Decompensated Heart Failure - Wiley Online Library

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REVIEW PAPER

Decompensated Heart Failure: Is There a Role for the Outpatient Use of Nesiritide? Heart failure (HF) management has seen enormous advances in the past two decades, including publication of HF management guidelines targeted at further reduction of morbidity and mortality. Nonetheless, the morbidity of HF has steadily increased and now represents one of the largest health care expenditures in this country. Because hospitalization for HF is most likely for patients with more advanced HF, they share a disproportionate burden of the hospitalization costs and will require treatment regimens beyond the current guidelines, if this burden is to be alleviated. In June 2004, a group of investigators who helped establish the natriuretic peptide treatment paradigm, met to discuss the potential role of nesiritide as an outpatient treatment option for patients with symptomatic HF who were at high risk for repeated admissions, a syndrome now described as “chronic decompensated HF.” This report presents their considerations on the contribution of natriuretic peptide physiology to the amelioration of progressive left ventricular dysfunction, the therapeutic use of B-type natriuretic peptide, and its potential application to the outpatient management of acute and chronic decompensated HF. The use of outpatient IV nesiritide was considered a promising treatment option for symptomatic chronic decompensated HF patients that merits further investigation. Such an approach, once validated, should be integrated into an evidence-based HF disease management program. (CHF. 2004;10:230–236) ©2004 CHF, Inc.

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n most industrialized nations, heart failure (HF) has become a major health problem. In contrast to other cardiovascular conditions, HF is increasing in incidence—in part because of better survival after cardiovascular events, and in part because of the burden of risk factors known to be associated with HF, such as diabetes and uncontrolled hypertension in an aging population. In the United States, acute decompensated HF (ADHF) is responsible for nearly 1 million hospital admissions yearly, and is the direct or indirect cause of over 260,000 deaths.1 HF is the cause of 5.3 million hospital-days each year, an average length of stay (LOS) of about 5.5 days, and mean hospital charges of $11,688,2–4

producing an estimated annual cost of treating HF of $25.8 billion.1,5 Given the aging of the US population, these costs can be expected to increase unless changes are made in the way HF is diagnosed and treated. Outpatient management of ADHF using parenteral natriuretic peptides is an emerging strategy that appears to be clinically effective, may lead to fewer hospitalizations, and is likely to improve quality of life. When combined with control of cardiovascular risk factors and correction of precipitating mechanisms for decompensation, it is plausible that treatment of acute episodes of decompensated HF with natriuretic peptides in the outpatient setting may reduce morbidity and mortality.

Nesiritide is a new vasoactive and renal-acting peptide based upon the known structure and function of B-type natriuretic peptide (BNP). Nesiritide possesses vasoactive properties that have been shown to be safe and effective in the management of HF patients with symptoms of acute decompensation. This paper will review the pathophysiology and treatment of decompensated HF, with a special focus on the recombinant form of human BNP (i.e., nesiritide).

Pathophysiology

HF is associated with increased activity of the renin-angiotensin-aldosterone system, increased secretion of vasoconstrictive molecules, and increased sympathetic nervous system activity.

Clyde W. Yancy, MD;1 John C. Burnett, Jr., MD;2 Gregg C. Fonarow, MD;3 Marc A. Silver, MD4 From the University of Texas Southwestern Medical Center, St. Paul University Hospital, and the Heart Failure/Heart Transplantation Director of the University of Texas Southwestern Medical Center, Dallas, TX;1 Cardiorenal Research Laboratory, Mayo Clinic College of Medicine, Rochester, MN;2 UCLA Cardiomyopathy Center, UCLA Medical Center, Los Angeles, CA;3 Department of Medicine, Advocate Christ Medical Center, and Heart Failure Institute, Oak Lawn, IL4 Address for correspondence: Clyde W. Yancy, MD, University of Texas Southwestern Medical Center, Department of Internal Medicine/Cardiology Division, CS7-102, 5323 Harry Hines Boulevard, Dallas, TX 75235 E-mail: [email protected] Manuscript received August 9, 2004; accepted August 24, 2004. 230

decompensated HF and nesiritide in outpatient use

september . october 2004

Congestive Heart Failure (ISSN 1527-5299) is published bimonthly (Feb., April, June, Aug., Oct., Dec.) by CHF, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by CHF, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in Congestive Heart Failure do not necessarily reflect those of the Editor and Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

