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APS
UUltrafiltratioltrafiltrationn versus IV Diuretics for versus IV Diuretics for Patients HospitaPatients Hospitallized fized foor r AAcute cute
DDecompensated Congestive Heart ecompensated Congestive Heart Failure: A Prospective Randomized Failure: A Prospective Randomized
ClinicalClinical TrialTrial
UNLOAD TrialUNLOAD Trial
APS
Investigators & SitesInvestigators & Sites Costanzo MR, Saltzberg M-Midwest Heart
Foundation, Lombard Il. (Coordinating Center)
Anderson A.-U of Chicago, IL
Oren R-U of Iowa, IA
Haynos W-Iowa VA, IA
Jaski B-Sharp Memorial Hospital, CA
Eichhorn E-Medical City Dallas, TX
Jessup M-U of Pennsylvania, PA
Fang J-Brigham & Women’s Hospital, MA
Haas G- Ohio State University, OH
Walsh M-St. Vincent’s Hospital, IN
Feller E, Gottlieb S-U of Maryland, MD
Bart B- HCMC, MN
Guglin M-Detroit Medical Center, MI
Cooke R-Washington Hospital, WA
Fesniak H-Geisinger, PA
Magalski A-St. Luke’s, MO
Insel J -Good Samaritan Hospital, MD
Mehta J-U of Arkansas, AR
Slawsky M-Bay State, MA
Tsao L-Beth Israel, MA
Lavine S-U of Florida, FL
Menon S-Christ Hospital, OH
Pisani B-St. Luke’s Hospital, WI
Restaino S-Columbia/ Presbyterian, NY
Patel J -UCLA, CA
Singer I-Methodist, CA
Kazi F-Dallas VA, TX
Teerlink JR-San Francisco/ VAMC, CA
APS
BackgroundBackground
90% of 1 million HF hospitalizations are due to 90% of 1 million HF hospitalizations are due to volume overloadvolume overload
Hypervolemia contributes to HF progression, Hypervolemia contributes to HF progression, mortality and high remortality and high re--hospitalization rates hospitalization rates
IV diuretics reduce congestionIV diuretics reduce congestion
IV diuretics may be associated with increased IV diuretics may be associated with increased morbidity and mortalitymorbidity and mortality
20%20%--30% of HF patients develop diuretic resistance30% of HF patients develop diuretic resistance
APS
Study HypothesesStudy Hypotheses
Compared to standard IV diuretic therapy for Compared to standard IV diuretic therapy for hypervolemichypervolemic heart failure patients, heart failure patients, venoveno--venous venous ultrafiltration is:ultrafiltration is:
•• Superior to aggressive IV diuretic therapy in reducing Superior to aggressive IV diuretic therapy in reducing volume overloadvolume overload
•• Associated with sustained clinical benefitsAssociated with sustained clinical benefits
•• Similar to IV diuretics in terms of safetySimilar to IV diuretics in terms of safety
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Primary End PointsPrimary End Points
Efficacy • Weight loss at 48 hours after randomization• Dyspnea score at 48 hours after randomization
Safety • Changes in serum blood urea nitrogen,
creatinine, and electrolytes at 8, 24, 48 and 72 hours after randomization, discharge, 10, 30 and 90 days
• Episodes of hypotension during the first 48 hours after randomization
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Secondary End PointsSecondary End Points
BNP levels at 48 hours after randomization, 30 and BNP levels at 48 hours after randomization, 30 and 90 days90 days
NYHA class, Minnesota Living with Heart Failure NYHA class, Minnesota Living with Heart Failure score, Global Assessment score at discharge and score, Global Assessment score at discharge and followfollow--up up
Diuretic doses after Ultrafiltration or Standard CareDiuretic doses after Ultrafiltration or Standard Care
Percentage of patients rePercentage of patients re--hospitalized for HFhospitalized for HF
Absolute number of reAbsolute number of re--hospitalizations for HFhospitalizations for HF
Days of reDays of re--hospitalization for HFhospitalization for HF
