- Email: [email protected]
Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event
International Elsevier
Journal of Cardiology,
15 (1987) 301-308
301
IJC 00537
Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event Nina Rehnqvist,
Gunnar
Department (Received
Olsson, Leif Erhardt,
Ann-Mari
of Medicine, Danderyd Hospital, Dandetyd,
9 September
1986; revision
accepted
Ekman
Sweden
16 December
1986)
Rehnqvist N, Olsson G, Erhardt L, Ekman A-M. Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event. Int J Cardiol 1987;15:301-308. Fifty three of the 5778 patients included in the MIAMI (Metoprolol in Acute Myocardial Infarction) trial were investigated with long-term ECG recordings in order to evaluate the effect of acute beta-blockade on premature ventricular complexes in and after acute myocardial infarction. Twenty five patients were given placebo and 28 metoprolol in a double-blind randomized fashion for 15 days. After this period the patients were put on open beta-blockade without breaking individual study codes. The mean number of premature ventricular complexes during the inclusion day (day 0) was the same in the two groups. The median numbers were also similar in the two groups: 190 and 154 in the placebo and metoprolol groups, respectively. Metoprolol significantly reduced the median number of premature ventricular complexes in the randomized period. The median numbers on days 1, 2 and 15 were 146, 101, 84 in the placebo group and 73, 59 and 10 in the metoprolol group, respectively (P c 0.05). Also during the further follow-up, when investigated 1, 3 and 6 months after the infarction, the median number of premature ventricular complexes was lower in the metoprolol group (74, 257, 142 in the placebo group and 7, 5 and 11 in the metoprolol group, P < 0.05). Thisindicates that metoprolol treatment in the acute phase of myocardial infarction reduces ventricular arrhythmias both in the early stage and also after the acute event.
Correspondence to: Nina Rehnqvist M.D., Department Danderyd, Sweden. Supported in part by the Swedish National Association Hlssle.
0167-5273/87/$03.50
0 1987 Elsevier Science Publishers
of Medicine, against
Heart
B.V. (Biomedical
Danderyd and Chest
Division)
Hospital. Diseases
S-182 88 and AH
302
Key words:
Myocardial
infarction;
Drug treatment;
Arrhythmia
Introduction The occurrence of premature ventricular complexes has been shown to increase during the year after an acute myocardial infarction [l]. The results of two studies indicate that this development is slowed down when beta-blockers are given after the infarction with the purpose of improved survival [2,3]. Concomitantly a reduction in mortality and particularly sudden deaths has been proven [4,5]. The mechanisms behind the reduced incidence of arrhythmias are unknown: both anti-ischemic effects and regular antiarrhythmic effects have been suggested. In two studies it has been shown that in the acute event beta-blockade reduces the number of ventricular fibrillations [6,7], but other studies have not confirmed these findings [8,9]. In order to evaluate the effect of acute beta-blockade on premature ventricular complexes in myocardial infarction, a subpopulation of the MIAMI (Metoprolol in Acute Myocardial Infarction) trial [lo] was investigated with long-term ECG recordings.
Methods The MIAMI trial was an international multicenter randomized placebo-controlled trial where a placebo or metoprolol was given for 15 days in 5778 patients admitted for suspected acute myocardial infarction [9]. The present population consists of 53 of the 64 patients admitted to our coronary care unit, who took part in the MIAMI trial. The inclusion criteria for the MIAMI trial were: age below 75 years, and chest pain of acute onset occurring within 24 hours and lasting for at least 15 minutes. Exclusion criteria were: current treatment with beta-blockers or calcium-antagonists, heart rate below 65 beats per minute, systolic blood pressure below 105 mm Hg, significant left ventricular failure or poor peripheral circulation and contraindications to beta-blockade such as asthma, uncontrolled diabetes mellitus, intermittent claudication. Other exclusion criteria were pacemaker treatment and resuscitation outside hospital. The 11 patients excluded from the present study were those included in the MIAMI trial in whom acute myocardial infarction was ruled out and ischemic heart disease considered unlikely. These patients were not followed-up beyond day 15. The patients were directly transferred from the emergency room to our coronary care unit. After 15 minutes of observation metoprolol or matching placebo was given as a bolus injection of 5-15 mg i.v. over 6 minutes followed by half a tablet metoprolol 100 mg or placebo 15 minutes later (Fig. 1). The inclusion day is considered to be day 0. The duration of day 0 thus varies to the individual patient from 1 minute to 24 hours. Oral therapy with 200 mg metoprolol daily or matching placebo was thereafter given in four doses for 2 days and in two doses until day 15. After the double-blind period all patients were put on open beta-blockade.
