Contemporary management of patients with heart failure

CONTEMPORARY ISSUES IN CARDIOLOGY

0025-7125/95 $0.00 + .20

CONTEMPORARY MANAGEMENT OF PATIENTS WITH HEART FAILURE James B. Young, MD

Heart failure is epidemic. Despite the fact that mortality rates in the United States are declining with respect to coronary heart disease and stroke, hospitalization for heart failure has dramatically increased. One explanation is that the prevalence of symptomatic heart failure rises as populations age. Because of the large at-risk group in the aging United States, the economic and personal impact of heart failure is dramatic and will worsen. It has been estimated that the prevalence of congestive heart failure (CHF), a small subset of the overall heart failure population, is as high as 3 million individuals with approximately 400,000 new cases diagnosed annually.'6, 23, 35, 48 CHF is the only cardiovascular disease with an increasing prevalence, and its incidence doubles in the general population with each decade over age 45.'6,35 Furthermore, heart failure is the third leading cause for hospitalization in all patients and the principal cause in individuals over 65 years of age. Additionally, approximately 35% of the diagnosed heart failure pool of patients are hospitalized annually.'6, 23, 35 In fact, a study by Vinson and associates40 demonstrated that multiple hospitalizations for heart failure patients, particularly elderly heart failure patients, are common. These investigators found that the 3-month readmission rate after an index CHF hospitalization was 47%. Many factors are related to the high rates of hospitalization for heart failure, including progression of underlying disease, inappropriate treatment plans, lack of patient compliance with prescribed regimens or diets, and use of detrimental drug therapy. It is extraordinarily important, therefore, to consider appropriate and aggressive contemporary management of patients with heart failure. Indeed, the most recent clinical practice guideline issued by the U.s. Department of Health and Human Services Agency for Health Care Policy and Research3-5, 13, 23 focused on evaluation and care of patients with left ventricular systolic dysfuncFrom The Section of Heart Failure and Cardiac Transplantation Medicine, Cleveland Clinic Foundation, Cleveland, Ohio MEDICAL CLINICS OF NORTH AMERICA VOLUME 79 • NUMBER 5' SEPTEMBER 1995

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tion and heart failure. To consider optimal management of these patients, one must establish a well-reasoned definition of heart failure, consider means of diagnosing the difficulty, understand the relationship of various therapies to heart failure physiology, and establish appropriate guidelines and recommendations. This article focuses on those topics.

DEFINITION

For some time now, heart failure has been principally viewed as a situation in which the heart's ability to pump blood adequately deteriorates and causes decrement in cardiac output, with subsequent alteration in peripheral bed perfusion!S In the past, heart failure was generally associated with increased venous pressure and dropsical states. Naturally, this definition focused more on latestage clinical settings when symptoms and physical findings are overt, obvious, and generally related to fluid congestion. Insight into the pathophysiology of myocardial and circulatory failure, however, requires contemporary clinicians to view heart failure quite differently.6. 23. 46. 48 We now know that this condition is a complicated, multifactorial milieu with perturbation of multiple neuroendocrine feedback loops occurring after some sort of myocardial injury causes hemodynamic changes, which at times can be extraordinarily subtle. In fact, because initial hOlneostatic compensation can be quite effective, symptoms and physical findings traditionally associated with CHF are often not detectable in heart failure's earliest stages. Subsequently, as compensatory mechanisms themselves become problematic, symptoms and physical findings, again generally related to congestion, develop. Presently, clinicians are moving toward a more encompassing definition of heart failure that highlights abnormalities noted at physiologic, hormonal, cellular, subcellular organelle, and genetic levels long before hemodynamic alterations traditionally associated with CHF can be seen. Table 1 summarizes a contemporary definition of heart failure that is key to consideration of appropriate management strategy. Indeed, heart failure should not be defined today solely as congestive but should include a broad spectrum of adjectives, such as acute or chronic, right-sided or left-sided, systolic or diastolic. It is likely that, in the future, additional adjectives will be included, many describing hormonal or humoral aberrations.

Table 1. A CONTEMPORARY DEFINITION OF HEART FAILURE: IMPORTANT CONSIDERATIONS Myocardial injLlry causes acute or chronic loading state change Peripheral vascular bed blood flow is altered Subsequent humoral, neurohormonal, and mechanical responses appear in an attempt to create circulatory compensation Compensatory mechanisms ultimately produce maladaptive circulatory state Patients may present without symptoms or suffer from a variety of fatigue, dyspnea, or dropsical states that fluctuate in severity based on treatment, diet, physical conditioning, and diseases precipitating the heart failure syndrome In addition to ameliorating symptoms with treatment strategies, early identification of patients with insidious hemodynamic and hormonal perturbation is critical to attenuate heart failure morbidity and decrease mortality

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DIAGNOSIS

To treat heart failure patients properly, an appropriate diagnosis must be made. The evaluation of suspected heart failure no longer simply consists of auscultating pulmonary rales and a gallop rhythm in dyspneic patients with dropsy.'8 Patients may have a wide spectrum of presentations based on predominance of diastolic or systolic dysfunction and selective cardiac chamber enlargement (atrial versus ventricular chambers and right-sided versus left-sided). Diagnostic evaluations must consider varied diseases that can precipitate abnormal chamber filling or emptying dynamics. Evaluation of these individuals must include efforts to determine the cause of heart failure, stage its severity, and identify factors that may have precipitated clinical decompensation. Furthermore, it is important to remember that all dropsical patients do not have heart failure, and complaints of dyspnea do not automatically point toward ventricular dysfunction. Critical questions that must be asked whenever a heart failure evaluation is planned include: (1) Is myocardial or circulatory failure present? (2) What caused the problem? (3) Is the patient's prognosis poor? (4) Can symptoms be eliminated or ameliorated? (5) What can be done to cure or treat the underlying difficulty? Data must be obtained that allows tailoring of appropriate therapeutic maneuvers to prevent, cure, or treat various aspects of the syndrome. As mentioned, it is essential to identify patients with heart failure early, before substantive symptoms develop, to have a greater chance of successfully addressing underlying diseases or, at the least, to prevent further myocardial dysfunction and clinical deterioration. Heart failure, specifically left ventricular systolic dysfunction, should be suspected in symptomatic patients presenting with congestive states (periinfarction patients, particularly those presenting with their second or third infarction); patients with large anterior wall myocardial infarctions; or patients with concomitant complicating diseases that have been present for many years, such as diabetes mellitus and hypertension. Asymptomatic presentations might include perturbed ventricular dysfunction discovered during population screening efforts focusing on patients at high risk of having asymptomatic left ventricular systolic dysfunction. 46 Again, it is important to emphasize that diagnostic maneuvers should be focused on excluding syndromes or diseases with similar symptoms and findings, properly diagnosing concomitant clinical pathology, and carefully staging the syndrome severity because all of these issues relate to choice of a therapeutic strategy. Table 2 summarizes some of the important considerations while diagnosing heart failure. RELATIONSHIP OF THERAPIES TO HEART FAILURE PHYSIOLOGY

