Drugs 39 (Suppl. 4): 4-9, 1990 00 12-6667/90/0400-0004/$3.00/0 © ADiS Press Limited All rights reserved. DRSUP1700.
Early Intervention in Heart Failure Mark A. Creager Brigham and Women's Hospital, Harvard Medical School, Boston, USA
Summary
Treatment for patients with congestive heart failure is primarily directed at reducing symptoms and improving functional capacity. In patients with moderate to severe heart failure, therapeutic interventions incorporating diuretics, digoxin and selected vasodilators, specifically angiotensin-converting enzyme (ACE) inhibitors, are designed to correct pathophysiological mechanisms such as left ventricular dysfunction, excessive vasoconstriction and renal reabsorption of sodium and water. Physician-investigators are turning their attention to identifying and treating patients early in the course of their disease. Vasodilator therapy in patients with mild symptoms of heart failure may not only improve exercise performance, but also reduce mortality. In addition, recent studies have suggested that ACE inhibitors may prevent progression of disease in patients with asymptomatic left ventricular dysfunction. It is hoped that ongoing research will demonstrate that early identification and treatment of these patients may prevent development of symptoms and improve survival.
The importance of understanding the pathophysiology and therapeutic implications of congestive heart failure is underscored by the frequent occurrence of this disorder in the general population. In the United States, it is estimated that 2.3 million individuals have congestive heart failure, and 400,000 new cases develop each year (McFateSmith 1985; Parmley 1989). Approximately 50% of patients have coronary artery disease (Franciosa et a1. 1983). Recent data from the Framingham Heart Study have emphasised the poor prognosis of patients who develop symptoms of heart failure (Kannel et a1. 1988). Five years after the onset of symptoms, approximately 50% of affected individuals died compared with 5% of an age- and sex-matched control population. 20 years after the onset of symptoms, the mortality rate was approximately 75% in
patients with heart failure versus 15% in the remainder of the Framingham population. Prognosis is worse in those patients with the more severe forms of heart failure usually seen in referral centres. The 2-year mortality rate in patients with moderate heart failure [New York Heart Association (NYHA) functional classifications II and III] is about 30%, whereas in patients with severe heart failure (class IV) it is closer to 75% (McFate-Smith 1985).
1. Pathophysiology of Heart Failure Before reviewing the implications of therapy, it is appropriate to discuss some of the pathophysiological mechanisms that operate in patients with heart failure. Left ventricular dysfunction occurs as a consequence of myocardial injury. Injury may re-
5
Early Intervention in Heart Failure
suit from myocardial infarction, hypertension, valvular heart disease, alcohol abuse, viral infection or other recognised causes of myocardial damage. As a result of left ventricular dysfunction, the body responds with a variety of so-called compensatory actions that are thought to initially preserve cardiac function and ensure adequate cardiac output. These may conveniently be categorised as peripheral and cardiac compensatory mechanisms. Peripheral mechanisms include activation of neural and hormonal systems that cause vasoconstriction and promote sodium and water retention. These include the sympathetic nervous system, the reninangiotensin system, and perhaps vasopressin (Creager et al. 1986; Leimbach et al. 1986; Levine et al. 1982; Thomas & Marks 1978). Activation of these neurohormonal systems initially serves to maintain perfusion pressure to vital organs and increases sodium and water retention. The latter increases venous return and augments cardiac filling, thereby improving stroke volume via the FrankStarling mechanism. However, as heart failure progresses, these vasoconstrictor systems may have adverse effects. Excessive afterload impairs cardiac function and decreases cardiac output, whereas excessive retention of sodium and water may contribute to pulmonary congestion and peripheral oedema. Structural change in the myocardium may also serve as a compensatory mechanism early in heart failure. For example, after myocardial infarction, the uninjured part of the heart is subjected to increased wall stress (Fletcher et al. 1981). As a consequence, the ventricle in this area may undergo hypertrophy and dilatation (Weisman et al. 1985). Lengthening of myocardial fibres in the undamaged parts of the ventricle may initially assure maintenance of an adequate stroke volume, because the degree of shortening in this part of the ventricle is preserved or increased (Fletcher et al. 1981). However, with continued stress on this part of the ventricle, progressive dilatation occurs, culminating in a deterioration of contractile force, even in the region of the ventricle that was not originally damaged. Thus, a mechanism that was initially compensatory ultimately contributes to the pro-
gressive deterioration of left ventricular function and the onset of symptoms of heart failure.
