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(Circulation. 1996;94:2689-2693.)
© 1996 American Heart Association, Inc.

Articles

Heart Failure Therapy in Evolution

Kanu Chatterjee, MB, FRCP

the Division of Cardiology, University of California, and the Cardiovascular Research Institute, San Francisco.

Correspondence to Kanu Chatterjee, MB, FRCP, Lucie Stern Professor of Cardiology, Vilensky Research Professor of Cardiology, Box 0124, University of California, San Francisco, CA 94143-0124.

Key Words: Editorials • heart failure • carvedilol • receptors, adrenergic, beta • angiotensin

	Introduction

Top Introduction References

 
During the past 25 years, considerable progress has been made in our understanding of the pathophysiological mechanisms for the development and progression of the heart failure syndrome. On the basis of this growing knowledge, a number of therapeutic approaches have been proposed and tested for the long-term management of chronic heart failure. One of the reasons for the continuing search for newer therapies is to improve prognosis further than achievable with an established therapy. It has been amply documented that clinical heart failure resulting from impaired left ventricular systolic function is associated with a substantial mortality and morbidity and that the more severe the clinical heart failure is, the worse the prognosis. Before the introduction of vasodilator and ACE inhibitor therapy, a 1-year mortality rate of 50% was observed with conventional therapy in patients with severe chronic heart failure.¹ In the CONSENSUS I trial,² in which patients with severe heart failure (NYHA functional class IV) were randomized to receive placebo or enalapril (an ACE inhibitor) in addition to contemporary conventional treatment (digitalis and diuretics), the mortality rates with conventional treatment at 6 months and 12 months were 44% and 54%, respectively. The prognosis of patients who initially present with mild to moderate clinical heart failure and are treated conventionally was assessed in the VA Heart Failure Trial I.³ The cumulative mortality rate of these patients over a period of 48 months was 53.6%. The realization that conventional treatment of established clinical heart failure with digitalis and diuretics is associated with very poor prognosis prompted the search for newer therapeutic modalities that might have the potential to correct the hemodynamic abnormalities of heart failure, improve ventricular function, relieve symptoms, and improve survival. Because it was initially postulated that the reduction of left ventricular outflow resistance and wall stress has the potential not only to improve hemodynamics or left ventricular function but also to retard progression of heart failure, vasodilator therapy was introduced.⁴ Indeed, it was demonstrated that the addition of the direct-acting vasodilators hydralazine and isosorbide dinitrate is associated with not only improved symptoms and left ventricular function but also a 38% reduction in the risk of mortality at 1 year. The mortality benefit persisted over the duration of follow-up. It was soon appreciated, however, that in addition to derangements of central and peripheral hemodynamics, abnormal left ventricular dynamics, and mechanical function, neurohormonal dysfunction also contributes to the pathogenesis of progressive heart failure.⁵ Experimental and clinical studies indicated that the renin-angiotensin system is activated in heart failure as a result of left ventricular systolic dysfunction and that angiotensin II, a vasoconstrictive, antinatriuretic, and mitogenic peptide, may play an important role in causing progression of heart failure. Many clinical studies documented beneficial effects of attenuation of the effects of angiotensin II with ACE inhibitors on central and peripheral hemodynamics and ventricular mechanical and metabolic function.⁶ Furthermore, in the CONSENSUS I trial, addition of enalapril to conventional treatment not only caused a substantial symptomatic improvement but also decreased the risk of mortality at 6 months and 1 year by 40% and 31%, respectively.² In the Studies of Left Ventricular Dysfunction (SOLVD) Trial, patients with reduced left ventricular ejection fraction of 35% and with mild to moderate clinical heart failure were randomized to conventional treatment alone or with enalapril added. The addition of enalapril to conventional therapy substantially decreased mortality and the rate of hospitalization for treatment of heart failure.⁷ In the Veterans Administration Heart Failure Trial II,⁸ the relative efficacy of a combination of hydralazine–isosorbide dinitrate and the ACE inhibitor enalapril was assessed in patients with mild to moderate clinical heart failure. Both hydralazine–isosorbide dinitrate and enalapril improved prognosis of these patients. However, the magnitude of reduction in the risk of mortality with enalapril was significantly greater than that with hydralazine–isosorbide dinitrate treatment. Because ACE inhibitors provide some advantages over the direct-acting vasodilators hydralazine–isosorbide dinitrate, ACE inhibitors have emerged as the preferred initial treatment of clinical heart failure. Thus, use of ACE inhibitors, diuretics, and digitalis has been accepted as present-day conventional and essential therapy of symptomatic clinical heart failure of all grades of severity. It should be realized, however, that the prognosis of patients with established clinical heart failure still remains unfavorable and poor, despite aggressive therapy with ACE inhibitors and direct-acting vasodilators. In the CONSENSUS I trial,² the mortality of patients with severe heart failure at 6 months and at 1 year was 26% and 36%, respectively, despite treatment with enalapril. In the VA Heart Failure Trial I,³ the cumulative mortality in patients with mild to moderate heart failure at 4 years was 49.7%, despite treatment with hydralazine–isosorbide dinitrate. In the VA Heart Failure Trial II,⁸ the 4-year cumulative mortality rate in patients with moderately severe heart failure treated with hydralazine–isosorbide dinitrate was 47%, and that with enalapril was 41%. These controlled prospective randomized studies therefore suggest that although vasodilators such as hydralazine–isosorbide dinitrate or ACE inhibitors improve symptoms and reduce the risk of mortality of patients with heart failure and should be considered essential therapy for their management, the long-term prognosis still remains poor once clinical heart failure develops. Thus, any newer therapeutic modality that has the potential to improve prognosis further than can be achieved with this current standard therapy should be welcome.

