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Diuretic Resistance in Heart Failure

Diuretic Resistance in Heart Failure. To Pee or Not to Pee…. Robert J. DiDomenico, PharmD Clinical Associate Professor Affiliate Faculty, Center for Phamacoeconomic Research University of Illinois at Chicago Colleges of Pharmacy & Medicine Cardiovascular Clinical Pharmacist

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Diuretic Resistance in Heart Failure

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  1. Diuretic Resistance in Heart Failure To Pee or Not to Pee… Robert J. DiDomenico, PharmD Clinical Associate Professor Affiliate Faculty, Center for Phamacoeconomic Research University of Illinois at Chicago Colleges of Pharmacy & Medicine Cardiovascular Clinical Pharmacist University of Illinois Medical Center at Chicago

  2. Disclosures • Scios, Inc. • Honoraria, consulting, research support • Sanofi-Aventis/Bristol Myers Squibb • Honoraria (c/o STRIVE™ network) • The Medicines Company • Honoraria (c/o University Pharmacotherapy Associates)

  3. 54yo M PMH: CHF HTN CAD s/p CABG DL DM OSA (morbid obesity) Meds Furosemide 160mg bid Spironolactone 25mg bid Enalapril 20mg bid Valsartan 80mg bid Digoxin 0.25mg daily ECASA 325mg daily Lovastatin 80mg qhs Insulin Advair Theoplylline BP 113/73, HR 118, RR 40 95% on 2L O2 Phys exam Wt 117kg JVD 10cm B crackles at bases w/wheezing 2+ LEE to knees Labs 138 101 41 (baseline 20) 4.1 191.7 (baseline 1.2) BNP 414 Initial Treatment (Med C) 80mg IV furosemide in ED, then 80mg IV q12h Response Urine output (18 hours) = 980ml Increasing dyspnea Case

  4. Typical ADHF Treatment Course ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84. DiDomenico RJ, et al. April, 2007.

  5. Typical ADHF Treatment Course ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84. DiDomenico RJ, et al. April, 2007.

  6. Typical ADHF Treatment Course ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84. DiDomenico RJ, et al. April, 2007.

  7. Diuretic Resistance • Commonly referred to as Cardiorenal Syndrome • Often associated with renal insufficiency (acute and/or chronic) • Definitions vary • Persistent edema despite adequate diuretic doses • Diminished natriuretic response to repeated doses • Daily furosemide doses > 80mg1 • Prevalence • Chronic: 35%1 • Acute: unknown 1Neuberg GW, et al. Am Heart J 2002;144:31-8.

  8. Diuretic Resistance & Mortality Eshaghian S, et al. Am J Cardiol 2006;97:1759-64.

  9. Greenhalgh E, DiDomenico RJ Retrospective analysis of ADHF admissions to UIMCC in 2006 Inclusion >18yo, ADHF with volume overload, Tx with IV diuretic Exclusion Initial Tx doesn’t include IV diuretic Use of IV vasoactives in 1st 24 hours N=264 Definition Urine output < 500ml within 2 hours of IV furosemide Urine output < 1000ml within 4 hours of IV furosemide Goals Characterize diuretic resistance in the acute setting Investigate if there are any reliable risk factors for diuretic resistance in ADHF Clinical characteristics Demographics, clinical presentation, NYHA FC LV Fxn, renal Fxn BP Dose of diuretic Home & inpatient Concomitant meds Diuretic ResistanceWhat About in ADHF?

  10. Diuretic Resistance Diuretic Mechanism of Action & Mechanisms of Diuretic Resistance

  11. Diuretic Mechanism/Site of Action De Bruyne LKM. Postgrad Med J 2003;79:268-71.

  12. Mechanisms of Diuretic Resistance • Diminished effect in heart failure & renal failure • Stimulation of neurohormonal axes • Hypertrophy of distal tubules impairs natriuretic response • Post-diuretic NaCl retention • Venous congestion impairs renal tubular function???

  13. Normal patients Furosemide 40mg IVP 200 – 250mEq Na 3 – 4 L over 3 – 4 hrs CHF patients  natriuretic response Absorption & peak effect delayed 1/3 – 1/4 that of normal patients Renal insufficiency (RI) 1/5 – 1/10 furosemide secreted into renal tubules Free concentrations of diuretic may be  in nephrotic syndrome due to  protein binding Diuretic PharmacodynamicsSodium & Water Excretion Brater DC. New Engl J Med 1998;339:387-95.

