Cardiovascular Drugs and Therapy 1991;5:589-604 9 Kluwer Academic Publishers, Boston. Printed in U.S.A.

Beta Receptor Antagonists in the Treatment of Heart Failure Hans Persson, L e i f E r h a r d t Department of Medicine

Summary. The use o f beta-receptor antagonists in the treatment o f heart failure is controversial. Available data do not allow general r e c o m m e n d a t i o n s regarding their use. In dilated cardiomyopathy, several studies suggest that long-term treatment in individual patients reduces symptoms and increases exercise capacity. Short-term treatment is u s u a l l y not beneficial, except in patients with ischemically induced left ventricular dysfunction. In heart failure, post myocardial infarction and in chronic ischemic heart disease, no proper long-term study has been performed to evaluate its effects. However, patients w i t h acute myocardial infarction tolerate beta blockers, despite the presence o f left ventricular dysfunction and long-term prognosis is improved. N e w e r agents, some with ancillary properties, such as intrinsic activity and vasodilatation, m a y have advantages. In the future w e need a better description o f the cardiac status in our patients in order to be able to select those that will respond favorably to beta-receptor antagonists. The m e c h a n i s m s by w h i c h some patients improve are still obscure. Protection against receptor downregulation, restoration o f receptor density, protection against cardiotoxicity o f catecholamines, and improvement in ischemic systolic and diastolic left ventricular function are all possible. The fear that beta-receptor antagonists are dangerous in heart failure is in most instances not warranted, but an initial deterioration m a y have to be accepted in order to gain long-term beneficial effects. O n g o i n g studies in both idiopathic cardiomyopathy and in postinfarction failure will hopefully help us to define the use o f beta-adrenoreceptor a n t a g o n i s t s in the future.

Cardiovasc Drugs Ther 1991;5:589-604

Key Words. beta-receptor antagonists, congestive heart failure, left ventricular dysfunction, cardiomyopathy, ischemic heart disease, acute myocardial infarction

H e a r t failure is a condition traditionally considered to be caused by a weakened heart muscle. This may either be due to a primary defect of the muscular cells (cardiomyopathy) or to destruction of myocardium caused by impaired myocardial circulation (ischemic heart disease). A unanimously accepted clinical definition of heart failure does not exist. A common feature, regardless of definition, is a disturbed ventricular function. This disturbance may affect both the systolic and/or the diastolic properties of the heart. Secondary changes with fluid retention, peripheral adaptation, and neurohormonal activation are also to be considered. Classification of patients according to

the New York H e a r t Association (NYHA) scale is very crude, and symptoms of heart failure are neither specific nor fully understood from a pathophysiologic point of view. F o r these reasons it is not surprising that opinions on how to t r e a t heart failure differ. Long-term t r e a t m e n t has been concentrated on three principles to support the failing myocardium: relief of fluid retention b y diuretics, unloading of the heart by vasodilators, and increasing contractility, primarily with digitalis. The use of these drugs as monotherapy or in combination is by no means uniform. The use of digitalis has diminished lately, since its efficacy has been questioned [1-3]. Furthermore, mortality in patients with ischemic heart disease may be adversely affected [4,5]. Diuretics are accepted as basic treatment in all stages of heart failure, whereas the opinions on when to start vasodilatation varies. Beta-blockers have been more or less regarded as contraindicated in patients with heart failure. This view has emanated from the acute hemodynamic effects of beta-blockers and on the assumption that only the systolic function, i.e., the contractile properties of the heart, are of importance. Recent studies, however, indicate that beta-blockers may have beneficial effects in some patients with heart failure. This review presents the current status of our knowledge regarding beta-blockers and heart failure.

Early Observations on Beta-Blockers Chamberlain et al. [6] measured cardiac dimensions in healthy students at rest and during exercise before and after treatment with the beta-receptor antagonist pronethalol. An increase both in systolic and diastolic dimensions at rest and exercise was found. Robinson et al. [7] reported reduced cardiac output at rest and during exercise after propranolol given to healthy volunteers. There was also a reduction in oxygen consumption on exercise, later confirmed by Petersen et

Address for correspondenceand reprint requests: L. Erhardt, Section of Cardiology, Department of Medicine, Karolinska Institutet at Danderyd Hospital, S-18288 Danderyd, Sweden. 589

