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  • In presenting the slide deck titled “Ultrafiltration in the Treatment of Acute Decompensated Heart Failure,” the presenter agrees to uphold the following: a)  The Company and Speaker recognize their duty to ensure that whatever is stated about the Company’s product is truthful, not misleading and fairly balanced. Thus, when choosing slides from the full complement of available slides, please ensure that as Presenter you are not only discussing the benefits of the Company’s product, but the risks as well. Please avoid making comparisons to other therapies, whether pharmacologic or otherwise, that are unsubstantiated.   b) The Presenter will only discuss the on-label uses of the Company’s product, and not potential off-label uses. In the event a question is asked from the audience about an off-label use, the Presenter will inform the audience that the question is about a use not approved by the FDA and only then may proceed to answer the question as a medical professional. Please ensure that the audience knows the opinion rendered is the Presenter’s own as a medical professional and not that of the Company’s. c) The Presenter will avoid reimbursement questions entirely, and if asked, forward any such inquiry to the appropriate Company representative.  
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    1. 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
    2. 3. Epidemiology of Heart Failure (HF) <ul><li>HF is a major public health problem resulting in substantial morbidity and mortality </li></ul><ul><li>Major cost-driver of HF is high incidence of hospitalizations 1,2 </li></ul><ul><li>JCAHO has initiated HF quality care indicators for hospitalized patients with HF </li></ul>1. Thom et al. Circulation . 2006;113:85-151. 2. Topol et al. Textbook of Cardiovascular Medicine . 3 rd ed. 2006 . 1 $29.6 billion 1,093,000 57,218 550,000 5,000,000 Total population Cost Hospital Discharges Mortality Incidence Prevalence Population Group
    3. 4. Hospitalizations for HF Are Increasing CDC/NCHS. AHA Heart Stroke and Statistical Update, 2001.
    4. 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
    5. 6. Most Admitted Patients Are Volume Overloaded <ul><li>Any dyspnea – 89% </li></ul><ul><li>Pulmonary congestion (CXR) – 74% </li></ul><ul><li>Rales – 67% </li></ul><ul><li>Dyspnea at rest – 34% </li></ul><ul><li>Peripheral edema – 65% </li></ul>ADHERE Registry. 3 rd Qtr 2003 National Benchmark Report. At Hospitalization—ADHERE ®1
    6. 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.
    7. 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
    8. 9. Common Compensatory Responses to Low- and High-Output Cardiac Failure Schrier. Ann Intern Med . 1990;113:155-59. Systemic Arterial Vasodilation High-Output Cardiac Failure Low-Output Cardiac Failure  Sympathetic Nervous System Arterial Underfilling Diminished Renal Hemodynamics and Renal Sodium and Water Excretion  Renin-Angiotensin-Aldosterone System  Nonosmotic AVP Release <ul><li>Cardiac Output </li></ul>
    9. 10. Cardiorenal Syndrome <ul><li>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 exacerbated 1 </li></ul><ul><li>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 function 1 </li></ul>NHLBI Working Group. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm. April 30, 2005.
    10. 11. Cardiorenal Syndrome <ul><li>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 exacerbated 1 </li></ul><ul><li>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 function 1 </li></ul>NHLBI Working Group. http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm. April 30, 2005.
    11. 12. <ul><li>In the context of CHF, the interaction of the heart and kidney contributes to worsening volume overload </li></ul>Cardiorenal Syndrome <ul><li>Renal elements include </li></ul><ul><li>Excessive neurohormonal, cytokine activation </li></ul><ul><li>Decreased effective renal perfusion, GFR, and acute renal failure </li></ul><ul><li>Diuretic resistance </li></ul><ul><li>Fibrosis (RAAS mediated) </li></ul>
    12. 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
    13. 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.
    14. 15. Renal Function Is Associated With Increased Morbidity and Mortality in HF <ul><ul><li>0.7 – </li></ul></ul><ul><ul><li>0.6 – </li></ul></ul><ul><ul><li>0.5 – </li></ul></ul><ul><ul><li>0.4 – </li></ul></ul><ul><ul><li>0.3 – </li></ul></ul><ul><ul><li>0.2 – </li></ul></ul><ul><ul><li>0.1 – </li></ul></ul><ul><ul><li>0.0 - </li></ul></ul><ul><li>Total of 1906 patients </li></ul><ul><li>NYHA class </li></ul><ul><ul><li>III (n=1138) </li></ul></ul><ul><ul><li>III/IV (n=607) </li></ul></ul><ul><ul><li>IV (n=161) </li></ul></ul><ul><li>Impaired renal function is a strong predictor of mortality </li></ul>Relationship of GFRc With Mortality in 1906 Patients With CHF Hillege et al. Circulation . 2000;102:203-210. <ul><ul><li>0 200 400 600 800 1000 1200 </li></ul></ul><ul><ul><li>Days </li></ul></ul><ul><ul><li>Proportion mortality </li></ul></ul><ul><ul><li><44 mL/min </li></ul></ul><ul><ul><li>44–58 mL/min </li></ul></ul><ul><ul><li>59–76 mL/min </li></ul></ul><ul><ul><li>>76 mL/min </li></ul></ul>
    15. 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
    16. 17. Diuretics and ADHF <ul><ul><li>No long-term studies of diuretics for the treatment of ADHF 1 </li></ul></ul><ul><ul><li>Despite widespread use in ADHF, their effect on morbidity and mortality is not known 2 </li></ul></ul>1. Ravnan et al. Congest Heart Fail . 2002;8:80. 2. Kramer et al. Nephrol Dial Transplant . 1999:14(suppl 4):39-42.
