Clinical experience with beta adrenergic blocking agents in myocardial ischaemia: A dilemma and a challenge

Pharma~.Ther. Vol

13, pp~ 285 320 © Pergamon Press Ltd 1981. Printed in Greal Britain

Specialist Subject Editor:

0163 72~8 81,0710 0285505.00/0

R. G . SHANKS

CLINICAL

EXPERIENCE

ADRENERGIC MYOCARDIAL AND

WITH

BLOCKING ISCHAEMIA:

BETA

AGENTS

IN

A DILEMMA

A CHALLENGE N. S. BABER

Medical Department~ Imperial Chemical Industries Ltd, Pharmaceuticals Division, Mereside AIderley Park, Macclesfield, Cheshire, SKIO 4TG, England

1. INTRODUCTION In 1959 Black (Black, 1967) proposed a hypothesis that the use of beta adrenergic blocking agents would be of benefit in patients with myocardial ischaemia. His theory was based on the effects of catecholamines on the heart during the ischaemic process, which effects could be specifically antagonised by these agents. It was foreseen that this action might not only reduce the symptoms of angina pectoris, but also prolong the lives of patients with myocardial infarction. Since that time, many studies have been published in which beta blocking drugs have been used in small and large numbers of patients with evolving and established myocardial infarction, but the exact role of these agents in the treatment of myocardial ischaemia is still not clearly defined. The earliest clinical trials in the mid and late '60s in myocardial ischaemia with propranolol, the first beta blocking drug to receive widespread clinical use, yielded conflicting results. But in the last decade, three main factors have led to an increased interest in the use of these agents in myocardial ischaemia. First, technicological advances have allowed for the quantification of changes in cardiac metabolism during ischaemia and methods for the sizing of infarcts have been developed. The development of 24 hr Holter monitoring for measurement of post infarction dysrhythmias has allowed for better definition of the relation between size of infarction and susceptibility to dysrhythmias, as well as for the testing of anti-dysrhythmic drugs. Second, the identification of risk factors in the community for myocardial infarction and sudden death has enabled prognostic indices to be established for the testing of drugs in clinical trials. Third, there is a general acceptance of the need for the execution and analysis of well designed clinical trials to assess the effect of drugs in myocardial ischaemia (Peto et al., 1976). When considering the use of beta blocking agents in myocardial ischaemia, the practicising physician must ask of the published literature: 1. What measures of improvement can be evaluated (e.g. sudden death, re-infarction, return to work)? 2. What evidence is there that beta blocking drugs are effective? 3. Are there any important differences between the various beta blocking drugs? 4. What is the appropriate dosage regimen? 5. When should beta blockade be started in relation to onset of myocardial ischaemia? 6. How long should treatment be maintained? 7. What are the risks or what is the risk-benefit ratio'? For the patient who is 'at risk' the only important question is, 'Will this drug allow me to live longer and leave me free of serious side effects'?'. None of the published studies allows for an unequivocal answer to this question. This article will review and reassess the clinical trials on morbidity and mortality where beta adrenergic blocking drugs have 285

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N.S. BABER

been used in myocardial ischaemia and will relate these to individual human studies on efficacy and mode of action of beta-blockers in specific areas of cardiovascular disease. 2. CLASSIFICATION OF USES OF BETA-BLOCKING AGENTS IN MYOCARDIAL ISCHAEMIA The use of beta adrenergic blocking drugs during myocardial infarction has been extensively reviewed (Gibson and Sowton, 1969; Fitzgerald, 1972; Jewitt and Singh, 1974; Fitzgerald, 1976; Mueller and Ayres, 1977; Mueller and Herron, 1977; Singh, 1978). Beta blocking agents have been administered before, during and after the acute ischaemic event with five apparent intentions: (1) (2) (3) (4) (5)

The elective use to suppress specific dysrhythmias. The prophylactic use to suppress dysrhythmias. To conserve viable myocardial tissue. Symptomatic relief to chest pain. To initiate therapy, as a secondary prophylactic measure after recovery from the acute event. 2.1. ELECTIVE USE TO SUPPRESS POST-INFARCTION DYSRHYTHM1AS

Most authorities agree that sudden (Lown and Graboys, 1977; Cobb and Werner. 1979), and probably some forms of non-sudden (Lovell, 1975), death after acute myocardial infarction is associated with prior ventricular dysrhythmias, rather than supraventricular dysrhythmias. However, there are relatively few studies where beta blocking drugs have been carefully assessed as post infarction antidysrhythmic agents. It is particularly important to evaluate the effect of different beta blocking drugs with different ancillary pharmacological properties and in variable doses. 2.1.1. Effect on Ventricular Dysrhythmias 2.1.1.1. Propranolol. Gianelly et al. (1967), noted that intravenous propranolol was ineffective in suppressing ventricular dysrhythmias, but only one of the five cases treated actually had a myocardial infarction. Kernohan et al. (1967) noted that oral propranolol abolished frequent ventricular ectopics in three patients after acute myocardial infarction and intravenous propranolol suppressed ventricular tachycardia in one patient where D.C. shock had failed. Sloman and Stannard (1967a), administered propranolol to two patients after acute infarction, one of whom had runs of ventricular tachycardia which was rapidly suppressed by oral propranolol. Ikram (1967), noted that (1 mg i.v.) propranolol suppressed ventricular fibrillation in patients after acute myocardial infarction. Gibson and Sowton (1969), reviewed published reports of the efficacy of propranolol in suppressing post infarction ventricular ectopic beats and ventricular tachycardia. Of twelve patients with ventricular tachycardia, six reverted to sinus rhythm, two of these having failed to respond to previous DC shock. Two of the patients who failed to respond to propranolol had prolonged periods of, hypotension. Two died, one developing complete heart block, the other ventricular fibrillation. Gibson himself had noted 38 reported cases where propranolol had been used after DC conversion of ventricular fibrillation. In 24 cases, sinus rhythm was maintained. Nielson and Jorgensen (1966), reported the use of propranolol in three patients with ventricular fibrillation, two of whom failed to respond, and the others developed asystole. Sloman et al. (1965), reported three cases of ventricular fibrillation, one of which followed acute myocardial infarction, and all of which responded to intravenous propranolol (15 22 mg).

/~-adrenergic agents in myocardial ischaemia

287

Bath (1966) documented three cases of ventricular tachycardia and ectopics after acute myocardial infarction. In two cases return to sinus rhythm occurred with clinical improvement. The other case failed to respond. In a study by Lemberg et al. (1970) thirty-eight patients with acute myocardial infarction complicated by ventricular tachycardia were given propranolol intravenously (2-4.5 rag), after they had failed to respond to lidocaine or quinidine. The patients had mild or moderate left ventricular failure, with heart rates between 78-120 beats per minute. All patients reverted to sinus rhythm and only one developed side effects, namely transient a.v. dissociation. 2.1.1.2. Other beta adrenergic blockin9 drugs. There are many sporadic reports of effects of other beta blocking drugs on post-infarction ventricular dysrhythmias. Jewitt et al. (1969) treated forty patients with ventricular tachycardia or ectopic beats with practolol and noted a return to sinus rhythm in twenty-two. Jewitt et al. (1971) noted that of five patients with ventricular fibrillation who failed to respond to DC counter shock therapy, three reverted to sinus rhythm with haemodynamic improvement with practolol. Allen et al. (1975) administered practolol intravenously (5 mg at 5 min intervals, to a maximum of 25 mg) to forty-nine patients with frequent ventricular ectopic beats, within the first 24 hr of the onset of symptoms (mean 6.9 +_ 0.7 hr). Practolol abolished the dysrhythmia in thirteen patients (26~o) and reduced the frequency of ectopic beats in a further sixteen (33~o). However, lignocaine was co-administered in forty-four of these patients and in only eight was practolol used as the initial therapy, being completely effective in abolishing ventricular ectopic activity in only one patient. In thirty patients who received lidocaine first, and who failed to respond, practolol abolished the ventricular ectopic beats in eight, reduced the frequency in a further ten and was without effect in twelve patients. There was no relation between the pre-treatment ventricular rate and the response rate to practolol administration. Six patients developed bradycardia requiring treatment with atropine, seven developed severe hypotension (less than 80/60) in the absence of bradycardia. Four of these patients showed signs of moderate left ventricular failure prior to practolol administration. Seventeen patients with frequent ectopic beats were treated between 1 and 28 days after the onset of symptoms of acute infarction. Only two (12~o) had complete abolition of their dysrhythmia and there was a reduction in the frequency in a further two (12~o). Twenty-five patients who had survived resuscitation from ventricular fibrillation and with persistent ventricular dysrythmias were also treated with intravenous practolol. In thirteen patients, the dysrhythmia was abolished and in a further two, it was reduced in frequency or severity. There was no difference in the effectiveness of practolol given in the first 24 hr or subsequently. The authors comment that hypotension after infarction is not prevented by the intrinsic sympathomimetic activity of practolol. In a further study, Jewitt and Croxon (1971) used practolol (5mg in 2min to a maximum of 25 mg) to treat sixteen patients who had sustained a myocardial infarction within the previous 7 days and who had ventricular tachycardia with rates of greater than 120 beats/min. All patients had previously received lidocaine and had failed to respond, all were hypotensive (systolic blood pressure below 90mm/Hg) and 11 had evidence of heart failure. Sinus rhythm returned in 7 of these patients. In a further twenty-four patients previously treated with lidocaine with frequent ventricular extrasystoles, practolol resulted in total suppression in thirteen and reduction to less than 25% of previous level in a further two patients. Of five patients who had persistent ventricular fibrillation after repeated DC shocks, three reverted to sinus rhythm after 5-10 mg practolol intravenously. Lemberg et al. (1972) administered alprenolol to forty-nine patients after acute myocardial infarction complicated by atrial and ventricular ectopic beats. The majority of patients were in mild or moderate heart failure at the time of administration. The drug was found to be effective in most cases, without any increased symptoms or signs of heart failure. In comparison with their experience with propranolol, the authors comment that

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on average, twice the intravenous dose of alprenolol was required and that there was a marked bradycardia with propranolol which required treatment with atropine in several cases. Kreus et al. (1970) treated ten patients with acute myocardial infarction, within 24 hr of onset of symptoms with intravenous alprenolol (initial dose 2.5 mg, up to maximum of 10mg). Six patients had ventricular dysrhythmias and three reverted to sinus rhythm. One patient with an initial heart rate of 148 beats/min and BP of 120../90 collapsed after 5 mg alprenolol and required resuscitation. Sandier and Pistevos (19711, noted suppression in 13 out of 18 cases of post-infarction ventricular ectopic beats with intravenous oxprenolol. The drug was less effective against ventricular tachycardia, and in their series of forty-three post-infarction patients, over half had falls in systolic and diastolic blood pressure. Wasir et al. (1977), in a series of forty-four patients, noted that two patients with ventricular tachydysrythmia after acute myocardial infarction reverted to sinus rhythm after intravenous atenolol (1-10 mg), which abolished ventricular ectopic beats in nine of fourteen patients and in a further two patients, when lidocaine was added. Two patients with paroxysmal ventricular tachycardia responded to atenolol alone. Jadrque and Jimenez (1974), reported 12 cases of ventricular ectopics (over 5 per min), and ventricular tachycardia treated with intravenous sotalol (20-40 mg). All responded with slowing of ventricular rate and in five cases there was a reversion to sinus rhythm. Four of these patients had signs of cardiac insufficiency before treatment, although this was not apparently made worse by treatment. Stroobandt et al. (1974), administered sotalol to six patients with a post-infarction ventricular dysrhythmia associated with heart failure. Four showed a good response, three a moderate response, but it is not clear from the report how many of these episodes of heart failure occurred as a complication of acute myocardial infarction. A more comprehensive study was reported by Myburgh et al. (1979) comparing sotolol and placebo in post myocardial infarction. Twenty patients, 6 96 months (mean 42 months) after myocardial infarction entered a 14 day placebo washout period, during which a 6 hr Holter tape recording was made. They were then randomly allocated to 28 days' treatment with either oral sotalol (320 mg once a day) or placebo. Patients were TABLE 1. Blood Pressure and Heart Rate Recordings in 20 Post-lnfi~retion Patients treated with Sotalo: mean (range) Systolic Blood pressure mm Hg Baseline Run-in Double-Blind phase Open Phase (3 mths)

*p **p ***p ****p

< < < <

Diastolic Blood pressure mm Hg

Heart Rate (resting) beats/minute

127(104 178) No change No change

83(71L100) *79 (68 110) No change

72(57 91) No change No change

*'120(100- 166)

*79(68 94) (2 mths) ****76 (64-90) (3 mths)

***60(43 80) (6 mths)

0.05 compared with base-line 0.01 compared with base-line 0.005 compared with base-line 0.001 compared with base-line

Table showing changes in blood pressure and heart rate in 20 post-infarction patients treated with Sotalol. During the base-line and placebo run-in period, there are no changes in these parameters. Administration of sotalol during the double-blind phase of the trial when the dose was fixed at 320 mg once a day, did not reduce blood pressure or heart rate. During the open phase, Sotalol dosage was titrated to a dose of 160-480mg/day; signiticant changes in blood pressure and heart rate were observed at 2, 3 and 6 months' follow-up. Acknowledqement This table is produced with kind permission of Dr. Myburgh and his colleagues.

