Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome (The CARRESS Study) (CARRESS)

CARdiorenal REScue Study in Acute Decompensated Heart Failure: CARRESS

Heart failure is a serious condition in which the heart's ability to pump blood through the body is impaired, often making a person feel weak or fatigued. When a person's condition worsens to the point of hospitalization, that person is said to have acute decompensated heart failure (ADHF). Abnormal kidney function in association with cardiac distress, known as cardiorenal syndrome, is a common complication of heart failure and causes further medical problems and need for hospitalization. While there are various effective treatments for heart failure, more research is needed to determine the best treatment for targeting both ADHF and cardiorenal syndrome. This study will compare the safety and effectiveness of ultrafiltration versus standard medical drug therapy in improving renal function and relieving fluid buildup in people hospitalized with ADHF and cardiorenal syndrome.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Stepped pharmacologic care; Device: Ultrafiltration

Detailed Description

Heart failure is a common condition that affects approximately 5 million people in the United States, with 550,000 new cases diagnosed each year. Common symptoms of heart failure include swelling and fluid buildup in the legs, feet, and/or lungs; shortness of breath; coughing; elevated heart rate; change in appetite; and fatigue. If left untreated, the condition of the heart may deteriorate so far that the person undergoes ADHF. The number of hospitalizations attributed to ADHF has risen significantly, with many people readmitted soon after discharge because of recurring symptoms or further medical complications, such as cardiorenal syndrome. Current heart failure treatments focus on removing excess fluid buildup, often by increasing urination with diuretic medications or by draining directly from the veins. Direct drainage from the veins, also known as ultrafiltration, may be the more effective method for treating people with ADHF and cardiorenal syndrome. This study will compare the safety and effectiveness of ultrafiltration versus standard medical drug therapy in improving renal function and relieving fluid buildup in people hospitalized with ADHF and cardiorenal syndrome.

Participation in this study will last 60 days. All potential participants will undergo initial screening, which will include a medical history, physical exam, blood draws, measurements of fluid intake and urine output, and questionnaires. These same evaluations and procedures will be repeated at various points during the hospital stay. Eligible participants will be randomly assigned to receive standard medical drug therapy or fluid removal by ultrafiltration. Standard medical drug therapy will involve the intravenous delivery of diuretics and possibly other doctor-recommended medications. Ultrafiltration will involve intravenously removing blood, passing it through an ultrafiltration device, and then returning the blood to the participant. During ultrafiltration, participants will be treated with a blood thinner through the IV, as well.

Follow-up assessments will occur at Days 30 and 60 after treatment. Follow-up assessments will include measurements of fluid intake, urine output, and vital signs; blood draws; physical exams; and questions about medications and status of recovery.

• Study Type: Interventional
• Enrollment (Actual): 188
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T - 1C8
      • Montreal Heart Institute
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • Georgia
    • Atlanta, Georgia, United States, 30310
      • Morehouse School Of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Minnesota Heart Failure Network
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Murray, Utah, United States, 84107
      • University of Utah Health Sciences Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont - Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• age 18 or older
• admitted to the hospital with a primary diagnosis of decompensated heart failure
• onset of cardiorenal syndrome after hospitalization or pre-hospitalization
• after hospitalization - onset of cardiorenal syndrome after hospitalization must occur within 10 days from the time of admission after receiving IV diuretics
• pre-hospitalization - onset of cardiorenal syndrome pre-hospitalization must occur within 12 weeks of the index hospitalization in the setting of escalating doses of outpatient diuretics
• persistent volume overload

Exclusion criteria:

