The risks of thrombolysis in patients without acute myocardial infarction

International

Journal

The risks of thrombolysis

of Cardiology

5 1 (1995)

177- 18 1

in patients without acute myocardial infarction

Jacqueline N. Adams*a, Morag Jamiesona, Roger J. Trent”, J. Rawlesb, Kevin P. Jennings” “Cardiac

Department, Aberdeen Royal InJrmary, Foresterhill, Aberdeen, AB9 ZZD, bMedicinces assessment research unit, Aberdeen University, Aberdeen, UK Received

2 May

1995; accepted

UK

8 June 1995

Abstract The risk of administering thrombolysis to patients with suspected myocardial infarction who subsequently do not sustain an infarct, but develop complications associated with thrombolysis is of concern to all physicians. The objective of this study was to ascertain the effect of altering the criteria for the administration of thrombolysis on the number of patients who received thrombolysis in the absence of infarction. During 1990 and 1992 details of all admissions with chest pain were recorded. During 1991 the policy for the administration of thrombolysis was altered so that only patients with ST elevation were eligible. A total of 1473 patients were admitted with chest pain in 1990 and 1967 in 1992. Of the patients admitted in 1990, 663 (45%) had confirmed infarction of whom 378 (57.0%) received thrombolysis. In 1992, 855 (43%) were admitted with infarction and of these 450 (52.6%) had thrombolytic therapy. 118 patients had no evidence of myocardial infarction, but received thrombolysis. 91 (77.1%) were admitted in 1990 and 27 (22.9%) in 1992 (P
Thrombolysis;

Myocardial

infarction;

Altered

criteria

1. Introduction Thrombolytic therapy is now established in the management of acute myocardial infarction [l-3]. There are however several significant complications which can result from thrombolysis. Intra* Corresponding author, The Ayr Hospital, Rd, Ayr, Scotland, KA6 6DX, UK. Tel.: +44 0292 610555; Fax: +44 0292 262427. 0167-5273/95/$09.50 0 1995 Elsevier SSDI 0167-5273(95)02421-R

Dalmellington

Science Ireland

Ltd. All rights

cranial haemorrhage [4-61, haemorrhage from other sites such as the gastro-intestinal tract [7-91 and hypersensitivity reactions [4, lo] are all potentially life threatening complications of thrombolytic therapy. When given to patients in the early stages of a myocardial infarction thrombolysis has been shown to improve mortality [ 1,2,1 l] and post-infarction left ventricular function [12-141, and t$ese benefits are felt to outweigh the risks of thrombolysis. Often however reserved

178

J.N. Adams

et al. /International

Journal

there is uncertainty in the early diagnosis of myocardial infarction and therefore inevitably some patients without infarction receive thrombolysis. The results of several large multi-centre studies have shown that thrombolysis confers no signilicant benefit unless there is ST segment elevation or left bundle branch block (LBBB) on the electrocardiograph (ECG) [4]. The objective of this study was to audit the effect of changes in the criteria for the administration of thrombolysis on the number of patients who received thrombolytic therapy but were subsequently found not to have sustained a myocardial infarct. 2. Patients and methods

In 1990 an audit was undertaken of all patients with chest pain admitted to the Coronary care unit or general medical wards of Aberdeen Royal Inlirmary and Woodend Hospitals. During 1990 all patients admitted with a history of chest pain consistent with myocardial infarction within 24 h of the onset of pain, in the absence of contraindications were given thrombolysis. This included a large number of patients in the Third International Study of Infarct Survival trial (ISIS 3) and the Grampian Regional Early Anistreplase Trial (GREAT). In 1991 the policy for the administration of thrombolysis was altered so that only patients admitted within six hours of onset of chest pain and with ST elevation or LBBB were eligible. A second chest pain audit was performed in 1992. From these data it was possible to identify all patients who had received thrombolytic therapy, but who had not been diagnosed as having a myocardial infarction during these two years. In each case it was confirmed that no new pathological Q waves had developed on the ECG and that there was no elevation of cardiac enzymes (aspartate aminotransferase and lactate dehydrogenase) before the patient was entered into the study. The admission ECG was assigned to one of four categories; no abnormality; non-specific abnormalities such as T wave inversion or ST segment depression; dysrhythmia (e.g. supraventricular tachycardia, atria1 fibrillation or flutter, ventricular tachycardia and heart block); ST segment elevation (1 mm in the limb leads or 2 mm in the precordial leads) or

of Cardiology

51 (1995)

177-181

bundle branch block. The diagnosis at time of discharge or death was also established from the notes and categorised as pain due to coronary artery disease, pain due to other cardiac causes or non-cardiac pain. Statistical analysis was performed using an unpaired Student’s t test. 3. Results