fl-adrenergic agentsin myocardialischaemia

289

then crossed over to the alternative therapy for 28 days. A 6-hour Holter taping was made at the end of each period. All patients then entered an open phase of dose titration of 160-480 mg per day for 28 days, followed by a further 28 days on placebo. The mean number of ventricular ectopic beats per minute during the placebo run-in was 119.6 (range 19-130), during the placebo phase of the double-blind trial 135.6 (range 1.3-603) and during the terminal placebo phase 171.1 (range 2.5-640). During the controlled phase of the trial, ectopic beats were reduced to a mean of 43.1 (range 0--370) by 320 mg sotalol, with a total suppression in four patients, 50-99~ in twelve patients, and less than a 50~o suppression in four. The mean reduction was -67.5~0 (p < 0.01), range - 1 0 0 ~ to + 368~o. In the open phase, seven patients had the best response on 160 mg, eight on 320 mg and five on 480mg sotalol. The mean reduction in ectopic frequency was 88.5~o (p < 0.001) at the optimal titrated dosage. Mortality and morbidity was not reported. Five patients complained of dizziness and loss of energy (four on sotolol). Changes in heart rate and blood pressure are shown in Table 1. The study is open to criticism on the different time points after infarction before patients were studied and in the relatively short periods of Holter monitoring. It is known that ectopics become less frequent with time after myocardial infarction (Roland et al., 1979) yet the three placebo periods have relatively comparable ectopic beat frequencies. It is not clear how the optimal dosage was determined in the dose-titration phase, and it would appear that some patients had a better response to a smaller dose, at different times in the trial. Vukovich et al. (1978) reported a single patient with a ventricular dysrhythmia complicating ventricular failure after acute myocardial infarction who responded to oral nadolol. After a cumulative dose of 30 mg the frequency of premature ventricular beats dropped by four fifths. Biron et al. (1975) gave acebutolol intravenously at a rate of 12.5 mg/min to a maximum dose of 50 mg to two patients with recent myocardial infarction, complicated by premature ventricular beats. Both patients appeared to respond. Ahumada et al. (1979) administered acebutolol (1-20mg every 4hr for 24hr) to twenty-eight patients, 6 hr after the first rise in plasma creatine kinase activity. Twentytwo patients were matched as controls for age, blood pressure and heart rate and for initial frequency of ventricular extrasystoles. To overcome the problem of a non-linear distribution of ventricular ectopic frequency with time, the results were expressed as logarithms. Both the total number of ventricular ectopic beats and the number of complex dysrhythmias were significantly reduced in the acebutoiol group, compared with initial values, but only during the first 5 hr after infarction (see Table 2). In the control group, there was no effect on the total or complex dysrhythmias numbers in the first and second 5-hr periods. There was no difference between the two groups in the number of dysrhythmias at any time points after infarction. 2.1.2. Effect on Supraventricular dysrhythmias Lemberg's series (Lemberg, 1970) included patients with supraventricular tachycardia, atrial fibrillation and atrial flutter. All but one patient responded with a return to sinus rhythm with ventricular rates of 80 beats/min or less after 0.5-0.25 mg propranolol intravenously. In Jewitt's series (Jewitt et al., 1971) of eighteen patients with atrial fibrillation, fourteen responded to intravenous practolol with a reduction of ventricular rate below 100 beats/min and return to sinus rhythm in five. Of thirteen patients with atrial flutter or atrial tachycardia, with ventricular rates of over 140 beats/min, twelve responded with reduced ventricular rates and clinical benefit. Eight reverted to sinus rhythm. In contrast, Allen et al. (1975) concluded that practolol was relatively ineffective in restoring sinus rhythm in patients with atrial fibrillation, or flutter. Of thirty-one patients with atrial fibrillation, only two returned to sinus rhythm and none of the six patients in

290

N. S.

BABER

TABLE 2. Effects q]" Acebutolol on Post-Infarction Ventrieular Arrythmias (Values expressed in logarithms) Acebutolol (N = 22) Time (hours) (~5 6~10 11 15

Total Ventricular Extrasystoles 2.82 ± 0.437 p < 0.025 2.11 ± 0.41 1.89 _+0.38

Repetitive Arrhythmias 0.337 ± 0.15 p < 0.05 0.138 ± 0.10 0.113 + 0.06

Control (N - 22) Total Ventricular Extrasystoles 2.76 ± 0.43

Repetitive Arrythmias 0.499 ± 0.17

2.81 ± 0.44 1.99 +_0.38

0.324 ± 0.15 0.207 + 0.09

Effects of intravenous Acebutolol on 22 patients with post-infarction ~entricular arrythmias, compared with a control group of 22 patients matched for age, blood pressure, heart rate and initial frequency of ventricular extrasystoles. Treatment was initiated 6 hours after the first rise of plasma creatine kinase activity. There were no significant changes in the control group. Acebuto1ol significantly reduced both total and repetitive arrythmias in the first five hours of treatment, but not subsequently. There were no significant changes between the treatment and control groups at any time points. Aeknowledgement Table produced by kind permission of Dr. Ahumada and his colleagues. atrial flutter responded. Seven of nine patients with supraventricular tachycardia responded. The effect of practolol did not appear to be related to the prior administration of digoxin. Similar results have been reported by Lemberg (Lemberg et al., 1972) for alprenolol. Sandler and Pistevos (1971) reported a 50°,o abolition rate with oxprenolol for post infarction supraventricular tachycardia and in a further 2 ~ -'/o ..... of patients, a reduction in the atrial rate below 110 beats/min was obtained. Response of ectopic beats and atrial fibrillation have been less satisfactory. Wasir et al. (1977) reported on the effects of metoprolol on supraventricular dysrhythmias of different origins. The effect was variable. O f eighteen patients with atrial fibrillation, three reverted to sinus rhythm, while in the remaining fifteen, atrial fibrillation persisted, t h o u g h the ventricular rate decreased from an average of 140 beats/min to 90 beats/min. All patients with paroxysmal atrial tachycardia reverted to sinus rhythm. Schley et al. (1978) noted in a small series, that atenolol produced sinus r h y t h m in one of three patients with supraventricular ectopic beats. S t r o o b a n d t et al. (1974) reported that in nine cases of postinfarction supraventricular tachycardia, there was a reversion to sinus r h y t h m in five, a slowing of ventricular rate to under 100 beats/min in a further three and no response in one with sotalol. J a d r q u e et al. (1974) reported 18 cases of supraventricular tachycardia, mainly atrial fibrillation, treated with sotalol, nine reverted to sinus rhythm, six had a slowing of a ventricular rate and three showed no effect. 2.1.3. Comparison o f Beta-Block(n9 A g e n t s There are studies in experimental myocardial infarction which suggest that betablocking agents with different pharmacological profiles, have different effects. K h a n et al. (1973) noted that in conscious dogs in the acute phase of c o r o n a r y occlusion, dl-propranolol, in doses of 0.1 mg/kg and 1.0 mg/kg, MJ-1999 (sotalol a drug with beta-blocking properties only), and AY-21,011 (practolol) all significantly reduced the incidence of ventricular fibrillation. D - p r o p r a n o l o l alone was ineffective and its addition to M J-1999 did not increase the percentage reduction of ventricular fibrillation. It can be concluded that card(o-selective beta-blockade alone is sufficient to decrease the incidence of ventricular fibrillation in this model. However, ventricular tachycardia (4 or m o r e VPB's) was significantly reduced by d - p r o p r a n o l o l alone, and in c o m b i n a t i o n with MJ-199a and so a m e m b r a n e stabilizing effect m a y have contributed to suppression of ventricular tachycardia. Pearle et al. (1978) noted that in anesthetized dogs with experimentally induced anterior myocardial infarction, pretreatment with practolol was superior to propranolol in reducing ventricular fibrillation. Doses were selected to give approximately equivalent

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291

degrees of beta-blockade, as assessed by shifts in the positive chronotropic dose response curve. Ventricular fibrillation was induced in 6 of the 7 propranolol-treated dogs, compared with 1 of 7 dogs pre-treated with practolol. The haemodynamic changes induced by the two drugs were the same, with the exception of a greater drop in heart rate immediately following coronary occlusion, in the propranolol treated group. It is not clear whether these differences are due to the cardioselective or partial agonist components of practolol. There are few studies in man comparing the effects of different beta-blocking agents in the same randomized prospective study. Taylor and Burley (1977) reported an open study in ninety-six male patients, treated for tachydysrhythmias, developing within 5 days of admission for myocardial infarction. The drugs, propranolol (2-16 rag), practolol (%40 mg), or oxprenolol (2-26 mg) were given intravenously and in random order. The three drugs were equally effective in the treatment of all cardiac tachy-dysrhythmias, being most effective in sinus tachycardia and least effective in atrial fibrillation. Sinus rhythm was restored in six of nine patients treated with propranolol for ventricular ectopic beats. The corresponding figures for practolol and oxprenolol were seven of eleven, and four of six. Four patients with ventricular tachycardia were treated with propranolol and sinus rhythm was restored in two. Corresponding figures for practolol and oxprenolol were two of five, and four of seven respectively. The authors comment that the suppression of ventricular ectopic beats occurred with the middle dose ranges, but assessment of dose-response effects for ventricular tachycardia was not possible because of the small numbers of patients. The authors were aware of the limitations of this study, in particular the relation between anti-dysrhythmic effect, infarct size and haemodynamic effect of the individual agents. There were no serious adverse effects in this study. Three of the twenty-eight patients treated with propranolol developed heart rates below 50 beats/min; four of thirty-eight patients treated with practolol developed a systolic blood pressure below 70 mm/Hg, without bradycardia; and oxprenolol did not produce hypotension or bradycardia in any of the thirty patients treated. However, details of infarct size in relation to the three drugs used, are not given. Few of the reported series used 24 hr Holter monitoring, and there is a lack of standardisation of protocol between clinical trials, making it difficult to compare the efficacy of different beta blocking drugs. These studies do not give a clear definition of likely responders after myocardial infarction, although the work of Lemberg et al. (1970; 1972) indicate that those patients with high heart rates, possibly associated with an element of heart failure where sympathetic activity is likely to be at its maximum, may show the best response. There is some support for this view from other studies. Gibson et al. (1968), administered practolol to eight patients with supraventricular tachycardia in congestive cardiac failure. Two of these patients had a documented myocardial infarction. The heart rate was reduced in six of the eight and sinus rhythm restored in one. There were no, or only minimal, changes in blood pressure. Clinical features of heart failure were not aggravated. Fogelman et al. (1974), using sotalol in twenty-three patients with ischaemic heart disease, associated with acute and chronic supraventricular and ventricular dysrhythmias, produced slowing of the ventricular rate or reversion to sinus rhythm in the majority of cases. There were no changes in blood pressure noted and heart failure was not apparently aggravated. It is not stated how many patients had acute myocardial infarction. Of a total of forty-three, twenty patients treated with sotolol had cardiac failure. Waagstein et al. (1975), cite unpublished data that practolol intravenously improved patients with acute congestive cardiac failure and supraventricular tachycardia after acute myocardial infarction. In the main paper, seven patients with congestive cardiomyopathy associated with a high resting heart rate were studied. Four patients had an immediate improvement in dyspnoea, and three a gradual improvement over the ensuing months. The author sug-

