Thrombolysis and its implications in the management of stroke in the Accident and Emergency department

O. Quaba, C. E. Robertson

Department of Accident and Emergency Medicine and Surgery

Royal Infirmary, Lauriston Place, Edinburgh

Correspondence to: 

Dr C E Robertson, Department of Accident and Emergency Medicine and Surgery, Royal Infirmary, Lauriston Place, Edinburgh EH3 9YW

Tel: 0131 536 4010 Fax: 0131 536 4041

Abstract

Objectives: Examination of initial management of stroke patients in the emergency setting to assess feasibility of thrombolysis for acute ischaemic stroke.

Methods: Retrospective analysis of all patients presenting with a clinical diagnosis of stroke over a two month period. Exclusion criteria for thrombolysis were applied to assess the number of patients that would potentially have been eligible for thrombolysis.

Results: Of 94 patients identified with clinical stroke, only 57 (60.6%) had a CT scan; 23 (24.4%) were confirmed as having had an acute ischaemic stroke. Mean delay in scanning was 2.2 days (range 0-15 days). Even if all patients had presented and been scanned within three hours (as required for thrombolysis), only six (6.4%) patients would have been eligible for thrombolysis.

Conclusions: The great majority of patients presenting with clinical stroke do not fulfil the criteria for thrombolysis. Current practice involves significant delays in CT scanning, which has implications for resource structuring should thrombolysis become widely available.

Keywords: Stroke, ischaemic, thrombolysis, computed tomography (CT), eligibility.

Introduction

The introduction of systemic thrombolysis has generated much interest and enthusiasm as a treatment option for acute ischaemic stroke.

The purpose of this study was to look at current practice in the initial management of stroke in a large Scottish teaching hospital Accident and Emergency department where thrombolysis is not presently used. By studying current practice and the profile of patients presenting with stroke, we hoped to consider their eligibility for thrombolysis and the practical implications of instituting such treatment.

Methods

An analysis was performed of all patients presenting with an initial clinical diagnosis of definite or possible stroke to the Accident and Emergency Department of the Royal Infirmary of Edinburgh during a two month period (October and November 1999). The Department currently sees 95,000 new adult (>13 years) attendances annually and serves as the sole Accident and Emergency Department for a catchment population of approximately 750,000.

The Accident and Emergency records for the study period were retrieved for all patients in whom the diagnosis of definite, or possible, stroke was made. Definite clinical stroke was defined as that with a typical presentation of rapid onset symptoms with well-defined clinical findings (hemiplegia, dysphasia, facial palsy, hemianopia etc). Possible stroke was defined as a non-classical presentation in which stroke was given as the most likely differential diagnosis. The number of patients who underwent CT scanning was noted together with the timing (in relation to admission) and result of scan.

In order to assess the potential impact of future thrombolysis the major exclusion criteria for thrombolysis, based on the National Institute of Neurological Disorders and Stroke (NINDS) Study,1 were extracted from the notes. The exclusion criteria for thrombolysis include: rapidly improving symptoms, mild symptoms, uncontrolled blood pressure (BP) (diastolic BP >110 or systolic BP >180mmHG), acute seizure at onset of stroke, intracranial haemorrhage and the concurrent use of oral anticoagulants.  All patients in the NINDS trial received treatment within three hours of symptom onset. Accordingly, we recorded the timing of onset of symptoms, where available, from the notes.

Results

During the study period, 94 patients were identified as having definite or possible stroke on the basis of history and clinical examination.

Mean age of the group was 70.6 years (range 38 – 94). There were 51 males and 43 females. 57 (60.6%) patients underwent CT scanning at some stage of their evaluation or in-hospital management. Of these 57 patients, 23 (24.4%) were confirmed as having had an acute ischaemic stroke and 12 (12.8%) had an intracranial bleed. Two patients had brain tumours diagnosed on CT. The mean time between admission and CT scanning was 2.2 days (range 0 – 15 days).

Table I details the differences between the initial management of the patient groups identified as having (1) definite, and (2) possible strokes.

Of the 41 patients defined as having definite stroke on clinical grounds 35 (85.4%) had a CT scan and of these 19 (46.3%) were shown to have ischaemic strokes. Of the 53 patients in the ‘possible stroke’ group 22 (41.5%) were scanned and only four (7.5%) had ischaemic strokes.

Table II shows the number of patients who would have been excluded from thrombolysis based on the major exclusion criteria of the NINDS trial.

The largest excluding factor (not including time exclusions) was the presence of mild symptoms in 53 (56.4%) patients, followed by uncontrolled BP in 25 (26.6%) patients. The time of onset of symptoms was documented in only 42 (44.7%) patients, and of these only 9 (9.6%) presented within three hours.

Even if all patients had been admitted within three hours of the onset of symptoms and had been scanned within that time, only six out of 94 patients (6.4%) would have been eligible for consideration of thrombolysis. Of these six patients, five had CT scans demonstrating an ischaemic infarct. The remaining patient had symptoms and signs of definite stroke and fulfilled the criteria for thrombolysis but did not have a scan.  Of these six patients the time of onset of symptoms was only documented in three, and all of these presented after three hours from onset of symptoms.

Discussion

Acute ischaemic stroke is a common neurological condition representing the clinical manifestation of a variety of possible underlying conditions. Stroke is the third commonest cause of death in the United Kingdom, where approximately 140,000 strokes occur annually. The acute mortality is approximately 40%, while for survivors the outlook depends upon the nature and severity of the neurological deficit. Overall, stroke is the commonest cause of disability and uses more than 5% of NHS and Social Services resources.2  Therapeutic approaches to the emergency management of stroke have focused upon three principal areas: anti-platelet drugs, neuronal protection agents and thrombolytic agents.

