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The Role for Ultrafiltration in the treatment of Acute

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The Role for Ultrafiltration in the treatment of Acute Powered By Docstoc
					Editors
William T. Abraham, MD, FACP, FACC, FAHA
Professor of Internal Medicine Director, Division of Cardiovascular Medicine Deputy Director, Dorothy M. Davis Heart & Lung Research Institute The Ohio State University College of Medicine Columbus, Ohio Ultrafiltration Sections edited by:

Maria Rosa Costanzo, MD, FACC, FAHA
Principal Investigator for the UNLOAD Trial Medical Director, Edward Center for Advanced Heart Failure Midwest Heart Specialists Naperville, Illinois Renal Section edited by:

Robert W. Schrier, MD
Professor of Internal Medicine University of Colorado Health Sciences Center Division of Renal Diseases and Hypertension Denver, Colorado
2

Epidemiology of Heart Failure (HF)
Population Group Total population

Prevalence 5,000,000

Incidence 550,000

Mortality 57,218

Hospital Discharges

Cost

1

1,093,000

$29.6 billion

• HF is a major public health problem resulting in substantial morbidity and mortality • Major cost-driver of HF is high incidence of hospitalizations1,2 • JCAHO has initiated HF quality care indicators for hospitalized patients with HF

1. Thom et al. Circulation. 2006;113:85-151. 2. Topol et al. Textbook of Cardiovascular Medicine. 3rd ed. 2006.

3

Hospitalizations for HF Are Increasing
600,000 500,000
Discharges

400,000 300,000 200,000 100,000 0
9 1 3 5 7 9 1 3 5 '9 '7 '8 '8 '8 '8 '8 '9 '9 '9 7

Women Men

CDC/NCHS. AHA Heart Stroke and Statistical Update, 2001.

4

Mortality Rates After First Hospitalization for HF
Age- and Sex-Stratified Case-Fatality Rates 30 Days and 1 Year After First Hospitalization for HF

Men
Mortality, % Age Group, y No. of Patients 30-Day 655 4.6 1-Year 15.0

Women
Mortality, % No. of Patients 375 30-Day 1-Year 10.9

20-49
50-64 65-74

4.3
5.4 6.8

3048 5923
9310 18,936

5.5 8.6
15.6 11.4

20.5 28.8
43.1 34.0

1892 4412
13,087 19,766

19.5 23.0 37.9
32.3

≥75 All Ages

14.7 11.8

Jong et al. Arch Intern Med. 2002;162:1689-1694.

5

Most Admitted Patients Are Volume Overloaded
At Hospitalization—ADHERE®1
• Any dyspnea – 89%

• Pulmonary congestion (CXR) – 74% • Rales – 67% • Dyspnea at rest – 34% • Peripheral edema – 65%

ADHERE Registry. 3rd Qtr 2003 National Benchmark Report.

6

Over 90% of All Hospitalizations for Acutely Decompensated Heart Failure (ADHF) Are Due to Fluid Overload1 The Majority of These Patients Have Failed Treatment With Oral Diuretics2

1. Aronson. ACC. 2000. 2. Adams et al. Am Heart J. 2005;149:209-216.

7

Decompensated ADHF1
Insult Cardiac Dysfunction Neurohormonal Activation
RAAS
Catecholamine Endothelin Renal Vasoconstriction/Fluid Retention

LV Remodeling

Hemodynamic Decompensation
Preload
Afterload Cardiac Output

Fluid Overload Symptoms
Morbidity Death
Colucci WS, Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. 1997:394.

8

Common Compensatory Responses to Lowand High-Output Cardiac Failure
High-Output Cardiac Failure
Low-Output Cardiac Failure

Systemic Arterial Vasodilation

 Cardiac Output

Arterial Underfilling

Nonosmotic AVP Release

 Sympathetic Nervous System

 Renin-AngiotensinAldosterone System

Diminished Renal Hemodynamics and Renal Sodium and Water Excretion
Schrier. Ann Intern Med. 1990;113:155-59.

9

Cardiorenal Syndrome
• In HF, it is the result of interactions between the kidneys and other circulatory compartments that increase circulating volume. HF symptoms and disease progression are exacerbated1 • At its extreme, cardiorenal dysregulation leads to what is termed cardiorenal syndrome, in which therapy to relieve congestive symptoms of HF is limited by further decline in renal function1

NHLBI Working Group. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm. April 30, 2005.

10

Cardiorenal Syndrome
• In the context of CHF, the interaction of the heart and kidney contributes to worsening volume overload
Renal elements include

• Excessive neurohormonal, cytokine activation
• Decreased effective renal perfusion, GFR, and acute renal failure • Diuretic resistance • Fibrosis (RAAS mediated)
12

The Cardiorenal Syndrome of HF

Increased Morbidity and Mortality

Diuretic Therapy Neurohormonal Activation

Development of Diuretic and Natriuretic Resistance Impaired Renal Function

Diminished Blood Flow

Decreased Renal Perfusion
13

Mild or Moderate Decreases in Renal Function Have Been Shown to Correlate With Significant Morbidity and Mortality in Patients With Asymptomatic and Symptomatic Congestive HF1-4

1. Dries et al. J Am Coll Cardiol. 2000;35:681-689. 2. The SOLVD Investigators. N Engl J Med. 1992;327:685-691. 3. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 4. Schrier. J Am Coll Cardiol. 2006;47:1-8.

14

Renal Function Is Associated With Increased Morbidity and Mortality in HF
Relationship of GFRc With Mortality in 1906 Patients With CHF
• Total of 1906 patients
Proportion mortality
0.7 –

•

NYHA class – III (n=1138) – III/IV (n=607) – IV (n=161)

0.6 – 0.5 –
0.4 – 0.3 – 0.2 –

<44 mL/min 44–58 mL/min

• Impaired renal function is a strong predictor of mortality

59–76 mL/min >76 mL/min

0.1 – 0.0 0 200 400 600 800 1000 1200

Days

Hillege et al. Circulation. 2000;102:203-210.

15

Most Common Intravenous Medications
All Enrolled Discharges (n=105,388) October 2001–January 2004 100

88%

90 80 70 60 50 40 30 20
10

Patients (%)

6%
IV Diuretic Dobutamine

6%
Dopamine

10%

10%

3%
Milrinone Nesiritide

1%
Nitroglycerin Nitroprusside

0

IV Vasoactive Meds
ADHERE® Registry. Benchmark Report. 2004.

16

Diuretics and ADHF

• No long-term studies of diuretics for the treatment of ADHF1 • Despite widespread use in ADHF, their effect on morbidity and mortality is not known2

1. Ravnan et al. Congest Heart Fail. 2002;8:80. 2. Kramer et al. Nephrol Dial Transplant. 1999:14(suppl 4):39-42.

17

Diuretics
• The use of loop diuretics in ADHF patients with dyspnea and shortness of breath is standard therapy
• In patients with ADHF, diuretics – May induce a natriuresis

– Decrease extracellular fluid (ECF) volume – Provide symptomatic relief

Schrier. J Am Coll Cardiol. 2006;47:1-8.

