Current medical therapy for advanced heart failure

Current medical therapy for advanced heart failure Mihai Gheorghiade, MD,a Robert J . Cody, MD,b Gary S . Francis, MD,c William J . McKenna, MD,d James B . Young, MD,c and Robert O . Bonow, MD,a Chicago, Illinois, Columbus, Ohio, London, United Kingdom, and Cleveland, Ohio

ignificant progress in the management of cardiovascular disorders has been made in the United States in the past 2 decades, as reflected by a 50% reduction in the age-specific coronary artery disease mortality rate . 1,2 Despite such advances, the prevalence of chronic heart failure has been increasing, 3-7 most likely because of the aging of the U .S . population . 8 In the Framingham study, for example, the prevalence of chronic heart failure was 1% in persons between the ages of 50 and 59 years and increased progressively with age, reaching 10% in persons older than 80 years . 8 Heart failure afflicts an estimated 4 to 5 million individuals in the United States at a cost in excess of $12 billion annually, excluding costs related to lost wages and productivity. 9 " 10 The cost of hospitalization alone exceeds $7 billion . 10,11 Only a relatively small fraction of this expenditure is attributable to drug management and physician visits . 9,12 Although approximately 4 to 5 million patients have chronic heart failure in the United States, only a few hundred thousand are estimated to have advanced heart failure . This group of patients with advanced heart failure is likely to consume most of our resources .

S

This review will examine current medical therapy for the management of advanced heart failure including digoxin, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, hydralazine and nitrates combination, Padrenergic blocking agents, calcium-channel blockers, oral and intravenous inodilators, antiarrhythmic agents, anticoagulants, and antiplatelet agents . Unfortunately, limited data are available in patients Reprinted from Am Heart 11998 ;135 :S23I-5248, copyright © 1998 by Mosby, Inc . From aNorthwestern University Medical School, Chicago : bOhio State University Medical School, Columbus ; CCleveland Clinic Foundation, Cleveland ; dSt . George's Hospital Medical School, London . Reprint requests : Mihai Gheorghiade . MD, Northwestern University Medical School, Division of Cardiology, 250 E Superior, Wesley 524, Chicago, IL 60611 . Heart Lung ® 2000 ;29 :16-32 . 0002-8703/2000/$12 .00 + 0

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with advanced heart failure . Most patients enrolled in studies conducted to date did not have New York Heart Association (NYHA) class IV or advanced heart failure . Although advanced heart failure was required for enrollment to the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) 13 and the Flolan International Randomized Survival Trial (FIRST),1 4 severe heart failure was present in only 2 .9% of patients in the U .S . Carvedilol Heart Failure Study, 15 3 .5% in the Second Veterans Administration Cooperative Vasodilator Heart Failure Trial (V-HeFT-11), 16 3 .9% in the Metoprolol in Dilated Cardiomyopathy trial, 17 1 .7% in the Study of Left Ventricular Dysfunction (SOLVD) treatment study, 18 10 .9% in the Vesnarinone Study Group trial, 19 and 2% in the Digitalis Investigation Group (DIG) trial . 20

EVOLVING CHARACTERISTICS OF CHRONIC HEART FAILURE The syndrome of heart failure in the United States in the 1990s may differ from heart failure encountered in the 1950s and 1960s . 21 Chronic heart failure today tends to be characterized by the following features . (I) Decreased prevalence of systemic and pulmonary congestion . Systemic or pulmonary congestion, which was a prerequisite in diagnosing and assessing the severity of heart failure decades ago, is now seen less frequently, even in patients with severe left ventricular (LV) dysfunction . 22,23 In the SOLVD Registry involving 6273 patients with an ejection fraction of <_45%, fewer than 35% had signs of systemic congestion . 23 The absence of this sign is probably the combined result of early recognition of LV dysfunction and the effective treatment currently available for the reduction or elimination of the signs or symptoms of congestion . (2) Increased prevalence of heart failure with preserved systolic function . The percentage of patients with chronic heart failure and preserved LV systolic function is apparently increasing and may account for 30% to 40% of inpatients admitted with a diagno-

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sis of chronic heart failure . 24-27 This increase may be related to the wide use of echocardiography for earlier detection but is also related to the fact that diastolic dysfunction of the left ventricle increases with age . An increase in the prevalence of diastolic rather than systolic dysfunction in patients older than age 65 years may have contributed to the rising number of hospital admissions for heart failure in the last 2 decades . Patients with chronic heart failure and preserved systolic function are usually older, more often female, and more often have a history of hypertension or atrial fibrillation than patients with heart failure and impaired systolic function . 28 (3) Increased rate of sudden death . Despite advances in the recognition and treatment of heart failure, its overall mortality rate showed no appreciable decrease from 1948 to 1988 and remains very high . 29,30 In the Framingham study the I-year and 5-year survival rates in men were 57% and 25%, respectively, and in women were 64% and 38%, respectively . 30 Moreover, most of the patients with heart failure who die today do so suddenly and unexpectedly, presumably of a ventricular arrhythmia, at a time when they appear clinically to be well compensated . 31 This pattern is much different from that seen in earlier decades when patients were dying of progressive, intractable congestive heart failure . Among patients who were enrolled in the CONSENSUS trial, which involved only patients with symptoms at rest at study entry, 25% of those who died did so suddenly and unexpectedly . 13 (4) Increased prevalence of coronary artery disease . The most common cause of chronic heart failure is no longer hypertension or valvular heart disease as in past decades, but rather coronary artery disease . 23,32 Coronary artery disease was the underlying cause of heart failure in approximately 70% of the more than 20,000 patients involved in the 13 multicenter heart failure treatment trials that excluded patients recovering from an acute myocardial infarction and were published in the New England Journal of Medicine over the past 10 years . 13,15,18,20,33-39 Apparently the prognosis in patients with severe LV dysfunction and coronary artery disease is worse than the prognosis of heart failure in patients with normal coronary arteries . 40 .41 DEFINITION AND PATHOPHYSIOLOGY OF ADVANCED HEART FAILURE Advanced heart failure may be defined as a clinical syndrome characterized by clinical findings predictive of a 50% to 75% I-year mortality rate or a >90% 2-year mortality rate . Generally, this defini-