303 MetoDrolol
4
Time Drug
p.o.50
4
Aftercare
Discharge
4
4 Placebo
4
Day 01 i.v. 5-15mg
LTER
4
CCU
2
mg x 4 xxx
3
Open
*
15 --+
betablockode
1 month
3 months
6 months
100 mg x 2
Fig. 1. Design of the study. LTER = long-term premature ventricular complexes.
w X
X
electrocardiographic
X
recordings
X
for the evaluation
of
The patients were treated according to a specific manual where all possible complications and their handling were listed. Mobilization was formalized and the patients were generally discharged after a hospital stay of 7-10 days. The patients returned to the out-patient clinic on day 15. After arrival at the coronary care unit a long-term ECG recording was immediately started and lasted up to day 3. During the acute phase the ECG was registered through a Hewlett Packard Recorder System 78171A, which has a 24-hour recapitulation memory, and a Printer 9866B was used for the editing of the ECG. The edited and summarized protocol was then used in the analysis. Long-term ECG recordings were performed 2 weeks. and 1, 3 and 6 months after the acute event. During the ambulatory period the long-term ECG recordings were registered with an Oxford Medilog I taperecorder. Fiberoptic printouts of the entire 24-hour period were analyzed manually in the evaluation of ventricular arrhythmias. Premature ventricular complexes were defined as QRS complexes wider than 0.12 seconds and not preceded by a P-wave. Those patients showing multiform, paired, the R-on-T phenomenon or ventricular tachycardia (defined as 3 consecutive premature ventricular complexes with a rate above lOO/min) were considered to have complex premature ventricular complexes. The number of ventricular fibrillations during the acute stage was also registered. Patients During the study period 53 patients were entered to the study, of whom 25 were given a placebo and 28 metoprolol. The mean age was 64 years and 74% were men. New Q-waves developed in leads V,-V, in 23 patients considered to have transmural anterior infarction, and in leads II, III or aVF in 14 patients considered to have transmural inferior infarction. No Q-waves developed in 10 patients considered to have subendocardial infarction. The enzyme levels remained within normal limits in 6 patients in whom the chest pain was considered to be due to angina pectoris. No patient was on antiarrhythmic therapy. There were no differences between the two therapy groups as regards these parameters.
304
statistics The mean and median numbers of premature ventricular complexes per instance of registration were calculated for the whole population as well as for the two groups separately, as were the proportions of patients with complex premature ventricular complexes. When comparing the two groups the proportion of patients showing premature ventricular complexes above and below the median value were tested with the &i-square method and the Wilcoxon rank sum test. The frequency of ventricular arrhythmia is expressed as mean * standard deviation, median values as well as the range. Student’s t-test for unpaired samples was used for testing differences in parameters chosen to reflect infarct size and patient delay. P -c0.05 has been considered as indicative of a significant difference and the lowest level of P has been given. All patients gave their informed consent for participation in the study, which was approved by the ethical committee at Karolinska Institutet.
Results The overall results of the MIAMI trial have been reported elsewhere [lo]. In the present report only the results from our subpopulation are given. The maximum level of creatinekinase was equal in the two groups 30 + 20 pkat/l and 23 + 16 pkat/l in the placebo and metoprolol groups, respectively. The normal value in our laboratory is below 2.9 in men and 2.4 in women. Mean delay from onset of pain to initiation of therapy was 7.5 f 5.2 hours in the placebo group and 7.4 + 4.7 in the metoprolol group (n.s.). The duration of day 0 was 11.4 k 7.0 hours in the placebo group and 10.0 _t 7.0 hours in the metoprolol group (n.s.). The major findings regarding ventricular arrhythmias in the two treatment groups are shown in Table 1. On day 0 the mean number of premature ventricular complexes was 267 f 46 in the placebo group and 237 + 55 in the metoprolol group (n.s.). The median number of premature ventricular complexes was also similar in the two groups: 190 and 154, respectively. Complex premature ventricular complexes were common in both groups. During metoprolol treatment the median number of premature ventricular complexes was significantly reduced. This reduction lasted throughout the randomized period. Furthermore, the median number of premature ventricular complexes was significantly reduced 1, 3 and 6 months after the acute event despite metoprolol treatment of all patients in both groups. Ventricular fibrillation occurred once in each treatment group during days O-5 and two patients in the placebo group had one ventricular fibrillation each during days 6-15. One patient in each group died during the 15-day follow-up. During the subsequent 6-month follow-up three further patients in the placebo group and one in the metoprolol group died. Neither in our study nor in the main study was there a significant reduction in mortality during the 15 days of randomized therapy.