Traditionally, therapies for heart failure were focused on relieving the congestive state (diuretics, for example) or increasing cardiac contractility (carTable 2. DIAGNOSIS OF HEART FAILURE: IMPORTANT CONSIDERATIONS

Recognize the heart failure milieu appropriately Clarify which underlying diseases are causing the problem Determine factors precipitating clinical deterioration Stage syndrome severity Establish patient prognosis Relate therapy to pathophysiologic observations and data

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diac glycosides, for example). Figure 1 diagrammatically relates the focus of several major drug classes used in heart failure patients to the major pathophysiologic events observed. Diuretics, for example, relieve congestion and decrease symptoms and physical findings related to volume overload. Antiarrhythmic drugs, theoretically, might diminish life-threatening arrhythmias. Angiotensinconverting enzyme (ACE) inhibitors interdict neurohormonal perturbation and improve hemodynamics by effecting impedance reduction. Some agents work at multiple points in the pathophysiologic milieu (such as ACE inhibitors), whereas others are directed specifically at one difficulty (such as antiarrhythmics). Also, it is important to emphasize that although some drug classes are theoretically beneficial, such as some antiarrhythmic or inotropic drugs, clinical trial data often demonstrate that they are actually dangerous. 2, 14, 34 As insight into the pathophysiology of heart failure grew, a variety of therapeutic end points have been employed to assess efficacy of new treatment paradigms. End points for clinical trials evaluating new drugs have focused on acute, short-term, or long-term goals, Acutely, hemodynamic changes have been believed most important. These generally include an increase in cardiac output with concomitant decrease in ventricular filling pressures. Short-term trial end points focus more on increased exercise tolerance and symptomatic improvement (quality of life issues), whereas long-term goals usually include a drug's effect on mortality reduction or morbidity attenuation. Other important longterm considerations are therapeutic effects on neurohormonal perturbation and cardiac size (both volume and mass), Whenever recommendations are made for using individual drugs or combinations of drugs, the ability of such strategies to achieve all of these end points must be placed into perspective, This can be done by analyzing clinical trial experience. Both large and small clinical studies, when carefully designed and rigorously performed, give great insight into

Pharmacotherapeutic Focus

Vasodilators ACE·I - - - - - - ) .~, .

ACE·I

Digoxin

.. ~

Anti· .....H--arrhylhmics

.ro,,-- Diuretics Figure 1. Venn diagram demonstrating where in the heart failure pathophysiologic milieu various drug classes might effect benefit.

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the best treatment strategies. Clinical trials can confirm or refute therapeutic hypotheses and establish reasonable and rational expectations with regard to various treatment regimens. Also important is the ability of clinical trials to delineate adverse therapeutic outcome or excessive risk. Clinical trials can precisely define best methods for prescription practice as well as directly compare varying approaches to a problem, determining the most advantageous strategies. Finally, clinical trial data can provide a wealth of outcome information so that cost-benefit analysis can be used to design rationally public health policy and patient treatment standards. Table 3 lists selected mortality end point clinical trials in patients with heart failure that have impacted strategies and forced design of a new therapeutic paradigm. Not only do these studies provide information regarding drugs that are beneficial in the heart failure patient, but also they clarify potential practices. The first mortality end point clinical trial that suggested a more therapeutic approach should be considered in patients with CHF was the initial Veterans Administration Cooperative Vasodilator-Heart Failure Trial (VheFT-I).7 This was a landmark study indicating that the direct-acting arterial and venous vasodilating combination of hydralazine and isosorbide dinitrate decreased mortality (although at a marginal statistical significance) in patients with New York Heart Association (NYHA) class II-III CHF when added to digoxin and diuretic therapy. Equally important was the concomitant observation that the peripheral alpha-adrenergic blocking agent prazosin had no significant mortality reduction effect. Although many vasodilators are capable of ameliorating hemodynamic perturbations seen in heart failure, various classes have different effects on mortality. Obviously the suggestion that certain vasodilators have an important role during long-term pharmacologic care of CHF patients was a radical departure from the traditional diuretic-digitalis-based protocols that had been employed for several decades. The second pivitol heart failure mortality trial using a new vasodilator paradigm was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),'0 which used the ACE inhibitor enalapril in severely ill NYHA class IV CHF patients. In addition to a profound 40% reduction in mortality, also noted was an improvement in heart failure signs or symptoms, heart size, functional class, and number of hospital admissions. The Multicenter Diltiazem Post Myocardial Infarction Trial (MDPIT)25 is an example of a clinical study not specifically focused on heart failure patients per se but ultimately providing a great deal of insightful information regarding drugs and ventricular dysfunction. In this double-blind, placebo-controlled trial, the calcium channel blocker diltiazem was given routinely to patients post infarction and continued during long-term follow-up. The patient group with an ejection fraction less than 40% actually had a statistically significant increase in adverse event rates. In a similar vein, the Cardiac Arrhythmia Suppression Trial (CAST)14 convincingly demonstrated that potent Vaughn-Williams class I antiarrhythmic drugs (in this case, flecainide and encainide) substantially increased mortality when given to suppress minimal ventricular arrhythmia observed after myocardial infarctions. Although not selecting patients with clinical heart failure or left ventricular dysfunction specifically, 80% of the trial population had an ejection fraction less than 50%. Xamoterol (Corwin) is a compound that, at one time, was thought beneficial in heart failure because of its intrinsic sympathomimetic effects. 2B,41 Study of this drug was propelled by the concept that increasing contractility in patients with left ventricular systolic dysfunction was important. Interestingly, marked increase in mortality was observed, pointing out that certain aspects of positive inotropism were actually detrimentaL The first report from the Studies of Left

.... ....

