ultrafilteration in heart failure

2. 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

4. Hospitalizations for HF Are Increasing CDC/NCHS. AHA Heart Stroke and Statistical Update, 2001.

5. Mortality Rates After First Hospitalization for HF Jong et al. Arch Intern Med. 2002;162:1689-1694. Age- and Sex-Stratified Case-Fatality Rates 30 Days and 1 Year After First Hospitalization for HF Men Women Mortality, % Mortality, % Age Group, y No. of Patients 30-Day 1-Year No. of Patients 30-Day 1-Year 20-49 50-64 65-74 ≥ 75 All Ages 655 3048 5923 9310 18,936 4.6 5.5 8.6 15.6 11.4 15.0 20.5 28.8 43.1 34.0 375 1892 4412 13,087 19,766 4.3 5.4 6.8 14.7 11.8 10.9 19.5 23.0 37.9 32.3

7. Over 90% of All Hospitalizations for Acutely Decompensated Heart Failure (ADHF) Are Due to Fluid Overload 1 The Majority of These Patients Have Failed Treatment With Oral Diuretics 2 1. Aronson. ACC . 2000. 2. Adams et al. Am Heart J. 2005;149:209-216.

8. Decompensated ADHF 1 Colucci WS, Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. 1997:394 . Insult Cardiac Dysfunction LV Remodeling Hemodynamic Decompensation Preload Afterload Cardiac Output Renal Vasoconstriction/Fluid Retention Neurohormonal Activation RAAS Catecholamine Endothelin Fluid Overload Symptoms Morbidity Death

13. The Cardiorenal Syndrome of HF Increased Morbidity and Mortality Diuretic Therapy Impaired Renal Function Decreased Renal Perfusion Development of Diuretic and Natriuretic Resistance Diminished Blood Flow Neurohormonal Activation

14. Mild or Moderate Decreases in Renal Function Have Been Shown to Correlate With Significant Morbidity and Mortality in Patients With Asymptomatic and Symptomatic Congestive HF 1-4 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.

16. Most Common Intravenous Medications 0 10 20 30 40 50 60 70 80 90 100 Patients (%) IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside IV Vasoactive Meds 88% 6% 6% 10% 3% 1% 10% ADHERE ® Registry. Benchmark Report. 2004. All Enrolled Discharges (n=105,388) October 2001 – January 2004

22. Diuretics Activate Neurohormonal Systems in HF Bayliss et al. Br Heart J. 1987;57:17 Before (n=12) Plasma Renin Activity (ng/mL/h) 50 10 2.5 0.5 Plasma Aldosterone (pmol/L) Mean, 95% Confidence Interval 1000 600 200 100 P =.0007 P =.0002 After Diuretic (n=11) Before (n=12) After Diuretic (n=11)

23. Effect of Loop Diuretics on Renin-Angiotensin-Aldosterone System in Cardiac Failure Schrier. J Am Coll Cardiol . 2006;47:1-8. Loop Diuretic Inhibition of Macula Densa Increased Renin-Angiotensin Increased Aldosterone Cardiac Remodeling and Fibrosis Left Ventricular Dysfunction CARDIAC FAILURE

24. Elevated Neurohormones Cause Diuretic Resistance Kr ä mer et al. Am J Med . 1999;106:90. Proximal Tubule Ang II increases sodium reabsorption Glomerulus Norepinephrine (and endothelin) decreases renal blood flow and GFR Collecting Duct Aldosterone increases sodium reabsorption

26. Furosemide Monotherapy Causes Significant Decline in Renal Function (GFR) -25 -20 -15 -10 -5 0 5 10 15 0 500 1000 1500 2000 2500 Urine Output (mL) 0 – 8 h GFR (% Change) Placebo IV furosemide Gottlieb et al. Circulation . 2002;105:1348. Change in GFR after IV furosemide 80 mg in CHF

28. Reaccumulation of Na + Despite Ongoing Furosemide Treatment 1 1. Wilcox et al. Kidney Int. 1987;31:135 . F = Furosemide Na + Reaccumulation Between Furosemide Doses Na + Intake Na + Excretion Net Diuresis After 4 Days of Rx = 0 mL 300 250 200 150 100 50 0 Before F F 1 F 2 F 3 F 4 Time, Days U Na V, mEq/6 h