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tion encompasses patients with severe congestion associated with a very low LV ejection fraction (LVEF), pulmonary hypertension, a markedly elevated LV filling pressure, and/or a low forward cardiac output refractory to medical therapy . 42 It should be recognized, however, that some patients with a preserved systolic function may also have symptoms refractory to medical therapy . Although survival in these patients may be better than in those with systolic dysfunction, they should also be considered to have advanced heart failure . Heart failure begins with impaired ventricular function that results in decreased cardiac output initially during exercise and subsequently at rest . Decreased cardiac performance activates neuroendocrine systems, resulting in systemic and pulmonary vasoconstriction . 43 The systemic vasoconstriction translates into increased afterload, which further reduces cardiac performance . 43 In patients with advanced heart failure, a marked increase in the LV diastolic pressure may be responsible for changes in the shape of the left ventricle from an ellipsoid to a more spherical configuration . 44 This change in ventricular geometry may result in papillary muscle rearrangement and secondary mitral insufficiency .45 In addition, the elevated LV end-diastolic pressure can cause subendocardial ischemia both in patients with coronary artery disease and in those with a primary cardiomyopathy. 46,47 Activation of the neuroendocrine systems may occur independently of hemodynamic alterations and may be related to the abnormal baroreceptor function present in the chronic heart failure state . 48 Neurohumoral activation occurs even in patients with asymptomatic LV dysfunction but may be particularly excessive in patients with advanced heart failure . 49,50 Excessive neurohumoral activation theoretically can cause tachycardia, resulting in reduced coronary perfusion and increased oxygen consumption, myocyte necrosis and/or apoptosis downregulation of (3-adrenergic receptors, LV hypertrophy, and endothelial dysfunction . These changes may lower the threshold for malignant ventricular arrhythmias . In addition to hemodynamic and neurohumoral abnormalities, progression of coronary artery disease resulting in myocardial infarction, ischemia, or endothelial dysfunction may also contribute independently to worsening of heart fail ure . 32,51-55 MANAGEMENT OF ADVANCED HEART FAILURE In 1994 the U .S . Agency for Health Care Policy and Research published the Heart Failure Guide-

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Gheorgh ade et41 lines for the Evaluation of Care of Patients with Left Ventricular systolic Dysfunction, 56 and in 1995 the American College of Cardiology (ACC) and American Heart Association (AHA) Task Force published guidelines for the evaluation and management of heart failure . 57 Neither of these guidelines addressed in-depth issues specifically related to the management of advanced heart failure . We believe that therapy for advanced heart failure should improve rest and exercise hemodynamics (but not at the expense of increasing neurohumoral abnormalities or ischemia), decrease the degree of secondary mitral insufficiency, 5 s,59 preserve LV shape, 60 and attenuate neurohumoral abnormalities . In patients with heart failure caused by coronary artery disease, therapy should also prevent new acute events, prevent progression of coronary artery disease, reduce or eliminate ischemia, and possibly improve endothelial function . Prevention or prompt treatment of ventricular fibrillation is critical in patients who have this arrhythmia in the absence of overt heart failure . 31 There are two possible approaches to maximizing therapy in patients with advanced heart failure, assuming that standard doses of digoxin, diuretics, and ACE inhibitors have been prescribed already . The first approach to additional therapy may be guided by invasive monitoring in the intensive care setting, where cardiac output, pulmonary artery wedge pressure, heart rate, and blood pressure are continuously monitored for several days . 61-63 Alternatively, another approach may be guided by symptoms, systemic blood pressure including orthostatic changes, and changes in renal function . The end points used in this approach are simple clinical parameters such as exercise tolerance, blood pressure, heart rate, serum sodium, blood urea nitrogen (BUN), and creatinine, or the development of side effects . At this time it is not clear which of the two approaches, invasive or noninvasive, results in fewer hospitalizations, less progression of heart failure, and improved survival . Randomized trials are required, especially in situations when patients must be admitted into an intensive care setting for several days for invasive monitoring. This may be a very costly proposition unless this approach results in a significant reduction in subsequent hospitalizations ; alternatively, it could be cost-saving if it reduces readmissions . As pointed out by the ACC/AHA guidelines, improvement in functional capacity is the major goal of therapy, particularly in patients with advanced heart failure in whom the mortality rate is very high despite maximal therapies . 57

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Chronic heart failure is not a single disease, and it is extremely unlikely that all patients should be treated in a similar manner . Before selecting the appropriate therapy, therefore, the clinician must first categorize and profile the patient with chronic heart failure . We believe that several steps should be taken when treating patients with advanced heart failure : (1) establish the cause, for example, primary cardiomyopathy versus heart failure caused by coronary artery disease ; it should be recognized, however, that in the same patient hypertension, coronary artery disease, an element of cardiomyopathy caused by smoking, excess alcohol intake, and valvular heart disease may coexist and contribute in various amounts to the clinical heart failure picture ; (2) define the syndrome, for example, heart failure with systolic dysfunction versus heart failure with preserved systolic function, rightsided versus left-sided heart failure, heart failure with congestion (wet) versus a low cardiac output state without congestion (dry), high-output versus low-output state ; (3) identify and correct precipitating causes such as noncompliance with drugs, use of nonsteroidal anti inflammatory therapy, nasal decongestants, anemia, infection, pulmonary emboli, dietary indiscretion, inactivity, hyperthyroidism ; and

(4)

identify and correct ischemia and

prevent coronary artery progression . In addition to pharmacologic therapy, interventions such as exercise, vitamin supplementation, diet, and treatment for sleep apnea 64 may also improve the prognosis. Digoxin Although digitalis preparations have been used for centuries in the management of chronic heart failure, particularly heart failure associated with atrial fibrillation . 65 Only recently the Food and Drug Administration approved digoxin for use in patients with heart failure who are in sinus rhythm or in atrial fibrillation . In patients with chronic systolic heart failure and regular sinus rhythm, digoxin therapy improves hemodynamics both at rest and during exercise, and these hemodynamic effects are sustained during chronic therapy .66- 70 In

patients with chronic heart failure digoxin has modulating neurohumoral effects 71 that result in a decrease in serum norepinephrine concentrations, 72,73 improved baroreceptor function, 72,74 and a decrease in sympathetic nerve activity . 75 Digoxin also has important electrophysiologic effects that result in a decrease in atrioventricular node conduction and control of the ventricular rate, particularly at rest, in patients with atrial fibrillation . 76,77 Digoxin discontinuation in patients with systolic

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Gheorghlade .et al heart failure receiving diuretics alone or diuretics and ACE inhibitors has been associated with increases in hospitalization, the need for cointervention or new medical therapy for worsening heart failure, and decreased exercise time . 34,37. 78-81 The worsening heart failure when digoxin is discontinued is associated with a significant reduction in LVEF and increases in heart rate, systemic diastolic pressure, body weight, cardiothoracic ratio on chest x-ray evaluation, and echocardiographic LV end-diastolic dimension . 37,78 The available data on the value of digoxin in patients with advanced heart failure are somewhat limited, because most studies to date included patients with class II or III heart failure . 82 However, data from the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme (RADIANCE) 37 and the Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin (PROVED) 78 suggest that patients with a more severe form of heart failure reflected by a high heart failure score, an increased heart size on chest x-ray evaluation, and NYHA functional class III or IV are more likely to benefit from chronic digoxin therapy .83 In the DIG study, digoxin had a neutral effect on the mortality rate in patients with systolic dysfunction and in those with preserved systolic function . 20,84 However, chronic digoxin therapy appeared to reduce mortality caused by worsening heart failure, although this benefit was offset by a nonsignificant increase in presumed arrhythmic death in patients receiving digoxin . This latter finding may be less of an issue in patients with advanced heart failure in whom death of progressive overt heart failure is more likely than sudden unexpected death . In the DIG study digoxin therapy was associated with a significant decrease in the rate of hospitalization, the need for medical cointervention for worsening heart failure, or both . These benefits were more marked in patients with a severe form of heart failure, as reflected by a higher NYHA functional class, greater cardiothoracic ratio on chest x-ray evaluation, or lower LVEF 85 In the DIG trial preliminary data suggest that there was a correlation between serum digoxin concentration and mortality rate, with higher serum digoxin levels associated with a higher mortality rate even when within the therapeutic range of 0 .5 to 2 ng/ml . This relation may be attributable to a direct effect of digoxin or to greater disease severity and other comorbidities in patients with a higher serum digoxin concentration reflected by diminished renal function . 86 Similar findings were observed in the Prospective Randomized Mild-

