Effects of captopril on ventricular arrhythmias in the early and late phase of suspected acute myocardial infarction. Randomized, placebo-controlled substudy of ISIS-4.

Abstract

The antiarrhythmic effect of oral captopril was studied during the early (day 3) and late (day 14) phase of acute myocardial infarction among 304 patients in a randomized placebo-controlled substudy of ISIS-4. Ventricular arrhythmias (ventricular ectopic beats per hour) occurred significantly less frequently among captopril-allocated patients than among those allocated placebo at day 3 (logarithmic scale: 0.48 +/- 0.8 captopril vs 0.84 +/- 1.3 placebo; P < 0.003) and at day 14 (0.51 +/- 1.0 vs 0.77 +/- 1.3; P < 0.05). The number of patients with frequent ventricular arrhythmias (more than 10 ventricular ectopic beats per hour) was also significantly lower among those allocated captopril at day 3 (7.3% vs 14.4%; P < 0.05) and at day 14 (7.3% vs 14.8%; P < 0.05). These results support the hypothesis that the activation of the renin-angiotensin-aldosterone and sympathetic system may underlie heart rhythm disturbances in acute myocardial infarction, and that early use of converting enzyme inhibitor therapy may ameliorate these disturbances.

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European Heart Journal (1996) 17, 1506-1510
Effects of captopril on ventricular arrhythmias in the
early and late phase of suspected acute myocardial
infarction
Randomized, placebo-controlled substudy of ISIS-4
A. Budaj, J. Cybulski, K. Cedro, S. Karczmarewicz, J. Maciejewicz*,
M. Wisniewski* and L. Ceremuzyriski
Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland, "Dietla Hospital, Cracow, Poland
The antiarrhythmic effect of oral captopril was studied
during the early (day 3) and late (day 14) phase of acute
myocardial infarction among 304 patients in a randomized
placebo-controlled substudy of ISIS^t.
Ventricular arrhythmias (ventricular ectopic beats per
hour) occurred significantly less frequently among
captopril-allocated patients than among those allocated
placebo at day 3 (logarithmic scale: 0-48 ± 0-8 captopril vs
0-84 ± 1-3 placebo; F<0O03) and at day 14 (0 51 ± 10 vs
0-77 ± 1-3; /><005). The number of patients with frequent
ventricular arrhythmias (more than 10 ventricular ectopic
beats per hour) was also significantly lower among those
allocated captopril at day 3 (7-3% vs 14-4%; /><0-05) and at
day 14 (7-3% vs 14-8%; /><005).
These results support the hypothesis that the activation of
the renin-angiotensin-aldosterone and sympathetic system
may underlie heart rhythm disturbances in acute myocar-
dial infarction, and that early use of converting enzyme
inhibitor therapy may ameliorate these disturbances.
(Eur Heart J 1996; 17: 1506-1510)
Key Words: Myocardial infarction, ventricular arrhyth-
mias, ACE inhibitors, captopril, antiarrhythmic effect.
Introduction
The renin-angiotensin-aldosterone system is activated
in the acute phase of myocardial infarction and this
is associated with various complications including
ventricular arrhythmias1'1. It seems likely that this
relationship is causal since activation of the renin-
angiotensin-aldosterone system increases systemic and
coronary vascular resistance, which results in a rise in
myocardial wall stress and a fall in coronary blood flow,
augments urinary excretion of potassium and mag-
nesium, and exerts a direct toxic effect on myocardial
cells'2'31. These effects adversely modify the electrophysio-
Revision submitted 19 January 1996, and accepted 15 February
1996.
The study supported by the grant CMKP-S-30/94 from Post-
graduate Medical School, Warsaw, Poland.
The results were presented at the XVII Congress of the European
Society of Cardiology, 20-24 August 1995 Amsterdam.
Correspondence Andrzej Budaj, MD, Department of Cardiology,
Postgraduate Medical School, Grochowski Hospital, Grenadier6w
51/59, 04/073 Warsaw, Poland.
logical properties of the heart leading to an increased
propensity to arrhythmias'451. Angiotensin converting
enzyme (ACE) inhibitor therapy has been reported to
produce antiarrhythmic effects in patients with congestive
heart failure16'71, while in 11 patients with frequent
ventricular ectopic beats and preserved left ventricular
systolic function captopril was not shown to suppress
ventricular ectopic activity181.