2. Strategy for Medical Management of Heart Failure On the basis of improved understanding of the pathophysiological mechanisms that occur in this disorder, treatment regimens have been devised that have been useful in the management of patients with heart failure. However, in developing a strategy for treatment, physicians generally ask themselves several questions that focus not only on why treatment should be started, but also when and in what manner. The reasons for initiating therapy are obvious to most practising physicians. There is a desire to reduce symptoms, improve functional capacity, prevent progression of disease and prolong life. The timing of therapy, however, has been controversial. Few would dispute that patients with severe symptoms of heart failure (NYHA functional classes III and IV) benefit from treatment, particularly in terms of symptomatology and functional capacity. But in patients with only mild symptoms of heart failure there have been insufficient studies to determine whether the benefits of treatment outweigh the risks of intervention. Even less information is available with regard to intervention in patients who have evidence of left ventricular dysfunction but no symptoms of heart failure. Such a situation may occur after myocardial infarction, when non-invasive or invasive measurements of left ventricular systolic function show impairment, yet patients do not complain of the usual symptoms associated with heart failure.
3. Sefere Heart Failure Many well-designed studies have evaluated the clinical efficacy of intervention in patients with more severe forms of heart failure. Long term trials have demonstrated the efficacy of diuretics, digoxin and selected vasodilators, particularly angiotensin-converting enzyme inhibitors, in patients with refractory heart failure (Captopril
6
Multicenter Research Group 1983; Creager et al. 1982, 1985; Guyatt et al. 1988; Lee et al. 1982; Richardson et al. 1987). Most patients and physicians in such studies report an improvement in symptoms following intervention with any ofthese agents. Although digitalis has been available for over 200 years, conflicting reports have resulted in COntroversy as to the clinical effectiveness of this drug (Parmley et al. 1988). Studies that have examined the haemodynamic effects of acute administration of digitalis glycosides, as well as the haemodynamic deterioration that occurs after withdrawal of digoxin, support its efficacy (Arnold et al. 1980; Gheorghiade et al. 1987; Sullivan et al. 1989). Furthermore, recent evidence has confirmed that digoxin plus a diuretic, when compared with placebo plus a diuretic, improves exercise capacity in patients with severe heart failure (DiBianco et al. 1989). Initial trials of vasodilator therapy in patients with severe heart failure heralded these agents to be effective forms of treatment. However, long term studies that examined the effects of many of these drugs on exercise capacity have been disappointing. In most studies, exercise capacity did not improve significantly after treatment with nitrates, hydralazine, prazosin or calcium channel blockers, although there were some exceptions (Franciosa & Cohn 1979; Franciosa et al. 1982; Markham et al. 1983; Nathan et al. 1982). In contrast to reports on these vasodilators, considerable evidence is available that attests to the efficacy of angiotensin-converting enzyme (ACE) inhibitors. Drugs in this class improve exercise capacity during long term treatment (Captopril Multicenter Research Group 1983; Cleland et al. 1985; Creager et al. 1985; Sharpe et al. 1984). The impact of treatment on survival in patients with severe heart failure has been examined in only a few studies. The CONSENSUS trial examined the effect of enalapril, an ACE inhibitor, on mortality in patients with class IV heart failure. Compared with placebo, enalapril significantly reduced mortality after 6 months (44 vs 26%) of therapy in this population (CONSENSUS Trial Study Group
Drug 39 (Suppl. 4) 1990
1987). Subset analysis suggested that the reduced mortality reflected fewer patients dying from progressive heart failure than from sudden death. Other studies that evaluated vasodilator therapy in patients with severe heart failure have included too few patients to address statistically the issue of mortality. A recent study evaluated the effect of digoxin and the phosphodiesterase inhibitor, milrinone, in patients with severe heart failure (DiBianco et al. in press). Although mortality was not a primary end-point of the study design, the data would suggest that digoxin neither improved nor adversely affected survival rates in these patients. Initial analysis suggested that milrinone may have increased patient mortality. But when the analysis was corrected for baseline differences in left ventricular ejection fraction, milrinone had no greater effect on mortality than placebo.
