C O N T I N U I N G M E D I C A L E D U C AT I O N : 2 C R E D I T S AVA I L A B L E

Transcription

1 Volume 3, Number 1 Spring 2006 THE CARDIOLOGY TM Gary S. Francis, MD Guest Editor The Cleveland Clinic Foundation, Cleveland, Ohio Heart Failure 2005: The Latest, Greatest, and Best for Our Patients Michael G. Dickinson, MD University of Arizona Sarver Heart Center, Tucson Chronic and Post-MI Heart Failure: Back to the Future? Suntharo Ly, MD University of Colorado Health Sciences Center, Denver Angiotensin II Receptor Blockers in the Management of Heart Failure Stacie A. Luther, MD University of North Carolina School of Medicine Chapel Hill Management of Heart Failure After Myocardial Infarction Kimberly Dulaney, MD Selected Reports from the Ninth Annual Scientific Meeting of the Heart Failure Society of America C O N T I N U I N G M E D I C A L E D U C AT I O N : 2 C R E D I T S AVA I L A B L E This activity is supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

2 Guest Editor: Gary S. Francis, MD The opinions or views expressed in this publication are those of the authors and do not necessarily refl ect the opinions or recommendations of Novartis Pharmaceuticals Corporation, Beam Institute, or the publisher, Direct One Communications, Inc. Please consult the full prescribing information before using any medication mentioned in this publication. This publication was made possible through an unrestricted educational grant from Novartis Pharmaceuticals Corporation. Copyright 2006 by Direct One Communications, Inc. Cover: Lightscapes Photography, Inc./Corbis. All rights reserved. Printed in the USA.

3 Contents Volume 3, Number 1 Spring 2006 THE CARDIOLOGY TM Selected Reports from the Ninth Annual Scientific Meeting of the Heart Failure Society of America The Cleveland Clinic Foundation, Cleveland, Ohio 3 Introduction Gary S. Francis, MD Gary S. Francis, MD, Guest Editor 5 Heart Failure 2005: The Latest, Greatest, and Best for Our Patients Michael G. Dickinson, MD University of Arizona Sarver Heart Center, Tucson 16 Chronic and Post-MI Heart Failure: Back to the Future? Suntharo Ly, MD University of Colorado Health Sciences Center, Denver 26 Angiotensin II Receptor Blockers in the Management of Heart Failure Stacie A. Luther, MD University of North Carolina School of Medicine, Chapel Hill 37 Management of Heart Failure After Myocardial Infarction Kimberly Dulaney, MD C O N T I N U I N G M E D I C A L E D U C AT I O N : 2 C R E D I T S A V A I L A B L E 2 About This CME Activity 47 CME Post Test and Evaluation 1

4 About This CME Activity Rationale and Purpose Heart failure affects millions of Americans, and a variety of conditions, including hypertension and myocardial infarction (MI), can greatly complicate its management. This issue of The Cardiology Report provides information on the importance of aggressive management of heart failure post MI; the usefulness of neurohormonal agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, and other drug therapies in managing the condition; indications for implantation of cardiac resynchronization therapy or defi brillators; differences among patients of different races that may impact the choice of heart failure therapy; current best practice guidelines for patients with heart failure complicated by other medical conditions; initiatives to design an appropriate management scheme and educate hospitalized heart failure patients; and the promise of stem-cell research in providing a replacement for dead myocardial tissue. It is based on presentations delivered at the Ninth Annual Scientific Meeting of the Heart Failure Society of America, held September 18 21, 2005, in Boca Raton, Florida. The articles in this issue, written from the academic perspective of physicians in training at leading medical institutions, summarize the import of these new fi ndings and place them into clinical context. This activity has been developed and approved by a planning committee of nationally recognized thought leaders, under the direction of Beam Institute, to meet a perceived educational need to provide medical practitioners with strategies to help them perform their role in identifying, treating, and, where possible, preventing heart failure. Learning Objectives After reading this issue of The Cardiology Report, participants in this educational activity should be able to: Understand the progressive changes in cardiac structure and tissue architecture associated with heart failure and how these changes may be prevented or corrected using drug therapy and/or surgery. Appreciate the importance of aggressive management strategies in heart failure patients who have experienced an MI. Explain the rationale for targeting the renin-angiotensin-aldosterone system in patients diagnosed with heart failure. Discuss the issues surrounding the US Food and Drug Administration s approval of candesartan and valsartan to manage symptomatic heart failure. Target Audience Cardiologists and other physicians signifi cantly involved in the diagnosis and management of patients with heart failure and other cardiovascular disorders should fi nd participation in this educational activity valuable. Accreditation Beam Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Faculty Disclosures In compliance with the ACCME s 2004 Standards for Commercial Support, any person who was in a position to control the content of this CME activity was required to disclose all relevant fi nancial relationships that created confl icts of interest. Beam Institute has identifi ed and resolved all confl icts of interest prior to the publication of this educational activity. All faculty have been offered a modest honorarium for their participation in this activity. Gary S. Francis, MD, is Professor of Medicine, The Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and Head, Clinical Cardiology Section, The Cleveland Clinic Foundation, Cleveland, Ohio. He is on the Advisory Boards of Amgen Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc., and Pfi zer Inc. Michael G. Dickinson, MD, a Heart Failure and Transplant Medicine Fellow at The Cleveland Clinic Foundation, Cleveland, Ohio, has nothing to disclose. Suntharo Ly, MD, a Cardiology Fellow at the University of Arizona Sarver Heart Center, Tucson, has nothing to disclose. Stacie A. Luther, MD, a Cardiology Fellow at the University of Colorado Health Sciences Center, Denver, has nothing to disclose. Kimberly Dulaney, MD, a Cardiology Fellow at the University of North Carolina School of Medicine, Chapel Hill, North Carolina, has nothing to disclose. Continuing Education Credit The Beam Institute designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Disclaimer This activity is an independent educational activity under the direction of Beam Institute. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the American Medical Association, the US Food and Drug Administration, the Offi ce of Inspector General of the US Department of Health and Human Services, and the Pharmaceutical Research and Manufacturers of America Code on Interactions With Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientifi c rigor, and objectivity. However, the planning committee, faculty, Beam Institute, Novartis Pharmaceuticals Corporation, and Direct One Communications, Inc. shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in this activity. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the planning committee or they may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Participants in this activity are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the faculty and do not necessarily reflect the views of the provider, producer, or grantors. Copyright Copyright owned by Direct One Communications, Inc. Copyright 2006, Direct One Communications, Inc. Contact Information We would like to hear your comments regarding this or other educational activities provided by Beam Institute. In addition, suggestions for future activities are welcome. Contact us at: Director of Continuing Education Beam Institute 11 West 19 th Street, 3 rd Floor New York, NY Phone: / Fax: beaminstitute@cmp.com Activity release date: March 31, 2006 Termination date: March 31,

5 Introduction Selected Reports from the Ninth Annual Scientific Meeting of the Heart Failure Society of America Gary S. Francis, MD The Cleveland Clinic Foundation, Cleveland, Ohio H eart failure continues to emerge the current role of angiotensin II receptor blockers (ARBs) in the management of patients with heart into the 21 st century as a formidable public health problem in failure; and terms of lives lost, hospitalizations the management of patients with heart failure after required, and the financial burden acute myocardial infarction. to healthcare systems. Treatment is continually being refined and improved. Mechanical Making Sense of All the Recent Trials strategies including defibrillators, cardiac resynchronization The multitude of clinical trials designed to test therapy therapy, assist devices, and remodeling restraining for heart failure are best thought of in a historical context. devices demonstrate continued promise. Pharmacologic The model of heart failure itself has shifted from what treatment has been carefully studied in patients with was considered to be largely a hemodynamic construct in heart failure complicated by acute myocardial infarction, the 1970s to a neurohormonally facilitated response to still a much feared complication, and in heart failure due injury that is characterized to chronically impaired, myopathic hearts. We know by progressive left ventricular much more than we did 20 or even 10 years ago. There remodeling. With are fewer data available regarding the management of this change has come new patients with heart failure and preserved left ventricular and more effective treatment. function, a now more widely appreciated problem. Socalled Drugs that block diastolic heart failure may be more challenging to the sympathetic nervous study in large clinical trials, as these patients tend to be system and the reninangiotensin-aldosterone older, have more comorbid conditions, and suffer more proportional events from noncardiac causes. Because of sy stem ( RAAS) have more noncardiac endpoints, very large sample sizes will be emerged as consistent, required. Acute decompensated heart failure is now better proven, and safe therapy. characterized by registries, but outcome studies will be Now the questions are challenging as we try to determine which endpoints are which drugs, for whom, Dr. Francis is Professor of Medicine, The Cleveland Clinic Lerner most clinically relevant. under what conditions, at College of Medicine of Case Western These and many other issues were discussed in various forums at the 2005 Annual Scientific Meeting of the employ them together. Clinical Cardiology Section, The what dose, and how best to Reserve University, and Head, Heart Failure Society of America (HFSA). This issue of Dr. Michael Dickinson Cleveland Clinic Foundation, Cleveland, Ohio. The Cardiology Report includes an analysis and in-depth of The Cleveland Clinic discussion of some of the most important issues presented at the HFSA meeting. Four key topics are described in detail: the treatment of patients with heart failure (chronic, low-ejection fraction) in 2005, according to the most recent trial data; the management of patients with heart failure today and in the future; Foundation presents a useful construct as to how these therapies should be employed during the natural history of heart failure. Using the new American College of Cardiology/American Heart Association guidelines and information from recent trials, he nicely outlines the nuances where we have good data and where there are holes and ambiguity. His paper stresses the important point that one size does not fit all, and therapy needs to be tailored 3