Several small studies of the effects on ventricular
arrhythmias of ACE inhibitor therapy during and after
acute myocardial infarction have been published. In
1992, our group reported that captopril suppressed
ventricular ectopic beats in the third week after myocar-
dial infarction'91. In 1993, Pipilis et al.ll0] observed a
non-significant reduction in the frequencies of idio-
ventricular rhythm and in the number of ventricular
ectopic beats per hour during the first 48 h after the start
of treatment in acute myocardial infarction among 32
patients allocated captopril compared with those allo-
cated placebo. More recently Di Pasquale et a/.'"1
reported that captopril given before thrombolysis
reduced the incidence of reperfusion arrhythmias, as
well as of predischarge ventricular arrhythmias, as
0195-668X/96/101506+05 $18.00/0
1996 The European Society of Cardiology
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Effect of captopril in AMI 1507
compared with those allocated captopril from the 3rd
day of myocardial infarction. Similarly, in CATS'121 the
incidence of reperfusion arrhythmias was significantly
reduced by giving captopril with thrombolytic therapy
during the acute phase of myocardial infarction.
Soogard et a/.1'31 did not observe an antiarrhythmic
effect as a result of captopril administration on day 30
after myocardial infarction but in that study the drug
was started on the 7th day after the onset of myocardial
infarction. However, captopril induced a significant
antiarrhythmic effect by 6 months, with a correlation
between left ventricular dysfunction and arrhythmias.
It may be that any antiarrhythmic effects as a
result of ACE inhibitor therapy are greatest when treat-
ment is started early in acute myocardial infarction. To
assess more reliably the effects on arrhythmias of the
early use of ACE inhibitor therapy we prospectively
planned a much larger Holter arrhythmia study than
had previously been conducted among a subset of
patients entering ISIS-4'14'.
Methods
Study group and treatment
ISIS-4 is described in detail elsewhere'14'. Patients were
eligible if symptoms of suspected acute myocardial in-
farction had started within 24 h and there were no clear
indications for, or contraindications to, oral ACE in-
hibitors, oral nitrates and intravenous magnesium, each
of which was tested in ISIS^t. Randomization was
performed by a central 24 h telephone randomization
service. A 2 x 2 x 2 factorial study design was used, with
half the patients randomly allocated to receive oral
captopril (initial dose 625 mg, followed 2 h later by
12-5 mg, 12 h later by 25 mg, and then 50 mg twice
daily) or matching placebo for 28 days. Apart from the
trial medications, routine treatment was administered at
the discretion of attending physicians.
Patients admitted to coronary care units at
Grochowski Hospital in Warsaw and Dietla Hospital in
Cracow between July 1991 and August 1993 with sus-
pected acute myocardial infarction were considered for
the arrhythmia substudy. This substudy was approved
by the institutional ethical committees of both hospitals.
Recording and analysis of arrhythmias in the
Holter substudy
Twenty-four hour Holter ambulatory monitoring was
performed on day 3 ± 1 and day 14 ± 2 after admission
to the CCU. Both recordings were available for reliable
analysis from 304 of 469 randomized patients (the
limited availability of Holter recorders prevented some
patients from undergoing the monitoring). Arrhythmias
were traced onto both MTM Multitechmed two chan-
nel recorders (Grochowski Hospital) and Oxford
Medilog II single channel recorders (Dietla Hospital).
Replay-under-visual-control analysis was conducted by
physicians unaware of the patients' allocated treatment
regimen.
The number of ventricular ectopic beats per hour
of recording time, ventricular tachycardia (defined as a
sequence of three or more ventricular ectopic beats at
a heart rate >110/min) were recorded as were the
presence of complex ventricular arrhythmias (multifocal
ventricular ectopic beats, pairs and/or ventricular
tachycardia).
Statistical analysis
Data are presented as means with standard deviations
(SD) or percentages. Ventricular ectopic beats/hour are
not normally distributed in patients with acute myo-
cardial infarction, and so the values obtained were
logarithmically transformed for statistical comparisons.
Statistical analysis was performed using the SPSS/PC+
program. Variance analysis and Student unpaired t-test
were used to compare the frequency of arrhythmias in
the treatment groups. The incidence of ventricular
arrhythmias as a categorical variable was also compared
by the chi-square test. A P value <005 was considered
significant.