4. Mild to Moderate Heart Failure Few studies have carefully examined the effects of therapy in patients who have only mild symptoms of heart failure. The role of digoxin, for example, in patients with only mild symptoms of heart failure is controversial, since too few trials have been conducted to test its efficacy. One recent trial examined the relative efficacies of digoxin and captopril in patients with mild to moderate heart failure (Captopril-Digoxin Multicenter Research Group 1988). In this study, digoxin improved ejection fraction but had no statistically significant effect on exercise capacity. In contrast, captopril did not alter ejection fraction, but did improve exercise tolerance time. Unfortunately, because of a flaw in the trial design, it is impossible to examine adequately the patients who were randomised to digoxin. Before randomisation, patients who had been treated with digoxin were withdrawn from this drug. Those who deteriorated were restarted on digoxin but not entered into the trial. Thus, a bias exists against demonstrating improvement with digoxin because those who were likely to have benefited were not included. Nonetheless, the importance of this study should not be dismissed, since it did show
Early Intervention in Heart Failure
that intervention in patients with mild to moderate heart failure may improve functional capacity. Several years ago, the findings of the Veterans' Administration Heart Failure Trial were published. They provided the first indication that intervention in patients with mild forms of heart failure may favourably influence survival rates (Cohn et al. 1986). Patients with mild forms of heart failure were randomised to placebo, prazosin or the combination of hydralazine and isosorbide dinitrate. There was significant decrease in mortality rates (26 vs 34%) after 24 months of therapy in patients randomised to the combination of hydralazine and isosorbide dinitrate compared with placebo. Prazosin did not affect survival rates. Thus, data exist indicating that intervention can improve exercise capacity and mortality in patients with mild to moderate forms of heart failure. The benefit of these interventions, however, must be considered in light of the potential adverse drug effects. In the Veterans' Administration Heart Failure Trial, approximately 19% of patients in the group randomised to hydralazine and isosorbide dinitrate withdrew because of adverse effects (Cohn et al. 1986). In the captopril-digoxin trial, 26% of patients randomised to captopril experienced transient symptomatic hypotension (CaptoprilDigoxin Multicenter Research Group 1988). However, these symptoms usually abated with continued therapy. Only a small percentage of patients in the captopril, digoxin and placebo groups ultimately withdrew from this trial because of side effects. It is important to note that patients randomised to either captopril or digoxin had fewer visits to emergency clinics or hospitals during the period of follow-up than those randomised to placebo.
5. Asymptomatic Left Ventricular Dysfunction Little information is available on the management of patients who have evidence of left ventricular dysfunction but who do not have symptoms of heart failure. It is certainly conceivable that the natural histulY of patients with asymptomatic left ventricular dysfunction may be progression of
7
disease and perhaps an increased mortality rate. A further insight into this possibility could be provided by studies evaluating progressive changes in left ventricular function in patients who have experienced myocardial infarction. Evidence now exists demonstrating that remodelling, progressive dilatation and impairment in contractility occurs in initially undamaged parts of the ventricle after an acute myocardial infarction (Fletcher et al. 1981; Weisman et al. 1985). Remodelling may occur within 2 weeks of the myocardial infarction (McKay et al. 1986). Serial echocardiographic evaluations in patients with myocardial infarction have indicated that left ventricular diastolic volume progressively increases over a period of 1 year, even though intervening myocardial infarction has not occurred (Warren et al. 1988). The importance of these observations is underlined by the fact that survival after myocardial infarction has been related to left ventricular size (Hammermeister et al. 1979; White et al. 1987). After myocardial infarction, mortality is substantially increased in patients who have the largest ventricular volumes, particularly those who show evidence of decreased left ventricular systolic function (Hammermeister et al. 1979; White et al. 1987). Studies examining the impact of therapeutic interventions on development of symptoms and mortality in patients with asymptomatic left ventricular dysfunction, such as those after a myocardial infarction, are in progress, but the results are not yet available. However, preliminary evidence would support the possibility of a beneficial effect with intervention. In an experimental model of myocardial infarction, Pfeffer and his colleagues examined the effect of ACE inhibition on ventricular remodelling and survival (Pfeffer et al. 1985a,b). After myocardial infarction, rats were randomised to water or captopril. The ACE inhibitor decreased ventricular remodelling and enlargement compared with water and improved survival in those rats with mild to moderate sized myocardial infarctions. In a follow-up study in humans, Pfeffer and associates examined the effects of captopril on ventricular enlargement in patients after acute myo-
8
Drugs 39 (Suppl. 4) 1990
cardial infarction (Pfeffer et a1. 1988). These patients had a depressed left ventricular ejection fraction but no symptoms of congestive heart failure. Patients were randomised to placebo or captopril in addition to their other medications. Before randomisation, cardiac filling pressures and left ventricular volumes were similar in each group. When examined I year later, the cardiac filling pressures were less in those patients who had received captopri1. Furthermore, end diastolic volumes increased in patients randomised to placebo but not in those randomised to the ACE inhibitor. In addition, exercise capacity was greater in the drug-treated patients. Similarly, Sharpe et al. (1988) used serial echocardiography to evaluate the effects of captopril, frusemide (furosemide) and placebo on cardiac size and function after myocardial infarction. The ACE inhibitor prevented progressive ventricular enlargement and preserved the left ventricular ejection fraction. These trials provide encouraging evidence that left ventricular remodelling and progression of disease is attenuated or prevented by therapeutic intervention in patients who have asymptomatic left ventricular dysfunction, but do not address the issue of survival. As mentioned previously, this question is the focus of several ongoing trials.