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al. [8] at submaximal and maximal work load. Hamer et al. [9] and SchrSder et al. [10] found similar changes in patients with ischemic heart disease. Sowton et al. [11] found an increase in pulmonary a r t e r y pressure after beta-blockade. Several small studies during the late 1960s and early 1970s assessed the hemodynamic effects of different beta-blockers, betal-selective and nonselective, with and without intrinsic sympathomimetic activity (ISA) in patients with a variety of heart conditions. Most studies showed an overall negative chronotropic effct, a fall in cardiac index, a decline in cardiac contractility, and a small rise in left ventricular end-diastolic pressure [12-18]. These observations indicated that beta-receptor antagonists produced signs that mimicked the findings in clinical heart failure: a) increasing heart size, b) reduced cardiac output at maximal and submaximal exercise, c) increase in filling pressure, and d) reduced oxygen consumption. This, t h e r e was an early consensus that beta-blockers should not be beneficial when used in patients with heart failure. They were in fact considered contraindicated. Uncontrolled Studies with Beta-Blockers

The hypothesis that beta-blockers could be of value in heart failure emerged from the experience with practolol in myocardial infaction, where the drug was given for relief of ischemia but was found to be tolerated also by patients with heart failure. Indeed, signs of congestion could disappear after injection of practolol [19,20]. The suggested mechanism was a reduction in left ventricular work as expressed by a diminished double product. The initial report of beneficial effects of betablocking drugs in clinical h e a r t failure was a small uncontrolled study by Waagstein et al. [19] in seven patients with severe dilated idiopathic nonalcoholic cardiomyopathy treated with either the betal-selective ISA drug practolol (six patients) or the nonselective ISA drug alprenolol (one patient). The patients were given therapy on a long-term oral basis, and improvements in clinical status, exercise capacity, and noninvasive parameters of systolic and diastolic function were noted during follow-up. Beneficial effects on mortality in the same category of patients treated for at least 6 months were reported later [21]. In this investigation 24 patients with a mean ejection fraction (EF) of 0.33 were included and compared to a group of historical controls consisting of 13 patients. Patients in the control group were older and had a shorter duration of symptoms, which could indicate that they were progressing more rap-

idly. T r e a t m e n t in both groups consisted of digitalis and diuretics, with the addition of either practolol, alprenolol, or metoprolol. There were changes in the use of the different beta-receptor antagonists during the study. The suggested effect could therefore neither be related to beta-receptor selectivity nor to the presence or absence of ISA. In the control group, all patients were dead after approximately 3 years while in the t r e a t m e n t group five patients were still alive even after 5 years, the difference being statistically significant. The authors proposed that the mechanism could be a protection against toxic myocardial effects of elevated catecholamines [22] in heart failure patients [23]. In 1980 the same group presented follow-up of data on functional capacity in 28 patients with cardiomyopathy (mean E F = 0.32) treated with beta-blockade for up to 62 months [24]. Therapy was introduced with low dosages that were gradually increased. Most patients were t r e a t e d with metoprolol, but practolol and alprenolol were also prescribed. The results showed clinical improvement in slightly more than 50% of the patients and deterioration in only one. Ten patients died during the study, seven of whom died suddenly. Almost half of the patients showed a decrease in left ventricular diastolic dimensions with an improvement in ejection fraction and circumferential fiber shortening. Exercise performance improved in more than half of the patients. Noninvasive p a r a m e t e r s of diastolic function improved. In most cases improvement was seen between 1 and 3 months after initiation of treatment. A further follow-up of 46 patients confirmed these beneficial effects during 9 years of t r e a t m e n t with beta-blockade [25]. The effect of withdrawal of betablockade in 15 patients with cardiomyopathy who previously had improved were also reported from the same group [26]. All functions as assessed by noninvasive investigation deteriorated, and changes were reversed after readministration of the drug. These studies accordingly suggest that t h e r a p y with beta-adrenergic antagonists improves symptoms and exercise performance, as well as noninvasive functional p a r a m e t e r s in some patients with severe heart failure due to idiopathic dilated cardiomyopathy. No prediction of nonresponders on the basis of clinical findings or investigations was possible. In a recently published study from the same authors [27], 33 patients with dilated cardiomyopathy and E F = 0.25 were investigated also with right and left heart catheterization and right ventricular biopsy. Mortality during 6 months was 21% and 24 of 26 survivals improved (NYHA 3.3 to 1.8); the final mean metoprolol dose was 154 mg.

