New trends in the use of angiotensin converting enzyme inhibitors in chronic heart failure

New Trends in the Use of Angiotensin Converting Enzyme Inhibitors in Chronic Heart Failure

BARRY M. MASSIE, M.D. San Francisco, California

From the Departmentof Medicine and Cardiovascular ResearchInstituteof the Universityof California. San Francisco. California. Requests for reprints should be addressedto Dr. BarryM. Massie, Cardiology Division (111C), Veterans Administration Medical Center, 4150 Clement Street, San Francisco, California94121.

36

Although the underlying pathophysiology in most patients with congestive heart failure is impaired myocardial contractility, hemodynamic and clinical benefit can be achieved by treatment with agents that alter the loading conditions of the left ventricle. This was initially accomplished with direct-acting vasodilators such as sodium nitroprusside, nitrates, and hydralazine. Subsequently, the angiotensin converting enzyme (ACE) inhibitors have been demonstrated to produce similar short-term hemodynamic improvement and have generally proved superior in their long-term hemodynamic and clinical efficacy. Although the ACE inhibitors were initially employed as adjunctive treatment in patients with refractory heart failure, recent studies indicate that they are also effective in patients with mild and moderate symptoms and that they are at least as effective as digitalis in this patient group. Furthermore, a growing body of data indicates that the ACE inhibitors improve the survival rate in patients with severe and, possibly, milder heart failure. As a result, the ACE inhibitors have emerged as useful agents in patients with mild symptoms and are being investigated for their potential to improve the survival rate and prevent clinical deterioration in patients with asymptomatic or minimally symptomatic left ventricular dysfunction. The treatment of congestive heart failure has evolved rapidly over the past decade. Prior to 1970, the digitalis glycosides and diuretics, together with activity, sodium, and fluid restriction, were the only modalities of treatment. In the 1970s, because of a growing understanding of the factors regulating cardiac performance and the availability of bedside hemodynamic monitoring, many investigators explored the use of drugs that altered the loading conditions of the failing left ventricle [1]. By the early 1980s, vasodilator therapy became widely accepted in patients with refractory heart failure and was often used in patients with more moderate symptoms [2]. However, it was not until the advent of orally administered angiotensin converting enzyme (ACE) inhibitors that this approach became widespread. In recent years, the ACE inhibitors have been employed not only in patients with refractory symptoms, but in those with moderate and even mild limitation. Moreover, their capacity to 15rolong life in patients with congestive heart failure has become evident, and recent data indicate that they are at least as effective as digitalis and perhaps preferable in patients with less advanced degrees of heart failure. This article will review the background for and early results with vasodilator therapy in congestive heart failure and will discuss the evolving indications for ACE inhibitors in patients with congestive heart failure.

April 15, 1988 The American Journal of Medicine Volume84 (suppl 4A)

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BACKGROUND Pathophysiology of Congestive Heart Failure. Congestive heart failure is usually caused by impaired systolic performance of the left ventricle. In general, this results from either loss of functional myocardium (as is the case with extensive myocardial infarction or pathologic processes that lead to fibrous replacement of normal contractile units) or processes that impair the contractile performance of the myocardium (such as long-term pressure or volume overloading, and some cardiomyopathies). However, the clinical syndrome of congestive heart failure can also occur due to pressure overload (aortic stenosis or severe hypertension with intact contractile function), volume overload (regurgitant valvular lesions or intracardiac shunting), conditions that increase systemic demand for blood flow and oxygen delivery (thyrotoxicosis, anemia, etc.), and conditions that impair left ventricular diastolic performance (pericardial disease, restrictive cardiomyopathy, or severe left ventricular hypertrophy), thus resulting in elevated left atrial and pulmonary pressures. Congestive heart failure due to left ventriculdr systolic myocardial dysfunction will be the focus of this review. This disorder can usually be recognized by reduced left ventricular ejection fraction and left ventricular dilation, and is the most common underlying pathophysiology in congestive heart failure. Other conditions should be excluded, because they may be amenable to specific therapy and often may deteriorate during vasodilator therapy. In the presence of chronic left ventricular dysfunction, a number of compensatory mechanisms are activated [1]. The left ventricle dilates, and the resulting increase in end-diastolic myocardial fiber length leads to greater systolic shortening (Starling's law of the heart). However, progressive dilatation may be associated with increasing left ventricular diastolic pressure, with resulting pulmonary venous hypertension and dyspnea. Similarly, right ventricular dysfunction may result in elevated central venous pressure and, ultimately, fluid retention and edema. Reduced cardiac output, particularly if it is associated with reduced arterial pressure or perfusion of the kidneys, will activate several neural and humoral systems [3,4]. Increased activity of the sympathetic nervous system is common, especially in advanced heart failure [5-7]. The sympathetic nervous system stimulates myocardial contractility, heart rate, and venous tone; the latter change results in a rise in the effective central blood volume, which further elevates ventricular preload. Again, although these adaptations are designed to increase cardiac output, they may themselves be deleterious. Thus, tachycardia and increased contractility may precipitate ischemia in patients with underlying coronary a~tery disease, and the rise in preload may worsen pulmonary congestion. Sympathetic nervous system activation also increases peripheral vascular resistance; this adaptation is

