1. Hospital Management of Decompensated Heart Failure Wilson S. Colucci, MD Chief, Cardiovascular Medicine

2. Acute Heart Failure Syndromes l Acute (i.e., new) onset of HF in patient without prior episodes or history of HF (e.g., acute MI, myocarditis) l Worsening (“decompensation”) of existing chronic, “compensated” heart failure l Persistently decompensated HF despite optimal medical management (often referred to as advanced or end-stage HF)

3. Natural History of HF Progression

4. AHFS l About 900,000 admissions per year l Average LOS 6-7 days l $23 billion annual costs l Affects most patients with chronic HF

5. Admissions for Heart Failure: Frequent Flyers Initial Admission 21% Readmission 79% Rates of readmission 2% in 2 days 20+% in 30 days 50% in 6 months

6. Causes of Readmission for HF 17% Other 19% Failure to Seek Care 16% Inappropriate Rx Rx Noncompliance 24% Diet Noncompliance 24% HFSA Research 2000

7. Overall Goals in Management of AHFS l Immediate relief of symptoms and hemodynamic stabilization l Identification and correction of underlying / precipitating factors l Optimize fluid status (optimal weight, renal function, edema) l Establishment of effective ambulatory regimen prior to discharge l Discharge planning and follow-up

8. Precipitants of AHFS l Diet indiscretion l Medication non-compliance l Uncontrolled hypertension l Myocardial ischemia/infarction l Cardiac arrhythmia (rapid heart beats, loss of atrial kicks) l Exacerbation of COPD l Medications (NSAID, glitazones, diltiazem verapamil)

9. Patient: W.C. l 67 year old man, ischemic CMP admitted with progressive DOE and fatigue l HR 98, tachypnea, BP 100/84, CVP 16 cm, bibasilar rales, 3+ edema to knees, cold feet l Labs: BUN 50, creat 2.5, BNP 1,500

10. Hemodynamic Profiles Volume Status A - NormalB C D Dry Wet Warm Cold Perfusion Dyspnea Rales CVP Edema Cold extremities Hypotension Narrow PP Renal insuff.

11. Acute HF: Clinical Signs l Intracardiac Filling Pressures –orthopnea, dyspnea on exertion –rales, jugular vein distention –bedside Valsalva maneuver –chest x-ray l Adequacy of Perfusion –narrow pulse pressure –cool extremities –mental obtundation –renal insufficiency, oliguria

12. LV Failure Easily Missed on Exam and/or CXR l By exam - rales, edema, and JVD often absent (e.g., 42% in Stevenson et al., JAMA 1989;261:884) l By CXR – congestion often absent (e.g., 27% had no congestion and 41% had minimal congestion in Mahdyoon et al., AJC 1989)

13. PA Catheter l Gold standard, but usually/often not needed l Adds little to management of uncomplicated case –ESCAPE Trial l Indicated/valuable in patient with known LV failure if: –Suspected low output / hypoperfusion –Unclear volume status –Ischemia, renal insufficiency, ARDS –Poor / unclear response to IV therapy / to optimize oral therapy

14. Predictors of In-Hospital Mortality l Three best predictors of mortality in hospitalized patients –BUN > 43 mg/dL –SBP < 115 m Hg –Creatinine > 2.75 mg/dL l But, information mainly retrospective from registry data (e.g., ADHERE Registry) l Therefore, not that useful in individual patient, but identifies patients to worry about Fonarow GC et al. JAMA 2005;293:572-80.

15. ? Inc Morbidity and Mortality Diuretic Therapy Worse renal function Diuretic & Natriuretic Resistance Diuretics can worsen renal function in HF Decreased preload Neurohormonal Activation Diminished Renal blood flow

16. Diuretics can improve renal function in HF 0.5 0.8 1.1 1.4 02468 0 6 12 19 25 0 GFR (ml/min) CVP, mm Hg Firth et al Lancet 5/7/88

17. Intensification of diuretic regimen When diuresis is inadequate to relieve congestion, as evidenced by clinical evaluation, the diuretic regimen should be intensified, using either: 1) higher doses of loop diuretics; 2) addition of a second diuretic (e.g. metolazone, spironolactone, or chlorothiazide); or 3) continuous infusion of a loop diuretic (Level of Evidence: C)

18. NIH “Dose” Trial: How to Diurese To evaluate the safety and efficacy of various initial strategies of furosemide therapy in patients with ADHF –Route »Q12 hours bolus »Continuous infusion – Dose »Low intensification (1 x oral dose) »High intensification (2.5 x oral dose)

19. Dose: Study Design Acute Heart Failure (1 symptom AND 1 sign) <24 hours after admission 2x2 factorial randomization Low Dose (1 x oral) Q12 IV bolus 48 hours 1) Change to oral diuretics 2) continue current strategy 3) 50% increase in dose Co-primary endpoints High Dose (2.5 x oral) Q12 IV bolus Low Dose (1 x oral) Continuous infusion High Dose (2.5 x oral) Continuous infusion 72 hours Clinical endpoints 60 days

20. Conclusions l There was no statistically significant difference in global symptom relief or change in renal function at 72 hours for either: –Q12 bolus vs. Continuous infusion –Low intensification vs. High intensification

21. Conclusions (2) l There was no evidence of benefit for continuous infusion compared to Q12 hour bolus on any secondary endpoint l Despite transient changes in renal function, there was no evidence for higher risk of clinical events at 60 days associated with the high intensification strategy l High intensification (2.5 x oral dose) was associated with trends towards greater improvement in multiple domains: –Symptom relief (global assessment and dyspnea) –Weight loss and net volume loss –Proportion free from signs of congestion –Reduction in NT-proBNP