6. Conclusions The incidence and prevalence of congestive heart failure are high. Therapeutic decisions must be made, based on an understanding of the pathophysiological mechanisms that exist in this disorder. Initially, peripheral and cardiac compensatory mechanisms occur that ensure perfusion pressure to vital organs and maintenance of stroke volume and cardiac output. However, with progressive heart failure, these mechanisms may adversely affect cardiac performance. Treatment programmes incorporating diuretics, digoxin and selected vasodilators, specifically ACE inhibitors, may correct some of these abnormal mechanisms, thereby improving cardiac performance, functional capacity and perhaps survival. Physician-investigators are now turning their attention to the patient
with asymptomatic left ventricular dysfunction. Early evidence would suggest a role for therapeutic intervention to prevent progression of disease. It is hoped that ongoing studies will provide evidence to show that early treatment prevents development of symptoms and prolongs survival in these patients.
References Arnold SB, Byrd RC. Meister W. Melmon K. Cheitlin MD, et al. Long-term digitalis therapy improves left ventricular function in heart failure. New England Journal of Medicine 303: 14431448, 1980 Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. Journal ofthe American Medical Association 259: 539-544, 1988 Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive heart failure. Journal of the American College of Cardiology 2: 755-763,1983 Cleland JGF, Dargie I\J, Ball SG, Gillen G. Hodsman GP, et al. Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state. British Heart Journal 54: 305-312, 1985 Cohn JN, Archibald OG, Ziesche S, Franciosa JA, Harston WE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration cooperative study. New England Journal of Medicine 314: 15471552, 1986 CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. New England Journal of Medicine 316: 1429-1435, 1987 Creager MA, Faxon DP, Cutler SS, Kohlmann 0, Ryan RJ, et al. Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system. Journal of the American College of Cardiology 7: 758-765, 1986 Creager MA, Faxon DP, Halperin JL, Melidossian CD, McCabe CH, et al. Determinants of clinical response and survival in patients with congestive heart failure treated with captopril. American Heart Journal 104: 1147-1154, 1982 Creager MA, Massie BM, Faxon OP, Friedman SO, Kramer BL, et al. Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. Journal of the American College of Cardiology 6: 163-170, 1985 DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant R, et al. Oral milrinone and digoxin in heart failure: results of a placebo-controlled, prospective trial of each agent and the combination. New England Journal of Medicine, in press. Retcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction: effects on systolic function. Circulation Research 49: 618-626, 1981 Franciosa jA, Cohn IN. Effect ofisosorbidedinitrate on response to submaximal and maximal exercise in patients with congestive heart failure. American Journal of Cardiology 43: 10091014, 1979 Franciosa JA, Weber KT, Levine TB, Kinasewitz GT, Janicki JS, et al. Hydralazine in the long-term treatment of chronic heart failure: lack of difference from placebo. American Heart Journal 104: 587-594, 1982 Franciosa JA, Wilen M, Ziesche S, Cohn J. Survival in men with
Early Intervention in Heart Failure
severe chronic left ventricular failure due to either coronary heart disease or idiopathic dilated cardiomyopathy. American Journal of Cardiology 51: 831-836, 1983 Gheorghiade M. St Clair J, St Clair C, Beller GA. Hemodynamic effects of intravenous digoxin in patients with severe heartfailure initially treated with diuretics and vasodilators. Journal of the American College of Cardiology 9: 849-857, 1987 Guyatt GH, Sullivan MJJ, Fallen El, Tihal H. Rideout E, et al. A controlled trial of digoxin in congestive heart failure. American Journal of Cardiology 61: 371-375, 1988 Hammermeister KE. DeRouen T A, Dodge HI. Variables predictive of survival in patients with coronary disease: selection by univariate and multivariate analyses from the clinical, electrocardiographic. exercise, arteriographic and quantitative angiographic evaluations, Circulation 59: 421-430, 1979 Kannel WB, Plehn JF, Cupples A. Cardiac failure and sudden death in the Framingham Study. American Heart Journal 115: 869-875, 1988 lee DC-S, Johnson RA, Bingham lB, Leahy M, Dinsmore RE, et al. Heart failure in outpatients: a randomized trial of digoxin versus placebo. New England Journal of Medicine 