    17. 18. Diuretics <ul><li>The use of loop diuretics in ADHF patients with dyspnea and shortness of breath is standard therapy </li></ul><ul><li>In patients with ADHF, diuretics </li></ul><ul><ul><li>May induce a natriuresis </li></ul></ul><ul><ul><li>Decrease extracellular fluid (ECF) volume </li></ul></ul><ul><ul><li>Provide symptomatic relief </li></ul></ul>Schrier. J Am Coll Cardiol . 2006;47:1-8.
    18. 19. <ul><li>Favorable aspects of diuretic therapy </li></ul><ul><ul><li>Increases urine output; reduces total body volume in majority of patients 4 </li></ul></ul><ul><li>Adverse aspects of diuretic therapy </li></ul><ul><ul><li>Direct activation of renin-angiotensin-aldosterone system 3,10 </li></ul></ul><ul><ul><li>Enhanced myocardial aldosterone uptake 12 </li></ul></ul><ul><ul><li>Loss of K, Mg, Ca, secondary myocyte Ca loading 12 </li></ul></ul><ul><ul><li>Indirect reduction of cardiac output 10,11 </li></ul></ul><ul><ul><li>Increased total systemic vascular resistance 11 </li></ul></ul><ul><ul><li>Reduced natriuresis 8 and GFR 7,9 </li></ul></ul><ul><ul><li>Associated with increased morbidity and mortality 2,5,6 </li></ul></ul>Current Options May Have Undesirable Clinical Impacts
    19. 20. Diuretic Resistance <ul><li>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 reached 1 </li></ul><ul><li>Affects 20%–30% of patients with HF 2 </li></ul>1. Kramer et al. Nephrol Dial Transplant . 1999;14(suppl 4):39-42. 2. Ellison. Cardiology . 2001;96:132-143.
    20. 21. Diuretic Resistance: Two Types <ul><li>“ Braking” phenomenon </li></ul><ul><ul><li>A decrease in response to a diuretic after the first dose has been administered </li></ul></ul><ul><li>Long-term tolerance </li></ul><ul><ul><li>Tubular hypertrophy to compensate for salt loss </li></ul></ul>Brater. N Engl J Med . 1998;339:387.
    21. 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)
    22. 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
    23. 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
    24. 25. The Use of Loop Diuretics in ADHF May Worsen Renal Function Schrier. J Am Coll Cardiol . 2006;47:1-8. <ul><li>In symptomatic ADHF patients, diuretics have an important role in treating congestion and symptoms </li></ul><ul><li>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 </li></ul>
    25. 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
    26. 27. Causes of Diuretic Resistance in HF 1-3 <ul><li>Decreased renal function and distal Na+ delivery </li></ul><ul><li>Variability in diuretic absorption (bioavailability) </li></ul><ul><li>Neurohormonal activation (RAAS/SNS) </li></ul><ul><li>Drugs/diet—increased sodium intake </li></ul><ul><li>Noncompliance with medications </li></ul><ul><li>Infrequent dosing </li></ul>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. 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
    28. 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
    29. 30. Management of Diuretic Resistance in HF <ul><li>Restrict daily fluid intake (1.0–1.5 L) </li></ul><ul><li>Moderate restriction of daily salt intake (≤2 g) </li></ul><ul><li>Avoid NSAIDs </li></ul><ul><li>Institute and uptitrate ACE inhibitors and/or angiotensin receptor blocker </li></ul><ul><li>Give short-acting loop diuretic orally in several divided (and increasing) doses, bolus, or continuous intravenous administration </li></ul><ul><li>Use sequential nephron blockade via combination loop diuretic and thiazide diuretic </li></ul><ul><li>Add small doses of spironolactone (12.5–25 mg) </li></ul><ul><li>Consider short-term acetazolamide in selected patients </li></ul>
    30. 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
    31. 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)
    32. 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.
    33. 34. Diuretic Therapeutic Dilemma <ul><li>Diminished renal function and concurrent sodium and water retention in ADHF presents a therapeutic dilemma with regard to submaximal diuretic therapy </li></ul><ul><li>Fluid removal by ultrafiltration may be recommended in this clinical setting </li></ul>Schrier. J Am Coll Cardiol . 2006;47:1-8.
    34. 35. <ul><li>ULTRAFILTRATION allows for the production of plasma water from whole blood across a semipermeable membrane in response to a transmembrane pressure gradient </li></ul><ul><li>The ensuing fluid or ultrafiltrate is isotonic to plasma </li></ul>Ronco et al. Cardiology . 2001;96:155-168.