22. Diuretic Resistance: Other Approaches to Consider l Addition of inotrope (e.g., dobutamine) –and / or vasodilator (e.g., nesiritide), –or inodilator (e.g., milrinone) to improve cardiac output, and hopefullly, renal perfusion l Addition of low-dose dopamine to increase renal perfusion l Vasopressin antagonists if hyponatremic (tolvaptan,i.v., lixivaptan, p.o.) l Ultrafiltration

23. Pre- and Post-Discharge Management l Stable weight (for at least 2 days) on stable doses of oral diuretics l Pre-discharge education (i.e., diet, weight, medications, activity level and what to do when problems arise) l Discharge planning with CMP nurse l Follow-up visits with CMP Clinic and primary physicians, etc

24. Patient: Not diuresing l 67 year old man, ischemic CMP admitted with progressive DOE and fatigue l Modest response to diuretics, still very sob l BP 100/84, HR 98, bibasilar rales, pedal edema, cool feet l Labs: BUN 50, creat 2.5, BNP 1,500 l Poor response to continuous infusion furosemide l PA catheter: RA 17, PCWP 34, CO 2.7 (CI 1.6), SVR 1870 l Which drug would you use next? 1. Dobutamine 2. Dopamine 3. Nitroglycerin 4. Milrinone 5. Nitroprusside 6. Nesiritide A - NormalB C D Dry Wet Warm Cold

25. “Typical” management of patients with ADHF who fail continuous furosemide No/Partial Response to Lasix Bolus 50% Continuous IV Lasix 76% Discharge 50%

26. “Typical” management of patients with ADHF who fail continuous furosemide No/Partial Response to Lasix Bolus Other 50% (750,000) Continuous IV Lasix Natrecor Inotropes Die/Mech Assist/Tx 76% 4% 18% 2% Die/Mech Assist/Tx 30% Discharge 70% Inotropes 20% Discharge 80% Natrecor 20% Discharge 50% Inotropes 30% Die/Mech Assist/Tx 5% Discharge 95% Inotropes 10% Discharge 90% Die/Mech Assist/Tx 10% Discharge 90% Die/Mech Assist/Tx 20% Discharge 80%

27. Inotropes: Beta-Agonists GsGs ACase  1 AR Agonist cAMP PKA Ca ++

28. Dobutamine: beta 1 -Adrenergic Agonist l Stimulates cAMP l Inotrope, weak vasodilator l Titrated to cardiac index l Side effects: Tachycardia, arrhythmias, ischemia l Hypo-responsiveness l Variable inotropic response, needs to be titrated Colucci et al., Circulation 1986;73:III175

29. Low-dose Dopamine

30. Dobutamine vs. Dopamine Leier et al., Circulation 1978 Dob: 2.5-10  g/kg/min Dopa: 2-8  g/kg/min CI

31. Inotropes: PDE Inhibitors GsGs ACase  1 AR Agonist PDEinh. PDE3 AMP cAMP PKA Ca ++

32. Milrinone: PDE Inhibitor l Inhibits phosphodiesterase, thereby increasing cAMP in myocardium and vasculature l Potent inotrope l Potent vasodilator l Side effects similar to dobutamine (tachycardia, arrhythmias, ischemia) plus hypotension l Simplified dosing

33. Hemodynamic effect of arterial dilation BP = CO X SVR Normal  SVR  CO  BP HF  SVR  CO  BP

34. Venous Arterial Venous Nitrates Vasodilator Classification Mixed Nitroprusside Nesiritide ACEI ARBs Arterial Hydralazine

35. Nitroprusside l Very potent, balanced, direct-acting vasodilator l Very rapid action l Requires central monitoring l Effects highly variable patient-to-patient l Cyanide and thiocyanide toxicity l Rebound after withdrawal

36. Fe -NO CN -- 2Na + Nitroprusside: Toxicity Liver dysfunction Cyanide toxicity Renal dysfunction Thiocyanate toxicity

37. Hemodynamic Effects of Hydralazine and Isosorbide Dinitrate Baseline HZ HZ + ISO As per Chatterjee K, Parmley WW, Massie B, et al. Circulation 1976; 54: 879-883. Stroke Volume Pulmonary Capillary wedge Pressure

38. NO-mediated vasodilation: Natriuretic peptides Vascular Smooth Muscle Cell Soluble Guanylate cyclase NO cGMP Endothelium NO-donating Drugs Vasodilation NP Receptor Particulate Guanylate Cyclase ANP BNP (nesiritide)

39. Nesiritide: A gentler nitroprusside Time (hours) 1.5 2 2.5 CI BL 1.5 3 4.5 6 (L/min/m 2 ) 15 20 25 30 35 PCWP * * * (mm Hg) Colucci, et al. NEJM 2000; 343:246-53 0.03 µg/kg/min placebo 0.015 µg/kg/min l Direct-acting balanced vasodilator l Less potent and rapid than NTP l But, does not require central monitoring and no direct toxicity l However, not a diuretic l Dose-related hypotension l Concerns about renal effects l Concerns about adverse outcomes l ASCEND Trial – neutral outcomes l Use as needed for symptoms and hemodynamics, not outcomes

40. Updated Guide to Initial Therapy COLow Low Low PCWPHigh High High SVRHigh Normal Low BNPBNP Dob SNPSNP Dopa TNGDob +/- VDMilrinone Modified from Stevenson and Colucci, Cardiovascular Therapeutics