- Email: [email protected]
Introduction and overview
Introduction and Overview Mihai Gheorghiade, MD, Robert O. Bonow, MD
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he goal of this supplement to The American Journal of Medicine is to highlight the importance and facilitate the implementation of -blocker therapy in a multidrug approach to the management of chronic heart failure (CHF). Approximately 5 million US citizens have CHF.1–3 Despite a significant decrease in age-adjusted mortality from coronary artery disease (CAD) in the United States,4 there is a steady increase in the prevalence of heart failure.5 This latter trend is probably related to the aging of our population and the fact that more patients are surviving acute myocardial infarction and then living with a damaged left ventricle. The prevalence of heart failure ranges from as high as 1% in individuals 50 to 59 years old and progressively increases to 10% in those older than 80 years.1 Indeed, heart failure is the most common discharge diagnosis in patients older than 65 years.6,7 Hospitalizations for heart failure totaled approximately 1 million in 19908 but increased to 1.5 million in 1995.9 The mortality rate remains high; once heart failure develops, the 6-year mortality rate is approximately 80% in men and 65% in women.10 In excess of $38 billion is spent each year for this condition,7,8,11 not taking into account lost productivity and lost wages. In the United States, the heart failure population has several characteristics. CAD is the most common cause of heart failure,12 accounting for nearly 70% of such diagnoses.13 However, hypertension also contributes significantly to the syndrome of heart failure, particularly in African Americans.12 The majority of patients with systolic heart failure do not have systemic congestion.12 As our population ages, there is an increased number of individuals with heart failure and preserved systolic function, accounting for as many as 40% of patients hospitalized for this condition.14,15 Most patients with systolic CHF who die do so suddenly and unexpectedly despite clinical compensation.16 Medical therapies for heart failure are limited. Clinical trials conducted to date have shown that a significant number of drugs are not beneficial and may even increase mortality.17 The only interventions that have been proven conclusively to improve mortality and morbidity in CHF resulting from systolic dysfunction is treatment with angiotensin-converting enzyme (ACE) inhibi-
From the Division of Cardiology, Northwestern University Medical School, Chicago, Illinois, USA. Requests for reprints should be addressed to Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University Medical School, 250 East Superior, Wesley 524, Chicago, Illinois 60611. © 2001 by Excerpta Medica, Inc. All rights reserved.
tors17–24 and, more recently, -blockers.25–27 Despite promising results from clinical trials, the use of -blocker therapy for CHF has been adopted more slowly than hoped. Theoretically, 60% to 70% of patients with systolic heart failure are candidates for -blocker therapy. Nonetheless, it is estimated that less than 20% of such patients are receiving this form of therapy. The major reasons for this gap are probably related to issues surrounding the syndrome of heart failure and the role of -blocker therapy in the total management plan.
GENERAL ISSUES RELATED TO CHF Definition of Heart Failure Although the term chronic heart failure is commonly used, there is no clear definition for this condition. According to Colucci and Braunwald,28 heart failure is “the pathophysiologic state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissue or can do so only from an elevated filling pressure.” The Advisory Council to Improve Outcomes Nationwide in Heart Failure (Action HF) Steering Committee define heart failure as “a complex clinical syndrome that can result from any cardiac disorder that impairs the ability of the ventricle to eject blood. The cardinal manifestations of heart failure are dyspnea and fatigue (which may limit exercise tolerance) and fluid retention (which may lead to pulmonary and peripheral edema).”29 According to the US Agency for Health Care Policy and Research guidelines,2 heart failure is “a clinical syndrome or condition characterized by signs and symptoms of intravascular and interstitial volume overload, including shortness of breath, rales and edema, or manifestations of inadequate tissue perfusion such as fatigue or poor exercise tolerance.” The American College of Cardiology and the American Heart Association (ACC/AHA) joint task force guidelines for the evaluation and management of heart failure do not provide a definition.2 Many patients with decreased left ventricular systolic function have minimal or no symptoms of heart failure. In the Marantz series, 20% of patients with an ejection fraction (EF) 40% or less met no clinical criteria for heart failure.30 Mattleman31 found that only 42% of patients with EF 30% or less had dyspnea. In the Studies of Left Ventricular Dysfunction (SOLVD) Prevention Trial Registry that evaluated 6,273 patients with an EF 45% or less, 80% of patients were in functional class I or II. On physical examination, only 32% of these patients had rales, 26% had edema, and 26% had jugular venous distention. A third heart sound was present in only 17%.12 Although physical examination can provide important 0002-9343/01/$20.00 1S PII S0002-9343(00)00553-2
A Symposium: Introduction and Overview/Gheorghiade and Bonow