  14. Diuretics PharmacodynamicsSodium & Water Excretion Ellison DH. Cardiology 2001;96:132-43.

  15. Proximal Tubule AT2 increases sodium reabsorbtion Glomerulus Norepinephrine, endothelin, AT2 decrease renal blood flow and GFR Collecting Duct Hypertrophy of distal tubules. Aldosterone increases sodium reabsorbtion Diuretics & NeurohormonesDiuretic Resistance & Renal Function Weber KT. NEJM. 2001;345:1689-1697. Francis GS et al. Ann Intern Med. 1984;101:370-377. Dzau VJ. Kidney Int. 1987;31:1402-1415.

  16. Diuretic ResistanceNeurohormonal Stimulation * * Baseline * 20 minutes * p<0.01 Francis GS, et al. Ann Intern Med 1985;103:1-6.

  17. Diuretic ResistanceHemodynamic Effects * * * * * * Baseline 20 minutes 3.5 hours 2085+1035ml urine * p<0.01 Francis GS, et al. Ann Intern Med 1985;103:1-6.

  18. Does Venous Congestion Impair Renal Function? Doty JM et al. J Trauma 1999;47:1000-3.

  19. Does Venous Congestion Impair Renal Function? Doty JM et al. J Trauma 1999;47:1000-3.

  20. Does Venous Congestion Impair Renal Function? Patel KP, Carmines PK. Am J Physiol Regulatory Integrative Comp Physiol 2001;281:R239-45.

  21. Treatment Options for Diuretic Resistance • Change diuretics? • Continuous infusion • Combination of Loop diuretic + thiazide • IV vasoactive drugs • Combination hypertonic saline + Loop diuretic??? • Investigational therapies • Vasopressin antagonists • Adenosine antagonists

  22. Treatment of Diuretic ResistanceAre All Diuretics Created Equal? • More frequent dosing of furosemide & bumetanide may be necessary to overcome postdiuretic NaCl retention Brater DC. New Engl J Med 1998;339:387-95.

  23. Treatment of Diuretic Resistance Continuous Infusion of Diuretic vs. Intermittent Bolus Dosing

  24. Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion Urine output (48hrs) IV bolus: 3790ml Cont inf: 4490ml P<0.01 Lahav M, et al. Chest 1992;102:725-31.

  25. Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion • Cumulative doses (area under the curve) of furosemide not significantly different Dormans TPJ, et al. J Am Coll Cardiol 1996;28:376-82.

  26. Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion • 39 patients with ADHF • 21 received IV bolus • 18 received continuous infusion • Daily urine output ~65% greater with continuous infusion vs IV bolus P=0.016 Thomson MR, et al. HFSA 2007[Abstract].

  27. Treatment of Diuretic Resistance Combination Diuretic Therapy

  28. Treatment of Diuretic ResistanceCombination Loop + Thiazide Channer KS, et al. Br Heart J 1994;71:146-50.

  29. Treatment of Diuretic ResistanceCombination Loop + Thiazide 26/40 (65%) Channer KS, et al. Br Heart J 1994;71:146-50.

  30. Treatment of Diuretic ResistancePractical Approach toCombination Therapy • Start with low dose metolazone (2.5 – 5mg daily) • Long half-life negates need for more frequent dosing • May give 1st dose 30 minutes prior to IV furosemide • Not substantiated in literature • May consider IV chlorothiazide 250 – 500mg • Consider brief course (< 3 days) to minimize hypovolemia & electrolyte deficiencies • Monitor volume status, electrolytes, & renal function diligently

  31. Treatment of Diuretic Resistance IV Vasoactive Therapy

  32. IV Vasoactive Therapy in ADHFADHERE Mortality Analysis Abraham WT, et al. JACC 2005;46:57-64.

  33. IV Vasoactive Therapy in ADHFEarly Initiation May Improve Outcomes Peacock WF, et al. HFSA 2006[Abstract].

  34. Nesiritide + Std therapy vs Placebo + Std therapy Minimum duration 24 hours Primary endpoint HF rehospitalization or all-cause mortality Relief of dyspnea at 6 & 24hrs N=7000 UIMCC & JBVA are participating sites Inclusion >18yo, hospitalized for ADHF Dyspnea at rest or minimal activity PLUS Tachypnea OR pulmonary congestion on exam PLUS + CXR OR BNP OR PCWP > 20 OR EF <40% ASCEND-HF TrialNesiritide in Patients with ADHF

  35. Treatment of Diuretic ResistanceHypertonic Saline & IV Diuretics • Rationale • Creates an osmotic gradient, mobilizing extracellular fluid into the intravascular space followed by immediate excretion • Hypertonic saline may increase renal blood flow, facilitating diuretic activity • Administration • IV furosemide 500 – 1000mg prepared together with hypertonic saline solution 1.4 – 4.6% • Administered as 30 minute infusion q12h • Also administered IV KCl to minimize hypokalemia Licata G, et al. Am Heart J 2003;145:459-66.