~

Table 3. MORTALITY END POINT CLINICAL TRIALS IN HEART FAILURE PATIENTS Trial' VheFT·I,81986

Treatment

N

Outcome

t Mortality with HYD/ISD -;. Mortality with prazosin t Mortality

642

CONSENSUS," 1987

HYD/ISD or prazosin vs placebo Enalapril vs placebo

MDPIT,25 1988

Diltiazem vs placebo

2466

t

CAST,14 1989

3549

t

Xamoterol,41 1990 SOlVD-Rx,37 1991

Encainide, flecainide, or morizicine vs placebo Xamoterol vs placebo Enalapril vs placebo

516 2569

t t Mortality t Mortality

VheFT 11,9 1991 PROMISE,26 1991 SOL VD-Prevent, 38 1992

Enalapril vs HYD/ISD Milrinone vs placebo Enalapril vs placebo

804 1088 4228

SAVE,30 1992

Captopril vs placebo

2231

Vesnarinone,'5 1993

Vesnarinone vs placebo

253

564

1

t

1

t t

Adverse events post MI when EF <40% t Mortality

Mortality t Mortaltiy -;. Mortality t Morbidity Mortality

t 1 Mortality (but 120 mg

AIRE,' 1993

Ramipril vs placebo

2002

t

SPRINT,20 1993

Nifedipine vs placebo

1358

i

GESICA,12 1994

Amiodarone vs placebo (unblinded)

516

i

deaths)

Mortality

Mortality in post-M I CH F patients t Mortality

Clinical Implication Vasodilator hypothesis attractive; not all affect decrease in mortality despite improved hemodynamics acutely ACE-I has profound impact on mortality in severe NYHA IVCHF Raises concern about diltiazem in post·MI patients with CHF Raises concerns about antiarrhy1hmic drugs in post-M I patients with heart failure (80% with EF <50%) Certain inotropes detrimental ACE-I benefits noted even in mild/moderate CHF (NYHA

111111)

ACE-I mortality effect greater than direct vasodilator PDE-I proarrhythmic ACE-I prevents CHF; suggests first-line therapy in minimally ill NYHA 1-11 patients Tested benefits of attenuating post MI remodeling when EF <40% Most profound decrease yet in CHF mortality, but reasons are unclear (antiarrhy1hmic effects? cy10kine effects? PDE?) Complements SAVE and SOlVD-Prevent observations in acute MI patients with CHF symptoms Nifedipine may be hazardous and seems contraindicated in high-risk post-M I patients Effect appears independent of antiarrhy1hmic actions

'See references for study abbreviations. ACE-I = Angiotensin-converting enzyme inhibitor; CHF = Congestive heart failure; EF = Ejection fraction; HYD/ISD infarction; NYHA = New York Heart Association; PDE = phosphodiesterase inhibitor. t = Increased; t = Decreased; -;. = No change.

Hydralazine/isosorbide dinitrate; MI

Myocardial

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Ventricular Dysfunction (SOL VD)38 group also detailed experience with the ACE inhibitor enalapril in heart failure. The Treatment Trial was designed to determine the effects of enalapril on mortality, morbidity, and quality of life when added to generally mild-to-moderate CHF when ejection fraction was less than 35%. Substantive reduction in mortality was noted. A second and subsequent Veterans Administration Cooperative Vasodilator Heart Failure Trial (VheFTII)8 further investigated the vasodilator in heart failure hypothesis with a comparison of the ACE inhibitor enalapril to the direct-acting drug combination of hydralazine and isosorbide dinitrate. As in VheFT-I, observations made suggested that not all vasodilators were alike in heart failure. Enalapril even further reduced mortality despite the fact that the combination of direct-acting vasodilators effected increased ejection fraction and improved exercise tolerance. Phosphodiesterase inhibitors have also been evaluated in heart failure patients because of their combined vasodilatory and inotropic effects. Unfortunately the Prospective Randomized Milrinone Survival Evaluation (PROMISE)26 had to be terminated early because of excessive drug treatment-linked mortality (34% increase in cardiovascular death). Milrinone appears to be dangerously proarrhythmic in the manner used in PROMISE. The SOLVD Prevention TriaP7 was identical in design to the SOLVD Treatment Trial with the exception that patients were to have asymptomatic (or minimally symptomatic), nonovert heart failure manifest by left ventricular systolic dysfunction (ejection fraction <35%). In this aspect of the SOLVD program, a less profound mortality reduction (8% overall and 12% cardiovascular, a finding that was not statistically significant) was observed, but symptomatic heart failure was delayed or prevented in 37% of patients, a highly significant observation and one that gave support to the contention that treatment strategies should be tailored to the severity of a patient's clinical state and that an ACE inhibitor likely was the first-line therapeutic choice in individuals with heart failure manifest by systolic left ventricular dysfunction. The Survival and Ventricular Enlargement (SAVE)"o trial randomized patients with an ejection fraction of 40% or less to captopril or placebo in addition to usual therapy 3 to 17 days post acute myocardial infarction. Patients generally did not exhibit classic evidence of CHF and, other than the time of randomization post infarction, closely resembled the SOLVD Prevention Trial population. A 17% reduction in cardiovascular mortality and a 24% reduction in reinfarction were evident in patients receiving the ACE inhibitor. Vesnarinone is a new, promising drug in heart failure that may effect benefit in novel fashion. The reported lS mortality reduction was the greatest yet seen in clinical heart failure trials. Although hemodynamics are not greatly affected, and the compound is but a weak inotropic agent (if it is one at all), this observation has produced great excitement. The Acute Infarction Ramipril Efficacy (AIRE) study! was similar in design to SAVE, with the exception that a different ACE inhibitor was studied, and rather than an entry criterion of depressed postinfarction ejection fraction, the clinical syndrome of CHF after myocardial infarct was studied. As with SAVE, a significant mortality reduction was observed. A more recent calcium channel blocker postinfarction study that employed nifedipine was similar to MDPIT. The Second Prevention Israeli Nifedipine Trial (SPRINT)2° demonstrated no benefit for the nifedipine group, and, indeed, early mortality was higher in patients assigned to nifedipine (7.8% versus 5.0%). Finally, the GESICA trial,12 a randomized, although unblinded, mortality end point clinical study of amiodarone in moderately severe chronic CHF with left ventricular systolic dysfunction, was positive in its result. Interestingly, reduction in mortality observed may have been independent of amiodarone's antiar-