    35. 36. A History of Ultrafiltration <ul><li>1979: Paganini and others reported the practical application of ultrafiltration in a volume-overloaded patient 4 </li></ul>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. 1949: Schneierson proposed intermittent peritoneal dialysis for refractive ADHF 1 1954: Kolff noted that ultrafiltration could be used for a “reduction of intractable edema” 2 1974: Silverstein described solitary ultrafiltration on 5 ESRD patients via a modified dialysis circuit 3 1940 1950 1960 1970 1980
    36. 37. A History of Ultrafiltration <ul><li>1979: Paganini and others reported the practical application of ultrafiltration in a volume-overloaded patient 4 </li></ul>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. 1949: Schneierson proposed intermittent peritoneal dialysis for refractive ADHF 1 1954: Kolff noted that ultrafiltration could be used for a “reduction of intractable edema” 2 1974: Silverstein described solitary ultrafiltration on 5 ESRD patients via a modified dialysis circuit 3 1940 1950 1960 1970 1980
    37. 38. Ultrafiltration Compared to Loop Diuretics Schrier. J Am Coll Cardiol . 2006;47:1-8. <ul><li>Ultrafiltrate is isotonic with plasma, whereas the diuresis of loop diuretics is virtually always hypotonic to plasma </li></ul><ul><li>Ultrafiltration removes more sodium than diuretic therapy </li></ul><ul><li>No electrolyte disturbances </li></ul><ul><li>Ultrafiltration decreases ECF volume more than a comparable volume of diuretic-induced fluid loss </li></ul>
    38. 39. Ultrafiltration <ul><li>A transmembrane pressure generated by the device allows for the formation of “ultrafiltrate” via convective transport 1,2 </li></ul>PRESSURE Uf  Uf   Uf  Uf Transmembrane Pressure (mmHg) Ultrafiltration (mL/h) Kf = mL/h/mmHg x m Qf = Kf - TMP 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. Na Na
    39. 40. Fluid Removal by Ultrafiltration <ul><li>Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue </li></ul><ul><li>The transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill (PR), aimed at minimizing this reduction 1,2 </li></ul>1. Lauer et al. Arch Intern Med . 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol . 2001;38:4. Vascular Space UF Vascular Space Interstitial Space (edema) Na Na Na Na K P H 2 O K P PR
    40. 41. Changes in Plasma Volume and Refilling Rate During Ultrafiltration <ul><li>Ultrafiltration can be done safely without significant changes in plasma volume </li></ul><ul><li>Plasma refill rates may decrease as volume removal continues </li></ul>Marenzi et al. J Am Coll Cardiol . 2001;38:963-968. 10 – 5 – 0 – – 5 – – 10 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF  PV (%) 20 – 15 – 10 – 5 – 0 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF PRR (mL/min)
    41. 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)
    42. 43. Ultrafiltration in Chronic Cardiac Insufficiency: Failure of Furosemide to Provide the Same Result <ul><li>16 stable, NYHA II–III chronic HF patients matched by age, gender, and peak VO 2 </li></ul><ul><li>Randomized to isolated ultrafiltration (500 mL/h) or IV furosemide </li></ul><ul><li>Removal of the same amount of fluid in both arms ( approximately 1600 mL) </li></ul><ul><li>Measurement of hemodynamics, peak VO 2 , norepinephrine, PRA, and aldosterone at baseline, end of treatment, and 3 months </li></ul>Agostoni et al. Am J Med. 1994;96:191-199.
    43. 44. Effects of Ultrafiltration vs IV Furosemide Neurohormones Triangles = Ultrafiltration Squares = Furosemide Agostoni et al. Am J Med. 1994;96:191-199. <ul><li>+ 80 – </li></ul><ul><li>+ 40 – </li></ul><ul><li>% 0 – </li></ul><ul><li>140 – </li></ul>NE PRA ALD d 0 1d 2d 3d 4d 3m <ul><li>+ 80 – </li></ul><ul><li>+ 40 – </li></ul><ul><li>% 0 – </li></ul><ul><li>140 – </li></ul>d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m + 170 – + 80 – + 40 – % 0 – - 40 -
    44. 45. Isolated Ultrafiltration Produces a Sustained Decrease in Body Weight in HF Patients Agostoni et al. Am J Med. 1994;96:191-199 . <ul><li>Ultrafiltration </li></ul><ul><li>Furosemide </li></ul><ul><li>* P < .01 </li></ul><ul><li>vs baseline </li></ul><ul><li>† P <.01 </li></ul><ul><li>vs furosemide </li></ul>B 1d 2d 3d 4d 1m 3m Time +2 +1 0 -1 -2  Body Weight (kg)
    45. 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
    46. 47. Enhanced Sodium Extraction With Ultrafiltration Compared With Intravenous Diuretics <ul><li>15 hospitalized ADHF patients with presumed diuretic resistance and clinical evidence of volume overload </li></ul><ul><li>Urine electrolyte concentrations measured after a dose of IV diuretics </li></ul><ul><li>Ultrafiltration was then begun and ultrafiltrate electrolyte concentrations were measured 8 h later and compared with the initial urine values </li></ul>Ali et al. J Card Fail . 2006;12(6 suppl):114.
    47. 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.