6 Gary S. Francis, MD to the context, condition, stage of heart failure, and even sometimes the ethnicity of the patient. Newer, highly innovative mechanical devices are emerging and discussed. The concept of how we measure our treatment strategy performance is addressed, as is the optimal management of African-American patients with heart failure. New data on educating inpatients and how best to implement the latest guidelines are described in detail. Patients need to be aware that heart failure is a spectrum, from risk factor identification to heart transplantation, and the treatment will vary to some extent each step of the way. Heart Failure: Back to the Future Dr. Suntharo Ly of the University of Arizona, Tucson, describes how heart failure becomes more prevalent with age and usually requires multiple drugs to control symptoms. High blood pressure is still a major driving force behind the development of both chronic heart failure (systolic and diastolic) and acute decompensated heart failure. Poorly controlled blood pressure and acute myocardial infarction have a prominent role in the development and maintenance of heart failure. Moreover, there is an interaction between hypertension and acute myocardial infarction. Patients with left ventricular hypertrophy tend to have a greater loss of myocardial tissue during acute myocardial infarction, whereas patients whose acute myocardial infarction is complicated by hypertension are more likely to develop heart failure. Of course, increased afterload stress further impairs left ventricular performance. Futuristic strategies include refinement of current device therapies and possibly stem-cell treatment. Clinical trials to date demonstrate modest improvement in left ventricular function with stem cells, but how best to deliver the cells, which cells to use, and the proper dose of cells have yet to be determined. Additionally, the stem cells may have important paracrine activity that is critical to the healing process. Clearly, stem-cell research will continue, and patients with heart failure may have perhaps the most to gain from successes in the field. The Role of ARBs in the Management of Heart Failure The importance of the RAAS in cardiovascular disease is undoubted. Although angiotensin-converting enzyme (ACE) inhibitors are now a staple for the treatment of cardiovascular risk factors, hypertension, and heart failure, intolerance due to incessant coughing can be a serious drawback. The development of ARBs occurred with the concept that they should be more effective than ACE inhibitors, as they directly block the angiotensin II receptor rather than simply reducing the putative ligand, angiotensin II. In fact, nearly all comparison studies indicate that ARBs are just as safe and effective as ACE inhibitors but are generally better tolerated. Dr. Stacie Luther of the University of Colorado Health Sciences Center in Denver discusses the current role of ARBs based on recent clinical trials. It is now quite clear that ARBs are excellent second-line therapy for patients who are unable to tolerate ACE inhibitors. Most of the data with ARBs are derived from clinical trials using candesartan and valsartan. More controversial is the concept of adding an ARB to an ACE inhibitor in patients whose symptoms persist despite concurrent ACE inhibitor therapy. Data suggest a favorable effect of adding candesartan to an ACE inhibitor in such patients, but some physicians might prefer to add an aldosterone-receptor blocker. There are a few data available on the safety of using an ACE inhibitor, ARB, and aldosterone-receptor blocker together; however, more hyperkalemia, renal insufficiency, and hypotension would be expected. Heart Failure Following Acute Myocardial Infarction Patients who survive an acute myocardial infarction complicated by heart failure have a substantial 90-day mortality regardless of how they are managed. However, ACE inhibitors, ARBs, and eplerenone (an aldosterone-receptor blocker) reduce mortality in this high-risk group, especially if these agents are begun early and are well tolerated. These important issues are discussed by Dr. Kimberly Dulaney of the University of North Carolina School of Medicine in Chapel Hill. All three classes of drugs seem to prevent progressive remodeling, which may be the key element driving improvement in mortality in patients following acute myocardial infarction. There seems to be little evidence to support adding an ARB to an ACE inhibitor in such patients, but the combination of an ACE inhibitor or ARB, β-adrenergic blocker, and eplerenone is seemingly safe and effective. The earlier eplerenone is added, the more benefit seems to be derived. Of course, antiplatelet therapy, statins, and, in some cases, myocardial revascularization are also used to maximize treatment. Patients with acute myocardial infarction and heart failure have a poor short-term, midterm, and long-term prognosis. Such patients need to be aggressively treated, as outlined by Dr. Dulaney. With aggressive therapy, there is a real opportunity to save lives in this setting. 4

7 Heart Failure 2005: The Latest, Greatest, and Best for Our Patients Michael G. Dickinson, MD Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio Despite growing awareness of the causes of heart failure and efforts to prevent it, the incidence of heart failure has not declined and, in fact, is increasing. Pathologic changes associated with heart failure include a complex interaction among physical, neurohormonal, and genetic factors that lead to adverse changes in the heart at the structural, tissue, and molecular levels. Drug therapy has progressed to wide use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers, and various combinations of these drugs. A review of the clinical trial data reveals optimal management patterns for patients of different racial backgrounds or those who have had a recent myocardial infarction. More recent progress includes implantation of mechanical devices in conjunction with drug therapy. National guidelines have classified heart failure patients and emphasized their need to be screened for risk factors to prevent serious pathology; results of a hospital-focused, national performance improvement initiative provide information on treatment and outcome trends and the implementation of heart failure guidelines by medical facilities. C urrently, there are about 970,000 hospitalizations for heart failure annually, and some 550,000 of these cases represent newly diagnosed patients. 1 According to a recent longitudinal analysis in Olmstead County, Minnesota, the incidence of heart failure has not declined over the past 20 years, although survival has improved over this same period. 2 Given the documented aging of the US population, the number of patients being treated for heart failure will increase significantly over the next two decades. It is essential that we, as Dr. Dickinson is a Heart Failure individual clinicians and Transplant and as a society, Medicine continue to develop Fellow at The Cleveland mechanisms to ensure optimal treat- Clinic Foundation, ment for our heart Cleveland, Ohio. failure patients. At the recent Ninth Annual Heart Failure Society of America (HFSA) meeting in Boca Raton, Florida, a satellite symposium entitled From New Guidelines to Clinical Practice: OPTIMIZING the Management of Heart Failure summarized the latest concepts in heart failure and heart failure management. The session included presentations by Gregg C. Fonarow, MD, Professor of Medicine and Director of the Ahmanson UCLA Cardiomyopathy Center at the David Geffen School of Medicine in Los Angeles, California; Barry H. Greenberg, MD, Professor of Medicine and Director of the Heart Failure/Cardiac Transplant Medicine Program at the University of California, San Diego, School of Medicine; Wendy Gattis Stough, PharmD, Assistant Consulting Professor of Medicine at Duke Clinical Research Institute, Durham, North Carolina; and Clyde W. Yancy, MD, Associate Professor of Internal Medicine, Division of Cardiology, at UT Southwestern Medical Center, Dallas, Texas. 3 6 This report will cover many of the key concepts presented at that symposium, as well as some updates from the recent literature. Another Paradigm Shift: The Remodeling or Biomechanical Model of Heart Failure The introduction of the neurohormonal model of heart failure in the 1980s was a significant paradigm shift from the previous hemodynamic model. Pharmacologic therapy graduated from digoxin and inotropic agents to angiotensin-converting enzyme (ACE) inhibitors and β-blockers, resulting in significantly improved mortality and long-term outcomes. 7 Recently, however, we may have reached the maximal benefit obtainable from neurohormonal therapy. Several newer neurohormonal modulators (for example, the endothelin antagonists 8,9 and tumor necrosis factor-α 5

8 Michael G. Dickinson, MD inhibitors 10,11 ) have failed to show clinical benefit. Further, mortality and morbidity reductions have been observed with mechanical therapies, such as biventricular pacemakers or ventricular assist devices, leading to the developing concept of mixed pharmacologic and mechanical therapies. Finding a Solution for Heart Failure Heart failure is characterized by progressive changes in structure and tissue architecture. Therapies are available today that can prevent or even reverse these abnormalities. For example, SOLVD (Studies Of Left Ventricular Dysfunction) 12 showed that use of enalapril, an ACE inhibitor, prevented progressive left ventricular dilatation. The Val-HeFT (Valsartan Heart Failure Trial) investigators found that treatment using the angiotensin II receptor blocker (ARB) valsartan decreased left ventricular dimensions and increased ejection fractions. 13,14 Further, the degree of adverse remodeling predicted clinical outcome. More dramatically, the use of β-blockers in heart failure patients has been shown to reverse left ventricular dilatation and improve ejection fraction when added to standard therapy, including ACE inhibitors. 15,16 This so-called reverse remodeling is also associated with significantly improved long-term outcomes. In addition, newer mechanical treatments for heart failure have led to improved remodeling. Studies of patients managed with left ventricular assist devices have demonstrated reversal of pathologic abnormalities at the structural, tissue, and molecular levels Further, cardiac resynchronization therapy (CRT) can significantly reduce ventricular size and improve ventricular function. 22,23 A Model for Explaining Heart Failure These observations have led to the development of a remodeling, or biomechanical, model of heart failure This model, depicted in Figure 1, suggests that the pathologic changes in heart failure encompass a complex interaction between physical, neurohormonal, and genetic factors that characterize the heart failure syndrome. At the structural level, adverse remodeling is characterized by the triad of progressive left ventricular dilatation, reduction in ejection fraction, and transition from an elliptical to a more spherical shape of the ventricle. At the tissue level, myocyte hypertrophy, apoptosis, and interstitial fibrosis herald the remodeling process. Finally, at the molecular or genetic level, remodeling is characterized by increased expression of fetal gene programming, including increases in c-fos, c-jun, c-myc, and other fetal messenger RNAs. This adverse remodeling is associated with adverse clinical outcomes, including symptoms of Figure 1 Remodeling, or biomechanical, model of heart failure. (and hospitalizations for) heart failure and arrhythmia and, ultimately, death. The currently held view is that multiple triggers cause adverse remodeling and, in turn, adverse clinical outcomes. Thus, both the triggers and the adverse remodeling they cause represent potential targets for therapy, and the impact of a therapy on remodeling can serve as a surrogate marker for future outcomes on the assumption that improved remodeling leads to improved outcomes. Putting Theory into Practice How are these concepts being carried into clinical practice? First, physicians are reemphasizing the importance of combining ACE inhibitors and β-blockers in preventing and reversing adverse remodeling. Importantly, prevention of progression of remodeling has been associated with ACE inhibitor therapy but reversal of remodeling has been recognized only after β-blockers were added to standard therapy. 12,15 Clinicians increasingly are recognizing the importance of adding a β-blocker to ACE inhibitor therapy early in the course of therapy. Further, as will be discussed in the following section, ARBs are playing a progressively more important role as alternatives to ACE inhibitors in treating heart failure. Second, CRT imparts a significant benefit in remodeling. 22,23 Recently, the degree of reverse remodeling, but not of improvement of symptoms, has been shown 6

9 Heart Failure 2005 to predict the mortality benefit from CRT. 29 CRT may have benefits early in the course of heart failure. For example, in the MIRACLE-ICD II (Multicenter InSync RAndomized CLinical Evaluation of Implantable Cardioverter Defibrillators II) trial, CRT given to patients with mild (New York Heart Association [NYHA] class II) heart failure resulted in reverse remodeling, as well as improvement in their ventilatory response to exercise, which is another marker that correlates with heart failure outcome. 30 Thus, further investigation is needed to explore the potential benefits of CRT in patients with less symptomatic heart failure, since the beneficial effects on remodeling may predict clinical benefits that would be evident if clinical trials were to follow patients for a longer time. Third, various mechanical and surgical therapies are being developed to reduce ventricular size or induce mechanical constraint. Such devices include the ACORN CorCap device (Acorn Cardiovascular, St. Paul, Minn) and the Myosplint (Myocor Inc, Maple Grove, Minn). 31 In addition, the STICH (Surgical Treatment for IschemiC Heart Failure) trial is a large-scale research project that is exploring a surgical approach to remodeling in heart failure. 32 The Importance of Prevention Despite significant improvements in managing cardiovascular disease and, specifically, coronary artery disease, the prevalence of heart failure has not declined. 2 More emphasis must be placed on preventing the development of symptomatic heart disease. In the 2001 revision of the joint American College of Cardiology/American Heart Association (ACC/AHA) guidelines for chronic heart failure, 33 a new staging system for heart failure that focused on the importance of preventing cardiovascular disease was introduced; it included a stage A to denote patients at risk for heart failure and a stage B to denote patients with asymptomatic left ventricular dysfunction. More recently, the ACC/AHA guidelines were revised. 34 The new guidelines reiterated this classification for heart failure and recognized that stage A and stage B patients need intervention to reduce the risk of developing symptomatic heart disease. The guidelines stipulated that all patients whether they belong to stage A, B, C, or D need to be screened for such cardiac risk factors as hypertension, diabetes, obesity, smoking, inactivity, and excessive alcohol intake and that definite actions need to be taken to modify these risk factors as soon as possible. The revised guidelines also expand the role of ACE inhibitors, ARBs, and β-blockers especially in stage B patients. The important changes reflected in this revision are summarized in Table Based on overwhelming data showing the benefit of ACE inhibitors in chronic heart failure and in the postmyocardial infarction setting, the indications have been expanded to include almost all cardiovascular Table 1 Changes in Indications for ACE Inhibitors, ARBs, and Beta-Blockers in Heart Failure Patients ACE-inhibitor recommendations ARB recommendations Beta-blocker recommendations All patients with reduced LVEF (even ACE-inhibitor intolerant: all patients All patients with reduced LVEF (even if there is no history of heart failure) with heart failure or reduced LVEF who if there is no history of heart failure) can tolerate ARB therapy All patients with a history of MI (even Patients already taking an ARB for other All patients with a history of MI (even if there are no symptoms of heart indications: an ARB is reasonable as an if there are no symptoms of heart failure or reduced LVEF and even if alternative to an ACE inhibitor in mild to failure or reduced LVEF and even if the MI was remote) moderate heart failure the MI was remote) ARB added: an ACE inhibitor plus an ARB can be considered in persistently symptomatic patients with a low LVEF Caveats: Therapy should use one of the three β-blockers proven to reduce mortality: bisoprolol, carvedilol, or sustainedrelease metoprolol succinate Therapy should be initiated in the hospital prior to discharge Chronic obstructive pulmonary disease, peripheral vascular disease, and diabetes mellitus are not contraindications in most patients ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; LVEF = left ventricular ejection fraction; MI = myocardial infarction. Adapted from Hunt et al. 34 7