information for the diagnosis of heart failure, this may not be a sensitive approach to rule out significant systolic dysfunction. Similarly, when questioned, even the patient with significant systolic dysfunction may deny symptoms. However, when tested, many have significant limitations. Accordingly, the absence of signs and symptoms does not always rule out significant systolic dysfunction and physical limitations. It is clear, however, that once systolic dysfunction develops even in patients with no or minimal symptoms, progressive systolic dysfunction always follows. In these patients, mortality may be as high as 10% to 15% within 2 years of follow-up, and a significant number of these patients may die suddenly before developing severe symptoms. Because the available therapies that include ACE inhibitors and -blockers will prevent progression of left ventricular dysfunction even in patients with minimal symptoms or physical findings, the definition of heart failure should incorporate such patients who have an increased mortality from this condition. We are therefore proposing that patients with an EF less than 35% to 40% who have any exercise limitation and/or any signs of heart failure may be classified as having systolic heart failure. The absence of congestion should not rule out this condition. Patients with clinical heart failure that includes radiographic and/or clinical congestion, absence of valvular abnormalities and pericardial abnormalities, and a normal systolic function should be classified as having heart failure with preserved systolic function. One reason why patients are not treated for heart failure may be that they are not diagnosed with it because their symptoms do not conform to the “traditional” definition of heart failure. Pathophysiology of Heart Failure For many years, it was thought that heart failure began with a decrease in cardiac performance, initially during exercise and then at rest, leading to an increase in preload and afterload that further reduces cardiac performance. Consequently, therapy has been directed at breaking this vicious cycle by decreasing preload and afterload and/or increasing cardiac contractility in the belief that such a strategy would prevent progression of the disease. Over the past two decades, however, several studies have demonstrated that there is a poor correlation between increased inotropy and/or vasodilation and survival.17,32 Medications that improve inotropy and/or decrease preload and afterload, while improving cardiac performance both at rest and during exercise, may actually increase mortality.17,32 In contrast, agents that have a neutral or even negative inotropic effect (such as ACE inhibitors and  blockers) prolong survival.18 –27,33 It must be recognized that whereas acute symptoms are related to abnormal hemodynamics, progression of heart failure, including death, may be related to neurohormonal activation, and ventricular and vascular remodel2S May 7, 2001 THE AMERICAN JOURNAL OF MEDICINE威
ing.34 The activation of neurohormones may cause myocardial necrosis, hypertrophy, and lower the threshold for malignant arrhythmias.35 Therefore, a major goal in heart failure is not only to improve hemodynamics but to prevent the activation of neurohormones (serum norepinephrine, angiotensin-II, aldosterone) that occurs in virtually all patients with systolic dysfunction.36 In addition, in patients with CAD, ischemia, endothelial dysfunction, and/or myocardial infarction(s) may cause or further aggravate heart failure.13,37 Accordingly, medications that have both neurohormonal and antiatherosclerotic effects (eg,  blockers, ACE inhibitors, or lipid-lowering agents) are likely to be beneficial in the treatment of CHF. In contrast, such medications as calcium channel blockers (eg, nifedipine), certain vasodilators (eg, epoprostenol and flosequinan), and inodilators (eg, milrinone and enoximone) improve hemodynamics at the expense of increasing neurohormonal activation and are deleterious in this setting.17 Prognostic Considerations It is well established that prognosis is very poor in patients who have depressed systolic function and severe symptoms. However, asymptomatic or minimally asymptomatic individuals also have a poor prognosis. Mortality rates reach as high as 10% to 15% at 2 years of follow-up in patients with no or minimal symptoms.21 Many of these patients die suddenly and unexpectedly before developing any symptoms.21,27 In effect, then, there is no such thing as mild heart failure. Thus, any patient with systolic dysfunction should be considered to have a poor prognosis and treated aggressively. Prevention of Sudden Death In the 1950s and 1960s, patients were dying in overt heart failure. Now, the majority of patients (particularly those with mild heart failure) who are dying do so suddenly and unexpectedly despite clinical compensation and before developing significant worsening of their disease.27 Sudden death may account for 60% to 70% of patients with CHF who die.38 The central challenge in the management of heart failure today is not only to control or prevent symptoms but to prevent the high mortality rate associated with the condition. It is no longer acceptable only to eliminate signs and symptoms in heart failure. As we obtain more effective therapies for hemodynamic improvement and clinical compensation, a greater proportion of the patients who die will do so suddenly and unexpectedly. Beta blockers are probably the best agents available today to prevent sudden death,26,27 particularly in patients with CAD and/or in patients with left ventricular systolic dysfunction (LVD). Although ACE inhibitors reduce the risk of mortality from the progression of heart failure, it is not clear whether these agents prevent sudden death.39 Several studies have shown that anti-arrhythmic therapy
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with the exclusion of amiodarone does not prevent sudden death.17,32 Patient Evaluation The dissociation between physical symptoms and severity of LVD in patients with heart failure must be recognized. Many patients with very depressed systolic function have minimal or no symptoms. For instance, although the term congestive heart failure continues to be used in the SOLVD Prevention Trial Registry, less than 30% of patients with a low left ventricular EF have been found to have any signs of clinical congestion.12 Therefore, we should not wait for signs of congestion before diagnosing or assessing the severity of heart failure; EF alone is a major predictor of survival. Identifying patients who have systolic dysfunction with minimal or no symptoms presents a major challenge. Nevertheless, a careful history and physical examination, in addition to an electrocardiogram (ECG) and chest roentgenogram, should identify the majority of patients with systolic dysfunction. Many individuals experience symptoms of heart failure only during exercise and subconsciously alter their lifestyles to adapt to their diminished capabilities. Close questioning will often reveal the ways in which such patients have curtailed their daily activities. The index of suspicion