292

N.S. BABI!k

gests that certain varieties of congestive cardiomyopathy may be more susceptible to sympathetic stimulation, which would be unfavorable to the myocardium. In two of their seven patients, the heart rate was raised before cardiac enlargement developed. Earlier work by this group (Waagstein et al., 1974), had shown that intravenous practolol (mean dose 18 mg), given to patients within 48 hr of uncomplicated acute myocardial infarction, did not reduce stroke volume, or aggravate congestive cardiac failure, as demonstrated by unchanged high a/H ratios. Clinical signs of heart failure did not appear. The authors commented that, 'Beta blocking agents should not be given to patients who need their increased sympathetic activity to main cardiac output at an adequate level'. However, they do not attempt to differentiate these patients from those who may be given betablockade. Jcwitt and Croxon (1971) administered practolol to fifty-one patients, after myocardial infarction, in whom heart failure was present and/or systolic blood pressure was below 90 mm/Hg. Five were also shocked. Apparently there was no deterioration of their clinical condition. A number of studies exemplify the problem of giving a dose sufficiently large enough to suppress ventricular dysrhythmias, but without significantly reducing cardiac function. Bay et al. (1967) gave 5 mg propranolol to eight patients within 12 48 hr of the onset of symptoms of acute myocardial infarction. Cardiac output fell from a mean of 5.2 litres/min to 1.5 litres/min with a reduction in heart rate from 93 68 beats/min. There was a moderate increase in right atrial pressure. In three patients with previous signs of cardiac failure, there was worsening of their clinical condition. In contrast, Letac et al, t1975), observed that ling propranolol intravenously given to fourteen patients after acute myocardial infarction (2-4 days), produced negligible effects on cardiac output and pulmonary wedge pressure. After 2 mg cardiac output fell by 20~'o (4.8 3.8 litres/min) and pulmonary wedge pressure rose by 5.27i,;. However, there were no signs of cardiac failure. Hutton et al. (1980) studied twenty-five patients with anterior myocardial infarction associated with an apparent inappropriate tachycardia, not associated with clinical heart failure and with pulmonary wedge pressures of 14 mm/Hg or less, selected 6 8 hr after the onset of chest pain. They were randomly allocated to oral propranolol (40 mg thrice daily), or to a matching placebo. Four patients developed cardiac failure or hypotension, three of whom were receiving propranolol. The authors conclude that 'inappropriate' tachycardia indicates left ventricular failure, and oral propranolol cannot be given safely at a time when salvage of ischaemic myocardium is feasible. These data are in contrast to the experience of Pantridge et al. (1975) and of Gratiansky et al. (1979). This latter group gave intravenous propranolol (5-15 rag) to fiftytwo patients within 24 hr of onset of acute myocardial infarction and to thirty patients within 6 hr of onset of myocardial infarction. Thirty-one patients had anterior and twenty-one patients diaphragmatic infarcts. There was a significant reduction in ST segment elevation (25'~ii in 10min 37?o in 30min), and despite a fall in cardiac index from 3.2 _+0.13 to 2.34 _+ 0.121/min/M~ 2, pulmonary artery diastolic pressure remained unchanged, and even decreased in seven patients, five of whom had initially elevated levels. Four patients died, one in pulmonary oedema. The authors conclude that propranolol does not significantly depress left ventricular function and, in selected patients, may even improve it. However. the study was not controlled. Mueller et al. (1974), Norris (1978), Peter et al. (1978) and Norris et al. (1979) have published an extensive experience with intravenous propranolol after acute myocardial infarction, where the incidence of heart failure and hypotension is small. 2.1.4. S u m m a r y and C o n c l u s i o n s These clinical findings suggest that, in general, beta adrenergic blockade will control about 50?/o of supraventricular and ventricular dysrhythmias after acute myocardial infarction. At present, the routine use of beta-blockers after acute infarction to unselected

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cases cannot be recommended. Some authorities (Gunnar et al., 1979) advocate the routine measurement of left ventricular filling pressure prior to beta-blockade. There are a number of individual reports of patients developing hypotension, bradycardia or circulatory collapse during and after intravenous administration of beta-blocking agents (Bay et al., 1967; Lund-Larsen and Silvertssen, 1969; Kreus et al., 1970; Allen et al., 1975; Taylor and Burley, 1977). The evidence for an increased safety margin for beta blocking agents which are cardio-selective, or have partial agonist activity (or both) remains conflicting. Finally, extreme caution must be exercised in extrapolating the results of these short-term studies in acute infarction to the long term intervention trials. 2.2.

PROPHYLACTIC USE TO SUPPRESS POST INFARCTION DYSRHYTHMIAS

While beta blocking agents have been administered in a number of trials as a prophylactic measure against sudden death, or non-fatal reinfarction (see below), there are few studies where they have been given specifically as prophylactic anti-dysrhythmic agents. Sloman and Stannard (1967a), gave propranolol (0.1 mg/kg), and atropine (1.2 mg) intravenously, followed by oral propranolol (10 mg every few hr), for up to three weeks, to twenty-six patients who had survived acute myocardial infarction. A further twenty-three patients acted as controls in a random study. The results are shown in Table 3. The overall incidence of serious dysrhythmias was low and propranolol had little effect on them, but the numbers of patients studied is small. One patient on propranolol developed cardiogenic shock, 'but hypotension and cardiac failure were neither severe nor frequent'. Kubik and Joshi (1973), compared the anti-dysrhythmic effects of oral practolol and D-propranolol with a placebo in 300 patients with a tentative diagnosis of myocardial infarction. Treatment was started within 18 hr of the onset of chest pain. There were no differences in the overall mortality between placebo and practolol groups (8/92 compared with 10/93 respectively), but there were only two deaths out of 94 cases in the D-propranolol group. There were no differences in the frequency of non-fatal dysrhythmias between the groups but there was only one early death in the D-propranolol group, associated with dysrhythmia, compared with five in the practolol treated and four in the placebo treated group. This trial is open to criticism from several points. Firstly, practolol was given orally in a dose of only 50 mg q.d.s.; secondly, patients with frequent ventricular ectopics were excluded; thirdly, the placebo mortality rate is very low and suggests unconscious patient selection. TABLE 3. Prophylactic Use of Propranolol in Acute Myo-

cardial Infarction: Effect on Arrythmias

Mild infarction Severe infarction Deaths No. of patients with serious arrythmias No. of episodes of serious arrythmias

Propranolol

Control

16 26 10 3 3

15 23 8 4 5

4

5

Effect of 0.1 mg/kg body weight of intravenous propranolol and 1.2 mg atropine, followed by 10 mg propranolol orally for 3~, weeks in 26 patients after acute myocardial infarction. There were 23 patients in the control group. Treatment was administered prophylactically. Acknowledgement This table is reproduced with the kind permission of Drs. Sloman and Stannard.

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Federman et al. (1976) studied the effects of practolol on ventricular tachydysrhythmias following transmural infarction. Fifty-five patients were randomly allocated to practolol (400rag/day), or placebo, starting two weeks after infarction. After three months they were crossed over to the other group for a further three months, and then crossed over twice more so that each patient received 2 active and 2 placebo treatment periods. Twenty-four hour Holter monitoring was performed at the end of each period. By three months forty-two patients were still in the study, thirty-two at 6 months, thirty-two at 9 months and twenty-nine at 12 months. Two deaths occurred in each group and two reinfarctions in the practolol group. There were no differences in the numbers of significant and non-significant ventricular dysrhythmias between the groups at any time point. This study demonstrates the difficulties of long term post-infarction dysrhythmia studies when the frequency and type of ventricular dysrhythmias varies considerably from time to time in the same patient. A recent study by Roland et al. (1979) compared propranolol (40 mg t.d.s.), atenolol (50mg b.d.) and placebo in their effects on post infarction supraventricular and ventricular dysrhythmias. No difference was demonstrated between the three groups when 24 hr Holter monitoring was performed at 1 and 6 weeks and compared with the number of dysrhythmias recording in the coronary care unit. Again the variation between patients was significant and the variation within patients from time to time, was also significant. Although ventricular dysrhythmias within the first l 2 weeks after infarction have long been held to be predictive of subsequent mortality (Moss et al., 1975), the exact relationship between these and early and the late post infarction dysrhythmias has not been established (Ruberman et al., 1977). Some authorities maintain (Moss et al., 1980) that the size and the site of infarct is a stronger prognostic indicator of subsequent mortality and morbidity and that the presence of a ventricular dysrhythmia is a dependent variable only. Recent work by Woosley et al. (1979), in patients with chronic stable ventricular dysrhythmias have highlighted the difficulties of assessing the efficacy of different doses of propranolol in suppression of these dysrhythmias. In some patients, it was necessary to give up to 960 mg propranolol a day to produce a greater than 70'~o suppression rate on 24 hr Holter monitoring. Moreover, some of the patients responded to intravenous propranolol and did not respond to oral propranolol and vice versa. 2.2.1. S u m m a r y and Conclusions It would seem, until satisfactory protocols can be established for the assessment of post-infarction dysrhythmias, until the relationship between post infarction dysrhythmias both early and late, and prognosis becomes clear, and until the relationship of ventricular dysrhythmias to infarct size have been better defined, that the use of beta blocking drugs in myocardial ischaemia to suppress dysrhythmias should be retained for elective and specific therapeutic indications only. 2.3. SYMPTOMATIC RELIEF OF CHEST PAIN Waagstein and Hjalmarson (1976), administered 3 beta adrenergic blocking drugs to fifty-four patients, forty-two of whom had transmural infarcts, all of whom were suffering from chest pain on admission to hospital. Eighteen patients received practolol (30 mg), and nine patients received metoprolol (15 mg). Fifteen patients were given saline and acted as a control group. Twelve patients received H87/07 (H87/07 is a selective beta blocking drug with more intrinsic sympathomimetic activity than practolol). None of the patients had clinical signs of congestive cardiac failure on admission to the study. All treatment groups experienced a significant improvement in the degree of pain (graded from 0-5), and this was accompanied by a significant fall in heart rate, which was most marked with practolol and metoprolol. Small but statistically significant falls in systolic and diastolic pressure were seen with metoprolol and in systolic pressure with practolol.

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There were no changes in blood pressure with H87/07. In thirty-one of the fifty-four patients, there were reductions of 30-40~o in the degree of S.T. segment elevation, noted on the electrocardiogram. None of the patients developed left ventricular failure. The authors suggest that the beta adrenergic blocking drugs had reduced myocardial ischaemia and, therefore, chest pain, in contrast to conventional analgesics (pethidine or morphia), which may reduce pain without any favorable effect on the myocardium. As suggested by Singh (1978), this study is open to a number of criticisms. Firstly, since the relief of chest pain was used as one of the two determinants of efficacy of therapy, it would have been desirable to use a defined regimen of conventional analgesic therapy in the control group at the outset, rather than allow the use of these agents as and when they were needed. It is not surprising, therefore, that the relief of pain was much more impressive in the groups given beta blocking drugs than in the control group. Secondly, the assumption that the beta blocking drug is reducing continuing myocardial ischaemia in acute infarction is largely based on the reduction of ST segment elevation following their intravenous administration. It is well known that spontaneous variations in ST segment changes occur in the early phases of acute myocardial ischaemia. Other indices of change in myocardial infarction will be needed to support these changes in the ST segments. This is particularly important now that the relationship between precordial ST segment elevation and myocardial ischaemia is coming under increasing criticism (Heng et al., 1976; Irvin et al., 1977). In particular, Norris et al. (1976), using practolol demonstrated a reduction in ST segment elevation during the subacute stage of myocardial infarction at a time when evidence of continuing ischaemic damage, as judged by serum enzyme release, was not present. Similar criticism can be made of the study by Gold et al. (1976). In this trial intravenous propranolol was infused at a rate of 1 mg every 2min to a total dose of 0.15 mg/kg (mean 6.5 mg), under haemodynamic control in twelve patients with uncomplicated anterior infarction, treated within 8 hr of the onset of chest symptoms. Patients with the usual contra-indications to beta blockade were excluded, as were those whose ST segments on the precordial ECG showed undue lability in the first hour of admission. Patients were monitored for five hours and efficacy was judged by the reduction in the extent of the precordial ST segment elevation and the relief of chest pain. After propranolol, nine of the twelve patients had relief of pain associated with significant reduction in the magnitude of the precordial ST segment elevation. This was especially marked in those whose subsequent coronary angiogram showed sub total rather than complete occlusion of the left anterior descending coronary artery. The authors relate the relief of pain and reduction in ST segment elevation to an improvement in the extent and severity of the continuing myocardial ischaemic injury. Unfortunately, there was no control group using adequate doses of morphine sulphate and the 6 mg dose of morphine sulphate in the propranolol group may be considered inadequate in marly patients to control pain and not to constitute a failure of conventional treatment. 2.3.1. S u m m a r y and Conclusions In view of these considerations it is difficult to support the conclusion which might be inferred from the studies of Waagstein and Gold, that the reduction in ST segment elevation and the relief of pain by beta blocking drugs in acute infarction are directly related to the improvement of myocardial ischaemia. This is not, however, to deny the possibility that these agents may reduce myocardial injury in man. 2.4. THE CONSERVATION OF VIABLE MYOCARDIAL TISSUE Proof of conservation of the myocardium relies on measurements made of changes in the ECG, on infarct imaging with radio active tracers, or on measurements of the products of cardiac metabolism. All depend upon the crucial fact that the beta-blocking agent must be present at the time when the ischaemic myocardium is still potentially

296

N.S. BABER

salvageable. The timing of introduction of the drug in the clinical setting of myocardial infarction or ischaemia, is often not precisely defined in these studies. Often the specific aims of these trials are not stated, which makes interpretation of the results difficult. Moreover, the specific intention of 'conserving ischaemic myocardium' overlaps with the suppression of potentially fatal dysrhythmias and the reduction in the incidence of "hard end points', such as sudden death, fatal reinfarction and non-fatal reinfarction. The introduction of methods to quantify infarct size from the early 1970s onwards has meant that most often the end points in these trials were geared to these measurements, whereas in the early studies, mortality and other complications of infarction were used as a measure of success or failure of treatment. There are two ways in which beta blocking drugs may be used so that they are in the circulation at a time when the myocardium is potentially viable: (1) Introduction of the drug within a few hours of the onset of myocardial infarction. (2) The presence of the drug in patients who are at risk from sustaining an infarction. In this latter group may be included patients with angina pectoris, hypertension, or patients who have recovered from a previous myocardial infarction. The effect of beta-blocking agents on survival in angina and hypertension have been reviewed elsewhere (Lambert, 1976 and Stewart, 1976). This section will deal only with the use of beta-blocking drugs after infarction. In the study by Fox et al. (1975) the beta-blocking agent was actually being taken by the patient at the time of myocardial ischaemic injury and the subsequent short term mortality and morbidity was studied. Ninety patients being treated with beta blocking drugs (mainly propranolol), were admitted to hospital with a prolonged attack of ischaemic myocardial pain. Ninety consecutive patients, not on beta blocking drugs, but who otherwise matched for age, sex, previous cardiac history and duration of chest pain, acted as controls. In the treated group, the beta-blocking drugs were withdrawn immediately the patient entered the coronary care unit. Thc short term outcome was assessed in terms of myocardial infarction, myocardial necrosis without infarction and coronary insufficiency. The results are shown in Table 4. It is difficult to interpret these results, particularly in view of the retrospective nature of the study. However, it would seem that in patients actually on beta-blocking drugs during the cardiac event, the incidence of myocardial cell death is halved, indicating preservation of functioning myocardium. Because the study is not prospective, significant bias may have occurred if more patients at high risk had died in the group receiving the beta-blocking drugs group before hospital admission. TABLE 4. Eff~'ct o1"Beta Blockade during4 Myocardial lschaemia

Group Patients on beta blockers N u m b e r C'o) Control Patients N u m b e r (%)

Myocardial Infarction

Myocardial Necrosis without infarction

30 (33j

20 (22)

62 (69)

14(15.5)

Coronary insufficiency

Total

Mortality

40145)

90 (100t

919)

14(15.51

90(100)

10(9)

In-hospital morbidity and mortality of 90 patients receiving a beta-blocking agent at the time of onset of chest pain. The drug was stopped on hospital admission. The control group consisted of 90 consecutive patients, matched for age, sex, cardiac history and duration of chest pain. Beta blockade reduced the rate of myocardial infarction, but appears to increase the number of patients classified as having coronary insufficiency. The mortality is the same in both groups. Acknowledgement This table is produced with kind permission of Dr. Fox and his colleagues.