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rhythmic actions. Still the observed results were in sharp contrast to the CAST trial. This spectrum of clinical trials studied drugs frequently used today, include ing ACE inhibitors, nitrates, direct-acting vasodilators, and antiarrhythmics, as well as compounds considered experimental. Of this latter category, xamoterol and oral milrinone will likely not become available; if subsequent vesnarinone studies confirm benefit, it undoubtedly will be employed with some frequency. With this clinical trial background, it is appropriate to review specific drug classes with respect to use in the heart failure patient. It is interesting and important to note that studies of diuretics and digitalis glycosides are absent from Table 3 and the previous discussion. Despite these drug classes being mainstays of therapy in CHF patients for a long period of time, no mortality end point clinical trials have yet been reported, although results of the DIG (Digitalis In Heart Failure Group) trial may be available in late 1995. SPECIFIC DJ:{UG CLASSES USED IN HEART FAILURE

Treatment of patients with heart failure must be highly individualized or tailored to clinical circumstances. Table 4 summarizes the principal effects of the basic classes of drugs used for heart failure therapy. It is important to consider these nuances to optimize treatment protocols. Diuretics

As mentioned, dropsy can be a component of heart failure. When pulmonary or peripheral edema is present, diuretics can be invaluable agents to alleviate salt and water retention. Generally the least toxic drugs in this class (thiazides such as hydrochlorothiazide or chlorthalidone) are prescribed in the lowest dose needed to create effective diuresis (Table 5). As congestion worsens, more potent loop diuretics (such as furosemide or bumetanide) are prescribed. Occasionally, for particularly refractory edematous conditions, combinations of different diuretic classes may be necessary and effective. By reducing blood volume, diuretics lower cardiac filling pressure with subsequent reduction in wall stress, pulmonary edema, and peripheral congestion. Diuretics are, however, associated with significant concomitant difficulties. 23,43 Electrolyte abnormalities can be life-threatening (hypokalemia with metabolic alkalosis or hypomagnesemia, for example), and reduction in plasma volume might reflexively activate the renin-angiotensin-aldosterone system as well as the sympathetic nervous system, paradoxically promoting further sodium and water retention while increasing impedance to left ventricular ejection. Theoretically, this effect could contribute to the progression of heart failure. For these reasons, diuretic therapy alone may not now be justified during heart failure treatment. Furthermore, the impact of long-term diuretic therapy in heart failure patients with respect to mortality is unknown. Controversy exists regarding optimum methods for diuretic prescriptionY Some patients may respond to a transient pulse of diuretics by resolving their congestive state and, with a low-salt diet, do not require long-term diuretic therapy. Other patients might need intermittent, but regular, pulses of diuretics, whereas some require continuing administration of diuretics in large doses (or combinations) because of chronic congestive states. Stopping the diuretics or creating interval drug holidays should be considered in patients who have been

Table 4. DRUG CLASSES USED IN HEART FAILURE: HEMODYNAMIC, NEUROHORMONAL, AND CLINICAL EFFECTS Short-Term Hemodynamic Effects

Class of Agent Diuretics

J, Blood volume J, Cardiac filling pressure

t t

Sympathetic activity Renin-angiotensin activity

ACE inhibitors (enalapril, captopril, lisinopril, quinapril)

t

Left ventricular filling pressure Systemic vascular resistance

t

Renin-angiotensin activity

Inotropic activity Cardiac output Left and right ventricular filling pressures Systemic vascular resistance

t t

Sympathetic activity Renin-angiotensin activity

Digoxin

t

t

t t t

t = Increased; ~ = decreased. ACE = Angiotensin'converting enzyme.

Long-Term Effects

Neurohormonal Effects

t t t

Edema Pulmonary congestion Exercise tolerance J, Symptoms t Exercise tolerance t Symptoms t Mortality Prevention of deterioration of left ventricular function Prevention of symptomatic failure in asymptomatic left ventricular dysfunction patients t Exercise tolerance J, Symptoms t Hospitalizations and emergency room visits

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Table 5. MEDICATIONS COMMONLY USED FOR HEART FAILURE

Drug

Initial Dose (mg)

Target Dose (mg)

Recommended Maximal Dose (mg)

Major Adverse Reactions

Thiazide diuretics Hydrochlorothiazide 25 once a day Chlorthalidone 25 once a day

As needed As needed

50 once a day 50 once a day

Loop diuretics Furosemide

Postural hypotension, hypokalemia, hyperglycemia, rash. Rare severe reaction includes pancreatitis, bone marrow suppression, and anaphylaxis

As needed

240 twice a day

Same as thiazide diuretics

As needed As needed

200 once a day 10 once a day

As needed

200 twice a day

As needed

10 once a day

Same as thiazide diuretics

As needed As needed As needed

100 twice a day 100 twice a day 40 once a day

Hypotension, especially if administered with ACE inhibitor; rash; gynecomastia (spironolactone only)

10-40 once a day Torsemide 10 once a day Bumetanide 0.5-1.0 once a day Ethacrynic acid 50 once a day Thiazide-related diuretic rIiIetolazone 2.5* Potassium-sparing diuretics Spironolactone 25 once a day Triamterene 50 once a day Amiloride 5 onCe a day

ACE inhibitors (approved for heart failure therapy) Enalapril 2.5 twice a day 10 twice a day Captopril 6.25-12.5 50 3 times/day 3 times/day lisinopril 5 once a day 20 once a day Quinapril 5 twice a day 20 twice a day Digoxin 0.25 once a As needed day Hydralazine

10-25 3 times/ day

75 3 times/day

Isosorbide dinitrate

10 3 times/day

40 3 times/day

20 twice a day Hypotension, 100 3 times/day hyperkalemia, renal insufficiency, cough, 40 once a day skin rash, angioedema, 20 twice a day neutropenia As needed Cardiotoxicity, confusion, nausea, anorexia, visual disturbances 100 3 times/day Headache, nausea, dizziness, tachycardia, lupuslike syndrome 80 3 times/day Headache, hopotension, flushing

*Given as a single test dose initially. ACE = Angiotensin·converting enzyme. Modified from Konstam M, Dracup K, Baker D, et al: Heart failure: Evaluation and care of patients with left ventricular systolic dysfunction. Clinical Practice Guideline No. 11. AHCPR Publication No. 94· 0612. Rockville, MD, Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, 1994.

on diuretics for chronic CHF but have had resolution of their fluid retention state. One caveat may be the use of diuretics for treating hypertension. Some clinical antihypertensive agent trials have demonstrated that long-term thiazide diuretic therapy prevents development of CHF failure in some patients with significant hypertension. Direct-Acting Vasodilators It is now well accepted that dilatation of the peripheral vasculature produces beneficial effects in heart failure patients. 6- 'o Relaxing venous capacitance