174 107 81 24 19 20 24
(O-l 212) (9-2615) (O-l 886) (O-2611) (O-2234) (o-6087) (O-9475) 190 146 101 84 74 257 142
(l760) (23- 950) (O-1 886) (O-2611) (O-l 595) (o-6087) (O-9475) ventricular
44 32 42 33 38 = 38 39
below median s
in the two groups.
PVCs = premature
* * * * * *
median n range
follow-up
are compared.
267k 46 222* 47 228i 79 351+ 145 252+113 694 _+455 1144*590
mean n+SD
median n range
the 6-month
Placebo PVCS
during
* P < 0.05 when the two groups
1 2 15 30 90 180
0
Day
arrhythmias
All pts PVCS
1
Ventricular
TABLE
complexes
68 76 58 67 69 69 67
complex %
237* 55 224klOO 84+ 20 115+ 82 232*135 115+ 77 257 & 161
mean n +SD
Metoprolol PVCS
154 73 59 10 7 5 11 * * * * * *
(O-l 212) (9-2615) (O- 557) (O-1 587) (O-2234) (0- 872) (O-2372)
median n range
57 62 60 68 64 67 61
%
below
68 62 62 58 58 33 53
complex %
306
Discussion There are at least three suggested mechanisms by which beta-blockers may reduce arrhythmias. A direct anti-arrhythmic action has been shown in pacemaker cells and in cells with autonomic activity [ll]. In ischemic heart disease increased automaticity has been shown to occur at least after the super-acute stage [12]. In this situation beta-blockers seem to have a beneficial effect [13]. During ischemia there is an increase in sympathetic stimulation leading to an increased excitability of myocardial cells. This effect may be counteracted by beta-blockade. The third mechanism by which beta-blockers may reduce arrhythmias is by reducing ischemia whereby conductivity in damaged areas is preserved. The reentry phenomena occurring during the super-acute phase of ischemia and acute myocardial infarction and also in the chronic ischemic stage may be influenced by this mechanism [12]. The effect on arrhythmias seen in this study may illustrate the various mechanisms of beta-blockers. The arrhythmias were not reduced on day 0 but on days 1 and 2, i.e. on average between 12 and 60 hours after the first administration of the drug. This suggests that instead of a direct antiarrhythmic action a more complex mechanism, e.g. antiadrenergic or preservation of myocardium at risk may be responsible for the reduction in arrhythmias. The complex situation is further illustrated by the observation that the arrhythmias were reduced not only during the randomized period, but also later when the patients in both groups were treated with open beta-blockade. The acute ischemia and infarct size may have been reduced by the beta-blockade as shown in previous studies, although in our small sample this was not shown [7,14]. Arrhythmias have previously been shown to correlate well with markers of infarct size [15]. Reduction in infarct size may also be accompanied by less derangement of myocardial function. Left ventricular failure after acute myocardial infarction is the strongest prognostic indicator and is also very closely related to ventricular arrhythmias [16]. An other possibility is that healing and, in some cases, the chronic ischemic situation may have been influenced, resulting in less impairment of conductivity, thereby leading to fewer arrhythmias. Atenolol has been shown to reduce ventricular arrhythmias in suspected acute myocardial infarction [17], but in the ISIS study only cardiac arrests were recorded and reduced although not significantly so [18]. Direct influence on arrhythmias by metoprolol in acute myocardial infarction has also previously been studied in the Gothenburg study [7]. In this study the incidence of ventricular fibrillation as well as atria1 fibrillation and other supraventricular arrhythmias were reduced. Another subgroup in the MIAMI trial has been studied with regard to the occurrence of ventricular arrhythmias. In that study a reduction of premature ventricular complexes was found in the early stage of convalescence [19], which is similar to our findings. However, these patients were not followed-up beyond the randomized period. Although ventricular arrhythmias have been shown to be independently correlated with poor prognosis, the reduction of arrhythmias by true antiarrhythmic drugs has not been shown to improve the outcome [4]. Although premature ventricular complexes have been reduced by the tested drug in some studies, the
307
mortality has not been influenced. An increased mortality has actually been suggested. The only studies in which an antiarrhythmic effect has been associated with an improved prognosis are the postinfarction beta-blocker trials [2,3]. This relationship has been specifically studied during metoprolol therapy [20]. The long-term implications of the initial antiarrhythmic effect have not been studied. Our findings, however, may suggest a maintained beneficial effect, as the reduction of ventricular arrhythmias occurred both during administration of the drug and after the randomized period. In the present study the occurrence of complex arrhythmias was not reduced in the placebo group following institution of metoprolol on day 15. In a previous study the spontaneously occurring increase in complex premature ventricular complexes was slowed down by metoprolol [2]. These findings are not contradictory to our previous finding that metoprolol slows down the spontaneous increase in complex arrhythmias after acute myocardial infarction [2]. In conclu.sion: Early institution of the beta-adrenoceptor blocker metoprolol in acute myocardial infarction is associated with a decreased incidence of ventricular arrhythmias not only during the initial 2-week randomised treatment but also during further follow-up. Whether this antiarrhythmic effect reflects a better prognosis is uncertain and requires further studies.
