treatment | Compare SF-36 weighted sums (0-100 scale; lower score means more disability) in patients between Intervention & Control groups | 7 days after outpatient treatment | 
| SF-36 at 30 days post-treatment | Compare SF-36 weighted sums (0-100 scale; lower score means more disability) in patients between Intervention & Control groups | 30 days after outpatient treatment | 
| SF-36 at 60 days post-treatment | Compare SF-36 weighted sums (0-100 scale; lower score means more disability) in patients between Intervention & Control groups | 60 days after outpatient treatment | 
| SF-36 at 90 days post-treatment | Compare SF-36 weighted sums (0-100 scale; lower score means more disability) in patients between Intervention & Control groups | 90 days after outpatient treatment | 
| Adverse events: bleeding incidents during Outpatient treatment | Compare number of Adverse Events (bleeding incidents) in patients between Intervention & Control groups: bleeding, line-related infection, etc. | Start of treatment to discharge, which is usually the same day, but up to 3 days post-treatment, if medically necessary. | 
| Adverse events: line infections during Outpatient treatment | Compare number of Adverse Events (line infections) in patients between Intervention & Control groups: bleeding, line-related infection, etc. | Start of treatment to up to 14 days post-treatment. | 
| Costs | Compare costs (dollars) between Intervention & Control groups | Baseline (Randomization) to 90 days post-discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aquapheresis, Diuresis