10 Michael G. Dickinson, MD disease patients, even those without any history of heart failure. The SOLVD prevention trial 37 demonstrated a lower risk of symptomatic heart failure and hospitalization for heart failure among patients with asymptomatic left ventricular dysfunction who were treated with enalapril. The HOPE (Heart Outcomes Prevention Evaluation) trial 42,43 revealed significant reductions in all-cause mortality, cardiovascular mortality, and the development of heart failure in patients with coronary artery disease and a normal ejection fraction with the use of ramipril. EUROPA (EUropean Trial on Reduction Of Cardiac Events with Perindopril in Stable Coronary Artery Disease) 44 also demonstrated reductions in mortality and cardiovascular events with use of perindopril in a similar, but even lower risk, population. For this reason, ACE inhibitors are now recommended for any patient who has a history of either myocardial infarction or reduced ejection fraction. The class I indications for β-blockers also have been expanded based on the overwhelming evidence for the benefits of use of this drug class in heart failure. In the post-myocardial infarction setting, β-blockers reduce mortality (23%), sudden cardiac death (30%), and nonfatal reinfarction (26%). 45 Five separate studies CAPRICORN (CArvedilol Post-InfaRct SurvIval COntRol in Left Ventricular DysfunctioN) study, 46 COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) trial, 47 CIBIS-II (Cardiac Insufficiency BIsoprolol Study II), 48 MERIT-HF (MEtoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure), 49 and the US Carvedilol Heart Failure Study 50 demonstrated a significant mortality benefit in heart failure, with reductions between 23% and 65% in all-cause mortality. Simply stated, β-blockers are recommended to all patients who have had a myocardial infarction (regardless of left ventricular ejection fraction or symptoms) and to all patients who have a decreased ejection fraction (regardless of history of myocardial infarction or symptoms). In the setting of heart failure, there is concern that not all β-blockers are alike. BEST (Beta-Blocker Evaluation of Survival Trial) 51 investigated the benefit of the β-blocker bucindolol in patients diagnosed with heart failure. The study was terminated early when the initial results did not demonstrate the benefit observed in other β-blocker trials. In COMET (Carvedilol Or Metoprolol European Trial), 52 the short-acting β-blocker metoprolol tartrate did not perform as well as did carvedilol, leading to the impression that not all β-blockers are equivalent in efficacy against heart failure. For this reason, the revised ACC/AHA guidelines recommend that one of the three β-blockers that have shown a mortality benefit in heart failure (bisoprolol, carvedilol, or sustained-release metoprolol succinate) should be used. The guidelines have also expanded the role of ARBs in the management of heart failure. Three separate randomized clinical trials VALIANT (VALsartan In Acute Myocardial INfarcTion), 53 Val-HeFT, 54 and CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) have proven the value of these medications in heart failure. Valsartan was as effective as captopril in the VALIANT trial. 53 The CHARM-Alternative trial demonstrated that candesartan therapy produced a significant benefit over placebo in patients intolerant to ACE inhibitors. 56,58 (Elsewhere in this issue of The Cardiology Report, Dr. Stacie A. Luther discusses the design, results, and clinical implications of the CHARM studies.) Thus, ARBs are firmly established as acceptable alternatives to ACE inhibitors in patients who are unable to tolerate ACE inhibitor therapy. In patients who are already being treated with an ARB for another reason, there is enough evidence to continue an ARB as initial therapy in patients who have mild to moderate symptoms of heart failure. The Val-HeFT investigators demonstrated a 13% reduction in the combined endpoint of morbidity and mortality (due largely to a 24% decrease in hospitalizations for worsening heart failure) among patients using valsartan, compared with placebo, in addition to standard therapy for heart failure. Moreover, among the population of patients who were not receiving an ACE inhibitor, treatment with valsartan resulted in a 44% reduction in combined morbidity and mortality and a 33% lower risk of death, compared with placebo. 54 Similarly, the results of the CHARM-Added trial showed a 16% reduction in cardiovascular mortality and a 15% reduction in the combined endpoint of cardiovascular mortality or hospitalization for heart failure when candesartan was added to standard therapy. 57 Either valsartan or candesartan, therefore, can be considered effective alternatives to ACE inhibitors when added to standard therapy for patients with persistent heart failure symptoms. The Right Drug for the Right Patient: How Important Is Race? A-HeFT (African-American Heart Failure Trial) was a double-blind, placebo-controlled study that examined the efficacy and safety of combined hydralazine/isosorbide dinitrate therapy in African-American patients with heart failure. The trial was halted in July 2004 after a significant survival benefit, among other endpoints, was shown in patients taking the drug raising the question of whether race or other factors ought to impact our selection of treatment for individual patients. 6 Several reports have suggested that not all patients 8

11 Heart Failure 2005 Table 2 Possible Differences in African-Americans with Heart Failure More likely to have a history of hypertension Less likely to have an ischemic etiology of heart failure More responsive to hydralazine/isosorbide dinitrate Less responsive to ACE inhibition (?) Less responsive to β-blockers (except carvedilol) Evidence of higher degree of nitric oxide-dependent endothelial dysfunction Younger (on average) Higher blood pressure (on average) Higher mortality (1.8 higher for men, 2.4 higher for women) Higher rates of hospitalization ACE = angiotensin-converting enzyme Adapted from Exner et al 59 and Dries et al. 60 benefit from heart failure therapies to a similar extent. Table 2 summarizes some of the differences that have been observed between African-American and non African- American patients with heart failure Results from V-HeFT More Differences in Racial Response Found V-HeFT (Vasodilator-Heart Failure Trial) 62 compared combined hydralazine/isosorbide dinitrate therapy with prazosin or placebo in patients of different races. Those patients who had been randomized to treatment with hydralazine/isosorbide dinitrate showed a reduction in 2-year mortality. A subsequent review of the data from that trial and V-HeFT II demonstrated a difference in clinical response in African-American patients versus non African-American patients. 63 In V-HeFT I, the African-American patients had a significant reduction in mortality from treatment with hydralazine/isosorbide dinitrate, but the non African-American patients did not exhibit any such benefit. In fact, most of the benefit observed in the overall V-HeFT results was related to the benefit observed in the African-American subgroup. Conversely, in V-HeFT II (which compared hydralazine/ isosorbide dinitrate with enalapril), only non African- American patients benefited from enalapril, and African- American patients did not, as a group, derive any benefit from enalapril. An ethnically based reexamination of the SOLVD data likewise revealed a differential effect of racial background, with non African-American patients having a significant 44% reduction in heart failure hospitalizations from treatment with enalapril and African- American patients showing no significant benefit. 59 The issue is not completely clear, however. Another study attempted to pool the ACE inhibitor data from multiple studies and suggested that there was no difference in response to ACE inhibitor therapy among African-American patients with heart failure, compared with non African-Americans. 63 This conclusion may reflect the fact that skin color is not the ideal marker for describing a heart failure phenotype. Further, they were all subgroup analyses; thus, it would be premature to conclude that all African-American patients do not benefit from ACE inhibitors. African-American patients also seem to have some differences in response to β-blockers. A comprehensive review of the impact of race on heart failure treatment showed an overall lack of benefit from β-blockers in African-American patients (when the results of the BEST trial were included in the analysis), 63 with the strongest effect noted with carvedilol use. An analysis of the racial subgroups in the US Carvedilol Heart Failure Study 64 confirmed that both African-American patients and non African-American patients obtained significant benefit from treatment with carvedilol, suggesting that this particular β-blocker may be a better choice for African-American patients. Why the Racial Differences? Some interesting early data suggest that a possible genetic variation in the β 1 -adrenergic receptor may result in altered adrenergic responses 65 and that such altered responses are more common in African-American patients. 66 Abnormal endothelial function has been demonstrated in normotensive African-American patients via independent pathways that share an end pathway of nitric oxide stimulation. 67 Thus, it is possible that oxidative stress and nitric oxide dysfunction play a larger role in the heart failure syndrome among African-American patients than among non African-Americans. If this is true, nitrates that increase nitric oxide concentrations would appear to be a reasonable treatment for heart failure. There is also evidence that chronic nitrate treatment increases the formation of reactive oxygen species (peroxynitrites). 68 Hydralazine can inhibit the formation of reactive oxygen species; thus, combination therapy with hydralazine and a nitrate may be beneficial. This suggestion led to A-HeFT. A-HeFT randomized 1,050 patients who identified themselves as being black (ie, of African descent) and who had NYHA class III/IV heart failure symptoms and systolic dysfunction to standard care versus standard care plus a combination of oral hydralazine and isosorbide dinitrate. The study was terminated early because of a 9