References 1 Rehnqvist N. Ventricular arrhythmias after an acute myocardial infarction. Prognostic weight and natural history. Em J Cardiol 1978:7:169-187. 2 Olsson G, Rehnqvist N. Ventricular arrhythmias during the first year after acute myocardial infarction: influence of long-term treatment with metoprolol. Circulation 1984;69:1129-1134. 3 Lichstein E. Morganroth J, Harrist R, Hubble E. Effect of propranolol on ventricular arrhythmia. The beta-blocker heart attack trial experience. Circulation 1983;67(suppl 1):5-10. 4 May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL. Secondary prevention after myocardial infarction: A review of long-term trials. Progr Cardiovasc Dis 1982;24:331-351. 5 Olsson G, Rehnqvist N, Sjogren A, Erhardt L, Lundman T. Long-term treatment with metoprolol after myocardial infarction: Effect on 3 year mortality and morbidity. J Am Coil Cardiol 1985;5:1428-1437. 6 Norris RM, Barnaby PF, Brown MA et al. Prevention of ventricular fibrillation during acute myocardial infarction by intravenous propranolol. Lancet 1984;ii:883-886. 7 The Goteborg Metoprolol Trial in Acute Myocardial Infarction. Am J Cardiol 1984;53/13:1 D-50D. 8 May GS, Furberg CD, Eberlein KA, Geraci BJ. Secondary prevention after myocardial infarction: a review of short-term acute phase trials, Progr Cardiovasc Dis 1983;25:335-359. 9 The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. Eur Heart J 1985;6:199-226. 10 Hjalmarson A, Ed. The Miami Trial Research Group. MIAMI: Metoprolol in Acute Myocardial Infarction. Am J Cardiol 1985;56:1G-576. 11 Wit AL. Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac-electrophysiologic effect of beta adrenergic receptor stimulation and blockade. Part A. Am Heart J 1975:90:521-533. 12 Wit AL, Bigger JT Jr. Treatment of arrhythmias in the acute phase of myocardial infarction. Electrophysiology of ventricular arrhythmias accompanying myocardial ischaemia and infarction. Postgrad Med J 1977;53(suppl 1):98-112.
308 13 Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac-electrophysioiogic effect of beta adrenergic receptor stimulation and blockade. Part B. Am Heart J 1975;90:665-675. 14 The International Collaborative Study Group. Acute myocardial infarction size reduction by timolol administration. Am J Cardiol 1986;57:28F-33F. 15 Rehnqvist N. Ventricular arrhythmias prior to discharge after acute myocardial infarction. Eur J Cardiol 1976;4:63-70. 16 Bigger JT Jr, Fleiss JL, IGeiger R, Miller JP, Rolnitzky LM, and the multicenter post-infarction research group. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984;69:250-258. 17 Rossi PR, Yusuf S, Ramsdale D, Furze L, Sleight P. Reduction of ventricular arrhythmias by early intravenous atenolol in suspected acute myocardial infarction. Br Med J 1983;286:506-510. 18 ISIS-1 Collaborative Group. Randomised trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction: ISIS-l. Lancet 1986;57-65. 19 Murray DP, Murray RG, Littler WA. The effects of metoprolol given early in acute myocardial infarction on ventricular arrhythmia. Eur Heart J 1986;217-222.