29. Dose Response Curves for Loop Diuretics in ADHF Are Altered Ellison. Cardiology . 2001;96:132-143. 20 18 16 14 12 10 8 6 4 2 0 [Furosemide], µg/mL 0.01 0.1 1 10 100 Normal CRF CHF Secretory Defect Decreased Maximal Response FE Na ,% Fractional Na Excretion

31. Congestive Heart Failure Negative Sodium and Water Balance Improved Pulmonary Congestion Decreased Cardiac Filling Pressure Decreased Ventricular Dilatation Decreased Ventricular Wall Stress and Endomyocardial Ischemia Decreased Functional Mitral Insufficiency Improved Myocardial Function Improved Renal Function Potential Benefits of Diuretics or UF in HF Schrier. J Am Coll Cardiol . 2006;47:1-8. Loop Diuretic or Ultrafiltration Treatment

32. Inadequate Diuresis During ADHF Treatment 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 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) The Nation n=26,757, 68% Change in Weight From Admission to Discharge 7% 6% 13% 24% 30% 15% 3% 2% 0 10 20 30 40 50 Enrolled Discharges (%) (<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lb)

33. Despite the Use of Diuretics in 90% of Patients, 20% Gain Weight on Discharge 1 Adams et al. Am Heart J . 2005;149:209-216.

42. Hemodynamic Effects of UF in CHF Marenzi et al. J Am Coll Cardiol . 2001;38:963-968. 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) 70 – 60 – 50 – 40 – 30 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF SV (mL) 25 – 20 – 15 – 10 – 5 – 0 - Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF RAP (mmHg) 30 – 25 – 20 – 15 – 10 - Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF PWP (mmHg)

46. Effects of Ultrafiltration vs IV Furosemide Lung Water Content Triangles: Ultrafiltration Squares: IV Furosemide Agostoni et al. Am J Med. 1994;96:191-199. - - 3500 - - 2500 - - 1500 ml Fluid input diuresis plus ultrafiltrate - 3000 - - 2000 - - 1000 – - mL Fluid output b 1d 2d 3d 4d 3m 21 - 17 - 13 - 9 - Chest x-ray score Δ Body Weight kg +2 - +1 - 0 - -1 - -2 - b 1d 2d 3d 4d 1m 3m

48. Urine vs UF Electrolytes After Intravenous Diuretics or Ultrafiltration Sodium Potassium Magnesium 0 20 40 60 80 100 120 140 IVD UF P =.000025 P =.000017 P =.017 mg/dL Ali et al. J Card Fail . 2006;12(6 suppl):114.

52. Comparison to Continuous Venovenous Hemofiltration Prisma 812 (patient numbers not available) NxStage 230 (23% MDR event per patient, 1000 patients) Aquadex™ 6 (0.12% MDR event per patient, 5000 patients) 0 device malfunctions Reported adverse events since June 2002 Central Peripheral or central Venous access 100–300 mL 33 mL Extracorporeal volumes 100–300 mL/min 10–40 mL/min Blood withdrawal rates ICU Inpatient/Outpatient Treatment venue Nephrologist Any who have received training (cardiologist, hospitalist, nephrologist, surgeon, etc) Prescriber Renal Fluid overload Patient CVVH Aquapheresis™

54. R elief for A cutely Fluid Overloaded P at i ents With D ecompensated C ongestive H eart F ailure The RAPID-CHF Trial Bart et al. J Am Coll Cardiol . 2005;46:2043-2046.

56. RAPID Trial: Total Fluid Removal 48 h P =.028 mL -11000 -9000 -7000 -5000 -3000 -1000 1000 UF Usual Care Bart et al. J Am Coll Cardiol . 2005;46:2043-2046.

58. E arly U ltrafiltration in P atients With Decompensated H F and O bserved R esistance to I ntervention With Diuretic A gents The EUPHORIA Trial Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051.

62. EUPHORIA Trial: Length of Stay 5 7 4 3 1 0 1 2 3 4 5 6 7 Patients 2 Days 3 Days 4 Days 5 Days 10 Days Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051.