for systolic dysfunction should be raised in patients who have symptoms of dyspnea or weakness without significant physical findings, as well as in those with longstanding hypertension, a history or ECG evidence of myocardial infarction, or an enlarged cardiac silhouette on chest roentgenogram. Patients with these characteristics should have their ventricular function evaluated with an echocardiogram or radionuclide ventriculography. Available Therapies Contrary to common belief, few therapies are able to improve both symptoms and survival while decreasing the rate of hospitalization for heart failure. The benefits of ACE inhibitors in this regard have been recognized for many years.17,32 More recently, data have shown that -blocker therapy improves symptoms, increases survival, and reduces hospitalization rates in patients already receiving ACE inhibitors and diuretics, with or without digoxin.25,26,28 Such therapies as digoxin, diuretics, and nitrates may improve symptoms without significantly changing outcomes.17,32 Accordingly, the physician should select therapies that will improve both symptoms and outcome first. For example, amlodipine is often used in patients with systolic heart failure, yet amlodipine neither improves survival nor reduces the rate of worsening heart failure, including hospitalization. More patients receiving amlodipine had pulmonary edema, leg edema, and worsening renal failure compared with subjects on placebo.40 Hydralazine and nitrate combination therapy was reviewed but not approved for the management of
CHF by the Federal Drug Administration, because this combination did not conclusively show prolonged survival or improve symptoms. Many other drugs that have been tested in this regard have yielded negative results. That is true for inotropic agents (eg, milrinone, xamoterol), vasodilators (eg, flosequinan, epoprostenol), and calcium channel blockers (eg, diltiazem, mibefradil).17,32 These considerations should be taken into account when approaching the patient with mild-to-moderate heart failure.
ISSUES RELATED TO -BLOCKER THERAPY Paradigm Shift For many years, -blocker therapy was considered contraindicated for heart failure. This recommendation was formulated based on conceptual concerns about negative inotropic effects and early experience with -blocking drugs when they were administered in relatively high doses in patients who were having severe symptoms. More recently, however, there has been a paradigm shift as the result of an improved understanding of the pathophysiology of CHF and the proper use of -blockers in this setting.29 One of the major determinants of progress in patients with low EF is related to the excessive activation of neurohormones. Beta blockers may be beneficial by decreasing this excessive activation. It should be realized that an initial decrease in cardiac contractility that may occur with -blockers is usually not deleterious in patients with mild to moderate heart failure. There should be a distinction between a hemodynamic effect and a biologic effect of -blocker therapy. Acutely there may be a slight decrease in contractility in response to -blockers, yet in the long run (months) there may be a major increase in left ventricular contractility (biologic effect). However, drugs that are associated with an initial improvement in symptoms and in hemodynamics have been linked with an increased risk of mortality17,33; acute beneficial hemodynamic effect and a long-term deleterious biologic effect. Moreover, although -blocker and ACE inhibitor therapies are the most important interventions in CHF, they in fact can initially decrease cardiac contractility.33,41 It is intriguing that -blocker therapy is the most powerful medical intervention that has been shown to increase left ventricular systolic function with long-term use. Patient Selection and Initiation of Therapy It is inadvisable to start -blockers during the initial days of hospitalization when many patients are being treated for worsening heart failure. The most important consideration is that patients be free of overt volume overload prior to initiation of -blockers. Such patients can be started either in hospital after successful treatment for an exacerbation or on an outpatient basis.
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For years, physicians have been taught to add medications if patients were getting worse. However, heart failure at any stage has a high mortality rate, particularly sudden death. Therefore, one of the main rationales for the use of -blockers is to prevent this excessive mortality, even in patients who improve symptomatically with other therapies. The patient with symptoms should be compensated with diuretics, ACE inhibitors, and possibly, digoxin to the point of having mild-to-moderate symptoms. A very small dosage of a -blocker should be added, and the dosage should not be increased for a period of weeks. Subsequent increases in the dosage should be undertaken gradually, over a period of months. Most patients will tolerate a -blocker used in this manner. Who Should Prescribe -Blockers? For years, primary care physicians were advised that only cardiologists should initiate -blocker therapy in patients with heart failure. However, we now know that when simple selection procedures are observed, -blocker therapy is both safe and effective in improving outcomes. The majority of patients with heart failure are seen by primary care providers. Typically, these are patients with mild symptoms who have much to gain from the use of -blockers.42 In contrast, cardiologists mainly see patients with advanced heart failure who are not ideal candidates for such treatment. It is therefore incumbent on the primary care physician to be knowledgeable about the use of -blockers in order to optimize the prospects for favorable outcomes in patients with mildly symptomatic heart failure.
CONCLUSIONS Both physicians and patients must become aware that it is no longer sufficient to improve symptoms related to hemodynamics in heart failure. We also need to prevent progression of the disease and sudden death. Used properly and in appropriate candidates, -blockers will reduce the devastating toll of heart failure. We must not continue to withhold one of the most important therapies from the very patients who stand to benefit the most.