designed to maintain perfusion pressure to vital organs, but when it is excessive, may itself reduce renal and other organ blood flow. Peripheral vascular resistance is also a major determinant of the left ventricular afterload, or resistance to left ventricular ejection, so excessive sympathetic activity may further depress cardiac function. Of note is that plasma norepinephrine levels, an indicator of sympathetic nervous system activity, are inversely related to survival in patients with heart failure [8]. One of the important effects of a low cardiac output is reduction of renal blood flow and glomerular filtration rate, which leads to sodium and fluid retention [9-12]. In moderate and severe heart failure, the renin-angiotensinaldosterone system is also activated, producing further increases in peripheral vascular resistance and left ventricular afterload, as well as sodium and fluid retention [11-14]. Heart failure is also associated with increased circulating levels of arginine vasopressin, which also serves as a vasoconstrictor and inhibitor of water excretion [15,16]. Although release of atrial natriuretic peptide is increased in heart failure due to the elevated atrial pressures [17,18], there is evidence of resistance to its natriuretic and vasodilating effects [19]. This resistance may, in part, be due to its inability to overcome the opposing actions of the renin-~,ngiotensin system [20]. Finally, circulating levels of prostaglandins are elevated in patients with severe heart failure [21]. These vasoactive substances may play a counter regulatory role in relation to the excess activity of vasoconstricting system. Many of the hemodynamic derangements characteristic of heart failure, including elevated pulmonary and systemic venous pressures and reduced organ blood flow, result from the compensatory adaptations to the underlying left ventricular dysfunction. These are often responsible for the major clinical manifestations of heart failure, including dyspnea, edema, exercise intolerance, and renal dysfunction. Therefore, the treatment of heart failure is often directed more toward correcting the excessive manifestations of these adaptive processes rather than the underlying cardiac dysfunction, which is often irreversible and not adequately responsive to agents that improve cardiac contractility, such as digitalis and the newer inotropic drugs. Clinical Use of Vasodilating Drugs. The initial approach to altering the loading conditions of the left ventricle was with parenteral vasodilators (reviewed in [1]). The most successful intravenous agent is sodium nitroprusside, which has the dual capability of reducing left ventricular afterload by dilating the arteriolar resistance bed, and reducing preload by increasing venous capacitance. This agent continues to be invaluable for the treatment of acute heart failure and can be very useful in reversing acute exacerbations of chronic heart failure. The next step was to reproduce the hemodynamic effects of nitroprusside with nonparenteral agents suitable

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for long-term outpatient therapy. It was soon recognized that the nitrates primarily reduce left and right ventricular filling pressures, but have little effect on peripheral vascular resistance and cardiac output. In contrast, hydralazine is a potent arteriolar dilator that consistently increases cardiac output but has little effect on ventricular filling pressures. The combination has additive hemodynamic benefits and has been popular in the treatment of severely symptomatic patients [22]. Prazosin, an alpha-adrenergic blocking agent, showed a similar ability to produce acute hemodynamic improvement, but tachyphylaxis was common during long-term therapy and this agent is now only infrequently used [23]. Other potent vasodilators such as minoxidil [24] and the calcium channel blockers have been investigated in heart failure [25], but the former is associated with very frequent side effects and the latter have the propensity to cause hemodynamic deterioration because of.their additional negative inotropic properties [26]. Although the use of vasodilators grew in the late 1970s and early 1980s, it was difficult to demonstrate their effi'cacy in well-controlled trials. Hydralazine and prazosin were unsuccessful in improving exercise tolerance [2729]. Oral isosorbide dinitrate proved to be superior to placebo in several controlled trials, but its effects were relatively modest [30,31]. The combination of hydralazine and nitrates appeared to be more promising, but was not subjected to a controlled trial [32]. An increased propensity toward fluid retention, in part due to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, often occurred during long-term therapy with these direct-acting vasodilators [33-35]. Often, diufetic requirements increased. As a result, these agents were primarily relegated to the treatment of the most refractory patients. ACE INHIBITORS

.