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none Survival Evaluation (PROMISE) trial, in which the mortality rate in patients with a serum digoxin concentration >1 .1 ng/ml was substantially greater than that in those with a serum concentration <1 .1 ng/ml irrespective of the use of milrinone therapy . 87 Given the retrospective nature of this analysis in both the DIG and PROMISE studies, those findings are hypothesis-generating only . However, a relatively low dose of digoxin appears also to be beneficial in patients with heart failure8 8, 89 and improves the neurohumoral profile . 89,90 In addition, an increase in serum digoxin concentration within the therapeutic range results in further improvement in LV function without further improvement in the neurohumoral profile . 91 Thus a low dose of digoxin may be sufficient in patients with compensated chronic heart failure . A higher dose resulting in a serum concentration more than I ng/ml may be more beneficial during short-term treatment for hemodynamic decompensation . Available data support the use of long-term digoxin therapy in patients with advanced heart failure including patients in sinus rhythm and those with atrial fibrillation . The DIG trial suggests that digoxin may also be beneficial in patients with heart failure and preserved systolic function . 20 Digoxin should be used with caution, preferably at a low dose, in patients with ischemia, because acute ischemic events may lower the threshold for arrhythmias in those receiving nontoxic doses of digoxin . 92-94 In experiments (3-blocking agents may prevent the proarrhythmic and sympathomimetic effects of digoxin during ischemia . 95 Digoxin is effective in controlling the ventricular response in patients with atrial fibrillation . This effect may be diminished, however, in patients with a high sympathetic tone and high levels of circulating catecholamines, as occurs in patients with advanced heart failure and in patients using medications that facilitate conduction through the atrioventricular node such as dobutamine, dopamine, milrinone, and bronchodilators . The effects of digoxin on atrioventricular node conduction in these settings may be potentiated by adding very low doses of (3-adrenergic blocking agents . In patients with very severe heart failure, rapid intravenous injection of digoxin should be avoided, because it may cause systemic vasoconstriction and potentially precipitate pulmonary edema . 96 Monitoring of serum digoxin concentrations is particularly useful in patients with renal failure and those receiving medications likely to interfere with digoxin metabolism such as amiodarone, quinidine, verapamil, and clarithromycin . 97-101 A serum

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sample for measuring digoxin concentration should be obtained at least 6 hours after the dose is administered and preferably immediately before the next dose is administered . The safety of digoxin in patients receiving other oral or intravenous inotropic agents has not been established .

Diuretics Diuretics are extremely useful in patients with advanced heart failure . 102,103 These drugs decrease preload and are usually associated with symptomatic improvement and a reduction in hospitalization .l° 4,105 In patients with compromised renal function, loop diuretics are preferred . 56 .57,106 We believe that in patients with recurrent fluid retention, a twice a day dose of a loop diuretic (furosemide up to 240 mg twice daily, 5 mg bumetanide twice daily, or 200 mg ethacrynic acid twice daily) 56 is indicated . A daily dose of metalozone may result in significant electrolyte depletion and contraction alkalosis . Other diuretics, when not in combination with loop diuretics such as hydrochlorothiazide or chlorthalidone and potassium-sparing diuretics such as spironolactone, triamterene, and amiloride, may be less effective . The dose of diuretics in patients with chronic heart failure is highly individualized, however . In patients with right-sided failure, oral torsemide may have better bioavailability than other oral loop diuretics . 107 The end point of diuretic therapy is relief of symptoms, the development of orthostatic changes in blood pressure, or a progressive increase in blood urea nitrogen and creatinine . The extent of jugular venous distention may also be used as a guide to diuretic dosage . If the right atrial pressure is not increased and there is no obvious fluid retention, occasionally patients may not require a diuretic or only intermittent diuretic use . Available criteria suggest that diuretic therapy should not be maximized at the expense of ACE inhibitors, because dehydration resulting in orthostatic changes may preclude the use of appropriate doses of an ACE inhibitor. The elimination of edema and congestion in response to diuretics in general should occur gradually, because rapid mobilization of extravascular fluid may result in significant metabolic abnormalities that may worsen the heart failure state such as contraction alkalosis, hyponatremia, hypokalemia, increased blood urea nitrogen and creatinine, and hypomagnesemia . Combination therapy is highly beneficial for patients refractory to a loop diuretic . 108 Most patients with advanced heart failure are likely to benefit from at least two diuretics : a loop diuretic

20

and a thiazide, a loop diuretic and spironolactone, or a loop diuretic and metolazone . 109-112 Compensatory hypertrophy of the distal nephron in response to aggressive loop diuretic therapy markedly increases distal sodium reabsorption, thereby attenuating the response to loop diuretics .''' A thiazide that prevents distal sodium reabsorption will allow a loop diuretic to be more effective . Daily metolazone therapy is associated with marked abnormalities in the electrolyte profile .' 13 Metolazone is recommended for use as needed for refractory congestion or edema once or twice weekly with careful monitoring of electrolytes . The role of spironolactone in treating patients with chronic heart failure is being addressed in the Randomized Aldactone Evaluation Study that is in progress . This trial is being conducted in 3500 patients with class III-IV heart failure and LVEF <35% . Because there is an inadequate database regarding the efficacy and safety of diuretic drugs in patients with chronic heart failure, 102 future studies should address the role of different diuretics and different doses and also their effects when used in combination in patients with advanced heart failure . In addition, there is a controversy about how "dry" the patient with advanced heart failure should be .

ACE inhibitors Patients with chronic heart failure have enhanced renin angiotensin-aldosterone system activity, resulting in elevation of angiotensin II, which contributes to increased preload and afterload and promotes sodium and water retention .' 14 ACE inhibitors are thought to act by decreasing the production of angiotension 11, which in turn results in improvement in hemodynamic function in patients with chronic heart failure . In addition, ACE inhibition is associated with a delay in the development of chronic heart failure . ACE inhibitors also block the catabolism of other biologically active peptides such as bradykinin . 114 The contribution of bradykinin and other biologically active molecules to the overall clinical effects of ACE inhibitors remains unclear . ACE inhibitors decrease both preload and afterload, have a mild negative inotropic effect,' 15 and have a favorable effect on ventricular remodeling' 16 and coronary vascular events .' 17 Recent evidence suggests that the beneficial effects of these drugs may be related not only to their effects on systemic hemodynamics but also to improvement in endothelial function .' 18 ACE inhibitors improve survival and reduce hospitalizations for chronic