    48. 49. Ultrafiltration and Renal Function <ul><li>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 </li></ul><ul><li>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 significant 2 </li></ul><ul><li>Costanzo et al reported no change in creatinine pre- and post-UF in both the EUPHORIA 3 and UNLOAD 4 trials </li></ul><ul><li>Marenzi et al reported no change in creatinine when utilizing UF in volume-overloaded patients 5 </li></ul>
    49. 50. Possible Contraindications to Ultrafiltration in Patients With HF <ul><li>Inadequate venous access </li></ul><ul><li>Hypotension </li></ul><ul><li>Hypercoagulable states </li></ul><ul><li>Stage V chronic kidney disease; requirement for hemodialysis </li></ul><ul><li>Patients responsive to diuretics </li></ul>
    50. 51. Aquadex TM FlexFlow TM UF Prescription: Only 3 Clinical Decisions <ul><li>Volume to be removed </li></ul><ul><ul><li>Total volume of excess fluid (intravascular and interstitial) </li></ul></ul><ul><li>Rate of removal </li></ul><ul><ul><li>Safe removal of fluid requires that filtration rate equal plasma refill rate (rate of recovery of third space fluid) </li></ul></ul><ul><li>Anticoagulation therapy </li></ul><ul><ul><li>Full anticoagulation is recommended to preserve filter function </li></ul></ul><ul><ul><li>However, if a filter clots, only 40 mL of whole blood are lost </li></ul></ul>
    51. 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™
    52. 53. <ul><li>Multicenter, prospective study, 21 patients (25 treatments) </li></ul><ul><li>Initial UF within 12 h of hospitalization and before any significant administration of IV diuretics and/or vasoactive drugs </li></ul><ul><ul><li>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) </li></ul></ul><ul><ul><li>On average, 2611 ± 1002 mL (maximum 3725 mL) of ultrafiltrate was removed per treatment </li></ul></ul><ul><ul><li>Patient weight decreased from 91.9±17.5 to 89.3±17.3 kg ( P <.0001) after ultrafiltration </li></ul></ul><ul><ul><li>No major adverse events occurred </li></ul></ul><ul><ul><li>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 </li></ul></ul>The SAFE Study Jaski. J Card Fail. 2003;9:227-231.
    53. 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.
    54. 55. RAPID Trial: Design <ul><li>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 </li></ul><ul><li>Single 8-h UF intervention compared with usual diuretic strategies </li></ul><ul><ul><li>Artificially constrained UF to 8 h </li></ul></ul><ul><ul><li>Therapy was not titrated against clinical or biochemical markers of congestion/edema/volume </li></ul></ul>Bart et al. J Am Coll Cardiol . 2005;46:2043-2046.
    55. 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.
    56. 57. RAPID Trial: Conclusions <ul><li>Ultrafiltration is superior to diuretic strategies in salt and water removal </li></ul><ul><li>Ultrafiltration is safe, in a variety of clinical sites </li></ul><ul><li>There is no clinical justification to delay ultrafiltration therapy until diuretics fail </li></ul>Bart et al. J Am Coll Cardiol . 2005;46:2043-2046.
    57. 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.
    58. 59. EUPHORIA Trial: Study End Points <ul><li>Primary efficacy end point </li></ul><ul><ul><li>Resolution of signs and symptoms of fluid overload permitting discharge in ≤3 days </li></ul></ul><ul><li>Primary safety end point </li></ul><ul><ul><li>Feasibility of achieving the primary efficacy objective without symptomatic hypotension, renal insufficiency (≥25% increase in serum creatinine), or other adverse events </li></ul></ul>Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051. .
    59. 60. EUPHORIA Trial: Patient Population <ul><li>Age: 74 ± 8.5 years </li></ul><ul><li>Gender: 75% male </li></ul><ul><li>Race: 95% Caucasian </li></ul><ul><li>Etiology of HF: 75% ischemic </li></ul><ul><li>Left ventricular ejection fraction: 31 ± 16% </li></ul>Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051. .
    60. 61. EUPHORIA Trial: Results <ul><li>Number of 8-h ultrafiltration courses: 2.6 ± 1.2 </li></ul><ul><li>Volume removed by ultrafiltration: 8653 ± 4314 mL </li></ul>Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051.
    61. 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.
    62. 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
    63. 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
    64. 65. <ul><li>Early ultrafiltration in patients with fluid overload and diuretic resistance permitted the discharge of 60% of high risk ADHF patients in ≤3 days </li></ul><ul><li>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 </li></ul><ul><li>Improvements in clinical status are preserved for 30–90 days following hospitalizations </li></ul>EUPHORIA Trial: Conclusions Costanzo et al. J Am Coll Cardiol . 2005;46:2047-2051.
    65. 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.