In this issue of Circulation, Bristow and colleagues, on behalf of the MOCHA investigators, report the potential beneficial effects of the addition of carvedilol, a third-generation ß-adrenergic antagonist, to currently recommended therapy for established clinical heart failure.⁹ In this study, patients with mild to moderately severe heart failure, almost all in NYHA functional class II or III, were randomized to receive either placebo or low-dose (6.25 mg BID), medium-dose (12.5 mg BID), or high-dose (25 mg BID) carvedilol. Left ventricular ejection fraction in all groups was markedly depressed, averaging 23%. Approximately 50% of patients had ischemic and the other 50% had nonischemic dilated cardiomyopathy as the cause of depressed left ventricular systolic function and clinical heart failure. Background therapy on entry consisted of ACE inhibitors, digitalis, and loop-active diuretics in >90% of patients, and 30% of patients in each group were also treated with vasodilators. Thus, almost all patients in this study, whether randomized to placebo or carvedilol, received adequate triple therapy as currently recommended for the long-term management of symptomatic systolic left ventricular failure. The duration of treatment after a 2- to 4-week up-titration period was, on average, 6 months. The primary objective of this trial was to assess the efficacy of carvedilol in improving exercise tolerance, and the secondary objectives were to assess changes in quality of life and functional class, left ventricular function, need for hospitalization for treatment of heart failure, and changes in signs and symptoms of heart failure. This study was not designed to evaluate the effect of carvedilol therapy on mortality, and the mortality rates were assessed primarily as a safety end point.

Also in this issue of Circulation, Packer and colleagues report the results of the PRECISE (Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise) trial.¹⁰ In this trial, patients with moderate to severe clinical heart failure, again almost all in NYHA functional class II or III, were randomized to receive either placebo or carvedilol. Left ventricular ejection fractions of patients randomized were markedly depressed, averaging 22%. Approximately 52% of patients had coronary artery disease and 48% had nonischemic dilated cardiomyopathy as the cause of clinical heart failure. The background treatments consisted of ACE inhibitors in >92% of patients and digitalis and loop-active diuretics in 90% and 100% of patients, respectively. In this study also, all patients entered an open-label run-in period during which patients received 6.25 mg carvedilol BID for 2 weeks. Patients who tolerated these doses of carvedilol were randomly assigned to carvedilol or placebo. During the up-titration phase, over a period of 2 to 6 weeks, the dosages of the drugs were increased. The primary end point was to assess changes in exercise tolerance, and secondary end points included changes in global assessments of heart failure, NYHA functional class, left ventricular ejection fraction, quality-of-life scores, and need for hospitalization. Mortality rates were determined as part of the assessments of safety.

The effects of carvedilol treatment in patients with mild heart failure due to left ventricular systolic dysfunction are also reported by Colucci et al in this issue of Circulation.¹¹ In this trial, patients with mild clinical heart failure, almost all (85%) in NYHA functional class II, were randomized to placebo or carvedilol. The left ventricular ejection fraction of patients randomized was markedly reduced, averaging 23%, although the clinical severity of heart failure was mild. The frequency of ischemic and nonischemic dilated cardiomyopathy as the cause of heart failure was similar. Almost all patients were receiving an ACE inhibitor (98% overall), digitalis (89% overall), and a loop diuretic (92% overall). In this study also, there was an open-label run-in phase and a 2- to 6-week double-blind up-titration phase during which the dosage of the drug was increased. In contrast to the MOCHA and PRECISE studies, the primary end point in this study was clinical progression of heart failure, defined as heart failure death, hospitalization for heart failure, or the need for sustained increases in heart failure medications. Secondary end points included changes in left ventricular ejection fraction, NYHA functional class, heart failure symptom score, global patient assessment, and quality of life.