18

Current Options May Have Undesirable Clinical Impacts
• Favorable aspects of diuretic therapy
– Increases urine output; reduces total body volume in majority of patients 4

• Adverse aspects of diuretic therapy
– Direct activation of renin-angiotensin-aldosterone system3,10 – Enhanced myocardial aldosterone uptake 12 – Loss of K, Mg, Ca, secondary myocyte Ca loading 12 – Indirect reduction of cardiac output 10,11
– Increased total systemic vascular resistance 11 – Reduced natriuresis8 and GFR7,9 – Associated with increased morbidity and mortality 2,5,6
19

Diuretic Resistance
• Can be described as a clinical state in which the diuretic response is diminished or lost before the therapeutic goal of relief from edema has been reached1 • Affects 20%–30% of patients with HF2

1. Kramer et al. Nephrol Dial Transplant. 1999;14(suppl 4):39-42. 2. Ellison. Cardiology. 2001;96:132-143.

20

Diuretic Resistance: Two Types
• “Braking” phenomenon
– A decrease in response to a diuretic after the first dose has been administered

• Long-term tolerance
– Tubular hypertrophy to compensate for salt loss

Brater. N Engl J Med. 1998;339:387.

21

Diuretics Activate Neurohormonal Systems in HF

50 Plasma Renin Activity (ng/mL/h)

1000 Plasma Aldosterone (pmol/L) 600 Mean, 95% Confidence Interval

10

2.5

200

0.5 Before (n=12)

P =.0002 After Diuretic (n=11)

100 Before (n=12)

P =.0007
After Diuretic (n=11)

Bayliss et al. Br Heart J. 1987;57:17

22

Effect of Loop Diuretics on Renin-AngiotensinAldosterone System in Cardiac Failure
CARDIAC FAILURE
Loop Diuretic Inhibition of Macula Densa
Increased ReninAngiotensin

Left Ventricular Dysfunction

Cardiac Remodeling and Fibrosis

Increased Aldosterone
Schrier. J Am Coll Cardiol. 2006;47:1-8.

23

Elevated Neurohormones Cause Diuretic Resistance
Glomerulus Norepinephrine (and endothelin) decreases renal blood flow and GFR
Proximal Tubule Ang II increases sodium reabsorption

Collecting Duct Aldosterone increases sodium reabsorption
Krämer et al. Am J Med. 1999;106:90.

24

The Use of Loop Diuretics in ADHF May Worsen Renal Function
• In symptomatic ADHF patients, diuretics have an important role in treating congestion and symptoms
• However, because even mild renal dysfunction has been associated with increased cardiovascular mortality, the positive and negative aspects of the use of diuretics in patients with CHF must be considered

Schrier. J Am Coll Cardiol. 2006;47:1-8.

25

Furosemide Monotherapy Causes Significant Decline in Renal Function (GFR)
Change in GFR after IV furosemide 80 mg in CHF 15 10 5 0 -5 -10 -15 -20 -25

Placebo

GFR (% Change)

IV furosemide

0

500

1000

1500

2000

2500
26

Urine Output (mL) 0–8 h
Gottlieb et al. Circulation. 2002;105:1348.

Causes of Diuretic Resistance in HF1-3
• Decreased renal function and distal Na+ delivery • Variability in diuretic absorption (bioavailability) • Neurohormonal activation (RAAS/SNS)
• Drugs/diet—increased sodium intake • Noncompliance with medications

• Infrequent dosing

1. Neuberg et al. Am Heart J. 2002;144:31-38. 2. Brater. N Engl J Med. 1998;339:387-395. 3. Wilcox. J Am Soc Nephrol. 2002;13:798-805.

27

Reaccumulation of Na+ Despite Ongoing Furosemide Treatment1
300

Na+ Excretion Net Diuresis After 4 Days of Rx = 0 mL

UNaV, mEq/6 h

250 200
150 100 50 0
Before F F1 F2

Na+ Intake

F3

F4

Time, Days

F = Furosemide

Na+ Reaccumulation Between Furosemide Doses
28

1. Wilcox et al. Kidney Int. 1987;31:135.

Dose Response Curves for Loop Diuretics in ADHF Are Altered
Fractional Na Excretion
20

18 16
14 FENa ,% 12 10

Normal

CRF
CHF

Secretory Defect

Decreased Maximal Response

8 6
4 2 0

0.01
Ellison. Cardiology. 2001;96:132-143.

0.1

1

10

100
29

[Furosemide], µg/mL

Management of Diuretic Resistance in HF
• Restrict daily fluid intake (1.0–1.5 L)
• Moderate restriction of daily salt intake (≤2 g) • Avoid NSAIDs • Institute and uptitrate ACE inhibitors and/or angiotensin receptor blocker

• Give short-acting loop diuretic orally in several divided (and increasing) doses, bolus, or continuous intravenous administration
• Use sequential nephron blockade via combination loop diuretic and thiazide diuretic

• Add small doses of spironolactone (12.5–25 mg) • Consider short-term acetazolamide in selected patients
30

Potential Benefits of Diuretics or UF in HF
Congestive Heart Failure
Improved Pulmonary Congestion

Loop Diuretic or Ultrafiltration Treatment

Negative Sodium and Water Balance

Decreased Cardiac Filling Pressure

Decreased Functional Mitral Insufficiency

Decreased Ventricular Dilatation Decreased Ventricular Wall Stress and Endomyocardial Ischemia

Improved Myocardial Function Improved Renal Function
Schrier. J Am Coll Cardiol. 2006;47:1-8.

31

Inadequate Diuresis During ADHF Treatment
All Enrolled Discharges in Over 12 Months (01.01.2003–12.31.2003) Who Were Discharged Home (including home with additional and/or outpatient care)

50 Enrolled Discharges (%)

The Nation
n=26,757, 68%

40

30%
30
20 10 0

24%

13%
7%
(<-20)

15% 3% 2%
(>10)

6%
(-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5)

(5 to 10)

Change in Weight (lb)

Change in Weight From Admission to Discharge
Note: For the chart, n represents the number of patients who have both baseline and discharge weight, and the percentage is calculated based on the total patients in the corresponding population. Patients without baseline or discharge weight are omitted from the histogram calculations.
ADHERE® Database

32

Despite the Use of Diuretics in 90% of Patients, 20% Gain Weight on Discharge1

Adams et al. Am Heart J. 2005;149:209-216.