M e c h a n i s m of Action. As noted, a number of neuroen• docrine systems are activated in congestive heart failure. In addition, therapeutic modalities such as diuretics and peripheral vasodilators may further increase the activity of these systems. As a result, it was natural to investigate captopril, the first orally active ACE inhibitor, in congestive heart failure [36]. Captopril, and subsequently developed agents in this class, inhibit the conversion of the inactive peptide angiotensin I to the potent vasoconstrictor and stimulant of adrenal aldosterone secretion, angiotensin It. Thus, peripheral vascular resistance and sodium and fluid retention are reduced [37-40]. Furthermore, it is now r e c ognized that ACE also degrades bradykinin and other kinins in tissue and plasma. These are vasodilators, but also stimulate prostaglandin synthesis; following ACE inhibition, there is an increase in vasodilating prostaglandins [21,41-43]. Another potentially important effect of ACE inhibitors is to decrease central sympathetic out-

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flow and release of norepinephrine from peripheral nerve terminals [44]. All of these actions are potentially beneficial in patients with congestive heart failure. H e m o d y n a m i c Effects of ACE Inhibition. The acute hemodynamic effects of captopril have been well described [45-48]. Our findings, which are illustrated in Figure 1, are comparable with those of a number of studies in patients with New York Heart Association class Ill or IV heart failure refractory to digitalis and diuretics. The left ventricular filling pressure was reduced by 42 percent (26 mm Hg to 15 mm Hg), and the cardiac and stroke indices increased by 35 to 44 percent, respectively (1.8 liters/ minute/m 2 to 2.4 liters/minute/m 2, and 22 ml/beat/m 2 to 31 ml/beat/m2). Mean arterial pressure decreased by 24 percent (85 mm Hg to 65 mm Hg), whereas heart rate declined from 65 to 75 beats/minute. With the exception of the decline in heart rate, these changes were directionally and quantitatively similar to those produced by sodium nitroprusside. The most marked declines in blood pressure occur in patients with very elevated plasma renin activity or marked hyponatremia (which usually indicates activation in the renin-angiotensin system) [49,50]. Indeed, hypotension remains the major difficulty in initiating and maintaining ACE inhibitor therapy. However, with the use of initial low dosages (12.5 mg or even 6.25 mg of captopril), withdrawal of other agents that could potentiate hypotension, downward adjustment in diuretic dosage, and most importantly, careful observation of the short-term response (which occurs within two hours after a captopril dose, but somewhat later with other ACE inhibitors), most patients can be safely started on an ACE inhibitor. Despite the precipitous decline in blood pressure, the initial dose of captopril is usually well tolerated, even in patients with known coronary artery disease. Indeed, there is rarely evidence of myocardial ischemia as judged by measurements in the arterial-coronary sinus lactate concentration [51]. This lack of ischemia despite the reduction in coronary perfusion pressure reflects the decrease in several determinants of myocardial oxygen demand. The decrease in heart rate, presumably reflecting a reduction in cardiac sympathetic nervous system stimulation, is probably critical, because a reflex tachycardia would'be deleterious. Captopril also reduces left ventricular volume and wall stress, and the decline in left ventricular diastolic pressure helps maintain the coronary perfusion gradient. The hemodynamic effects of captopril are relatively independent of dosage over a wide range (1215 to 100 mg) [52], but the duration of the response tends to increase at higher dosages. There are significant but relatively modest correlations between plasma renin activity and the short-term hemodynamic changes, though these correlations do not persist during long-term treatment [53,54]. These and other findings indicate that the beneficial long-