• intravascular volume depletion based on investigator"s clinical assessment
• acute coronary syndrome within 4 weeks
• indication for hemodialysis
• creatinine > 3.5 mg per deciliter at admission to the hospital
• systolic blood pressure < 90 mmHg at the time of enrollment
• alternative explanation for worsening renal function such as obstructive nephropathy,contrast induced nephropathy, acute tubular necrosis
• Hematocrit > 45%
• poor venous access
• clinical instability likely to require the addition of intravenous vasoactive drugs including vasodilators and/or inotropic agents
• allergy or contraindications to the use of heparin
• the use of iodinated radio contrast material in the last 72 hours or anticipated use of IV contrast during the current hospitalization
• known bilateral renal artery stenosis
• active myocarditis
• hypertrophic obstructive cardiomyopathy
• severe valvular stenosis
• complex congenital heart disease
• sepsis or ongoing systemic infection
• enrollment in another clinical trial involving medical or device based interventions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stepped pharmacologic care; Stepped care will provide treating physicians with guidelines for the intensification of diuretic therapy and the possible use of vasodilators and inotropes.	Drug: Stepped pharmacologic care; Stepped care will provide treating physicians with guidelines for the intensification of diuretic therapy and the possible use of vasodilators and inotropes.
Experimental: Ultrafiltration; All loop diuretics will be discontinued. Treatment will involve slow continuous ultrafiltration until an optimal volume status has been achieved. Ultrafiltration therapy will be initiated after the placement of appropriate intravenous access and will continue until the participant's signs and symptoms of congestion have been optimized. Fluid status will be managed exclusively by ultrafiltration using the Aquadex system 100 (CHF Solutions, Inc.) according to the manufacturer's specifications. The use of vasodilators or inotropic agents will be prohibited unless deemed necessary for rescue therapy.	Device: Ultrafiltration; All loop diuretics will be discontinued. Treatment will involve slow continuous ultrafiltration until an optimal volume status has been achieved. Ultrafiltration therapy will be initiated after the placement of appropriate intravenous access and will continue until the participant's signs and symptoms of congestion have been optimized. Fluid status will be managed exclusively by ultrafiltration using the Aquadex system 100 (CHF Solutions, Inc.) according to the manufacturer's specifications. The use of vasodilators or inotropic agents will be prohibited unless deemed necessary for rescue therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Serum Creatinine	Change from Baseline to Day 4
Change in Weight	Change from Baseline to Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glomerular Filtration Rate		Change from Baseline to Day 4
Change in Serum Creatinine		Change from Baseline to Day 7
Change in Glomerular Filtration Rate		Change from Baseline to Day 7
Changes in Weight		Change from Baseline to Day 1
Changes in Weight		Change from Baseline to Day 2
Change in Weight		Change from Baseline to Day 3
Changes in Weight		Change from Baseline to Day 5
Change in Weight		Change from Baseline to Day 6
Cumulative Net Fluid Loss		Randomization through Day 1
Cumulative Net Fluid Loss		Randomization through Day 2
Cumulative Net Fluid Loss		Randomization through Day 3
Cumulative Net Fluid Loss		Randomization through Day 4
Cumulative Net Fluid Loss		Randomization through Day 5
Cumulative Net Fluid Loss		Randomization through Day 6
Cumulative Net Fluid Loss		Randomization through Day 7
Dyspnea Visual Analog Scale	Scale range: -100 , +100 -100=worse, +100=better	Change from Baseline to Day 4
Change in Global Visual Analog Scale	Scale range: -100 , +100 -100=worse, +100=better Participants asked to mark their global well being on a 10 cm vertical line, with the top labeled "best you have ever felt" and the bottom labeled "worst you have ever felt".	Change from Baseline to Day 4
Change in Dyspnea Visual Analog Scale	Scale range: -100 , +100 -100=worse, +100=better	Baseline to Day 7/Discharge
Change in Global Visual Analog Scale	Scale range: -100 , +100 -100=worse, +100=better Participants asked to mark their global well being on a 10 cm vertical line, with the top labeled "best you have ever felt" and the bottom labeled "worst you have ever felt".	Baseline to Day 7/Discharge
Change in Furosemide-Equivalent Dose	Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)	Baseline to Day 7/Discharge
Change in Blood Sodium Level		Baseline to Day 4
Change in Blood Potassium Level		Baseline to Day 4
Change in Blood Urea Nitrogen/Urea		Baseline to Day 4
Change in Blood Bicarbonate Level		Baseline to Day 4
Change in Blood Hemoglobin Level		Baseline to Day 4
Change in Blood Sodium Level		Baseline to Day 7/Discharge
Change in Blood Potassium Level		Baseline to Day 7/Discharge
Change in Blood Urea Nitrogen/Urea		Baseline to Day 7/Discharge
Change in Blood Bicarbonate Level		Baseline to Day 7/Discharge
Change in Blood Hemoglobin Level		Baseline to Day 7/Discharge
Change in Blood Cystatin C		Baseline to Day 4
Change in Uric Acid		Baseline to Day 4
Change in Blood N- Terminal Pro- BNP		Baseline to Day 4
Change in Plasma Renin Activity		Baseline to Day 4
Change in Blood High Sensitivity Troponin I		Baseline to Day 4
Change in Blood Aldosterone		Baseline to Day 4
Change in Blood Procollagen III N-terminal Propepide		Baseline to Day 4
Change in Blood Endothelin-1		Baseline to Day 4
Change in Blood High Sensitivity C-Reactive Protein		Baseline to Day 4
Change in Blood Carboxy-terminal Telopeptide of Collagen Type I		Baseline to Day 4
Change in Blood Cystatin C		Baseline to Day 7/Discharge
Change in Blood Uric Acid		Baseline to Day 7/Discharge
Change in Blood N Terminal Pro-Natriuretic Peptide		Baseline to Day 7/Discharge
Change in Plasma Renin Activity		Baseline to Day 7/Discharge
Change in Blood High Sensitivity Troponin I		Baseline to Day 7/Discharge
Change in Blood Aldosterone		Baseline to Day 7/Discharge
Change in Blood Procollagen III N-terminal Propepide		Baseline to Day 7/Discharge
Change in Blood Endothelin-1		Baseline to Day 7/Discharge
Change in Blood Carboxy-terminal Telopeptide of Collagen Type I		Baseline to Day 7/Discharge
Change in Blood High Sensitivity C-Reactive Protein		Baseline to Day 7/Discharge
Weight Change		Baseline to Day 30
Change in Furosemide-Equivalent Dose	Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)	Baseline to Day 30
Creatinine Change		Baseline to Day 30
Glomerular Filtration Rate Change		Baseline to Day 30
Weight Change		Baseline to Day 60
Change in Furosemide-Equivalent Dose	Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)	Baseline to Day 60
Best Available Serum Creatinine Change	Core laboratory when available. If not available, local laboratory results were used.	Baseline to Day 60
Best Available Glomerular Filtration Rate Change	Core laboratory when available. If not available, local laboratory results were used.	Baseline to Day 60
Change in Blood Uric Acid		Baseline to Day 60
Change in Blood Cystatin C		Baseline to Day 60
Change in Blood N Terminal Pro - B Natriuretic Peptides		Baseline to Day 60
Change in Plasma Renin Activity		Baseline to Day 60
Change in Blood High Sensitivity Troponin I		Baseline to Day 60
Change in Blood Aldosterone		Baseline to Day 60
Change in Blood Procollagen III N-terminal Propepide		Baseline to Day 60
Change in Blood Endothelin-1		Baseline to Day 60
Change in Blood High Sensitivity C-Reactive Protein		Baseline to Day 60
Change in Blood Carboxy-terminal Telopeptide of Collagen Type I		Baseline to Day 60