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The difference in the number of patients classified as suffering from coronary insufficiency in the two groups is hard to explain. The authors define this group as 'typical ischaemic and cardiac pain without ECG or enzyme evidence of recent infarction or necrosis'. As other studies, previously discussed, have suggested that beta blockers may ameliorate chest pain, it is tempting to conclude that, as the beta-blocking drugs were withdrawn on hospital admission, the figures reflect an apparent increase in the incidence of pain and, therefore, as classification of coronary insufficiency in the beta-blocked group. The so-called beta-blocking withdrawal syndrome (Shand and Woods, 1978), is now well recognised, and the fact that the mortality rate in the two groups is the same, is reassuring. 2.4.1. Studies on Infarct Size Mueller et al. (1974) demonstrated that propranolol reduced myocardial oxygen consumption, despite a reduction in coronary blood flow, in patients given i.v. propranolol (0.1 mg/kg), within the first 12hr of acute myocardial infarction. All patients were in Killip Classes I or II (Wolk et al., 1972). Heart rate, mean arterial pressure and cardiac work fell by 20~o, but the heart extracted more lactate from the arterial circulation, indicating a more favorable balance between myocardial oxygen supply and demand. Since then, many studies (Mueller and Ayres, 1977) in over 100 patients have shown that propranolol can be given safely to selected patients after myocardial infarction. In these trials interest was not directed towards the suppression of dysrhythmias but to a decrease in cardiac work through a reduction in oxygen demand. The relative safety of propranolol in these patients has been shown by only small changes in the pulmonary arterial wedge pressure and, indeed, in some patients, the pressures, previously above 15 mm of mercury have decreased. In none of these studies was it categorically stated that infarct size could be reduced, only that the parameters which measured infarct size changed in the direction which would indicate reduction of myocardial oxygen consumption. However, a more recent study by Peter et al. (1978), using serum creatine kinase levels to measure infarct size in patients after myocardial infarction has demonstrated that, provided propranolol is started within 4 hr of the onset of chest symptoms, a reduction in the peak, the total and the rate of release of creatine kinase can be demonstrated. These authors state that this indicates a reduction of infarct size. The dose of propranolol they used was 0.1 mg/kg given intravenously over 10 min, followed by 320 mg orally over the next 27 hr. There were no reductions in the creatine kinase levels in patients treated with propranolol four hours after the onset of chest symptoms and these levels remained as high as those of an untreated group studied early or late after infarction. Unfortunately, the number of patients in this study was too small to assess an effect on mortality and non-fatal reinfarction. The study has been criticised (Fox and Oliver, 1979), on the grounds that the placebo control group had an abnormally high infarction rate. Certainly, this important study needs to be repeated in larger numbers of patients. The same group of workers has shown similar results in twenty patients with threatened infarction (Norris et al., 1978). Again, only those patients treated with propranolol within 4 hr of the onset of symptoms showed a reduction in creatine kinase. In neither of these two studies was there any difference in the incidence of overt heart failure between the propranolol and the control groups, although in the first study it was thought that propranolol might have exacerbated heart failure in two cases. There is support for these findings in a study by O'Rourke (1979) with pindolol. Seventeen patients with acute myocardial infarction were given intravenous pindolol (3 mg every 8 hr for 24 hr), commencing 7 hr (range 2-12 hr) after the onset of symptoms. Only one patient developed heart failure, which responded promptly to diuretic therapy. There were no instances of hypotension or bradycardia and no hospital deaths. The author sta~es that, in agreement with Norris's findings, only patients treated under 4 h r of symptoms had a reduction in creatine phospho-kinase release, although the figures are not given.

298

N.S. BABER

That early intervention is crucial if an effect on infarct size is to be demonstrated. has recently been shown in a study by Thompson et al. (1979). Ninety-seven patients who had, on admission to hospital, or subsequently proved to have, an acute myocardial infarction were randomly allocated to practolol (100mg orally, followed by 100 mg 2 hr later, followed by 200 mg 10 hr later and subsequently at 12 hr periods according to pulse rate), or to placebo. The mean time from onset of cardiac symptoms to randomisation was 11.1 + 2 h r for practolol and 10.3 _+ 1.1 hr for placebo. Two reinfarctions occurred in the practolol group, three in the placebo group during the in-hospital phase. There were eight deaths on practolol and nine on placebo within the first year and there was no difference in the pattern of deaths over the year. There were no differences in the peak, the duration, or the total creatine kinase release in the two groups. The authors conclude that the study may not have shown a reduction in infarct size because of the late introduction of practolol in the treatment group. A similar result was obtained by Ahumada et al. (1979) using intravenous acebutolol. 1 20 mg of acebutolol was given to twenty-five patients with myocardial infarction confirmed by history, electrocardiogram and rise in plasma creatine kinase activity, if their heart rate exceeded 75 beats/min, blood pressure exceeded 90/60 mm Hg and pulmonary artery occlusion pressure was less than 22 mm Hg. Twenty-five patients were matched as controls; both groups had a predicted infarct size of 25 gm equivalents (mean _+ 4 gm) and there was no difference in the enzymatically determined infarct size of the two groups (30 __+ 5 CK gram-equivalents on acebutolol, 37 + 5 CK gram-equivalent control). Moreover, observed infarct size exceeded that predicted in each group, presumably due to infarct extension. These negative findings are probably due to a delay in starting therapy (7--10 hr after hospital admission). From these studies, it is apparent that beta blocking agents can be given to patients early after myocardial infarction, provided the patients are carefully selected and carefully monitored. However, it is difficult to draw comparisons between the patients in each study, even though the selection criteria are usually stated. The convincing data of Norris in line with experimental animal observations, strongly suggests that if cumulative myocardial enzyme release can be correlated with myocardial ischaemic injury, then beta adrenergic blocking agents will reduce infarct size. Whilst both the accuracy of ST segment elevation changes by beta blocking drugs and patterns of CK release have been seriously questioned in terms of their accuracy' in relation to infarct size, clinical studies in which both enzyme and ECG changes have been measured, support the contention that early intervention will be necessary if myocardial ischaemia is to be reduced (Yusuf et al., 1979). Fox and Oliver (1979) have shown similar parallel changes in dogs. A recent clinical study by Yusuf et al. (1980) clearly demonstrates that early intervention with a beta-blocking agent can reduce infarct size. Two hundred and fifteen patients with a history suggestive of myocardial infarction within the previous 12 hr, with or without suspicious or definite E C G evidence were randomly allocated to treatment with atenolol (5 mg i.v. over 5 rain, followed by 100mg once a day for 10 days) or to a control group receiving the usual care on a coronary unit. Patients were excluded from the trial for severe heart failure (requiring more than 80 mg frusemide), bradycardia (below 40 beats/rain), hypotension (systolic blood pressure under 90 mm/Hg), and treatment with beta-blocking drugs within the previous 24 hr. Patients were also excluded if they were on active therapy for bronchial asthma. Based on the initial ECG, patients were subdivided into 3 groups" (a) definite infarction (with or without Q waves), (b) threatened infarction (either (i) good history and T wave inversion or ST segment depression, or (ii) good history and a normal ECG), (c) bundle branch block on ECG with no other abnormality. The threatened infarction group were considered to have had an infarct if they showed at

/~-adrenergic agents in myocardialischaemia

299

least a 20'~'/oreduction in R wave amplitude or enzyme levels twice the normal range for the CKMB in any of the serial samples. There was good matching of patients for age, sex, previous history of infarction, history of failure at entry, and time from chest pain to randomization. There were thirty-five patients with threatened infarcts subsequently treated with atenolol, and eleven developed definite infarcts. The corresponding figures for the control group were forty-four and twenty-seven. This difference in percentages of 31~o and 61~o is significant (p < 0.01). It is of interest that in the threatened infarct group, there were 18 patients treated with atenolol and 18 controls, who had a good history and T wave inversion or S T segment depression, but 17 patients in the atenolol group and 26 in the control group with normal ECGs. It is not clear which of these 2 subgroups contributed most to the development of infarction. This could be important, however, when considering the exact group of patients to whom atenolol could be given in the acute phase. Of the group with definite infarcts, the mean plateau CKMB levels were 121.2 _+ 9.7 in the atenolol group and 177.3 + 16.7 in the control group (p < 0.005), which supports the findings of Peter et al. (1978) with propranolol. In all patients randomized (195), there were significant differences between the groups developing late heart failure (i.e. number patients receiving diuretics (thirty-six atenolol, forty-seven control p < 0.01), patients discharged on diuretics (nineteen atenolol, thirty-one control p < 0.05), and in the mean frusemide dose given during the stay in hospital (144 mg _+ 33 atenolol, 247 _+ 54 mg control, p < 0.05). There were no statistically significant differences in the frequency of hypotension (twenty-four atenolol, sixteen control), bradycardia (seventeen atenolol, seven control), or heart block. There were four in-hospital deaths in the atenolol group, and nine in the control group. Two recent trials attempted to relate modification of infarct size by early post-infarction intervention to subsequent ventricular function. Evemy and Pentecost (1978) administered practolol to ninety patients after myocardial infarction, in a randomized, placebo controlled trial. Admission to the study was approximately 6 hr after infarction. There was no difference between treatment and control groups in the early or late mortality, nor was there any difference in the ability to perform stress testing at follow-up 6 months later. The incidence of early post infarction dysrhythmias was not reduced by practolol, with the exception of atrial fibrillation. Norris et al. (1979) studied the effect of intravenous propranolol (0.1 mg/kg) followed by oral propranolol (320 mg over 27 hr) on infarct size in thirty-three patients seen within 4 hr of the onset of uncomplicated myocardial infarction. Twenty-nine patients acted as controls and the study was randomized. The total amount of creatine kinase released and peak activity levels measured during the acute phase were reduced by 23'Yo (p < 0.05) in treated, compared with control, patients. A subgroup of fifteen treated and thirteen control patients subsequently underwent treadmill exercise testing and biplane left ventriculography, one month later. There were no significant differences between the exercise performances of the subgroups (two of fifteen treated patients experienced angina on exercise testing, compared with four of twelve controls and one of fifteen showed ischaemia ST segment changes after exercise in the treatment group, compared with two of twelve controls). Nor was there a statistically significant difference between the groups in the degree of contractability assessed by angiography. It is not stated how the subgroups were chosen, but it is worth noting that the fifteen patients studied at one month in the propranolol treated group did not show the initial enzyme reduction recorded for the group as a whole. 2.4.2. Studie,s on Clinical Outcome The alternative approach to measuring infarct size has been the empirical introduction of beta blocking drugs early after myocardial infarction, studying specifically the clinical outcome in the short and the long term. Table 5 summarizes the major studies. The

300

N.S. BABER

TABLE 5. Studie,s with Beta-Blocking Druos in Patients with Myocardial lr~/'arction: Treatment ,started < 4 8 Hours

aper Event

Author Snow (1965) Snow (1966) Multicentre (1966) Balcon et al. (1966) Clauscn et al. (1966) Barber cta/. (1967) Sloman and Stannard (1967) Norris et al. (1968) Kahler et al. (1968) Fucella (19681 Briant and Norris 11970) Reynolds and Whiflock Barber et al. (19751 Barber et al. (1975) (HR > 100 bts,min) Mitchell (1978)

Andersen et al. (1979) Andersen et at. (1979) ( <65 years old) Peltola (unpublishedl

Drug Propranolol Propranolol Propranolol Propranolol Propranolol Propranolol Propranolol Propranolol Propranolol Oxprenolol Alprenolol Alprenolol Practolol Practolol

Propranolol/ Atenolol Alprenolol Alprenolol Propranolol

Total No. of Patients

Duration of treatment (days)