306: 699705, 1982 Leimbach WN, Wallin BG, Victor RG, Aylward PE, SundlofG, et al. Direct evidence from intraneuronal recordings from increased sympathetic outflow in patients with heart failure. Circulation 73: 913-919, 1986 levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn IN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. American Journal of Cardiology 49: 1659-1666, 1982 Markham Jr RV, Corbett JR, Gilmore A, Pettinger WA, Firth BG. Efficacy of prazosin in the management of chronic congestive heart failure: a 6-month randomized, double-blind, placebo-controlled study, American Journal of Cardiology 51: 13461352, 1983 McFate-Smith W. Epidemiology of congestive heart failure. American Journal of Cardiology 55: 3A-8A, 1985 McKay RG, Pfeffer MA, Pasternak RC, Markis JE, Come PC, et al. left ventricular remodeling after myocardial infarction: a corollary to infarct expansion. Circulation 74: 693-702, 1986 Nathan M, Rubin SA, Siemienczuk D, Swan HJC. Effects of acute and chronic minoxidil administration on rest and exercise hemodynamics and clinical status in patients with severe, chronic heart failure. American Journal of Cardiology 50: 960966, 1982 Parmley WW. Pathophysiology and current therapy of congestive
9
heart failure, Journal of the American College of Cardiology 13: 771-785, 1989 Parmley WW, Smith TW, Pitt B. Should digoxin be the drug of first choice after diuretics in chronic congestive heart failure? Journal of the American College of Cardiology 12: 265-273, 1988 Pfeffer MA, Lamas GA, Vaughan DE, Braunwald E. Effect of captopril on progressive ventricular dilatation after myocardial infarction. New England Journal of Medicine 319: 80-86, 1988 Pfeffer JM, Pfeffer MA, Braunwald E. Influence of chronic captopril therapy on the infarcted left ventricule of the rat. Circulation Research 57: 84-95, 1985a Pfeffer MA, Pfeffer JM, Steinberg C, Finn P. Survival after an experimental myocardial infarction: beneficial effects of longterm therapy with captopriL Circulation 72: 406-412, 1985b Richardson A, Bayliss J, Scriven A, Parameshwar J, Poole-Wilson PA, ct aL Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. lancet 2: 709711, 1987 Sharpe DN, Murphy J, Conn R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized. double-blind study, Circulation 70: 271-278. 1984 Sharpe N, Murphy J, Smith H, Yam on S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet I: 255-259, 1988 Sullivan M, Atwood JE, Myers J, Feuer J. Hall P, et aL Increased exercise capacity after digoxin administration in patients with heart failure. Journal of the American College of Cardiology 13: 1138-1143, 1989 Thomas JA, Marks BH. Plasma norepinephrine on congestive heart failure. American Journal of Cardiology 41: 233-243,1978 Warren SE, Royal HD, Marks JE, Grossman M, McKay RG. Time cause of left ventricular dilation after myocardial infarction: influence and infarct-related artery and success of coronary thrombolysis. Journal of the American College of Cardiology II: 12-19, 1988 Weisman HF, Bush DE, Mannisi JA, Bulkley BH. Global cardiac remodeling after acute myocardial infarction: a study in the rat model. Journal of the American College of Cardiology 5: 1355-1362, 1985 White HD, Norris RM. Brown MA, Brandt PWT, Whitlock RML, et aL Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 76: 44-51, 1987 Author's address: Dr Mark A, Creager. Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA,
Early Intervention in Heart Failure Mark A. Creager Brigham and Women's Hospital, Harvard Medical School, Boston, USA
Summary
Treatment for patients with congestive heart failure is primarily directed at reducing symptoms and improving functional capacity. In patients with moderate to severe heart failure, therapeutic interventions incorporating diuretics, digoxin and selected vasodilators, specifically angiotensin-converting enzyme (ACE) inhibitors, are designed to correct pathophysiological mechanisms such as left ventricular dysfunction, excessive vasoconstriction and renal reabsorption of sodium and water. Physician-investigators are turning their attention to identifying and treating patients early in the course of their disease. Vasodilator therapy in patients with mild symptoms of heart failure may not only improve exercise performance, but also reduce mortality. In addition, recent studies have suggested that ACE inhibitors may prevent progression of disease in patients with asymptomatic left ventricular dysfunction. It is hoped that ongoing research will demonstrate that early identification and treatment of these patients may prevent development of symptoms and improve survival.