63. EUPHORIA Trial: Clinical and Laboratory Outcomes Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051. .063 11% 5 % 37 % 39 % NYHA FC IV .03 NA 816 ± 494 988 ± 847 1236 ± 747 BNP (pg/mL) .532 2.18 ± 0.7 2.38 ± 1.1 2.20 ± 0.8 2.12 ± 0.6 Cr (mg/dL) .306 116 ± 24 120 ± 26 114 ± 22 120 ± 17 SBP (mmHg) .006 80 ± 18 84 ± 21 81 ± 22 87 ± 23 Weight (kg) P Value 90 Days 30 Days Disch. Pre-UF Variable

64. Serum Sodium 140 139 138 137 136 135 134 133 132 131 130 129 Pre-UF Discharge 30 Day 90 Day *Pre-UF to discharge † Pre-UF to 90 days Na (mg/dL) n=13 ns* ns † n=7 * P =.042 † P =.017

66. U ltrafiltratio n versus IV Diuretics for Patients Hospita l ized f o r A cute D ecompensated Congestive HF: A Prospective Randomized Clinical Trial UNLOAD Trial Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

72. METHODS

79. Baseline Demographics and Comorbidities Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .755 30 27 COPD (%) .890 49 50 Diabetes (%) 1.000 74 74 History of hypertension (%) .474 48 56 Coronary heart disease (%) .489 52 40 8 55 41 4 Race (%) Caucasian African American Other .879 68 70 Male Sex % .823 63 ± 14 62 ± 15 Age – Years (M±SD) P Value Standard Care (N=100) Ultrafiltration (N=100) Characteristic

80. Baseline HF Characteristics Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. P Value Standard Care (N=100) Ultrafiltration (N=100) Characteristic .343 51 60 Pulmonary rales (%) .860 79 81 Peripheral edema (%) .363 62 68 JVD >10 cm (%) .109 32 44 S 3 (%) .736 70 71 % of patients LVEF ≤40% .981 1.5 ± 1.7 1.6 ± 1.9 Hospitalizations for HF in ≤ 12 months (M ± SD) 1.000 95 95 Prior HF (%)

81. Baseline Functional Capacity and Vital Signs Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .861 3.4 ± 0.6 48 45 3.4 ± 0.6 52 45 NYHA Class M ± SD III (%) IV (%) .707 74 ±18 70 ± 23 MLWHF Score M ± SD .233 129 ± 24 126 ± 26 Systolic BP (mmHg) M ± SD P Value Standard Care (N=100) Ultrafiltration (N=100) Characteristic .381 83 ± 16 81 ± 17 Heart rate (bpm) M ± SD .194 96 ± 29 101 ± 27 Weight (kg) M ± SD

82. Baseline Laboratory Values Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .840 1309 ± 1494 1256 ± 1203 Serum BNP (pg/mL) M ± SD P Value Standard Care (N=100) Ultrafiltration (N=100) Characteristic .643 36 ± 6 36 ± 5 Hematocrit (%) M ± SD .028 4.2 ± 0.6 4.0 ± 0.6 Serum potassium (mg/dL) M ± SD .751 139 ± 5.0 139 ± 4.9 Serum sodium (mg/dL) M ± SD .834 1.5 ±0.5 1.5 ± 0.5 Serum creatinine (mg/dL) M ± SD .920 33 ± 20 32 ± 16 BUN (mg/dL) M ± SD

83. Baseline Medications Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. 1.000 8 8 Calcium channel blockers (%) .517 77 72 Loop (%) 1.000 15 14 Thiazide (%) .860 80 78 Diuretics (%) .864 22 21 Aldosterone antagonists (%) 1.000 11 10 Both (%) P Value Standard Care (N=100) Ultrafiltration (N=100) Characteristic .559 119 ± 116 129 ± 122 Furosemide equivalent mg M ± SD 1.000 66 65 Beta-blockers (%) .446 19 14 ARBs (%) 1.000 49 49 ACE Inhibitors (%)

84. RESULTS

85. I I I Primary End Point Weight Loss at 48 H Weight Loss (kg) Ultrafiltration Arm Standard Care Arm P =.001 M = 5.0, CI + 0.68 kg (N=83) M = 3.1, CI + 0.75 kg (N=84) 6 - 5 - 4 - 3 - 2 - 1 - 0 - Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

86. Primary End Point Dyspnea Score at 48 H P =.35 M = 6.4, CI + 0.11 (N=80) M = 6.1, CI + 0.15 (N=83) Dyspnea Score Ultrafiltration Arm Standard Care Arm 7 6 5 4 3 2 1 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