30 60 30- 60 80 80 40 160 60 80 80 120 400 400 600 600

91 107 195 114 t30 99 49 454 69 220 172 78 298 53

28 28 28 28 14 28 21 21 21 21 3 1 yr 2 yrs 1 yr

16 13 15 23 28 19.4 11.5 13.7 7.9 13.2 8 7.9 27 9

35 29 12.6 24 25 25.5 17.5 10.5 19.3 7.9 7 7.7 31 43

120/150 5-10 i.v. 400 oral 5 10i.v. 400 oral 60

265 480

42 1 yr

10.2 25.6

11.2 26.4

NS NS

480

1 yr

9.3

20.4

<0.01

159

in hospital

20.3

38.1

<0.01

Dose (mg/day)

Mortality Drug Placebo <0.025 <0.05 NS NS NS NS NS NS NS NS NS NS NS <0.05

Summary of the major post-infarction studies in which a beta-adrenergic blocking agent has been given within the lirst 24 48 hr of the onset of chest symptoms. The studies are listed according to date of publication. The majority of the reports do not state the mean time or ranges of administration of the beta-blocking agent. The following studies give this data: Barber et al. (1975) 50"0 commenced treatment within 3M hr (range 7 min 7 days). Andersen et al. (1979) > 5 0 % patients commenced treatment under 6 hr. Peltola (unpublished) All patients admitted under 4 hr. Aekno~led~#,ments This table is published with the kind permission of all the authors concerned.

earliest of these studies was conducted by Snow (1965 and 1966), in which propranolol was given to the patient within 48 hr of onset of infarction, although it is not clear from the paper how many of these patients received propranolol very early after infarction. The main end points of the study were morbidity and mortality. A substantial reduction in the in-hospital mortality was reported with between 30 and 60 mg of propranolol given orally each day 1353o control 16~o propranolol group). However, the trial did not have a placebo control group and was non-randomised. Subsequently seven further studies with propranolol in doses ranging from 40-160 mg day have been published. These trials were prospective, placebo controlled and in all of them, propranolol was introduced within 24 48 hr of the onset of infarction. In most instances the follow-up was for a period of one month. In none of these studies did propranolol apparently produce a reduction in mortality. In a trial with alprenolol (Briant and Norris, 1970), again there was no reduction in mortality in the short term when the drug was introduced within 24~48 hr of the onset of myocardial infarction. Similar negative results were reported in a small trial by Reynolds and Whitlock (1972) with alprenolol. Barber et al. (1975), studied the effect of practolol (300mgi, by mouth or placebo given within 12 hr of the onset of chest pain in 500 patients admitted to a mobile coronary care unit, suffering from acute myocardial infarction. Therapy commenced on admission (7 min-several days), and 50% of the patients were treated within 3¼ hr. Two hundred and ninety-eight patients subsequently proved to have acute myocardial infarction and 151 of these received practolol and 147 placebo. By three months, one year and two years, there was no difference in the mortality between practolol and placebo groups (15/171!;. 20/25~!~;. 27/31'~o respectively). However, in the sub-group of patients whose initial untreated heart rate was over 100 beats per minute, there was a statistically

fl-adrenergic agents in myocardial ischaemia

301

significant reduction in mortality at 24 hr after infarction, at the time of hospital discharge and at one year in the practolol treated group compared with the placebo group. However, this significant difference was not present at two years. In an unpublished study by Peltola (personal communication), propranolol was given early after myocardial infarction, often under four hours of the onset of chest symptoms. Patients were allocated, according to birth date, to propranolol 20 mg three times a day orally, or placebo within 4 hr of the onset of chest pain, which subsequently proved to be due to myocardial infarction. Ninety patients received propranolol and 69 received placebo. The three week mortality was reduced from 39~, to 20.3 (p < 0.01) and there was no difference in the incidence of heart failure. These two studies support the contention of Norris that early intervention with beta-blocking drugs may improve outcome.

TABLE6. Study of Propranolol, Atenolol and Placebo in Suspected and Definite Myocardial lnJarction

No. dead of patients No. while entered: on treatment No. withdrawn from treatment No. who died after withdrawal Total cardiac mortality at six weeks

Propranolol

Atenolol

Placebo

@i!

~ 8 2~ 49

1(k8 904 7l ) 34 3~, 1

Effects of oral administration of propranolol, atenolol or placebo to 265 randomly allocated to the three groups at the time of hospital admission ((~12 hr after onset of chest pain). There is a high withdrawal rate, mainly for hypotension or bradycardia in the two beta-blocker groups, but over a third of patients are withdrawn on placebo. The number of early deaths while the patient remains on treatment is markedly reduced by propranolol and atenolol, but this effect is nullified when the deaths after treatment withdrawal are included. Acknowledgement Table produced by kind permission of Prolessor Mitchell and his colleagues.

A more recent study by Mitchell et al. (1978) compared the effects of oral propranolol (40 mg three times a day), the cardioselective beta-blocking agent atenolol (50 mg twice a day with midday placebo) and placebo, in patients treated within 6-12 hr of the onset of chest pain. The study was randomized and double blind, with a follow up at 6 weeks and one year. Table 6 gives the results for mortality at six weeks. It can be seen that there are no differences in the number of deaths in the groups when patients remaining in the trial and those who have been withdrawn, are considered together. When a comparison of the number of deaths for patients who have remained on treatment at 6 weeks and one year is made, the results for both active treatment groups compared with placebo, look promising. This dilemma of comparing total and in trial mortality is discussed below. Anderson et al. (1979) studied the effects of alprenolol given to patients early after definite or suspected acute myocardial infarction: fifty per cent of patients received treatment less than 6 hr after the onset of chest pain. Four hundred and eighty patients were stratified into 3 risk groups according to age, heart rate and degree of consciousness and then randomly allocated to treatment with alprenolol (5 mg intravenously, followed by a further 5 mg according to blood pressure and heart rate response), or placebo. Three hours later alprenolol 200 mg twice daily or placebo was given and continued for one year. Patient matching for risk factors was good, except that there were more patients who had suffered a previous infarct in the alprenolol group. When all age groups are considered together there is no difference in the total, in-trial or out of trial mortality, between the two groups (see Table 7). The total mortality in patients at, or below, 65 years old is significantly reduced, but only after the first month of treatment. There is a trend for a mortality reduction in the alprenolol group in those who die while remaining in the trial and for those who are

302

N.S. BABER

withdrawn. For patients over 65, the mortality is higher on alprenolol, but this difference does not achieve statistical significance. The authors conclude that routine treatment with alprenolol can be advocated t\)r patients aged 65 or less, with chest pain and suspected infarction. While the results for the younger age group is striking, there are a number of problems that remain with this study. It is not possible to claim that a reduction in mortality was shown in the suspected infarcts, as there were only 3 deaths in the placebo group and none in the alprenolol group, in patients at, or under 65. It is not clear why age, of the three risk factors stratified for, was selected as the basis for presentation of the results. There were more withdrawals because of cardiogenic shock or heart block in the alprenolol group (twelve alprenolol, two placebo). It is of interest, however, that for the younger age group, there was a reduction in mortality in the alprenolol treated group whether the patients died before or after withdrawal. This implies that the beneficial effect of alprenolol occurred early, but was not manifest until after 28 days. There have been two studies with oxprenolol, a beta-adrenergic blocking agent with partial agonist activity. In a study coordinated by Fucella (19681, 257 patients were randomized to treatment with oxprenolol (120 mg/day) or placebo, within 48 hr of myocardial infarction. There were 14 deaths (13.2'!~i) in the oxprenolol treated group and 9 (7.9'!o) in the placebo group. In the second study L o m b a r d o et al. (1979) treated 260 patients with 120rag/day oxprenolol or placebo. It is not stated if the trial was randomized, or if the patients were matched for risk factors. Treatment was initiated within 24 hr of the onset of acute myocardial infarction and continued for 3 weeks. Mortality was the same in both groups (oxprenolol 6.2!~;,, placebo 8.5')0). There was no difference in effects on serious ventricular dysrhythmias. Withdrawal, which included cases of cardiac failure, asthma and atrioventricular block, were the same in the two groups (31.50o oxprenolol, 27.70~; placebo!. 2.4.3. S u m m a r y and Conclusions At the time of writing, it is difficult to draw conclusions about all these trials where beta-blocking drugs have been started within 24 48 hr of the onset of chest pain. The promising results on infarct size reduction by Norris and Yusuf, the reduction in mortality in the study by Peltola, and in subgroups in the studies by Barber and Anderson, would indicate that the early administration of beta-blocking agents may be of benetit early after infarction, with a subsequent reduction in mortality. There are a number of possible explanations for the negative results of some of these studies (see Section 2.6), but administration of drug after 4-6 hr, may be pertinent. A critical study is needed in the long term follow up of patients who receive a betablocking drug within 4 hr of symptoms, and who are treated for only 48 hr.

2.5. To INITIATE THERAPY AS A SECONDARY PROPHYLA('TI(' MEASURE AFTER RECOVERY FROM THE ACUTE EVENT Previous myocardial infarction is a well recognised risk factor for a subsequent infarct (Peel et al., 1962; Editorial, B.M.J., 1979). There are four published studies in which betablocking agents have been introduced after recovery from the infarct and maintained for at least six months in trials designed to reduce infarction rate and death rate (Table 8). The largest of these trials was conducted with practolol (Green et al., 1976: Green et al., 1977), 3053 patients were randomly allocated to treatment with either practolol (200 mg twice a day) or matching placebo. The mean time after infarction to randomization was 13 days (range 7 28). Patients were followed up for two years and the main end points were mortality and non-fatal re-infarction. Matching of patients for known risk factors prior to randomization was good. Table 9 gives the number of patients at entry and follow up and total numbers withdrawn.

fl-adrenergic agents in myocardial ischaemia

303

TABLE 7. One Year Mortality in Patients with Definite or Suspected Myocardial Infarction treated with AIprenolol or Placebo

Alprenolol

Placebo

p

61/238 45/178 16/59

64/242 49/193 15/49

NS NS NS

13/140 10/111 3/29

29/142 21/l 17 8/25

< 0.0 l NS NS

48/98 35/68 13/30

35/100 28/76 7/24

NS NS NS

All ages

All patients In-Trial patients Patients withdrawn Patients <65 years

All patients In-trial patients Patients withdrawn Patients >65 years

-All patients --In-trial patients Patients withdrawn

Effects on mortality in 480 patients randomly allocated to alprenolol or placebo after definite or suspected myocardial infarction. The trial commenced under 6 hours of onset of symptoms in > 50% cases. There is no difference in the one year mortality when all patients are considered together. Pre-randomization stratification identified a subgroup of patients <65 years of age, whose total mortality was significantly reduced by alprenolol. Older patients had a higher mortality on alprenolol, but this did not achieve statistical significance. Acknowledoement--This table is produced with kind permission of Dr. Andersen and his colleagues.

A statistically significant difference in the number of deaths whilst patients were still receiving treatment was demonstrated (Table 10). The non-fatal re-infarction rate is also shown. Patients who had initially sustained an anterior infarction accounted almost entirely for the difference. In the first four weeks after an inferiorly situated infarction, there was an increase in the number of deaths in the practolol treated group, but it is interesting to note that the proportionate reduction in sudden death was similar whether the initial infarct was anterior (34 placebo vs 20 practolol), or inferior (21 vs 11). The multivariate analysis revealed a number of treatment effects within patient subgroups. The most interesting of these interactions was with trial entry diastolic blood pressure. Patients who had an anterior infarct and whose trial entry diasto!ic blood pressure was at, or below, the mean for the trial (78 mm/Hg mercury), had the lowest mortality of any group, particularly if they had dysrhythmias in the acute trial phase (practolol 4 vs placebo 24). Unfortunately, the number of withdrawals from this large trial was high (28%). There were 42 deaths after withdrawal in the practolol group and 41 in the placebo.

TABLE 8. Studies with Beta-blocking Drugs in Patients with Myocardial Infarction.. Treatment Started

> 1

week

after Event

Author 1. 2. 3a. 3b. 4.

Ahlmark et al. (1974) Wilhelmsson et al. (1974) Multicentre Study (1975) Multicentre Study (1975) Anterior M.I. Baber et al. (1979)

Drug

Total Duration of Dose No. of Treatment Mortality (%) (mg/day) Patients (yrs) Drug Placebo

p

Alprenolol Alprenolol Practolol

400 400 400

162 230 3053

2 2 2

1.5 2.6 3.2

10.5 9.5 5.1

<0.05 <0.05 <0.0l

Practolol Propranolol

400 120

1539 720

2 0.75

2.6 7.9

5.6 7.4

<0.01 NS

Summary of four studies in which a beta-adrenergic blocking agent has been given after recovery from myocardial infarction. The mean starting times, in days (ranges), were: Ahlmark et al. 14; Wilhelmsson et al. 7-21; Multicentre 13 (7-28); Barber et al. 8.4 (2-13). The most convincing reduction in mortality has been demonstrated for patients with anterior infarction, 'treated with practolol. Acknowledgement--This table was produced with the kind permission of the authors.

