International Journal of Cardiology, 31 (1991) 395-304 0 1991 Elsevier Science Publishers B.V. 0167-5273/91/$03.50 ADONIS 016752739100140L

CARD10

295

01263

Effects of xamoterol in acute myocardial infarction: blood pressure, heart rate, arrhythmias and early clinical course J. McMurray,

C.C. Lang, D. MacLean,

A.D. Struthers

and D.G. McDevitt

Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee DDI 9SY, U.K. (Received

McMurray

1 October

1990; revision

accepted

28 January

1991)

J, Lang CC, MacLean

myocardial infarction; 1991;31:395-304.

blood

D, Struthers AD, McDevitt DG. Effects of xamoterol in acture pressure, heart rate, arrhythmias and early clinical course. Int J Cardiol

Xamoterol is a novel partial agonist of j3, adrenoceptors that reduces myocardial ischaemia and improves ventricular function in patients with mild to moderate heart failure. In a double blind, random&d, placebo controlled study, the effects of xamoterol given in a dose of 200 mg twice daily were studied in 51 consecutive patients with acute myocardial infarction, including 17 receiving diuretics for left ventricular failure. Treatment was started on the third day of admission and continued for 7 days. Blood pressure was recorded at 0900 daily, and 24 hour ambulatory electrocardiogram monitoring was commenced at this time on days 1 (pre-treatment), 4, 6 and 9 of admission. Additional drug therapy was recorded daily throughout the study. One patient died prior to randomisation and three were withdrawn (1 placebo, 2 xamoterolj. with ventricular arrhythmias and/or disturbances of conduction. Compared to placebo, xamoterol had no effect on the rate of vent&&u premature beats or ventricular tachycardia. Xamoterol increased nocturnal heart rate (0000-0600 hrs 79 f 2; placebo 72 f bcats/min; P -c 0.03) but did not change blood pressure. Three patients receiving xamoterol, and 7 on placebo, required new (after randomisation) antianginal therapy. One patient treated with placebo developed new heart failure. These results show that xamoterol can be administered safely to selected patients following myocardial infarction, including those treated for mild heart failure. Key words:

Xamoterol;

Myocardial

infarction;

Adrenoceptor,

Introduction Xamoterol is a new Pi-adrenoceptor partial agonist indicated for the treatment of mild heart failure [1,2]. Treatment with xamoterol results in sustained improvements in symptoms, left ventric-

Correspondence Western Infirmary,

to: Dr J. McMurray, Dept. of Cardiology, Glasgow Gil 6NT, U.K.

partial

agonist

ular systolic and diastolic function, and exercise tolerance in patients with heart failure [I -71. These benefits are obtained without an increase in consumption of myocardial oxygen [3]. Xamoterol also reduces myocardial ischaemia on exercise in patients with left ventricular dysfunction and coronary arterial disease [%-lo]. In view of this favourable pharmacological profile, we have examined the effects of xamoterol in the early convalescent phase subsequent to

296

myocardial infarction. Beta-adrenoceptor antagonists have been shown to be of benefit in such patients. “High risk” patients, who may have most to gain from beta-blockers, may be least tolerant of pure antagonists [I 11. Partial agonists, therefore, may be an alternative for these patients. Though judged by some to be less efficacious than pure antagonists, there is recent evidence that partial adrenoceptor antagonists may be of considerable benefit if given to patients at high risk early after myocardial infarction [12,13]. Also, when given late after myocardial infarction, xamoterol has been shown favourably to influence ventricular remodelling [14]. Patients

and Methods

The study was approved mittee on Medical Ethics written informed consent.

by the Hospital Comand all patients gave

Patients All patients admitted to the Coronary Care Unit, under the care of the participating physicians, with a diagnosis of myocardial infarction were considered for enrolment in the trial. Myocardial infarction was diagnosed on the basis of a typical clinical history and the appearance of pathological Q-waves on the electrocardiogram or a rise in cardiac enzymes in excess of twice the normal laboratory levels. Exclusions The following exclusion criteria were applied: (a) Chest pain for longer than 12 hours prior to admission; (b) Age greater than 80 years; (c) Women capable of bearing children; (d) Patients with chronic obstructive airways disease, insulin treated diabetes mellitus or significant renal, endocrine, hepatic or haemopoietic disease; (e) Concurrent treatment with a beta-blocker or verapamil; (f) Patients with severe heart failure (defined as New York Heart Association Class IV or a diuretic requirement of more than 80 mg of frusemide or equivalent); (g) Systolic blood pressure of less than 90 mmHg; (h) Second or third