12 Michael G. Dickinson, MD significant reduction in all endpoints, including a 43% reduction in all-cause mortality, a 33% reduction in the rate of heart failure hospitalization, and a significant improvement in quality-of-life scores. In a fascinating subsequent analysis of the A-HeFT data, the investigators noted that patients with a genetic variant of the nitric oxide synthase gene (NOS3) were the patients who primarily benefited from treatment. 69 Interestingly, this genetic variant was present in almost 80% of the patients in the A-HeFT trial. The results of this trial suggest that not all patients will benefit from heart failure therapy to the same degree. In the case of A-HeFT, race was used to define a population more likely to benefit from hydralazine/isosorbide dinitrate but race may not be the best marker, since it represents a genetically heterogeneous group. In fact, the NOS3 genetic variant recently was found in a study population that was almost 90% Caucasian. 70 Targeting Therapy to the Correct Population Perhaps a better way to consider the issue is in relation to several groupings or phenotypes of heart failure patients who will respond better to a specific therapy. The phenotypes may best be defined by observing, among other factors: clinical parameters (eg, ischemic heart disease, hypertension, diabetes, viral cardiomyopathy, etc); hemodynamic parameters (eg, persistent relative hypertension despite normally adequate ACE inhibitor and β-blocker therapy); hemodynamic responses to therapy (eg, an acute fall in blood pressure after starting therapy); and clinical responses to therapy (eg, progressive remodeling despite usual care). Other factors that may help to define the phenotype may include race, sex, and age. The precise details of how these phenotypes will be discovered and defined remain to be determined. However, this task should be the focus of attention and research in the future. Finally, certain genotypes may assist in this process; however, the number of genetic variations may prove limiting. Beyond Pharmacology: Integrated Pharmacologic, Electrical, and Mechanical Therapies The new chronic heart failure management guidelines include information on the use of electrical therapies, such as CRT and implantable cardioverter-defibrillators. 34 In addition, these guidelines describe the possible use of additional neurohormonal or vasodilatory medications, referred to as the third drug beyond ACE inhibitors and β-blockers. Options for the third drug include aldosterone antagonists, ARBs (added to ACE inhibitor therapy), and, possibly, the fixed-dose hydralazine/isosorbide dinitrate combination. With the myriad choices available to the heart failure clinician, these additional therapies no longer can be considered something just to tack on to baseline treatments. Instead, they must be viewed as a part of our comprehensive treatment plan for our patients. The heart failure clinician should be a choreographer of the short- and long-term management plan for each individual patient. This role necessitates an understanding of medications or interventions to be used immediately and knowledge of what other therapies could be added and when these additions should occur-. A suggested approach is depicted in Figure 2, which summarizes the chronic heart failure management guidelines, 34 current reimbursement guidelines, 71 and current thought. 3 6 One of the key debates yet to be resolved is which third neurohormonal medication or therapy to institute in the patient with persistent symptoms. Unfortunately, head-to-head trials of such therapies have not been done. Certainly, there is hope that markers for distinct genotypes or phenotypes will be developed to predict which patients are more likely to benefit from one therapy over another. In the absence of head-to-head randomized control trial data, a few guidelines can be considered. First, the post-myocardial infarction period is one of intense remodeling; this includes interstitial fibrosis even in myocardium that is not involved in the infarction Strong evidence exists for the antifibrotic effects of spironolactone and eplerenone. 73,75 Eplerenone use produced significant reductions in mortality and improved outcomes in EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and SUrvival Study). 76 It is important, therefore, to initiate aldosterone blockade early in post-infarct management, after starting ACE inhibitors and β-blockers. Second, only candesartan has been tested and observed to have benefit when added to ACE inhibitor and β- blocker therapy in less-ill chronic heart failure patients who fall into NYHA functional class II. 57 Third, in the severely ill patient, any of the agents could be used justifiably. RALES (Randomized Aldactone Evaluation Study), 77 which was done before the β-blocker era of heart failure therapy, exhibited a remarkable 30% reduction of mortality in treated patients. Thus, the addition of spironolactone is reasonable in patients who are NYHA class III/IV and β-blocker intolerant. Finally, in patients who describe themselves as African-Americans, especially those with a strong history of hypertension, combination hydralazine/isosorbide dinitrate therapy should be considered as the next-best 10

13 Heart Failure 2005 Figure 2 Suggested management of chronic heart failure. ACE = angiotensin-converting enzyme; A-HeFT = African-American Heart Failure Trial; ARB = angiotensin II receptor blocker; CABG = coronary artery bypass grafting; CHARM = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; ICD = implantable cardioverter defi brillator; NIDCM = nonischemic dilated cardiomyopathy; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; RALES = Randomized Aldactone Evaluation Study. Adapted from Fonarow, 3 Greenberg, 4 Stough, 5 Yancy, 6 Hunt et al, 34 and the Centers for Medicare & Medicaid Services

14 Michael G. Dickinson, MD agent. However, in spite of the promising A-HeFT data, it is important to initiate this combination only against a background of standard therapy. Improving Heart Failure Care: OPTIMIZE-HF Although clear evidence-based guidelines on managing heart failure have been issued, their implementation has been poor. The Joint Commission on Accreditation of Healthcare Organizations ( JCAHO) has established the following indicators of quality of care for heart failure 78 : adequate discharge instructions, including advice to record daily weights, follow a sodium-restricted diet (eg, 2 g/d), prescribe activity, plan action if symptoms worsen, make a follow-up appointment, and keep a list of medications; assessment of left ventricular function; ACE inhibitor prescription at discharge for appropriate patients; and smoking cessation advice/counseling. Previous reports have described the use of lifesaving heart failure therapies as disappointing. In fact, the ADHERE (Acute Decompensated HEart Failure REgistry) study observed poor compliance with these JCAHO indicators; just 29% of participating patients had complete discharge instructions, and just 36% received smoking cessation advice. 79 An international survey observed disappointing rates of ACE inhibitor (60%) and β-blocker use (34%) in patients with stage C symptomatic heart failure due to systolic dysfunction. 80 Further, a recent review of treatment of heart failure in Canada observed that the patients most likely to benefit from such therapies are least likely to receive them. 81 The key to improving patient management may be to initiate treatment during hospitalization, which represents a teachable moment. Members of multiple disciplines, including nurses, pharmacists, social workers, nutritionists, and physical therapists, may help to design an appropriate management scheme and educate the hospitalized patient. Predictably, the quality of hospital care influences the risk of early mortality and heart failure rehospitalization, with the risk for early readmission increasing 55% with inpatient care of relatively low quality. 82,83 Thus, improved management of hospitalized patients may be helpful in improving heart failure care. Initiatives to Improve Heart Failure Outcomes OPTIMIZE-HF (Organized Program To Initiate Life-Saving TreatMent In HospitaliZEd Patients with Heart Failure) 84 is a hospital-focused, national performance improvement initiative that hoped to address these problems with three specific goals: to improve the medical care and education of patients hospitalized for heart failure; to accelerate the initiation of evidence-based heart failure therapies by starting these therapies prior to discharge from the hospital; and to increase understanding of the use of guidelinerecommended therapies and of barriers to the use of these therapies through establishment of a World Wide Webbased registry (the OPTIMIZE-HF database). The project involved 259 hospitals, including academic, nonacademic, small, and large facilities. The patients represented in the database included individuals who were much older, with more women, and had many comorbid medical conditions that normally would have restricted them from participation in clinical trials. In addition, patients with both systolic dysfunction and heart failure with preserved systolic function were included in the database. Thus, the institutions and patients involved in OPTIMIZE-HF represented a real world setting that more closely reflected the average care received by heart failure patients in the United States. Quality improvement in the OPTIMIZE-HF project included the concept of cycles of quality improvement. Hospitals initially would submit their data to the registry, monitor their progress via a Web-based system, and compare their performance with national benchmarks. This process would lead the facilities to initiate processes to improve their results on the key indicators. Indeed, such improvements were observed, with appropriate discharge instructions being given to 66% of patients in late 2004, as compared with 47% who received such instructions in early Patients had a fairly high level of recommended therapies at hospital discharge, with 84% of patients being placed on an ACE inhibitor or ARB and 83% of patients, on a β-blocker. The OPTIMIZE-HF database also provides an opportunity to study the impact of therapy in a real world setting. Many patients in the OPTIMIZE-HF database and those treated for heart failure in the United States have never been studied in any randomized clinical trials; these individuals included patients considered to be too old to participate, women, and patients with diastolic dysfunction or comorbid illnesses. Despite relatively good medical therapy, at 90 days, the researchers noted a remarkable 10% mortality rate and a 30% re-hospitalization rate. Interestingly, patients who were discharged on a β-blocker had a significantly lower mortality rate (6.6% vs 13.3%) and incidence of rehospitalization. Some interesting conclusions have been culled from the OPTIMIZE-HF experience: A hospital-focused performance improvement initiative can improve patient treatment. Clinicians inti- 12

15 Heart Failure 2005 mately involved in the treatment of heart failure patients must involve their hospitals in such performance-improving endeavors. A hospital-focused program is feasible on a national scale using largely preexisting resources. Patients discharged on β-blockers tolerate this therapy well and have improved outcomes. In spite of this improved management, heart failure poses many challenges, including high rates of mortality and recurrent hospitalization. Conclusion Heart failure will remain a growing concern in the coming years. Fortunately, the dynamic field of heart failure offers several exciting and evolving concepts and tools. The remodeling or biomechanical model of heart failure will help in the understanding of optimal patient management and will direct further research. Instituting preventive measures before systolic dysfunction develops and beginning therapy with an appropriate ARB (valsartan or candesartan) or ACE inhibitor and a β-blocker early in the course of systolic dysfunction hopefully will reduce the percentage of patients who go on to develop significant symptomatic heart failure. For patients who ultimately will develop heart failure, clear guidelines are available to direct the best therapy for them. Clinicians must take an active leadership role in using heart failure hospitalization to the patient s advantage. National performance improvement initiatives, such as OPTIMIZE- HF, already have begun improving such inpatient heart failure care. With the continued growth of these concepts and measures, the latest, greatest, and best care for our heart failure patients truly may be provided. 76 References 1. American Heart Association. Heart Disease and Stroke Statistics 2005 Update. Dallas, Texas: American Heart Association; Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA. 2004;292: Fonarow GC. Closing the treatment gap: impact of hospitalbased HF disease management programs. Presented at the Ninth Annual Scientific Meeting of the Heart Failure Society of America; September 18, 2005; Boca Raton, Fla. 4. Greenberg BH. Optimal medical and device management of HF: what do the 2005 guidelines recommend? Presented at the Ninth Annual Scientific Meeting of the Heart Failure Society of America; September 18, 2005; Boca Raton, Fla. 5. Stough WG. New insights into the characteristics, treatment, and outcomes of patients hospitalized with HF. Presented at the Ninth Annual Scientific Meeting of the Heart Failure Society of America; September 18, 2005; Boca Raton, Fla. 6. Yancy CW. Special populations with HF: what is different? Presented at the Ninth Annual Scientific Meeting of the Heart Failure Society of America; September 18, 2005; Boca Raton, Fla. 7. Francis GS. Neurohumoral activation and progression of heart failure: hypothetical and clinical considerations. J Cardiovasc Pharmacol. 1998;32:S16 S Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol. 2002;85: Teerlink JR. Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail. 2002;8: Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-tnf Therapy Against Congestive Heart Failure (ATTACH) trial. Anti-TNF Therapy Against Congestive Heart Failure Investigators. Circulation. 2003;107: Coletta AP, Clark AL, Banarjee P, Cleland JG. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and AT- TACH. Eur J Heart Fail. 2002;4: Greenberg B, Quinones MA, Koilpillai C, et al. Effects of longterm enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction: results of the SOLVD echocardiography substudy. Circulation. 1995;91: Wong M, Staszewsky L, Latini R, et al. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002;40: Wong M, Staszewsky L, Latini R, et al. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan Heart Failure Trial (Val-HeFT) echocardiographic data. J Am Coll Cardiol. 2004;43: Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997;29: Doughty RN, Whalley GA, Walsh HA, Gamble GD, Lopez- Sendon J, Sharpe N. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation. 2004;109: Zafeiridis A, Jeevanandam V, Houser SR, Margulies KB. Regression of cellular hypertrophy after left ventricular assist device support. Circulation. 1998;98: Heerdt PM, Holmes JW, Cai B, et al. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000;102: Margulies KB. Reversal mechanisms of left ventricular remodeling: lessons from left ventricular assist device experiments. J Card Fail. 2002;8:S500 S Chen Y, Park S, Li Y, et al. Alterations of gene expression in failing myocardium following left ventricular assist device support. Physiol Genomics. 2003;14: Kucuker SA, Stetson SJ, Becker KA, et al. Evidence of improved right ventricular structure after LVAD support in patients with end-stage cardiomyopathy. J Heart Lung Transplant. 2004;23: Woo GW, Petersen-Stejskal S, Johnson JW, Conti JB, Aranda JA, Jr, Curtis AB. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of the MIRACLE study. J Interv Card Electrophysiol. 2005;12: St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation. 2003;107: McDonald KM, Carlyle PF, Matthews J, et al. Early ventricular remodeling after myocardial damage and its attenuation by converting enzyme inhibition. Trans Assoc Am Physicians. 1990;103:

16 Michael G. Dickinson, MD 25. Francis GS, McDonald KM, Cohn JN. Neurohumoral activation in preclinical heart failure: remodeling and the potential for intervention. Circulation. 1993;87:IV90 IV Cohn JN. Structural basis for heart failure: ventricular remodeling and its pharmacological inhibition. Circulation. 1995;91: Cohn JN, Ferrari R, Sharpe N, on behalf of an International Forum on Cardiac Remodeling. Cardiac remodeling concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol. 2000;35: Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation. 2005;111: Yu CM, Bleeker GB, Fung JW, et al. Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy. Circulation. 2005;112: Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110: Schenk S, Reichenspurner H. Ventricular reshaping with devices. Heart Surg Forum. 2003;6: Doenst T, Velazquez EJ, Beyersdorf F, et al. To STICH or not to STICH: we know the answer, but do we understand the question? J Thorac Cardiovasc Surg. 2005;129: Hunt SA, Baker DW, Chin MH, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001;104: Hunt SA, American College of Cardiology, American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol ;46:e1 e The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316: The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325: The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327: The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342: Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. N Engl J Med. 1995;332: Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327: Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333: Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342: Arnold JM, Yusuf S, Young J, et al. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003;107: Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339: Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRI- CORN randomised trial. Lancet. 2001;357: Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353: Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334: Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344: Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003;362: Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349: Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. Valsartan Heart Failure Trial Investigators. N Engl J Med. 2001;345: Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362: Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362: McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362: Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362: Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as com- 14

17 Heart Failure 2005 pared with white patients with left ventricular dysfunction. N Engl J Med. 2001;344: Dries DL, Exner DV, Gersh BJ, Cooper HA, Carson PE, Domanski MJ. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med. 1999;340: Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314: Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5: Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol. 2003;41: Yancy CW, Fowler MB, Colucci WS, et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med. 2001;344: Mason DA, Moore JD, Green SA, Liggett SB. A gain-offunction polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999;274: Lang CC, Stein CM, Brown RM, et al. Attenuation of isoproterenol-mediated vasodilatation in blacks. N Engl J Med. 1995;333: Stein CM, Lang CC, Nelson R, Brown M, Wood AJ. Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther. 1997;62: Hink U, Oelze M, Kolb P, et al. Role for peroxynitrite in the inhibition of prostacyclin synthase in nitrate tolerance. J Am Coll Cardiol. 2003;42: McNamara DM TS, Sabolinski ML, et al. The genetic riskassessment substudy of the African-American Heart Failure Trial (A- HeFT): impact of genetic variation of NOS3. Presented at the Ninth Annual Scientific Meeting of the Heart Failure Society of America; September 21, 2005; Boca Raton, Florida. 70. McNamara DM, Holubkov R, Postava L, et al. Effect of the ASP298 variant of endothelial nitric oxide synthase on survival for patients with congestive heart failure. Circulation. 2005;107: Centers for Medicare & Medicaid Services. Summary of coverage for implantable cardioverter defibrillators (ICDs) as of January 27, Available at: Accessed October 10, Katada J, Meguro T, Saito H, et al. Persistent cardiac aldosterone synthesis in angiotensin II type 1A receptor-knockout mice after myocardial infarction. Circulation. 2005;111: Hayashi M. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. J Cardiol. 2004;43: Hayashi M, Tsutamoto T, Wada A, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation. 2003;107: Enomoto S, Yoshiyama M, Omura T, et al. Effects of eplerenone on transcriptional factors and mrna expression related to cardiac remodelling after myocardial infarction. Heart. 2005;91: Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348: Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341: Joint Commission on Accreditation of Healthcare Organizations. Specification Manual for National Hospital Quality Measures (2005). Available at: manual.htm. Accessed October 10, Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure quality-of-care indicators in US hospitals: analysis of the AD- HERE Registry. Arch Intern Med. 2005;165: Cleland JG, Cohen-Solal A, Aguilar JC, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet. 2002;360: Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA. 2005;294: Ashton CM, Del Junco DJ, Souchek J, Wray NP, Mansyur CL. The association between the quality of inpatient care and early readmission: a meta-analysis of the evidence. Med Care. 1997;35: Ashton CM, Kuykendall DH, Johnson ML, Wray NP, Wu L. The association between the quality of inpatient care and early readmission. Ann Intern Med. 1995;122: Fonarow GC, Abraham WT, Albert NM, et al. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design. Am Heart J. 2004;148:

18 Chronic and Post-MI Heart Failure: Back to the Future? Suntharo Ly, MD University of Arizona Sarver Heart Center, Tucson Heart failure becomes more common with age and poses a serious morbidity and mortality risk to patients. Results from many clinical trials in heart failure patients have helped direct drug therapy toward management of this complicated condition. Multiple studies have investigated the role of hypertension and myocardial infarction (MI) in dealing with heart failure; hypertensive survivors of MI have a substantially greater risk of developing heart failure than do individuals with normal blood pressure. In addition, an appreciation of the mechanics of the heart and ways to optimize the organ s efficiency broadens understanding of how the challenges of the heart failure patient may be met; use of echocardiography may help diagnose weaknesses in certain areas of the heart and indicate targets for more efficient treatment. Further, the implantation of devices such as implantable cardiac defibrillators and biventricular pacemakers has led to new insights in controlling the devastating effects of heart failure. More recently, researchers have delved into one more promising application for stem cell research how it may impact the treatment of heart failure. H ypertension, advancing age, coronary artery disease, and prior myocardial infarction (MI) are major risk factors for the development of heart failure, a medical condition that becomes more common with age and that poses a serious morbidity and mortality risk to patients. Fortunately, early recognition and treatment of the major heart failure risk factors can prevent or retard disease progression. 1 Recent years have brought a greater understanding of heart failure and its ramifications. Echocardiography can be helpful in diagnosing acute MI and in predicting future cardiac events. 2 The results of numerous heart failure clinical trials have helped to direct drug therapy for heart failure and to provide a glimpse into how stemcell research may impact patient management. However, there are other options for treatment of heart failure, including implantation of such therapeutic devices as implantable cardiac defibrillators (ICDs) and the use of chronic resynchronization therapy (CRT). At a recent symposium held at the Ninth Annual Scientific Meeting of the Heart Failure Society of America in Boca Raton, Florida, leading heart failure experts presented evidence about the significance of hypertension that presents before an MI or that occurs in a heart failure patient after an MI, the use of echocardiography in post-mi patients, findings from heart failure and post-mi trials, and new therapeutic options for managing patients diagnosed with heart failure complicated by other medical problems. Hypertension and Heart Failure: A Love-Hate Relationship Adapted from a presentation by Marc Pfeffer, MD, PhD, Program Chair, and Professor of Medicine, Harvard Medical School, Cardiovascular Division, Brigham and Women s Hospital, Boston, Massachusetts. Hypertension is a major risk factor for stroke, renal dysfunction, coronary artery disease, heart failure, and cardiovascular mortality. 1 About million adults in the United States approximately 25% of the nation s population is hypertensive. 3 Unfortunately, as the US population ages, this number is expected to increase, since more than half of persons over 65 years of age have high blood pressure. 4 The seventh report of the Joint National Committee Dr. Ly is a Cardiology Fellow at the University of Arizona Sarver Heart Center, Tucson. on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ( JNC 7) 5 defines a normal blood pressure as being under 120/80 mm Hg; should these numbers rise, the patient is considered to have prehypertension or hypertension (Table 1). Cardiovascular risk begins at a blood pressure of 115/75 mm Hg and doubles for each 20/10 mm Hg increment detected. 6,7 16

19 Chronic and Post-MI Heart Failure Table 1 Classification and Management of Blood Pressure in Adults Initial drug therapy Blood pressure SBP,* DBP,* Lifestyle Without compelling With compelling classification mm Hg mm Hg modification indications indications Normal < 120 and < 80 Encourage No antihypertensive Drug(s) for compelling drug indicated indications Prehypertension or Yes No antihypertensive Drug(s) for compelling drug indicated indications Stage or Yes Thiazide-type Drug(s) for compelling hypertension diuretics for most; indications ; other may consider ACE antihypertensive drugs inhibitor, ARB, BB, (diuretic, ACE inhibitor, or combination ARB, BB, or CCB) as needed Stage or 100 Yes Two-drug combination Same as for stage 1 hypertension for most (usually a hypertension thiazide-type diuretic and ACE inhibitor or ARB or BB or CCB) ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; BB = β-blocker; CCB = calcium channel blocker; DBP = diastolic blood pressure; SBP = systolic blood pressure * Treatment determined by highest blood pressure category Treat patients with chronic kidney disease or diabetes to blood pressure goal of < 130/80 mm Hg. Initial combination therapy should be used cautiously in patients at risk for orthostatic hypotension. Adapted from Chobanian et al. 5 Quantitatively, hypertension is the major risk factor for cardiovascular disease 8 ; it can lead to heart failure in patients at any age and may occur through ischemic and nonischemic pathways related to a structural cardiac abnormality. Hypertensive survivors of MI have a substantially greater risk of developing heart failure than do persons having normal blood pressure. 9 The Impact of LV Hypertrophy Hypertensive patients may have left ventricular (LV) hypertrophy as found on an electrocardiogram (ECG) or echocardiogram. 5 This structural heart anomaly is important, as it is associated with an increased incidence of arrhythmia, decreased LV ejection fraction (LVEF), heart failure, post-mi mortality, and sudden cardiac death. 4 Findings from the Framingham Heart Study, which examined LV mass, LV hypertrophy, and sudden death, showed that LV hypertrophy carried a 2.16 risk factoradjusted hazard ratio for sudden cardiac death; this rose by 1.45 for every 50-g/m increment in LV mass. 6 One reason for this statistic is that hypertrophied myocardium may have a decreased capillary density and a lesser ability to dilate in response to stress. 10,11 Thus, decreased coronary reserve may be responsible for the increased cardiac risk associated with LV hypertrophy. 10,11 In addition, LV hypertrophy causes altered repolarization and easily provoked early afterpotentials, which are associated with a susceptibility to ventricular arrhythmia and sudden death. 12 Moreover, LV hypertrophy is a strong and independent risk factor for the development of heart failure. 13 Getting to the Basics of Heart Failure About 5 million people in the US have heart failure, and over 550,000 cases of this condition are diagnosed each year. 1 Heart failure is the most common diagnosis made among Medicare patients. In fact, according to the American Heart Association s (AHA s) 2005 statistical update, approximately $27.9 billion were spent on patients given this diagnosis last year representing the largest area related to Medicare spending. 1 The American College of Cardiology (ACC)/AHA Practice Guidelines define heart failure as a complex clinical syndrome that may result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood (Figure 1). 14 Risk factors for heart failure include increasing age, obesity, diabetes mellitus, cigarette smoking, valvular heart disease, hypertension, and coronary artery disease. Interestingly, the first National Health and Nutrition Examination 17