REFERENCES 1. Ho KKL, Anderson KM, Kannel WB, et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation. 1993;88:107–115. 2. Clinical Practice Guidelines. Heart Failure: Evaluation and Care of Patients with Left Ventricular Systolic Dysfunction. Rockville, MD: US Department of Health and Human Services, 1994:11–23. AHCPR publication no. 94-0612. 3. Williams JF Jr, Bristow MR, Fowler MB, et al. Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure). J Am Coll Cardiol. 1995;26:1376 –1398. 4S May 7, 2001 THE AMERICAN JOURNAL OF MEDICINE威
4. Sytkowski PA, Kannell WB, D’Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease: the Framingham Heart Study. N Engl J Med. 1990; 322:1635–1641. 5. Ghali JK, Cooper R, Ford E. Trends in hospitalization rates for heart failure in the United States, 1973–1986: evidence for increasing population prevalence. Arch Intern Med. 1990;150:769 –773. 6. Detailed Diagnoses and Procedures. National Hospital Discharge Survey, 1990: Vital and Health Statistics. Series 13, no. 113. Hyattsville, MD: National Center for Health Statistics, 1992. DHHS publication no. 92-1774. 7. Graves EJ. National Hospital Discharge Survey: Annual Summary, 1993. Vital and Health Statistics. Series 13. National Health Survey, 1995;121:1– 63. 8. Levit KR, Lazenby HC, Cown CA. National health expenditures, 1990. Health Care Financ Rev. 1991;13:29 –54. 9. Heart and Stroke Facts. Dallas, Texas: American Heart Association, 1996:15. 10. Kannel WB. Epidemiological aspects of heart failure. Cardiol Clin. 1989;7:1–9. 11. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant. 1994;13(suppl):S107–S112. 12. Bourassa MG, Burne O, Bangdiwala SI, et al. National history and patterns of current practice in heart failure. J Am Coll Cardiol. 1993;22(suppl A):14A–19A. 13. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97:282–289. 14. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features, and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995;26:1565–1574. 15. McDermott MM, Feinglass J, Lee PI, et al. Systolic function, readmission rates, and survival among consecutively hospitalized congestive heart failure patients. Am Heart J. 1997; 134:728 –736. 16. O’Connor CM, Carson PE, Miller AB, et al. Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol. 1998;82: 881– 887. 17. Gheorghiade M, Benatar D, Konstam MA, et al. Pharmacotherapy for systolic dysfunction: a review of randomized clinical trials. Am J Cardiol. 1997;80:14H–27H. 18. 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;316:1429 –1435. 19. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302. 20. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303–310. 21. 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;327:685– 691. 22. Pfeffer MA, Braunwald E, Moye LA, et al, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669 – 677.
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A Symposium: Introduction and Overview/Gheorghiade and Bonow 23. 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;342:821– 828. 24. Korber L, Torp-Pedersen C, Carlsen JE, et al, for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670 –1676. 25. Packer M, Bristow M, Cohn JC, et al, for the US Heart Failure Carvedilol Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349 –1355. 26. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9 –13. 27. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007. 28. Colucci W, Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart Disease. Philadelphia: WB Saunders, 1997:394 – 420. 29. Steering Committee and membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure. Consensus recommendations for the management of chronic heart failure. Am J Cardiol. 1999;83:1A–38A. 30. Marantz PR, Tobin JM, Wasserthiel-Smoller S, et al. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation. 1988;77:607– 612. 31. Mattleman SJ, Hakki AH, Iskandrian AS, et al. Reliability of bedside evaluation in determining left ventricular function: correlation with left ventricular ejection fraction determined by radionuclide ventriculography. J Am Coll Cardiol. 1983; 1:417– 420. 32. Gheorghiade M, Cody RJ, Francis GS, et al. Current med-
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
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ical therapy for advanced heart failure. Am Heart J. 1998; 132:S231–S248. Foult JM, Tavolaro O, Antony I, et al. Direct myocardial and coronary effects of enalaprilat in patients with dilated cardiomyopathy: assessment by a bilateral intracoronary infusion technique. Circulation. 1988;77:337–344. Baig MK, Mahon N, McKenna WJ, et al. The pathophysiology of advanced heart failure. Am Heart J. 1998;135:S216 – S230. Komajda M, Pousset F, Isnard R, Lechat P. The role of the neurohormonal system in heart failure. Heart. 1998; 79(suppl 2):S17–S23. Sacker-Bernstein JD, Mancini D. Rationale for the use of chronic adrenergic blockade in patients with chronic heart failure. JAMA. 1995;274:1462–1467. Treasure CB, Alexander RW. The dysfunctional endothelium in heart failure. J Am Coll Cardiol. 1993;22(suppl A): 129A–134A. Stevenson WG, Stevenson LW, Middlekauf HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation. 1993;88:2953–2961. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450 – 1456. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107–1114. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with -adrenergic blockade. J Am Coll Cardiol. 1993;80(suppl A):139A–144A. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996;94:2800 –2806.