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Nuwellis, Inc.

Publications and helpful links

General Publications

• Bart BA, Goldsmith SR, Lee KL, Givertz MM, O'Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, LeWinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012 Dec 13;367(24):2296-304. doi: 10.1056/NEJMoa1210357. Epub 2012 Nov 6.
• Rao VS, Ahmad T, Brisco-Bacik MA, Bonventre JV, Wilson FP, Siew ED, Felker GM, Anstrom KK, Mahoney DD, Bart BA, Tang WHW, Velazquez EJ, Testani JM. Renal Effects of Intensive Volume Removal in Heart Failure Patients With Preexisting Worsening Renal Function. Circ Heart Fail. 2019 Jun;12(6):e005552. doi: 10.1161/CIRCHEARTFAILURE.118.005552. Epub 2019 Jun 5.
• Kitai T, Grodin JL, Kim YH, Tang WH. Impact of Ultrafiltration on Serum Sodium Homeostasis and its Clinical Implication in Patients With Acute Heart Failure, Congestion, and Worsening Renal Function. Circ Heart Fail. 2017 Feb;10(2):e003603. doi: 10.1161/CIRCHEARTFAILURE.116.003603. Erratum In: Circ Heart Fail. 2017 Mar;10 (3):e000016.
• de Denus S, Rouleau JL, Mann DL, Huggins GS, Cappola TP, Shah SH, Keleti J, Zada YF, Provost S, Bardhadi A, Phillips MS, Normand V, Mongrain I, Dube MP. A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials. Pharmacogenomics J. 2017 Mar;17(2):192-200. doi: 10.1038/tpj.2016.4. Epub 2016 Mar 1.
• Lala A, McNulty SE, Mentz RJ, Dunlay SM, Vader JM, AbouEzzeddine OF, DeVore AD, Khazanie P, Redfield MM, Goldsmith SR, Bart BA, Anstrom KJ, Felker GM, Hernandez AF, Stevenson LW. Relief and Recurrence of Congestion During and After Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF). Circ Heart Fail. 2015 Jul;8(4):741-8. doi: 10.1161/CIRCHEARTFAILURE.114.001957. Epub 2015 Jun 3.
• Mentz RJ, Stevens SR, DeVore AD, Lala A, Vader JM, AbouEzzeddine OF, Khazanie P, Redfield MM, Stevenson LW, O'Connor CM, Goldsmith SR, Bart BA, Anstrom KJ, Hernandez AF, Braunwald E, Felker GM. Decongestion strategies and renin-angiotensin-aldosterone system activation in acute heart failure. JACC Heart Fail. 2015 Feb;3(2):97-107. doi: 10.1016/j.jchf.2014.09.003. Epub 2014 Oct 31.

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): June 1, 2012

Study Registration Dates

• First Submitted: January 25, 2008
• First Submitted That Met QC Criteria: January 25, 2008
• First Posted (Estimate): February 6, 2008

Study Record Updates

• Last Update Posted (Estimate): June 24, 2013
• Last Update Submitted That Met QC Criteria: May 15, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Cardiorenal Syndrome; Acute Decompensated Heart Failure; Acute Decompensated Heart Failure With Cardiorenal Syndrome; Persistent Congestion; Ultra Filtration
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Heart Failure; Cardio-Renal Syndrome
• Other Study ID Numbers: Pro00018064; U01HL084904-04 (U.S. NIH Grant/Contract); U01HL084904 (U.S. NIH Grant/Contract); 522

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No