Unscheduled office and ED visitsUnscheduled office and ED visits
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MethodsMethodsInclusion CriteriaInclusion Criteria
≥18 years of age Hospitalized with evidence of volume overload by
at least two of the following:• peripheral edema ≥2+ • jugular venous distension ≥7 cm • radiographic pulmonary edema or pleural
effusion• enlarged liver or ascites• pulmonary rales, paroxysmal nocturnal
dyspnea or orthopnea Randomization within 24 hours of hospitalization
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MethodsMethodsExclusion CriteriaExclusion Criteria
Acute coronary syndrome
Serum creatinine > 3.0 mg/dl
Hemodynamic instability requiring inotropic drugs
Hematocrit > 45%
Administration of vasoactive drugs prior to randomization
Contraindications to anticoagulation
Heart transplant
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MethodsMethodsStudy ProceduresStudy Procedures
Once randomized, all patients:– Daily 2 g sodium, 2000 ml fluid intake
restriction – Oral diuretics discontinued– ACE inhibitors, ARBs, β-blockers and digoxin
continued
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MethodsMethodsStudy ProceduresStudy Procedures
Ultrafiltration arm:• Ultrafiltration rate up to 500 cc/hour • Duration/rate of fluid removal decided by
treating physicians • IV diuretics prohibited during ultrafiltration
Standard Care arm:• IV diuretics as bolus or continuous infusions • IV doses at least 2 times daily PO dose for the
first 48 hours after randomization
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MethodsMethodsUltrafiltration DeviceUltrafiltration Device
Blood flow adjustable (10-40 ml/minute)
Total extracorporeal blood volume 33 ml
Peripheral, midline, or central venous access
Anticoagulation with heparin recommended
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Baseline Demographics Baseline Demographics and Comorbiditiesand Comorbidities
0.7550.75530302727COPD %COPD %
0.8900.89049495050Diabetes %Diabetes %
1.0001.00074747474History of Hypertension %History of Hypertension %
0.4740.47448485656Coronary Heart Disease %Coronary Heart Disease %
0.4890.4895252404088
5555414144
RaceRaceCaucasian %Caucasian %African American %African American %Other %Other %
0.8790.87968 68 7070Male Sex %Male Sex %
0.8230.82363 63 ±± 141462 62 ±± 1515Age Age –– years (m years (m ±± sd)sd)
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.7550.75530302727COPD %COPD %
0.8900.89049495050Diabetes %Diabetes %
1.0001.00074747474History of Hypertension %History of Hypertension %
0.4740.47448485656Coronary Heart Disease %Coronary Heart Disease %
0.4890.4895252404088
5555414144
RaceRaceCaucasian %Caucasian %African American %African American %Other %Other %
0.8790.87968 68 7070Male Sex %Male Sex %
0.8230.82363 63 ±± 141462 62 ±± 1515Age Age –– years (m years (m ±± sd)sd)
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.7550.75530302727COPD %COPD %
0.8900.89049495050Diabetes %Diabetes %
1.0001.00074747474History of Hypertension %History of Hypertension %
0.4740.47448485656Coronary Heart Disease %Coronary Heart Disease %
0.4890.4895252404088
5555414144
RaceRaceCaucasian %Caucasian %African American %African American %Other %Other %
0.8790.87968 68 7070Male Sex %Male Sex %
0.8230.82363 63 ±± 141462 62 ±± 1515Age Age –– years (m years (m ±± sd)sd)
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.7550.75530302727COPD %COPD %
0.8900.89049495050Diabetes %Diabetes %
1.0001.00074747474History of Hypertension %History of Hypertension %
0.4740.47448485656Coronary Heart Disease %Coronary Heart Disease %
0.4890.4895252404088
5555414144