Neurohormonal activation is an important factor in the development and progression of adverse changes in myocardial function and structure. As decreased cardiac output and reduced blood pressure (BP) activate baroreceptors in the left ventricle, aortic arch, and carotid sinus, vasomotor regulatory centers in the brain activate the sympathetic nervous system, the renin-angiotensin-aldosterone system, and the arginine-vasopressin system, producing increased heart rate, myocardial contractility, peripheral vasoconstriction, and sodium and water retention. Neurohormonal stimulation, initially a compensatory mechanism, ultimately leads to cardiac dysfunction. Baroreceptor sensitivity is often downregulated in HF; even when normal arterial pressures are restored, sympathetic stimulation is maintained. Targeting this process with neurohormonal antagonists (e.g., β blockers, angiotensin-converting enzyme inhibitors, and aldosterone inhibitors) has been highly beneficial in treating HF. A major homeostatic force is the natriuretic peptide system secreted to counterbalance the vasoconstrictive and salt and water retentive effects of sustained neurohormonal secretion. The natriuretic peptides are ultimately cleared by endocytosis or enzymatically destroyed by endopeptidases found in the vascular epithelium and renal tubules.6 However, in HF patients, when the effects of natriuretic peptides are potentiated, either by administration of an endopeptidase inhibitor or recombinant BNP, sympathetic stimulation may be reduced; natriuresis, diuresis, and vasodilation increased; cyclic guanosine monophosphate increased; and, based on experimental evidence, fibrosis may be moderated.7,8 As one would expect from an endogenous homeostatic hormone system, these peptides have multiple effects (Figure 1).9 BNP is synthesized and released by cardiac myocytes in response to ventricular stretch and volume overload. The increase in plasma BNP with the severity of HF suggested its use as a biomarker in HF. BNP immunoassays

can aid in the diagnosis of HF, as BNP levels are more accurate than the use of signs, symptoms, and ejection fractions in the identification of patients with ADHF, although normal BNP levels have been reported in individuals with established left ventricular (LV) dysfunction and symptomatic HF.10,11 A comprehensive review of BNP has recently been published that addresses the applications and limitations of BNP testing.12 Staging. Patients with HF are classified according to New York Heart Association (NYHA) system and/or as defined in the American College of Cardiology (ACC) American Heart Association (AHA) Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult.13 These two classifications provide complementary information. The ACC/AHA classification describes the evolution of HF from stage A (risk factors for HF) to stage B (asymptomatic LV dysfunction) to stages C and D, which are symptomatic stages. The NYHA system categorizes patients by the extent of dysfunction; as patients decompensate, they may pass from NYHA class III to IV, whereas successful treatment can improve a patient from class IV to III or II. Approximately 25% of patients with HF are class III and 5% are class IV, yet this population generates most HFrelated health care costs. The health care costs for patients with NYHA class III/IV HF are estimated to be 8–30 times those with class II,14 and rehospitalization has been reported to be 44% within 6 months following the index admission.15 Because stage C/D HF patients often require repeated and prolonged hospitalization when they become acutely decompensated, they are suitable targets for novel therapies that reduce the need for hospitalization, improve quality of life, and possibly provide a survival advantage.