The importance of understanding the pathophysiology and therapeutic implications of congestive heart failure is underscored by the frequent occurrence of this disorder in the general population. In the United States, it is estimated that 2.3 million individuals have congestive heart failure, and 400,000 new cases develop each year (McFateSmith 1985; Parmley 1989). Approximately 50% of patients have coronary artery disease (Franciosa et a1. 1983). Recent data from the Framingham Heart Study have emphasised the poor prognosis of patients who develop symptoms of heart failure (Kannel et a1. 1988). Five years after the onset of symptoms, approximately 50% of affected individuals died compared with 5% of an age- and sex-matched control population. 20 years after the onset of symptoms, the mortality rate was approximately 75% in
patients with heart failure versus 15% in the remainder of the Framingham population. Prognosis is worse in those patients with the more severe forms of heart failure usually seen in referral centres. The 2-year mortality rate in patients with moderate heart failure [New York Heart Association (NYHA) functional classifications II and III] is about 30%, whereas in patients with severe heart failure (class IV) it is closer to 75% (McFate-Smith 1985).
1. Pathophysiology of Heart Failure Before reviewing the implications of therapy, it is appropriate to discuss some of the pathophysiological mechanisms that operate in patients with heart failure. Left ventricular dysfunction occurs as a consequence of myocardial injury. Injury may re-
5
Early Intervention in Heart Failure
suit from myocardial infarction, hypertension, valvular heart disease, alcohol abuse, viral infection or other recognised causes of myocardial damage. As a result of left ventricular dysfunction, the body responds with a variety of so-called compensatory actions that are thought to initially preserve cardiac function and ensure adequate cardiac output. These may conveniently be categorised as peripheral and cardiac compensatory mechanisms. Peripheral mechanisms include activation of neural and hormonal systems that cause vasoconstriction and promote sodium and water retention. These include the sympathetic nervous system, the reninangiotensin system, and perhaps vasopressin (Creager et al. 1986; Leimbach et al. 1986; Levine et al. 1982; Thomas & Marks 1978). Activation of these neurohormonal systems initially serves to maintain perfusion pressure to vital organs and increases sodium and water retention. The latter increases venous return and augments cardiac filling, thereby improving stroke volume via the FrankStarling mechanism. However, as heart failure progresses, these vasoconstrictor systems may have adverse effects. Excessive afterload impairs cardiac function and decreases cardiac output, whereas excessive retention of sodium and water may contribute to pulmonary congestion and peripheral oedema. Structural change in the myocardium may also serve as a compensatory mechanism early in heart failure. For example, after myocardial infarction, the uninjured part of the heart is subjected to increased wall stress (Fletcher et al. 1981). As a consequence, the ventricle in this area may undergo hypertrophy and dilatation (Weisman et al. 1985). Lengthening of myocardial fibres in the undamaged parts of the ventricle may initially assure maintenance of an adequate stroke volume, because the degree of shortening in this part of the ventricle is preserved or increased (Fletcher et al. 1981). However, with continued stress on this part of the ventricle, progressive dilatation occurs, culminating in a deterioration of contractile force, even in the region of the ventricle that was not originally damaged. Thus, a mechanism that was initially compensatory ultimately contributes to the pro-
gressive deterioration of left ventricular function and the onset of symptoms of heart failure.
2. Strategy for Medical Management of Heart Failure On the basis of improved understanding of the pathophysiological mechanisms that occur in this disorder, treatment regimens have been devised that have been useful in the management of patients with heart failure. However, in developing a strategy for treatment, physicians generally ask themselves several questions that focus not only on why treatment should be started, but also when and in what manner. The reasons for initiating therapy are obvious to most practising physicians. There is a desire to reduce symptoms, improve functional capacity, prevent progression of disease and prolong life. The timing of therapy, however, has been controversial. Few would dispute that patients with severe symptoms of heart failure (NYHA functional classes III and IV) benefit from treatment, particularly in terms of symptomatology and functional capacity. But in patients with only mild symptoms of heart failure there have been insufficient studies to determine whether the benefits of treatment outweigh the risks of intervention. Even less information is available with regard to intervention in patients who have evidence of left ventricular dysfunction but no symptoms of heart failure. Such a situation may occur after myocardial infarction, when non-invasive or invasive measurements of left ventricular systolic function show impairment, yet patients do not complain of the usual symptoms associated with heart failure.
