International Journal of Cardiology, 33 (1991) 413-418 0 1991 Elsevier Science Publishers B.V. All rights reserved

CARD10

413 0167-5273/91/$03.50

01360

Increased occurrence of exercise-induced silent ischemia after treatment with aspirin in patients admitted for suspected acute myocardial infarction Per K. Rmnevik

‘, Magne Foiling 2, Dag Pedersen and Gerhard von der Lippe ’

‘, Svein A. Rodt ’

’ Cardiac Section, Department of Medicine; ’ Department of Clinical Physiology, University Clinic Haukeland Hospital. Bergen, Norway (Received

6 February

1991; revision

accepted

17 June 1991)

Rsnnevik PK, Foiling M, Pedersen D, Rodt SA, Von der Lippe G. Increased occurrence of exercise-induced silent &hernia after treatment with aspirin in patients admitted for suspected acute myocardial infarction. Int J Cardiol 1991;33:413-418. Patients admitted for suspected acute myocardial infarction within 6 hours (mean 3 hours 42 minutes) after onset of symptoms were randomised to double-blind treatment with low-dose oral aspirin or placebo. Early exercise ischemic responses, exercise capacity and resting IeR ventricular ejection fraction (radionuclide ventriculography) were estimated in 77 survivors 2-4 weeks later. Exercise performance and ejection fraction in patients with confirmed acute myocardial infarction were equal in the two groups. During exercise, patients treated with aspirin had significantly more silent ischemia (ST depression without chest pain) compared to placebo (28% versus 6%; P = 0.015). The occurrence of positive exercise tests (chest pain or ST-segment depression), however, was similar in the two groups. The results indicate that the administration of aspirin early after acute myocardial infarction increases the occurrence of silent ischemia but has no effect on left ventricular function. Key words: Acute myocardial ischemia

infarction;

Aspirin; Exercise capacity; Left ventricular

Introduction Platelet inhibitors nonfatal reinfarctions

Correspondence Dept. of Medicine, way.

reduce vascular mortality, and nonfatal stroke after

to: P.K. Ronnevik MD, Cardiac Section, Haukeland Hospital, N-5021 Bergen, Nor-

function;

Silent

acute myocardial infarction [l]. Low-dose aspirin administered early after the onset of suspected acute myocardial infarction produced a 23% odds reduction of 5-week vascular mortality independent of concomitant fibrinolytic therapy [2]. The mechanisms by which improvement of survival after acute myocardial infarction by low-dose aspirin is achieved is unknown, as no effect of aspirin on left ventricular ejection fraction or

414

extent of infarction has been reported [3-51. Long-term prognosis after acute myocardial infarction is related to resting global left ventricular ejection fraction [6,7], degree of coronary arteriosclerosis [8], exercise capacity [9] and ischemic responses at early exercise testing [lO,ll]. In patients receiving aspirin after acute myocardial infarction, maintenance of the patency of coronary vessels has been postulated to contribute to improving prognosis [12]. The purpose of this study was to investigate the effect of early intervention with low-dose aspirin on exercise-induced ischemic responses and exercise capacity in patients with suspected acute myocardial infarction. Materials

and Methods

Study population The study population was drawn from 85 patients admitted to the coronary care unit for suspected acute myocardial infarction less than 6 hours after onset of chest pain and without contraindications for treatment with aspirin or streptokinase. After giving informed consent, they were randomly assigned to treatment with 162.5 mg oral aspirin a day or matching placebo, and half of the patients in each treatment group received intravenous streptokinase. The study was designed prospectively as a part of the Second International Study of Infarct Survival (ISIS-2), and was approved by the Hospital Ethics Committee

PI. Definitions Acute myocardial infarction was diagnosed by increased cardiac enzymes [two values above the normal range of creatine kinase (normal below 150 U/l for women, 200 U/l for men)] and acute electrocardiographic changes (appearance of new significant Q waves in the electrocardiogram, or loss of R waves, or ST-segment elevation of 2 1.0 mm in leads I, II, III, aVL, aVF, V,, V, or 2 2.0 mm in leads V,_, followed by T wave inversion). Delay is the time from onset of chest pain to administration of trial medication.