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Glieorahiade et al.•, heart failure in patients who have had a myocardial infarction 119,120 and in those with chronic LV systolic dysfunction . 13 .18,36 This improvement is irrespective of the presence or absence of symptoms and occurs in all NYHA classes but is most striking in patients with the greatest reduction in LVEF. 121 In addition, in patients with coronary artery disease and LV dysfunction, ACE inhibitors may reduce the rate of myocardial infarction and unstable angina 122,123 despite the exclusion from those studies of patients with residual ischemia after myocardial infarction . The effects of ACE inhibitors on atherosclerotic disease progression in patients without heart failure is being addressed by large ongoing, randomized, double-blind, placebo-controlled trials such as Heart Outcomes Prevention Evaluation (HOPE) (approximately 9000 patients), the Study to Evaluate Carotid Ultrasound Changes with Ramipril and Vitamin E (SECURE) (700 patients), the Quinapril Ischemic Event Trial (QUIET) (1775 patients), the Simvastatin and Enalapril Coronary Atherosclerosis Trial (SCAT) (468 patients), and the Prevention of Atherosclerosis with Ramipril Therapy (PART) (600 patients) .' 17 ACE inhibitor therapy is the only therapy that has been shown conclusively to reduce the mortality and morbidity rate in patients with heart failure . This is particularly important because to date, trials that examined the effects of inotropic agents (enoximone, amrinone, vesnarinone, pimobendan, ibopamine, xamoterol, and milrinone), calcium channel blockers (diltiazem, verapamil, nifedipine, and amlodipine), antiarrhythmic agents (flecainide, encanaide, d-sotalol, moricizine), and vasodilators (flosequinan, epoprostenolol) have shown no beneficial effects or have actually demonstrated increased mortality rates in patients with heart failure . 124 Nevertheless, ACE inhibitors are underused, most likely because of their side effect profile . Limitations to the use of ACE inhibitors are related to changes in renal function and the development of hypotension, cough, or both . Patients with advanced heart failure may be more sensitive to ACE inhibitors because many have hypotension, worsening renal failure, or both related to their underlying condition . However, cough, hypotension, and increases in BUN and creatinine per se are not contraindications to ACE inhibition . Orthostatic changes, although rarely seen in patients with advanced heart failure, should be measured in relatively hypotensive patients before ACE inhibitor therapy is initiated . If a patient has orthostatic changes or a baseline systolic blood pressure <90 mm Hg, it is prudent to start with a very low dose of

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Current me~il~a1';thetaP#fa

d

a short-acting ACE inhibitor such as 6 .25 mg captopril and to observe the patient for I or 2 hours . 125 If hypotension develops, it can usually be controlled satisfactorily by raising the legs . The hypotensive response to an ACE inhibitor may be particularly evident in patients who are hyponatremic . 126 If BUN and creatinine increase during chronic ACE inhibitor therapy, the diuretic dose should first be readjusted . Normalization of BUN and creatinine may not be possible in patients with advanced heart failure, however, because such patients have a chronic low output state . In some patients it may be necessary to have some degree of prerenal azotemia with a BUN level of approximately 50 mg/dI and a creatinine up to 3 mg/dl to maintain patients free of congestion . Although maximal tolerated doses of ACE inhibitors have been recommended for patients with advanced heart failure, 127 there continues to be a debate on the optimal dose . 128 Large ongoing trials looking at different doses of ACE inhibitors are addressing this issue . 129 For example, the Assessment of Treatment with Lisinopril on Survival study (ATLAS) is comparing the effects of two once-daily doses of lisinopril, 2 .5 to 5 mg and 32 .5 to 35 mg, on morbidity and mortality rates in patients with heart failure . The study was started in 1993 and enrolled 3164 patients with NYHA class 11 to IV and LVEF <_30% at 300 sites in 18 countries . All patients were to be monitored for 3 to 4 .5 years . The primary end point in the study was all-cause mortality ; the study also compared the effects of high and low doses of lisinopril on nonfatal end points such as the development of progressive heart failure . The results were recently presented at the American College of Cardiology meeting in Atlanta by Dr . Milton Packer. Although the overall mortality was similar in the "low" and "high" dose groups, the combined endpoint of mortality and worsening heart failure favored the highest dose . The use of a therapeutic dose of an ACE inhibitor is probably more important than choosing a specific ACE inhibitor 130 A therapeutic dose may be defined as a dose of ACE inhibitor used in the large mortality trials . 56

Angiotensin II receptor antagonists An important discovery in the development of new drugs to inhibit the renin-angiotensin-aldosterone system occurred in 1990, when the biologic activity of antagonists of the angiotensin II receptor was reported . These agents block the action of angiotensin II at the receptor level and conceivably could block the effects of angiotensin II produced not only through the classical ACE pathway but also

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by the chymase pathway . Because some of the side effects of ACE inhibitors such as angioeclema and dry nonproductive cough may be bradykinin-related, an angiotensin II receptor blocker could provide the same beneficial effects as an ACE inhibitor with fewer side effects . The Evaluation of Losartan in the Elderly (ELITE) trial 131 randomized 722 ACE inhibitor-naive patients with NYHA functional class II-IV symptoms and an ejection fraction <40% to either an angiotensin II receptor antagonist, losartan, titrated to 50 mg once daily (352 patients), or captopril titrated to 50 mg three times daily (370 patients) for 48 weeks . The primary end point of the study was renal dysfunction . The frequency of persistent increases in serum creatinine was the same in both groups . Fewer patients receiving losartan discontinued therapy for adverse experiences, 12% versus 29% for captopril . Death, hospital admission for heart failure, or both occurred in 9 .4% of the patients treated with losartan and 13 .2% of the patients treated with captopril, corresponding to a risk reduction of 32% with losartan . Admissions for heart failure were the same in both groups ; however, admission to the hospital for any reason was less frequent in the losartan group, 22 .2% versus 29 .7%. The impact of angiotensin II blockade on the heart failure mortality rate is being evaluated further in ELITE II, a comparative study of losartan versus captopril with mortality as the primary end point . Several other studies using angiotensin II receptor antagonists in heart failure are being conducted . The Valsartan in Heart Failure Trial will study approximately 3600 patients with an LVEF <40% who are in NYHA class II to IV and who will be randomized to valsartan versus placebo plus standard therapy . The Randomized Evaluation of strategies for left ventricular dysfunction (RESOLVED) studied 769 patients with heart failure who were randomized to receive either the ACE inhibitor enalapril, the angiotensin II antagonist candesartan, or a combination of the two drugs . Salim Yusuf recently presented the results of the study at the American College of Cardiology meeting in March 1998 in Atlanta . It appeared that although the combination therapy with anolopril and candesartan had a favorable effect on ventricular remodeling, there were not significant clinical benefits on clinical endpoints in response to candesartan . The role of angiotensin II blockade in the treatment of patients with advanced heart failure instead of ACE inhibitors or in combination with ACE inhibitors remains to be determined . At this time we believe that an angiotensin II receptor

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therapy for advanced heart failure

antagonist should not be a substitute for ACE inhibitors unless the ACE inhibitor is contraindicated or clearly not tolerated .