A total of 1473 patients were admitted with chest pain in 1990 and 1967 in 1992. Of the patients admitted in 1990, 663 (45.0%) had confirmed myocardial infarction of whom 378 (57.0%) received thrombolysis. In 1992, 855 (43.5%) were admitted with infarction and of these 450, (52.6%) had thrombolytic therapy. During the two years of audit 130 (3.8%) patients were recorded as having received thrombolytic therapy in the absence of myocardial infarction. 128 sets of case notes were available for review and of these 118 patients (81 male, 68.6O/) had no evidence of myocardial infarction, but had received thrombolysis. 91 (77.1%) were admitted in 1990 and 27 (22.9%) in 1992. This represents 6.2% of the patients admitted with chest pain in 1990 and 1.4% of those in 1992 (P < 0.01, confidence interval 3.1%-6.6%). The median age of the study group was 63 years in 1990 and 56 years in 1992. By comparison the median age for those patients who received thrombolytic therapy and had a myocardial infarction was 64 years in 1990 and 67 years in 1992. In 1990, 55 (60.4%) of the subjects were admitted to the coronary care unit and 36 (39.6%) to general medical wards compared with 21 (77.8%) and 6 (22.2%), respectively in 1992. The decision to give thrombolytic therapy was made in 85 (72.0%) cases by a senior house officer or registrar, in 24 cases(20.4%) by a general practitioner, and in nine (7.6%) by a consultant or a junior house officer. During 1990, 59 (50%) patients received thrombolytic therapy as part of a clinical trial compared with only one patient in 1992. 3. I. Reasons for giving thrombolysis

In 109 (92%) cases the history was felt to be suggestive of myocardial infarction. Of the nine remaining cases the history was atypical, but there

J.N. Adams Table 1 Number of patients

with

et al. /International

each electrocardiogram

category

Journal

of Cardiology

on admission

51 (1995)

to hospital

177-181

179

(%)

Year

ST elevation or bundle branch block

Non specific abnormality

Dysrhythmia

Normal

1990 n = 91 1992 n = 21

15 (16%)

31 (34%)

5 (6%)

40 (44%)

9 (33%)

17 (63%)

0

1 (4%)

24 (20%)

48 (41%)

5 (4%)

41 (35%)

Total

was some degree of abnormality in the electrocardiogram which resulted in the administration of thrombolysis. Table 1 shows the electrocardiogram categories on admission. 3.2. Complications arising from thrombolysis Four patients had potentially life-threatening complications associated with thrombolytic therapy and of these one patient died giving a mortality rate of 0.8%. In this case three hours after receiving thrombolysis the patient developed cardiac tamponade. Two other patients had significant haematemeses requiring transfusion. One patient had a severe anaphylactic reaction. None of the patients who had major complications had significant ST segment elevation on their admission electrocardiogram, but all had a history which was felt to be suggestive of infarction. 3.3. Final diagnoses The diagnoses at the time of discharge or death are shown in Table 2. 18 (15%) patients at a later

Table 2 Diagnosis

at time of discharge

date underwent coronary arteriography. Five of these patients were at the time of discharge categorised as having non-cardiac pain and all had normal coronary arteries at catheterisation. The remaining 13 (11%) patients who were catheterised all had a diagnosis, at time of discharge, of coronary artery disease. Angiography subsequently showed that of these, three had normal coronary arteries, four had single vessel coronary artery disease and six had lesions in more than one coronary artery. Of the 13 patients categorised as having other cardiac pain all 13 had investigations other than angiography which confirmed the diagnosis at discharge. 4. Discussion The advent of thrombolytic therapy has produced yet another therapeutic dilemma; to withhold thrombolysis from a patient in the early stages of myocardial infarction denies them the proven benefits of this treatment. Conversely to adminis-

or death

Year

Coronary disease

artery

Other

cardiac

pain

Non-cardiac

1990 (n = 91) 1992 (n = 27) Total

66 (72.5%)

9 (9.9%)

16 (17.6%)

14 (51.9%)

4 (14.8%)

9 (33.3%)

80 (67.8%)

13 (11.0%)

25 (21.2%)

pain

180

J.N. Adams

et al. /International

ter thrombolytic therapy to a patient who does not have a myocardial infarction exposes them to small but not insignificant risks. Whatever criteria are used to determine which patients receive thrombolytic therapy they must ensure that as many patients as possible with myocardial infarction are given thrombolytic agents as soon as possible after admission whilst excluding those who have chest pain due to other causes. In a paper published in the British Medical Journal [ 151, we concluded that rigidly defined ST elevation may be an unsatisfactory precondition for thrombolytic therapy and that an acceptable risk:benefit ratio would be obtained if thrombolytic treatment were given to all patients with a convincing clinical history and any abnormality in an electrocardiogram. In the present study 77 (64%) patients had some abnormality in their electrocardiogram and if these recommendations had been applied would therefore have received thrombolytic therapy. If the stricter criterion of ST elevation or bundle branch block on the electrocardiogram were applied 24 (20%) patients would have received thrombolysis in the absence of acute myocardial infarction. Although some of these patients could actually have been in the early stages of infarction which was then aborted by the appropriate administration of thrombolysis. In this series the use of ST elevation as the prerequisite for thrombolysis significantly reduced the number of patient without infarction who received thrombolysis. Whilst the rate of thrombolysis in those with infarction was also reduced this did not reach statistical significance. None of the four patients who had major complications had significant ST elevation on their electrocardiogram. If electrocardiogram changes are to be used as the criterion for giving thrombolysis then it is necessary to have medical staff with sufficient knowledge and experience to identify these changes. However it is often the most junior medical staff who make the decision to administer thrombolytic therapy. Even for the most experienced physician it can sometimes be difficult to distinguish between new and old changes. Old tracings may then prove invaluable, but are not always available. Despite the change of criterion 18 subjects with non-specific changes or a normal ECG still received thrombolysis in 1992. This