20 Suntharo Ly, MD Figure 1 Stages in the development of heart failure and recommended therapy by stage. ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker. Adapted from Hunt et al. 14 Survey (NHANES), which followed over 13,500 patients for 19 years and sought more information about the risk factors for heart failure, found that hypertension carried a relative risk of 1.4, with 10% of the population being at risk, whereas coronary artery disease carried a relative risk of 8.1, with 62% of the population being at risk. 15 Echocardiography in the Post-MI Patient: What Does It Really Tell You? Adapted from a presentation by Scott D. Solomon, MD, Associate Professor of Medicine, Harvard Medical School, Director, Noninvasive Cardiology, Cardiovascular Division, Brigham and Women s Hospital, Boston, Massachusetts. Echocardiography is invaluable for assessing patients presenting to the emergency room with chest pain. This accessible, portable, fast, and noninvasive diagnostic tool may help to differentiate between a pulmonary embolus, aortic dissection, tamponade, pericarditis, or an acute MI. 16 In addition, it can detect regional wall motion abnormalities that occur both before ECG changes can be pinpointed and within seconds of coronary arterial occlusion. 17,18 The 2003 task force of the ACC/AHA/American Society of Echocardiography gave the use of echocardiography a class I recommendation in diagnosing patients suspected of having acute myocardial ischemia or an MI that is not evident by standard means. 2 Echocardiography may be used to detect a regional wall motion abnormality, which is defined as a localized area of decreased myocardial excursion and decreased myocardial thickening due to ischemia, focal myocarditis, prior infarction site, prior surgery, right ventricular volume overload, or left bundle-branch block. 18 Thus, echocardiography features high sensitivity but low 18

21 Chronic and Post-MI Heart Failure specificity for acute coronary syndrome. 16 Echocardiography may also help to detect papillary muscle rupture with acute mitral regurgitation, a factor that may predict an increased risk of cardiovascular mortality. 19 Mitral regurgitation is usually related to compromised blood flow to the posterior descending artery that supplies the posteromedial papillary muscle, resulting in necrosis of the posteromedial papillary muscle. Echocardiography in Predicting the Post-MI Course The echocardiographic subgroup analysis of the HEART (Healing and Early Afterload Reduction Therapy) study examined ventricular function measured by echocardiography at days 1, 14, and 90 after an STelevation MI. Three groups of patients were given variable doses of ramipril for different durations with subsequent reperfusion therapy. Change in LVEF varied widely, with 66% of patients experiencing improvement by day 90; most of the changes were noted during the first 14 days after an ST-elevation MI (Figure 2). Thus, the utility of echocardiography as a predictive tool during the first few days post-mi is limited. In the VALIANT (VALsartan In Acute Myocardial INfarcTion) trial, however, data culled from echocardiography performed on day 5 post MI were equal to information obtained at 1 month for determining longterm prognosis. 20 Functional Data Yield Important Information In addition to providing prognostic information obtained from both systolic and diastolic blood pressure measurements, the left atrial volume index may be used for further risk stratification in predicting mortality post MI. Left atrial volume reflects both the duration and severity of increased left atrial pressure over time and thus reflects chronic changes in the left atrium. On the other hand, an early deceleration time reflects the instantaneous measurement of left atrial pressure or diastolic dysfunction. 21 Thus, post-mi patients with systolic or diastolic dysfunction and increased left atrial volume index have a higher risk of increased mortality when compared with post-mi patients having only systolic and diastolic dysfunction without an increased left atrial volume index. 22 The right ventricle is extremely sensitive to changes in afterload and a major determinant in these changes is left atrial pressure. Because patients who have experienced MI have an increased prevalence of right ventricular dysfunction (50.6%), right ventricular function may be a sensitive integrator of left atrial pressure over time. 23 In the SAVE (Survival And Ventricular Enlargement) echocardiographic substudy, right ventricular fractional Figure 2 Distribution of change in left ventricular ejection fraction from day 1 to day 90. Adapted from Solomon et al. 20 area change (RV FAC), or the percent change in cavity area from end diastole to end systole, was related to clinical outcome. Investigators reported a 16% increased risk of cardiovascular mortality for every 5% decrease in the RV FAC (95% confidence interval [CI], 4.3% 29.2%; P = 0.006). Thus, RV FAC is an independent predictor of poor outcome, including death and heart failure, in patients found to have LV dysfunction after an acute MI. 24 Applying Trial Evidence in Post-MI and Heart Failure: From Trial to Bedside Adapted from a presentation by John J.V. McMurray, MD, Professor of Medical Cardiology and Honorary Consultant Cardiologist, Department of Cardiology, Western Infirmary, Glasgow, United Kingdom. A number of clinical trials have investigated various drugs and devices alone and in combination to save the lives of heart failure patients who have suffered an MI. The following is a summary of important research projects in this patient population with results that translate well to clinical practice. What Are the Benefits of ACE Inhibitors? A systematic overview of three long-term, randomized, double-blind, placebo-controlled trials that sampled over 1,000 patients per study provided information on the usefulness of angiotensin-converting enzyme (ACE) inhibitor therapy in patients who experienced an MI

22 Suntharo Ly, MD These landmark trials SAVE, AIRE (Acute Infarction Ramipril Efficacy), and TRACE (TRAndolapril Cardiac Evaluation) included 5,966 patients showing evidence of LV dysfunction or heart failure. These individuals were assigned randomly to ACE inhibitor therapy or placebo during the 3 16 days following MI (median treatment duration, 31 months). In these trials, patients treated with an ACE inhibitor showed an overall 28% reduction in death and repeated MI and hospitalization for heart failure. Further, ACE inhibitor treatment for an average of 2.5 years produced a mortality reduction of 25% or an absolute reduction of approximately 6%; looked at in another way, the results suggested that 15 patients would need to be treated with an ACE inhibitor for an average of 2.5 years to avoid one death. Patients treated with an ACE inhibitor exhibited a 20% relative reduction in MI rate when compared with those given placebo. Surprisingly, there was no apparent effect on stroke rate. However, the mean blood pressure of patients taking part in all three studies was low (116/72 mm Hg). Investigators also noted that the proportional benefit of ACE inhibitors was unaffected by aspirin use at baseline. Finally, although there was an increase in symptomatic hypotension and renal dysfunction among patients using ACE inhibitors, the benefits of therapy outweighed the risks. 25 Adding a β-blocker to an ACE Inhibitor to Improve Outcome The CAPRICORN (CArvedilol Post-InfaRct SurvIval COntRolled EvaluatioN) trial was a randomized, double-blind, placebo-controlled trial studying the longterm efficacy of carvedilol on morbidity and mortality in post-mi patients with LV dysfunction who already were receiving ACE inhibitors. 26 In all, 1,959 patients with an LVEF 40% were randomized at some point from days 3 21 post MI to placebo or to 6.25 mg of carvedilol twice daily to start and then were titrated up to 25 mg twice daily over 4 6 weeks; therapy continued until the primary endpoint of all-cause mortality or hospital admission for cardiovascular problems was met. No difference in the primary endpoint was found, although those using the β-blocker showed a lower rate of cardiovascular mortality (11% in the carvedilol group vs 14% in the placebo group; P = 0.024), all-cause mortality (12% vs 15%, respectively; P = 0.031), and all-cause mortality or nonfatal MI (14% 26 vs 20%, respectively; P = 0.002). ARB Use in Post-MI Patients with LVSD or Heart Failure An analysis of the VALIANT registry 27 showed that approximately 42% of post-mi patients had left ventricular systolic dysfunction (LVSD) and/or heart failure. Additionally, 83% of all inpatient deaths occurred in this patient population. Thus, post-mi patients with LVSD and/or heart failure are both at high risk and in need of secondary preventive measures. The VALIANT study was a randomized, double-blind trial that compared the effects of valsartan, an angiotensin II receptor blocker (ARB), and/or captopril, an ACE inhibitor, in patients with LVSD or heart failure who had experienced an acute MI. 27 A total of 14,703 patients with an LVEF 35% on echocardiography or 40% on radionuclide ventriculography were randomized immediately after MI to valsartan monotherapy, captopril monotherapy, or valsartan plus captopril; there were approximately 5,000 patients in each group. Patients had a serum creatinine level < 2.5 mg/dl and a systolic blood pressure > 100 mm Hg and may have received an ACE inhibitor or ARB up to 12 hours before randomization. These patients received initial therapy of 20 mg of valsartan twice daily and/or 6.25 mg of captopril three times daily; the team sought to increase valsartan doses to 80 mg twice daily, captopril doses to 25 mg three times daily, or combination doses to 40 mg of valsartan twice daily plus 25 mg of captopril three times daily during the initial hospitalization. If clinically possible at 3 months, investigators tried to increase the dose of valsartan to 160 mg twice daily, of captopril to 50 mg three times daily, or of combination therapy to 80 mg of valsartan twice daily plus 50 mg of captopril three times daily. The primary VALIANT trial endpoint was death from all causes and noninferiority of treatment. During a median follow-up of about 25 months, all-cause mortality and cause-specific mortality were similar for the three treatment groups (10.9% for the valsartan group, 19.5% for the captopril group, and 19.3% for the combination therapy group; P < 0.001). The team reported that 160 mg of valsartan twice daily was as effective as was captopril in improving survival and reducing cardiovascular morbidity. The valsartan group suffered more hypotension and renal dysfunction, whereas the captopril group experienced more cough, rash, and taste disturbances. Thus, although combining valsartan with captopril did not improve survival, 27 valsartan was as effective as captopril in patients at high risk for cardiovascular events following MI. In the CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trials, 7,601 patients with heart failure were enrolled, stratified into one of three arms, and given the ARB candesartan at a titrated goal dose of 32 mg/d. Patients in the CHARM-Added trial had an LVEF 40% when using β-blockers plus an ACE inhibitor, those in the CHARM- Alternative arm had an LVEF 40% and were not on 20