33

Diuretic Therapeutic Dilemma
• Diminished renal function and concurrent sodium and water retention in ADHF presents a therapeutic dilemma with regard to submaximal diuretic therapy

• Fluid removal by ultrafiltration may be recommended in this clinical setting

Schrier. J Am Coll Cardiol. 2006;47:1-8.

34

• ULTRAFILTRATION allows for the production of plasma water from whole blood across a semipermeable membrane in response to a transmembrane pressure gradient • The ensuing fluid or ultrafiltrate is isotonic to plasma

Ronco et al. Cardiology. 2001;96:155-168.

35

A History of Ultrafiltration
1949: Schneierson proposed intermittent peritoneal dialysis for refractive ADHF1
1940 1950 1960

1974: Silverstein described solitary ultrafiltration on 5 ESRD patients via a modified dialysis circuit3
1970 1980

1954: Kolff noted that ultrafiltration could be used for a ―reduction of intractable edema‖ 2

1979: Paganini and others reported the practical application of ultrafiltration in a volume-overloaded patient4

1. Schneierson SJ. Am J Med Soc. 1949;298. 2. Kolff et al. Cleve Clin Q. 1954;21. 3. Silverstein et al. N Engl J Med. 1974;291:747-751. 4. Paganini et al. Adv Ren Replace Ther. 1996;3:166-173.

36

Ultrafiltration Compared to Loop Diuretics
• Ultrafiltrate is isotonic with plasma, whereas the diuresis of loop diuretics is virtually always hypotonic to plasma

• Ultrafiltration removes more sodium than diuretic therapy • No electrolyte disturbances • Ultrafiltration decreases ECF volume more than a comparable volume of diuretic-induced fluid loss

Schrier. J Am Coll Cardiol. 2006;47:1-8.

38

Ultrafiltration
PRESSURE

Na

Uf 
Uf 
Na

 Uf
 Uf

• A transmembrane pressure generated by the device allows for the formation of ―ultrafiltrate‖ via convective transport1,2

Ultrafiltration (mL/h)

Qf = Kf - TMP

Transmembrane Pressure (mmHg)
1. Paganini et al. Trans Am Soc Artif Intern Organs. 1982:28:615-620. 2. Costanzo MR. Curr Treat Options Cardiovasc Med. 2006;8:301-309.

39

Fluid Removal by Ultrafiltration
Interstitial Space (edema)

•

Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue

Na
P

H2O

Na

K

UF

K

•

The transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill (PR), aimed at minimizing this reduction1,2

PR
P

Na Vascular Space

Vascular Space
1. Lauer et al. Arch Intern Med. 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.

Na
40

Changes in Plasma Volume and Refilling Rate During Ultrafiltration
10 – 5–
0–
D PV (%)

–5 –
–10 – 20 – 15 –
Before 1 UF liter
2 liter 3 liter 4 liter After UF 24h after UF

• Ultrafiltration can be done safely without significant changes in plasma volume
• Plasma refill rates may decrease as volume removal continues

PRR (mL/min)

10 – 5– 0–
Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF

Marenzi et al. J Am Coll Cardiol. 2001;38:963-968.

41

Hemodynamic Effects of UF in CHF
5.0 – 4.0 – 3.0 – 2.0 –
Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF

CO (L/m)

SV (mL)

70 – 60 – 50 –

40 – 30 –
Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF

RAP (mmHg)

PWP (mmHg)

25 – 20 – 15 – 10 – 5– 0 - Before
UF

30 –

25 – 20 –
15 –
1 liter 2 liter 3 liter 4 liter After UF 24h after UF

10 - Before
UF

1 liter

2 liter

3 liter

4 liter

After UF

24h after UF 42

Marenzi et al. J Am Coll Cardiol. 2001;38:963-968.

Ultrafiltration in Chronic Cardiac Insufficiency: Failure of Furosemide to Provide the Same Result
• 16 stable, NYHA II–III chronic HF patients matched by age, gender, and peak VO2
• Randomized to isolated ultrafiltration (500 mL/h) or IV furosemide • Removal of the same amount of fluid in both arms (approximately 1600 mL)

• Measurement of hemodynamics, peak VO2, norepinephrine, PRA, and aldosterone at baseline, end of treatment, and 3 months

Agostoni et al. Am J Med. 1994;96:191-199.

43

Effects of Ultrafiltration vs IV Furosemide
Neurohormones
NE + 80 –
+ 40 – %0–

PRA + 170 – + 80 – + 40 –
%0– - 40 -

ALD + 80 –
+ 40 – %0–

-140 – d 0 1d 2d 3d 4d 3m

-140 – d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m

Triangles = Ultrafiltration Squares = Furosemide

Agostoni et al. Am J Med. 1994;96:191-199.

44

Isolated Ultrafiltration Produces a Sustained Decrease in Body Weight in HF Patients
+2

D Body Weight (kg)

+1 0

Ultrafiltration Furosemide *P <.01 vs baseline
†P

-1
-2

<.01 vs furosemide

B
Agostoni et al. Am J Med. 1994;96:191-199.

1d

2d

3d

4d

1m

3m
45

Time

Effects of Ultrafiltration vs IV Furosemide
Lung Water Content
Chest x-ray score 21 -

17 13 9-

mL
Fluid output

-

ml - 3500 - 2500 - 1500

Fluid input

3000 2000 -

Δ Body Weight

kg +2 +1 0-

1000 – b 1d 2d 3d 4d 1m 3m diuresis plus ultrafiltrate

-1 -2 -

Triangles: Ultrafiltration Squares: IV Furosemide
Agostoni et al. Am J Med. 1994;96:191-199.

b

1d

2d

3d

4d

3m
46

Enhanced Sodium Extraction With Ultrafiltration Compared With Intravenous Diuretics
• 15 hospitalized ADHF patients with presumed diuretic resistance and clinical evidence of volume overload • Urine electrolyte concentrations measured after a dose of IV diuretics • Ultrafiltration was then begun and ultrafiltrate electrolyte concentrations were measured 8 h later and compared with the initial urine values

Ali et al. J Card Fail. 2006;12(6 suppl):114.

47

Urine vs UF Electrolytes After Intravenous Diuretics or Ultrafiltration
140 120

IVD UF

P =.000025

100

mg/dL

80 60 40 20 0

P =.000017

P =.017

Sodium
Ali et al. J Card Fail. 2006;12(6 suppl):114.