    66. 67. Investigators & Sites <ul><li>Costanzo MR, Saltzberg M: Midwest Heart Foundation, Lombard IL (Coordinating Center) </li></ul><ul><li>Anderson A: U of Chicago, IL </li></ul><ul><li>Oren R: U of Iowa, IA </li></ul><ul><li>Haynos W: Iowa VA, IA </li></ul><ul><li>Jaski B: Sharp Memorial Hospital, CA </li></ul><ul><li>Eichorn E: Medical City, Dallas, TX </li></ul><ul><li>Jessup M: U of Pennsylvania, PA </li></ul><ul><li>Fang J: Brigham & Women’s Hospital, MA </li></ul><ul><li>Haas G: Ohio State University, OH </li></ul><ul><li>Walsh M: St. Vincent’s Hospital, IN </li></ul><ul><li>Feller E, Gottlieb S: U of Maryland, MD </li></ul><ul><li>Bart B: HCMC, MN </li></ul><ul><li>Guglin M: Detroit Medical Center, MI </li></ul><ul><li>Cooke R: Washington Hospital, WA </li></ul><ul><li>Fesniak H: Geisinger, PA </li></ul><ul><li>Magalski A: St. Luke’s, MO </li></ul><ul><li>Insel J: Good Samaritan Hospital, MD </li></ul><ul><li>Mehta J: U of Arkansas, AR </li></ul><ul><li>Slawsky M: Bay State, MA </li></ul><ul><li>Tsao L: Beth Israel, MA </li></ul><ul><li>Lavine S: U of Florida, FL </li></ul><ul><li>Menon S: Christ Hospital, OH </li></ul><ul><li>Pisani B: St. Luke’s Hospital, WI </li></ul><ul><li>Restaino S: Columbia/Presbyterian, NY </li></ul><ul><li>Patel J: UCLA, CA </li></ul><ul><li>Singer I: Methodist, CA </li></ul><ul><li>Kazi F: Dallas VA, TX </li></ul><ul><li>Teerlink JR: San Francisco/VAMC, CA </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    67. 68. Study Hypotheses <ul><li>In hypervolemic HF patients, ultrafiltration is </li></ul><ul><ul><li>Superior to aggressive IV diuretic therapy in reducing volume overload </li></ul></ul><ul><ul><li>Associated with sustained clinical benefits </li></ul></ul><ul><ul><li>Similar to IV diuretics in terms of safety </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    68. 69. Study Design <ul><li>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 </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    69. 70. Primary End Points <ul><li>Efficacy </li></ul><ul><ul><li>Weight loss at 48 h after randomization </li></ul></ul><ul><ul><li>Dyspnea score at 48 h after randomization </li></ul></ul><ul><li>Safety </li></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Episodes of hypotension during the first 48 h after randomization </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    70. 71. Secondary End Points <ul><li>Brain natriuretic peptide levels at 48 h after randomization, 30 and 90 days </li></ul><ul><li>NYHA class, Minnesota Living With Heart Failure (MLWHF) score, Global Assessment score at discharge, and follow-up </li></ul><ul><li>Diuretic doses after ultrafiltration or standard care </li></ul><ul><li>Percentage of patients rehospitalized for HF </li></ul><ul><li>Absolute number of rehospitalizations for HF </li></ul><ul><li>Days of rehospitalization for HF </li></ul><ul><li>Unscheduled office and emergency department visits </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    71. 72. METHODS
    72. 73. Methods <ul><li>Enrollment June 2004 until July 2005 at 28 US centers </li></ul><ul><li>Randomization schedule via secure Web site </li></ul><ul><li>Two independent adjudicators of causes of death </li></ul><ul><li>CHF Solutions funded the trial and provided a study manager </li></ul><ul><li>Data were entered by investigators, sent to a data management group, and verified with source documents </li></ul><ul><li>Investigators had complete access to the database and directed all statistical analyses, which were performed by an independent statistician </li></ul><ul><li>Study was approved by the ethics committee of each hospital, and all patients provided written informed consent </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    73. 74. Methods: Inclusion Criteria <ul><li>≥ 18 years of age </li></ul><ul><li>Hospitalized with evidence of volume overload by at least two of the following: </li></ul><ul><ul><li>peripheral edema ≥2+ </li></ul></ul><ul><ul><li>jugular venous distension ≥7 cm </li></ul></ul><ul><ul><li>radiographic pulmonary edema or pleural effusion </li></ul></ul><ul><ul><li>enlarged liver or ascites </li></ul></ul><ul><ul><li>pulmonary rales, paroxysmal nocturnal dyspnea, or orthopnea </li></ul></ul><ul><li>Randomization within 24 h hospitalization </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    74. 75. Methods: Exclusion Criteria <ul><li>Acute coronary syndrome </li></ul><ul><li>Serum creatinine >3.0 mg/dL </li></ul><ul><li>Hemodynamic instability requiring inotropic drugs </li></ul><ul><li>Hematocrit >45% </li></ul><ul><li>Administration of vasoactive drugs prior to randomization </li></ul><ul><li>Contraindications to anticoagulation </li></ul><ul><li>Heart transplant </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    75. 76. Methods: Study Procedures <ul><li>Daily 2 g sodium, 2000 mL fluid intake restriction </li></ul><ul><li>Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β -blockers, and digoxin continued </li></ul><ul><li>1 diuretic unit = </li></ul><ul><ul><li>20 mg of furosemide </li></ul></ul><ul><ul><li>10 mg of torsemide </li></ul></ul><ul><ul><li>0.5 mg of bumetamide </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    76. 77. Methods: Study Procedures <ul><li>Ultrafiltration Arm </li></ul><ul><ul><li>Ultrafiltration rate ≤ 500 mL/h </li></ul></ul><ul><ul><li>Duration/rate of fluid removal decided by treating physicians </li></ul></ul><ul><ul><li>IV diuretics prohibited during ultrafiltration </li></ul></ul><ul><li>Standard Care Arm </li></ul><ul><ul><li>IV diuretics as bolus or continuous infusions </li></ul></ul><ul><ul><li>IV doses ≥2 times daily PO dose for the first 48 h after randomization </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    77. 78. Methods: Statistical Analysis <ul><li>Differences between treatment groups: </li></ul><ul><ul><li>Pearson’s chi-square or Fisher’s exact test for categorical variables </li></ul></ul><ul><ul><li>Wilcoxon’s rank sum test for continuous variables </li></ul></ul><ul><li>The effects of covariates on weight loss at 48 h tested using analysis of variance (ANOVA) </li></ul><ul><li>Change over time within treatment groups: Wilcoxon’s matched pairs signed ranks test </li></ul><ul><li>P values ≤.05 considered statistically significant </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    78. 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
    79. 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 (%)
    80. 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
    81. 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
    82. 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 (%)
    83. 84. RESULTS
    84. 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.