3. Sefere Heart Failure Many well-designed studies have evaluated the clinical efficacy of intervention in patients with more severe forms of heart failure. Long term trials have demonstrated the efficacy of diuretics, digoxin and selected vasodilators, particularly angiotensin-converting enzyme inhibitors, in patients with refractory heart failure (Captopril
6
Multicenter Research Group 1983; Creager et al. 1982, 1985; Guyatt et al. 1988; Lee et al. 1982; Richardson et al. 1987). Most patients and physicians in such studies report an improvement in symptoms following intervention with any ofthese agents. Although digitalis has been available for over 200 years, conflicting reports have resulted in COntroversy as to the clinical effectiveness of this drug (Parmley et al. 1988). Studies that have examined the haemodynamic effects of acute administration of digitalis glycosides, as well as the haemodynamic deterioration that occurs after withdrawal of digoxin, support its efficacy (Arnold et al. 1980; Gheorghiade et al. 1987; Sullivan et al. 1989). Furthermore, recent evidence has confirmed that digoxin plus a diuretic, when compared with placebo plus a diuretic, improves exercise capacity in patients with severe heart failure (DiBianco et al. 1989). Initial trials of vasodilator therapy in patients with severe heart failure heralded these agents to be effective forms of treatment. However, long term studies that examined the effects of many of these drugs on exercise capacity have been disappointing. In most studies, exercise capacity did not improve significantly after treatment with nitrates, hydralazine, prazosin or calcium channel blockers, although there were some exceptions (Franciosa & Cohn 1979; Franciosa et al. 1982; Markham et al. 1983; Nathan et al. 1982). In contrast to reports on these vasodilators, considerable evidence is available that attests to the efficacy of angiotensin-converting enzyme (ACE) inhibitors. Drugs in this class improve exercise capacity during long term treatment (Captopril Multicenter Research Group 1983; Cleland et al. 1985; Creager et al. 1985; Sharpe et al. 1984). The impact of treatment on survival in patients with severe heart failure has been examined in only a few studies. The CONSENSUS trial examined the effect of enalapril, an ACE inhibitor, on mortality in patients with class IV heart failure. Compared with placebo, enalapril significantly reduced mortality after 6 months (44 vs 26%) of therapy in this population (CONSENSUS Trial Study Group
Drug 39 (Suppl. 4) 1990
1987). Subset analysis suggested that the reduced mortality reflected fewer patients dying from progressive heart failure than from sudden death. Other studies that evaluated vasodilator therapy in patients with severe heart failure have included too few patients to address statistically the issue of mortality. A recent study evaluated the effect of digoxin and the phosphodiesterase inhibitor, milrinone, in patients with severe heart failure (DiBianco et al. in press). Although mortality was not a primary end-point of the study design, the data would suggest that digoxin neither improved nor adversely affected survival rates in these patients. Initial analysis suggested that milrinone may have increased patient mortality. But when the analysis was corrected for baseline differences in left ventricular ejection fraction, milrinone had no greater effect on mortality than placebo.
4. Mild to Moderate Heart Failure Few studies have carefully examined the effects of therapy in patients who have only mild symptoms of heart failure. The role of digoxin, for example, in patients with only mild symptoms of heart failure is controversial, since too few trials have been conducted to test its efficacy. One recent trial examined the relative efficacies of digoxin and captopril in patients with mild to moderate heart failure (Captopril-Digoxin Multicenter Research Group 1988). In this study, digoxin improved ejection fraction but had no statistically significant effect on exercise capacity. In contrast, captopril did not alter ejection fraction, but did improve exercise tolerance time. Unfortunately, because of a flaw in the trial design, it is impossible to examine adequately the patients who were randomised to digoxin. Before randomisation, patients who had been treated with digoxin were withdrawn from this drug. Those who deteriorated were restarted on digoxin but not entered into the trial. Thus, a bias exists against demonstrating improvement with digoxin because those who were likely to have benefited were not included. Nonetheless, the importance of this study should not be dismissed, since it did show
Early Intervention in Heart Failure
that intervention in patients with mild to moderate heart failure may improve functional capacity. Several years ago, the findings of the Veterans' Administration Heart Failure Trial were published. They provided the first indication that intervention in patients with mild forms of heart failure may favourably influence survival rates (Cohn et al. 1986). Patients with mild forms of heart failure were randomised to placebo, prazosin or the combination of hydralazine and isosorbide dinitrate. There was significant decrease in mortality rates (26 vs 34%) after 24 months of therapy in patients randomised to the combination of hydralazine and isosorbide dinitrate compared with placebo. Prazosin did not affect survival rates. Thus, data exist indicating that intervention can improve exercise capacity and mortality in patients with mild to moderate forms of heart failure. The benefit of these interventions, however, must be considered in light of the potential adverse drug effects. In the Veterans' Administration Heart Failure Trial, approximately 19% of patients in the group randomised to hydralazine and isosorbide dinitrate withdrew because of adverse effects (Cohn et al. 1986). In the captopril-digoxin trial, 26% of patients randomised to captopril experienced transient symptomatic hypotension (CaptoprilDigoxin Multicenter Research Group 1988). However, these symptoms usually abated with continued therapy. Only a small percentage of patients in the captopril, digoxin and placebo groups ultimately withdrew from this trial because of side effects. It is important to note that patients randomised to either captopril or digoxin had fewer visits to emergency clinics or hospitals during the period of follow-up than those randomised to placebo.