Journal of Cardiology,
15 (1987) 301-308
301
IJC 00537
Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event Nina Rehnqvist,
Gunnar
Department (Received
Olsson, Leif Erhardt,
Ann-Mari
of Medicine, Danderyd Hospital, Dandetyd,
9 September
1986; revision
accepted
Ekman
Sweden
16 December
1986)
Rehnqvist N, Olsson G, Erhardt L, Ekman A-M. Metoprolol in acute myocardial infarction reduces ventricular arrhythmias both in the early stage and after the acute event. Int J Cardiol 1987;15:301-308. Fifty three of the 5778 patients included in the MIAMI (Metoprolol in Acute Myocardial Infarction) trial were investigated with long-term ECG recordings in order to evaluate the effect of acute beta-blockade on premature ventricular complexes in and after acute myocardial infarction. Twenty five patients were given placebo and 28 metoprolol in a double-blind randomized fashion for 15 days. After this period the patients were put on open beta-blockade without breaking individual study codes. The mean number of premature ventricular complexes during the inclusion day (day 0) was the same in the two groups. The median numbers were also similar in the two groups: 190 and 154 in the placebo and metoprolol groups, respectively. Metoprolol significantly reduced the median number of premature ventricular complexes in the randomized period. The median numbers on days 1, 2 and 15 were 146, 101, 84 in the placebo group and 73, 59 and 10 in the metoprolol group, respectively (P c 0.05). Also during the further follow-up, when investigated 1, 3 and 6 months after the infarction, the median number of premature ventricular complexes was lower in the metoprolol group (74, 257, 142 in the placebo group and 7, 5 and 11 in the metoprolol group, P < 0.05). Thisindicates that metoprolol treatment in the acute phase of myocardial infarction reduces ventricular arrhythmias both in the early stage and also after the acute event.
Correspondence to: Nina Rehnqvist M.D., Department Danderyd, Sweden. Supported in part by the Swedish National Association Hlssle.
0167-5273/87/$03.50
0 1987 Elsevier Science Publishers
of Medicine, against
Heart
B.V. (Biomedical
Danderyd and Chest
Division)
Hospital. Diseases
S-182 88 and AH
302
Key words:
Myocardial
infarction;
Drug treatment;
Arrhythmia
Introduction The occurrence of premature ventricular complexes has been shown to increase during the year after an acute myocardial infarction [l]. The results of two studies indicate that this development is slowed down when beta-blockers are given after the infarction with the purpose of improved survival [2,3]. Concomitantly a reduction in mortality and particularly sudden deaths has been proven [4,5]. The mechanisms behind the reduced incidence of arrhythmias are unknown: both anti-ischemic effects and regular antiarrhythmic effects have been suggested. In two studies it has been shown that in the acute event beta-blockade reduces the number of ventricular fibrillations [6,7], but other studies have not confirmed these findings [8,9]. In order to evaluate the effect of acute beta-blockade on premature ventricular complexes in myocardial infarction, a subpopulation of the MIAMI (Metoprolol in Acute Myocardial Infarction) trial [lo] was investigated with long-term ECG recordings.
Methods The MIAMI trial was an international multicenter randomized placebo-controlled trial where a placebo or metoprolol was given for 15 days in 5778 patients admitted for suspected acute myocardial infarction [9]. The present population consists of 53 of the 64 patients admitted to our coronary care unit, who took part in the MIAMI trial. The inclusion criteria for the MIAMI trial were: age below 75 years, and chest pain of acute onset occurring within 24 hours and lasting for at least 15 minutes. Exclusion criteria were: current treatment with beta-blockers or calcium-antagonists, heart rate below 65 beats per minute, systolic blood pressure below 105 mm Hg, significant left ventricular failure or poor peripheral circulation and contraindications to beta-blockade such as asthma, uncontrolled diabetes mellitus, intermittent claudication. Other exclusion criteria were pacemaker treatment and resuscitation outside hospital. The 11 patients excluded from the present study were those included in the MIAMI trial in whom acute myocardial infarction was ruled out and ischemic heart disease considered unlikely. These patients were not followed-up beyond day 15. The patients were directly transferred from the emergency room to our coronary care unit. After 15 minutes of observation metoprolol or matching placebo was given as a bolus injection of 5-15 mg i.v. over 6 minutes followed by half a tablet metoprolol 100 mg or placebo 15 minutes later (Fig. 1). The inclusion day is considered to be day 0. The duration of day 0 thus varies to the individual patient from 1 minute to 24 hours. Oral therapy with 200 mg metoprolol daily or matching placebo was thereafter given in four doses for 2 days and in two doses until day 15. After the double-blind period all patients were put on open beta-blockade.