RaceRaceCaucasian %Caucasian %African American %African American %Other %Other %
0.8790.87968 68 7070Male Sex %Male Sex %
0.8230.82363 63 ±± 141462 62 ±± 1515Age Age –– years (m years (m ±± sd)sd)
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
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Baseline Heart Failure Baseline Heart Failure CharacteristicsCharacteristics
0.3430.34351516060Pulmonary Rales %Pulmonary Rales %
0.8600.86079798181Peripheral Edema %Peripheral Edema %
0.3630.36362626868JVD > 10 cm %JVD > 10 cm %
0.1090.10932324444SS33 %%
0.7360.73670707171% of patients LVEF % of patients LVEF ≤≤ 40 %40 %
0.9810.9811.5 1.5 ±± 1.71.71.6 1.6 ±± 1.91.9Hospitalizations for HF in Hospitalizations for HF in ≤≤ 12 Mos. (m 12 Mos. (m ±± sd)sd)
1.0001.00095959595Prior Heart Failure %Prior Heart Failure %
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.3430.34351516060Pulmonary Rales %Pulmonary Rales %
0.8600.86079798181Peripheral Edema %Peripheral Edema %
0.3630.36362626868JVD > 10 cm %JVD > 10 cm %
0.1090.10932324444SS33 %%
0.7360.73670707171% of patients LVEF % of patients LVEF ≤≤ 40 %40 %
0.9810.9811.5 1.5 ±± 1.71.71.6 1.6 ±± 1.91.9Hospitalizations for HF in Hospitalizations for HF in ≤≤ 12 Mos. (m 12 Mos. (m ±± sd)sd)
1.0001.00095959595Prior Heart Failure %Prior Heart Failure %
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
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Baseline Functional Capacity Baseline Functional Capacity and Vital Signsand Vital Signs
0.8610.8613.4 3.4 ±± 0.60.648484545
3.4 3.4 ±± 0.60.652524545
NYHA ClassNYHA Classm m ±± sdsdIII %III %IV %IV %
0.7070.70774 74 ±± 181870 70 ±± 2323MLWHF Score MLWHF Score m m ±± sdsd
0.2330.233129 129 ±± 2424126 126 ±± 2626Systolic BP (mmHg)Systolic BP (mmHg)m m ±± sdsd
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.3810.38183 83 ±± 161681 81 ±± 1717Heart Rate (bpm)Heart Rate (bpm)m m ±± sdsd
0.1940.19496 96 ±± 2929101 101 ±± 2727Weight (kg)Weight (kg)m m ±± sdsd
0.8610.8613.4 3.4 ±± 0.60.648484545
3.4 3.4 ±± 0.60.652524545
NYHA ClassNYHA Classm m ±± sdsdIII %III %IV %IV %
0.7070.70774 74 ±± 181870 70 ±± 2323MLWHF Score MLWHF Score m m ±± sdsd
0.2330.233129 129 ±± 2424126 126 ±± 2626Systolic BP (mmHg)Systolic BP (mmHg)m m ±± sdsd
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.3810.38183 83 ±± 161681 81 ±± 1717Heart Rate (bpm)Heart Rate (bpm)m m ±± sdsd
0.1940.19496 96 ±± 2929101 101 ±± 2727Weight (kg)Weight (kg)m m ±± sdsd
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Baseline Laboratory ValuesBaseline Laboratory Values
0.8400.8401309 1309 ±± 149414941256 1256 ±± 12031203Serum BNP (pg/ ml)Serum BNP (pg/ ml)m m ±± sdsd
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.6430.64336 36 ±± 6636 36 ±± 55Hematocrit %Hematocrit %m m ±± sdsd
0.0284.2 ± 0.64.0 ± 0.6Serum Potassium (mg/ dl)m m ±± sdsd
0.7510.751139 139 ±± 5.05.0139 139 ±± 4.94.9Serum Sodium (mg/ dl)Serum Sodium (mg/ dl)m m ±± sdsd
0.8340.8341.5 1.5 ±± 0.50.51.5 1.5 ±± 0.50.5Serum Creatinine (mg/ dl)Serum Creatinine (mg/ dl)m m ±± sdsd
0.9200.92033 33 ±± 202032 32 ±± 1616BUN (mg/ dl)BUN (mg/ dl)m m ±± sdsd
0.8400.8401309 1309 ±± 149414941256 1256 ±± 12031203Serum BNP (pg/ ml)Serum BNP (pg/ ml)m m ±± sdsd
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.6430.64336 36 ±± 6636 36 ±± 55Hematocrit %Hematocrit %m m ±± sdsd
0.0284.2 ± 0.64.0 ± 0.6Serum Potassium (mg/ dl)m m ±± sdsd
0.7510.751139 139 ±± 5.05.0139 139 ±± 4.94.9Serum Sodium (mg/ dl)Serum Sodium (mg/ dl)m m ±± sdsd
0.8340.8341.5 1.5 ±± 0.50.51.5 1.5 ±± 0.50.5Serum Creatinine (mg/ dl)Serum Creatinine (mg/ dl)m m ±± sdsd
0.9200.92033 33 ±± 202032 32 ±± 1616BUN (mg/ dl)BUN (mg/ dl)m m ±± sdsd
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Baseline MedicationsBaseline Medications