  36. Treatment of Diuretic ResistanceHypertonic Saline & IV Diuretics Licata G, et al. Am Heart J 2003;145:459-66.

  37. Treatment of Diuretic ResistanceUltrafiltration Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-83.

  38. Treatment of Diuretic ResistanceUltrafiltration Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-83.

  39. Future Approaches for Diuretic Resistance in ADHF New Drug Classes: Vasopressin Antagonists

  40. V1a receptor Found in vascular smooth muscle cells Vasoconstriction → peripheral vascular resistance and afterload May induce ischemia due to coronary vasoconstriction V2 receptor Found on renal tubular cells Mediates free water retention through aquaporin channels Vasopressin Antagonists in Development Conivaptan (Vaprisol®) Duel V1a & V2 antagonist IV form available PO form in development Tolvaptan V2 >> V1a (30 times)  urine output without sodium loss Vasopressin Receptor Antagonists

  41. Treatment of Diuretic ResistanceRole for Conivaptan? Udelson JE, et al. Circulation 2001;104:2417-23.

  42. Treatment of Diuretic ResistanceRole for Conivaptan? Udelson JE, et al. Circulation 2001;104:2417-23.

  43. Future Approaches for Diuretic Resistance in ADHF New Drug Classes Adenosine Receptor Antagonists

  44. Adenosine Receptors and Function • Other receptor subtypes: A2b, A3 • Adenosine also responsible for sodium transport in proximal renal tubules (mechanism unknown) • Adenosine levels increased in patients with heart failure Modlinger PS et al. Curr Opin Nephrol Hypertens. 2003; 12:497-502.

  45. 15 Placebo 10 5 0 GFR (% change) -5 IV Furosemide -10 -15 -20 -25 0 500 1000 1500 2000 2500 Urine Output (ml) 0–8 hours Adenosine Antagonism in Heart FailureUrinary Output & Renal Function BG9719 BG9719 + IV Furosemide n = 16 (NYHA class III HF Gottlieb SS et al. Circulation. 2002;105:1348-1353.

  46. PROTECT Studies:Adenosine Receptor Antagonist, KW-3902 Patients with ADHF and renal dysfunction requiring i.v. diuretic IV KW-3902 plus Standard therapy Expected enrollment n=920 Placebo plus Standard therapy Primary endpoints: symptomatic relief and renal function Secondary endpoints: safety, medical costs http://www.clinicaltrials.gov. Identifier: NCT00354458 & NCT00328692. Accessed 10/12/06.

  47. Diuretic Resistance (HFSA) 12.11 When congestion fails to improve in response to diuretic therapy, the following options should be considered: • Sodium and fluid restriction • Increased doses of loop diuretic • Continuous infusion of a loop diuretic, or • 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) Adams KF, et al. J Card Fail 2006;12:10-38.

  48. Vasodilators (HFSA) 12.15 In the absence symptomatic hypotension, intravenous nitroglycerin, nitroprusside, or nesiritidemay be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with ADHF. Frequent blood pressure monitoring is recommended with these agents. (Strength of Evidence = B). Adams KF, et al. J Card Fail 2006;12:10-38.

  49. Vasodilators (HFSA) 12.16 Intravenous vasodilators (intravenous nitroglycerin or nitroprusside) and diureticsare recommended for rapid symptom relief in patients with acute pulmonary edema or severe hypertension. (Strength of Evidence = C) 12.17 Intravenous vasodilators (nitroprusside, nitroglycerin, or nesiritide) may be considered in patients with ADHF and advanced HF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies. (Strength of Evidence = C) Adams KF, et al. J Card Fail 2006;12:10-38.

  50. Inotropic Agents (HFSA) 12.18 (continued) These agents may be considered in similar patients with evidence of fluid overload if they respond poorly to intravenous diuretics or manifest diminished or worsening renal function. (Strength of Evidence = C) When adjunctive therapy is needed in other patients with ADHF, administration of vasodilatorsshould be consideredinstead of intravenous inotropes (milrinone or dobutamine). (Strength of Evidence = B) Adams KF, et al. J Card Fail 2006;12:10-38.

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