Thus, in these three studies reported in this issue of Circulation,^{9 10 11} the study protocols were very similar and the overall objectives were to assess the effects of addition of carvedilol to present-day standard therapy (ACE inhibitors, digitalis, loop diuretics) on symptoms, exercise tolerance, quality of life, progression of heart failure, and mortality in patients with markedly depressed ejection fraction but with varying severity of clinical heart failure (mild, moderate, and moderate to severe). The results of these three studies were similar in some aspects and dissimilar in others. In all three studies, addition of carvedilol was associated with an increase in left ventricular ejection fraction, although the mechanisms for increases in ejection fraction were not investigated. During chronic ß-blocker therapy, left ventricular ejection fraction increases primarily from increased total stroke volume, which usually results from a substantial decrease in left ventricular end-systolic volume. The two major mechanisms for the decreased end-systolic volume are decreased left ventricular outflow resistance and increased contractile response. In some studies, an increase in end-systolic pressure/volume ratio, a relatively load-independent measure of contractility, has been observed during chronic ß-blocker therapy.¹² The mechanisms for improved contractile response during chronic treatment with ß-adrenergic antagonists, which clearly exert a negative inotropic effect, remain unresolved. In the study by Bristow et al,⁹ evidence for more complete adrenergic receptor blockade with carvedilol was reported, and the enhanced contractile response resulting from upregulation of the ß-adrenergic receptors as the mechanism for the increased ejection fraction seems unlikely.

Although it has been postulated that improvement in the myocardial intrinsic biological function is the mechanism for the improved left ventricular function, such postulations require confirmation by further clinical studies. Furthermore, attenuation of the inverse force-frequency relation associated with decreased heart rate and/or decreased left ventricular systolic wall stress as possible mechanisms for the increase in left ventricular ejection needs to be explored.

It should be also appreciated that the mechanism for increase in ejection fraction may have significant clinical relevance. For example, increase in ejection fraction resulting from therapy with nonglycosidic positive inotropic agents may be associated with increased mortality.¹³ Thus, therapeutic interventions that not only enhance cardiac performance but also do not increase or may even decrease mortality are clearly preferable. From the patient's perspective, however, whether left ventricular ejection fraction improves or not is probably least important. The therapies that have the potential to relieve symptoms, improve quality of life, and prolong survival with or without changes in ejection fraction are likely to be welcome.

The benefit of addition of carvedilol to triple therapy on the symptomatic status of patients with mild, mild to moderate, and moderate to severe heart failure appears to be marginal. In the study by Bristow et al,⁹ carvedilol had no detectable effects on submaximal exercise, quality of life, or heart failure symptoms. Global assessments by both patients and physicians did not detect any significant symptomatic improvement with carvedilol. There was also no improvement in NYHA functional class. In the PRECISE trial,¹⁰ patients were more symptomatic and had more severe clinical heart failure than the patients in the MOCHA trial. It is unlikely, however, that there were any significant differences in the 6-minute walk distances achieved by the patients in these two studies, which were used to categorize severity of clinical heart failure. In the PRECISE trial¹⁰ also, there was no significant increase in the 6-minute walk distance with carvedilol treatment or in the distance traversed on the 9-minute treadmill test, another method used in these studies to assess changes in exercise tolerance. There were also no changes in the quality-of-life scores.

However, in the PRECISE trial,¹⁰ both patients' and physicians' assessments indicated that carvedilol treatment caused symptomatic improvement. It should be appreciated that a considerable number of patients in the placebo group as well had mild to moderate symptomatic improvement. The number of patients who experienced marked clinical improvement as assessed by physicians during carvedilol treatment is too small to be of any clinical relevance. Nevertheless, in the PRECISE trial,¹⁰ a greater number of patients had improvement in NYHA functional class after treatment with carvedilol than with placebo. In patients with mild heart failure, addition of carvedilol to ACE inhibitors, digitalis, and diuretics produced mild symptomatic improvement only in a small percentage of patients (12% versus 9%), and the functional class remained unchanged in the majority of patients.¹¹ Global assessments both by patients and by physicians indicated that a substantial number of patients experienced symptomatic improvement with or without addition of carvedilol to standard triple therapy, although a greater percentage of patients treated with carvedilol experienced symptomatic improvement. However, most practicing physicians appreciate the difficulties in such clinical assessment. Furthermore, in this study also, there were no changes in quality-of-life scores or in distances walked in 9 minutes on the self-powered treadmill. It should be appreciated that in the MOCHA and PRECISE trials, virtually no patients with severe heart failure (NYHA class IV) were enrolled. In the mild heart failure trial, by study design, no NYHA class IV patients were enrolled. Thus, the effects of carvedilol treatment on the symptomatic status of patients with severe clinical heart failure cannot be assessed from the results of these studies. Clinical experience and some previous studies indicate that ß-adrenergic–blocking drugs may cause rapid and severe clinical and hemodynamic deterioration in patients with severe and clinically unstable heart failure.¹⁴ Because carvedilol is a potent ß-adrenergic antagonist, it may also produce similar deleterious effects in patients with severe, unstable heart failure.