Exercise testing Following informed consent, a symptomlimited exercise test was performed 13-15 days after inclusion. Patients with unstable angina, decompensated heart failure, late ventricular tachyarrhythmias, reinfarctions or other diseases precluding them to exercise, were excluded (7 patients; 2 aspirin treated, 5 patients allocated placebo). The exercise test was performed on an electrically-braked bicycle ergometer with stepwise increase of load until fatigue, significant chest pain or dyspnea, claudication, fall in systolic blood pressure of more than 10% below the peak blood pressure during the protocol period, ventricular tachycardia or high-degree atrioventricular block. A 12-lead electrocardiogram was recorded before and after the test, a 6-lead chest-head electrocardiogram and systolic blood pressure were recorded every second minute, and the electrocardiogram monitored continuously on displays. A flat or downsloping ST-segment depression of 1 mV or more measured 0.08 second after the J point was considered significant. A positive test was defined as a test limited by chest pain or a test with significant ST-segment depression. Significant ST-segment depression without chest pain was considered as silent ischemia. Radionuclide ventriculography Four weeks after inclusion, left ventricular ejection fraction at rest was assessed by equilibrium radionuclide technique after in vivo labelling of red blood cells. Eight patients did not perform this test; 3 had been treated with aspirin and 5 had been allocated placebo. Acquisition in 3 projections was done with a Siemens LFOV gamma camera connected to a Scintiview computer. The view best separating the right and the left ventricle was chosen for ejection fraction calculation, usually 30-45 degree left anterior oblique projection. Statistics Statistical comparisons were made using Student’s t-test and Wilcoxon’s rank sum test for

41.5

unpaired data. Multiple linear regression techniques were applied to examine the correlation between peak enzyme values, workload or left ventricular ejection fraction. The MSUSTAT software package [13] was used. All results are given as means + SD. All tests were two-sided, and P values lower than 0.05 were considered significant. Results

responses

A positive exercise test was observed in 18 patients treated with aspirin and in 12 patients receiving placebo (difference not significant) (Table 2). No difference in the occurrence of exercise-limiting chest pain was detected. Aspirin-

TABLE

1

Characteristics

Ischemic

2 responses

at exercise

testing. Placebo N=34

Chest pain Silent ischemia Positive exercise test Peak heart rate (beats/mini Workload (watts x time) ST-depression

Eight of the randomised patients died inhospital; 5 in the aspirin-treated group, 3 in the placebo group. These patients are not included in the statistical analyses. The study group comprised 77 survivors, described in Table 1. The groups were comparable except that those treated with aspirin had larger infarcts than those given placebo, with peak creatine kinase 2120 U/l compared to 1418 U/l (P < 0.05). Ischemic

TABLE

Aspirin N=36

10 8 2 10 12 18 118& 24 114+ 23 719k522 424&347 8 15

( + chest pain)

P

> 0.05 0.015 > 0.05 > 0.05 > 0.05 > 0.05

treated patients had significantly more silent ischemia compared to the group given placebo (28% compared to 6%; P = 0.015). In patients with a positive exercise test, 8 (45%) patients treated with aspirin had the test limited by chest pain compared to 10 (83%) patients receiving placebo (P = 0.03). No difference regarding peak heart rate or workload at which the exercise tests became positive was observed. Exercise capacity

Maximum work capacity expressed as load x time (watts X minutes) was the same in the two groups when analysing all included patients, patients with confirmed myocardial infarction or a first myocardial infarction, and in patients who had initiated therapy with beta-blockers as secondary prophylaxis (Table 3).

of patients.

Male gender Previous myocardial infarction Age (mean years f SD) Delay (mean mink SD) Confirmed myocardial infarction Max. CK (mean U/l i SD) Anterior location Inferior location Uncertain location Beta-blocker treatment * P < 0.05. SD = standard

Placebo (N=39)

Aspirin (N = 38)

29

30

9 61 f 8.7 222 + 80 28 1418 1113 20 8 _ 23 deviation;

Maximum

10 64+ 6.3 223 + 88 29 2120* 1257 16 9 4 21

CK = creatine

TABLE

kinase.

3 work capacity

(mean

(N 1

+ SD).

Aspirin(N)

P

702 + 525 (341

502 k 346 (36)

0.15

534 f 486 (25)

513 f 335 (28)

0.64

497 f 498 (201

586 z!z338 (22)

0.14

665 +485 (221

560 k 339 (21)

0.60

Placebo All exercised Confirmed acute myocardial infarction (including previous MI) Acute first myocardial infarction Beta-blocker treatment

watts x minutes

416 TABLE 4 Resting left ventricular ejection fraction (mean % k SD).

All examined Confirmed acute myocardial infarction Acute first myocardial infarction Beta-blocker treatment

Placebo (NJ

Aspirin (N)

P

49+12(34)

46k 13 (35)

0.2

45 + 12 (24)

44 + 12 (26)

0.67

45 f 12 (20)

46 + 12 (22)

0.82

49+ 12 (21)

49* 14 (19)

0.89

Left ventricular ejection fraction Global left ventricular ejection fraction at rest was found to be similar in both groups (Table 4). Patients treated with aspirin within 4 hours (N = 35) were found to have the same left ventricular ejection fraction as patients starting treatment later. There was no significant correlation between delay in treatment and left ventricular ejection fraction, or between left ventricular ejection fraction and exercise capacity examined by multiple linear regression analysis.