degree atrioventricular block; (i) Persistent sinus bradycardia (i.e. less than 50 beats per minute lasting beyond day 2 of admission); (j) Requirement for a pacemaker: (k) Patients with atria1 fibrillation; (1) Recurrent ventricular tachycardia or ventricular fibrillation despite treatment. Study design The trial was a double blind, randomised, between group comparison of xamoterol and placebo. The present need for diuretic therapy was prospectively determined in all patients. Diuretic therapy was only administered where there was clinical evidence of left ventricular dysfunction (pulmonary oedema, third heart sound, raised jugular venous pressure). The day of admission to Coronary Care Unit was designated day 0. Consent was obtained on the morning of day 1. Patients were usually transferred to the ward on the morning of day 2. Treatment randomisation took place on day 3. Xamoterol 200 mg twice daily or matching placebo was prescribed at 10.00 hrs and 22.00 hrs for seven days. The study ended on day 10 at 10.00 hrs (see scheme, Fig. 1). Measurements Pulse rate and blood pressure. Heart rate was recorded by counting the radial pulse daily at approximately 09.00 hrs, after at least 20 minutes supine rest. Blood pressure was recorded immediately afterwards with a mercury sphygoma-

291

nometer. These measurements were used to calculate double product (heart rate x systolic blood pressure). 24-Hour electrocardiogram recordings. On days 1, 4, 6 and 9 a 24-hour electrocardiogram recording was commenced immediately after measurement of heart rate and blood pressure. The recordings were made using Oxford Instruments Medilog 1 recorders and analysed independently (Liverpool Cardiac Diagnostic Clinic, Liverpool Ll 9EW). Each 24-hour tape was analysed for the following parameters: (1) Hourly mean and maximum heart rate. (2) Hourly rate of ventricular premature beats. (3) Presence of ventricular tachycardia (> 3 beats) and total number of times sustained (greater than 30 seconds) or unsustained (less than 30 seconds or spontaneous resolution). (4) Operator controlled printouts of 2 and 3 were used to Lown grade each recording. (5) Presence of atria1 fibrillation and total duration. (6) Presence of supraventricular tachycardia and total duration. (7) Bradyarrhythmias: presence of sinus bradycardia, nodal bradycardia and idioventricular rhythm and their duration. (8) Presence of asystole (pause greater than 1.5 seconds), sinus arrest and sinoatrial conduction block; number of occurrences and/or duration. (9) Presence and degree of atrioventricular block; total duration of complete heart block if present. (10) Presence and total number of atria1 premature beats. All analyses were performed blind to treatment allocation. Additional medication. Any requirement for anti-angina1 therapy (oral nitrates or calcium blockers), diuretics for heart failure or oral antiarrhythmic therapy after day 3 of the study (i.e. after randomisation to xamoterol or placebo) was recorded. Serum potassium. Serum potassium was measured on the morning of day 1 and day 10. Venous blood was taken from an antecubital vein at or around 09.00 hrs after the patient had rested supine for at least 20 minutes and after the blood pressure had been recorded.

Statistical analysis. The heart rate, blood pressure and double product data for days 4-10 were analysed using a repeated measures analysis of variance. In the absence of significant treatment by time interactions, the mean of each variable over days 4-10 was calculated for each treatment and analysed using analysis of variance (correcting for baseline where necessary). The hourly minimum, maximum and mean 24hour electrocardiogram heart rate were divided into two time bands midnight-06.00 hrs and 06.00 hr-midnight. The data in each of these time bands were analysed using a repeated measures analysis of variance. As before, treatment by time interactions were not detected and the means over days 4, 6 and 9 were calculated for each time band and treatment. These were subsequently subjected to analysis of variance correcting for baseline where necessary to assess treatment effect. The total ventricular premature beat count over 24 hours and Lown grade data were analysed to assess treatment effect by using a Wilcoxon rank sum test on the difference from day 1 to days 4, 6 and 9 respectively. The change in incidence of unsustained ventricular tachycardia was expressed as an increase, no change or decrease from day 1 to each of days 4, 6 and 9. The treatment effect was assessed using a &i-squared test.