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term effect of ACE inhibitors is not clearly limited to the activity of the circulating renin-angiotensin system. Most early studies with captopril were conducted in patients with advanced heart failure. These were usually persons who remained in New York Heart Association class III or class IV despite optimal therapy with digitalis and diuretics. Studies in this patient substrate clearly indicated a sustained hemodynamic benefit during long-term captopril therapy, in contrast to patients who received a placebo in addition to their previous regimens (Figure 2) [55]. After three months, patients taking captopril underwent continued reductions in left ventricular filling pressure and increases in cardiac and stroke output. Blood pressure tended to return toward baseline during maintenance therapy, although approximately 10 percent of patients could not tolerate long-term therapy with ACE inhibitors due to symptomatic hypotension. Most importantly,

April 15, 1988

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these patients exhibited an improvement in exercise tolerance as measured by bicycle ergometry (Figure 3) [56]. The pivotal study that established the clinical efficacy of ACE inhibitors in heart failure was a multicenter evaluation of captopril in patients with congestive heart failure who remained symptomatic while receiving digitalis and diuretics [57]. After rigorous baseline evaluation, 91 patients were randomly assigned to receive captopdl or placebo while continuing on their previous regimen. Fortynine patients randomly assigned to receive captopril completed the study; in contrast, only 28 of 42 placebo patients completed the study, whereas four died and eight experienced deterioration during the 12-week follow-up period. Exercise tolerance improved by 24 percent during captopril treatment and was unchanged during placebo therapy. Of note is that treadmill exercise duration increased gradually over the 12-week period and appeared

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SYMPOSIUMON ACE INHIBITORS--MASSIE

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April 15, 1988

Figure 2. Top panel, hemodynamic measurements prior to captopril (Pre), after 48 hours of captopril 25 or 50 mg three times daily (acute), and after three months of captopril therapy. 0 , 10 patients who received captopril both short and long term; Q, patients who received captopril for the first 48 hours, but in whom the three-month measurements were performed during placebo treatment. Left ventricular filling pressure (LVFP) underwent a short-term decrease, and remained lower at three months in the patients randomly assigned to captopril. Cardiac and stroke indices (CI and SI) rose and remained elevated during long-term treatment with captopril. Bottom panel uses the same format to illustrate the exercise hemodynamic measurements. LVFP at maximal exercise tended to undergo a short-term decrease with captopril and was significantly lower than baseline during long-term therapy. The patients randomly assigned to placebo were unchanged after three months. Similarly, CI and SI tended to rise short-term and were both significantly elevated after three months, whereas there was no change from baseline in the placebo group. *p <0.05; "*p <0.01; ***p <0.001 pre-versus postcaptopril values. Reproduced from [56], by permission of the American Heart Association, Inc.

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Figure 3. Changes in exercise capacity. During bicycle ergometry, exercise duration, maximal workload and maximal oxygen uptake all rose after three months of captopril treatment (0) but did not change with placebo (0). Reproduced from [56], by permission of the American Heart Association, Inc.

SYMPOSIUM ON ACE INHIBITORS--MASSlE

strated a significant decrease in heart size on radiqgraphic examination and a modest rise in ejection fraction, both of which were maintained during long-term follow-up.

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C o m p a r i s o n of Captopril to Direct-Acting Vasodilatots. Although a number of well-controlled studies have

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"Significantly > baseline(p<0.001) tSignificantly > placebo (p<0 008) Figure 4. Results of treadmill exercise testing in the Captopril Multicenter Study. The captopril group showed a gradual and progressive increase in exercise tolerance during the 12 weeks of randomized follow-up. At no point did the placebo group show a significant improvement compared with baseline, and the intergroup differences were highly significant. Reprinted with permission from [57].

to be still improving at the end of the study (Figure 4). Most importantly, 80 percent of the patients classified themselves as having improvement during captopril therapy and only 4 percent considered themselves as having a worsened condition. During placebo treatment, 30 percent considered themselves as having an improved condition and 38 percent thought that their condition had worsened. Although survival was not a predetermined endpoint of this relatively small study, four deaths occurred in the placebo group and one occurred in the patients receiving captopril. When an intention-to-treat analysis was performed, which included the patients withdrawing prematurely due to worsening symptoms, a total of 11 deaths was seen in the placebo group compared with only two in the captopril group, indicating a significant improvement in short-term survival with active therapy [58]. We have subsequently studied and followed a number of these patients for several years [59]. Initial beneficial responses in clinical status and exercise tolerance were maintained or improved further in most patients. Although this follow-up was not conducted as a prospective, controlled study, both the number and duration of hospitalizations were lower during follow-up with captopril therapy than they had been during a similar period of time prior to ACE inhibition (Figure 5). These patients also demon-