It is of interest that the proportions of patients in NYHA functional classes II and III are similar in the PRECISE and MOCHA trials,^{9 10} and the background and active treatments were almost identical. Yet, in the PRECISE trial,¹⁰ there was some clinical improvement overall with treatment with carvedilol that was not observed in the MOCHA trial.⁹ In patients with mild heart failure, there was also some symptomatic improvement. The reasons for the different responses to carvedilol in these studies are not clear. It is apparent, however, that marked or consistent symptomatic improvement should not be expected with addition of carvedilol in patients with mild, moderate, or moderate to severe heart failure already treated with ACE inhibitors, diuretics, and digitalis.

Does carvedilol improve survival of patients with chronic heart failure due to left ventricular systolic dysfunction? The results of the PRECISE trial¹⁰ suggest that there may not be any survival benefit with treatment with carvedilol in patients with moderately severe clinical heart failure. There were 6 deaths (4.5%) in the carvedilol-treated group during the double-blind period, compared with 11 deaths (7.6%) in the placebo group. This difference in mortality in the two groups was not statistically significant. Furthermore, during the carvedilol up-titration period, there were an additional 5 deaths, and thus, a total of 11 deaths in the carvedilol group, identical to the placebo group. In the MOCHA trial,⁹ however, 12 of 261 patients receiving carvedilol (1 additional patient during up-titration) died, with mortality rates of 6.0%, 6.7%, and 1.1% in the low-, medium-, and high-dose groups, respectively. In the placebo group, 13 of 84 patients died, with a crude mortality rate of 15.8%, during the same duration of follow-up. In the carvedilol-treated subjects, the relative risk of mortality decreased significantly, by 73%. The survival benefit was similar in patients with ischemic and nonischemic dilated cardiomyopathy. Furthermore, the relative risks of both sudden and pump failure deaths decreased during treatment with carvedilol. In the mild heart failure study,¹¹ there was a statistically significant reduction in the risk of mortality with addition of carvedilol; it should be appreciated that mortality was quite low in patients who remained in mild clinical heart failure with treatment with ACE inhibitors, digitalis, and diuretics.

It is rather obvious that the survival benefit with carvedilol treatment was not apparent in the PRECISE trial¹⁰ but was obvious in the MOCHA trial⁹ and in the mild heart failure study.¹¹ The reasons for the disparate results in these similarly designed and well-performed studies are not clear. Because the number of patients randomized to active treatment in the PRECISE trial¹⁰ was considerably smaller than in the MOCHA and the mild heart failure trials,^{9 11} it is possible that the differences in survival benefits in these trials were related to sample size.