Beta-Receptor Antagonists in Heart Failure

The acute hemodynamic effect of IV injection of 15 mg metoprolol showed no increase in left ventricular filling pressure but a fall in cardiac index. During long-term t r e a t m e n t (mean 15.9 months), left ventricular end-diastolic pressure fell from 24.1 to 13.4 mmHg, and cardiac index and systolic blood pressure increased, whereas systemic vascular resistance decreased. Beta-receptor density was low before metoprolol t r e a t m e n t but increased with 60% after treatment. Echo-Doppler showed improvements in systolic and diastolic function and reductions in left ventricular dimensions. During a later withdrawal of metoprolol in 24 patients, noninvasive p a r a m e t e r s deteriorated but improved again after reinstitution of metoprolol. Ikram et al. [28] performed an invasive acute study in 10 patients with stable dilated cardiomyopathy (mean E F = 0.44) who were given 25 mg IV of acebutolol, a betal-selective antagonist with ISA. They found increases in end-diastolic and end-systolic volumes, as well as a small nonsignificant fall in ejection fraction. Contractility decreased significantly in contrast to the findings of Swedberg et al. [24]. Improvement of diastolic compliance and a small reduction of end-diastolic filling pressure confirmed the Swedish reports of improvement in diastolic function. In an open study b y Dell'Italia et al. [29], 12 mg metoprolol was given IV to 16 patients within 48 hr of a myocardial infarction. Biplane cineventriculography and left- and right-sided heart catheterization were performed. Ejection fraction was slightly reduced (mean 0.46) at baseline, with a moderate increase in filling pressure (mean 22 mmHg). Reductions in both systolic and diastolic function with a decrease in ejection fraction, cardiac and stroke index, as well as an increase in systemic vascular resistance, end-systolic volume, and a prolongation of left ventricular relaxation time were observed. There were no changes in left ventricular filling pressure or wedge pressure. The authors suggest that beta-blockade diminishes determinants of myocardial oxygen demand and that it might reduce systemic venous return. This study does not point to favorable effects on cardiac function of beta-blockers in patients with mild to moderate failure in the early postinfarction phase, although filling pressures were not changed.

Controlled Studies with Beta-Blockers in Heart Failure

Cardiomyopathy There are five early controlled studies on beta-adrenergic blockade in patients with dilated cardiomyopathy. Three have assessed functional capacity, one

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acute hemodynamics, and one study has mortality as primary endpoint. Ikram et al. [30] performed a double-blind crossover study in 17 patients with stable congestive cardiomyopathy N Y H A I I - I I I (Mean E F = 0.46) who received placebo or acebutolol 200 mg orally b.i.d, for 1 month. Endpoints were exercise capacity and echocardiographic assessment of left ventricular function and cardiothoracic ratio. Twelve patients had alcoholinduced cardiomyopathy. The results are somewhat contradictive. There was an increase in cardiothoracic ratio, but a small decrease in echocardiographic diameters in both systole and diastole, with a higher ejection fraction. The echocardiographic changes were, however, not significant. There was a significant reduction in exercise time by approximately 50 seconds with acebutolol, but no significant difference was observed in oxygen consumption at anaerobic threshold or maximal exercise. No patient reported clinical improvement. The study has been claimed to be too short to demonstrate a beneficial effect, since in the Swedish reports much of the improvement was seen between 1 and 3 months after beta-blockade was introduced. Similar results were reported by Currie et al. [31] in a 1-month double-blind cross-over trial with metoprolol in 10 patients with severe dilated cardiomyopathy (mean E F = 0.27), N Y H A functional class III. Patients with previous alcohol abuse were excluded. After completion of the study it was revealed that four of the patients had occult coronary a r t e r y disease on coronary angiograms. The dose of metoprolol was determined by a prestudy titration protocol, mean dose 130 mg/day. Endpoints were exercise tolerance, hemodynamics, and left ventricular ejection fraction at rest and during steady-state exercise at three predetermined levels. Exercise tolerance did not change. The hemodynamic study showed reduced heart rates at rest and during exercise on metoprolol and also a reduction of cardiac index with an increase in stroke volume index. There was no change in filling pressures. Ejection fraction increased in both the placebo and the metoprolol group. A reduction in plasma renin activity was noted after treatment, suggesting a mechanism through which beta-blockade could be beneficial in heart failure. However, no clinically beneficial effects could be detected. Engelmeier et al. [32] performed a double-blind randomized tong-term trial with metoprolol for 1 year in 25 patients with severe dilated cardiomyopathy, NYHA I I - I I I . Although these patients were in a better functional class than the patients in the Swedish trials, ejection fractions were lower (approximately 0.16). The patients were stable when they entered the