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demonstrated clinical and hemodynamic improvement during captopril therapy, as noted previously this has not been the case with most of the direct-acting vasodilators. This, together with their own clinical experience, has led most experts to employ ACE inhibitors more frequently than other vasodilators in the management of congestive heart failure. This approach is supported by the few available studies that have compared ACE inhibitors with other classes of agents [34,35,60-63]. Captopril has produced superior hemodynamic and exercise tolerance responses when compared with prazosin, hydralazine, and nifedipine. In addition, several of these studies have shown that although the vasodilators stimulate the sympathetic nervous system and renin-angiotensin-aldosterone system, captopril attenuates these neuroendocrine responses [34,35,60,61]. These changes have been associated with relative improvement in ventricular ectopy and serum electrolyte concentrations. Unfortunately, little information is available comparing the ACE inhibitors with the nitrates for which there is greatest evidence for clinical efficacy, or to the combination of hydralazine and isosorbide dinitrate. Efficacy of O t h e r A C E Inhibitors. Two newer ACE inhibitors, enalapril and lisinopril, are now available in the United States, although they have not been specifically approved for the treatment of congestive heart failure. As might be expected from the previous discussion concern-

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ing the pathophysiology of congestive heart failure, we and others found that enalapril also improves hemodynamic measurements, exercise tolerance, and electrolyte imbalances in patients with congestive heart failure (Figure 6) [64-70]. The same is likely to be true for the growing number of ACE inhibitors currently under investigation. However, several important pharmacokinetic differences between captopril and enalapril influence the manner in which these drugs must be used in congestive heart failure. Although captopril itself inhibits ACE, enalapril is an inactive ethyl ester of the biologically active moiety, enelaprilic acid. De-esterification occurs in the liver, and the kinetics of this process are unpredictable in patients with hepatic dysfunction or passive congestion of the liver. Therefore, in congestive heart failure hepatic metabolism may be delayed and the already greater duration of action of enalapril may be further prolonged. With both captopril and enalapril, the peak hemodynamic response coincides with the peak levels of the active drug [71]. This occurs between 30 and 60 minutes in virtually all patients treated with captopril, but the peak concentration of enalaprilic acid, which occurs after two to four hours in normal subjects and hypertensive patients, is not seen until a mean of five hours in patients with heart failure, and the variation can be very large and unpredictable. Thus, peak hemodynamic effects and hypotension have been observed as late as 24 hours after dosing. Furthermore, because enalapril is cleared more slowly than captopril and inhibits ACE for a longer duration, the peak effect may be quite prolonged [65,72]. These pharmacokinetics have led to a greater incidence of symptomatic hypotension in several centers and to warnings from regulatory agencies that enalapril should be initiated under careful observation in patients with heart failure. Obviously the same precautions should be taken with enalapril as with

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captopril; these include discontinued use of other agents that could exacerbate hypotension, reduction in diuretic dosages, and most importantly, careful patient selection and observation. Utilizing these approaches, most patients can receive initial and maintenance therapy safely with enalapril and the newer ACE inhibitors under investigation. Packer and associates [73] published a study in which the short- and long-term hemodynamic responses of patients who were randomly assigned to treatment with captopril or enalapril were compared. This study is instructive with regard to the physiology of the renin-angiotensinaldosterone system in patients with severe heart failure, but it does not accurately reflect usual patterns of clinical practice in that relatively high dosages of the two drugs were employed (captopril 150 mg daily, enalapril 40 mg daily), downward dose adjustment was not permitted, and diuretic dosages were kept constant. As would be expected from the preceding discussion of the pharmacokinetics of the two drugs, the hypotensive response after the initial dosage, though comparable with both agents, occurred later and was more prolonged with enalapril. Of more clinical importance was the finding that during maintenance therapy, the blood pressure remained continuously lower than the pretreatment level in most patients treated with enalapril, whereas it decreased after captopril

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TABLE I

Comparison of Captopril, Digoxin, and Placebo in Mild to Moderate Heart Failure Change from Baseline

Exercise time NYHA class Ejection fraction~t Ventricular premature beats/hours"