87. Secondary End Point Net Fluid Loss at 48 H P =.001 M = 3.3, CI + 0.29 L (N=82) M = 4.6, CI + 0.29 L (N=81) Net Fluid Loss (liters) Ultrafiltration Arm Standard Care Arm 5.5 5 4.5 4 3.5 3 2.5 2 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

89. Standard Care Arm Ultrafiltration Arm Safety End Points: Change in Serum Creatinine Serum Creatinine Change (mg/dL) UF: N=72 N=90 N=69 N=47 N=86 N=71 N=75 N=66 SC: N=84 N=91 N=75 N=52 N=90 N=75 N=67 N=62 P >.05 at all time points Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. 8 h 24 h 48 h 72 h Discharge 10 Days 30 Days 90 Days 0 0.5 1 1.5

91. Adverse Events Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .154 NA 5 Filter .156 0 3 Catheter/Needle .202 9 4 Other .315 0 1 Catheter related Infection .070 15 5 Neurological .987 6 4 Cardiac arrest .968 7 10 Arrhythmias .988 2 3 Myocardial infarction .094 63 39 Worsening HF .315 0 1 Dialysis .080 0 3 Anemia .113 10 22 Hypotension .032 7 1 Bleeding P Value Standard Care Ultrafiltration

93. Effect of Ultrafiltration on Weight Loss: Subgroup Analysis Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

94. Lack of Correlation Between Change in Dyspnea Score and Weight Loss at 48 H R 2 = .0241 R 2 = .017 -20 -15 -10 -5 0 5 10 -3 -2 -1 0 1 2 3 4 Dypsnea Score Weight Loss (kg) UF Arm SC Arm Linear (UF Arm) Linear (SC Arm) Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

95. Vasoactive Drugs Requirement P =.015 Ultrafiltration Arm Standard Care Arm Patients Requiring Vasoactive Drugs (%) 20 18 16 14 12 10 8 6 4 2 0 UF: N=98 SC: N=99 P =.086 UF: N=100 SC: N=100 48 h Entire Hospitalization 3 12 8 17 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

96. Change in BNP Levels Ultrafiltration Arm Standard Care Arm BNP (pg/mL) 0 -100 -200 -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 P =.463 P =.684 48 hours 30 days 90 days Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

97. Resources Utilization for HF in 90 Days Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .022 330 123 Days rehospitalized P Value SC UF Resource .009 44 21 Unscheduled office + ED visits (%) .022 3.8 1.4 Number of rehospitalization days per patient .037 0.46 0.22 Rehospitalizations/Patient .022 32 18 Patients rehospitalized (%)

98. Freedom From Rehospitalization for HF 100 - 80 - 60 - 40 - 20 - - 10 20 30 40 50 60 70 80 90 Days Percentage of Patients Free From Rehospitalization No. Patients at Risk Ultrafiltration Arm 88 85 80 77 75 72 70 66 64 45 Standard Care Arm 86 83 77 74 66 63 59 58 52 41 P =.037 Ultrafiltration Arm (16 Events) Standard Care Arm (28 Events) 0 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

99. UNLOAD Trial Diuretic Arm Undertreated? Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. 51 (68) 28 (52) >4.5 kg loss 17 24 >2.3 kg to 4.5 kg loss 19 (32) 32 (48) >0 to 2.3 kg loss 13 16 No wt loss or gain UNLOAD Diuretic Patients (%) ADHERE Registry Patients (%) Change in Weight Admission

100. Diuretic Requirements at Discharge 12 ± 53-mg increase P =.058 P =.049 11 ± 79-mg decrease 10 days 11 ± 61-mg increase 14 ± 68-mg decrease Discharge Usual Care (Diuretic) Arm Ultrafiltration Arm Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

102. UF vs Bolus/Continuous Diuretics Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .232 3.9 <.001 3.0 4.6 Fluid (liters) .145 3.6 .001 2.9 5.0 Wt (kg) P value Cont. P value Bolus UF At 48 H

103. UNLOAD: Effects of Ultrafiltration vs Bolus and Continuous-Infusion Diuretic Therapy at 48 H * P =.003 vs continuous. † P =.001 vs bolus. Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. Continuous Diuretics (N=32) Bolus Diuretics (N=68) Ultrafiltration (N=100) Parameter 3.6 2.5 5.0 † Weight loss (kg) 22 8* 1 Change in serum K <3.5 mEq/L (%) 3 3 4 Hypotension (%)