Hydralazine and nitrates combination The V-HeFT II trial suggested that a combination of hydralazine and nitrates improves survival in patients with class II and III heart failure . 33 Some benefits from hydralazine/nitrates combination have been seen by others . 132 Although nitrates alone may also be beneficial in patients with chronic heart failure, 133- ' 35 hydralazine alone has not been found to be beneficial in patients with heart failure .] 32,136,137 However, hydralazine may reduce the development of nitrate tolerance . 138,139 The effects of hydralazine may mimic the hemodynamic effects of dobutamine 140 and may precipitate ischemic events in patients with heart failure caused by coronary artery disease . 141 The combination of hydralazine and isosorbide dinitrate does not appear, however, to reduce the rate of worsening heart failure and is associated with more side effects than placebo . 33 This combination is indicated in patients who cannot tolerate ACE inhibitors or who have a contraindication to their use . The dose of hydralazine should be between 50 and 100 mg four times daily, and the dose of isosorbide dinitrate should be between 10 and 80 mg three times daily . Hydralazine can cause some fluid retention, and patients may require increased doses of diuretics to achieve a dry body weight . 142 Given the fact that the use of hydralazine and nitrate combination is largely predicated on a relatively small number of patients from the V-HeFT-I study and some anecdotal experience, this combination should be considered as adjunctive therapy not supported by strong evidence . Recently the Cardiovascular and Renal Advisory Panel of the U .S . Food and Drug Administration as part of a drug evaluation process, considered the fixed combination of hydralazine and isosorbide dinitrate as adjunctive therapy to digitalis or diuretics in chronic heart failure . Because the mortality benefit from this combination was not found to be statistically significant in the V-HeFT-I study when protocol-defined methods of analysis were used, the Panel did not approve the hydralazine/isosorbide dinitrate combination for use in patients with chronic heart failure . 143

Combination therapy In patients with moderate heart failure, the lowest rate of clinical deterioration occurs with triple therapy with digoxin, diuretics, and ACE

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Gheorghiade et all'

Current medical therapy for advanced heartiaillure :

inhibitors . 144 There are, however, few prospective

data on combination therapies for advanced heart failure . Because the combination of hydralazine and nitrates is more likely to cause initial hemo-dynamic improvement compared with ACE inhibitors, 16

adding hydralazine and isosorbide dinitrate to an ACE inhibitor may result in further improvement in patients with advanced heart failure . 145 .' 46 At this time the addition of nitrates and hydralazine to ACE inhibitors may be beneficial in selected patients with refractory symptoms . Future trials may have to address the role of combining ACE inhibitors with hydralazine and nitrates, different diuretics, and angiotensin II receptor antagonists .

(3-Adrenergic blocking agents A large carvedilol database supports the contention that this drug improves survival and reduces the rate of hospitalization and worsening heart failure in both patients with heart failure caused by coronary artery disease and those with primary cardiomyopathy . 15,147-151 Although a trial to

evaluate the effect of carvedilol on mortality as a primary end point has not been conducted, the advisory panel of the U .S . Food and Drug Administration has recently approved carvedilol for the treatment of patients with chronic heart failure, because the data presented support a beneficial effect that may include reduction in hospitalizations, cointervention with other heart failure medications, and possibly mortality . 143

However,

3-adrenergic blocking agents may lead to worsening heart failure before improvement is seen . LVEF tends to worsen initially in response to (3-blockers but subsequently improves after 6 to 12 months of therapy . 152 This very consistent improvement in

LVEF is not seen with other drugs for heart failure . Experience with (3-adrenergic blocking agents in patients with advanced heart failure is extremely limited, but such patients are likely to have worsening heart failure in response to (3-blocker administration . Accordingly, (3-adrenergic blocking agents should not be used in patients with advanced heart failure with class IV (NYHA) symptoms (symptoms at rest), particularly when they are in the intensive care unit . Very low doses such as 3 .125 mg twice daily carvedilol should be used initially in patients with class II and III heart disease after they have been stabilized with diuretics, digoxin, and ACE inhibitors and there are no signs of overt heart failure (e .g ., rates, jugular venous distention) . If the dose is tolerated, the dosage may be increased at intervals of not fewer than 2 weeks to 6 .25 mg twice daily followed by 12 .5 mg twice daily and thereafter 25 mg

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twice daily . The maximum recorded dose is 50 mg twice daily . Carvedilol may result in an increase in serum digoxin concentrations in patients receiving digoxin . Once patients are started on (3-adrenergic blocking agents, careful follow-up is absolutely critical, and one can expect that a small percentage of patients will deteriorate . In addition, alterations in concomitant therapy will be frequently necessary (e .g., increase in diuretic dose) . (3-Adrenergic blocking agents may also be particularly useful in patients with atrial fibrillation and a fast ventricular response in whom a high sympathetic tone prevents rate control with digoxin alone . Future trials should address the safety and efficacy of selective (3-adrenergic blocking agents or (3-adrenergic blocking agents with vasodilatory effects in patients with advanced heart failure . Several trials examining the role of (3-adrenergic blocking agents in patients with advanced heart failure are ongoing : Bucindolol Evaluation Survival Trial (BEST) and Metoprolol Randomized Intervention Trial in Congestive Heart Failure (MERITHF) . In the BEST trial bucindolol is compared with placebo in 2800 patients who will be monitored an average of 18 months . In the MERIT-HF trial 3200 patients are randomized to metoprolol versus placebo . The Cardiac Insufficiency Bisoprolol Study CIBIS-II was terminated prematurely due to a significant decrease in mortality in the bisoprolol group when compared to placebo . Carvedilol, is in the process of being evaluated in patients with severe heart failure (COPERNICUS : approximately 2000 patients were monitored for 36 months), compared with metoprolol (COMET: 3000 patients monitored for 36 months), in patients with coronary artery disease (CHRISTMAS), compared with ACE inhibitors (CARMEN), and in patients recovering from an acute myocardial infarction (ECLIPS) .

Calcium-channel blockers First- and second-generation calcium-channel blockers do not appear to be beneficial in patients with systolic heart failure .' 53-155 Diltiazem, nifedip-

ine, and nicardipine have been shown to increase symptoms or decrease survival in heart failure patients . 156-158 These adverse consequences are

probably related to the negative inotropic effects of calcium-channel blockers and their adverse effects on neurohormones . 155 Amlodipine, 39 felodipine, 159 and possibly verapamil 16 o appear to have a neutral

effect on survival . The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) data generated the hypothesis that amlodipine lowers the mortality rate in patients with primary cardiomyopathy. 39 This somewhat unexpected finding is

23



Oil

;t >ahed11cal therapy for advanced heart failure

Gheorghiade et al

being tested in PRAISE-II . At this time amlodipine should not be used routinely in all patients with heart failure caused by coronary artery disease, because it does not appear to reduce the mortality rate nor to reduce the rate of worsening heart failure or hospitalization . In addition, it appears that the use of amlodipine may be associated with a higher rate of pulmonary edema, ankle edema, and worsening renal failure . Further data are required before this therapy can be recommended for patients with advanced heart failure . Amlodipine may be considered in patients with advanced heart failure who continue to be hypertensive despite other therapies such as ACE inhibitors or hydralazine/nitrates or in patients with a primary cardiomyopathy .