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vessels diminishes preload, while peripheral arteriolar bed vasodilation drops afterload and, therefore, impedance to ventricular emptying. Venous capacitance vessels can be dilated by nitrates (such as nitroglycerin, isosorbide dinitrate, and nitroprusside). Arterial resistance vessels are dilated by hydralazine. Combination of arterial and venous dilation occurs with ACE inhibitors and some alphaadrenergic blockers (prazosin and phentolamine). Calcium channel blocking drugs are arterial dilators as well, but concern exists regarding their use in the heart failure setting.ll, 1B, 20, 25 Dilatation of the arteriolar bed alone, without concomitant venous dilatation, likely fails to achieve sustained benefit in chronic CHF. Likewise, although acute dyspnea can be alleviated with ad hoc administration of short-acting sublingual nitroglycerin, long-term attenuation of neurohormonal perturbation or mechanical responses to the failing ventricle may not be seen. Interestingly, combinations of hydralazine and nitrates in doses that provide balanced vasodilatory effects prove beneficial as demonstrated in VheFT-I (see Table 3), in which mortality was reduced by more than 38% in moderate CHF patients when this vasodilator regimen was added, generally, to digoxin and diur~tic therapy. Angiotensin-Converting Enzyme Inhibitors

As might be anticipated from study of heart failure clinical trials (see Table 3), ACE inhibitors have now assumed the role of first-line drug of choice in patients with heart failure. This is because of their multifactorial benefits,>4 including interdiction of renin-angiotensin-aldosterone system activation and balanced arterial and venous vasodilator effects. Although these drugs block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and aldosterone-release stimulator, the drugs may have additional benefit by promoting activation of vasodilating prostaglandins. Furthermore the broadest spectrum of heart failure patient has been studied with ACE inhibitors. 6,7, 9, 10, 19,30,32, 33,37, 3B, 45, 49 Clinical trials studying asymptomatic patients with systolic left ventricular dysfunction as well as terminally ill, NYHA class IV, chronic CHF patients justify their use in such a broad spectrum,45,49 Many double-blind, placebo-controlled, clinical trials have demonstrated the ability of ACE inhibitors to relieve dyspnea, improve exercise tolerance, decrease incidence of hospitalization and emergency room care for patients with mild-to-moderate heart failure, and prevent the development of symptomatic CHF in those patients with asymptomatic systolic left ventricular dysfunction (see Table 3), In patients without symptomatic CHF, ACE inhibitors should be considered first-line drug therapy (even as monotherapy), As congestive symptoms develop, combining ACE inhibitors with digoxin and diuretics becomes important. Of the many clinically available agents in this class in the United States, clinicians should probably prescribe those that have been well studied in clinical trials of heart failure.2l, 31, 32, 50 Cardiac Glycosides

The cardiac glycosides (today principally meaning digoxin) are the only drugs with positive inotropic effects available for long-term, outpatient, oral use. Digoxin acts principally by inhibiting the cardiac muscle cell's sodium pump, which effects intracellular calcium buildup and subsequent force of myocardial contraction. 27 Higher levels of intracellular sodium, secondary to

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sodium pump inhibition, produce a shortened refractory period (heightened cell excitability) as a result of reduced muscle cell membrane potential. Improved ventricular contractility leads to increased cardiac output, decreased filling pressures and volumes, and decreased systemic vascular resistance. Digitalis glycosides also inhibit the renin angiotensin system and reduce fluid retention. Debate has raged for many years over the clinical utility of digitalis glycosides in heart failure. This debate was spurred mainly by concerns for potential toxicity and difficulties encountered during study of some patient groups with regard to clinical benefit. No large-scale mortality end point clinical trial data are yet available with respect to digoxin. Two clinical trials,17, 27, 39, 42 however, the Prospective Randomized Study of Ventricular Failure and the Effect of Digoxin (PROVED) and the Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme (RADIANCE), were designed to assess the contribution of digoxin treatment to patients' clinical status when used in a setting of either diuretic therapy or combination diuretic-ACE inhibitor therapy.27,39 Both clinical trials were similarly designed with patients having mild-to-moderate CHF (ejection fraction <35%) treated with digoxin and diuretics (PROVED) or digoxin, diuretics, and ACE inhibitors (RADIANCE). In both studies, a blinded randomization schedule determined which patients were to have digoxin replaced by placebo. End points of the study included maximal exercise capacity, incidence and probability of treatment failure with and without digoxin, control of the signs and symptoms of CHF, and changes in 'certain parameters of ventricular function. Patients were all in sinus rhythm. Both studies demonstrated that withdrawal of digoxin therapy led to significant increase in the probability that heart failure would worsen over time with reduction in exercise tolerance. Digoxin therapy was also related to better ventricular performance. CONTROVERSIAL DRUGS USED IN SOME HEART FAILURE PATIENTS

Although certain therapeutic strategies make intuitive sense when heart failure is diagnosed, clinical trials have not always proved logical hypotheses correct. It is equally important to avoid potentially problematic compounds as to prescribe efficacious agents. 2 , 48 Calcium Channel Blockers

Calcium channel blockers, as a group, are an example of drugs that may create problems in patients with heart failure.'" 18, 20, 25 Although these agents lower systemic vascular resistance, they have negative inotropic effects. Newer drugs in this class (nicardipine, nitrendipine, felodipine) seem to have less negative inotropic activity and more potent selective peripheral vasodilatory effects; however, to date, no sustaining symptomatic benefit has been demonstrated for these compounds. Indeed, in patients who have had acute myocardial infarction with left ventricular systolic dysfunction, some of the calcium channel blockers have proved detrimental with a greater chance of adverse effects noted in patients randomized to calcium channel blocker groups. Because patients with heart failure frequently have concomitant ischemic heart disease or hypertension, these drugs are frequently found as concomitant therapeutic regimens!7 This strategy might best be reassessed on an individual patient basis, In the

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patient with heart failure, control of hypertension with ACE inhibitors and treatment of angina pectoris with nitrates could be considered as substitutes for calcium channel blocker use. Antiarrhythmic Drugs

One of the more difficult issues to address in patients with heart failure is arrhythmia. 14,34 The prevalence of substantive ventricular dysrhythmia is high, and the temptation to use antiarrhythmic drugs can be great. Unfortunately the vast majority of clinical trials have demonstrated an inverse relationship between ventricular function and antiarrhythmic drug benefit. 34 In fact, as left ventricular ejection fraction falls, the likelihood of arrhythmia control diminishes, with risk of proarrhythmia and adverse events substantially increasing. Amiodarone may be the one exception. One clinical trial suggested that low-dose amiodarone was safe and efficacious in patients with heart failure. This was, however, an unblinded study, and the hypothesis awaits confirmationY Furthermore the beneficial effects of amiodarone may have been independent of antiarrhythmic action of the drug. Anticoagulants