303 MetoDrolol
4
Time Drug
p.o.50
4
Aftercare
Discharge
4
4 Placebo
4
Day 01 i.v. 5-15mg
LTER
4
CCU
2
mg x 4 xxx
3
Open
*
15 --+
betablockode
1 month
3 months
6 months
100 mg x 2
Fig. 1. Design of the study. LTER = long-term premature ventricular complexes.
w X
X
electrocardiographic
X
recordings
X
for the evaluation
of
The patients were treated according to a specific manual where all possible complications and their handling were listed. Mobilization was formalized and the patients were generally discharged after a hospital stay of 7-10 days. The patients returned to the out-patient clinic on day 15. After arrival at the coronary care unit a long-term ECG recording was immediately started and lasted up to day 3. During the acute phase the ECG was registered through a Hewlett Packard Recorder System 78171A, which has a 24-hour recapitulation memory, and a Printer 9866B was used for the editing of the ECG. The edited and summarized protocol was then used in the analysis. Long-term ECG recordings were performed 2 weeks. and 1, 3 and 6 months after the acute event. During the ambulatory period the long-term ECG recordings were registered with an Oxford Medilog I taperecorder. Fiberoptic printouts of the entire 24-hour period were analyzed manually in the evaluation of ventricular arrhythmias. Premature ventricular complexes were defined as QRS complexes wider than 0.12 seconds and not preceded by a P-wave. Those patients showing multiform, paired, the R-on-T phenomenon or ventricular tachycardia (defined as 3 consecutive premature ventricular complexes with a rate above lOO/min) were considered to have complex premature ventricular complexes. The number of ventricular fibrillations during the acute stage was also registered. Patients During the study period 53 patients were entered to the study, of whom 25 were given a placebo and 28 metoprolol. The mean age was 64 years and 74% were men. New Q-waves developed in leads V,-V, in 23 patients considered to have transmural anterior infarction, and in leads II, III or aVF in 14 patients considered to have transmural inferior infarction. No Q-waves developed in 10 patients considered to have subendocardial infarction. The enzyme levels remained within normal limits in 6 patients in whom the chest pain was considered to be due to angina pectoris. No patient was on antiarrhythmic therapy. There were no differences between the two therapy groups as regards these parameters.
304
statistics The mean and median numbers of premature ventricular complexes per instance of registration were calculated for the whole population as well as for the two groups separately, as were the proportions of patients with complex premature ventricular complexes. When comparing the two groups the proportion of patients showing premature ventricular complexes above and below the median value were tested with the &i-square method and the Wilcoxon rank sum test. The frequency of ventricular arrhythmia is expressed as mean * standard deviation, median values as well as the range. Student’s t-test for unpaired samples was used for testing differences in parameters chosen to reflect infarct size and patient delay. P -c0.05 has been considered as indicative of a significant difference and the lowest level of P has been given. All patients gave their informed consent for participation in the study, which was approved by the ethical committee at Karolinska Institutet.
Results The overall results of the MIAMI trial have been reported elsewhere [lo]. In the present report only the results from our subpopulation are given. The maximum level of creatinekinase was equal in the two groups 30 + 20 pkat/l and 23 + 16 pkat/l in the placebo and metoprolol groups, respectively. The normal value in our laboratory is below 2.9 in men and 2.4 in women. Mean delay from onset of pain to initiation of therapy was 7.5 f 5.2 hours in the placebo group and 7.4 + 4.7 in the metoprolol group (n.s.). The duration of day 0 was 11.4 k 7.0 hours in the placebo group and 10.0 _t 7.0 hours in the metoprolol group (n.s.). The major findings regarding ventricular arrhythmias in the two treatment groups are shown in Table 1. On day 0 the mean number of premature ventricular complexes was 267 f 46 in the placebo group and 237 + 55 in the metoprolol group (n.s.). The median number of premature ventricular complexes was also similar in the two groups: 190 and 154, respectively. Complex premature ventricular complexes were common in both groups. During metoprolol treatment the median number of premature ventricular complexes was significantly reduced. This reduction lasted throughout the randomized period. Furthermore, the median number of premature ventricular complexes was significantly reduced 1, 3 and 6 months after the acute event despite metoprolol treatment of all patients in both groups. Ventricular fibrillation occurred once in each treatment group during days O-5 and two patients in the placebo group had one ventricular fibrillation each during days 6-15. One patient in each group died during the 15-day follow-up. During the subsequent 6-month follow-up three further patients in the placebo group and one in the metoprolol group died. Neither in our study nor in the main study was there a significant reduction in mortality during the 15 days of randomized therapy.