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trial, and wedge pressures in the metoprolol group at baseline were not raised. A low dose of metoprolol, 6.25 mg, was used initially and increased to 100 mg/ day over 4-6 weeks if no adverse reactions occurred. The mean dose was 92 mg/day. The endpoints were exercise capacity, radionuclide ejection fraction, and left ventricular end-diastolic dimensions by echocardiography. When the patients had fulfilled the study, or deteriorated, those on placebo were entered in a cross-over unblinded study with metoprolol for 1 year. During the double-blind phase there were no beneficial effects in the placebo group. Only 10 out of 16 patients remained blinded for 12 months, one died and heart failure deteriorated in four. In the metoprolol group (n = 9), one patient had an early dropout because of bradycardia, and one patient was in severe heart failure after 6 months. Eight patients improved their exercise capacity with b e t t e r ejection fraction, but no reduction in end-diastolic dimensions. There was also an improvement in functional class compared to the placebo group. In the cross-over study 12 patients were entered and followed for at least 10 months an open t r e a t m e n t with metoprolol, with changes comparable to the improvements seen in the metoprolol group in the double-blind part of the study. Thus, the majority of the patients improved on betablocker therapy. In another trial Shanes et al. [33] looked at differences in acute hemodynamic response to either placebo, propranolol, or pindolol given intravenously in a double-blind randomized fashion to 30 patients with an ejection fraction less than 0.35. The mean total dose of pindolol was 0.76 mg and propranolol 7.2 mg. The drugs were given in four gradually increasing doses until clinical deterioration or a 25% reduction in heart rate or blood pressure was observed. In the placebo group, there was an increase in left ventricular filling pressures and right atrial pressures. In the propranolol group four patients deteriorated and needed inotropic support. H e a r t rate and cardiac output were reduced. A rise in wedge pressure from 13.9 mmHg to 17.3 and a rise in systemic vascular resistance was noted. In the pindolol group all patients tolerated the injections, and there was only a significant decrease in h e a r t r a t e and a rise in right atrial pressure, but also a nonsignificant fall in systemic vascular resistance and end-diastolic filling pressure, indicating some hemodynamic advantage. Anderson et al. [34] performed a mortality study in 50 patients with stable idiopathic dilated cardiomyopathy, mean ejection fraction 0.27. Half of the randomized patients openly received metoprolol. Alcohol abusers were not entered and ischemic heart disease was ruled out by angiography in all patients older than

30. Metoprolol was introduced at a dose of 12.5 mg b.i.d, and increased over days up to 50 mg b.i.d., when tolerated, with a mean dose 61 mg/day. There were three early dropouts due to deterioration of symptoms and two late dropouts due to aggravation of heart failure. There w e r e lower death rates than expected in the control group. Mortality was approximated from the historical control group used in the study by Swedberg et al. [21]. Intention to treat analysis showed no difference in mortality. There were five deaths in the metoprolol group and six deaths in the control group after a mean follow-up time of 19 months. By actual t r e a t m e n t there was a trend towards improved survival in the metoprolol group, with three deaths compared to eight in the control group. The authors also claim that functional outcome favors beta-blockade. H o w e v e r , 20% of metoprolol patients deteriorated, and t h e r e were no significant differences in functional class or score when analyzed by intention to treat. Nor w e r e there significant differences in exercise capacity, but results were obtained in only about half of the patients. The number of patients is too small to detect a difference in mortality because of a lower than expected mortality in the control group.

Summary Acute administration of beta-blockade to patients with idiopathic cardiomyopathy induces hemodynamic changes similar to previously noted findings in open studies of healthy subjects or patients with heart disease, i.e., reduction of cardiac output and heart rate, a small rise in filling pressure and also a rise in vascular resistance. Less pronounced effects occur with an ISA drug. It should, however, be noted that some of the study patients had normal filling pressure at baseline. During 1-month chronic administration, there are no beneficial clinical effects and exercise capacity is reduced or unchanged, whereas ejection fraction improves. During long-term t r e a t m e n t for 1 year, exercise capacity, functional class, and ejection fraction improve, although heart size remains unchanged. Thus, the improvements seen are time dependent and may occur despite initial deterioration. It should be stressed that the response is individual and improvement does not occur in all patients. W h e t h e r mortality is reduced with beta-blockade in these patients still remains an open question.