0.5170.51777777272Loop %Loop %
1.0001.00015151414Thiazide %Thiazide %
0.8600.86080807878Diuretics %Diuretics %
1.0001.000
0.8640.864
88
2222
88
2121
Calcium Channel Blockers %Calcium Channel Blockers %
Aldosterone Antagonists %Aldosterone Antagonists %
1.0001.00011111010Both %Both %
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.5590.559119 119 ±± 116116129 129 ±± 122122Furosemide equivalent mgFurosemide equivalent mgm m ±± sdsd
1.0001.00066666565Beta Blockers %Beta Blockers %
0.4460.44619191414ARBs %ARBs %
1.0001.00049494949ACE Inhibitors %ACE Inhibitors %
0.5170.51777777272Loop %Loop %
1.0001.00015151414Thiazide %Thiazide %
0.8600.86080807878Diuretics %Diuretics %
1.0001.000
0.8640.864
88
2222
88
2121
Calcium Channel Blockers %Calcium Channel Blockers %
Aldosterone Antagonists %Aldosterone Antagonists %
1.0001.00011111010Both %Both %
P P ValueValue
Standard CareStandard CareN=100N=100
UltrafiltrationUltrafiltrationN=100N=100
CharacteristicCharacteristic
0.5590.559119 119 ±± 116116129 129 ±± 122122Furosemide equivalent mgFurosemide equivalent mgm m ±± sdsd
1.0001.00066666565Beta Blockers %Beta Blockers %
0.4460.44619191414ARBs %ARBs %
1.0001.00049494949ACE Inhibitors %ACE Inhibitors %
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RESULTSRESULTS
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Primary End PointPrimary End PointWeight Loss at 48 HrWeight Loss at 48 Hr
Primary End PointPrimary End PointWeight Loss at 48 HrWeight Loss at 48 Hr
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Primary End PointPrimary End PointDyspnea Score at 48 HrDyspnea Score at 48 Hr
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Secondary End PointSecondary End PointNet Fluid Loss at 48 HrNet Fluid Loss at 48 Hr
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Worsening Heart Failure Worsening Heart Failure in 90 daysin 90 days
0.0220.022330330123123Days ReDays Re--hospitalizedhospitalized
P ValueP ValueSCSCUFUF
0.0090.00944442121(Unscheduled office + ED visits) %(Unscheduled office + ED visits) %
0.0220.0223.83.81.41.4Number of ReNumber of Re--hospitalization hospitalization days/patientdays/patient
0.0370.0370.460.460.220.22ReRe--hospitalizations/patienthospitalizations/patient
0.0220.02232321818Patients RePatients Re--hospitalized %hospitalized %
0.0220.022330330123123Days ReDays Re--hospitalizedhospitalized
P ValueP ValueSCSCUFUF
0.0090.00944442121(Unscheduled office + ED visits) %(Unscheduled office + ED visits) %
0.0220.0223.83.81.41.4Number of ReNumber of Re--hospitalization hospitalization days/patientdays/patient
0.0370.0370.460.460.220.22ReRe--hospitalizations/patienthospitalizations/patient
0.0220.02232321818Patients RePatients Re--hospitalized %hospitalized %
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Freedom From Freedom From Re-hospitalization for Re-hospitalization for
Heart FailureHeart Failure
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Secondary End PointsSecondary End Points
Similar improvements occurred in the ultrafiltration and Similar improvements occurred in the ultrafiltration and standard care groups in:standard care groups in:
•• BNP levelsBNP levels
•• NYHA classNYHA class
•• MLWHF scoresMLWHF scores
•• Global Assessment scoresGlobal Assessment scores
•• 66--Minute Walk DistanceMinute Walk Distance
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Safety End Points: Change Safety End Points: Change in Serum Creatininein Serum Creatinine
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Adverse events up to 90 Adverse events up to 90 daysdays
0.1540.154NANA55FilterFilter
0.1560.1560033Catheter/ NeedleCatheter/ Needle
0.2020.2029944OtherOther