Results Fifty-one patients were recruited into the trial. Demographic details are given in Table 1. Eight patients in each group received diuretics. Withdrawals One patient died prior to receiving the first treatment dose. Three patients were withdrawn after commencement of treatment. One patient receiving placebo developed sustained ventricular tachycardia on day 8 of the study. One patient receiving xamoterol was withdrawn on day 5 after developing ventricular fibrillation; this arrhythmia occurred during documented reinfarction and was treated successfully. A patient receiving xamoterol was also withdrawn on day 4 after developing

298 TABLE

1

Demographic details of patients in this study. Unless otherwise indicated, values are given as means.

Number Age (yr) Sex Site of infarct Anterior Inferior Posterior Time of onset of chest pain to CCU admission Killip Class I/II Peak AST level Previous MI Receiving diuretic for heart failure ’

Placebo

Xamoterol

26 * 58 (range 34-78) 19M, 7F

25 59 (range 47-74) 16M, 9F

17(1*) 8 0

15 9 1

5.3 hr (range 0.5-12) 21/5 230 a/l 2 patients

3.6 hr (range 0.5-12) 21/4 188 /J/l 5 patients

8

8

* One placebo patient died prior to receiving the first treatment dose. ” Patients treated with diuretic for heart failure before day of randomisation (day 3) were prospectively identified.

second degree atrioventricular block. This patient had suffered an inferior myocardial infarction and had first degree atrioventricular block at the time of randomisation; the 24 hour electrocardiogram on day 4 also showed episodes of complete heart block. Whenever possible, data continued to be collected as specified for these patients and was included in the statistical analysis. Pulse rate, blood pressure, double product Pulse rate, blood pressure and double product (measured at 0900 hrs) did not differ between the xamoterol and placebo treated patient groups on any of the ten study days (systolic blood pressure, Fig. 3). 24 Hour electrocardiogram

the analysis. Forty-four had analysable data.

of the 50 treated

patients

Heart rate Mean hourly heart rate for the recordings commenced on day 1 (pre-treatment), day 4 (second treatment day), day 6 and day 9 are given in Fig. 2. Xamoterol increased heart rate. This effect was most noticeable at night (OO.OC-06.00 hrs) where the nocturnal dip in minimum, mean and maximum heart rate was either abolished or greatly attenuated (P > 0.05 over whole treatment period). Some diurnal fluctuation in heart rate did, however, still occur in the xamoterol group. Similarly, a tendency for overall heart rate to decline during the 10 days of the study (most noticeable at night) also appeared to be preserved in the xamoterol group. Ventricular premature beats Median, minimum and maximum ventricular premature beat rates for the xamoterol and placebo groups on days 1, 4, 6 and 9, which did not differ, are shown in Table 2. The percentage of patients within the three ventricular premature beat rate bands 0, l-720 and greater than 720/min did not differ either. Ventricular tachycardia One patient had sustained ventricular tachycardia (see withdrawals). Ten placebo patients had episodes of unsustained ventricular tachycardia prior to treatment and six had episodes during treatment. Twelve xamoterol patients had episodes of unsustained ventricular tachycardia prior to treatment and four had episodes during treatment (difference not significant).

analysis Lawn grading

Complete 24 hour recordings were not obtained for all patients on all specified days because of technical failures such as electrode detachment and cable fracture. Only recordings with more than 12 hours of usable material were included in

The proportion of patients in Lown grades 3-5 for each recording period are shown in Fig. 4. Xamoterol treatment was not associated with any increase in complex ventricular arrhythmias.

299 140

Atrial fibrillation

130

Two patients developed atria1 fibrillation. One developed this arrhythmia on the first day of xamoterol therapy and required treatment with digoxin and amiodarone. The other patient, receiving placebo, had intermittent non-sustained atria1 fibrillation which was not treated and which persisted for the duration of the study. Supraventricular

‘;;I

0 "0 100 73 P E '0

tachycardia

Eleven xamoterol and six placebo patients had episodes of non-sustained supraventricular tachycardia during the treatment period; the longest of these was 23 seconds. The incidence of supraventricular tachycardia did not differ significantly between the xamoterol and placebo groups.

06.00

1

2

3

5

4

6

7

6

9

10

11

day

Fig. 3. Mean systolic

blood pressure study.

at 09.00 on days l-10

of

the treatment period (difference not significant). One xamoterol and one placebo patient had an episode of idioventricular rhythm during the treatment period.