174 107 81 24 19 20 24
(O-l 212) (9-2615) (O-l 886) (O-2611) (O-2234) (o-6087) (O-9475) 190 146 101 84 74 257 142
(l760) (23- 950) (O-1 886) (O-2611) (O-l 595) (o-6087) (O-9475) ventricular
44 32 42 33 38 = 38 39
below median s
in the two groups.
PVCs = premature
* * * * * *
median n range
follow-up
are compared.
267k 46 222* 47 228i 79 351+ 145 252+113 694 _+455 1144*590
mean n+SD
median n range
the 6-month
Placebo PVCS
during
* P < 0.05 when the two groups
1 2 15 30 90 180
0
Day
arrhythmias
All pts PVCS
1
Ventricular
TABLE
complexes
68 76 58 67 69 69 67
complex %
237* 55 224klOO 84+ 20 115+ 82 232*135 115+ 77 257 & 161
mean n +SD
Metoprolol PVCS
154 73 59 10 7 5 11 * * * * * *
(O-l 212) (9-2615) (O- 557) (O-1 587) (O-2234) (0- 872) (O-2372)
median n range
57 62 60 68 64 67 61
%
below
68 62 62 58 58 33 53
complex %
306
Discussion There are at least three suggested mechanisms by which beta-blockers may reduce arrhythmias. A direct anti-arrhythmic action has been shown in pacemaker cells and in cells with autonomic activity [ll]. In ischemic heart disease increased automaticity has been shown to occur at least after the super-acute stage [12]. In this situation beta-blockers seem to have a beneficial effect [13]. During ischemia there is an increase in sympathetic stimulation leading to an increased excitability of myocardial cells. This effect may be counteracted by beta-blockade. The third mechanism by which beta-blockers may reduce arrhythmias is by reducing ischemia whereby conductivity in damaged areas is preserved. The reentry phenomena occurring during the super-acute phase of ischemia and acute myocardial infarction and also in the chronic ischemic stage may be influenced by this mechanism [12]. The effect on arrhythmias seen in this study may illustrate the various mechanisms of beta-blockers. The arrhythmias were not reduced on day 0 but on days 1 and 2, i.e. on average between 12 and 60 hours after the first administration of the drug. This suggests that instead of a direct antiarrhythmic action a more complex mechanism, e.g. antiadrenergic or preservation of myocardium at risk may be responsible for the reduction in arrhythmias. The complex situation is further illustrated by the observation that the arrhythmias were reduced not only during the randomized period, but also later when the patients in both groups were treated with open beta-blockade. The acute ischemia and infarct size may have been reduced by the beta-blockade as shown in previous studies, although in our small sample this was not shown [7,14]. Arrhythmias have previously been shown to correlate well with markers of infarct size [15]. Reduction in infarct size may also be accompanied by less derangement of myocardial function. Left ventricular failure after acute myocardial infarction is the strongest prognostic indicator and is also very closely related to ventricular arrhythmias [16]. An other possibility is that healing and, in some cases, the chronic ischemic situation may have been influenced, resulting in less impairment of conductivity, thereby leading to fewer arrhythmias. Atenolol has been shown to reduce ventricular arrhythmias in suspected acute myocardial infarction [17], but in the ISIS study only cardiac arrests were recorded and reduced although not significantly so [18]. Direct influence on arrhythmias by metoprolol in acute myocardial infarction has also previously been studied in the Gothenburg study [7]. In this study the incidence of ventricular fibrillation as well as atria1 fibrillation and other supraventricular arrhythmias were reduced. Another subgroup in the MIAMI trial has been studied with regard to the occurrence of ventricular arrhythmias. In that study a reduction of premature ventricular complexes was found in the early stage of convalescence [19], which is similar to our findings. However, these patients were not followed-up beyond the randomized period. Although ventricular arrhythmias have been shown to be independently correlated with poor prognosis, the reduction of arrhythmias by true antiarrhythmic drugs has not been shown to improve the outcome [4]. Although premature ventricular complexes have been reduced by the tested drug in some studies, the
307
mortality has not been influenced. An increased mortality has actually been suggested. The only studies in which an antiarrhythmic effect has been associated with an improved prognosis are the postinfarction beta-blocker trials [2,3]. This relationship has been specifically studied during metoprolol therapy [20]. The long-term implications of the initial antiarrhythmic effect have not been studied. Our findings, however, may suggest a maintained beneficial effect, as the reduction of ventricular arrhythmias occurred both during administration of the drug and after the randomized period. In the present study the occurrence of complex arrhythmias was not reduced in the placebo group following institution of metoprolol on day 15. In a previous study the spontaneously occurring increase in complex premature ventricular complexes was slowed down by metoprolol [2]. These findings are not contradictory to our previous finding that metoprolol slows down the spontaneous increase in complex arrhythmias after acute myocardial infarction [2]. In conclu.sion: Early institution of the beta-adrenoceptor blocker metoprolol in acute myocardial infarction is associated with a decreased incidence of ventricular arrhythmias not only during the initial 2-week randomised treatment but also during further follow-up. Whether this antiarrhythmic effect reflects a better prognosis is uncertain and requires further studies.