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T
he goal of this supplement to The American Journal of Medicine is to highlight the importance and facilitate the implementation of -blocker therapy in a multidrug approach to the management of chronic heart failure (CHF). Approximately 5 million US citizens have CHF.1–3 Despite a significant decrease in age-adjusted mortality from coronary artery disease (CAD) in the United States,4 there is a steady increase in the prevalence of heart failure.5 This latter trend is probably related to the aging of our population and the fact that more patients are surviving acute myocardial infarction and then living with a damaged left ventricle. The prevalence of heart failure ranges from as high as 1% in individuals 50 to 59 years old and progressively increases to 10% in those older than 80 years.1 Indeed, heart failure is the most common discharge diagnosis in patients older than 65 years.6,7 Hospitalizations for heart failure totaled approximately 1 million in 19908 but increased to 1.5 million in 1995.9 The mortality rate remains high; once heart failure develops, the 6-year mortality rate is approximately 80% in men and 65% in women.10 In excess of $38 billion is spent each year for this condition,7,8,11 not taking into account lost productivity and lost wages. In the United States, the heart failure population has several characteristics. CAD is the most common cause of heart failure,12 accounting for nearly 70% of such diagnoses.13 However, hypertension also contributes significantly to the syndrome of heart failure, particularly in African Americans.12 The majority of patients with systolic heart failure do not have systemic congestion.12 As our population ages, there is an increased number of individuals with heart failure and preserved systolic function, accounting for as many as 40% of patients hospitalized for this condition.14,15 Most patients with systolic CHF who die do so suddenly and unexpectedly despite clinical compensation.16 Medical therapies for heart failure are limited. Clinical trials conducted to date have shown that a significant number of drugs are not beneficial and may even increase mortality.17 The only interventions that have been proven conclusively to improve mortality and morbidity in CHF resulting from systolic dysfunction is treatment with angiotensin-converting enzyme (ACE) inhibi-
From the Division of Cardiology, Northwestern University Medical School, Chicago, Illinois, USA. Requests for reprints should be addressed to Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University Medical School, 250 East Superior, Wesley 524, Chicago, Illinois 60611. © 2001 by Excerpta Medica, Inc. All rights reserved.
tors17–24 and, more recently, -blockers.25–27 Despite promising results from clinical trials, the use of -blocker therapy for CHF has been adopted more slowly than hoped. Theoretically, 60% to 70% of patients with systolic heart failure are candidates for -blocker therapy. Nonetheless, it is estimated that less than 20% of such patients are receiving this form of therapy. The major reasons for this gap are probably related to issues surrounding the syndrome of heart failure and the role of -blocker therapy in the total management plan.
GENERAL ISSUES RELATED TO CHF Definition of Heart Failure Although the term chronic heart failure is commonly used, there is no clear definition for this condition. According to Colucci and Braunwald,28 heart failure is “the pathophysiologic state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissue or can do so only from an elevated filling pressure.” The Advisory Council to Improve Outcomes Nationwide in Heart Failure (Action HF) Steering Committee define heart failure as “a complex clinical syndrome that can result from any cardiac disorder that impairs the ability of the ventricle to eject blood. The cardinal manifestations of heart failure are dyspnea and fatigue (which may limit exercise tolerance) and fluid retention (which may lead to pulmonary and peripheral edema).”29 According to the US Agency for Health Care Policy and Research guidelines,2 heart failure is “a clinical syndrome or condition characterized by signs and symptoms of intravascular and interstitial volume overload, including shortness of breath, rales and edema, or manifestations of inadequate tissue perfusion such as fatigue or poor exercise tolerance.” The American College of Cardiology and the American Heart Association (ACC/AHA) joint task force guidelines for the evaluation and management of heart failure do not provide a definition.2 Many patients with decreased left ventricular systolic function have minimal or no symptoms of heart failure. In the Marantz series, 20% of patients with an ejection fraction (EF) 40% or less met no clinical criteria for heart failure.30 Mattleman31 found that only 42% of patients with EF 30% or less had dyspnea. In the Studies of Left Ventricular Dysfunction (SOLVD) Prevention Trial Registry that evaluated 6,273 patients with an EF 45% or less, 80% of patients were in functional class I or II. On physical examination, only 32% of these patients had rales, 26% had edema, and 26% had jugular venous distention. A third heart sound was present in only 17%.12 Although physical examination can provide important 0002-9343/01/$20.00 1S PII S0002-9343(00)00553-2
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information for the diagnosis of heart failure, this may not be a sensitive approach to rule out significant systolic dysfunction. Similarly, when questioned, even the patient with significant systolic dysfunction may deny symptoms. However, when tested, many have significant limitations. Accordingly, the absence of signs and symptoms does not always rule out significant systolic dysfunction and physical limitations. It is clear, however, that once systolic dysfunction develops even in patients with no or minimal symptoms, progressive systolic dysfunction always follows. In these patients, mortality may be as high as 10% to 15% within 2 years of follow-up, and a significant number of these patients may die suddenly before developing severe symptoms. Because the available therapies that include ACE inhibitors and -blockers will prevent progression of left ventricular dysfunction even in