Potassium

Magnesium
48

Ultrafiltration and Renal Function
• Jaski et al reported no difference in mean creatinine
before UF (1.6mg/dL +/- 0.6mg/dL) and 24 h after UF (1.7 mg/dL +/- 0.6 mg/dL)1

• Bart et al reported an average pre-UF creatinine of
1.6 mg/dL and 48 h post-UF creatinine of 1.9 mg/dL, which was not statistically significant2

• Costanzo et al reported no change in creatinine pre- and
post-UF in both the EUPHORIA3 and UNLOAD4 trials

• Marenzi et al reported no change in creatinine when
utilizing UF in volume-overloaded patients5
49

Possible Contraindications to Ultrafiltration in Patients With HF
• Inadequate venous access
• Hypotension • Hypercoagulable states

• Stage V chronic kidney disease; requirement for hemodialysis • Patients responsive to diuretics

50

AquadexTM FlexFlow TM UF Prescription: Only 3 Clinical Decisions
• Volume to be removed
– Total volume of excess fluid (intravascular and interstitial)

• Rate of removal
– Safe removal of fluid requires that filtration rate equal plasma refill rate (rate of recovery of third space fluid)

• Anticoagulation therapy
– Full anticoagulation is recommended to preserve filter function – However, if a filter clots, only 40 mL of whole blood are lost
51

Comparison to Continuous Venovenous Hemofiltration
Aquapheresis™
Patient
Fluid overload

CVVH
Renal

Prescriber

Any who have received training (cardiologist, hospitalist, nephrologist, surgeon, etc)
Inpatient/Outpatient 10–40 mL/min 33 mL

Nephrologist

Treatment venue Blood withdrawal rates Extracorporeal volumes

ICU 100–300 mL/min 100–300 mL

Venous access
Reported adverse events since June 2002

Peripheral or central
Aquadex™ 6 (0.12% MDR event per patient, 5000 patients) 0 device malfunctions

Central
Prisma 812 (patient numbers not available) NxStage 230 (23% MDR event per patient, 1000 patients)

52

The SAFE Study
• Multicenter, prospective study, 21 patients (25 treatments)

• Initial UF within 12 h of hospitalization and before any significant administration of IV diuretics and/or vasoactive drugs
– Primary end point of greater than 1 L fluid removal in less than 8 h was achieved in 92% of treatments (treatment period 6:43±1:47 h:min) – On average, 2611±1002 mL (maximum 3725 mL) of ultrafiltrate was removed per treatment – Patient weight decreased from 91.9±17.5 to 89.3±17.3 kg (P <.0001) after ultrafiltration – No major adverse events occurred
Conclusion: Rapid removal of extracellular and intravascular fluid volume excess can be safely achieved via peripherally inserted ultrafiltration without the need for central venous catheter placement
Jaski. J Card Fail. 2003;9:227-231.

53

Relief for Acutely Fluid Overloaded Patients With Decompensated Congestive Heart Failure The RAPID-CHF Trial

Bart et al. J Am Coll Cardiol. 2005;46:2043-2046.

54

RAPID Trial: Design
• Multicenter (7), randomized, controlled study (40 patients) comparing the treatment effects of early ultrafiltration treatment strategy of 8 h, to diuretic therapy for patients who are hospitalized for decompensated HF of any etiology • Single 8-h UF intervention compared with usual diuretic strategies – Artificially constrained UF to 8 h – Therapy was not titrated against clinical or biochemical markers of congestion/edema/volume

Bart et al. J Am Coll Cardiol. 2005;46:2043-2046.

55

RAPID Trial: Total Fluid Removal 48 h
1000 -1000 UF Usual Care

-3000

mL

-5000 -7000
-9000 -11000

P =.028
Bart et al. J Am Coll Cardiol. 2005;46:2043-2046.

56

RAPID Trial: Conclusions
• Ultrafiltration is superior to diuretic strategies in salt and water removal

• Ultrafiltration is safe, in a variety of clinical sites • There is no clinical justification to delay ultrafiltration therapy until diuretics fail

Bart et al. J Am Coll Cardiol. 2005;46:2043-2046.

57

Early Ultrafiltration in Patients With Decompensated HF and Observed Resistance to Intervention With Diuretic Agents The EUPHORIA Trial

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

58

EUPHORIA Trial: Study End Points
• Primary efficacy end point
– Resolution of signs and symptoms of fluid overload permitting discharge in ≤3 days

• Primary safety end point
– Feasibility of achieving the primary efficacy objective without symptomatic hypotension, renal insufficiency (≥25% increase in serum creatinine), or other adverse events

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

59

EUPHORIA Trial: Patient Population
• Age: 74 ± 8.5 years • Gender: 75% male • Race: 95% Caucasian • Etiology of HF: 75% ischemic
• Left ventricular ejection fraction: 31 ± 16%

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051..

60

EUPHORIA Trial: Results
• Number of 8-h ultrafiltration courses: 2.6 ± 1.2
• Volume removed by ultrafiltration: 8653 ± 4314 mL

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

61

EUPHORIA Trial: Length of Stay
7 7

6
5 Patients 4

5
4

3

3
1 2 1

0 2 Days 3 Days 4 Days 5 Days 10 Days

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

62

EUPHORIA Trial: Clinical and Laboratory Outcomes
Variable
Weight (kg)

Pre-UF
87 ± 23

Disch.
81 ± 22

30 Days
84 ± 21

90 Days
80 ± 18

P Value
.006

SBP (mmHg)

120 ± 17 2.12 ± 0.6
1236 ± 747 39 %

114 ± 22 2.20 ± 0.8
988 ± 847 37 %

120 ± 26 2.38 ± 1.1
816 ± 494 5%

116 ± 24 2.18 ± 0.7

.306

Cr (mg/dL) BNP (pg/mL)
NYHA FC IV

.532

NA 11%

.03 .063

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

63

Serum Sodium
140 139 138 137 136 135 134 133 132 131 130 129

n=13

ns* ns†
†P

Na (mg/dL)

=.017

*P =.042

n=7

*Pre-UF to discharge †Pre-UF to 90 days

Pre-UF

Discharge

30 Day

90 Day

64

EUPHORIA Trial: Conclusions
• Early ultrafiltration in patients with fluid overload and diuretic resistance permitted the discharge of 60% of high risk ADHF patients in ≤3 days • A treatment strategy to use ultrafiltration early in patients with volume overload and evidence of diuretic resistance results in reduced length of stay and improved clinical status • Improvements in clinical status are preserved for 30–90 days following hospitalizations

Costanzo et al. J Am Coll Cardiol. 2005;46:2047-2051.