Trial (VEST) subsequently showed that a 60 mg dose of vesnarinone was associated with an increased

Recently, mibefradil, a new calcium-channel blocker, was approved by the Food and Drug Administration to treat patients with hypertension and angina . Mibefradil is a nonvoltage-regulated T channel blocker that differs from all the other currently available L-channel calcium blockers . The drug does not appear to have any clinical negative inotropic activity . The Mortality Assessment in Congestive Heart Failure (MACH-I) study is assessing the effects of mibefrodil on survival in 2400

the mortality rate 1 .8-fold . 168 Therefore at this time

patients with class II-IV chronic heart failure . 161 The

however, are available only to a small and highly selected group of patients . Unfortunately, patients with advanced heart failure suffer greatly, and hospitalizations are frequent . In an attempt to improve the well-being of these patients, facilitate hospital discharge, and prevent subsequent readmission, clinicians use long-term and pulse parenteral infusion of inotropic compounds in both inpatient and outpatient settings . The use of these drugs has been based largely on anecdotal results . A variety of techniques have been used including continuous parenteral infusion, 4- to 6hour pulse infusion several days a week, and a single 72-hour infusion once weekly . One clinical trial with dobutamine was terminat-

last patient was randomized in October 1996 . In general, calcium-channel blockers should be considered under investigation at this time in the treatment of patients with advanced coronary heart failure .

Oral inotropic agents Several studies have shown that oral inotropic agents with vasodilatory properties such as amrinone, 162 milrinone, 35 enoximone, 163 and xam-

oterol 164 are associated with increased mortality rates irrespective of the cause of heart failure and its severity . 165 The same is true for vesnarinone, 166 ibopamine, 167 and possibly pimobendan, 168 three originally promising compounds . It is interesting that vasodilators may also increase the mortality

rate in patients with severe heart failure . 14,169 In an initial evaluation low-dose vesnarinone (60 mg/day) was associated with a 63% reduction in mortality rate at 6 months in patients with chronic

heart failure . 19 In contrast, a higher dose of 120 mg/day was associated with a fivefold increase in the mortality rate in the same cohort of patients . A low dose of vesnarinone appears to have a minimal hemodynamic effect, does not activate neurohormones, and results in a significant reduction in tumor necrosis factor . Despite these initial promising results, the Vesnarinone Evaluation of Survival

24

mortality rate compared with placebo . 166 Ibopamine has been shown to improve signs and symptoms of chronic heart failure without acti-

vation of neurohormones . 73 Despite earlier promising results, however, patients with heart failure treated with ibopamine in the second Prospective, Randomized Study of Ibopamine on Mortality and Efficacy in Heart Failure (PRIME-2) had an increase in mortality rate . This increase was particularly evi-

dent in patients with advanced heart failure . 167 Treatment with the calcium sensitizer pimobendan in the Pimobendan in Congestive Heart Failure trial produced no improvement and actually increased no oral inotropic agents except for digoxin should

be used in patients with advanced heart failure .

169

Intravenous agents As conventional therapies fail to maintain reasonable compensation in patients with advanced heart failure, alternatives such as cardiac transplantation are sometimes used to ameliorate the

symptoms and prolong life . 170 These procedures,

ed early because of an increased mortality rate . 171 Although most clinicians report that patients receiving this therapy have improved functional status, sample sizes have generally been small, and results of studies have been difficult to interpret . To date, no large clinical trials of outpatients receiving parenteral inotropic therapy have demonstrated convincing evidence of improved quality or length of life . The phosphodiesteraseinhibiting compound milrinone has both inotropic and vasodilatory effects and may produce benefits

in patients with advanced heart failure . 172,173 Data to guide home inotropic infusion are limited . Furthermore there is no consensus regarding the rela-

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tive merits of home inotropic infusions, as reflected by the wide variation among heart failure centers, some of which manage more than 100 patients on regular home infusions, whereas others of similar volume and disease profile manage only a few annually. Patients with advanced heart failure caused by systolic dysfunction may be candidates for chronic parenteral inotropic therapy . We believe that these patients should receive maximal tolerated doses of ACE inhibitors, digoxin, diuretics, and possibly hydralazine and nitrates and should have a positive hemodynamic response to inotropic infusion during right heart cardiac catheterization . Furthermore these patients should receive appropriate therapy for symptomatic arrhythmias and other metabolic abnormalities, have a stable psychosocial profile, and have demonstrated compliance with previous therapies . The parenteral inotrope should be administered with a pump through a central venous access catheter . Administration of the lowest effective dose of the most effective medication as demonstrated by hemodynamic monitoring seems appropriate . There is a great deal yet to learn from clinical trials with chronic parenteral inotropic therapy including the most appropriate patient selection, best drug, defining circumstances, optimal dose, administration technique, and proper weaning protocol through an analysis of the risk/benefit ratio of therapy . The ACC/AHA guidelines appear to recommend the use of dobutamine and milrinone for patients with chronic heart failure refractory to therapy or during exacerbations for which hospitalization is necessary . This treatment may temporarily improve cardiac output and renal blood flow, ameliorate symptoms, and relieve salt and water retention in patients refractory to maximal oral therapy with ACE inhibitors . 57 Low-dose dobutamine (2 to 5 mg/kg/min) is recommended because larger doses may produce tachycardia, ventricular arrhythmias, hypokalemia, and myocardial ischemia . Alternatively, intravenous milrinone as a 50 µg/kg loading dose followed by a continuous infusion of 0 .375 gg/kg or 0 .75 ltg/kg/min may be used . Maintenance dose without a loading dose may also be used . However, the therapeutic levels are seen after 6 hours . The milrinone dosage may require adjustment in patients with renal dysfunction . Patients with symptomatic improvement as a result of longterm, low-dose dobutamine infusion may receive this drug through an in-dwelling central catheter on a long-term outpatient basis . Continuous outpatient therapy with gradual weaning is most useful in patients who cannot be weaned from inotropic

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therapy as inpatients . Intermittent outpatient or inpatient therapy for 12 to 24 hours may be beneficial in patients who require repeated hospital admissions or emergency department visits for management of volume overload or symptoms of low cardiac output. The guidelines recognize that the value of long-term, low-dose inotropic support in an outpatient setting remains uncertain . There is also concern about the safety of such treatment in light of an increased mortality rate reported with high-dose outpatient dobutamine infusion 171 and long-term oral milrinone therapy. 35 Long-term dobutamine therapy has been associated with an increase in mortality rate . 171,174 intravenous inotropic agents have the potential to precipitate an ischemic event in patients with severe coronary artery disease . The available data suggest that patients with chronic heart failure caused by coronary artery disease may have ischemic, hibernating, and stunned myocardium . 175 Low-dose dobutamine results in short-term improvement in contractility of the stunned or hibernating myocardium . 176 It is possible that chronic stimulation of the hibernating or stunned myocardium by dobutamine without restoration of blood flow or in the territory of marginal blood flow reserve may precipitate myocardial necrosis (apoptosis) . 177-182 Accordingly, the safety of intravenous inotropic therapy in patients with advanced heart failure caused by coronary artery disease remains to be established . Every effort should be made to maximize alternative treatments, and intravenous inotropic agents should be used only when other therapies have failed . Before intravenous inotropic therapy is initiated, we believe that patients should be evaluated for ischemia, hibernation, or both 175 and, if present, measures should be undertaken to improve coronary blood flow or reduce ischemia. The ischemia or hibernation can be identified by relatively routine testing with dobutamine echocardiography or myocardial perfusion scintigraphy . 175 The status of hibernating and stunned myocardium should be followed when intravenous inotropic therapy is initiated . Few data exist on the safety and efficacy of intravenous inotropic therapy in patients hospitalized with exacerbation of heart failure . The Outcome of a Prospective Trial of Intravenous Milrinone for Exacerbation of Chronic Heart Failure trial (OPTIME CHF), which is in progress, is a multicenter, randomized, placebo-controlled trial of a treatment strategy using early intravenous milrinone for acute exacerbations of coronary heart failure . Patients with known systolic heart failure (LVEF <_40%) requiring admission for exacerbation of heart