Nine placebo patients and six xamoterol patients had episodes of sinus bradycardia during

-

20

0

Bradyarrbythmias

00.00

120

$

5 t& 110

06.00

hours

-

OO..OO hours

00

I

so

70

10

0 Xamoterol 0 Placebo I 0

1

I 2

I

1

3

4

1

1 0

I 7

I

I

s

0

0 10

0 Xamoterol o Placebo I

I

1

I

1

I

1

I

1 0

012345178

10

w Fig. 2. Mean

heart

rates in placebo and xamoterol Statistical comparison

treatment groups for 24-hour electrocardiograms is for the time periods 0000-0600 and 0600-0000.

applied

days

1. 4, 6 and 9.

300

Sinus block

arrest, asystole

and sinoatrial

conduction

TABLE

2

Ventricular premature beats (VPBs). Number per 24 hours on each of study days (median

No episodes were recorded. Ahioventricular

of these conduction

disturbances

block

One patient receiving xamoterol developed second degree atrioventricular block (Wenkebach and Mobitz type II) on day 1 of treatment and eventually third degree atrioventricular block (see withdrawals). A second patient on xamoterol developed Mobitz type II atrioventricular block on day 1 of treatment which was clinically undetected. A placebo patient developed first degree atrioventricular block on day 3 of treatment. Serum potassium Serum potassium concentrations on day 1 were placebo 3.98 k 0.09; xamoterol 4.12 k 0.09. On day 10 the respective values were 4.37 + 0.1 and 4.25 4 0.08 (p = not significant). Additional medication Seven patients receiving placebo and three patients receiving xamoterol required new or additional antianginal therapy after randomisation. One patient in the placebo group required diuretic therapy for heart failure instituted after day 3. Two patients in each group received oral antiarrhythmic therapy.

1

Day Placebo VPBs/24h Median Range Xamoterol VPBs/24h Median Range

and range). 4

53 (O-1 139)

I203 (O-8995)

6

9

5 (O-611)

8 (O-814)

9 (O-854)

9 (O-8874)

7 (O-9355)

7 (O-9475)

ular arrhythmias, particularly in the setting of left ventricular dysfunction [15]. It is a concern that any form of adrenergic stimulation could further increase the arrhythmogenic potential of this period [16,17]. We did not, however, find any evidence for such an adverse consequence in post-myocardial infarction patients treated with the partial /3,-agonist xamoterol, a proportion of whom had heart failure. Similarly, we did not find that xamoterol caused hypokalaemia, one of the possible arrhythmogenic mechanisms of adrenergic stimulation [ 18,191. These findings concur with those of other investigators. In a smaller

1001

All ~~Iients

Discussion This study has shown that xamoterol is well tolerated by selected patients in the early convalescent phase, postmyocardial infarction. Specifthere was no evidence of increased ically. arrhythmias, need for antianginal therapy or heart failure requiring treatment. It is important to consider each of these points in turn. In the early period after a myocardial infarction. there is a relatively high incidence of ventric-

Fig. 4. Percentage (%) of patients from each treatment group with Lown grades 3-5 ventricular arrhythmias identified on 24-hour electrocardiograms applied days 1 (pre-treatment). 4, 6 and 9.

301

study of 14 patients with myocardial infarction complicated by heart failure, intravenous xamoterol was not associated with any increase in arrhythmias during two three hour periods of electrocardiogram monitoring over four days of treatment [20]. In the different, but still highly arrhythmogenic, setting of chronic heart failure treatment, there is no evidence that xamoterol increases the incidence of ventricular arrhythmias [1,21-231. Indeed, it has recently been shown that xamoterol has an antiarrhythmic effect when given as an adjunct to amiodarone in patients with refractory ventricular arrhythmias secondary to ischaemic left ventricular dysfunction [24]. Nevertheless, further evaluation of the potential arrhythmogenic risk of xamoterol should be undertaken, for example by assessment of its effect on heart rate variability and baroreceptor sensitivity post myocardial infarction. A second concern with a drug with positive inotropic and chronotropic effects, in the setting of cardiac infarction, is that myocardial consumption of oxygen might be increased [25]. Rate pressure product was not, however, raised by xamoterol therapy. This index of myocardial work was calculated from measurements made at 09.00 hrs, when there was little difference in heart rate between the two groups. By contrast, nocturnal heart rate was increased by xamoterol. This might be expected to increase myocardial demand for oxygen [20]. Such an effect was not detected by the relatively crude method of assessing requirement for antianginal therapy. The impact of treatment with xamoterol on myocardial consumption of oxygen in the setting of acute ischaemia and infarction clearly requires further investigation. One approach could be to monitor changes in the ST-segments to quantify ischaemia over prolonged periods. The third concern about the use of a drug such as xamoterol when used after an episode of myocardial infarction is that it has the potential to behave as a beta-blocking drug and, therefore, to worsen ventricular function in those patients with severe acute or chronic heart failure and myocardial infarction. Though partial agonists are better tolerated than pure antagonists [27] in patients with left ventricular dysfunction. there is recent