65

Ultrafiltration versus IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive HF: A Prospective Randomized Clinical Trial UNLOAD Trial

Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

66

Investigators & 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 • Eichorn E: Medical City, Dallas, TX • 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

• •
• • •

• • • • • •
• •

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

• • • • • •

•

Teerlink JR: San Francisco/VAMC, CA

Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

67

Study Hypotheses
• In hypervolemic HF patients, ultrafiltration is
– Superior to aggressive IV diuretic therapy in reducing volume overload – Associated with sustained clinical benefits – Similar to IV diuretics in terms of safety

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68

Study Design
• Prospective, randomized multicenter trial comparing the effects of early venovenous ultrafiltration alone versus IV diuretics alone on weight loss, symptoms, and hospitalizations of hypervolemic HF patients

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Primary End Points
• Efficacy
– Weight loss at 48 h after randomization – Dyspnea score at 48 h after randomization

• Safety
– Changes in serum blood urea nitrogen, creatinine, and electrolytes at 8, 24, 48, and 72 h after randomization, discharge at 10, 30, and 90 days – Episodes of hypotension during the first 48 h after randomization

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Secondary End Points
• Brain natriuretic peptide levels at 48 h after randomization, 30 and 90 days
• NYHA class, Minnesota Living With Heart Failure (MLWHF) score, Global Assessment score at discharge, and follow-up

• Diuretic doses after ultrafiltration or standard care
• Percentage of patients rehospitalized for HF • Absolute number of rehospitalizations for HF • Days of rehospitalization for HF

• Unscheduled office and emergency department visits
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METHODS

72

Methods
• Enrollment June 2004 until July 2005 at 28 US centers • Randomization schedule via secure Web site • Two independent adjudicators of causes of death • CHF Solutions funded the trial and provided a study manager • Data were entered by investigators, sent to a data management group, and verified with source documents

• Investigators had complete access to the database and directed all statistical analyses, which were performed by an independent statistician
• Study was approved by the ethics committee of each hospital, and all patients provided written informed consent
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Methods: Inclusion 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 h hospitalization

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Methods: Exclusion 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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Methods: Study Procedures
• Daily 2 g sodium, 2000 mL fluid intake restriction

• Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and digoxin continued • 1 diuretic unit =
– 20 mg of furosemide – 10 mg of torsemide – 0.5 mg of bumetamide

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Methods: Study Procedures
• Ultrafiltration Arm
– Ultrafiltration rate ≤500 mL/h – 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 ≥2 times daily PO dose for the first 48 h after randomization

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Methods: Statistical Analysis
• Differences between treatment groups: – Pearson’s chi-square or Fisher’s exact test for categorical variables – Wilcoxon’s rank sum test for continuous variables • The effects of covariates on weight loss at 48 h tested using analysis of variance (ANOVA) • Change over time within treatment groups: Wilcoxon’s matched pairs signed ranks test
• P values ≤.05 considered statistically significant

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Baseline Demographics and Comorbidities
Characteristic

Ultrafiltration (N=100) 62 ± 15 70 55 41 4 74
56

Standard Care (N=100) 63 ± 14 68 52 40 8 74
48

P Value

Age – Years (M±SD) Male Sex %
Race (%) Caucasian African American Other

.823 .879 .489

History of hypertension (%)
Coronary heart disease (%)

1.000
.474

COPD (%)
Diabetes (%)

27
50

30
49

.755
.890

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Baseline HF Characteristics
Characteristic

Ultrafiltration (N=100) 95
1.6 ± 1.9 71 44 68 60 81

Standard Care (N=100) 95
1.5 ± 1.7 70 32 62 51 79

P Value 1.000
.981 .736 .109 .363 .343 .860

Prior HF (%) Hospitalizations for HF in ≤12 months (M ± SD)
% of patients LVEF ≤40% S3 (%) JVD >10 cm (%) Pulmonary rales (%) Peripheral edema (%)

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Baseline Functional Capacity and Vital Signs
Characteristic

Ultrafiltration (N=100)
3.4 ± 0.6 52 45

Standard Care (N=100)
3.4 ± 0.6 48 45

P Value

NYHA Class M ± SD III (%) IV (%)
MLWHF Score M ± SD

.861

70 ± 23
101 ± 27 126 ± 26 81 ± 17

74 ±18
96 ± 29 129 ± 24 83 ± 16

.707
.194 .233 .381

Weight (kg) M ± SD Systolic BP (mmHg) M ± SD
Heart rate (bpm) M ± SD

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Baseline Laboratory Values
Characteristic BUN (mg/dL) M ± SD

Ultrafiltration (N=100) 32 ± 16
1.5 ± 0.5

Standard Care (N=100) 33 ± 20
1.5 ±0.5

P Value .920
.834

Serum creatinine (mg/dL) M ± SD
Serum sodium (mg/dL) M ± SD

139 ± 4.9
4.0 ± 0.6 1256 ± 1203

139 ± 5.0
4.2 ± 0.6 1309 ± 1494

.751
.028 .840

Serum potassium (mg/dL) M ± SD Serum BNP (pg/mL) M ± SD
Hematocrit (%) M ± SD
Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

36 ± 5

36 ± 6

.643
82

Baseline Medications
Characteristic ACE Inhibitors (%)

Ultrafiltration (N=100)
49

Standard Care (N=100)
49

P Value 1.000

ARBs (%) Beta-blockers (%) Calcium channel blockers (%)
Aldosterone antagonists (%) Diuretics (%) Loop (%) Thiazide (%)

14 65 8
21 78 72 14

19 66 8
22 80 77 15

.446 1.000 1.000
.864 .860 .517 1.000

Both (%) Furosemide equivalent mg M ± SD
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10
129 ± 122

11
119 ± 116

1.000
.559
83

RESULTS

84

Primary End Point Weight Loss at 48 H
6-

Weight Loss (kg)

5 4 3 2 -

P =.001

M = 5.0, CI + 0.68 kg (N=83) M = 3.1, CI + 0.75 kg (N=84) I Ultrafiltration Arm Standard Care Arm
85

1 0 I

I

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Primary End Point Dyspnea Score at 48 H
7 6 P =.35

Dyspnea Score

5 4
3 2

M = 6.4, CI + 0.11 (N=80)

M = 6.1, CI + 0.15 (N=83)

1
Ultrafiltration Arm
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Standard Care Arm
86

Secondary End Point Net Fluid Loss at 48 H
Net Fluid Loss (liters)
5.5 5 4.5 4 3.5 3 2.5 2 Ultrafiltration Arm
Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

P =.001 M = 4.6, CI + 0.29 L (N=81)

M = 3.3, CI + 0.29 L (N=82)

Standard Care Arm
87

Secondary End Points
• Similar improvements occurred in the ultrafiltration and standard care groups in
– Brain natriuretic peptide levels – NYHA class
– MLWHF scores

– Global assessment scores – 6-Minute walk distance

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Safety End Points: Change in Serum Creatinine
Serum Creatinine Change (mg/dL)

Ultrafiltration Arm
1.5

Standard Care Arm

1

P >.05 at all time points

0.5

0

8h
UF: N=72 SC: N=84

24 h
N=90 N=91

48 h

72 h Discharge 10 Days 30 Days 90 Days
N=47 N=52 N=86 N=90 N=71 N=75 N=75 N=67 N=66 N=62
89

N=69 N=75

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Safety End Points
• No clinically significant differences at each assessment interval in serum BUN, Na, Cl-, and HC3 • 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=.018)
• Episodes of hypotension during the first 48 h after randomization were similar in the ultrafiltration 4 (4.4%) and standard care 3 (3%)