25

t;,

failure will be randomized within 24 hours of admission to receive either a 48-hour infusion of intravenous milrinone or intravenous placebo in addition to standard therapy . No invasive hemodynamic monitoring is required . Patients will be excluded if they require intravenous vasopressor/inotrope support, require admission primarily for concurrent morbidity, or have evidence of myocardial ischemia within the past 3 months . The primary end point is a reduction in the total number of days of hospitalization for cardiovascular events within 60 days after therapy . An important secondary outcome is the proportion of patients achieving target dosing of ACE-inhibitor therapy at discharge . Other secondary end points include reduction in treatment failures at 48 hours, improved subjective outcome, and a reduction in all hospital days, death, and adverse events at 60 days . An estimated sample size of 500 patients per treatment arm will allow greater than 80% power to detect a I-day difference in hospitalization at a 0 .05 significance level (two-sided) . Enrollment of 1000 patients began in July 1997 at 80 U .S . centers and should conclude within 2 years .

Antiarrhythmic agents Antiarrhythmic drugs have been associated with an increase in mortality rate in patients with LV dysfunction despite their capability of suppressing ventricular premature depolarizations and short runs of nonsustained ventricular tachycardia . 183 Antiarrhythmic agents other than amiodarone are contraindicated in patients with advanced heart failure . 184-186 The only possible exception may be d-sotalol, which increased the mortality rate in patients with moderate LV dysfunction but did not appear to increase the mortality rate in patients with very low LVEF . Further studies may have to clarify the role of d-sotalol in patients with advanced heart failure . Amiodarone is the first-line antiarrhythmic agent for patients with chronic heart failure . 187-189 Hemodynamically, it is well tolerated and has a low potential for inducing arrhythmias . It may decrease the mortality rate in patients with severe heart failure, particularly if their heart rate is higher than 90 beats/min . 190 These effects appear to be more striking in patients with a primary cardiomyopathy than in patients with heart failure related to coronary artery disease . 38 Bradyarrhythmias may present a problem in patients receiving amiodarone therapy, and some of these patients may require pacemaker therapy . 191 Before treatment with amiodarone is started,

26

Gheorghiade ;et al hyperthyroidism and advanced liver disease should be excluded . The maintenance dose for amiodarone should be between 200 and 300 mg/day, keeping in mind the potential for interference with the warfarin dosage and serum digoxin concentration . High doses of amiodarone may cause initial cardiac decompensation in patients with very abnormal hemodynamics, and it is therefore prudent to avoid the use of high loading doses in patients with very severe forms of heart failure . 192 In addition to being useful for suppressing or controlling ventricular arrhythmias, amiodarone may convert or prevent the development of atrial fibrillation . 193

Implantable cardiac defibrillator in patients with advanced heart failure The Multicenter Automatic Defibrillator Implantation Trial (MADIT) 194 has shown that in patients with LV dysfunction and a previous myocardial infarction who are at high risk for ventricular arrhythmias, prophylactic therapy with an implantable cardiac defibrillator leads to improved survival compared with conventional medical therapy . This form of therapy may not be as beneficial in patients with advanced heart failure, because most of those patients are dying of progressive heart failure and secondary ventricular fibrillation (ventricular fibrillation resulting from hemodynamic decompensation) . In addition, it is possible that repeated defibrillation can worsen the hemodynamics that is already compromised in patients with advanced heart failure . 195

Anticoagulants According to the ACC/AHA guidelines anticoagulation with warfarin should be reserved for patients with atrial fibrillation, a history of embolic events, and possibly those with LV thrombi and an ejection fraction <20% . 57 Although the embolic event rate is relatively low in patients with heart failure, 196,197 the risk of such events may be higher in patients with advanced disease . 198 Warfarin has also been shown to be beneficial in patients at high risk after myocardial infarction . 199,200 Data from the Third Stroke Prevention in Atrial Fibrillation Study (SPAF-111) 201 and the Coumadin Aspirin Reinfarction Study (CARS) 202 suggest that lowlevel anticoagulation is not effective in patients with nonrheumatic atrial fibrillation or in patients who have had a myocardial infarction receiving aspirin, and it may be associated with an increase in the rate of intracerebral events . Accordingly, if warfarin is used in patients with heart failure who are in sinus rhythm or atria] fibrillation, the inter-

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Ow

,s,Yr

national normalized ratio (INR) should be maintained between 2 and 3 . We believe that in patients at high risk for embolic events such as those with a previous embolic event, it is prudent to use intravenous heparin for several days together with warfarin until the INR is between 2 and 3, because the use of warfarin alone reduces proteins S and C and may increase the risk of thromboembolic events during the initiation of therapy . 203 The use of warfarin therapy in patients with advanced heart failure may be difficult, because some of these patients already have an increased INR as a result of right-sided failure and secondary liver abnormalities . Warfarin requirements may also decrease during exacerbation of heart failure . Recent data suggest that warfarin may be beneficial in patients with moderate to severe heart failure caused by coronary artery disease . 204,205

Aspirin Aspirin therapy has been shown to be particularly effective in reducing ischemic events in patients with stable or unstable angina and patients recovering from a myocardial infarction . 206,207 Aspirin may also be beneficial in reducing embolic and ischemic events in patients with heart failure . 204,208 However, data suggest that therapy with nonsteroidal anti inflammatory agents and aspirin, particularly in high doses, may attenuate the beneficial effects of ACE inhibitors . 209,210 Accordingly, if aspirin is being used concomitantly in patients receiving ACE inhibitors, a low aspirin dose of 81 or 162 mg should probably be used . In addition, we believe that aspirin should not be used in patients with a primary cardiomyopathy in whom an ischemic cardiac event is unlikely to occur. Combining lowdose aspirin and warfarin is not contraindicated . Studies have demonstrated the safety of this combination, particularly when the aspirin dose is low and the INR is maintained between 2 and 3 .211

CONCLUSIONS At this time it appears that ACE inhibitors in combination with diuretics and digoxin is the most important therapy for patients with advanced heart failure, resulting in symptomatic improvement, decreased hospitalizations, and improved survival . In patients unresponsive to therapeutic doses of ACE inhibitors, diuretics, and digoxin, a second or third diuretic should be added . For example, a thiazide or spironolactone might be added to a loop diuretic, particularly if the patient has right-sided failure . Metolazone taken as needed may also be