evidence that xamoterol. given in full dosage, can worsen prognosis in patients with severe heart failure [26]. In the present study, nonetheless, where patients with severe left ventricular dysfunction were excluded, there was no evidence of worsening of heart failure or need for new or increased diuretic therapy in the xamoterol treated group. This study suggests, therefore. that xamoterol can be given safely in the early convalescent phase after myocardial infarction. There are, however, important limitations to this conclusion. Firstly, a highly selected group of patients were treated. Generalisation of the safety of xamoterol to all patients subsequent to infarction cannot be made. Secondly, treatment was only initiated on the fourth day after infarction (day 3 of the study). By this stage, even those patients with mild clinical heart failure had been stabilised with diuretic therapy before xamoterol was given. Thirdly, xamoterol was given after the peak of adrenergic hyperactivity that characteristics acute myocardial infarction [28,29]. Consequently, xamoterol behaved as a beta-agonist in this study but might behave primarily as a beta-blocker if given earlier after cardiac infarction. This would alter the haemodynamic impact of the drug in patients with left ventricular dysfunction [30,31]. In summary, this study has shown that xamoterol, when given as 200 mg twice daily to a selected group of patients from the fourth day of myocardial infarction, is well tolerated. Specifically, there was no evidence of increased angina, arrhythmias or heart failure following treatment. These findings suggest that it is appropriate to consider further studies of the place of xamoterol in the setting of acute myocardial infarction.

Acknowledgements We acknowledge the assistance of Drs G. MacNeill, T. Pringle and the staff of the Coronary Care Unit during this investigation. We are grateful to Miss E. Brown for typing the manuscript. We are grateful to ICI Pharmaceuticals for financial support and for the statistical analysis. This

302

study was supported by a grant maceuticals plc, U.K.

from

ICI Phar-

References 1 The German and Austrian Xamoterol Study Group. Double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet 1988;i:489-493. 2 Waller DC, Webster J. Sykes CA, Bhalla KK, Wray R. Clinical efficacy of xamoterol a &-adrenoceptor partial agonist, in mild to moderate heart failure. Eur Heart J 1989:10:1003-1010. 3 Rousseau MF. Pouleur H, Vincent MF. Effects of a cardioselective beta, partial agonist (Corwin) on left ventricular function and myocardial metabolism in patients with previous myocardial infarction. Am J Cardiol 1983;51:1267-1274. 4 Molajo AO, Bennett DH. Effect of xamoterol (ICI 119587). a new beta adrenoceptor partial agonist on resting haemodynamic variables and exercise tolerance in patients with left ventricuIar dysfunction. Br Heart J 1985;54:17-21. 5 Pouleur H, van Eyll C, Cheron P, Hanet C. Charlier AA. Rousseau MF. Changes in left ventricular filling dynamics after long term xamoterol therapy in ischaemic left ventricular dysfunction. Heart Failure 1986;2:176-184. 6 Virk SJS, Anfilogoff NH, Lawson N et al. The acute effects of intravenous xamoterol on resting and exercise haemodynamics in patients with mild to moderate heart failure. Eur Heart J 1989:10:227-234. 7 V&oh-Sorensen E. Faergeman 0. Snow HM. Effects of xamoterol, a &-adrenoceptor partial agonist. in patients with ischaemic dysfunction of the left ventricle. Br Heart J 1989;62:335-341. 8 Detry JMR, Decoster PM. Buy JJ, Roussean MF, Brasseur LA. Antianginal effects of Corwin, a new beta-adrenoceptor partial agonist. Am J Cardiol 1984;53:439-443. 9 Barrios L, Geboers J, Piessens JH, De Geest H. Effects of xamoterol a new beta-adrenoceptor partial agonist in patients with angina pectoris. Eur J Clin Pharmacol 1986;29:667-671. 10 Bostrom PA, Jahansson BW, Lecerof H, Lilja B, Tarp A. Effect of xamoterol on exercise capacity and left ventricular function in angina pectoris and in dilated cardiomyopathy. J Intern Med 1989;226:331-335. 11 Beta-Blocker Pooling Project Research Group (BBPP). Subgroup findings from randomised trials in post infarction patients. Eur Heart J 1988;9:8-16. 12 Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term acute myocardial infarction interventional trials. Am J Cardiol 1986:57:43F-49F. 13 Boissel JP. Leizorovicz A. Picolet H. Peyrieux JC. Secondary prevention after high risk acute myocardial infarction with low dose acetbutolol. Am J Cardiol 1990:66:251260. 14 Pouleur H. van Eyll C, Hanet C. Cheron P, Charlier AA.