Decompensated HF

In later stages of HF, the main treatment goal is to control the symptoms of HF. Disease management


approaches utilize a combination of agents, including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, aldosterone antagonists, diuretics, β blockers, and digitalis. For selected patients, cardiac resynchronization, implantable cardiac defibrillators, and/or cardiac resynchronization with a defibrillator are reasonable strategies to complement pharmacotherapy. Mechanical devices, such as LV or biventricularassist devices, and cardiac transplantation are additional options for highly selected patients with severe HF.13 Stage C/D HF patients are most likely to require parenteral agents to treat episodes of acute decompensation, despite maximally tolerated medications. Table I shows treatment strategies commonly used to deal with acute decompensation. None of the listed strategies have data supporting a mortality advantage. Moreover, there are no governing guidelines on the management of ADHF, leaving the practitioner to rely on clinical experience, anecdote, and empiricism. Traditionally, acute decompensation results in an emergency department (ED) visit for evaluation, observation, and possibly admission to the hospital. The Breathing Not Properly Multinational Study16,17 incorporated BNP assessment (using a cutoff of 100 pg/mL) into ED evaluation of 1538 patients with dyspnea, and improved the accuracy of HF diagnosis from 74% to 81.5%. Of 721 patients considered to have a low probability of HF by the ED clinician, 123 (17.1%) eventually had a final diagnosis of HF, 90% of whom were identified by BNP testing. The B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) trial18 was a prospective, randomized study of 452 patients presenting in the ED with acute dyspnea. In addition to clinical evaluation, a BNP ≥100 pg/mL distinguished dyspnea caused by HF from other origins. The use of BNP improved the amount of time to effective treatment, reduced the proportion of patients admitted and/or admitted to intensive care, september . october 2004

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Table I. Parenteral Drugs Used to Treat Acute Decompensated Heart Failure (ADHF) DRUG SYMPATHOMIMETICS

MECHANISM

Dopamine

α1- and α2-stimulation β1-stimulation

Decreased norepinephrine release Increased positive inotropy Peripheral vasoconstriction Venoconstriction

Dobutamine

β1-stimulation β2-stimulation α1-stimulation

Increased positive inotropy Peripheral vasodilation Peripheral vasoconstriction

Norepinephrine

β1-stimulation α1-stimulation

Increased cAMP Increased positive inotropy Peripheral vasoconstriction

Epinephrine

β1-stimulation β2-stimulation α1-stimulation

Increased positive inotropy Peripheral vasodilation Peripheral vasoconstriction

Isoproterenol

β1-stimulation

Increased positive inotropy Increased heart rate Peripheral vasodilation

OF

ACTION

β2-stimulation

OUTCOME

VASODILATORS Nitroglycerin Nitroprusside

Nitric oxide donors

Increased cellular cAMP Venous and arterial vasodilation

Enalaprilat

ACE inhibition

Venous and arterial vasodilation Natriuresis

Hydralazine

Arteriolar relaxation

Arteriolar vasodilation

Phosphodiesterase III inhibition

Increased cellular cAMP Increased positive inotropy Peripheral vasodilation

Binding to guanylate cyclase receptor

Increased cellular cGMP Natriuresis Diuresis Vasodilation Decreased endothelin and aldosterone production Positive lusitropy Decreased sympathetic activity Decreased connective tissue proliferation8 Decreased inflammation8

PHOSPHODIESTERASE INHIBITORS Milrinone

NATRIURETIC PEPTIDES Nesiritide

β1=beta-1 receptor; β2=beta-2 receptor; α1=alpha-1 receptor; α2=alpha-2 receptor; cAMP=cyclic adenosine monophosphate; ACE=angiotensin-converting enzyme; cGMP=cyclic guanosine monophosphate. Adapted with permission from Tallaj JA, Bourge RC. The Management of Acute Decompensated Heart Failure 2003. Available at: http://www.fac.org.ar/tcvc/llave/c038/bourge.htm. Accessed July 8, 2004; 3rd International Congress of Cardiology on the Internet 2003. Available at: http://www.fac.org.ar/tcvc/ index.html. Accessed July 8, 2004.