    85. 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.
    86. 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.
    87. 88. Secondary End Points <ul><li>Similar improvements occurred in the ultrafiltration and standard care groups in </li></ul><ul><ul><li>Brain natriuretic peptide levels </li></ul></ul><ul><ul><li>NYHA class </li></ul></ul><ul><ul><li>MLWHF scores </li></ul></ul><ul><ul><li>Global assessment scores </li></ul></ul><ul><ul><li>6-Minute walk distance </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    88. 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
    89. 90. Safety End Points <ul><li>No clinically significant differences at each assessment interval in serum BUN, Na, Cl-, and HC3 </li></ul><ul><li>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) </li></ul><ul><li>Episodes of hypotension during the first 48 h after randomization were similar in the ultrafiltration 4 (4.4%) and standard care 3 (3%) </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    90. 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
    91. 92. Deaths <ul><li>Ultrafiltration Group </li></ul><ul><li>9 (9.6%) </li></ul><ul><ul><li>3 HF </li></ul></ul><ul><ul><li>1 acute renal failure </li></ul></ul><ul><ul><li>5 unrelated to either HF or treatment </li></ul></ul><ul><li>Standard Care Group </li></ul><ul><li>11 (11.6%) </li></ul><ul><ul><li>5 HF </li></ul></ul><ul><ul><li>1 myocardial infarction </li></ul></ul><ul><ul><li>3 unrelated to either HF or treatment </li></ul></ul><ul><ul><li>2 unknown causes </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    92. 93. Effect of Ultrafiltration on Weight Loss: Subgroup Analysis Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    93. 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.
    94. 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.
    95. 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.
    96. 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 (%)
    97. 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.
    98. 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
    99. 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.
    100. 101. <ul><ul><li>In the UNLOAD Trial </li></ul></ul><ul><ul><ul><li>67% of patients in standard care arm received IV bolus </li></ul></ul></ul><ul><ul><ul><li>33% of patients in standard care received IV continuous drip </li></ul></ul></ul><ul><ul><ul><li>Average dose in 24-h period for loop diuretic was </li></ul></ul></ul><ul><ul><ul><ul><li>IV bolus 117 mg </li></ul></ul></ul></ul><ul><ul><ul><ul><li>IV continuous 127 mg </li></ul></ul></ul></ul>UF vs Bolus/Continuous Diuretics Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    101. 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
    102. 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 (%)
    103. 104. Ultrafiltration vs Continuous Diuretic Infusions <ul><li>Ultrafiltration patients had fewer rehospitalizations </li></ul><ul><li>Ultrafiltration patients had fewer rehospitalization days/patient </li></ul><ul><li>Ultrafiltration patients had fewer unscheduled visits </li></ul><ul><li>All differences were statistically significant </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    104. 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 (%)
    105. 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
    106. 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
    107. 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
    108. 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.
    109. 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
    110. 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.
    111. 112. Limitations <ul><li>Neither patients nor investigators were blinded to the therapy </li></ul><ul><li>Rate and duration of volume removal not specified in the study protocol </li></ul><ul><li>Total sodium removed not documented </li></ul><ul><li>Lack of measurements of blood volume and plasma refill rate, cardiac performance, hemodynamics, or interstitial water </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    112. 113. Conclusions <ul><li>Early ultrafiltration produces greater weight loss than IV diuretics, without changes in renal function </li></ul><ul><li>An early ultrafiltration strategy reduces 90-day </li></ul><ul><ul><li>Percentage of patients requiring rehospitalization for HF </li></ul></ul><ul><ul><li>Number of HF rehospitalizations </li></ul></ul><ul><ul><li>Days of rehospitalization for HF </li></ul></ul><ul><ul><li>Emergency department and unscheduled office visits </li></ul></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    113. 114. Conclusions <ul><li>Symptoms and biomarkers of congestion may not be sufficiently sensitive to detect differences in volume loss produced by the two therapies </li></ul><ul><li>Future studies should be focused on unraveling the mechanisms linking specific methods and rates of fluid removal to subsequent clinical benefit </li></ul>Costanzo MR et al. J Am Coll Cardiol. 2007;49:675-683.