Ischemic Heart Disease Our knowledge concerning the use of beta-blockers in patients with ischemic heart disease is limited. Only

Beta-Receptor Antagonists in Heart Failure

few controlled studies with the primary objective to study patients with heart failure are available. Vedin et al. [35] assessed the importance of ISA activity in a small double-blind cross-over study of eight patients with previous myocardial infarction and symptoms of heart failure N Y H A functional class II. All patients deteriorated at least one functional class when digoxin was discontinued and improved when reintroduced. After stabilization and noninvasive investigation two periods of 2 weeks double-blind treatment with either 160 mg propranolol or penbutolol 40 mg b.i.d, commenced with a washout period of 4 weeks. Endpoints were cardiac function as assessed noninvasively. After beta-blockade there was a reduction in heart rate, a small rise in end-diastolic dimension, and a reduction in the fourth heart sound interpreted as improved diastolic function. There were no differences in response between propranolol or penbutolol, the latter being a nonselective ISA drug. F o u r patients reported improvement in dyspnea while on beta-blockade, probably an antiischemic effect. In the Gothenburg metoprolol trial [36], 1395 patients were prescribed 100 mg b.i.d, or placebo in a double-blind fashion and followed for 3 months after an acute myocardial infarction. The first dose was given intravenously within 48 hours of myocardial infarction. The primary endpoint was mortality but analysis was also made prospectively of the incidence of heart failure during the study, as well as the need for frusemide during the first 4 days of the trial. The incidence of heart failure before entering the trial was slightly higher in the metoprolol group (12% versus 9%). During the study period there was a similar proportion of patients developing heart failure in both groups, approximately 30%. The need for frusemide during the initial phase of the study was significantly higher in the placebo group. The authors suggest a reduction in infarct size as the possible cause for the observed effects. As part of the multicenter MIAMI trial [37,38], metoprolol was given within 12 hours of onset of myocardial infarction in an optional study in 14 centers with hemodynamic evaluation of 212 patients before and during the first 24 hours after administration of 15 mg metoprolol IV or placebo. Patients with more severe signs of heart failure were excluded. There was a significant fall in heart rate, systolic and mean arterial blood pressure, as well as a reduction in cardiac and stroke work index after metoprolol. The differences were most pronounced early and t h e r e a f t e r declined, although oral t r e a t m e n t with metoprolol was continued. Right atrial and wedge pressures were significantly increased by metoprolol in the group with initial low filling pressures ( NEGATIVE INOTROPISM

Fig. 1. Beta-blockade in C H F - - I H D vs. cardiomyopathy

tions require better definitions of the patients. Longterm studies included exercise tests and description of c a r d i a c s t a t u s w i t h r e g a r d t o s y s t o l i c - d i a s t o l i c function a n d i s c h e m i a n e c r o s i s a r e n e e d e d [104]. S h o r t t e r m h e m o d y n a m i c s t u d i e s a r e o f l i m i t e d v a l u e , since t h e y do not p r e d i c t l o n g - t e r m effects. I f t h e f a v o r a b l e effects of b e t a - b l o c k a d e a r e r e l a t e d m o r e to p r o t e c t i o n a g a i n s t c a t e c h o l a m i n e t o x i c i t y a n d u p r e g u l a t i o n of b e t a - r e c e p t o r s , a b e t a - b l o c k e r w i t h o u t I S A is p r o b a b l y to b e p r e f e r r e d . If, on t h e o t h e r h a n d , t h e s e effects a r e d e r i v e d f r o m t h e a n t i i s c h e m i c p r o p e r t i e s , b o t h I S A and n o n - I S A d r u g s will b e effective. Ancill a r y p r o p e r t i e s (beta1 I S A , b e t a 2 I S A , a l p h a I blocka d e ) could be h e m o d y n a m i c a l l y a d v a n t a g e o u s and t h u s f u r t h e r i m p r o v e v e n t r i c u l a r function. I n s t u d i e s w i t h x a m o t e r o l [84] a n d cicloprolol [98], a r e d u c t i o n in h e a r t size w a s found, w h i c h w o u l d i n d i c a t e a beneficial effect on o x y g e n d e m a n d . T h i s a s p e c t f a v o r s t h e use of an I S A d r u g in t h e t r e a t m e n t of i s c h e m i c h e a r t failure. T h e d e g r e e of h e a r t f a i l u r e m a y b e of i m p o r t a n c e in t h i s s e t t i n g , since I S A d r u g s will act m o r e like p u r e b e t a - b l o c k e r s in p a t i e n t s w i t h a h i g h s y m p a t h e t i c tone. H o p e f u l l y , o n g o i n g clinical t r i a l s like M I D I C (Metoprolol I n D i l a t e d C a r d i o m y o p a t h y ) a n d M E X I S ( M e t o p r o l o l and X a m o t e r o l I n f a r c t i o n S t u d y ) will help to clarify t h e r o l e of b e t a - b l o c k e r s in p a t i e n t s w i t h h e a r t failure of d i f f e r e n t o r i g i n in t h e n e a r f u t u r e . This work has been supported by the Swedish Heart Lung foundation.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

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