median LOS, and median treatment cost. Both the Breathing Not Properly and BASEL studies demonstrated that BNP levels provide diagnostic, prognostic, and pharmacoeconomic value in ADHF, but the clinician must remember that BNP levels can be affected by age, gender, ischemia, infarction, or renal dysfunction.16 The Acute Decompensated Heart Failure National Registry (ADHERE)19,20 is a national, multicenter, observational 232

database that incorporates patient characteristics, patterns of care, and clinical outcomes of patients hospitalized with ADHF. ADHERE has enrolled over 130,000 ADHF patients from over 250 hospitals nationwide and shows that 77% of these patients present initially at the ED, while 21% are admitted directly to an inpatient unit. The mean door-to-treatment time for ED presentations was 2 hours (for IV diuretic and vasoactive therapies), whereas the


mean amount of time to treatment for inpatient vasoactive therapy was 23 hours.4 Patients who received vasoactive therapy in the ED showed lower in-hospital mortality, decreased time in the intensive care unit, decreased LOS, and fewer invasive procedures than did patients who received inpatient vasoactive therapy (Table II). The Use of Nesiritide as Therapy for ADHF. Nesiritide is recombinant september . october 2004


human BNP that mimics the actions of endogenous BNP by binding to guanylate cyclase receptors (natriuretic peptide receptors) in the heart, vasculature, kidneys, and other organ systems to increase intracellular levels of cyclic guanosine monophosphate.21 Nesiritide has been shown to significantly improve dyspnea and rapidly reduce pulmonary capillary wedge pressure.21 Nesiritide has also been shown to increase diuresis and natriuresis while maintaining renal blood flow.22,23 Animal and in vitro studies suggest that nesiritide may reduce ventricular remodeling by exerting an antifibrotic effect on cardiac fibroblasts, reducing deposition of collagen and fibronectin in extracellular matrix, and reducing production of inflammatory mediators.8,9,24 In addition, experimental studies demonstrated that BNP may reduce aldosterone activation in response to furosemide.25 Although nesiritide is eliminated, in part, through renal clearance, clinical data suggest that dosage adjustment is not required in patients with renal insufficiency.21 The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial26 compared the efficacy and safety of nesiritide vs. IV nitroglycerin and placebo in 489 patients with ADHF at 55 hospitals. Patients received standard care plus placebo, IV nitroglycerin, fixed-dose nesiritide (2 µg/kg bolus followed by 0.01 µg/ kg/min infusion for at least 24 hours), or variable-dose nesiritide infusion. Nesiritide had a positive effect on patient symptoms, with a significant and rapid reduction in dyspnea as early as 15 minutes as compared with placebo. Nesiritide had a more rapid onset and produced a greater reduction in pulmonary capillary wedge pressure than did nitroglycerin. The incidence of symptomatic hypotension was similar between nesiritide and IV nitroglycerin (4% vs. 5% respectively), but hypotension lasted longer in nesiritide-treated patients. The Prospective Randomized Outcomes Study of Acutely Decompensated Congestive Heart Failure Treated Initially in Outpatients

Figure 1. Diagram of interaction of heart, kidney, vasculature, brain, and renin angiotensin-aldosterone system with natriuretic peptide system. ET=endothelin; ANP=A-type natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide. Reprinted with permission from Congest Heart Fail. 2004;10(5 suppl 3):1–30.

with Heart Failure using Nesiritide (PROACTION) trial27 was a multiinstitutional, randomized, doubleblind study of 250 established HF patients presenting to the ED with acute decompensation. In addition to standard care, patients were randomized to receive nesiritide (2 µg/kg bolus followed by 0.01 µg/kg/min infusion) or placebo. Nesiritide therapy was associated with trends toward decreased admissions, reduced readmission rates, and decreased LOS when readmission did occur. The costs associated with HF treatment, admission, readmission, and LOS were lower with nesiritide therapy than with placebo.27 Patients with an initial systolic BP >140 mm Hg had a decrease of 27.8 mm Hg over 12 hours (8.4 mm Hg with standard care, p