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important in preventing the development of worsening heart failure . Although not tested, hydralazine and nitrates may be added to ACE inhibitors, digoxin, and diuretics in patients who continue to be refractory to therapy. Hydralazine and nitrates may also be used in patients in whom ACE inhibitors are contraindicated . Angiotensin II receptor blocking antagonists may also be effective in the management of chronic heart failure, although these data require confirmation . In patients not responding to maximally tolerated doses of digoxin, diuretics, ACE inhibitors, and hydralazine and nitrates, intravenous therapy with milrinone, dobutamine, or lowdose dopamine may be considered . However, we believe that this form of therapy may be contraindicated in patients with ischemia and hibernating or stunned myocardium . (3-Adrenergic blocking agents should be considered only for patients receiving triple therapy with ACE inhibitors, digoxin, and diuretics who have hemodynamic compensation and who no longer have NYHA class IV or III symptoms . (3-Adrenergic blocking agents should be initiated at extremely low doses . REFERENCES I . American Heart Association . Heart and stroke facts : 1996 statistical supplement . p . 15 . 2 . Centers for Disease Control . Trends in ischemic heart disease mortality-United States, 1980-1988 . MMWR 1992 ;41 :548-9 . 555-6 . 3 . Eriksson H . Heart failure : a growing public health problem . I Intern Med 1995 ;237 :135-41 . 4 . Ghali IK, 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 :150:769-73 . 5 . National Center for Health Statistics . Detailed diagnoses and procedures, National Hospital Discharge Survey, 1990 . Vital and health statistics, Series 13, No . 113 . Hyattsville (MD) : The Center; 1992 . DHHS publication No. 92-1774 . 6 . McKee PA, Castelli WP, McNamara PM, Kannel WB . The natural history of congestive heart failure : the Framingham Study. N Engl I Med 1971 ;285 :1441-6 . 7 . Massie BM, Shah NB . The heart failure epidemic . Curr Opin Cardiol 1996:11 :221-6 . 8 . Ho KKL, Pinsky IL, Kannel WB, Levy D . The epidemiology of heart failure : the Framingham Study. I Am Coll Cardiol I993 ;22(suppl A) :6A-I3A . 9 . Levit KR, Lazenby HC, Cown CA, et al . National health expenditures, 1990 . Health Care Fin Rev 1991 ;13 :29-54 . 10 . O'Connell lB, Bristow MR . Economic impact of heart failure in the United States : time for a different approach . I Heart Lung Transplant 1994 ;13 :107-12 . It . Schoken DD, Arrieta MI, Leaverton PE . Prevalence and mortality rate of congestive heart failure in the United States . I Am Coll Cardiol 1992 ;20 :301-6. 12 . Gillum RF Heart failure in the United States 1970-1985 . Am Heart 11987 ;113 :1043-5 . 13 . 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 I Med 1987 ;316 :1429-35 . 14 . Califf RM, Adams KF McKenna, et al . A randomized controlled trial of epoprostenol therapy for severe congestive heart fail-

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36 . 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 I Med 1992 ;327 :685-91 . 37 . Packer M, Gheorghiade M, Young IB, et al . for the RADIANCE Study Group . Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors . N Engl I Med 1993 ;329 :1-7 . 38 . Singh SN, Fletcher RD, Fisher SG . et al ., for the Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure . Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia . N Engl I Med 1995 ;333 :77-82 . 39 . Packer M, O'Connor CM, Ghali IK, et al ., for the Prospective Randomized Amlodipine Survival Evaluation Study Group . Effect of amlodipine on morbidity and mortality in severe chronic heart failure . N Engl I Med 1996 ;335 :1107-14 . 40 . Bart BA, Shaw LK, McCants CB, Fortin DF Lee KL, O'Connor CM . The clinical and angiographic diagnosis of ischemic cardiomyopathy : a need to reassess our diagnostic criteria (abstr) . Circulation 1996 ;94 :1-338 . 41 . Bart BA, Shaw LK, McCants CB, et al . Clinical determinants of mortality in patients with angiographically proven ischemic and non-ischemic cardiomyopathy I Am Coll Cardiol 1997 ;30 :1002-8 . 42 . Cody RI . Management of refractory congestive heart failure . Am I Cardiol 1992 ;4 :141-9 . 43 . Cohn IN . The management of chronic heart failure . N Engl I Med 1996 ;335 :490-8. 44 . Kono T. Sabbah HN, Stein PD, Brymer IF Khaja F Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy . Am I Cardiol 1991 ;68 :355-9 . 45 . Nass 0, Rosman H, Al-Khaled N, et al . Relation of left ventricular chamber shape in patients with low (<_40%) ejection fraction to severity of functional mitral regurgitation . Am I Cardiol 1995 ;76 :402-4 . 46 . Edwards NC, Sinusas Al, Bergin ID, Watson DD, Ruiz M, Beller GA . Influence of subendocardial ischemia on transmural myocardial function . Am I Physiol 1992 :262 :H-568-H-576 . 47 . Unverferth DV, Magorien RD . Lewis RP, Leier CV . The role of subendocardial ischemia in perpetuating myocardial failure in patients with nonischemic congestive cardiomyopathy . Am Heart 11983 ;105 :176-9 . 48 . Packer M . The neurohormonal hypothesis : a theory to explain the mechanism of disease progression in heart failure . I Am Coll Cardiol 1992 ;20 :248-54 . 49 . Benedict CR, Johnstone DE, Weiner DH, et al ., for the SOLVD Investigators . Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction : a report from the registry of studies of left ventricular dysfunction . I Am Coil Cardiol 1994 ;23 :1410-20 . 50 . Rockman HA, Juneau C, Chatterjee K, Rouleau IL . Long-term predictors of sudden and low output death in chronic congestive heart failure secondary to coronary artery disease . Am I Cardiol 1989 ;64 :1344-8 . 51 . Dzau VI, Gibbons GH, Cooke DP, Omoigui N . Vascular biology and medicine in the 1990s : scope, concepts, potentials, and perspectives . Circulation 1993 ;87 :705-19. 52 . Treasure CB, Alexander RW . The dysfunctional endothelium in heart failure . I Am Coll Cardiol 1993 ;22(suppl A) :I29A-134A . 53 . Colucci WS . Myocardial endothelin : does it play a role in myocardial failure? Circulation 1996 :93 :1069-72 . 54 . LOscher TF, Boulanger DM, Dohi Y, Yang Z . Endotheliumderived contracting factors . Hypertension 1992 ;19 :1 17-30. 55 . Harrison DG . Endothelial dysfunction in atherosclerosis . Basic Res Cardiol 1994 ;89(suppl 1) :87-102 . 56 . Clinical Practice Guidelines . Heart failure : evaluation and care of patients with left ventricular systolic dysfunction . AHCPR Publication No . 940612 . June 1994 ; Rockville, Md . U .S . Dept of Health and Human Services .

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JANUARY/FEBRUARY 2000

HEART & LUNG