patients with minimal symptoms or physical findings, the definition of heart failure should incorporate such patients who have an increased mortality from this condition. We are therefore proposing that patients with an EF less than 35% to 40% who have any exercise limitation and/or any signs of heart failure may be classified as having systolic heart failure. The absence of congestion should not rule out this condition. Patients with clinical heart failure that includes radiographic and/or clinical congestion, absence of valvular abnormalities and pericardial abnormalities, and a normal systolic function should be classified as having heart failure with preserved systolic function. One reason why patients are not treated for heart failure may be that they are not diagnosed with it because their symptoms do not conform to the “traditional” definition of heart failure. Pathophysiology of Heart Failure For many years, it was thought that heart failure began with a decrease in cardiac performance, initially during exercise and then at rest, leading to an increase in preload and afterload that further reduces cardiac performance. Consequently, therapy has been directed at breaking this vicious cycle by decreasing preload and afterload and/or increasing cardiac contractility in the belief that such a strategy would prevent progression of the disease. Over the past two decades, however, several studies have demonstrated that there is a poor correlation between increased inotropy and/or vasodilation and survival.17,32 Medications that improve inotropy and/or decrease preload and afterload, while improving cardiac performance both at rest and during exercise, may actually increase mortality.17,32 In contrast, agents that have a neutral or even negative inotropic effect (such as ACE inhibitors and  blockers) prolong survival.18 –27,33 It must be recognized that whereas acute symptoms are related to abnormal hemodynamics, progression of heart failure, including death, may be related to neurohormonal activation, and ventricular and vascular remodel2S May 7, 2001 THE AMERICAN JOURNAL OF MEDICINE威
ing.34 The activation of neurohormones may cause myocardial necrosis, hypertrophy, and lower the threshold for malignant arrhythmias.35 Therefore, a major goal in heart failure is not only to improve hemodynamics but to prevent the activation of neurohormones (serum norepinephrine, angiotensin-II, aldosterone) that occurs in virtually all patients with systolic dysfunction.36 In addition, in patients with CAD, ischemia, endothelial dysfunction, and/or myocardial infarction(s) may cause or further aggravate heart failure.13,37 Accordingly, medications that have both neurohormonal and antiatherosclerotic effects (eg,  blockers, ACE inhibitors, or lipid-lowering agents) are likely to be beneficial in the treatment of CHF. In contrast, such medications as calcium channel blockers (eg, nifedipine), certain vasodilators (eg, epoprostenol and flosequinan), and inodilators (eg, milrinone and enoximone) improve hemodynamics at the expense of increasing neurohormonal activation and are deleterious in this setting.17 Prognostic Considerations It is well established that prognosis is very poor in patients who have depressed systolic function and severe symptoms. However, asymptomatic or minimally asymptomatic individuals also have a poor prognosis. Mortality rates reach as high as 10% to 15% at 2 years of follow-up in patients with no or minimal symptoms.21 Many of these patients die suddenly and unexpectedly before developing any symptoms.21,27 In effect, then, there is no such thing as mild heart failure. Thus, any patient with systolic dysfunction should be considered to have a poor prognosis and treated aggressively. Prevention of Sudden Death In the 1950s and 1960s, patients were dying in overt heart failure. Now, the majority of patients (particularly those with mild heart failure) who are dying do so suddenly and unexpectedly despite clinical compensation and before developing significant worsening of their disease.27 Sudden death may account for 60% to 70% of patients with CHF who die.38 The central challenge in the management of heart failure today is not only to control or prevent symptoms but to prevent the high mortality rate associated with the condition. It is no longer acceptable only to eliminate signs and symptoms in heart failure. As we obtain more effective therapies for hemodynamic improvement and clinical compensation, a greater proportion of the patients who die will do so suddenly and unexpectedly. Beta blockers are probably the best agents available today to prevent sudden death,26,27 particularly in patients with CAD and/or in patients with left ventricular systolic dysfunction (LVD). Although ACE inhibitors reduce the risk of mortality from the progression of heart failure, it is not clear whether these agents prevent sudden death.39 Several studies have shown that anti-arrhythmic therapy
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with the exclusion of amiodarone does not prevent sudden death.17,32 Patient Evaluation The dissociation between physical symptoms and severity of LVD in patients with heart failure must be recognized. Many patients with very depressed systolic function have minimal or no symptoms. For instance, although the term congestive heart failure continues to be used in the SOLVD Prevention Trial Registry, less than 30% of patients with a low left ventricular EF have been found to have any signs of clinical congestion.12 Therefore, we should not wait for signs of congestion before diagnosing or assessing the severity of heart failure; EF alone is a major predictor of survival. Identifying patients who have systolic dysfunction with minimal or no symptoms presents a major challenge. Nevertheless, a careful history and physical examination, in addition to an electrocardiogram (ECG) and chest roentgenogram, should identify the majority of patients with systolic dysfunction. Many individuals experience symptoms of heart failure only during exercise and subconsciously alter their lifestyles to adapt to their diminished capabilities. Close questioning will often reveal the ways in which such patients have curtailed their daily activities. The index of suspicion for systolic dysfunction should be raised