Baseline Mean

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Placebo

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+ 10% -0.09 +4.4%§ +2

+ 6% +0.02 +0.9% - 16

+ = increase. °p <0.05 versus placebo. tlmprovement (decrease) in NYHAclass; p <0.01 versus placebo. tExpressed as absolutechange in mean ejection fraction. §p <0.01 versus placebo; p <0.05 versus captopril. "Restricted to patients with more than 10 ventricularpremature beats per hour at baseline. ~p <0.05, captopril versus digoxin group. From [77].

dosing but rose again prior to the next dose (Figure 7). Enalapril treatment over an eight-week period was associated with a significantly greater decline in creatinine clearance, most likely reflecting physiologically significant decreases in renal perfusion. Almost certainly these adverse reactions can be avoided by appropriate titration of the ACE inhibitor and diuretic dosages, but they indicate the need for particular caution in following renal function in patients being treated with long-acting ACE inhibitors [74]. This need is supported by the preliminary findings of a multicenter trial in which another long-acting ACE inhibitor, lisinopril, was compared with captopril in patients with congestive heart failure. Again, a greater rise in blood urea nitrogen was noted in the lisinopril group even though the dosages of the ACE inhibitors and the diuretics could be adjusted in this study [75]. ACE INHIBITOR T H E R A P Y IN MILD HEART FAILURE

Virtually all of the studies of ACE inhibitors in congestive heart failure involved patients with advanced symptoms and were designed to evaluate the effect of adding an ACE inhibitor to a previous therapeutic regimen that included digitalis and diuretics. Nonetheless, the few patients with milder symptomatology appeared to display the same degree of improvement as more symptomatic persons. As the efficacy of ACE inhibitors became widely accepted, two additional questions naturally arose. The first was whether these agents would prove to be as effective or even more potent than digitalis and, the second, whether they should be employed earlier in the natural history of heart failure. Both issues are of fundamental importance. The effectiveness of digitalis in patients with normal sinus rhythm has been repeatedly questioned and some workers have raised concerns about its safety, particularly in patients with ischemic heart disease. The very high mortality rates of patients with congestive heart failure have long been recognized [76], and the early experience with ACE inhibitors that demonstrated their propensity to

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reduce activity of the sympathetic nervous system, correct electrolyte abnormalities, and possibly reduce mortality rates raised hope that they might improve long-term survival. If this were the case, it would provide a strong justification for using ACE inhibitors at the earliest stages of left ventricular dysfunction. The preliminary results of several important trials addressing these issues have recently become available, and these warrant discussion in this context. A multicenter trial that compared the effectiveness of captopril and digoxin in patients with mild to moderate heart failure has recently been completed [77]. Three hundred patients in normal sinus rhythm with mild to moderate symptoms of congestive heart failure and ejection fractions less than 40 percent were studied. Digoxin, captopril, or placebo was added according to a randomized, double-blind protocol. Patients underwent serial measurements of exercise tolerance, ejection fraction, functional class, and ventricular ectopy over the first six months of treatment. The results are summarized in Table I. Exercise tolerance, as measured by time on a gradual treadmill protocol, increased by 14 percent in the captopril group and by somewhat lesser amounts during treatment with digoxin and placebo. Only the difference between the captopril and placebo group was statistically significant. In 41 percent of patients, an improvement in functional class was exhibited with captopril, compared with 31 percent and 22 percent receiving digoxin and placebo. The improvement (reduction) in clinical class was significant with captopril but not with digoxin when compared with the placebo group. Ejection fraction rose significantly only during digoxin treatment. Ventricular ectopy decreased with captopril, whereas it increased slightly in the patients given digoxin. These findings indicate that captopril is at least as effective as digoxin in patients with mild symptoms of heart failure and is perhaps, a preferable second line mode of therapy. Several other considerations support the potential advantage of using ACE inhibitors before digitalis. ACE in-