304

N. S. BABER

TABLE 9. Practolol Multicentre Trial. Numbers oj Patients at Risk up to 24 Months and Numbers Withdrawn Practolol

Placebo

1,533 1,421 1,334 1,234 1,071 609 478

1,520 1,401 1,294 1,188 1,038 608 481

437

421

No. at entry: No. at: 1 m o n t h 3 months 6 months 12 m o n t h s 18 months 24 months Total number of withdrawals:

N u m b e r s of patients randomized to practolol and placebo groups 7-28 days after myocardial infarction and n u m b e r s of patients attending follow-up.

There is no doubt that practolol reduced mortality and, probably, non-fatal re-infarctions, particularly in patients who had recovered from anterior myocardial infarction. As a negative correlation was found between body weight and blood level of practolol, it is arguable as to whether lighter patients were better protected than heavier patients. Unfortunately, with the removal of practolol because of the oculomuco-cutaneous syndrome (Nicholls, 1976) this, and other critical questions, will never be answered. In a smaller trial, alprenolol was compared with placebo in a prospective, randomized study (Wilhelsson et al., 1974). Two hundred and thirty patients were stratified into four risk groups (I, low risk IV high risk), according to acute post-infarction criteria, and each subgroup was randomized to treatment or placebo (Table 11). It would appear that treatment started six weeks or more after recovery from infarction. Follow-up was for two years. Table 12 shows the mortality and morbidity of all patients, according to their stratification prior to randomization. There is no difference in the non-fatal reinfarction rate, nor in the total mortality, although there is a clear trend in favour of alprenolol. There is a significant reduction in the number of sudden deaths on alprenolol, most of the sudden deaths occurring in the original groups II and IV, which implied the presence of a large infarct, or a combination of a large infarct and electrical damage. There were no deaths out-of-trial and there were no differences between patients who had sustained anterior or inferior infarctions. TABLE 10. Practolol Multicentre Trial Numbers O( Deaths and Reinfarctions

*Sudden cardiac deaths in trial Cardiac deaths after withdrawal Non-fatal myocardial infarction in trial Pre-entry anterior infarctions Pre-entry inferior infarctions

Practolol

Placebo

Signiticance

48

78

p < 0.01

42

41

NS

75

97

p < 0.09

23

50

p < 0.01

25

28

NS

*Death within 24 hours of onset of new symptoms. The reduction of in-trial sudden deaths by practolol was accounted for almost entirely by a reduction in mortality in patients whose original infarct was situated anteriorly. The reduction in the number of non-fatal reinfarctions does not reach statistical significance, but there is a trend in the right direction. The number of deaths after withdrawal is the same in treatment and placebo groups. Acknowledgement--The data for Tables 9 and 10 are quoted with the kind permission of Dr. K. Green.

fl-adrenergic agents in myocardial ischaemia

305

Alprenolol Post-Infarction Trial." Numbers of Patients Stratified into Risk Groups Prior to Randomization

TABLE 1 1.

Risk G r o u p

Alprenolol

Placebo

I II III IV

28 54 4 28 114

29 57 3 27 116

Late intervention (1-3 weeks) post-infarction study comparing Alprenolol with placebo. Each treatment group is subdivided into four risk categories prior to randomization.

A third small, placebo controlled randomized study, has been conducted with alprenolol (Ahlmark et al., 1976). Treatment and follow up lasted two years and a significant reduction in mortality 5 (9~o) in alprenolol group; 11 (12%) in control), and non-fatal reinfarction 4 (6~o) alprenolol; 15 (15~o) control, was shown. Propranolol has been investigated in two multicentre studies (Baber et al., 1980) in patients with anterior infarctions only. These two studies were conducted in parallel, following a common protocol, but at separate hospitals. In the double blind study, 720 patients were randomly allocated to treatment with propranolol 40 mg thrice daily, or placebo, starting 8 days after recovery from anterior infarction (range 2 14). The customary contra indications to beta blockade applied and, in this respect, the criteria were identical to those of the Practolol Multicentre Trial (Green et al., 1976). In the open multicentre study, 501 patients started treatment with the same dose of propranolol at the same time, after recovery from myocardial infarction. Matching for risk factors at trial entry was good. Patients were followed up for up to 9 months and mortality and non-fatal reinfarctions were determined in all those entered (Table 13). There were no differences in total mortality, or in the non-fatal reinfarction rate between the groups. A number of risk factors, independent of treatment, were identified (age, entry heart rate), but none of these interacted with treatment at a statistically significant level. Patients whose age was above the mean for the trial had a higher mortality on propranolol, as did those whose acute hospital admission systolic blood pressure was below the mean, and those whose trial entry diastolic blood pressure was below the mean. Also, patients with a history of congestive cardiac failure in the acute pre-trial phase had an increased mortality when subsequently treated with propranolol (Table 14). TABLE 12. AIprenolol Post-Infarction Trial: Mortality and Morbidity

Accordin 9 to Pre-trial Risk Factor Grouping Alprenolol

Placebo

Significance

Total N o n fatal reinfarction rate Total number of deaths Sudden Deaths*

16 7 3

18 14 11

NS NS p < 0.05

Subgroups Non-fatal reinfarction Total number of deaths Sudden deaths

I 4 0 0

II 9 4 1

III 0 0 0

IV 3 3 2

I 4 0 0

II 7 7 6

III 0 0 0

IV 7 7 5

*Death within 24 hr onset of new symptoms. The number of sudden deaths was significantly reduced by alpreno1ol. These deaths occurred in risk subgroups II and IV, which include patients with large infarctions. The non-fatal reinfarction rate is not reduced. Acknowledgement~Tables 11 and 12 are published with kind permission of Dr. Wilhelmsson and his colleagues.

306

N. S. BABER

TABLE 13. Multicentre Post-lnJarction Propranolol Trial Double Blind Trial No. at entry: Total mortality : Non-fatal reinfarction :

Placebo 365 27 (7.41~o) 15 (4.0'~;;)

Open Trial

Propranolol 355 28 (7.9!~o) 15 (4.2!?,,)

PropranoM 501 31 (6.Y~3 25 (4.9",3

Total mortality and non-fatal reinfarction rates were the same in the two propranolol and placebo groups. TABLE 14. Death rate by Signs of Congestive Cardiac Failure in the Acute Pre-Randomisation Phase (No. o~) Double-Blind Congestive Cardiac Failure: Absent Present

Placebo 22 (7.6) 5 (6.5)

Propranolol 21 (7.3) 7 (10.6)

Open

Propranolol 17 (4.3) 14 (13.0)

More patients who had signs of congestive cardiac failure in the acute, pre-randomisation phase, died when they were subsequently given propranolol, compared with the placebo group. The differences are not statistically significant.

2.6. CONCLUSIONS AND EXPLANATIONS In seeking to draw some conclusions from these early and late intervention clinical studies, a number of theories present themselves, which may, in total or in part, help to reconcile these diverse results. These theories can be examined under statistical and pharmacological headings. 2.6.1. Statistical 2.6.1.1. Trial Si=e. When a drug produces a dramatic reduction in mortality in a high risk group of patients, a statistical analysis is not required to support the obvious clinical efficacy. In a population of patients with a relatively good prognosis (BMJ Editorial, 1979), such as those studied in the majority of the published post infarction trials, it is more difficult to demonstrate an indisputable beneficial effect of a drug, which is not due to chance alone, without recourse to statistical analysis. Where the extent of a reduction in mortality is small, the size of trial required to demonstrate a statistically significant reduction in mortality is consequently much larger. As the trials become larger, the chances of missing, or masking, beneficial or deleterious effects on patient subgroups, increases. With the exception of the Practolol Multicentre Study (Green et al., 1976) and, possibly, the recent propranolol study (Baber et al., 1980) all the other trials can be regarded as small, particularly if it is hoped that a decision on the routine use of beta-blocking agents at a community level, can be taken as a result of these studies. On the other hand, the dismissal of potentially useful agents, based on the results of inadequate sample size, must be seriously considered. The subject has been recently reviewed by Frieman et al. (1978). For the published post-infarction trials with beta blockers, the confidence limits can be calculated (Fig. 1). It can be seen that, because of the small size of most of these trials and the resulting wide confidence limits, in 14 out of 18 studies, a 50~,, reduction in mortality cannot be excluded from the published data, and in 17 of the 18 studies, a 25°J~, reduction cannot be excluded. It should be noted that the converse is also true, i.e. some of the trials, if continued, could have demonstrated a statistically significant result against the active treatment. Nevertheless, many of these studies could be reassessed in the light of a lesser reduction in expected benefit.

//-adrenergic agents in myocardial ischaemia

-67.4%[ Propranolol, J-82.1 Propranolol [-91.2 Alprenolol 1-152.0

Oxprenolol

29.9%JMultinational Trial 2116f Norris et al 53.7 Multicentre

1-164.8%

-30.3 I -18.8 I -14.8 I

-6.6[ -2.6 Propranolol L-57.5 3.91 Propranolol -3g.8 p.4 Propranolol

Alprenolol [-166.7

Propranolol 1-37.1 Atenolol

122.41 Braint et at

i

4t.11 Present Study

] -54.3

Pr~to,o,

307

161.51 Reynoldsel al

1165.2[ Baiconelal ~.61 Clausenet al

i

1-16.d13.zl = ,3o1

,arber, Boyle st al

~ 24.7/ 86.41 Barber, Murphyetal I-..4 | 25.5| 85.51 Mitchell etal Propranolol -84.4 | 33.61 151.71 Slomanet al Pro~rano,o, I-Z3.2/ ~81 ~.91 Mitche, et a, Alprenolol [-37.6 [ !38.7[ 115.01 Ahlmark et al Pr..,o,o, p..63901 h41 Mo.~centreIGr~neta., Alprenolol I-4.6 i 49.1i 107.71 Wilhelmssonetal Propranolol| 2.5 Propranolol -25. / I

I

-2f10%

-100~,

Increase in mortality on treatment

0

i

~3.71

lo5o I

5g.2[ I

I

I

25%

50%

100'/.

Snowetal 143.51 Kahler et al

I 200%

Decrease in mortality on treatment

FIG. I. The effect of beta-adrenergic blocking agents on postinfarction mortality; percentage reduction in mortality and 90% confidence limit. The effects on total mortality, comparing beta-blocker with placebo, or controlled group, in 18 published studies is shown. The five betablocking agents, propranolol, alprenolol, practolol, oxprenolol and atenolol are shown left, and the source of the data on the right. Each horizontal bar represents the observed percentage effect of the drug, and the extremes of each bar represent the upper and lower 90% confidence limits of this effect. The figures in each bar give the exact percentage represented on the horizontal axis. It can be seen that only for the practolot muir|centre trial (Green et al.. 1976) and for the proprano1ol trial (Snow, 1965) is the lower confidence limit to the right of the zero point on the horizontal axis. For 14 of the 18 studies, the upper confidence limit includes a 50% possible reduction in mortality on treatment, and for 17 of the 18 studies, the upper confidence limit includes a 25% possible reduction in mortality.

If a reduction of 25% could be consistently demonstrated in several studies, it is pertinent to ask if this warrants the routine use of these agents (Rose, 1978). Most of these studies have been conducted in relatively good risk patients, with an expected annual placebo rate of about 6% (Green et al., 1975). Thus, in every 100 patients treated, 1.5 patients would be saved. 2.6.1.2. Time o f Death in Relation to Start o f Trial. It is well known that mortality is highest during the first few hours after acute myocardial infarction (Pantridge et al., 1975). Thereafter, the mortality rate declines. It becomes more difficult to demonstrate clinically significant reductions in mortality, therefore, with the passage of time. Moreover, if the mortality rate should be different in the placebo groups of different trials, caution must be exercised in comparing the treatment groups in their effects on the pattern of mortality reduction. A comparison of the survival curves of the placebo groups in the Practolol Multicentre Trial (Green et al., 1975) and in the Propranolol trial (Baber et al., 1980) (Fig. 2), shows that the mortality rate is comparable for the first 60 days, but differs after 100 days. The timing of intervention is also important with respect to the pharmacological action of beta adrenergic blocking drugs. Pantridge et al. (1975) have shown that after inferior infarction, the heart is predominantly under the influence of the vagus. This effect appears to be prolonged for 2-4 weeks after recovery from the acute event and during this period beta blockade would be contra-indicated. This may, at least in part, explain why the patients who suffered an inferior infarction in the Practolol Multicentre Trial (Green et at., 1976) had an increased mortality within the first 3 weeks after the acute event (Table 15). (Exclusions of the deaths within the first month following inferior infarction gives figures which are not significantly different (18 deaths in the practolol group and 27 in the placebo group.) In future studies a critical evaluation of mortality differences with respect to time must be made.

308

N . S . BABER 1.00

3.99

098

o•

PlaCebo

•

;'~%

groups

Propranolol trial

•

n

~359

O Practolol trial n - 5 4 5

0.97 •o 0%

oo

°o

E o

o

0.95

o

•

o

° o°

°o °

0.94

o 00

o

0

0.93 -

o

%

0 92 0.91 0.90

E 2O

I 40

6~)

l0

100

1~

140

160

180

~0

220

240

260

~0

~0

Days since intarct

FIG. 2. Survival curves for the placebo groups from the Practolol and Propranolol Multicentre trials. The circles represent the death of one patient. Survival is plotted from 14 days after infarct for both trials, up to 9 months. This has excluded some patients from both studies, because entry times were different, Practolol Multicentre trial (Green et al., 1976) mean 13 days, Propranolol trial (Baber et al., 1980) mean 8.5 days. The mortality rates were comparable up to 60 days, but different from 100 days onwards. Acknowledgements--The data for this figure was kindly provided by Mr. Lewis and Mr. S. Ellis.