Results
Patient characteristics
Baseline
(Table 1) were well-balanced between the treatment
groups. Patients were randomized at an average of 11 h
from the onset of symptoms of suspected acute myo-
cardial infarction. ST segment elevation of the initial
ECG was present in 73% of the patients (33% in anterior
leads, 38% in inferior leads alone and 2% in both or
other leads). Slightly more of the patients allocated
captopril had evidence of inferior infarction but this
excess was not statistically significant.
Following randomization, infarction was con-
firmed in 92% of the randomized patients. There were no
significant differences in non-trial medications between
the groups, except that antiarrhythmic drugs were used
more often in the placebo group (16% captopril vs 30%
placebo). None of these patients received any non-trial
ACE inhibitor in hospital.
pre-randomization patient characteristics
Ventricular arrhythmias
The overall prevalence of ventricular arrhythmias is
shown in Table 2. More than 10 ventricular ectopic
beats/hour were observed in about 10-11% of patients,
ventricular tachycardia in about 2-3% and complex
ventricular arrhythmia in about 10-12%, with little
difference between the prevalence at day 3 and that at
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1508 A. Budaj et al.
Table 1 Clinical characteristics of patients (mean ± SD or number and percentage)
No of patients with Holter monitoring
Pre-randomization data
Male n
Age (years)
Systolic BP (mmHg)
Heart rate (beats . min ~ ')
Symptoms of CHF
Time from pain onset (h)
Electrocardiogram
ST elevation, anterior
ST elevation: inferior
ST elevation: other
No ST elevation
Post-randomization data
Infarction confirmed
Other trial treatment in hospital
Nitrates p.o.
Magnesium sulphate
Non-trial treatment in hospital
Fibrinolytic
Aspirin
Nitrates i.v.
Beta-blockers
Antiarrhythmics
Captopnl
151
112(74%)
58-3 ± 100
125 ± 18
80 ± 13
20(13%)
10-3 ±4-9
50(33%)
61(40%)
2(1%)
37(25%)
142(94%)
76(50%)
76(50%)
54(36%)
149(99%)
118(78%)
29(19%)
25(16%)
Placebo
153
116(76%)
591 ±10-6
121 ± 18
84±17
16(10%)
11-5 ± 6-2
49(32%)
55(36%)
4(3%)
44(29%)
138(90%)
77(50%)
78(51%)
68(44%)
145(95%)
109(72%)
37(24%)
46(30%)
Statistical
significance
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
/><0-025
CHF = congestive heart failure.
Table 2 Prevalence of ventricular arrhythmias
Day 3
Day 14
0
133(43-2%)
138(45-8%)
VEBs/hour
0-1-10
138(46-3%)
128(43-2%)
>10
28(10-5%)
33(10-7%)
VT
9(2-9%)
7(2-3%)
Complex VA
38(12-3%)
31(10-3%)
VEBs = ventricular ectopic beats; VT=ventricular tachycardia; VA = ventricular arrhythmia.
Table 3 Ventricular ectopic beats . h ~~' in each treatment group
No of patients
Day 3
Day 14
Logarithmic
(and corresponding
Captopnl
151
0-48 ±0-8
(1-8 ±5-4)
0 51 ±10
(3-2 ±2-2)
mean ± SD
linear mean ± SD)
Placebo
153
0-84 ± 1-3
(8-1 ±30-8)
0-77 ± 1-3
(9-2 ± 49-7)
Statistical
significance
/><0003
/><005
day 14. The mean number of ventricular ectopic
beats. h~' was significantly lower among those allo-
cated captopnl, both at day 3 and at day 14 (Table 3,
Fig. 1).
The number of patients with frequent ventricular
arrhythmias (defined as ventricular ectopic beats/hour
>10) was also significantly lower at day 3 and at
day 14 in the captopril group (Table 4, Fig. 2). No
Eur Heart J, Vol. 17, October 1996
significant differences in the incidence of ventricular
tachycardia or of complex ventricular arrhythmias were
demonstrated.