References 1 Rehnqvist N. Ventricular arrhythmias after an acute myocardial infarction. Prognostic weight and natural history. Em J Cardiol 1978:7:169-187. 2 Olsson G, Rehnqvist N. Ventricular arrhythmias during the first year after acute myocardial infarction: influence of long-term treatment with metoprolol. Circulation 1984;69:1129-1134. 3 Lichstein E. Morganroth J, Harrist R, Hubble E. Effect of propranolol on ventricular arrhythmia. The beta-blocker heart attack trial experience. Circulation 1983;67(suppl 1):5-10. 4 May GS, Eberlein KA, Furberg CD, Passamani ER, DeMets DL. Secondary prevention after myocardial infarction: A review of long-term trials. Progr Cardiovasc Dis 1982;24:331-351. 5 Olsson G, Rehnqvist N, Sjogren A, Erhardt L, Lundman T. Long-term treatment with metoprolol after myocardial infarction: Effect on 3 year mortality and morbidity. J Am Coil Cardiol 1985;5:1428-1437. 6 Norris RM, Barnaby PF, Brown MA et al. Prevention of ventricular fibrillation during acute myocardial infarction by intravenous propranolol. Lancet 1984;ii:883-886. 7 The Goteborg Metoprolol Trial in Acute Myocardial Infarction. Am J Cardiol 1984;53/13:1 D-50D. 8 May GS, Furberg CD, Eberlein KA, Geraci BJ. Secondary prevention after myocardial infarction: a review of short-term acute phase trials, Progr Cardiovasc Dis 1983;25:335-359. 9 The MIAMI Trial Research Group. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. Eur Heart J 1985;6:199-226. 10 Hjalmarson A, Ed. The Miami Trial Research Group. MIAMI: Metoprolol in Acute Myocardial Infarction. Am J Cardiol 1985;56:1G-576. 11 Wit AL. Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac-electrophysiologic effect of beta adrenergic receptor stimulation and blockade. Part A. Am Heart J 1975:90:521-533. 12 Wit AL, Bigger JT Jr. Treatment of arrhythmias in the acute phase of myocardial infarction. Electrophysiology of ventricular arrhythmias accompanying myocardial ischaemia and infarction. Postgrad Med J 1977;53(suppl 1):98-112.
308 13 Wit AL, Hoffman BF, Rosen MR. Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac-electrophysioiogic effect of beta adrenergic receptor stimulation and blockade. Part B. Am Heart J 1975;90:665-675. 14 The International Collaborative Study Group. Acute myocardial infarction size reduction by timolol administration. Am J Cardiol 1986;57:28F-33F. 15 Rehnqvist N. Ventricular arrhythmias prior to discharge after acute myocardial infarction. Eur J Cardiol 1976;4:63-70. 16 Bigger JT Jr, Fleiss JL, IGeiger R, Miller JP, Rolnitzky LM, and the multicenter post-infarction research group. The relationships among ventricular arrhythmias, left ventricular dysfunction, and mortality in the 2 years after myocardial infarction. Circulation 1984;69:250-258. 17 Rossi PR, Yusuf S, Ramsdale D, Furze L, Sleight P. Reduction of ventricular arrhythmias by early intravenous atenolol in suspected acute myocardial infarction. Br Med J 1983;286:506-510. 18 ISIS-1 Collaborative Group. Randomised trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction: ISIS-l. Lancet 1986;57-65. 19 Murray DP, Murray RG, Littler WA. The effects of metoprolol given early in acute myocardial infarction on ventricular arrhythmia. Eur Heart J 1986;217-222.