Routine anticoagulation in patients with heart failure is not recommended. s Patients with substantive CHF also frequently have significant hepatic congestion, and, because of this, anticoagulation can be difficult to achieve safely. Furthermore, with the large number of drugs taken by patients with heart failure, an important tenet is to continue only those medications with demonstrable effectiveness. This practice ensures compliance with drug treatment regimens. Routine anticoagulation in heart failure patients has never been demonstrated to be beneficial by well-designed clinical trials. Heart failure patients with a history of systemic or pulmonary embolism, recent atrial fibrillation, or mobile left ventricular thrombi might be considered candidates for anticoagulation with a goal of an International Normalization Ratio of 2.0:3.0. Nonsteroidal Anti-Inflammatory Drugs

Because of their effect on prostaglandin pathways, nonsteroidal antiinflammatory drugs are known to alter renal flow dynamics and promote problems, including fluid retention states and worsening renal function, when prescribed in patients with CHFY, 23, 47, 48 Ad hoc utilization of this class of compounds needs to be considered in any patient having unexplained clinical deterioration, including increased congestion or worsening renal function. The benefits and risks of regular use of these agents must be carefully weighed. END-STAGE HEART FAILURE

End-stage heart failure can be defined as a clinical syndrome in those individuals with heart failure and clinical findings predicting a 50% to 75% 1year and greater than 90% 2-year mortality, Generally, this includes patients with severe, chronic, and profound circulatory congestion, in the face of low

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ejection fraction and pulmonary hypertension with markedly elevated left ventricular filling pressures. Patients with dysrhythmias, hyponatremia, marked cytokine activation (tumor necrosis factor-alpha, for example), high catecholamine levels, markedly dilated hearts, and MVo 2 levels less than 10 mL/kg/min are generally characteristic of this group. In addition to the triple therapy options for management of heart failure described subsequently, long-term parenteral drug infusion (usually with dobutamine, dopamine, milrinone, or amrinone) can sometimes be helpful. 48 Occasionally, these patients benefit from high-risk coronary artery bypass graft placement, valve replacement or repair, or left ventricular aneurysmectomy (Table 6). Long-term peritoneal dialysis can alleviate volume loading difficulties when renal insufficiency and volume overload become tremendously problematic. Rarely a patient may be a reasonable candidate for cardiac transplantation. Experimental options for these individuals to date include dynamic cardiomyoplasty and a variety of temporary and permanent ventricular assist devices. Insufficient progress has been made with total artificial hearts to view them as a realistic option for the near future. GENERAL PRINCIPLES OF HEART FAILURE TREATMENT STRATEGIES

Table 7 summarizes the general principles of heart failure therapeutics. It must be again emphasized that, first, an appropriate diagnosis should be made. 3 , 23,28,48 Dyspnea, edema, and rales are not always due solely to CHF, Next, appropriate staging of the syndrome'S severity must be accomplished, The discovery of asymptomatic left ventricular systolic dysfunction is extraordinarily important so that early intervention with ACE inhibitors can be accomplished to prevent left ventricular functional deterioration and to promote beneficial remodeling. Furthermore, staging ultimately relates to number of drugs used because a diagnosis of heart failure does not always mean congestive heart failure. As mentioned previously, only those patients with a congestive state should receive diuretics. Treatment of underlying diseases or precipitating problems is critical." 23, 48 Heart failure per se cannot be cured unless the underlying disease state is eliminated. This, unfortunately, is rarely possible. Still, heart failure caused by hyperthyroidism or hypothyroidism, for example, might be totally alleviated with creation of a euthyroid state. Additionally, treating coronary heart disease

Table 6. CONSIDERATIONS IN END-STAGE HEART FAILURE PATIENTS Long-term parenteral drug infusion Dobutamine, dopamine, milrinone, amrinone Higher-risk standard operative procedures CABG, valve repair/replacement, left ventricular aneurysmectomy Long-term peritoneal dialysis Cardiac transplantation Experimental operative procedures Dynamic cardiomyoplasty (cardiac wrap, extracardiac pump wrap) Ventricular assist devices Total artificial heart implantation CABG

=

Coronary artery bypass.

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Table 7. HEART FAILURE THERAPEUTICS: GENERAL PRINCIPLES Make appropriate diagnosis Dyspnea, edema, and rales are not always congestive heart failure Stage syndrome severity Discover asymptomatic left ventricular systolic dysfunction Heart failure does not always mean congestive heart failure Therapeutics of heart failure varies with severity of syndrome Treat underlying diseases Address etiologic problems Eliminate exacerbating factors Consider surgical options Stop potentially harmful drugs or those of unproven benefit Antiarrhythmic agents Calcium channel blockers Nonsteroidal anti-inflammatories Antihistaminics Beta-blockers (?) Anticoagulants (?) Begin therapeutic regimens with proven efficacy Drugs to prevent functional deterioration ACE inhibitors Drugs to reduce mortality ACE inhibitors Hydralazine/isosorbide dinitrate Drugs to control symptoms Diuretics Digoxin ACE inhibitors Hydralazine/isosorbide dinitrate Prescribe rational polypharmacy Fewest side effects possible Program designed to ensure compliance Consider cost of drugs employed ACE

= Angiotensin-converting enzyme.

that is causing myocardial ischemia could beneficially affect left ventricular function. Because heart failure patients frequently are on many drugs, some possibly harmful or of unproven benefit, discontinuation of those compounds is important. One should always ask whether antiarrhythmic agents, calcium channel blockers, nonsteroidal anti-inflammatory compounds, or antihistaminics have played a role in patients' deterioration or, in fact, are necessary. The use of betablockers and anticoagulants is more controversial because, in certain patient subsets, improvement might be noted. Still, it is wise to ask oneself if these drugs are required. Next, one should begin therapeutic regimens with proven efficacy.6, 9, 31, 32 This would include drugs (such as ACE inhibitors) to prevent functional deterioration, particularly in the asymptomatic patient with left ventricular systolic dysfunction. Inclusion of drugs that reduce mortality in any treatment protocol is also obviously important. In addition to ACE inhibitors, the combination of hydralazine and isosorbide dinitrate is available. When symptomatic CHF is present, particularly with depressed ejection fraction and cardiomegaly, diuretics and digoxin become extraordinarily important. Indeed, taken together, the