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Adverse Events
Ultrafiltration Catheter/Needle
Filter Infection

Standard Care 0
NA

P Value .156
.154

3
5

Catheter related Other
Bleeding Hypotension

1 4
1 22

0 9
7 10

.315 .202
.032 .113

Anemia Dialysis
Worsening HF Myocardial infarction

3 1
39 3

0 0
63 2

.080 .315
.094 .988

Arrhythmias Cardiac arrest
Neurological
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10 4
5

7 6
15

.968 .987
.070
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Deaths
• Ultrafiltration Group • Standard Care Group

9 (9.6%)
– 3 HF – 1 acute renal failure – 5 unrelated to either HF or treatment

11 (11.6%)
– 5 HF – 1 myocardial infarction

– 3 unrelated to either HF or treatment – 2 unknown causes

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Effect of Ultrafiltration on Weight Loss: Subgroup Analysis

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Lack of Correlation Between Change in Dyspnea Score and Weight Loss at 48 H
10

R2 = .0241

R2 = .017

Weight Loss (kg)

5 0 -5 -10

-15
-20

-3

-2

-1

0

1

2

3

4

Dypsnea Score
UF Arm SC Arm Linear (UF Arm) Linear (SC Arm)
94
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Vasoactive Drugs Requirement
Ultrafiltration Arm Standard Care Arm

20 18 16 14 12 10 8 6 4 2 0

Patients Requiring Vasoactive Drugs (%)

P =.015

P =.086

17

12 8

3
48 h UF: N=98 SC: N=99 Entire Hospitalization
UF: N=100 SC: N=100
95

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Change in BNP Levels
Ultrafiltration Arm
48 hours
0 -100 -200 BNP (pg/mL)

Standard Care Arm
30 days 90 days

-300 -400 -500 -600
-700 -800
UF: N=92 SC: N=88 UF: N=80 SC: N=76 UF: N=71 SC: N=66

P=.576
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P=.463

P=.684

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Resources Utilization for HF in 90 Days
Resource
Patients rehospitalized (%) Rehospitalizations/Patient

UF
18 0.22 1.4 123

SC
32 0.46 3.8 330

P Value
.022 .037 .022 .022

Number of rehospitalization days per patient
Days rehospitalized

Unscheduled office + ED visits (%)

21

44

.009

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Freedom From Rehospitalization for HF
Percentage of Patients Free From Rehospitalization

100 80 60 40 20 0
10
P=.037

Ultrafiltration Arm (16 Events)

Standard Care Arm (28 Events)

20

30

40
Days

50

60

70

80

90

No. Patients at Risk Ultrafiltration Arm Standard Care Arm

88 86

85 83

80 77

77 74

75 66

72 63

70 59

66 58

64 52

45 41
98

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UNLOAD Trial Diuretic Arm Undertreated?
Change in Weight Admission No wt loss or gain >0 to 2.3 kg loss >2.3 kg to 4.5 kg loss ADHERE Registry Patients (%) 16 32 (48) 24 UNLOAD Diuretic Patients (%) 13 19 (32) 17

>4.5 kg loss

28 (52)

51 (68)

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Diuretic Requirements at Discharge
Discharge
Ultrafiltration Arm Usual Care (Diuretic) Arm

14 ± 68-mg decrease

11 ± 61-mg increase
P =.058

10 days

11 ± 79-mg decrease

12 ± 53-mg increase

P =.049

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UF vs Bolus/Continuous Diuretics
• In the UNLOAD Trial
– 67% of patients in standard care arm received IV bolus – 33% of patients in standard care received IV continuous drip – Average dose in 24-h period for loop diuretic was
• IV bolus 117 mg

• IV continuous 127 mg

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UF vs Bolus/Continuous Diuretics

At 48 H Wt (kg) Fluid (liters)

UF 5.0 4.6

Bolus 2.9 3.0

P value .001 <.001

Cont. 3.6 3.9

P value .145 .232

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UNLOAD: Effects of Ultrafiltration vs Bolus and Continuous-Infusion Diuretic Therapy at 48 H
Ultrafiltration (N=100) 4 Bolus Diuretics (N=68) 3 Continuous Diuretics (N=32) 3

Parameter
Hypotension (%) Change in serum K <3.5 mEq/L (%) Weight loss (kg)

1
5.0†

8*
2.5

22
3.6

*P=.003 vs continuous. †P=.001 vs bolus.

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Ultrafiltration vs Continuous Diuretic Infusions
• • • • Ultrafiltration patients had fewer rehospitalizations Ultrafiltration patients had fewer rehospitalization days/patient Ultrafiltration patients had fewer unscheduled visits All differences were statistically significant

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90-Day HF-Related Outcomes
Ultrafiltration (N=100) 18 1.4
0.65† 9.6 Bolus Diuretics (N=68) Continuous Diuretics (N=32)

Parameter

P, Ultrafiltration vs Continuous Diuretics .037 .016
.016 NS

Rehospitalization (%)
Rehospitalization days per patient (d)

29 3.3
1.31 7.8

39 4.9
2.29 19.4

Rehospitalization equivalents, mean*
Mortality (%)

*Number of HF-related rehospitalizations plus unscheduled office and emergency department visits. †P=.050 vs bolus.
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Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: analysis from the UNLOAD Trial

Costanzo MR, Saltzberg MT, Jessup ML, Teerlink JR, Sobotka PA, and the UNLOAD Investigators

106

Worsening Heart Failure in 90 Days
IV Bolus Diuretic 29 (17/59) IV Continuous Diuretic 39 (11/28) UF vs IV Bolus Diuretic UF vs IV Continuous Diuretic IV Bolus vs IV Continuous Diuretic

Characteristic
Patients rehospitalized, % Rehospitalizations per patient (m ± sd) Rehospitalization days per patient (m ± sd) Days rehospitalized

UF
18 (16/89) 0.23 ± 0.54 n=89 1.4 ± 4.1 n=89

P value

P value

P value

.158

.037

.338

0.43 ± 0.75 n=59
3.3 ± 7.4 n=59

0.54 ± 0.79 n=28
4.9 ± 10.5 n=28

.091

.018

.405

.095

.016

.387

123 22 (14/65)

193 40 (18/45)

137 52 (11/21) .054 .012 .428

Unscheduled office + ED visits, %

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Rehospitalization Equivalents at 90 Days
Ultrafiltration (N=65) Bolus Diuretics (N=45)

Characteristic Rehospitalization equivalents per patient (mean ± sd)

Continuous Diuretics (N=21) 2.29 (3.23)

0.65 (1.36)

1.31 (1.87)

UF vs Bolus Diuretic: P=.050 UF vs Continuous Diuretic: P=.016 Bolus vs Continuous Diuretics: P=.362