in patients who have symptoms of dyspnea or weakness without significant physical findings, as well as in those with longstanding hypertension, a history or ECG evidence of myocardial infarction, or an enlarged cardiac silhouette on chest roentgenogram. Patients with these characteristics should have their ventricular function evaluated with an echocardiogram or radionuclide ventriculography. Available Therapies Contrary to common belief, few therapies are able to improve both symptoms and survival while decreasing the rate of hospitalization for heart failure. The benefits of ACE inhibitors in this regard have been recognized for many years.17,32 More recently, data have shown that -blocker therapy improves symptoms, increases survival, and reduces hospitalization rates in patients already receiving ACE inhibitors and diuretics, with or without digoxin.25,26,28 Such therapies as digoxin, diuretics, and nitrates may improve symptoms without significantly changing outcomes.17,32 Accordingly, the physician should select therapies that will improve both symptoms and outcome first. For example, amlodipine is often used in patients with systolic heart failure, yet amlodipine neither improves survival nor reduces the rate of worsening heart failure, including hospitalization. More patients receiving amlodipine had pulmonary edema, leg edema, and worsening renal failure compared with subjects on placebo.40 Hydralazine and nitrate combination therapy was reviewed but not approved for the management of
CHF by the Federal Drug Administration, because this combination did not conclusively show prolonged survival or improve symptoms. Many other drugs that have been tested in this regard have yielded negative results. That is true for inotropic agents (eg, milrinone, xamoterol), vasodilators (eg, flosequinan, epoprostenol), and calcium channel blockers (eg, diltiazem, mibefradil).17,32 These considerations should be taken into account when approaching the patient with mild-to-moderate heart failure.
ISSUES RELATED TO -BLOCKER THERAPY Paradigm Shift For many years, -blocker therapy was considered contraindicated for heart failure. This recommendation was formulated based on conceptual concerns about negative inotropic effects and early experience with -blocking drugs when they were administered in relatively high doses in patients who were having severe symptoms. More recently, however, there has been a paradigm shift as the result of an improved understanding of the pathophysiology of CHF and the proper use of -blockers in this setting.29 One of the major determinants of progress in patients with low EF is related to the excessive activation of neurohormones. Beta blockers may be beneficial by decreasing this excessive activation. It should be realized that an initial decrease in cardiac contractility that may occur with -blockers is usually not deleterious in patients with mild to moderate heart failure. There should be a distinction between a hemodynamic effect and a biologic effect of -blocker therapy. Acutely there may be a slight decrease in contractility in response to -blockers, yet in the long run (months) there may be a major increase in left ventricular contractility (biologic effect). However, drugs that are associated with an initial improvement in symptoms and in hemodynamics have been linked with an increased risk of mortality17,33; acute beneficial hemodynamic effect and a long-term deleterious biologic effect. Moreover, although -blocker and ACE inhibitor therapies are the most important interventions in CHF, they in fact can initially decrease cardiac contractility.33,41 It is intriguing that -blocker therapy is the most powerful medical intervention that has been shown to increase left ventricular systolic function with long-term use. Patient Selection and Initiation of Therapy It is inadvisable to start -blockers during the initial days of hospitalization when many patients are being treated for worsening heart failure. The most important consideration is that patients be free of overt volume overload prior to initiation of -blockers. Such patients can be started either in hospital after successful treatment for an exacerbation or on an outpatient basis.
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For years, physicians have been taught to add medications if patients were getting worse. However, heart failure at any stage has a high mortality rate, particularly sudden death. Therefore, one of the main rationales for the use of -blockers is to prevent this excessive mortality, even in patients who improve symptomatically with other therapies. The patient with symptoms should be compensated with diuretics, ACE inhibitors, and possibly, digoxin to the point of having mild-to-moderate symptoms. A very small dosage of a -blocker should be added, and the dosage should not be increased for a period of weeks. Subsequent increases in the dosage should be undertaken gradually, over a period of months. Most patients will tolerate a -blocker used in this manner. Who Should Prescribe -Blockers? For years, primary care physicians were advised that only cardiologists should initiate -blocker therapy in patients with heart failure. However, we now know that when simple selection procedures are observed, -blocker therapy is both safe and effective in improving outcomes. The majority of patients with heart failure are seen by primary care providers. Typically, these are patients with mild symptoms who have much to gain from the use of -blockers.42 In contrast, cardiologists mainly see patients with advanced heart failure who are not ideal candidates for such treatment. It is therefore incumbent on the primary care physician to be knowledgeable about the use of -blockers in order to optimize the prospects for favorable outcomes in patients with mildly symptomatic heart failure.
CONCLUSIONS Both physicians and patients must become aware that it is no longer sufficient to improve symptoms related to hemodynamics in heart failure. We also need to prevent progression of the disease and sudden death. Used properly and in appropriate candidates, -blockers will reduce the devastating toll of heart failure. We must not continue to withhold one of the most important therapies from the very patients who stand to benefit the most.