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PROVED and RADIANCE trials demonstrated that, in patients with CHF, triple therapy with digoxin, ACE inhibitor, and diuretic proved best with respect to controlling heart failure symptoms and preventing clinical deterioration.23 Because polypharmacy is so frequent in the heart failure patient (they are taking a median of four drugs), rational prescription of multiple drugs is necessary.48 When many drugs are simultaneously dispensed, each compound prescribed should affect pathophysiologic processes via different and complementary mechanisms. Compounds used should, ideally, have different sites of metabolism or excretion, the toxicity of one drug should not be increased by another, and each drug's beneficial effects should be enhanced. Furthermore a program designed to ensure optimal compliance is essential as well as consideration of the cost of drugs employed. Thought must also be given to use of drugs studied adequately in clinical trials such that enough information is available regarding appropriate dose, administration technique, anticipated adverse effects, and likelihood of mortality reduction. This is particularly relevant to a discussion of ACE inhibitors. Four of the eight clinically available compounds have been approved for use in patients with heart failure (enalapril, captopril, lisinopril, and quinapril). To date, however, only enalapril and captopril and lisinopril (post myocardial infarction) have been studied in large clinical trials with a focus on mortality end points. 3},32 Furthermore, all of these drugs have been used with target dosing principles in mind rather than by giving the drug in a fashion related to clinical improvement or benefit. Two additional issues to consider are activity recommendations and dietary restrictionY There is reasonable agreement that regular aerobic exercise, such as walking, bicycling, or rowing, should be encouraged for all patients with stable NYHA class I through III heart failure. Although insufficient evidence is available to recommend routine supervised rehabilitation programs, this may be of benefit, particularly in patients who are dyspneic at low work levels or who have had angina pectoris, a recent myocardial infarction, or recent coronary artery bypass graft procedure. Although sudden vigorous exercise is unwise, no longer do clinicians recommend avoidance of aerobic tasks when heart failure is present. Long-term bed rest as practiced in decades past is not necessary for most heart failure patients. In many senses, the left ventricular unloading effected in the past by bed rest is today captured with vasodilators. It has been demonstrated that improvement noted with prudent exercise training in heart failure results from beneficial effects on peripheral muscle metabolism rather than amelioration of myocardial function. Dietary recommendations are important as well and should include sodium restrictionY' 23 Generally, a 2-g sodium diet is recommended, although the necessity for this degree of sodium restriction is not truly known. This stringent degree of sodium restriction is usually quite unpalatable and costly. Noncompliance with diet may occur, and this is one prime reason for deterioration requiring hospital admission. Excessive salt intake may make diuretics ineffective and cause potassium wasting. A 3-g sodium diet may be much more reasonable and is achieved generally by not adding salt to foods and avoiding commercially prepared items that are particularly salty. Because alcohol depresses myocardial contractility, patients should be careful about the quantity of alcohol ingested. This may be particularly significant in certain heart failure patients haVing cardiomyopathy as their underlying difficulty. Complete alcohol abstinence is critical in those with a diagnosis of alcohol-induced cardiomyopathy. Other dietary considerations should include adequate magnesium consumption and reasonable protein intake, Because patients with severe heart failure may suffer

CONTEMPORARY MANAGEMENT OF PATIENTS WITH HEART FAILURE

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• Heart transplant • Mechanical support • Cardiomyoplasly

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• ACE InhibitorsJor hydralazinel isosorbide initrate) • Diuretics (for congested state) • Digitalis

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• Select ACE Inhibitors (Captopril. Enalapril. lisinopril. Quinapril)

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• Stage severity of syndrome • Disease specific therapy

Figure 2. Contemporary heart failure treatment strategy that is based on symptomatic severity with patients' treatment schemes individualized or personally tailored. Today, ACE inhibitors are first-line therapies for heart failure, even when patients are asymptomatic. In symptomatic (usually congestive) heart failure, other strategies are helpful, including digitalization and diuretic addition.

from cardiac cachexia, adequate protein and vitamin consumption should be encouraged. No proven role exists for high-dose antioxidant vitamin therapy or Co-QlO ingestion to treat heart failure. SUMMARY

Treatment of patients with heart failure has become extremely challenging. A complicated interplay of myocardial, hemodynamic, and humoral factors marking this condition requires a delicate balancing of medication use, procedural intervention, and lifestyle changes. Judicious prescription of therapies in stepwise fashion as the syndrome severity worsens (Fig. 2) is critical to success. ACKNOWLEDGMENT The author would like to thank Marlane Kayfes for her editorial and graphic design assistance. The author was a principal investigator in the SOL VD, PROVED, and RADIANCE trials discussed in this article.

References 1. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarctions with clinical evidence of heart failure. Lancet 324:821-828, 1993