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Rehospitalization Equivalents at 90 Days
4
Rehosp. Equivalents/Pt
UF vs Bolus Diuretic: P=.050 UF vs Continuous Diuretic: P =.016 Bolus vs Continuous Diuretic: P =.362

2

0

m = 0.31, CI + 0.33

m = 1.31, CI + 0.55

m = 2.29, CI + 1.35

UF (N=65)

Bolus Diuretic (N=45)

Cont. Diuretic (N=21)
109

Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

Relationship Between Fluid Loss and Rehospitalization
Ultrafiltration (N=89) Bolus Diuretics (N=59)
Continuous Diuretics (N=28)

Characteristic Correlation of net fluid loss during hosp. and number of times rehosp. for HF

-0.082

0.005

0.100

P values

.442

.972

.612

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Freedom from Rehospitalization UF vs IV Bolus Diuretic vs IV Continuous Diuretic
1.00 Freedom From Rehospitalization (%) .80 .60

.40 .20

UF vs Bolus Diuretic: P=.138 UF vs Continuous Diuretic: P=.022 Bolus vs Continuous Diuretic: P=.344

UF Arm
.00

IV Bolus 50 60

IV Continuous 70 80 90 100
111

0

10

20

30

40

Days
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Limitations
• Neither patients nor investigators were blinded to the therapy • Rate and duration of volume removal not specified in the study protocol • Total sodium removed not documented
• Lack of measurements of blood volume and plasma refill rate, cardiac performance, hemodynamics, or interstitial water

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Conclusions
• Early ultrafiltration produces greater weight loss than IV diuretics, without changes in renal function
• An early ultrafiltration strategy reduces 90-day
– Percentage of patients requiring rehospitalization for HF – Number of HF rehospitalizations – Days of rehospitalization for HF
– Emergency department and unscheduled office visits
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Conclusions
• Symptoms and biomarkers of congestion may not be sufficiently sensitive to detect differences in volume loss produced by the two therapies
• Future studies should be focused on unraveling the mechanisms linking specific methods and rates of fluid removal to subsequent clinical benefit

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Therapeutic Goals for ADHF
Goals
• • Relieve symptoms Reverse acute hemodynamic abnormalities Initiate treatments that will slow disease progression and improve long-term survival Apply treatment cost-effectively Prevent end-organ dysfunction

End Points
• • • Dyspnea and other signs and symptoms of HF1 Lower PCWP with adequate systemic perfusion1 Use of ACE inhibitors, aldosterone antagonists, and β-blockers before hospital discharge1 Shorten length of stay, minimize use of intensive care unit, reduce readmissions 1 Inhibit RAAS system, monitor inflammation caused by infection following a major surgery or trauma2,3

•
• •

• •

• Achieve Euvolemia

1. Fonarow GC. Rev Cardiovasc Med. 2002;3(suppl 4):S18-S27. 2. Stier et al. Cardiol Rev. 2002;10:97-107. 3. Masai et al. Ann Thorac Surg. 2002;73:549-555.

115

Conventional Treatments for ADHF*
Diuretics1 Vasodilators1 Inotropes1

Reduce fluid volume

Decrease preload and/or afterload– Do not reduce volume

Augment contractility. Do not reduce volume

Use in ADHERE®1–3

88%*3

21%*3

15%*3

* Data for IV preparations used in all enrolled discharges (n = 105,388) for period October 1, 2001 to December 31, 2003.
1. Fonarow GC. Rev Cardiovasc Med. 2001;2(suppl 2):S7. 2. Fonarow GC, for the ADHERE Scientific Advisory Committee. Rev Cardiovasc Med. 2003;4(suppl 7):S21. 3. Fonarow GC. Slide presentation. http://dme.cybersessions.com/conference/23feb04.

116

Persistent Symptoms at Discharge in Large Fraction of Patients Admitted for Acute CHF
ADHERE®1,2: Patients Discharged From September 1, 2002, to October 30, 20031 N=46,218
Asymptomatic 51%

Improved (but still symptomatic) 39%

No change Not applicable Worse

<1% <1% <1%

No mention 10%
117

1. ADHERE Registry. 3 rd Quarter. 2003 National Benchmark Report. http://www.adhereregistry.com/national_BMR/index.html. 2. Fonarow GC, for ADHERE Scientific Advisory Committee. Rev Cardiovasc Med. 2003;4(suppl 7):S21.

Improvement of Congestion Predicts Survival in Patients With Class IV Symptoms of ADHF
• 146 Patients hospitalized with class IV HF • Assessed 4 to 6 weeks after hospitalization for congestion • Patients with persistent orthopnea (n=33)
– 2-year survival: 38%

• Patients with resolution of orthopnea (n=113)
– 2-year survival: 77% (P=.0001)

Lucas C et al. Am Heart J. 2000;140:840-847.

118

Diuretics and ADHF
• Although diuretics can be effective in relieving symptoms and improving cardiovascular hemodynamics, there are no consensus dosing guidelines on their use in ADHF, and there is no common definition of what deems a patient diuretic resistant1-3

There have been no long-term studies of diuretic therapy for the treatment of HF and, thus, its effects on morbidity and mortality are not known4

1. Kramer et al. Nephrol Dial Transplantation. 1999;14(suppl 4):39-42. 2. Silke. Cardiology. 1994;84(suppl 2):115-123. 3. Hanesful et al. Clin Cardiol. 1987;10:83-89. 4. Ravnan et al. Congest Heart Fail. 2002;8:80-85.

119

Consequences of Therapeutic Limitations in CHF
• In spite of current treatment strategies, a significant percentage of patients admitted for acute decompensated CHF are discharged with little or no weight loss and persistent symptomatology1

ADHERE® Registry. 3rd Quarter. 2003 National Benchmark Report. http://www.adhereregistry.com/national_BMR/index.html .

120

ACC/AHA Guidelines
4.4.1. Management of Fluid Status
• In general, patients should not be discharged from the hospital until a stable and effective diuretic regimen is established, and ideally, not until euvolemia is achieved

• Patients who are sent home before these goals are reached are at high risk of recurrence of fluid retention and early readmission because unresolved edema may itself attenuate the response to diuretics

Hunt et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. American College of Cardiology and the American Heart Association, Inc. 2001. http://www.acc.org/clinical/guidelines/failure/hf_index.htm.

121

Current Options Are Not Achieving the Standard of Care
• ―… ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention. The use of such mechanical methods of fluid removal can produce meaningful clinical benefits in patients with diureticresistant HF and may restore responsiveness to conventional doses of loop diuretics.‖

Hunt et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. American College of Cardiology and the American Heart Association, Inc. 2001. http://www.acc.org/clinical/guidelines/failure/hf_index.htm.