2.6.1.3. Patient Selection. Most of the published post-infarction studies state the patient selection criteria in some detail. A prospective randomized trial has a better chance of having an equal distribution of risk factors between the two groups. However, extreme caution must be exercised in comparing mortality and morbidity from different trials, particularly if multicentre in design. In a study by Wilcox et al. (personal communication) the annual placebo mortality in definite and suspected post-infarction patients after the acute hospital phase was 6~0. In a subsequent study, by the same group of workers, using the same selection criteria and drawing patients from the same district, the placebo annual mortality rate was 15~o (Wilcox, Personal communication). Different conclusions could be drawn on the effectiveness of each treatment, depending upon which placebo group is used for comparison. 2.6.1.4. Mode of Death in Relation to Time after lnfi~rction. Mortality after myocardial infarction may be sudden or non-sudden. While the definition of sudden death may vary from one trial to another, it is generally agreed that a fatal dysrhythmia is the terminating TABLE 15. Practolol Multicentre Trial. Numbers of Death in Patients with Inferior Infarction related to Time

Time from entry (months)

Practolol

Placebo

<1 1 3 36 6-12 >12

7 3 1 10 4 25

l 5 6 8 8 28

In the first 3 weeks after inferior myocardial infarction, there are more deaths in the practolol group compared with placebo. This may be accounted for by the predominance of vagal activity in the early weeks after acute inferior infarction. Acknowledgement This table is produced with kind permission of Dr. Green and his colleagues.

fl-adrenergic agents in myocardial ischaemia

309

event. Moss et al. (1980) found that in the first four months after infarction, the predominant mode of death is non-sudden and thereafter the number of sudden and non-sudden deaths is approximately equal. Thompson et al. (1979) have published similar data showing that patients with large infarcts, determined by creatine kinase levels, had an increased rate of death from cardiac decompensation, but not of sudden death, and that the increased mortality in these patients was more marked in the early post-infarction period (up to 6 weeks). If beta-blocking agents exert their effect through a predominantly antiarrhythmic effect, and their negative inotropic effects are potentially undesirable during the course of a new cardiac event, then these agents may not be the drugs of choice for the first three or four months after myocardial infarction. However, this observation is not supported by the results of the Practolol Multicentre Trial (Green et al., 1976) or the Alprenolol trials (Wilhelmsson et al., 1974; Ahlmark et al., 1976). In the Propranolol Multi-centre study (Baber et al., 1980), there was no increase in the number of deaths from pump failure in the first three months in the propranolol compared with the placebo group, even though no overall reduction in mortality was demonstrated. 2.6.1.5. Analysis of In-Trial and Out-of-Trial Mortality. Table 6 shows the total and in-trial deaths from the study by Mitchell et al. (1978) and Table 16 shows the same data for the Practolol Multicentre Study (Green et al., 1976). The dilemma in interpreting these figures is evident and must be considered in all studies of this type where there is a large withdrawal rate. The major argument in favour of accepting total mortality comparisons in deciding whether a drug is useful or not, is that a selected, high risk group of patients may be withdrawn, which, if excluded from analysis, could bias the results. In contrast, those who suggest comparisons for in-trial mortality argue that treatment can be expected to be effective only if present at the time of a new cardiac event. Consideration must be given to the plasma and biological half-lives of the drug in relation to the time of the new event after withdrawal, as well as to the 'withdrawal phenomenon' described for patients with coronary artery disease (Shand and Wood, 1978). In the Practolol Multicentre Trial (Green et al., 1976), and the study with propranolol and atenolol by Mitchell (1978), it was reassuring to note that the times of death after withdrawal in treatment and placebo groups, were similar. In future studies, in-trial and total mortality and morbidity figures must be published. If both sets of figures, taken together, show a significant effect of the treatment under test, considerable confidence can be put on the result. 2.6.1.6. Patient Compliance. It is unlikely, in a randomised study with matching placebo treatment, that patients would be less compliant on the beta-blocking drug compared with the placebo group. Practolol blood levels were estimated in the Practolol Multicentre Study (Green et al., 1976), in 900 patients and indicated good compliance, while in one alprenolol study (Wilhelmsson et al., 1974), urinary alprenolol estimations were made, A compliance rate of 88-96~o was noted from 6-102 weeks. TABLE16. Practolol Multicentre Trial Number of Cardiac Deaths No. patients entered No. died while in treatment

1533 48~ ~

No. withdrawn from treatment

1

No. who died after withdrawal

!0~/42

Total cardiac mortality

4~7

1520 78~

~

~

4~1

}~1 119

p<0.01 NS p < 0.04

The number of deaths in the practolol group during the course of the trial is significantly less than in the placebo group. Even though the number of deaths after withdrawal is the same in the two groups, when the total cardiac mortality is compared, the statistical significance decreases. However, there is still an important difference between the groups. Compare these figures with those in Table 6, Acknowledgement This table was produced by kind permission of Dr. Green and his colleagues.

310

N.S. BABtR

In the Propranolol Multicentre Study (Baber et al., 1980) the mcan heart rates at follow-up were significantly lower than corresponding figures in the placebo group. 2.6.2. Pharmacological 2.6.2.1. Benefit and Harm to Patient Subgroups. There are well established absolute contra-indications to the use of beta adrenergic blocking drugs after myocardial infarction, which include heart failure, hypotension and bronchospasm. However, there is considerable variation in the clinical diagnosis of heart failure between physicians. The dependence of the acutely ischaemic and chronically diseased myocardium on sympathetic stimulation may not be manifest in the clincal condition of the patient at the time of starting therapy. Several authors refer to individual patients (Kreus et al., 1970; Hutton et al., 1980) who, clinically, had none of the contra-indications to beta blockade, and yet whose subsequent clinical deterioration was certainly the result of beta blockade. The studies of Mueller (Mueller and Ayres, 1977; Mueller and Herron, 1977i, and Norris (Norris et al., 1978) have shown that careful patient selection and monitoring can be rewarded, but in large trials, it is pertinent to ask whether the harm afforded to certain subgroups does not out-weigh the benefit to others and whether such "weighting" is not balanced by the randomization procedure. The identification of subgroups may also give insight into the relation of dose and ancillary pharmacological properties to outcome. In the Propranolol Multicentre Study (Baber et al., 1980), there was a non-significant treatment interaction with history of heart failure in the acute phase (i.e. hospital admission), systolic blood pressure, trial entry (8.5 days, mean), diaslolic blood pressure and also with age. The data relating to heart failure is shown in Table 14 and that for blood pressure, in Table 17. Patients, though not necessarily the same ones, whose age was below the mean (55) for the trial, without a history of heart failure in the acute phase, with admission systolic pressure and trial entry diastolic blood pressures above the mean for the trial, had a reduced mortality compared with the placebo control group. The converse was also true. In the Practolol Multicentre Trial (Green et al., 1976), the specific st|bgroup who benefited most from therapy were patients with anterior infarctions with trial entry diastolic blood pressures below the mean. Can any clinical decisions be drawn from subgroup analyses? What seems to be emerging is the following pattern: there is a group of patients, possibly the majority after infarction, who can safely be given a beta-blocking agent either acutely, or as a secondary prophylactic measure. However, the majority of these patients will probably recover anyway, though it is possible that a beta-blocking agent will reduce the size of the infarct which they sustain. The group of high risk patients who would benefit most from safe prophylactic therapy, both in the acute phase and in the long-term, undoubtedly contain TABI,E 17. Propranolol Muhicentre Post-h!]arction 7)'ial. Deaths-Related

to

Acute Systolic and Entry Diastolic Blood Pressure~

Nos. (!~5)deaths with acute systolic blood pressure above mean Nos. (~0) deaths with acute systolic blood pressure below mean Nos. ("i;) deaths with entry diastolic blood pressure above mean Nos. (!~{;)deaths with entry diastolic blood pressure below mean

Placebo

Propranolol

14(8.2~

I0 (6.7)

13 (6.71

18 (8.81

21 (9.51

15 (7.3)

6(4.2!

13 (8.7)

Patients were randomized to propranolol or placebo at 8.5 days (mean) after acute anterior myocardial infarction. When subsequent mortality' is related to the earliest recorded systolic blood pressure, and to the trial entry diastolic blood pressure, it can be seen that there were fewer deaths in the propranolol group for patients with recordings above the mean for the trial as a whole. The converse is also true.

/#adrenergic agenls in myocardialischaemia

311

a number of patients in whom a beta-blocking drug will be harmful, although this may not be evident at the time of starting treatment. Whether such patients would benefit from a different beta-blocking drug to propranolol, is discussed below. However, the dilemma remains: if a well defined group of patients, be they high or low risk, can be conclusively shown to be afforded protection by one beta-blocking agent in two or more studies, can such data be extrapolated to other patients and other beta-blocking drugs'.) Is the data so restrictive as to be of little value to the general group of post infarction patients? 2.6.2.2. Importance ~/" Cardioselectivity and Intrinsic Sympothomimetic Activity (Partial Agonist Actit~ity). Selective blockade of the cardiac beta receptors has been demonstrated in animal studies (Fitzgerald, 1979). The relevance of this property to the maintenance of cardiac function, to suppression of arrhythmias and to limitation of infarct size is less clear. In dogs with experimentally induced myocardial ischaemia, Stephan et al. (1975) have shown that atenolol produces a greater reduction in dp/dt max than propranolol and practolol. Robinson et al. (1978) have shown that the cardioselective agent atenolol in patients with coronary artery disease, reduced stroke volume independent of heart rate. This fall in stroke volume was significant and progressive with doses of 0.03, 0.06, and 0.12 mg/kg intravenously. These observations are comparable with those reported with propranolol (Hamer and Sowton, 1965). In contrast, there was only a modest fall in cardiac output with practolol in equivalent beta-blocking doses and this fall was rate dependent, and stroke volume rose (Sowton et al., 1968; Jewitt et al., 1970). Jewitt et al. (1970) showed that when intravenous practolol was given to patients with acute myocardial infarction, 5 mg produced no change in stroke volume, and 25 mg produced modest and inconsistent falls in stroke volume. These authors explain the differences between practolol and propranolol on the grounds that practolol is 1,/3-1/4 as active as proprano1ol in blocking cardiac beta-receptors, but as the higher doses of practolol produce only modest falls in cardiac output, the differences must also lie in the cardio-selective and partial agonist properties of practolol. Gibson and Coltart (1972) argued that the different haemodynamic effects of propranolol and practolol are not due to partial agonist activity, because oxprenolol and alprenolol, which possess this property, cause a dose-related reduction in cardiac output similar to propranolol, with no significant change in stroke volume. These authors also argue that the lack of effect on the peripheral circulation of selective beta blockade, leading to a reduction in venous return, also contributes to the smaller effect on stroke volume. However, Robinson et al. (1978) point out that these authors did not measure peripheral vascular changes to support this contention; peripheral vascular resistance increased significantly at rest, in patients studied by Robinson et al., following atenolol administration. This is in agreement with observations with propranolol (Astrom, 1968) and in contrast with effects of practolol given to patients with coronary artery disease (Sowton et al., 1968; Jewitt et al., 1970). Robinson et al. (1978) observed that the only major difference between practolol and atenolol is the possession of intrinsic activity by practolol. At the present time the balance of evidence would be in favour of partial agonist activity of a dose related type rather than cardioselectivity, to explain the differences on resting haemodynamic changes observed with different beta-blocking agents. Theoretically, it can be argued that cardioselectivity is both beneficial and harmful during acute ischaemia and infarction. If the peripheral beta-2 receptors, which have a predominantly vasodilator activity are left intact, then an acute rise in blood pressure due to unopposed alpha activity would be offset. However, it can be argued that if a patient sustains a large infarct, with a significant fall in output, a non-selective beta blocking drug may help to maintain the diastolic pressure. Recently, Sobel (1979) has argued in favor of a nonselective beta-blocking drug on the grounds that, while in normal myocardium, beta-2 receptors mediate coronary vasodilatation, the high interstitial fluid potassium concentrations in ischaemic tissue may induce beta-2 mediated coronary constriction.

