Management of Acute Decompensated Heart Failure Washington Metropolitan Society of Health-System Pharmacists September 28, 2013 Rockville 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

A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines 2013 ACCF/AHA Guideline for the Management of Heart Failure A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Heart Failure Guidelines

Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Class III Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Level A: Data derived from multiple randomized clinical trials or meta-analyses Multiple populations evaluated Multiple populations evaluated Level B: Data derived from a single randomized trial or nonrandomized studies Limited populations evaluated Limited populations evaluated Level C: Only consensus of experts opinion, case studies, or standard of care Very limited populations evaluated Very limited populations evaluated Applying Classification of Recommendations and Level of Evidence Level of Evidence:

Definitions of HF r EF and HF p EF circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.citation

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

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. The Hospitalized Patient New Diagnosis of HF New

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 The Hospitalized Patient New Precipitating Factors for Acute HF

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. The Hospitalized Patient 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 Patients Being Evaluated for Dyspnea

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

Recommended Therapies for Hospitalized HF Patients

Recommended Therapies for Hospitalized HF Patients

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). The Hospitalized Patient Treatment With Intravenous Loop Diuretics New

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

The Hospitalized Patient Intensifying the Diuretic Regimen New 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.

Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy. The Hospitalized Patient 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. Ultrafiltration and Intravenous Inoptropic Drugs New

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. The Hospitalized Patient Monitoring and Measuring Fluid Intake and Output New

Diuretic Strategies in Patients with Acute Decompensated Heart Failure A. 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:

Diuretic Strategies in Patients with Acute Decompensated Heart Failure

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

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

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

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

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 Restriction in Acute Decompensated Heart Failure A 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):

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013;173(12):

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013;173(12):

Aggressive Fluid and Sodium Restriction in Acute Decompensated Heart Failure A Randomized Clinical Trial JAMA Intern Med. 2013;173(12):

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

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. 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. The Hospitalized Patient Preserving End-Organ Performance New

Intravenous Inotropic Agents Used in ADHF

Inotropic Support in Acute Heart Failure In the presence of significant hypotension, dopamine may enhance both blood pressure and peripheral organ perfusion. 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 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 Initial choice of therapy Weaning Weaning Patient related variables Patient related variables Differences in efficacy Differences in efficacy Adverse effect profile Adverse effect profile Survival data Survival data “Long-term” infusions “Long-term” infusions

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. The Hospitalized Patient I IIaIIbIII Invasive Hemodynamic Monitoring 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. Use of parenteral inotropes in normotensive patients with acute decompensated HF without evidence of decreased organ perfusion is not recommended. The Hospitalized Patient I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III I I I IIa IIb III Parenteral Inotropes 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. 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. Titration of infusion rate is initailly based on invasive hemodynamic monitoring.

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

Vasodilator Support in Acute Heart Failure Nitroprusside toxicities: 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 infusion may be preferred in patients an active or recent history of ischemia. Nitroglycerin is a less potent arteriolar dilator than nitroprusside 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. 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 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 Reduces LV filling pressure, variable effect on CO, urine output, sodium excretion Better than diuretics for dyspnea Better than diuretics for dyspnea Longer t ½ than nitroglycerin or nitroprusside Longer t ½ than nitroglycerin or nitroprusside Adverse renal outcomes Adverse renal outcomes

History of New Treatments in ADHF 1988: Milrinone approved based on small hemodynamic studies 1988: Milrinone approved based on small hemodynamic studies 2000: Levosimendan approved in Sweden then 40 countries 2000: Levosimendan approved in Sweden then 40 countries 2001: Nesiritide based on 489 patient VMAC trial 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 700 patients, placebo controlled Primary endpoint: Clinical composite based on patient global assessment during first 5 days of treatment (positive) Primary endpoint: Clinical composite based on patient global assessment during first 5 days of treatment (positive) Increased ventricular/atrial arrhythmias, symptomatic hypotension, early mortality Increased ventricular/atrial arrhythmias, symptomatic hypotension, early mortality JCHF. 2013;1(2): doi: /j.jchf

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

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

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

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

Medications should be reconciled in every patient and adjusted as appropriate on admission to and discharge from the hospital. The Hospitalized Patient In patients with reduced ejection fraction experiencing a symptomatic exacerbation of HF requiring hospitalization during chronic maintenance treatment with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta-blocker therapy, it is recommended that these therapies be continued in most patients in the absence of hemodynamic instability or contraindications. Reconciling and Adjusting Medications New

Serelaxin Recombinant human relaxin-2 (peptide that regulates maternal adaptations to pregnancy) Increased arterial compliance, cardiac output, renal blood flow. Suggested benefit on dyspnea and post- discharge clinical outcomes in patients admitted with evidence of congestion, normal to elevated blood pressure, mild to moderate renal dysfunction.