23 Chronic and Post-MI Heart Failure an ACE inhibitor, and those in the CHARM-Preserved arm had a preserved LVEF 40% and were not on an ACE inhibitor. Data from the CHARM-Added and CHARM-Preserved arms showed a significant decline in all-cause mortality among patients given candesartan (28%) as compared with those given placebo (31%; P = 0.018). 28,29 Data from all three arms showed a significant decrease in cardiovascular death and non-fatal MI among the candesartan group as compared with the placebo group (20.4% vs 22.9%; P = 0.004). 30 Results from these trials varied, with some showing little improvement with combination therapy and others showing benefits with use of more than one agent. Whether ARB types or doses significantly affect outcomes remains unclear. Currently, two ARB trials known as ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE INtolerant Subjects with Cardiovascular Disease) are ongoing. 31,32 Adding an Aldosterone Blocker in Severe Heart Failure EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and SUrvival Study) 33 was a randomized, doubleblind, placebo-controlled trial that evaluated the efficacy of eplerenone, a new, selective aldosterone receptor blocker, in patients with acute MI complicated by heart failure and systolic LV dysfunction. At 3 14 days post MI, 3,313 patients were randomized to 25 mg of eplerenone, titrated to 50 mg/d, and 3,319 patients were assigned to placebo added to standard heart failure therapy. The primary endpoints were death from any cause or from cardiovascular causes and hospitalization for heart failure, acute MI, stroke, or ventricular arrhythmia. At a mean follow-up of 16 months, the eplerenone group had fewer deaths when compared with the placebo group (14.4% vs 16.7%, respectively; relative risk [RR], 0.85; P = 0.008). Cardiovascular deaths or hospitalizations also occurred less frequently in the eplerenone group (26.7% vs 30.0%; RR, 0.87; P = 0.002), as did deaths or hospitalizations from any cause (RR, 0.92; P = 0.02). The researchers concluded that adding eplerenone at a maximal dose of 50 mg/d in patients with acute MI complicated by heart failure and LVSD who were on optimal medical therapy (eg, ACE inhibitors or ARBs, β-blockers, aspirin, diuretics) led to a further reduction in overall mortality and mortality from cardiovascular causes or hospitalization and to benefits when the prespecified secondary endpoints were examined. Except for hyperkalemia, no serious additional side effects in the eplerenone arm were noted. In addition, the incidence of gynecomastia and impotence among men in the eplerenone group was not different from that associated with the use of placebo. Although eplerenone reduced coronary vascular inflammation and endothelial dysfunction and attenuated platelet aggregation, the precise mechanism by which eplerenone exerted its cardioprotective effects in patients experiencing acute MI complicated by LVSD and heart failure, however, was not completely clear. 33 Should CHF Therapy Start with an RAAS Inhibitor or a β-blocker? Both ARBs and ACE inhibitors exert their salutary effects in heart failure by inhibiting the renin-angiotensin-aldosterone system (RAAS), albeit through different mechanisms. The question arises whether therapy of chronic heart failure (CHF) should begin with an RAAS inhibitor or a β-blocker. CIBIS (Cardiac Insufficiency BIsoprolol Study) III was a prospective, randomized, open-label, blinded endpoint evaluation trial that investigated whether initiating therapy for CHF patients with a β-blocker was as effective and as safe as starting with an ACE inhibitor. 34 In all, 1,010 patients with mild-to-moderate CHF and an LVEF 35% who were not receiving treatment with an ACE inhibitor, β-blocker, or ARB were randomized to open-label monotherapy; 505 patients received a target bisoprolol dose of 10 mg/d, and 505 others received a target dose of 10 mg/d of enalapril twice daily for 6 months, followed by a combination of the two agents for 6 24 months. The primary endpoint was time to the first event of combined all-cause mortality or all-cause hospitalization throughout the study. The initial use of bisoprolol was not inferior to initial use of enalapril in the intention-to-treat population; the primary endpoint was reached in 178 patients in the bisoprolol-first group, compared with 186 patients in the enalapril-first group (hazard ratio [HR], 0.94; 95% CI, ; P = 0.09). However, in the perprotocol sample, 163 patients in the bisoprolol-first group and 176 in the enalapril-first group reached a primary endpoint (HR, 0.97; 95% CI, ; P = 0.046). The per-protocol analysis did not show initial bisoprolol use to be non-inferior to initial use of enalapril. However, the results came close to proving non-inferiority, indicating that initial CHF treatment using bisoprolol may be as safe and effective as using enalapril. 34 The caveat is that β-blockers are not appropriate for all patients and should not be used as first-line therapy of congestive heart failure in patients with shortness of breath, chronic obstructive pulmonary disease, bradycardia, or diabetes mellitus. As described in a previous section, both VALIANT and the CHARM-Alternative studies demonstrated that valsartan and candesartan, 21

24 Suntharo Ly, MD Figure 3 Effect of medical therapies that affect the natural history of heart failure based on the primary site of action. CRT-(D) = cardiac resynchronization therapy plus defi brillator; ACE = angiotensin-converting enzyme. Adapted from Mann and Bristow. 36 respectively, provide the same benefits, in terms of improving survival and reducing the risk of cardiovascular events and hospitalizations, as do ACE inhibitors in the treatment of CHF and may be better tolerated. Both valsartan and candesartan have recently been approved by the US Food and Drug Administration for the treatment of patients with heart failure, including but not limited to those who cannot tolerate ACE inhibitors. Defibrillator Use in Post-MI Patients Scarred myocardium from a previous MI may trigger ventricular arrhythmia. MADIT (Multicenter Automatic Defibrillator Implantation Trial) II evaluated the potential survival benefit of implanting a prophylactic defibrillator in post-mi patients having an LVEF 30% without the need for electrophysiological testing to induce arrhythmia. 35 In all, 742 patients were given an implantable defibrillator, and 490 subjects received conventional medical therapy. The primary outcome was death from any cause. At an average follow-up of 20 months, mortality was 14.2% in the defibrillator group and 19.8% in the conventional medical therapy group (HR, 0.69; 95% CI, ; P = 0.016). Thus, prophylactic implantation of a defibrillator improved survival in patients with prior MI and an LVEF 30% (Figure 3). 36 New Horizons Drug and Device: Therapeutic Options Adapted from a presentation by Michael R. Bristow, MD, PhD, Co-Director, CU-CVI, Denver, Boulder and Aurora Colorado S. Gilbert Blount Professor of Medicine (Cardiology) University of Colorado HSC Denver and Aurora, Colorado. Our understanding of heart failure over the past several decades has changed, leading to newer pharmacological therapies. In the interest of finding better treatments for the heart failure population, research to identify new drugs continues. Understanding the Mechanism of Heart Failure Heart failure may be viewed as a progressive model in which an index event (pressure overload, volume overload, hereditary MI) occurs and causes a decline in LV function over time. However, decreased LV function alone is insufficient to explain the syndrome of heart failure, because most people diagnosed with the condition are asymptomatic or minimally symptomatic when an initial index event occurs. Compensatory mechanisms (eg, early activation of the adrenergic nervous system and salt and water retention; vasodilatory molecules such as natriuretic peptides, prostaglandins, and nitric oxide) that modulate LV function and allow a delay in functional capacity partially explain the slowing of heart failure symptoms. 37,38 The Role of Norepinephrine Flux Adrenergic activity is an important determinant of outcome in chronic heart failure patients. 39,40 In advanced chronic heart failure, baseline norepinephrine level is a predictor of adverse outcomes but not of therapeutic response. BEST (Beta-Blocker Evaluation of Survival Trial) 41 examined the baseline and serial changes in venous norepinephrine blood levels and clinical outcomes when placebo or bucindolol, a third-generation β-blocker with sympatholytic properties, was given. Compared with placebo, bucindolol therapy decreased norepinephrine levels by 19% at 3 months but was associated with an increased risk of adverse events, particularly sudden death. However, both increases and decreases in norepinephrine levels at 3 months predicted adverse outcomes. Finally, a subset of patients in the bucindolol group had an increased risk of death due to sympatholysis when compared with those receiving placebo (18% vs 1%, respectively). Newer Drug Therapies Newer agents used in heart failure patients include low-dose, type III phosphodiesterase inhibitors that provide inotropic support without exerting proarrhythmic effects, vasopressin receptor antagonists, and antidiuretic hormone (ADH) antagonists. Levosimendan Levosimendan, a new phosphodiesterase inhibitor with calcium-sensitizing properties, increases myocardial contractility by enhancing the sensitivity of myofilaments to calcium without increasing the intracellular calcium concentration at therapeutic doses. Use of this drug has 22

25 Chronic and Post-MI Heart Failure posed a similar risk of cardiac arrhythmia when compared with placebo and has not increased myocardial oxygen demand. 42 In the Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure after an Acute Myocardial Infarct (RUSSLAN), 43 a randomized, placebo-controlled, double-blind trial of 504 post-mi patients with heart failure, µg/kg of levosimendan given intravenously for 6 hours did not induce hypotension or cause myocardial ischemia. A post hoc analysis showed that levosimendan reduced mortality at 14 days compared with placebo (11.7% vs 19.6; P = 0.031). Tolvaptan Tolvaptan is an oral, once-daily, nonpeptide vasopressin receptor 2 (V 2 ) antagonist without intrinsic agonist properties; it blocks the effects of the V 2 receptor, which is responsible for decreasing water excretion and causing water retention and hyponatremia. The phase II ACTIV (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure) trial was a randomized, double-blind, placebocontrolled study that enrolled 319 patients with an LVEF < 40%; these individuals were hospitalized for worsening heart failure and treated with standard therapy, including diuretics. The patients were given 30, 60, or 90 mg/d of tolvaptan or placebo for up to 60 days. Investigators were interested in such outcome measures as 24-hour inpatient body weight after one dose of study medication and outpatient worsening heart failure (defined as death, rehospitalization for heart failure, or unscheduled visit for heart failure) at 60 days after randomization. Researchers noted that tolvaptan decreased 24-hour body weight at all doses as compared with placebo (P 0.008) without affecting heart rate or renal function. Although they found no differences in the 60-day outcome, a post hoc analysis found that patients with severe renal dysfunction or severe heart failure who were treated with tolvaptan had a lower 60-day mortality rate than did 44 those given placebo (5.6% vs 17.8%; P = 0.03). Investigating the Success of Devices In the biomechanical model of heart failure, deleterious changes in cardiac function and remodeling from sustained neurohormonal activation result in development and progression of heart failure. The biomechanical model also predicts that heart failure eventually will progress independent of the patient s neurohormonal status, which partially explains the beneficial effects of many devicebased therapies. 36 For example, LV dyssynchrony is associated with interventricular conduction delay (IVCD). About 15% 30% of IVCD occurs in heart failure patients with dilated cardiomyopathy. In patients with IVCD, biventricular stimulation improves LV systolic function. When compared with optimal pharmacologic therapy alone in patients with moderate to severe heart failure due to ischemic or nonischemic cardiomyopathy who had a prolonged QRS > 120 ms, cardiac resynchronization therapy (CRT) with implantation of a pacemaker alone or with pacemakerdefibrillator treatment produced a significant reduction in both hospitalization and mortality. 45 New Horizons Stem Cells Adapted from a presentation by Piero Anversa, MD, Professor of Medicine, Director, Cardiovascular Research Institute, New York Medical College, Valhalla, New York. Regeneration of a damaged organ has the ideal goal of providing a complete structural and functional replacement. However, accomplishment of this goal has been difficult and elusive. The myocardium previously was considered to be a postmitotic organ that was differentiated terminally with little or no capacity to regenerate. Recent experimental advances, however, suggest that stem-cell research may provide hope to many patients with damaged hearts. Urbanek and others 46 tested the hypothesis that the human heart contains cardiac stem cells that promote regeneration after MI. They studied 20 hearts obtained from patients who died after an acute MI, 20 hearts from post heart transplant patients with chronic ischemic cardiomyopathy, and 12 control hearts, using Western blotting to define senescence and growth of cardiac stem cells and telomeric function. The identification of these stem cells was accomplished using the c-kit, MDR1, and Sca-1 like epitopes. Cardiac stem cell activation was evaluated using markers of cell proliferation, including histone H3 phosphorylation as a marker of mitosis. 47 Senescence of these stem cells was examined by age-associated protein expression and the presence of DNA oxidative stress and apoptosis; telomere length was evaluated because of its effects on cell growth and viability. Investigators discovered that these multipotent cardiac stem cells divided and differentiated into myocytes, smooth muscle cells, and endothelial cells in response to MI. Growth of the stem cells correlated with an increased telomerase-competent division, ranging from 1.5% in the control group to 14% in the chronic infarct group to 28% in the acute infarct group. Additionally, cardiac stem cells committed to myocytes, smooth muscle cells, and endothelial cells increased by approximately 25-fold in the chronic infarct group and 28-fold in the 23