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hibitors will help preserve total body and serum potassium concentrations in the face of diuretic-induced kaliuresis. They also counteract the activation of the renin-angiotensin-aldosterone system that accompanies diuretic therapy. Finally, additional evidence supports the finding of decreased ventricular ectopy in patients while receiving ACE inhibitors. Effect of Treatment with Vasodilators and ACE Inhibitors on Survival in Congestive Heart Failure. In patients with even mild congestive heart failure, high mortality rates are exhibited during the follow-up period, as previously noted. One-year mortality rates range from 30 to 70 percent of patients with advanced heart failure referred to major medical centers [76]. Most studies have shown that 30 to 50 percent of the deaths are sudden and probably arrhythmic in origin. With the clear-cut demonstration that the ACE inhibitors produce clinical improvement in congestive h.eart failure, recent attention has focused on whether they and other treatments alter this high mortality rate. The Veterans Administration Cooperative Heart Failure {V-Heft) study, which demonstrated a significant decrease in mortality rates in a large population of patients with heart failure treated with the combination of hydralazine and isosorbide dinitrate, showed for the first time that a substantial impact could be made on these high mortality rates [78]. Unfortunately, the efficacy of ACE inhibitors in heart failure had not been demonstrated at the time this trial was initiated and these agents were not included in V-Heft. However, it now appears likely that the ACE inhibitors will be at least as successful as the hydralazinenitrate combination in prolonging survival of patients with advanced heart failure. As mentioned earlier, the initial captopril multicenter trial in patients with New York Heart Association class III and IV heart failure demonstrated a significant decrease in three-month mortality by an intention-to-treat anal~/sis [58]. Furberg and Yusuf [79] have shown by meta-analysis techniques that the pooled results of several trials with ACE inhibitors also indicate that short-term mortality rates can be significantly improved. Finally, a recently published Scandinavian multicenter trial showed a highly significant improvement in survival in severely symptomatic patients treated with enalapril in comparison with the control group [80]. Ongoing trials sponsored by the National Institutes of Health, the Veterans Administration, and pharmaceutical companies should indicate whether these relatively shodterm benefits are sustained during Iong4erm follow-up and whether they extend to patients with milder degrees of heart failure. Prevention of Progression to Severe Heart Failure. In addition to an improvement in long-term survival, a second consideration that will determine the place of ACE inhibitors in the treatment of patients with mild heart failure is whether they can prevent the evolution of more severe 44

symptoms and left ventricular dysfunction. The ability of captopril to prevent hemodynamic evidence of left ventricular dysfunction following myocardial infarction has been elegantly demonstrated in an animal model [81,82]. If progressive functional and clinical deterioration can be prevented in patients with left ventricular dysfunction, it is likely that survival will also be improved. Kleber [83] has shown a similar trend toward prevention of clinical deterioration in a group of patients with very mild heart failure. They randomly selected 59 patients with predominantly New York Heart Association class I or II heart failure who received maintenance therapy with digitalis or diuretics, or both. This group was randomly assigned to treatment with captopril or placebo and followed for a mean of 298 days at the time of their published preliminary analysis. During this period, eight patients died and another eight experienced severe deterioration of heart failure status. Eleven of these 16 patients were receiving placebo, and only five were receiving captopril. CURRENT STATUS OF ACE INHIBITION IN CONGESTIVE HEART FAILURE

From the information reviewed in this article, the current role of ACE inhibitors in the treatment of heart failure can be delineated, and possible future indications can be anticipated. The ACE inhibitors are clearly effective in patients with refractory heart failure, in whom they improve hemodynamics, symptoms, and where relevant, exercise tolerance. In addition, they prolong life in this severely symptomatic group. Patients with more moderate symptoms (New York Heart Association class II and III) also experience clinical and exercise tolerance improvement when ACE inhibitors are added to digitalis and diuretic treatment. Suggestive evidence also indicates that survival can be prolonged in this group, although definitive data are not yet available. In patients with milder symptoms (New York Heart Association class II), captopril has been shown to be at least as effective as digitalis in improving symptoms and exercise tolerance. For patients who are in normal sinus rhythm, particularly if they have relatively normal renal function and are not hypotensive, captopril would seem to be a preferable agent to add to their diuretic regimen. The remaining questions concern the role of ACE inhibitors in patients with asymptomatic left ventricular dysfunction (ejection fractions less than 40 percent), and the relative role of ACE inhibitors and diuretics as initial treatment in patients with mild symptoms. A definitive answer to these questions will not be available until it is known whether the ACE inhibitors improve survival and prevent the progression of heart failure in patients who are asymptomatic or only mildly symptomatic. Until then, it seems reasonable to add ACE inhibitors when patients remain symptomatic while receiving low doses of diuretics, and to consider the combined use of diuretics and ACE inhibitors as initial treatment in symptomatic patients.

April 15, 1988 The American Journal of Medicine Volume 84 (suppl 4A)

SYMPOSIUM ON ACE INHIBITORS--MASSIE

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