Journal

of Cardiology

51 (1995)

177-181

probably occurred due to a combination of ignomisrance concerning the new policy, interpretation of the ECG and deliberate clinical decisions. Fortunately no patient in this study had an intracranial haemorrhage, although other studies have reported an incidence of approximately 0.5% [4-61. Most of the larger thrombolytic trials [ 1,2,7] include figures on the complications associated with thrombolytic therapy but do not report figures for those without infarction separately. Other studies [5] have looked at the incidence of haemorrhage with thrombolytic therapy, but only in those with confirmed infarction. The active components of both streptokinase and anistreplase are produced by group C /3haemolytic Streptococci. Consequently the administration of these drugs causes a sustained rise in antibody levels [ 161. Due to the risks of hypersensitivity and antibody neutralisation, if a patient without infarction receives streptokinase or anistreplase and then at a later date sustains a myocardial infarct they must be treated instead with TPA. Whilst the patient does not suffer clinically the widespread use of TPA has financial implications. 5. Conclusions

The implementation of ECG criteria resulted in a significant reduction in the number of patients without infarction who received thrombolysis, but did not significantly alter the rate of thrombolysis in those with definite myocardial infarction. The incidence of complications in patients receiving thrombolysis in the absence of acute myocardial infarction was however low in both years. References [I]

[2]

[3]

Gruppo Italian0 per lo Studio della Streptochinasi nell’brfarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; I: 397-401. Second International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, or aspirin, both or neither among I7 187 cases of suspected acute myocardial infarction: ISIS-2,. Lancet 1988; ii: 349-360. GREAT Group. Feasibility, safety and efficacy of

J.N. Adams

t41

PI 161

et al. /International

domiciliary thrombolysis by general practitioners: Grampian region early anistreplase trial. Br Med J 1992; 30.5: 548-553. Third International Study of Infarct Survival Collaborative Group. ISIS 3: A randomised comparison of streptokinase vs tissue plasminogen activator vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753-770. The ISAM Study Group. A prospective trial of intravenous streptokinase in acute myocardial infarction (ISAM). N Engl J Med 1986; 314: 1465-1471. De Jaegere P, Arnold A, Balk A, Simoons M. Intracranial haemorrhage in association with thrombolytic therapy: Incidence and clinical predictive factors. J Am COB Cardiol 1992; 19: 289-294. Muller HS, Rao AK, Forman SA and the TIM1 Investigators. Thrombolysis in Myocardial Infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Co11 Cardiol 1987; 10: 479-490. Califf RM, Top01 EJ, George BS. Haemorrhagic complications associated with the use of intravenous tissue plasminogen activator in the treatment of acute myocardial infarction. Am J Med 1988; 85: 353-359. Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) Trial-phase I: haemorrhage manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Co11 Cardiol 1988; 11: 1- 11. Gruppo Italian0 per lo Studio della Sopravvivenza

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[121

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nell’Infarto Miocardico. GISSI 2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71. AIMS Trial Study Group: Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1: 545-549. Mortelmans I, Vanhaecke J, Lesaffre E, et al. Evaluation of the effect of thrombolytic treatment on infarct size and left ventricular function by enzymatic and angiographic methods. Am Heart J 1990; 119: 1231-1237. Serruys PW, Simoons ML, Suryapranata H, et al. Preservation of global and regional left ventricular function after early myocardial infarction. J Am Co11 Cardiol 1986; 7: 729-742. National Heart Foundation of Australia Coronary Thrombosis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen activator given up to 4 h after onset of myocardial infarction. Lancet 1988; 1: 203-208. Adams JN, Trent R, Rawles J on behalf of the GREAT group. Earliest electrocardiographic evidence of myocardial infarction: implications for thrombolytic treatment. Br Med J, 1993; 307: 409-413. Lee HS, Cross SJ, Davidson RJL, Reid T, Jennings KP. Raised anti-streptokinase antibodies and neutralization titres from three days to 54 months after previous streptokinase or anistreplase for acute myocardial infarction. Eur Heart J 1992; 13: 9l(suppl).