105. 90-Day HF-Related Outcomes *Number of HF-related rehospitalizations plus unscheduled office and emergency department visits. † P =.050 vs bolus. Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .016 2.29 1.31 0.65 † Rehospitalization equivalents, mean* 19.4 4.9 39 Continuous Diuretics (N=32) P , Ultrafiltration vs Continuous Diuretics Bolus Diuretics (N=68) Ultrafiltration (N=100) Parameter NS 7.8 9.6 Mortality (%) .016 3.3 1.4 Rehospitalization days per patient (d) .037 29 18 Rehospitalization (%)

106. 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

107. Worsening Heart Failure in 90 Days Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. .338 .037 .158 39 (11/28) 29 (17/59) 18 (16/89) Patients rehospitalized, % .405 .018 .091 0.54 ± 0.79 n=28 0.43 ± 0.75 n=59 0.23 ± 0.54 n=89 Rehospitalizations per patient (m ± sd) .387 .016 .095 4.9 ± 10.5 n=28 3.3 ± 7.4 n=59 1.4 ± 4.1 n=89 Rehospitalization days per patient (m ± sd) 137 193 123 Days rehospitalized .428 .012 .054 52 (11/21) 40 (18/45) 22 (14/65) Unscheduled office + ED visits, % IV Continuous Diuretic UF vs IV Bolus Diuretic P value UF vs IV Continuous Diuretic P value IV Bolus vs IV Continuous Diuretic P value IV Bolus Diuretic UF Characteristic

108. Rehospitalization Equivalents at 90 Days UF vs Bolus Diuretic: P =.050 UF vs Continuous Diuretic: P =.016 Bolus vs Continuous Diuretics: P =.362 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. 2.29 (3.23) 1.31 (1.87) 0.65 (1.36) Rehospitalization equivalents per patient (mean ± sd) Continuous Diuretics (N=21) Bolus Diuretics (N=45) Ultrafiltration (N=65) Characteristic

109. Rehospitalization Equivalents at 90 Days 0 2 4 UF (N=65) Bolus Diuretic (N=45) Cont. Diuretic (N=21) Rehosp. Equivalents/Pt UF vs Bolus Diuretic: P =.050 UF vs Continuous Diuretic: P =.016 Bolus vs Continuous Diuretic: P =.362 m = 0.31, CI + 0.33 m = 2.29, CI + 1.35 m = 1.31, CI + 0.55 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

110. Relationship Between Fluid Loss and Rehospitalization Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683. 0.100 0.005 -0.082 Correlation of net fluid loss during hosp. and number of times rehosp. for HF .612 .972 .442 P values Continuous Diuretics (N=28) Bolus Diuretics (N=59) Ultrafiltration (N=89) Characteristic

111. Freedom from Rehospitalization UF vs IV Bolus Diuretic vs IV Continuous Diuretic .00 .20 .40 .60 .80 1.00 0 10 20 30 40 50 60 70 80 90 100 Days Freedom From Rehospitalization (%) UF Arm IV Bolus IV Continuous UF vs Bolus Diuretic: P =.138 UF vs Continuous Diuretic: P =.022 Bolus vs Continuous Diuretic: P =.344 Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.

116. Conventional Treatments for ADHF* 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. * Data for IV preparations used in all enrolled discharges (n = 105,388) for period October 1, 2001 to December 31, 2003. Diuretics 1 Reduce fluid volume Vasodilators 1 Decrease preload and/or afterload– Do not reduce volume Inotropes 1 Augment contrac- tility. Do not reduce volume 88%* 3 21%* 3 15%* 3 Use in ADHERE ®1 – 3

117. N=46,218 No mention 10% Asymptomatic 51% Improved (but still symptomatic) 39% 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. ADHERE ®1,2 : Patients Discharged From September 1, 2002, to October 30, 2003 1 No change <1% Not applicable <1% Worse <1% Persistent Symptoms at Discharge in Large Fraction of Patients Admitted for Acute CHF

126. What is the Aquadex TM FlexFlow TM ? 1 required setting Highly automated operation Less than 10 min Quick and easy setup 10–500 mL/h Precise fluid removal rates 33 mL Low blood volume 10–40 mL/min Low blood flow

128. The Process of Ultrafiltration