REFERENCES 1. Ho KKL, Anderson KM, Kannel WB, et al. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation. 1993;88:107–115. 2. Clinical Practice Guidelines. Heart Failure: Evaluation and Care of Patients with Left Ventricular Systolic Dysfunction. Rockville, MD: US Department of Health and Human Services, 1994:11–23. AHCPR publication no. 94-0612. 3. Williams JF Jr, Bristow MR, Fowler MB, et al. Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure). J Am Coll Cardiol. 1995;26:1376 –1398. 4S May 7, 2001 THE AMERICAN JOURNAL OF MEDICINE威
4. Sytkowski PA, Kannell WB, D’Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease: the Framingham Heart Study. N Engl J Med. 1990; 322:1635–1641. 5. Ghali JK, Cooper R, Ford E. Trends in hospitalization rates for heart failure in the United States, 1973–1986: evidence for increasing population prevalence. Arch Intern Med. 1990;150:769 –773. 6. Detailed Diagnoses and Procedures. National Hospital Discharge Survey, 1990: Vital and Health Statistics. Series 13, no. 113. Hyattsville, MD: National Center for Health Statistics, 1992. DHHS publication no. 92-1774. 7. Graves EJ. National Hospital Discharge Survey: Annual Summary, 1993. Vital and Health Statistics. Series 13. National Health Survey, 1995;121:1– 63. 8. Levit KR, Lazenby HC, Cown CA. National health expenditures, 1990. Health Care Financ Rev. 1991;13:29 –54. 9. Heart and Stroke Facts. Dallas, Texas: American Heart Association, 1996:15. 10. Kannel WB. Epidemiological aspects of heart failure. Cardiol Clin. 1989;7:1–9. 11. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant. 1994;13(suppl):S107–S112. 12. Bourassa MG, Burne O, Bangdiwala SI, et al. National history and patterns of current practice in heart failure. J Am Coll Cardiol. 1993;22(suppl A):14A–19A. 13. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation. 1998;97:282–289. 14. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features, and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol. 1995;26:1565–1574. 15. McDermott MM, Feinglass J, Lee PI, et al. Systolic function, readmission rates, and survival among consecutively hospitalized congestive heart failure patients. Am Heart J. 1997; 134:728 –736. 16. O’Connor CM, Carson PE, Miller AB, et al. Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation. Am J Cardiol. 1998;82: 881– 887. 17. Gheorghiade M, Benatar D, Konstam MA, et al. Pharmacotherapy for systolic dysfunction: a review of randomized clinical trials. Am J Cardiol. 1997;80:14H–27H. 18. 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;316:1429 –1435. 19. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302. 20. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303–310. 21. 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;327:685– 691. 22. Pfeffer MA, Braunwald E, Moye LA, et al, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669 – 677.
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A Symposium: Introduction and Overview/Gheorghiade and Bonow 23. 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;342:821– 828. 24. Korber L, Torp-Pedersen C, Carlsen JE, et al, for the Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670 –1676. 25. Packer M, Bristow M, Cohn JC, et al, for the US Heart Failure Carvedilol Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349 –1355. 26. CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial. Lancet. 1999;353:9 –13. 27. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007. 28. Colucci W, Braunwald E. Pathophysiology of heart failure. In: Braunwald E, ed. Heart Disease. Philadelphia: WB Saunders, 1997:394 – 420. 29. Steering Committee and membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure. Consensus recommendations for the management of chronic heart failure. Am J Cardiol. 1999;83:1A–38A. 30. Marantz PR, Tobin JM, Wasserthiel-Smoller S, et al. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation. 1988;77:607– 612. 31. Mattleman SJ, Hakki AH, Iskandrian AS, et al. Reliability of bedside evaluation in determining left ventricular function: correlation with left ventricular ejection fraction determined by radionuclide ventriculography. J Am Coll Cardiol. 1983; 1:417– 420. 32. Gheorghiade M, Cody RJ, Francis GS, et al. Current med-
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
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ical therapy for advanced heart failure. Am Heart J. 1998; 132:S231–S248. Foult JM, Tavolaro O, Antony I, et al. Direct myocardial and coronary effects of enalaprilat in patients with dilated cardiomyopathy: assessment by a bilateral intracoronary infusion technique. Circulation. 1988;77:337–344. Baig MK, Mahon N, McKenna WJ, et al. The pathophysiology of advanced heart failure. Am Heart J. 1998;135:S216 – S230. Komajda M, Pousset F, Isnard R, Lechat P. The role of the neurohormonal system in heart failure. Heart. 1998; 79(suppl 2):S17–S23. Sacker-Bernstein JD, Mancini D. Rationale for the use of chronic adrenergic blockade in patients with chronic heart failure. JAMA. 1995;274:1462–1467. Treasure CB, Alexander RW. The dysfunctional endothelium in heart failure. J Am Coll Cardiol. 1993;22(suppl A): 129A–134A. Stevenson WG, Stevenson LW, Middlekauf HR, Saxon LA. Sudden death prevention in patients with advanced ventricular dysfunction. Circulation. 1993;88:2953–2961. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995;273:1450 – 1456. Packer M, O’Connor CM, Ghali JK, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107–1114. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with -adrenergic blockade. J Am Coll Cardiol. 1993;80(suppl A):139A–144A. Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation. 1996;94:2800 –2806.
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