Serelaxin (RELAX-AHF) Prospective, randomized, double-blind, placebo-controlled, parallel group trial 1161 patients comparing serelaxin to placebo. Prospective, randomized, double-blind, placebo-controlled, parallel group trial 1161 patients comparing serelaxin to placebo. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnea relief compared with patients treated with standard care and placebo Lancet 2013; 381: 29–39

Serelaxin (RELAX-AHF) Inclusion Criteria Acute heart failure within past 16 hours, Dyspnea at rest or minimal exertion Acute heart failure within past 16 hours, Dyspnea at rest or minimal exertion Pulmonary congestion on CXR Pulmonary congestion on CXR BNP > BNP > 350 ng/L, NT-proBNP > 1400 ng/L GFR 30 – 75 ml/min/1.73 m 2 Systolic BP > 125 mm Hg Treated with > 40 mg iv furosemide Lancet 2013; 381: 29–39

RELAX-AHF Trial

Lancet 2013; 381: 29–39

RELAX-AHF Trial Lancet 2013; 381: 29–39

Serelaxin June 2013: FDA grants serelaxin “breakthrough- therapy” designation based on RELAX-HF Trial Breakthrough designation therapy reserved for the development or review of drugs seen as poteentiaal game changers for serious and life-threatening conditions that have preliminary evidence in at least one clinically significant endpoint over other available therapies

Other Investigational Drugs for AHF TRV027 – –Β-arrestin-biased AT1R ligand, competitively inhibits G-protein signaling – –Reduces MAP, increases cardiac contractility, maintains stroke volume, preserves GFR – –Anti-apoptotic effect Ularitide – –Synthetic foem of urodilatin (naturetic peptide produced by kidneys) – –Binds to specific naturetic peptide receptors, imcreasing intracellular cyclic GMP – –Relaxes smooth muscle cells, vasodilation and increased renal blood flow – –Ongoing TRUE-AHF study: Symptoms, HF improvement, and death

Other Investigational Drugs for AHF Omecamtiv mecarbil – –Selective cardiac myosin activator –ATOMIC-AHF was a randomized, double-blind, placebo-controlled Phase II clinical trial that enrolled 613 patients hospitalized with acute heart failure (AHF) treated for 48 hours with an intravenous formulation of omecamtiv mecarbil or placebo and designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and potential efficacy of omecamtiv mecarbil in patients with AHF –The primary efficacy endpoint of dyspnea symptom response was not met; favorable trends between the dose and plasma concentration of omecamtiv mecarbil and dyspnea response. The incidence of worsening heart failure within seven days of initiating treatment appeared lower in each of the cohorts on omecamtiv mecarbil. Rates of adverse events (AEs), serious AEs, adjudicated deaths and hospitalizations were similar between omecamtiv mecarbil and placebo groups. Omecamtiv mecarbil was not associated with an increased incidence of tachyarrhythmias nor were heart rate or blood pressure adversely affected.

Continuation of Outpatient ACE/ARB Therapy Blood pressure Blood pressure Renal function Renal function Volume dependency Volume dependency Substitution of hydralazine/nitrates Substitution of hydralazine/nitrates

Beta Blocker Use in ADHF Foranow GC. J Am Coll Cardiol 2008;52:190-9

Beta Blockers in Acute Decompensated Heart Failure Foranow GC. J Am Coll Cardiol 2008;52:190-9

The Hospitalized Patient In patients hospitalized with HF with reduced ejection fraction not treated with oral therapies known to improve outcomes, particularly ACE inhibitors or ARBs and beta- blocker therapy, initiation of these therapies is recommended in stable patients prior to hospital discharge. Initiation of beta-blocker therapy is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. Beta-blocker therapy should be initiated at a low dose and only in stable patients. Particular caution should be used when initiating beta-blockers in patients who have required inotropes during their hospital course. New

In patients with evidence of severely symptomatic fluid overload in the absence of systemic hypotension, vasodilators such as intravenous nitroglycerin, nitroprusside or neseritide can be beneficial when added to diuretics and/or in those who do not respond to diuretics alone. The Hospitalized Patient Severe Symptomatic Fluid Overload New I IIaIIbIII

The Hospitalized Patient Comprehensive written discharge instructions for all patients with a hospitalization for HF and their caregivers is strongly recommended, with special emphasis on the following 6 aspects of care: diet, discharge medications, with a special focus on adherence, persistence, and uptitration to recommended doses of ACE inhibitor/ARB and beta- blocker medication, activity level, follow-up appointments, weight monitoring, and what to do if HF symptoms worsen. Reconciling and Adjusting Medications New

Recommendations for Hospital Discharge

Improvement of Guideline Beta-Blocker Prescribing in Heart Failure: A Cluster-Randomized Pragmatic Trial of a Pharmacy Intervention. We conducted a pragmatic cluster-randomized trial, where facilities (n 5 12) with patients (n 5 220) were the clusters. Eligible patients had a beta-blocker prescription that was not guideline concordant. Level 1 intervention included information to a pharmacist on facility guideline concordance. Level 2 also provided a list of patients not meeting guideline goals. Intervention and follow-up periods were each 6 months. Achievement of full concordance with recommendations was low (4%e5%) in both groups, primarily due to lack of tolerability. However, compared with level 1, the level 2 intervention was associated with 1.9- fold greater odds of improvement in prescribing (95% confidence interval [CI] 1.1e3.2). Level 2 patients also had greater odds of a higher dose (1.9, 95% CI 1.1e3.3). The intervention was aided by the patient lists provided, the electronic medical record system, and staff support. Journal of Cardiac Failure Vol. 19 No

Acute Decompensated Heart Failure Few well controlled trials Few well controlled trials Little data to demonstrate improved morbidity/mortality Little data to demonstrate improved morbidity/mortality Need for newer, more effective, lower ADR-inducing agents Need for newer, more effective, lower ADR-inducing agents