    114. 115. <ul><li>Dyspnea and other signs and symptoms of HF 1 </li></ul><ul><li>Lower PCWP with adequate systemic perfusion 1 </li></ul><ul><li>Use of ACE inhibitors, aldosterone antagonists, and β -blockers before hospital discharge 1 </li></ul><ul><li>Shorten length of stay, minimize use of intensive care unit, reduce readmissions 1 </li></ul><ul><li>Inhibit RAAS system, monitor inflammation caused by infection following a major surgery or trauma 2,3 </li></ul>Therapeutic Goals for ADHF <ul><li>Relieve symptoms </li></ul><ul><li>Reverse acute hemodynamic abnormalities </li></ul><ul><li>Initiate treatments that will slow disease progression and improve long-term survival </li></ul><ul><li>Apply treatment cost-effectively </li></ul><ul><li>Prevent end-organ dysfunction </li></ul><ul><li>Achieve Euvolemia </li></ul>Goals End Points 1. Fonarow GC. Rev Cardiovasc Med. 2002;3(suppl 4):S18- S 27. 2. Stier et al. Cardiol Rev. 2002;10:97-107. 3. Masai et al. Ann Thorac Surg. 2002;73:549-555.
    115. 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
    116. 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
    117. 118. Improvement of Congestion Predicts Survival in Patients With Class IV Symptoms of ADHF <ul><li>146 Patients hospitalized with class IV HF </li></ul><ul><li>Assessed 4 to 6 weeks after hospitalization for congestion </li></ul><ul><li>Patients with persistent orthopnea (n=33) </li></ul><ul><ul><li>2-year survival: 38% </li></ul></ul><ul><li>Patients with resolution of orthopnea (n=113) </li></ul><ul><ul><li>2-year survival: 77% ( P =.0001) </li></ul></ul>Lucas C et al. Am Heart J . 2000;140:840-847 .
    118. 119. <ul><li>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 resistant 1-3 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 known 4 </li></ul>Diuretics and ADHF 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. 120. Consequences of Therapeutic Limitations in CHF <ul><li>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 symptomatology 1 </li></ul>ADHERE ® Registry. 3rd Quarter. 2003 National Benchmark Report. http://www.adhereregistry.com/national_BMR/index.html .
    120. 121. ACC/AHA Guidelines <ul><li>4.4.1. Management of Fluid Status </li></ul><ul><li>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 </li></ul><ul><li>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 </li></ul>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. 122. Current Options Are Not Achieving the Standard of Care <ul><li>“… 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 diuretic-resistant HF and may restore responsiveness to conventional doses of loop diuretics.” </li></ul>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. 123. HFSA 2006 Guidelines <ul><li>12.11 </li></ul><ul><li>When congestion fails to improve in response to diuretic therapy, the following options should be considered: </li></ul><ul><ul><li>Sodium fluid restriction </li></ul></ul><ul><ul><li>Increasing doses of loop diuretic </li></ul></ul><ul><ul><li>Continuous infusion of loop diuretic </li></ul></ul><ul><ul><li>Addition of a second type of diuretic orally (metolazone or spironolactone) or intravenously (chlorothiazide) </li></ul></ul><ul><li>A fifth option, ultrafiltration , may be considered (strength of evidence:c) </li></ul>
    123. 124. <ul><li>Advanced form of ultrafiltration </li></ul><ul><li>Inpatient or outpatient settings </li></ul><ul><ul><li>ICU, CCU, MICU, telemetry, step-down, observation, ED, outpatient clinics </li></ul></ul><ul><li>Peripheral or central venous access </li></ul><ul><ul><li>Flexible access sites and catheters </li></ul></ul><ul><li>Diverse physician prescription </li></ul><ul><li>Highly automated operation </li></ul><ul><li>No clinically significant impact on electrolyte balance, blood pressure, or heart rate * </li></ul>What Is the Aquadex TM FlexFlow TM ? *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. 125. <ul><li>The Aquadex TM System received 510 k market clearance from the FDA in June 2002 and is indicated for:   </li></ul><ul><ul><li>Temporary (up to 8 h) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy (outpatient) </li></ul></ul><ul><ul><li>and </li></ul></ul><ul><ul><li>Extended (longer than 8 h) ultrafiltration treatment of patients with fluid overload who have failed diuretic therapy and require hospitalization </li></ul></ul><ul><li>All treatments must be administered by a healthcare provider, under physician prescription, both of whom having received training in extracorporeal therapies </li></ul>Indication for Use
    125. 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
    126. 127. <ul><li>Transportable console with simple operator interface </li></ul><ul><li>Disposable single-use extracorporeal blood circuit </li></ul><ul><li>Venous access that can provide 10–40 mL/min of blood </li></ul>What’s Needed?