5. Asymptomatic Left Ventricular Dysfunction Little information is available on the management of patients who have evidence of left ventricular dysfunction but who do not have symptoms of heart failure. It is certainly conceivable that the natural histulY of patients with asymptomatic left ventricular dysfunction may be progression of
7
disease and perhaps an increased mortality rate. A further insight into this possibility could be provided by studies evaluating progressive changes in left ventricular function in patients who have experienced myocardial infarction. Evidence now exists demonstrating that remodelling, progressive dilatation and impairment in contractility occurs in initially undamaged parts of the ventricle after an acute myocardial infarction (Fletcher et al. 1981; Weisman et al. 1985). Remodelling may occur within 2 weeks of the myocardial infarction (McKay et al. 1986). Serial echocardiographic evaluations in patients with myocardial infarction have indicated that left ventricular diastolic volume progressively increases over a period of 1 year, even though intervening myocardial infarction has not occurred (Warren et al. 1988). The importance of these observations is underlined by the fact that survival after myocardial infarction has been related to left ventricular size (Hammermeister et al. 1979; White et al. 1987). After myocardial infarction, mortality is substantially increased in patients who have the largest ventricular volumes, particularly those who show evidence of decreased left ventricular systolic function (Hammermeister et al. 1979; White et al. 1987). Studies examining the impact of therapeutic interventions on development of symptoms and mortality in patients with asymptomatic left ventricular dysfunction, such as those after a myocardial infarction, are in progress, but the results are not yet available. However, preliminary evidence would support the possibility of a beneficial effect with intervention. In an experimental model of myocardial infarction, Pfeffer and his colleagues examined the effect of ACE inhibition on ventricular remodelling and survival (Pfeffer et al. 1985a,b). After myocardial infarction, rats were randomised to water or captopril. The ACE inhibitor decreased ventricular remodelling and enlargement compared with water and improved survival in those rats with mild to moderate sized myocardial infarctions. In a follow-up study in humans, Pfeffer and associates examined the effects of captopril on ventricular enlargement in patients after acute myo-
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Drugs 39 (Suppl. 4) 1990
cardial infarction (Pfeffer et a1. 1988). These patients had a depressed left ventricular ejection fraction but no symptoms of congestive heart failure. Patients were randomised to placebo or captopril in addition to their other medications. Before randomisation, cardiac filling pressures and left ventricular volumes were similar in each group. When examined I year later, the cardiac filling pressures were less in those patients who had received captopri1. Furthermore, end diastolic volumes increased in patients randomised to placebo but not in those randomised to the ACE inhibitor. In addition, exercise capacity was greater in the drug-treated patients. Similarly, Sharpe et al. (1988) used serial echocardiography to evaluate the effects of captopril, frusemide (furosemide) and placebo on cardiac size and function after myocardial infarction. The ACE inhibitor prevented progressive ventricular enlargement and preserved the left ventricular ejection fraction. These trials provide encouraging evidence that left ventricular remodelling and progression of disease is attenuated or prevented by therapeutic intervention in patients who have asymptomatic left ventricular dysfunction, but do not address the issue of survival. As mentioned previously, this question is the focus of several ongoing trials.
6. Conclusions The incidence and prevalence of congestive heart failure are high. Therapeutic decisions must be made, based on an understanding of the pathophysiological mechanisms that exist in this disorder. Initially, peripheral and cardiac compensatory mechanisms occur that ensure perfusion pressure to vital organs and maintenance of stroke volume and cardiac output. However, with progressive heart failure, these mechanisms may adversely affect cardiac performance. Treatment programmes incorporating diuretics, digoxin and selected vasodilators, specifically ACE inhibitors, may correct some of these abnormal mechanisms, thereby improving cardiac performance, functional capacity and perhaps survival. Physician-investigators are now turning their attention to the patient
with asymptomatic left ventricular dysfunction. Early evidence would suggest a role for therapeutic intervention to prevent progression of disease. It is hoped that ongoing studies will provide evidence to show that early treatment prevents development of symptoms and prolongs survival in these patients.
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