Rousseau MF. Long term effects of xamoterol on left ventricular diastolic functioning and late remodelling: a study in patients with anterior myocardial infarction and single vessel disease. Circulation 1988:77:1081-1089. 15 Biggar TJ. Relation between left ventricular dysfunction and ventricular arrhythmias after myocardial infarction. Am J Cardiol 1986:57:8B-14B. 16 Lown B. Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med 1976;294:1165-1170. 17 Szekeres L, Boros E, Pataricza J. Udvary E. Sympathetic neural mechanisms in cardiac arrhythmias. J Mel Cell Cardiol 1986;18:369-373. 18 Nordrehaug JE, Johannessen KA. Von der Lippe G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation 1985;71:645-649. 19 Helfant RH. Hypokalaemia and arrhythmias. Am J Med 1986:8O(suppl 4A):13-22. 20 Svensson G, Rehnqvist N, Sjogren A, Erhardt L. Haemodynamic effects of ICI 118.587 (Corwin) in patients with mild cardiac failure after myocardial infarction. J Cardiovasc Pharmacol 1985;7:97-101. 31 Connelly D. McAlpine H, Henderson E. Dargie H. Effect of xamoterol on arrhythmias in severe chronic heart failure. Eur Heart J 1988:9(suppl 1):278. 22 Virk SJS, Anfilogoff NH, Lawson N, Qiang F, Murray RG. Littler WA, Davies MK. The effect of xamoterol on arrhythmias in patients with mild to moderate heart failure. Eur J Clin Pharm 1989:36(suppI):A71. 23 Erlemier HH. Kupper W. Bleifeld W. Exercise capacity, arrhythmias, humoral and clinical parameters during longterm therapy with xamoterol. Int J Cardiol 1990:28:197208. 24 Paul V, Griffith M, Ward DE. Camm AJ. Adjuvant xamoterol or metoprolol in patients with malignant ventricular arrhythmia resistant to amiodarone. Lancet 1989:i: 302-305. 25 Quyyumi AA, Wright CA, Mockus LJ, Fox KM. Mechanisms of nocturnal angina pectoris: importance of increased myocardial oxygen demand in patients with severe coronary artery disease. Lancet 1984;i:1207-1209. 26 Shanes JG, Wolfkiel C, Ghali J, Dierenfeldt BJ, Kondos T, Bauman JL. Acute haemodynamic effects of pindolol and propranolol in patients with dilated cardiomyopathy: relevance of intrinsic sympathomimetic activity. Am Heart J 1988;116:1268-1275. 27 Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 199O:ii:l-7. 28 Jewitt DE. Mercer CJ. Reid D, Valori C, Thomas M. Shillingford JP. Free noradrenaline and adrenaline excretion in relation to the development of cardiac arrhythmias and heart-failure in patients with acute myocardial infarction. Lancet 1969:i:635-641. 29 Benedict CR. Grahame-Smith DC. Plasma adrenaline and noradrenaline concentrations and dopamine+hydroxylase activity in myocardial infarction with and without cardiogenie shock. Br Heart J 1979;42:214-220.

303 30 Siike B, Frais MA, Verma SP, Reynolds G, Taylor SH. Differences in haemodynamic response to beta-blocking drugs between stable coronary artery disease and acute myocardial infarction. Eur J Clin Pharmacol 1986;29:659665. 31 Sato H. Michitoshi

I, Matsuyama

T, Gzaki H, Schimazu

T,

Takeda H, Ishida Y, Kamada T. Haemodynamic effects of the &-adrenoceptor partial agonist xamoterol in relation to plasma norepinephrine levels during exercise in patients with left ventricular dysfunction. Circulation 1987:75:213220.