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The clinical relevance of cardioselectivity in acute ischaemia remains in doubt at the present time. The recently published study by Mitchell et al. (1978) showed that the reduction in mortality with atenolol was the same as that for propranolol in comparison with placebo. Moreover, the withdrawal rate for hypotension and/or bradycardia was highest in the atenolol group. It could well be that the common effects shared by selective and nonselective beta blocking drugs (reduction in heart rate and blood pressure) outweigh any minor and largely theoretical advantages of cardioselectivity. It must also be remembered that the property of cardioselectivity, at least as regards the lung, is dose related. Partial agonist activity can be demonstrated in animals who have been depleted of their endogenous catecholamine stores (Bilkski et al., 1975). Stephan et al. (1975) have shown in dogs with experimental myocardial ischaemia that the blocking agent practolol, which has partial agonist activity, produces less depression of d p / d t max compared with propranolol and atenolol. Hope et al. (1974) have shown the importance of the negative chronotropic effects of propranolol in delaying the progress and spread of the ischaemic zone measured by the epicardial electrocardiogram and in delaying the time to the onset of ventricular tachycardia. Propranolol slowed the heart rate by 20'j'~, protected against dysrhythmlas and delayed the development of ischaemia. These effects were reversed by atrial pacing. Beta-blockers with partial agonist activity do not slow the heart as much as those without. If rate reduction contributes critically to infarct size reduction, then in some situations partial agonist activity may not be a beneficial property. As noted previously, Robinson et al. (1978) have argued for the importance of partial agonist activity in patients after myocardial infarction, with reference to cardiac function. Both practolol and alprenolol, in the long-term late intervention studies (Green et al., 1976; Wilhelmsson et al., 1974; Ahlmark and Saetre, 1976), have partial agonist activity, and as has been noted, a significant reduction in mortality was demonstrated with these drugs. However, two small alprenolol trials (Briant and Norris, 1970), one practolol trial (Reynolds and Whitlock, 1972) and two oxprenolol trials (Fucella, 1968; Lombardo et al., 1979), (oxprenolol also has partial agonist activity), were inconclusive. If any beneficial property of practolol can be apportioned to partial agonist activity, it is not at all clear whether this is the greater safety this may afford to the drug, or to some other as yet unidentified effect of this pharmacological property which increases its efficacy. McDevitt et al. (1977) and Bilkski et al. (1975), have demonstrated partial agonist activity in volunteers. The latter workers have demonstrated that with practolol compared with oxprenolol, partial agonist activity can be demonstrated at a lower dose. Lysbo et al. (1979) have compared five beta-blocking drugs in healthy volunteers for effects on cardiac output and heart rate. They showed that, when given in equipotent beta-blocking doses, propranolol and atenolol (without partial agonist activity) reduced cardiac output and heart rate by 270Jo and 21~,/~respectively, practolol (with some partial agonist activity) reduced cardiac output and heart rate by 12'~o and 11~0 respectively and pindolol and ICI 89,406 (with the most agonist activity) produced no changes in these parameters (Figs 3 and 4). What is particularly important about this study is the fact that the top of the dose response curve appears to have been achieved for each drug. Mueller and Ayres (1977), have shown that propranolol reduces coronary flow in patients after acute infarction, although the overall effect on myocardial metabolism (reduction in oxygen consumption and increase in lactate extraction) is beneficial. Marshall and Parratt (1976) showed in closed-chest dogs with acute coronary artery ligation that both propranolol and practolol, given in equipotent beta-blocking doses reduced flow to normal myocardium, but only with propranolol was there a reduction in flow to the ischaemic areas. Conversely, Vatner et al. (1977) in conscious dogs with regional myocardial ischaemia, showed that propranolol induced a redistribution of myocardial blood flow, with a fall in normal zones, and a rise in moderately and severely ischaemic zones. The clinical relevance of these observations remains uncertain, because

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FIGS 3 and 4. Reduction in cardiac output and heart rate after intravenous administration of five beta-adrenergic blocking drugs in normal subjects. Pindolol, ICI 89,406, practolol, propranolol and atenolol were administered as single intravenous injections in increasing doses, each respective dose chosen to be equipotent in reducing exercise-induced tachycardia. Three groups of curves can be distinguished: pindolol and ICI 89,406, practolol, propranolol and atenolol. For the first group the reduction in cardiac output and heart rate is minimal and no further reduction occurs on increasing dosage. For the third group, there is a significant reduction after the smallest dose, and reductions are progressive with increasing dose. The second group, practolol, is intermediate in its effect. Acknowledgements--This figure is reproduced by kind permission of Dr. Trap Jensen and his colleagues.

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the weight of data from human studies indicates that propranolol improves myocardial metabolism. Patients with 'high sympathetic tone' with an anterior myocardial infarct might be expected to be at risk from succumbing to a fatal dysrhythmia from high circulating levels of catecholamines. That these patients respond well has been shown by Pantridge and his colleagues (Pantridge et al., 1975), and by Barber el al. (1975). However, Hutton et al. (1980), have recently shown that the initial high heart rate can be a clinical manifestation of latent heart failure, even in the presence of normal pulmonary wedge pressure. Such patients, dependent on their sympathetic drive, will deteriorate on beta-blocking therapy. It is of interest that in the Practolol Multicentre Trial (Green et ell., 1976), 3.4",, patients were withdrawn for heart failure from the treatment group. The comparable figure for the Propranolol Multicentre Trial (Baber eta/., 1980), was 6.2",,. For the individual patient it remains extremely difficult to determme the correct balance between the desirable level of sympathetic drive and potentially detrimental increased sympathetic activity. During chronic beta blockade, this relationship may change, as has been suggested by the work of Raine and Picketing (1977). Should a further change in the balance occur as a result of another ischaemic event, it is not surprising that the results of the post-infarction studies are difficult to reconcile. The effective dose and partial agonist activity may be important when considering the effects of different beta-blocking drugs on the haemodynamic parameters in post-infarction patients. The follow-up blood pressures in patients in the propranolol multicentre study (Baber et al., 1980). were lower than those in the practolol multicentre trial {Green et al., 1975). Mulcahy et al. (1975) and Moss (personal communication) have shown that the follow-up systolic and diastolic pressures in patients who die in the long term after infarction is significantly lower than those who survive. Fox et al. (1975bl. have shown the same relationship for short term prognosis. The inappropriate beta blockade and consequent hypotension at the crucial time of the next ischaemic event could also explain some of the differences between drugs with partial agonist activity and those without. 2.6.2.3. D o s e amt M e t a b o l i s m (~l" B e t a - B l o c k i n q A g e m s . There is considerable controversy over the effective dose rangc of propranolol in the treatment of hypertension (Orme et al., 1980) and angina pectoris (Jackson et al., 1975: korimer. 1977). In the treatment of myocardial infarction, the early clinical studies were conducted with doses of 10 20 mg three times a day. The recent multicentre propranolol post-infarction trial (Baber et ,l., 1980) was conducted with a fixed dose of 40 mg three times daily. Blood levels were not measured but, using heart rate as a guide to beta-blockade, only 52°0 of patients had falls in heart rate of 10 beats/min or more at follow-up. After oral dosing, propranolol undergoes avid hepatic extraction, which process eventually becomes saturated. Even so, there is a wide variation in the bioavailability of the drug between patients and even within patients at different times. This difficulty is overcome when propranolol is administered intravenously early after infarction, but returns when oral therapy ensues. The problem is that the mechanism of prevention of sudden death and reinfarction is unknown. It is generally regarded as being anti-dysrhythmic, but the relation of the dose required to suppress potentially fatal dysrhythmias and to produce beta blockade (as measured by changes in heart rate)is poorly defined. Coltart and Shand (1970) have shown in volunteers that after oral dosing with propranolol, blood levels of between 50 100 ng. ml are required to produce significant falls in exercise heart rate. Coltart et ,I. (1971) produced suppression of ectopic beats in 8 of 12 cases with plasma levels below 100 150ng/ml, but in two of the remaining 4 levels of 100 200ng.ml were achieved without significant suppression. As previously noted, Woosley et al. (1980) have reported in patients with chronic stable ventricular dysrhythmias, that doses of propranolol between 640 and 960 mg/day, producing blood levels of up to 1000 ng/ml may be required to produce a 70",, suppression. Roland et al. (1979) showed that 40 mg three times a day of propranolol was ineffective in suppressing post infarction dysrhythmias. Peter et al. (1978), using intravenous proprano1ol, inft.sed into patients 4 12 hr after infarction, showed that blood levels of wopranolol

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FIG. 5. Serum propranolol levels (ng/ml) in 47 patients with acute myocardial infarction. All patients experienced onset of symptoms within the previous 12 hr. 0.1 mg/kg propranolol was given intravenously over 10 min immediately after hospital admission, followed by 320 mg propranolol orally over the next 27 hr in divided doses of 40 rag. The next dose was omitted if the heart rate fell below 50 beats/minute. Blood levels were within the range generally accepted to produce beta-blockade up to 36 hr, but dropped below that level by 48 hr. Acknowledgements--This figure is produced by kind permission of Dr. Peter and his colleagues.

were 80 ng/ml up to 12 hr after start of injection, after which levels peaked at 24 hr, but tailed off to 40 ng/ml at 48 hr (Fig. 5). It is also possible that the metabolism of propranolol is disturbed by the haemodynamic changes occurring as a result of infarction, with significant changes in the free levels. Age, too, may be an important factor and recent evidence suggests that beta receptor sensitivity deteriorates with advancing years (Vestal et al., 1979). Johansson et al. (1972) have shown that alpha 1 acid glycoprotein, rises significantly after acute myocardial infarction. Piafsky et al. (1978) have shown that alpha ~ acid glycoprotein can bind propranolol, which would leave less free drug available to exert its beneficial effect. The two or three times daily regimen which is commonly prescribed in the long term treatment of angina pectoris or hypertension, may produce troughs in the blood levels of propranolol at the critical time of a new ischaemic event. Practolol does not undergo extensive metabolism and the variation between individuals after the same dose is only two fold (Carruthers et al., 1974). These authors have shown that 200 mg twice a day orally (as in the Practolol Multicentre Trial), produces steady blood levels above 1.0/~g/ml over 24 hr, sufficient to reduce exercise heart rate by 25-30~o. However, in the Practolol Multicentre Trial (Green et al., 1976), there was the suggestion that heavier patients had sub-therapeutic plasma levels of the drug, which would suggest that the benefit shown in this trial may have been even greater on larger doses. Recently, O'Rourke et al. (1979), found that the blood levels achieved after oral pindolol, which has a small first pass effect, in patients treated within a mean of 9 hr after onset of infarction, were very variable. Clearly, the pharmacokinetics of each beta blocking agent during and after myocardial ischaemia require further study and inadequate dosing may account, at least in part, for the conflicting results obtained. 3. CONCLUSION Beta-adrenergic blocking drugs have a place in the treatment of established dysrhythmias, especially of supraventricular dysrhythmias. Their potential as prophylactic antidysrhythmic agents in the peri-infarction period has not been established by clinical J . P . T 13 2

(~

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practice, although detailed studies with attention to dose, time of administration, and type of dysrhythmia studied, are lacking. Evidence from both animals and man for reduction in myocardial oxygen consumption and limitation of infarct size is considerable, provided the agent is introduced within 4--6 hr of the onset of symptoms. Whether such an intervention improves ventricular function and reduces morbidity and mortality remains unanswered. Specific treatment of cardiac pain by beta-blocking agents cannot yet be regarded as a routine procedure, and further controlled studies are required against standard regimens. The late intervention trials have not yielded conclusive evidence of a reduction in mortality and morbidity and it is not possible to recommend the routine administration of these drugs to all patients after recovery from acute myocardial infarction. At present, the indications in the late post infarction period would seem to be continuing or recurrent chest pain, especially if accompanied by hypertension. Great caution must be exercised in extrapolating data from acute short term intervention studies designed to study infarct size reduction specifically, to these long term trials in relatively unselected groups of patients. At present the relevance of the pharmacological differences between the beta-blocking agents in the peri-infarction period remain speculative, but future studies must pay particular attention to dosage and to blood levels of free drug. In the immediate future, two areas seem worth pursuing: Firstly, studying the effect of very early intervention on morbidity and mortality in a well defined population of patients: secondly, studying more closely the relation between dose and ancillary pharmacological property on the one hand, and cardiac function and infarct size limitation on the other, in an attempt to define which patients can be given a particular betablocking drug at a time point after infarction. But herein lies the major dilemma: if benefit can be demonstrated in a well defined group of patients, can those results be justifiably extrapolated to a wider population? Acknowled.qements My thanks to Dr. D. Fitzgerland, Dr. K. Green, and Mr. J. Lewis for their detailed and critical comments My thanks also to Mrs. P. Wilson and Mrs. E. Husband for their patient preparation of the manuscript

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(1965) Cardiac output after beta-adrenergic blockade in ischaemic heart disease. Br. Heart J. 27:892 895. HENG, M., SINGH, B., NORRIS, R., JOHN, M. and ELLIOT, R. (1976) Relationship between epicardial ST-segment elevation and myocardial ischaemic damage after experimental coronary artery occlusion in dogs. J. clin. Invest. 58: 1317-1326. HOPE, R. R., WILLIAMS,D. O., EL-SHERIF, N., LAZZORA, R. and SCHERLAG,B. J. (1974) The efficacy of antiarrhythmic agent during acute myocardial ischaemia and the role of heart rate. Circulation 50:507 514. HUTTON, I. (1980) (personal communication). IKRAM, H. (1976) Propranolol in persistent ventricular fibrillation complicating acute myocardial infarction. Am. Heart J. 75: 797-798. IRVIN, R. and COBB, F. (1977) Relationship between epicardial ST-segment elevation, regional myocardial blood flow and extent of myocardial infarction in awake dogs. Circulation 55:825 832. JACKSON, G,, ATK1NSON,L. and ORAM, S. 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