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

APS

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

APS

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

APS

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

APS

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

APS

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

APS

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

APS

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 %

APS

Freedom From Freedom From Re-hospitalization for Re-hospitalization for

Heart FailureHeart Failure

APS

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

APS

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

APS

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

APS

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

APS

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.