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2. Amidon TM, Parmley WW: Is there a role for positive inotropic agents in congestive heart failure: Focus on mortality. Clin Cardiol 17:641-647, 1994 3. Baker DW, Konstam MA, Bottorff M, et al: Management of heart failure: I. Pharmacologic treatment. JAMA 272:1361-1366, 1994 4. Baker DW, Jones R, Hodges J, et al: Management of heart failure: Ill. The role of tevascularization in the treatment of patients with moderate or severe left ventricular systolic dysfunction. JAMA 272:1528-1534, 1994 5. Baker DW, Wright RP: Management of heart failure: IV. Anticoagulation for patients with heart failure due to left ventricular systolic dysfunction. JAMA 272:1614-1618, 1994 6. Braunwald E: ACE inhibitors-a cornerstone of the treatment of heart failure. N Engl J Med 325:351-353, 1991 7. Cohn IN: The prevention of heart failure-a new agenda. N Engl J Med 327:725-727, 1992 8. Cohn IN, Archibald DG, Ziesche S, et al: Effects of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl JMed 314:1547-1552, 1986 9. Cohn IN, Johnson G, Ziesche S, et al: A comparison of enalapril with hydralazineisosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 325:303-310, 1991 10. CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure. N Engl J l1ed 316:1429-1435, 1987 11. Deedwania pe, Carbajal EV: Secondary prevention after myocardial infarction: Too many choices, which ones work? Arch Intern Med 153:285-288, 1993 12. Doral He, Nul DR, Grancelli HD, et al: Randomized trial of low-dose amiodarone in severe congestive heart failure. Lancet 344:493-498, 1994 13. Dracup K, Baker DW, Dunbar SB, et al: Management of heart failure: H. Counseling, . education, and lifestyle modifications. JAMA 272:1442-1446,1994 14. Epstejn AE, Hallstrom AP, Rogers WJ, et al: Mortality following ventricular arrhythmia suppression by encainide, flecainide and morizicine after myocardial infarction. J Am Coil CardioI270:2451-2455, 1993 15. Feldman AM, Bristow MR, Parmley WW, et al: Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 329:149-155, 1993 16. Ghali JK, Cooper R, Ford E: Trends in hospitalization rates for heart failure in the United States 1973-1986. Arch Intern Med 150:769-772, 1990 17. Gheorghiade M, Young JB, Uretsky B, et al on behalf of the PROVED and RADIANCE Investigators: Predicting clinical deterioration after digoxin withdrawal in heart failure: Insights from the PROVED and RADIANCE trials. Eur Heart J 14:198, 1993 18. Goldbourt U, Behar S, Reicher-Reiss H, et al for the SPRINT Study Group: Early administration of nifedipine in suspected acute myocardial infarction. Arch Intern Med 153:345-353, 1993 19. Gruppo Italiano per 10 Studio della Sporavvivenza nell'Infarto Miocardico: GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6w~ek mortality and ventricular function after acute myocardial infarction. Lancet 343:1115-1122, 1994 20. Israeli SPRINT Study Group: The Secondary Prevention Israeli Nifedipine Trial (SPRINT): A randomized intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 9:354-364, 1989 21. Jessup M: Angiotensin-converting enzyme inhibitors: Are there significant clinical differences? [edit]. J Am Coil CardioI13:1248-1250, 1989 22. Konstam M, Dracup K, Baker D, et al: Heart failure: Evaluation and care of patients with left ventricular systolic dysfunction. Clinical Practice Guideline No. 11. AHCPR Publication No. 94-0612. Rockville, MD, Agency for Health Care Policy and Research, Public Health Service, U.5. Department of Health and Human Services, 1994 23. Konstam MA, Kronenberg MW, Rousseau MF, et al: Effects of the angiotensin converting enzyme inhibitor enalapril on long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation 88(part 1):22772283, 1993

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24. Lonn EM, Yusuf S, Jha P, et al: Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 90:2056-2069, 1994 25. Multicenter Diltiazem Postinfarction Trial Research Croup: The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 319:385-392, 1988 26. Packer M, Carver JR, Rodeheffer RI, et al: The effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 325:1468-1475,1991 27. Packer M, Cheorghiade M, Young JB, et al on behalf of the RADIANCE Study: Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. N Engl J Med 329:1-7, 1993 28. Parmley WW: Clinical practice guidelines: Does the cookbook have enough recipes? JAMA 272:1374-1375, 1994 29. Pfeffer MA, Braunwald E, Moye LA, et al: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 327:668-677, 1992 30. Pfeffer MA, Lamas CA, Vaughn DE, et al: Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 319:80-86, 1988 31. Pitt B: Angiotensin-converting inhibitors in patients with congestive heart failure: A class effect? Am J Cardiol 68:106-108,1991 32. Pitt B: Use of "Xapril" in patients with chronic heart failure: A paradigm or epitaph for our times? Circulation 90:1550-1551, 1994 33. Pouleur H, Rousseau MF, Oakley C et al: Difference in mortality between patients treated with captopril or enalapril in the xamoterol in severe heart failure study. Am J Cardiol 68:71-74, 1991 34. Pratt CM, Eaton T, Francis M, et al: The inverse relationship between baseline left ventricular ejection fraction and outcome of antiarrhythmic therapy: A dangerous imbalance in the risk-benefit ratio. Am Heart J 118:433-440, 1989 35. Schocken DD, Arrieta MI, Leaverton PE, et al: Prevalence and mortality rate of congestive heart failure in the United States. J Am Coll Cardiol 20:301-306, 1992 36. Silver MT, Rose CA, Paul SO, et al: A clinical rule to predict preserved left ventricular ejection fraction in patients after myocardial infarction. Ann Intern Med 121:750-756, 1994 37. SOLVD Investigators: Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 325:293-302, 1991 38. 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 327:685-691, 1992 39. Uretsky BF, Young JB, Shahidi FE, et al on behalf of the PROVED Investigative Croup: Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: Results of the PROVED Trial. J Am Coll Cardiol 22:955-962, 1993 40. Vinson JM, Rich MW, Sperry JC, et al: Early readmission of elderly patients with congestive heart fai\ure. J Am Ceriatr Soc 38:1290, 1990 41. Xamoterol in Severe Heart Failure Study Croup: Xamoterol in severe heart failure. Lancet 336:1-6, 1990 42. Young JB: Heart failure, ventricular remodelling and the renin-angiotensin system: Insights from recently completed clinical trials. Eur Heart J 14(suppl C):14-17, 1993 43. Young JB: Angiotensin-converting enzyme inhibitors in heart failure: New strategies justified by recent clinical trials. Int J CardioI43:151-163, 1994 44. Young JB: Asymptomatic left ventricular dysfunction: To treat or not to treat? J Heart Lung Transplant 13:5135-140, 1994 45. Young JB, Farmer JA: The diagnostic evaluation of patients with heart failure. In Hosenpud JD, Creenberg BH (eds): Congestive Heart Failure: Pathophysiology, Diagnosis and Approach to Management. New York, Springer-Verlag, 1994, pp 597-621 46. Young JB, Cheorghiade M, Packer M, et al on behalf of the PROVED and RADIANCE Investigators: Are low serum levels of digoxin effective in chronic heart failure? Evidence challenging the accepted guidelines for a therapeutic serum level of the

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drug. American College of Cardiology 42nd Annual Scientific Session. J Am Coil Cardiol 21(suppl A):378A, 1993 Young JB, Roberts R: Heart failure. In Dirks JH, Sutton RAL (eds): Diuretics: Physiology, Pharmacology and Clinical Use. Philadelphia, WB Saunders, 1986, pp 151-167 Young JB, Weiner DH, Yusuf S, et al: Patterns of medication use in patients with heart failure: A report from the Registry of Studies of Left Ventricular Dysfunction (SOLVD). South Med J 88:514-523, 1994 Yusuf 5, Garg R, McConachie D: Effect of angiotensin-converting enzyme inhibitors in left ventricular dysfunction in the context of other similar trials. J Cardiovasc Pharmacol 22(suppl 9):528-535, 1993 Zusman RM: Angiotensin-converting enzyme inhibitors: More different than alike? Focus on cardiac performance. Am J Cardiol 72:25H-36H, 1993

Address reprint requests to James B. Young, MD 20 Wilding Chase Chagrin Falls, OH 44022