122

HFSA 2006 Guidelines
12.11

• When congestion fails to improve in response to diuretic therapy, the following options should be considered:
– Sodium fluid restriction – Increasing doses of loop diuretic – Continuous infusion of loop diuretic – Addition of a second type of diuretic orally (metolazone or spironolactone) or intravenously (chlorothiazide)

• A fifth option, ultrafiltration, may be considered (strength of evidence:c)
123

What Is the AquadexTM FlexFlow TM?
• Advanced form of ultrafiltration
• Inpatient or outpatient settings – ICU, CCU, MICU, telemetry, step-down, observation, ED, outpatient clinics

• Peripheral or central venous access – Flexible access sites and catheters • Diverse physician prescription • Highly automated operation • No clinically significant impact on electrolyte balance, blood pressure, or heart rate*

*If an appropriate rate of ultrafiltration is selected and where vascular refill rate is not exceeded. The specific clinical circumstances at the time of device use may also have an impact on patient hemodynamics..

124

Indication for Use
• The AquadexTM System received 510 k market clearance from the FDA in June 2002 and is indicated for:
– Temporary (up to 8 h) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy (outpatient) and – Extended (longer than 8 h) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy and require hospitalization

• All treatments must be administered by a healthcare provider, under physician prescription, both of whom having received training in extracorporeal therapies
125

What is the AquadexTM FlexFlow TM?
Low blood flow Low blood volume 10–40 mL/min 33 mL

Precise fluid removal 10–500 mL/h rates Quick and easy Less than 10 min setup Highly automated 1 required setting operation

126

What’s Needed?
1.

Transportable console with simple operator interface Disposable single-use extracorporeal blood circuit Venous access that can provide 10–40 mL/min of blood

2.

3.

127

The Process of Ultrafiltration

128

How Much? How Fast?
• Setting the appropriate fluid removal rate to not exceed this intravascular refilling is crucial to minimizing risk of – Hypovolemia – Hypotension – Transient renal hypoperfusion (reduction of renal blood flow) – Decrease in glomerular filtration rate (GFR) – Increase in serum creatinine level – Arrhythmias • This can be easily achieved with a periodic monitoring of the systolic blood pressure and setting specific limits that would warrant a reduction in the fluid removal rate • For details, refer to your hospital’s AquapheresisTM Standing Orders
129

How Much? How Fast?
• The rate of fluid removed per hour from the intravascular space (IVS) must not exceed the rate of fluid entering the intravascular space from extravascular spaces (interstitial, intracellular) • The rate of fluid removed from the intravascular space = UF rate (UFR)

Extravascular fluid

PRR

Intravascular fluid

• The rate of fluid entering the intravascular space = Plasma Refill Rate (PRR)
Therefore, UFR ≤ PRR

IVS

UFR

130

Advantages Over Loop Diuretics
• Complete control over rate and total volume of fluid removed
• Ultrafiltration, differently from diuretics, removes isotonic fluid and therefore
– Removes the greatest possible amount of sodium per unit of fluid withdrawn1 – Not associated with electrolyte depletion (Na, K, Mg, Ca) 1,2,3

• May decrease or eliminate neurohormonal activation4,5 • Reduce length of stay and rehospitalizations3,5,6,7

131

Responsibilities
Physician
• Identifies appropriate patient(s) according to accepted criteria. • Completes Standing Orders for Ultrafiltration/Aquapheresis TM
– Establishes/coordinates venous access site, catheter, and insertion

– Defines quantity of total fluid to be removed (in liters) and/or total duration of treatment (in hours)
– Defines initial fluid removal rate (UF Rate) – Defines/details/clarifies criteria for adjusting fluid removal rate and/or blood flow

– Prescribes and communicates anticoagulation plan – Establishes fluid restriction

132

Responsibilities
Nurse
• Treatment set up • Begin per physician’s orders • Basic Monitoring
– Enforce and record intake and output (I & Os) – Monitor patient as appropriate

– If necessary, adjust the fluid removal rate as prescribed – Listen for possible alarms and respond as necessary – Perform basic troubleshooting to assure proper functioning
– Assess venous access sites periodically – If required, titrate anticoagulation as ordered
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Responsibilities (continued)
Nurse
• Confirm patient at physician-prescribed amount of fluid removed or duration of therapy

• Treatment completion
– Stop treatment and discontinue patient access from device – Care or dispose of blood set and catheters according to institutional policy
– Routine console cleaning

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Setting the Fluid Removal Rate
• Using the UF Rate key, , users can set the fluid removal rate from 10 to 500 mL/h in increments of 10 mL/h. Default is 0 mL/min • With this feature, users can set the fluid removal rate that is best for each, individual patient

F

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Anticoagulation
• For optimal treatment, a therapeutic range of anticoagulation, that is, twice normal (eg, an ACT of 180 - 220 s) • Refer to the appropriate institutional policy (ie, weight-based protocol) for recommended bolus and drip requirements and make sure that all parties involved understand what is expected and required

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Choosing Venous Access
• 2 catheters or lumens are needed
• Required blood flow range is 10 to 40 mL/min

• Many venous access sites and types of catheters can be used • The exact choice is determined by the prescribing physician

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Possible Venous Access Catheters
• A sample of possible venous access choices follow:
– The Extended Length Catheter (ELC) placed in the antecubital by a PICC team preferably into the basilic vein (withdrawal only)

– Common 16-18 gauge PIVs placed antecubitally or higher
– 16 gauge/distal port on Arrow Triple Lumen CVC – Dual lumen/Quad Lumen Arrow CVC, 20 cm in length

– Standard dialysis catheters
– No PICCs, no SWANs, or anything smaller than 18 gauge or longer than 20 cm
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AquapheresisTM/AquadexTM FlexFlow TM Observations
Treatment Detail
Patient selection

Average or Typical Value*
• ≥5 lb over dry weight, diuretic resistant within 12 h of hospitalization • Before any significant administration of IV diuretics and/or vasoactive drugs 250 mL/h (= 6 L in 24 h)

Fluid removal rate (UF rate)

Blood flow rate (blood flow) Treatment time Anticoagulation
Venous access

30-40 mL/min 20 h 2 times normal
Peripheral or central

Salt removal

Approximately 3200 mg/L

*Monitor patient for clinical signs of hypovolemia and hypotension.
Jaski. J Card Fail. 2003;9(3):227-231; Bart. J Am Coll Cardiol. 2005;46:2043-2046; Costanzo. J Am Coll Cardiol. 2005;46:2047-2051; Costanzo et al. Am Coll Cardiol. Smaller Trial Late-Breaking Clinical Trials II, American College of Cardiology 2006 Scientific Sessions; 2006 (publication in JACC expected Feb 13, 2007); Ali et al. Heart Failure Society of America 2006 Scientific Meeting; 2006; Abstract 374.

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