    127. 128. The Process of Ultrafiltration
    128. 129. How Much? How Fast? <ul><li>Setting the appropriate fluid removal rate to not exceed this intravascular refilling is crucial to minimizing risk of </li></ul><ul><ul><li>Hypovolemia </li></ul></ul><ul><ul><li>Hypotension </li></ul></ul><ul><ul><li>Transient renal hypoperfusion (reduction of renal blood flow) </li></ul></ul><ul><ul><li>Decrease in glomerular filtration rate (GFR) </li></ul></ul><ul><ul><li>Increase in serum creatinine level </li></ul></ul><ul><ul><li>Arrhythmias </li></ul></ul><ul><li>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 </li></ul><ul><li>For details, refer to your hospital’s Aquapheresis TM Standing Orders </li></ul>
    129. 130. How Much? How Fast? <ul><li>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) </li></ul><ul><li>The rate of fluid removed from the intravascular space = UF rate (UFR) </li></ul><ul><li>The rate of fluid entering the intravascular space = Plasma Refill Rate (PRR) </li></ul><ul><li>Therefore, UFR ≤ PRR </li></ul>UFR Extravascular fluid PRR Intravascular fluid IVS
    130. 131. Advantages Over Loop Diuretics <ul><li>Complete control over rate and total volume of fluid removed </li></ul><ul><li>Ultrafiltration, differently from diuretics, removes isotonic fluid and therefore </li></ul><ul><ul><li>Removes the greatest possible amount of sodium per unit of fluid withdrawn 1 </li></ul></ul><ul><ul><li>Not associated with electrolyte depletion (Na, K, Mg, Ca) 1,2,3 </li></ul></ul><ul><li>May decrease or eliminate neurohormonal activation 4,5 </li></ul><ul><li>Reduce length of stay and rehospitalizations 3,5,6,7 </li></ul>
    131. 132. Responsibilities <ul><li>Physician </li></ul><ul><li>Identifies appropriate patient(s) according to accepted criteria. </li></ul><ul><li>Completes Standing Orders for Ultrafiltration/Aquapheresis TM </li></ul><ul><ul><li>Establishes/coordinates venous access site, catheter, and insertion </li></ul></ul><ul><ul><li>Defines quantity of total fluid to be removed (in liters) and/or total duration of treatment (in hours) </li></ul></ul><ul><ul><li>Defines initial fluid removal rate (UF Rate) </li></ul></ul><ul><ul><li>Defines/details/clarifies criteria for adjusting fluid removal rate and/or blood flow </li></ul></ul><ul><ul><li>Prescribes and communicates anticoagulation plan </li></ul></ul><ul><ul><li>Establishes fluid restriction </li></ul></ul>
    132. 133. Responsibilities <ul><li>Nurse </li></ul><ul><li>Treatment set up </li></ul><ul><li>Begin per physician’s orders </li></ul><ul><li>Basic Monitoring </li></ul><ul><ul><li>Enforce and record intake and output (I & Os) </li></ul></ul><ul><ul><li>Monitor patient as appropriate </li></ul></ul><ul><ul><li>If necessary, adjust the fluid removal rate as prescribed </li></ul></ul><ul><ul><li>Listen for possible alarms and respond as necessary </li></ul></ul><ul><ul><li>Perform basic troubleshooting to assure proper functioning </li></ul></ul><ul><ul><li>Assess venous access sites periodically </li></ul></ul><ul><ul><li>If required, titrate anticoagulation as ordered </li></ul></ul>
    133. 134. Responsibilities (continued) <ul><li>Nurse </li></ul><ul><li>Confirm patient at physician-prescribed amount of fluid removed or duration of therapy </li></ul><ul><li>Treatment completion </li></ul><ul><ul><li>Stop treatment and discontinue patient access from device </li></ul></ul><ul><ul><li>Care or dispose of blood set and catheters according to institutional policy </li></ul></ul><ul><ul><li>Routine console cleaning </li></ul></ul>
    134. 135. Setting the Fluid Removal Rate <ul><li>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 </li></ul><ul><li>With this feature, users can set the fluid removal rate that is best for each, individual patient </li></ul>F
    135. 136. Anticoagulation <ul><li>For optimal treatment, a therapeutic range of anticoagulation, that is, twice normal (eg, an ACT of 180 - 220 s) </li></ul><ul><li>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 </li></ul>
    136. 137. Choosing Venous Access <ul><li>2 catheters or lumens are needed </li></ul><ul><li>Required blood flow range is 10 to 40 mL/min </li></ul><ul><li>Many venous access sites and types of catheters can be used </li></ul><ul><li>The exact choice is determined by the prescribing physician </li></ul>
    137. 138. Possible Venous Access Catheters <ul><li>A sample of possible venous access choices follow: </li></ul><ul><ul><li>The Extended Length Catheter (ELC) placed in the antecubital by a PICC team preferably into the basilic vein (withdrawal only) </li></ul></ul><ul><ul><li>Common 16-18 gauge PIVs placed antecubitally or higher </li></ul></ul><ul><ul><li>16 gauge/distal port on Arrow Triple Lumen CVC </li></ul></ul><ul><ul><li>Dual lumen/Quad Lumen Arrow CVC, 20 cm in length </li></ul></ul><ul><ul><li>Standard dialysis catheters </li></ul></ul><ul><ul><li>No PICCs, no SWANs, or anything smaller than 18 gauge or longer than 20 cm </li></ul></ul>
    138. 139. Aquapheresis TM /Aquadex TM FlexFlow TM Observations Peripheral or central Venous access <ul><li>≥ 5 lb over dry weight, diuretic resistant </li></ul><ul><li>within 12 h of hospitalization </li></ul><ul><li>Before any significant administration of IV diuretics and/or vasoactive drugs </li></ul>Patient selection Approximately 3200 mg/L Salt removal 2 times normal Anticoagulation 20 h Treatment time 30-40 mL/min Blood flow rate (blood flow) 250 mL/h (= 6 L in 24 h) Fluid removal rate (UF rate) Average or Typical Value* Treatment Detail *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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