26 Suntharo Ly, MD acute infarct group. However, senescent cells with nuclei positive for p16 INK4a -p53 increased by 10% in the control group, 40% in the chronic infarct group, and 18% in the acute infarct group. Thus, human cardiac stem cells are enhanced acutely after MI but are attenuated in chronic heart failure. 46 In summary, the mammalian heart contains a stem cell compartment that may regenerate myocytes and coronary vessels. This type of myocardial regeneration in humans occurs after ischemic and nonischemic injury. The existence of cardiac stem cells in humans is important, since replicating myocytes constitute a subpopulation of rapidly growing amplifying cells that originated from more primitive cells. 47 Cardiac stem cells located within the myocardial infarct zone or its proximity could divide and differentiate to replace dead myocardium. This important finding means that an eventual decrease in myocardial infarct size, improvement in function, and decline in mortality among post-mi patients are possible. 48 Conclusion Our current understanding of the pathophysiology of chronic heart failure and heart failure after MI has established the use of ARBs, ACE inhibitors, β-blockers, and aldosterone antagonists to reduce heart failure symptoms and improve survival. The additional implantation of a defibrillator and/or CRT further reduces mortality and hospitalizations. Many newer pharmacological agents, including thirdand fourth-generation β-blockers, positive inotropes, vasopressin-receptor blockers, and phosphodiesterase inhibitors, are being developed to treat post-mi heart failure. In addition, advances in stem cell research continue, although full myocardial regeneration by replacing dead myocardium with enhanced growth of cardiac stem cells and development of a new functional heart may be realized many years down the road. References 1. American Heart Association. Heart Disease and Stroke Statistics: 2005 Update. Dallas, Tex: American Heart Association; Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/ AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108: Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA. 2002;287: Pastor-Barriuso R, Banegas JR, Damian J, Appel LJ. Systolic blood pressure, diastolic blood pressure, and pulse pressure: an evaluation of their joint effect on mortality. Ann Intern Med. 2003;139: Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003; 289: Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased incidence of coronary heart disease. Arch Intern Med. 1993;153: Zanchetti A, Mancia G. Benefits and cost-effectiveness of antihypertensive therapy: the actuarial versus the intervention trial approach. J Hypertens. 1996;14: Wang JG, Staessen JA. Antihypertensive drug therapy in older patients. Curr Opin Nephrol Hypertens. 2001;10: Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997;278: Domanski M, Mitchell G, Pfeffer M, et al. Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 2002; 287: Sytkowski PA, D Agostino RB, Belanger AJ, Kannel WB. Secular trends in long-term sustained hypertension, long-term treatment and cardiovascular mortality. The Framingham Heart Study 1950 to Circulation. 1996;93: Wolf-Maier K, Coope, RS, Banegas JR,et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289: Vakili BA, Okin PM, Devereux RB. Prognostic implications of left ventricular hypertrophy. Am Heart J. 2001;141: Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis and management of chronic heart failure in the adult summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112: Millar JA, Isles CG, Lever AF. Blood pressure, white-coat pressor responses and cardiovascular risk in placebo-group patients of the MRC Mild Hypertension Trial. J Hypertens. 1995;13: Kimura BJ, Bocchicchio M, Willis CL, Demaria AN. Screening cardiac ultrasonographic examination in patients with suspected cardiac disease in the emergency department. Am Heart J. 2001;142: Hauser AM, Gangadharan V, Ramos R, Gordon S, Timmis GC. Sequence of mechanical, electrocardiographic and clinical effects of repeated coronary occlusion in human beings: echocardiographic observations during coronary angioplasty. J Am Coll Cardiol. 1985;5: Sabia P, Afrookteh A, Touchstone DA, Keller MW, Esquivel L, Kaul S. Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction: a prospective study using two-dimensional echocardiography. Circulation. 1991;84:I85 I Lim YJ, Masuyama T, Nanto S, Mishima M, Kodama K, Hori M. Papillary muscle perfusion. Am J Cardiol. 1996;78: Solomon SD, Glynn RJ, Greaves S, et al. Recovery of ventricular function after myocardial infarction in the reperfusion era: the healing and early afterload reducing therapy study. Ann Intern Med. 2001;134: Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr. 1995;8: Moller JE, Hillis GS, Oh JK, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation. 2003;107: Rigolin VH, Robiolio PA, Wilson JS, Harrison JK, Bashore 24

27 Chronic and Post-MI Heart Failure TM. The forgotten chamber: the importance of the right ventricle. Cathet Cardiovasc Diagn. 1995;35: Zornoff LA, Skali H, Pfeffer MA, et al. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol. 2002;39: Flather MD, Yusuf S, Kober L, et al. Long-term ACEinhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355: Otterstad JE, Ford I. The effect of carvedilol in patients with impaired left ventricular systolic function following an acute myocardial infarction: how do the treatment effects on total mortality and recurrent myocardial infarction in CAPRICORN compare with previous betablocker trials? Eur J Heart Fail. 2002;4: Velazquez EJ, Francis GS, Armstrong PW, et al. An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: the VALIANT registry. Eur Heart J. 2004;25: Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362: Young JB, Dunlap ME, Pfeffer MA, et al. Mortality and morbidity reduction with candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110: Demers C, McMurray JJV, Swedberg K, et al. Impact of candesartan on nonfatal myocardial infarction and cardiovascular death in patients with heart failure. JAMA. 2005;294: McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ. 2005;331: Teo K, Yusuf S, Sleight P, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148: Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348: Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112: Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346: Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation. 2005;111: Eisenhofer G, Friberg P, Rundqvist B, et al. Cardiac sympathetic nerve function in congestive heart failure. Circulation. 1996;93: Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986;73: Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20: Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105: Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344: Coats AJ. Positive inotropy for acute heart failure complicating myocardial infarction. Eur Heart J. 2002;23: Moiseyev VS, Poder P, Andrejevs N, et al. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction: a randomized, placebo-controlled, double-blind study (RUSSLAN). Eur Heart J. 2002;23: Gheorghiade M, Gattis WA, O Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291: Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350: Urbanek K, Torella D, Sheikh F, et al. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A. 2005;102: Hans F, Dimitrov S. Histone H3 phosphorylation and cell division. Oncogene. 2001;20: Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev. 2005;85:

28 Angiotensin II Receptor Blockers in the Management of Heart Failure Stacie A. Luther, MD University of Colorado Health Sciences Center, Denver Stimulation of the renin-angiotensin-aldosterone system (RAAS) may play a role in the hemodynamic and hormonal alterations associated with chronic heart failure. In patients with left ventricular dysfunction, treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) attenuates the RAAS via different mechanisms to decrease mortality. The recently completed CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trials showed that ARB therapy in patients with symptomatic heart failure improves survival in both patients unable to tolerate ACE inhibitors and those who had persistent symptoms despite concurrent ACE inhibitor therapy. The findings also suggest that combined ACE inhibitor and ARB therapy may have an additive mortality benefit. Recently, the American College of Cardiology/American Heart Association 2005 Task Force expanded the indications for the use of ARBs in heart failure, due in part to the results of the CHARM trials and two large randomized clinical trials that compared another ARB, valsartan, with ACE inhibitors in patients with chronic heart failure. sartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trials emphasize the importance of ARBs, both alone and in combination with ACE inhibitor therapy, in managing heart failure. At the Ninth Annual Scientifi c Meeting of the Heart Failure Society of America (HFSA), held in Boca Raton, Florida, a panel of CHARM investigators, chaired by Marc A. Pfeffer, MD, PhD, Professor of Medicine at Harvard Medical School, Boston, reviewed the trials C hronic heart failure is a growing public health problem that affects approximately 5 million patients in the United States; another 550,000 patients in this country are newly diagnosed with chronic heart failure annually. 1 Despite current therapies, the number of hospitalizations and deaths from this condition continues to rise. 1 New strategies to attack chronic heart failure are critical to improve survival and decrease morbidity among this growing population. One target for heart failure therapy is the renin-angiotensin-aldosterone system (RAAS). Stimulation of the RAAS may contribute significantly to the hemodynamic alterations, hormonal release, and cellular growth seen in chronic heart failure. 2,3 Two widely available classes of drugs that target the RAAS are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). The results of large trials have established that ACE inhibitors exert a mortality benefit in patients with left ventricular (LV) dysfunction. 4,5 In addition, ARBs are considered to be an alternative means of targeting the RAAS. 6,7 In fact, in patients with LV systolic dysfunction, the physiologic and clinical benefits of ARBs are similar to those of ACE inhibitors These two drug classes target the RAAS at different levels, and studies have shown an added mortality benefit when these two types of drugs are used together. Results of the recently completed CHARM (Candedesign and results and discussed the process of obtaining US Food and Drug A d m i n i s t r a t i o n (FDA) approval for candesartan therapy in managing symptomatic heart failure. Dr. Luther is a Cardiology Fellow at the University of Colorado Health Sciences Center, Denver. This article summarizes important information culled from these presentations. It begins with a review of the mechanistic and clinical benefits of ARB and ACE inhibitor therapy and includes data from several large clinical trials using ARB therapy in patients with LV dysfunction, with particular focus on the CHARM trials. This report also reviews questions that the FDA posed to the CHARM investigators concerning combined ARB and ACE inhibitor therapy before candesartan received 26