Discussion
The present study demonstrates that captopril starting
from the first day of suspected myocardial infarction
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Effect of captopril in AMI 1509
Table 4 Incidence of ventricular arrhythmias in each
treatment group
VEB.h~'>10
Day 3
Day 14
Complex VAs
Day 3
Day 14
VT
Day 3
Day 14
Number of patients
(and percentage)
Captopril
11(7-3%)
11(7-3%)
15(9-8%)
16(10-7%)
3(2-0%)
3(2-0%)
Placebo
22(14-4%)
22(14-8%)
23(14-8%)
15(10-0%)
6(3-9%)
4(2-7%)
Statistical
significance
/><005
P<00S
ns
ns
ns
ns
Xt
m
rvi
•s
m
-13
C
-.n
03
O
bo
3
tis
See Table 2 for explanation of abbreviations.
03
i <0.003
r- P<0.05-|
0.84
§&
0.51
0.77
n = 151 n = 153
Dav3
n=151 n = 153
Dav 14
Figure 1 Frequency of ventricular ectopic beats per hour
(VEB.h"1 mean±SD) on a logarithmic scale in the
captopril Q and placebo-allocated D groups as recorded on
day 3 and day 14.
produces antiarrhythmic effects in both early and late
phases of acute myocardial infarction. These results
confirm the observation in our earlier small study191 and
are consistent with the trends in other studies1'0"12'.
Although one small study did not observe an anti-
arrhythmic effect of captopril on day 30 after myocar-
dial infarction, treatment started 7 days after myocardial
infarction in that study (and a significant reduction in
ventricular arrhythmias was observed at 6 months). In
GISSI-2[I5) it was reported that >10 ventricular ectopic
beats/hour was one of the strongest prognostic predic-
tors in patients recovering from myocardial infarction
following treatment with fibrinolytic agents. We found
that captopril treatment led to a significant decrease in
the number of patients with frequent ventricular ectopic
beats. >10.h~'.
What mechanisms may be involved in the
antiarrhythmic properties of ACE inhibitors? Ex-
perimental electrophysiological evidence of direct
antiarrhythmic action by
controversial'18"201, and it is likely that the metabolic
ACE inhibitors is
10
rp<0.05-,
14.8
7.3
7.3
n = 11 n = 22
Dav .3
n = l l n = 22
Dav 14
Figure 2 Percentage of patients with frequent ventricular
ectopic beats (VEB.h-•> 10) in the captopril Q and
placebo-allocated • groups as recorded on day 3 and
day 14.
action of these compounds constitutes the main mech-
anism of benefit. (Similarly, metabolic properties of
/J-blockers'21>22' and amiodarone123'241 seem to be respon-
sible for beneficial effects in secondary prevention after
myocardial infarction, and is related to the electrical
stabilization exerted by these drugs'251).
ACE inhibitor therapy reduces angiotensin II
production, and this results in decreased peripheral
resistance, as well as a reduction in the load imposed on
the heart, along with alleviation of sympathetic nervous
strain'16'171. ACE inhibitors also reduce the generation
of aldosterone with subsequently diminished loss of
magnesium and potassium and better preservation
of electrolyte balance. Blockade of the toxic effects of
angiotensin II on the myocardial cells may also be
important.
In our study, antiarrhythmic drugs were more
frequently used in the placebo group (30%) than in the
captopril group (16%). The question arises as to whether
this may have influenced the results. For example if
these antiarrhythmic drugs produced proarrhythmic
effects, increasing the number of ventricular ectopic
beats, then this could bias the treatment comparisons.
This seems unlikely, however, as all major trials with
antiarrhythmics after myocardial infarction, including
CAST12 '271, resulted in reductions in ventricular ectopic
beats despite an increased mortality.
In conclusion, starting captopril early in acute
myocardial infarction has an antiarrhythmic effect dur-
ing the early (day 3) and late (day 14) phases of acute
myocardial infarction. These antiarrhythmic properties
have particular clinical relevance since in the post-CAST
era we are fully aware of the proarrhythmic effects of
classical antiarrhythmic drugs. ACE inhibitor therapy is
devoid of the above adverse effects while still being able
to stabilize cardiac rhythm. This antiarrhythmic effect of
ACE inhibitor therapy may play a role, along with
attenuation of remodelling, in reducing mortality when
ACE inhibitors are used early in acute myocardial
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1510 A. Budaj et al.
infarction (as in ISIS-4[14] and in GISSI-3[28]) as well as
long-term following myocardial infarction'29'301.
The authors thank Dr Rory Collins and Dr Marcus Flather for
valuable comments and revision of the manuscript.
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