Discussion This study demonstrates that, in a selected group of patients treated with oral low-dose aspirin within 6 hours after onset of chest pain suggestive of acute myocardial infarction, an increased occurrence of silent myocardial ischemia is detected at early exercise testing, although the total number of positive exercise tests in each group is similar. No improvement of left ventricular ejection fraction or exercise capacity was detected. Similar results have been published by Verheugt et al. [3], who found a marked reduction of the rate of reinfarction in patients with acute infarction of the anterior ventricular wall treated with streptokinase and allocated 100 mg aspirin or placebo, but no significant difference in left ventricular ejection fraction, indicating no effect by aspirin on the extent of infarction. In two recent studies examining the effect of 100 mg aspirin given daily in patients with acute myocardial infarction, the combined occurrence of cardiac death or reinfarctions during hospitalisation,

and the three-month rate of reinfarction, was significantly lower in patients allocated aspirin [4,5]. No effect of aspirin on the extent of infarction as estimated by maximum creatine B fraction or cumulative lactate dehydrogenase release was observed. A limiting factor for this study is the relatively small number of patients studied, enhancing the chance of a type II error (false negative result). An 80% chance (1-p) of detecting a 10% improvement of ejection fraction with a significance level of (Y= 0.05 would require a sample size of 32 patients in each group, therefore any improvement of ejection fraction of less than 10% achieved by administration of aspirin would not have been detected. Another limiting factor is the higher values of enzymes, indicating larger infarcts, in patients allocated to treatment with aspirin. This difference was not present when analysing all 85 patients randomised to aspirin or placebo. The patients allocated to placebo who died during hospitalisation, however, had 38% higher maximum values of creatine kinase compared to patients treated with aspirin, explaining the observed imbalance in enzymic values among survivors. In patients with confirmed acute myocardial infarction treated with aspirin, peak values of enzymes were similar in patients with silent ischemia and in patients with exercise-induced chest pain. No correlation was observed between peak values of enzymes, left ventricular ejection fraction, or exercise capacity. The reason for the beneficial effect of aspirin on mortality and morbidity after myocardial infarction is not clear. It has been suggested that aspirin prevents thrombotic coronary reocclusion after spontaneous or streptokinase-induced vessel recanalisation, thereby preventing recurrent ischemic events and death [121. The importance of patent coronary vessels for prognosis after acute myocardial infarction was clearly demonstrated in The Western Washington Trial, where a reduction in mortality was observed only among those in whom thrombolysis resulted in coronary arterial reperfusion [ 141. Silent ischemia is frequently detected during exercise testing in patients after acute myocardial infarction. The coronary angiographic character-

417

istics, and exercise performance, in patients with silent ischemia are similar to those in patients with painful ischemia [15]. In our study, significantly more patients were found to have silent &hernia in the group treated with aspirin, an observation which was independent of concomitant fibrinolytic therapy. The number of patients with a positive exercise test was similar in the two groups, but more patients receiving placebo had the exercise test limited by chest pain compared to those treated with aspirin. The possible mechanisms by which aspirin may produce these findings have not been elucidated. It has been reported that silent ischemia represents less severe ischemia than the painful form, although the evidence is weak [16]. One possible explanation for our observation is that aspirin enhances the flow of blood in coronary arteries by platelet inhibition or by increasing collateral flow [17], thereby reducing the severity of the ischemic episodes. Another explanation might be the possible effect of aspirin on the threshold for perceiving painful stimuli. We conclude that aspirin administered within 6 hours after onset of chest pain suggestive of acute myocardial infarction increases the occurrence of silent ischemia detected at early exercise testing, but has no effect on left ventricular ejection fraction or early exercise capacity.

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Acknowledgements The authors gratefully acknowledge Arvid Hovland for expert technical assistance, Jan Erik Nordrehaug for helpful comments and suggestions, and Karl Arne Johannessen for statistical assistance. References 1 Antiplatelet trialists’ collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988;296:320-331. 2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS 2. Lancet 1988;ii:349-360. 3 Verheugt FWA, Funke-Kbpper AJ, Galema TW, Roos JP. Low dose aspirin after early thrombolysis in anterior wall

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