Following the introduction of systemic thrombolysis as a treatment option for acute ischaemic stroke, there has been much interest and enthusiasm about the emergency management of the condition. The challenging and emotive term "brain attack" is frequently quoted to emphasise the time-dependent nature of the condition, analogous, and with similar implications, to that of thrombolysis in acute myocardial infarction.  Currently, thrombolysis for acute ischaemic stroke is licensed for use only in the USA and New Zealand and is not widely used in the UK. Several reports have questioned the benefits and feasibility of such thrombolysis.3-5 Of seven randomised controlled trials (RCTs) of thrombolysis to date1 and 6-11, only one - the NINDS trial – showed benefit in a primary clinical outcome measure. All the other RCTs showed no benefit with thrombolysis or were terminated because of increased mortality in the thrombolysis group - principally due to haemorrhagic complications.

In addition, all the trials were performed on highly selected patients admitted to specialised units. It is therefore appropriate to consider the potential application and implications of such treatment in unselected patients presenting to ‘routine’ emergency services.  As mentioned previously, if we assumed that all of the patients in our study had been admitted within three hours of the onset of symptoms and had been scanned within that time, only six out of 94 patients (6.4%) would have been eligible for consideration of thrombolysis. Of these six patients, five had CT scans demonstrating an ischaemic infarct. The remaining patient had symptoms and signs of definite stroke and fulfilled the criteria for thrombolysis but did not have a scan.

In reality, of these six patients the time of onset was known in three, and all of these presented after three hours from onset of symptoms. Thus for the entire group, the total number of eligible patients for thrombolysis was three (3.2%). This figure matches the prediction by Jorgensen et al3 that, at best, less than 4% of general stroke patients would potentially benefit from thrombolysis.

The diagnosis of stroke is usually considered to be obvious but it is relevant that when a group of general practitioners (who commonly will be more senior and experienced than junior doctors in an Accident and Emergency Department) were asked their reasons for admitting to hospital patients who had a first stroke; doubt as to the accuracy of the clinical diagnosis was given as the only reason in 8% of patients, but as a contributing factor in 42%.12 This demonstrates the importance of treating patients with atypical symptoms (i.e. the ‘possible stroke’ group in this study) as potential candidates for thrombolysis.

Furthermore, neuroimaging, usually by CT scan, is essential prior to the institution of thrombolysis. Given the current constraints upon acute medical and imaging services, and the need to have these facilities available on a 24 hour a day, seven day a week basis, it would be unusual, for a patient to be able to have undergone CT scanning in less than one hour from presentation to hospital. Thus a three hour window for onset of symptoms to institution of thrombolysis (if appropriate) is, in effect, shortened to two hours from symptom onset to presentation. Also, there is evidence that few general radiologists, neurologists or emergency clinicians can identify subtle haemorrhages on CT scanning.13, and this will potentially lead to patients receiving thrombolysis inappropriately and with greater risk.

While it is acknowledged that one of the most important exclusions to thrombolysis is the time delay from onset of symptoms to presentation3, and that this study had limited data on this factor, it is still fair to conclude that even if patients had presented within the required time period very few would have been eligible for thrombolysis.

Therefore, while it may be theoretically attractive to draw parallels between thrombolysis for acute myocardial infarction and its application to acute ischaemic stroke, both the time-frame and investigations necessary mitigate against the applicability and practicality of such intervention. At best, the proportion of patients likely to benefit from such treatment is less than one in 20 and this figure may be a considerable over-estimate.

In summary, serious doubts exist as to the potential use and benefits of intravenous thrombolysis for acute stroke. Alternative approaches, such as the well proven benefits accruing from the treatment and rehabilitation of patients in specialised stroke units, irrespective of age, severity of stroke and co-morbidity, may be a more cost-effective and rational approach to this major problem.

R E F E R E N C E S

 1 National Institute of Neurological Disorders and Stroke rt-PA Stoke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med 1995; 333:1581-7

 2 Bath PMW, Lees KR. Acute stroke. Br Med J 2000; 320:920-923

 3 Jorgensen H, Nakayama H, Kammersgaard L, Raaschou H, Olsen T. Predicted impact of intravenous thrombolysis on prognosis of general population of stroke patients: simulation model. Br Med J 1999; 319:288-9

 4 Hoffman JR. Against: and just what is the emperor of stroke wearing? West J Med 2000; 173:149-50

 5 Siu YC, Wong TW, Lau CC. Candidates for thrombolytic treatment in acute ischaemic stroke - where are our patients in Hong Kong? J Accid Emerg Med 1999; 16:412-7

 6 The ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995; 274:1017-25

 7 Multicentre Acute Stroke Trial – Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346:1509-1514

 8 Multicentre Acute Stroke Trial – Europe Study Group. Thrombolytic therapy with streptokinase in acute ischaemic stroke. N Engl J Med 1996; 335:145-150

 9 Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996; 276:961-966

10 The ECASS II Study Group. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352:1245-51

11 Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute noninterventional Therapy in Ischemic Stroke. JAMA 1999; 282:2019-26

12 Bamford J, Sandercock P, Warlow C, Gray M. Why are patients with acute stroke admitted to hospital? Br Med J 1986; 292:1369-72

13 Hoffman JR. Predicted impact of intravenous thrombolysis. Another trial is needed [letter; comment]. Br Med J 2000; 320:1007

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