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

• ClinicalTrials.gov Identifier: NCT00608491
• Recruitment Status: Completed
• First Posted: February 6, 2008
• Results First Posted: June 24, 2013
• Last Update Posted: June 24, 2013
• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Nuwellis, Inc.
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Drug: Stepped pharmacologic care; Device: Ultrafiltration	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 188 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CARdiorenal REScue Study in Acute Decompensated Heart Failure: CARRESS
• Study Start Date: March 2008
• Actual Primary Completion Date: March 2012
• Actual Study Completion Date: June 2012

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Change in Serum Creatinine [ Time Frame: Change from Baseline to Day 4 ]
2. Change in Weight [ Time Frame: Change from Baseline to Day 4 ]

Secondary Outcome Measures :

1. Change in Glomerular Filtration Rate [ Time Frame: Change from Baseline to Day 4 ]
2. Change in Serum Creatinine [ Time Frame: Change from Baseline to Day 7 ]
3. Change in Glomerular Filtration Rate [ Time Frame: Change from Baseline to Day 7 ]
4. Changes in Weight [ Time Frame: Change from Baseline to Day 1 ]
5. Changes in Weight [ Time Frame: Change from Baseline to Day 2 ]
6. Change in Weight [ Time Frame: Change from Baseline to Day 3 ]
7. Changes in Weight [ Time Frame: Change from Baseline to Day 5 ]
8. Change in Weight [ Time Frame: Change from Baseline to Day 6 ]
9. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 1 ]
10. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 2 ]
11. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 3 ]
12. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 4 ]
13. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 5 ]
14. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 6 ]
15. Cumulative Net Fluid Loss [ Time Frame: Randomization through Day 7 ]
16. Dyspnea Visual Analog Scale [ Time Frame: Change from Baseline to Day 4 ]

    Scale range: -100 , +100

    -100=worse, +100=better

17. Change in Global Visual Analog Scale [ Time Frame: Change from Baseline to Day 4 ]

    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".

18. Change in Dyspnea Visual Analog Scale [ Time Frame: Baseline to Day 7/Discharge ]

    Scale range: -100 , +100

    -100=worse, +100=better

19. Change in Global Visual Analog Scale [ Time Frame: Baseline to Day 7/Discharge ]

    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".