0.3150.3150011Catheter relatedCatheter related
InfectionInfection
0.0700.070151555NeurologicalNeurological
0.9870.9876644Cardiac ArrestCardiac Arrest
0.9680.968771010Arrhythmias Arrhythmias
0.9880.9882233Myocardial InfarctionMyocardial Infarction
0.0940.09463633939Worsening Heart FailureWorsening Heart Failure
0.3150.3150011DialysisDialysis
0.0800.0800033AnemiaAnemia
0.1130.11310102222HypotensionHypotension
0.0320.0327711BleedingBleeding
P ValueP ValueStandard CareStandard CareUltrafiltrationUltrafiltration
0.1540.154NANA55FilterFilter
0.1560.1560033Catheter/ NeedleCatheter/ Needle
0.2020.2029944OtherOther
0.3150.3150011Catheter relatedCatheter related
InfectionInfection
0.0700.070151555NeurologicalNeurological
0.9870.9876644Cardiac ArrestCardiac Arrest
0.9680.968771010Arrhythmias Arrhythmias
0.9880.9882233Myocardial InfarctionMyocardial Infarction
0.0940.09463633939Worsening Heart FailureWorsening Heart Failure
0.3150.3150011DialysisDialysis
0.0800.0800033AnemiaAnemia
0.1130.11310102222HypotensionHypotension
0.0320.0327711BleedingBleeding
P ValueP ValueStandard CareStandard CareUltrafiltrationUltrafiltration
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Deaths up to 90 daysDeaths up to 90 days
Ultrafiltration groupUltrafiltration group
9 (9.6%)9 (9.6%)
•• 3 heart failure 3 heart failure
•• 1 acute renal failure1 acute renal failure
•• 5 unrelated to either 5 unrelated to either heart failure or heart failure or treatmenttreatment
Standard Care groupStandard Care group
11 (11.6%)11 (11.6%)
•• 5 heart failure5 heart failure
•• 1 myocardial infarction1 myocardial infarction
•• 3 unrelated to either heart 3 unrelated to either heart failure or treatment failure or treatment
•• 2 unknown causes 2 unknown causes
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Safety End PointsSafety End Points
No clinically significant differences at each assessment interval in serum BUN, Sodium, Chloride and Bicarbonate levels
During treatment, a serum potassium level <3.5 mEq/L occurred in 1 (1%) patient in the ultrafiltration group and in 9 (12 %) patients in the standard care group (p=0.018)
Episodes of hypotension during the first 48 hours after randomization were similar in the ultrafiltration 4 (4.4%) and standard care 3 (3%)
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Vasoactive Drugs Vasoactive Drugs RequirementRequirement
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SummarySummary
Early ultrafiltration produces greater weight and Early ultrafiltration produces greater weight and fluid loss than IV diuretics, without adverse impact fluid loss than IV diuretics, without adverse impact on renal functionon renal function
An early ultrafiltration strategy reduces 90 day:An early ultrafiltration strategy reduces 90 day:
•• Percentage of patients requiring rePercentage of patients requiring re--hospitalization hospitalization for HFfor HF
•• Number of HF reNumber of HF re--hospitalizations hospitalizations
•• Days of reDays of re--hospitalization for HFhospitalization for HF
•• ED and unscheduled office visits ED and unscheduled office visits
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ConclusionsConclusions
UNLOAD is the first trial to demonstrate the UNLOAD is the first trial to demonstrate the superiority of ultrafiltration compared to superiority of ultrafiltration compared to intravenous diuretics in the treatment of intravenous diuretics in the treatment of hospitalized volume overloaded heart failure hospitalized volume overloaded heart failure patients.patients.
These results challenge current medical practice These results challenge current medical practice and recommendations. and recommendations.