David S. Roffman, PharmD, BCPS/AQ Cardiology Professor Pharmacy Practice and Science

Management of Acute Decompensated Heart FailureWashington Metropolitan Society of Health-System PharmacistsSeptember 28, 2013Rockville Maryland David S. Roffman, PharmD, BCPS/AQ Cardiology Professor Pharmacy Practice and Science School of Pharmacy University of Maryland

Financial Disclosures for David S. Roffman, PharmD Nothing to disclose

Learning Objectives At the completion of the lecture, the participants will be able to: 1. Describe the typical presentation of acute decompensated heart failure (ADHF) 2. List the therapeutic objectives associated with pharmacologic therapy for ADHF 3. State the indications, adverse effects, and monitoring parameters for the use of inotropes, vasodilators, pressors, and loop diuretics in the treatment of ADHF 4. Describe emerging pharmacotherapeutic options for ADHF

Heart Failure Guidelines 2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation

Applying Classification of Recommendations and Level of Evidence Level of Evidence:

Definitions of HFrEF and HFpEF http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation

Clinical Profiles of Hospitalized HF Patients • Volume overload • pulmonary/systemic vascular congestion • precipitated by acute BP increase • Profound depression of CO • hypotension • renal insufficiency • shock syndrome • Signs/symptoms of both

The Hospitalized Patient Diagnosis of HF • The diagnosis of heart failure is primarily based on signs and symptoms derived from a thorough history and physical exam. Clinicians should determine the following: • a. adequacy of systemic perfusion; • b. volume status; • c. the contribution of precipitating factors and/or co-morbidities • d. if the heart failure is new onset or an exacerbation • of chronic disease; and • e. whether it is associated with preserved, normal, or reduced • ejection fraction. • Chest radiographs, echocardiogram, and echocardiography are key tests in this assessment. New New

The Hospitalized Patient Precipitating Factors for Acute HF • It is recommended that the following common potential precipitating factors for acute HF be identified as recognition of these comorbidities, is critical to guide therapy: • • acute coronary syndromes/coronary ischemia • • severe hypertension • • atrial and ventricular arrhythmias • • infections • • pulmonary emboli • • renal failure • • medical or dietary noncompliance New

The Hospitalized Patient Patients Being Evaluated for Dyspnea Concentrations of BNP or NT-proBNP should be measured in patients being evaluated for dyspnea in which the contribution of HF is not known. Final diagnosis requires interpreting these results in the context of all available clinical data and ought not to be considered a stand-alone test. New Acute coronary syndrome precipitating HF hospitalization should be promptly identified by electrocardiogram and cardiac troponin testing, and treated, as appropriate to the overall condition and prognosis of the patient. New

Therapeutic Objectives for Acute Decompensated Heart Failure • Improve survival? • Resolve pulmonary vascular congestion • Preserve end organ performance • Achieve previous baseline heart failure status (NYHA Classification) • Reduce the risk of rehospitalization

Recommended Therapies for Hospitalized HF Patients http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation

The Hospitalized Patient Treatment With Intravenous Loop Diuretics Patients admitted with HF and with evidence of significant fluid overload should be treated with intravenous loop diuretics. Therapy should begin in the emergency department or outpatient clinic without delay, as early intervention may be associated with better outcomes for patients hospitalized with decompensated HF (Level of Evidence: B). If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose. Urine output and signs and symptoms of congestion should be serially assessed, and diuretic dose should be titrated accordingly to relieve symptoms and to reduce extracellular fluid volume excess. (Level of Evidence: C). New

Diuretic Therapy in ADHF Hunt et.al. 2009. J Am Coll Cardiol 53;15:1-90

The Hospitalized Patient Intensifying the Diuretic Regimen When diuresis is inadequate to relieve congestion, as evidence by clinical evaluation, the diuretic regimen should be intensified using either: a. higher doses of loop diuretics; b. addition of a second diuretic (such as metolazone, spironolactone or intravenous chlorthiazide) or c. Continuous infusion of a loop diuretic. New

IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I IIa IIa IIa IIa IIb IIb IIb IIb III III III III I I I B The Hospitalized Patient Ultrafiltration and Intravenous Inoptropic Drugs Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy. New Intravenous inotropic drugs such as dopamine, dobutamine or milrinone might be reasonable for those patients presenting with documented severe systolic dysfunction, low blood pressure and evidence of low cardiac output, with or without congestion, to maintain systemic perfusion and preserve end-organ performance. New

The Hospitalized Patient Monitoring and Measuring Fluid Intake and Output Effect of HF treatment should be monitored with careful measurement of fluid intake and output; vital signs; body weight, determined at the same time each day; clinical signs (supine and standing) and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of intravenous diuretics or active titration of HF medications. New

Diuretic Strategies in Patients with Acute DecompensatedHeart Failure A. Bolus dosing more effective B. Continuous infusion more effective C. Higher dose more effective than lower dose D. Both B and C are correct

Diuretic Strategies in Patients with Acute Decompensated Heart Failure In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The co-primary end points were patients’ global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805

Diuretic Strategies in Patients with Acute Decompensated Heart Failure Felker GM, Lee KL, Bull DA, et.al., N Engl J Med 2011;364:797-805

Fluid and Sodium Restriction in Acute Decompensated Heart Failure Fluid and sodium restriction in ADHF patients improves weight loss and clinicaal stability in hospitalized ADHF patients • A. True • B. False

Aggressive Fluid and Sodium Restrictionin Acute Decompensated Heart FailureA Randomized Clinical Trial To compare the effects of a fluid-restricted (maximum fluid intake, 800 mL/d) and sodium restricted (maximum dietary intake, 800 mg/d) diet (intervention group [IG]) vs. a diet with no such restrictions (control group [CG]) on weight loss and clinical stability during a 3-day period in patients hospitalized with ADHF JAMA Intern Med. 2013;173(12):1058-1064

Aggressive Fluid and Sodium Restrictionin Acute Decompensated Heart FailureA Randomized Clinical Trial JAMA Intern Med. 2013;173(12):1058-1064

The Hospitalized Patient In all patients hospitalized with HF, both with preserved and low ejection fraction, transition should be made from intravenous to oral diuretic therapy with careful attention to oral diuretic dosing and monitoring of electrolytes. With all medication changes, the patient should be monitored for supine and upright hypotension and worsening renal function and HF signs/symptoms. New

The Hospitalized Patient Preserving End-Organ Performance In patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures (e.g., elevated jugular venous pressure; elevated pulmonary artery wedge pressure), intravenous inotropic or vasopressor drugs should be administered to maintain systemic perfusion and preserve end-organ performance while more definitive therapy is considered. New Invasive hemodynamic monitoring should be performed to guide therapy in patients who are in respiratory distress or with clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from clinical assessment. New

Intravenous Inotropic Agents Used in ADHF http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation

Inotropic Support in Acute Heart Failure • In the presence of significant hypotension, dopamine may enhance both blood pressure and peripheral organ perfusion. • Dopamine, in pressor doses (greater than 5 mcg/kg/min), increases myocardial oxygen demand and potentially limits augmentation of peripheral perfusion via peripheral vasoconstriction

Issues with Intravenous Inotropes • Initial choice of therapy • Weaning • Patient related variables • Differences in efficacy • Adverse effect profile • Survival data • “Long-term” infusions

I IIa IIb III The Hospitalized Patient Invasive Hemodynamic Monitoring • Invasive hemodynamic monitoring can be useful for carefully selected patients with acute HF who have persistent symptoms despite empiric adjustment of standard therapies, and • a. whose fluid status, perfusion, or systemic or • pulmonary vascular resistances are uncertain; • b. whose systolic pressure remains low, pr is associated with symptoms, despite initial • therapy; • c. whose renal function is worsening with therapy; • d. who require parenteral vasoactive agents; or • e. who may need consideration for advanced device • therapy or transplantation. New

IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb III III III III III III I I I I I I IIa IIa IIa IIa IIa IIa IIb IIb IIb IIb IIb IIb III III III III III III I I I I I I The Hospitalized Patient Parenteral Inotropes Use of parenteral inotropes in normotensive patients with acute decompensated HF without evidence of decreased organ perfusion is not recommended. New Routine use of invasive hemodynamic monitoring in normotensive patients with acute decompensated HF and congestion with symptomatic response to diuretics and vasodilators is not recommended. New

Vasodilator Support in Acute Heart Failure Nitroglycerin, nitroprusside, and nesiritide, have been demonstrated to improve symptoms and hemodynamics in acute heart failure.

Vasodilator Support in Acute Heart Failure • Nitroprusside infusions (initial dose 0.1 mcg/kg/min) improve symptoms of pulmonary congestion, and signs of peripheral perfusion. • Titration of infusion rate is initailly based on invasive hemodynamic monitoring.

Vasodilator Support in Acute Heart Failure • Nitroprusside patient variables: • Chronic liver disease • Renal insufficiency • Blood pressure • Malnourished patients

Vasodilator Support in Acute Heart Failure • Nitroprusside toxicities: • Cyanide intoxication: metabolic acidosis • Thiocyanate toxicity: Hyper-reflexia, seizures, altered mental status. Serum concentration assay available

Vasodilator Support in Acute Heart Failure • Nitroglycerin infusion may be preferred in patients an active or recent history of ischemia. • Nitroglycerin is a less potent arteriolar dilator than nitroprusside

Vasodilator Support in Acute Heart Failure • Nesiritide is a brain naturetic peptide (BNP) which has significant vasodilator effects. • Dosing regimen, 0.2 mcg/kg bolus followed by 0.01 mcg/kg/min continuous infusion • Reduces LV filling pressure, variable effect on CO, urine output, sodium excretion • Better than diuretics for dyspnea • Longer t ½ than nitroglycerin or nitroprusside • Adverse renal outcomes

History of New Treatments in ADHF • 1988: Milrinone approved based on small hemodynamic studies • 2000: Levosimendan approved in Sweden then 40 countries • 2001: Nesiritide based on 489 patient VMAC trial

Research on Drugs for Acute Heart Failure • PubMed search for “heart failure” (19,154)/”randomized controlled trials”(2176)/”acute disease”(61) for novel, intravenous treatments for acute heart failure • Search results: Levosimendan, nesiritide, rolofylline, tezosentan

Levosimendan (REVIVE I and II) • 700 patients, placebo controlled • Primary endpoint: Clinical composite based on patient global assessment during first 5 days of treatment (positive) • Increased ventricular/atrial arrhythmias, symptomatic hypotension, early mortality JCHF. 2013;1(2):103-111. doi:10.1016/j.jchf.2012.12.004

Levosimendan vs. Dobutamine (SURVIVE) • 1327 patients • Primary endpoint: All cause mortality at 180 days not achieved • No secondary endpoints achieved • Decreased BNP JAMA. 2007 May 2;297(17):1883-91

Nesiritide (ASCEND-HF) • Placebo controlled post approval trial • Prespecified primary endpoint (dyspnea relief) not met • No beneficial effect on hospital readmisiion, all-cause mortality, worsening renal function N Engl J Med 2011;365:32-43

Rolofylline (Protect) • 2033 patients • Failed to meet primary clinical composite endpoint • No reduction in hospital readmissions • Complicated by seizures and stroke N Engl J Med 2010; 363:1419-28

Tezosentan (VERITAS) • 1448 patients • No improvement in dyspnea • No improvement in worsening heart failure or death at 7 days • No improvement in renal function, hospital readmission or mortality JAMA 2007;298:2009-19

David S. Roffman, PharmD, BCPS/AQ Cardiology Professor Pharmacy Practice and Science