It is also plausible, however, that carvedilol is less effective in patients with more severe clinical heart failure. The US Carvedilol Heart Failure Study Group¹⁵ reported a substantial survival benefit in patients with heart failure treated with carvedilol in addition to digitalis, diuretics, and ACE inhibitors. In that report, however, very few patients with severe heart failure were included. Furthermore, it appears that the same patients in the MOCHA,⁹ PRECISE,¹⁰ and mild heart failure studies,¹¹ as reported in this issue of Circulation, were included in this study. It appears, therefore, that the survival benefit with carvedilol treatment reported by the US Carvedilol Heart Failure Study Group¹⁵ was related predominantly to the survival benefit observed in patients included in the MOCHA and mild heart failure trials.^{9 11} An earlier, smaller, double-blind study also reported lack of survival benefit or increased risk of worsening heart failure during the dosage up-titration of carvedilol.¹⁶ Uncontrolled studies and clinical experience also suggest that patients with clinically overt severe and unstable heart failure do not tolerate ß-adrenergic antagonists, and the survival benefit of ß-blocker therapy in such patients has not been established. It should also be emphasized that in previous prospective randomized clinical trials in which patients with clinical heart failure of varying severity associated with depressed left ventricular ejection fraction were evaluated, no survival benefit was observed with treatment with cardioselective (metoprolol) or third-generation (bisoprolol) ß-adrenergic blocking agents.^{17 18} The reasons for these different results are not clear but may be related to the differences in the sample sizes in these studies, differences in the pharmacological properties of the various ß-adrenergic blocking agents used, or the inclusion of patients with more severe clinical heart failure in these studies than in the MOCHA and mild heart failure trials.^{9 11} Admittedly, without further, appropriately designed prospective studies, the questions about which subsets of patients are likely to benefit or which types of ß-adrenergic–blocking agents are likely to produce beneficial effects, particularly in relation to the reduction of the risk of mortality, will not be resolved. Nevertheless, the presently available data suggest that the patients with mild clinical heart failure associated with decreased left ventricular ejection fraction and receiving background treatment with ACE inhibitors and also probably digitalis and diuretics are the more appropriate candidates for treatment with ß-adrenergic blocking agents with the pharmacological characteristics of carvedilol. Patients with more severe clinical heart failure or patients with unstable clinical heart failure are unlikely to benefit from ß-blocker therapy, and there is increased risk of inducing worsening heart failure in these patients with ß-blocker therapy. Thus, ß-adrenergic–blocking agents, including carvedilol, should not be considered for treatment of severe refractory heart failure except in special circumstances.

The results of the three carvedilol studies^{9 10 11} reported in this issue of Circulation and the long-term follow-up results of the study by the Australia–New Zealand Heart Failure Research Collaborative group¹⁹ suggest that the major beneficial effect of carvedilol therapy in addition to therapy with ACE inhibitors is to retard progression of heart failure, as evident from the decreased frequency of hospitalization rates, decreased frequency of progression to more severe clinical heart failure, decreased need for adjustments of other antifailure drugs, and decreased cardiovascular mortality. How carvedilol can attenuate progression of heart failure, however, is not known and remains speculative. The mechanisms for the development of clinical heart failure, with subsequent progression after the initial ischemic or nonischemic myocardial injury and the onset of "threshold" magnitude of systolic dysfunction, are incompletely understood. That activated renin-angiotensin-aldosterone systems might play an important role is evident from the facts that when the deleterious effects of angiotensin II are attenuated by ACE inhibitors, progression of heart failure can be retarded and that cardiovascular mortality can be decreased significantly.^{20 21} Thus, inhibition of the angiotensin system should be considered an essential therapeutic principle for the management of heart failure. Enhanced systemic and cardiac adrenergic activity in heart failure has also been thought to produce deleterious effects on central and peripheral hemodynamics, left ventricular dynamics, and myocardial metabolic function. Thus, adequate attenuation of adrenergic activity is expected to produce beneficial effects on progression of heart failure. Carvedilol has been shown to produce complete or near-complete adrenergic receptor blockade,⁹ and its observed beneficial effects clearly may be due to its antiadrenergic activity. An increase in oxidative stress due to an increase in free radicals, a relative deficiency in the endogenous antioxidant reserve, or both has been suggested to be one of the contributing factors in the pathogenesis of heart failure. In experimental animals, an improved myocardial redox state with long-term antioxidant therapy has been shown to modulate the development and progression of heart failure.²³ Carvedilol, in addition to being an adrenergic antagonist and a vasodilator, appears to be an antioxidant and free radical scavenger as well.²⁴ Whether the observed beneficial effects of carvedilol are also due to its antioxidant effects cannot be resolved without further clinical studies comparing ß-adrenergic antagonists with and without antioxidant properties. Nevertheless, the presently available information suggests that carvedilol, when added to ACE inhibitors in patients with depressed left ventricular systolic function, can retard progression of heart failure and therefore should be considered a therapeutic agent for prevention of progressive clinical heart failure rather than for treatment of refractory heart failure.

	Acknowledgments

 
I thank Dr James T. Willerson, Editor-in-Chief of Circulation, for asking me to write this editorial. I acknowledge that I have attended "Carvedilol Meetings" sponsored by SmithKline Beecham Pharmaceuticals as a consultant; the opinions expressed in this editorial, however, are entirely personal. I also sincerely thank Ronald Sutherland and Betsy Williamson for their secretarial help.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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13. Packer M, Carver JR, Rodeheffer RJ, et al and the Promise Study Investigators. Effect of oral milrinone on mortality in severe chronic heart failure: results of the prospective randomized milrinone survival evaluation (PROMISE). N Engl J Med.. 1991;325:1468-1475.[Abstract]
    
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