20. Change in Furosemide-Equivalent Dose [ Time Frame: Baseline to Day 7/Discharge ]
    Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)
21. Change in Blood Sodium Level [ Time Frame: Baseline to Day 4 ]
22. Change in Blood Potassium Level [ Time Frame: Baseline to Day 4 ]
23. Change in Blood Urea Nitrogen/Urea [ Time Frame: Baseline to Day 4 ]
24. Change in Blood Bicarbonate Level [ Time Frame: Baseline to Day 4 ]
25. Change in Blood Hemoglobin Level [ Time Frame: Baseline to Day 4 ]
26. Change in Blood Sodium Level [ Time Frame: Baseline to Day 7/Discharge ]
27. Change in Blood Potassium Level [ Time Frame: Baseline to Day 7/Discharge ]
28. Change in Blood Urea Nitrogen/Urea [ Time Frame: Baseline to Day 7/Discharge ]
29. Change in Blood Bicarbonate Level [ Time Frame: Baseline to Day 7/Discharge ]
30. Change in Blood Hemoglobin Level [ Time Frame: Baseline to Day 7/Discharge ]
31. Change in Blood Cystatin C [ Time Frame: Baseline to Day 4 ]
32. Change in Uric Acid [ Time Frame: Baseline to Day 4 ]
33. Change in Blood N- Terminal Pro- BNP [ Time Frame: Baseline to Day 4 ]
34. Change in Plasma Renin Activity [ Time Frame: Baseline to Day 4 ]
35. Change in Blood High Sensitivity Troponin I [ Time Frame: Baseline to Day 4 ]
36. Change in Blood Aldosterone [ Time Frame: Baseline to Day 4 ]
37. Change in Blood Procollagen III N-terminal Propepide [ Time Frame: Baseline to Day 4 ]
38. Change in Blood Endothelin-1 [ Time Frame: Baseline to Day 4 ]
39. Change in Blood High Sensitivity C-Reactive Protein [ Time Frame: Baseline to Day 4 ]
40. Change in Blood Carboxy-terminal Telopeptide of Collagen Type I [ Time Frame: Baseline to Day 4 ]
41. Change in Blood Cystatin C [ Time Frame: Baseline to Day 7/Discharge ]
42. Change in Blood Uric Acid [ Time Frame: Baseline to Day 7/Discharge ]
43. Change in Blood N Terminal Pro-Natriuretic Peptide [ Time Frame: Baseline to Day 7/Discharge ]
44. Change in Plasma Renin Activity [ Time Frame: Baseline to Day 7/Discharge ]
45. Change in Blood High Sensitivity Troponin I [ Time Frame: Baseline to Day 7/Discharge ]
46. Change in Blood Aldosterone [ Time Frame: Baseline to Day 7/Discharge ]
47. Change in Blood Procollagen III N-terminal Propepide [ Time Frame: Baseline to Day 7/Discharge ]
48. Change in Blood Endothelin-1 [ Time Frame: Baseline to Day 7/Discharge ]
49. Change in Blood Carboxy-terminal Telopeptide of Collagen Type I [ Time Frame: Baseline to Day 7/Discharge ]
50. Change in Blood High Sensitivity C-Reactive Protein [ Time Frame: Baseline to Day 7/Discharge ]
51. Weight Change [ Time Frame: Baseline to Day 30 ]
52. Change in Furosemide-Equivalent Dose [ Time Frame: Baseline to Day 30 ]
    Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)
53. Creatinine Change [ Time Frame: Baseline to Day 30 ]
54. Glomerular Filtration Rate Change [ Time Frame: Baseline to Day 30 ]
55. Weight Change [ Time Frame: Baseline to Day 60 ]
56. Change in Furosemide-Equivalent Dose [ Time Frame: Baseline to Day 60 ]
    Furosemide-Equivalent Dose is the dose bumetanide or torsemide converted to furosemide equivalent (Torsemide dose x 2,Bumetanide dose x 40)
57. Best Available Serum Creatinine Change [ Time Frame: Baseline to Day 60 ]
    Core laboratory when available. If not available, local laboratory results were used.
58. Best Available Glomerular Filtration Rate Change [ Time Frame: Baseline to Day 60 ]
    Core laboratory when available. If not available, local laboratory results were used.
59. Change in Blood Uric Acid [ Time Frame: Baseline to Day 60 ]
60. Change in Blood Cystatin C [ Time Frame: Baseline to Day 60 ]
61. Change in Blood N Terminal Pro - B Natriuretic Peptides [ Time Frame: Baseline to Day 60 ]
62. Change in Plasma Renin Activity [ Time Frame: Baseline to Day 60 ]
63. Change in Blood High Sensitivity Troponin I [ Time Frame: Baseline to Day 60 ]
64. Change in Blood Aldosterone [ Time Frame: Baseline to Day 60 ]
65. Change in Blood Procollagen III N-terminal Propepide [ Time Frame: Baseline to Day 60 ]
66. Change in Blood Endothelin-1 [ Time Frame: Baseline to Day 60 ]
67. Change in Blood High Sensitivity C-Reactive Protein [ Time Frame: Baseline to Day 60 ]
68. Change in Blood Carboxy-terminal Telopeptide of Collagen Type I [ Time Frame: Baseline to Day 60 ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Arizona

Phoenix, Arizona, United States, 85054

United States, Georgia

Morehouse School of Medicine

Atlanta, Georgia, United States, 30310

United States, Minnesota

Minnesota Heart Failure Network

Minneapolis, Minnesota, United States, 55415

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27705

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

United States, Utah

University of Utah Health Sciences Center

Murray, Utah, United States, 84107

United States, Vermont

University of Vermont - Fletcher Allen Health Care

Burlington, Vermont, United States, 05401

Canada, Quebec

Montreal Heart Institute

Montreal, Quebec, Canada, H1T - 1C8

Sponsors and Collaborators

Duke University

National Heart, Lung, and Blood Institute (NHLBI)

Nuwellis, Inc.

Investigators

• Principal Investigator: Kerry L. Lee, PhD; Duke Clinical Research Institute

More Information

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00608491
• Other Study ID Numbers: Pro00018064; U01HL084904-04 ( U.S. NIH Grant/Contract ); U01HL084904 ( U.S. NIH Grant/Contract ); 522
• First Posted: February 6, 2008
• Results First Posted: June 24, 2013
• Last Update Posted: June 24, 2013
• Last Verified: May 2013

Keywords provided by Duke University:

Acute Decompensated Heart Failure; Acute Decompensated Heart Failure With Cardiorenal Syndrome; Cardiorenal Syndrome; Persistent Congestion; Ultra Filtration

Additional relevant MeSH terms:

Cardio-Renal Syndrome; Heart Failure; Heart Diseases; Cardiovascular Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases