The enormous success of treating coronary thrombosis with thrombolytic therapy makes the treatment of ischaemic stroke the obvious next step.

• Only 80% of strokes are ischaemic and giving thrombolysis for a haemorrhagic stroke would be disastrous.
• Stroke tends to be more gradual in onset and may even start during sleep. Hence patients tend to present later.
• The window of opportunity for effective thrombolysis is 3 hours from the onset of the stroke and in that time a firm diagnosis of ischaemic stroke must be made.
• As a result, only about 1-11% of patients fulfil the criteria.

Epidemiology²

• The incidence of stroke doubles for every decade after 45 years.
• It rises from 104 per 100,000 per year for aged 45 to 54 years to 1113 per 100,000 per year between age 75 and 84 years.
• 70% of strokes occur in the over 65s.
• There is no age limit to the use of thrombolytic therapy although there are few RCTs of treatment in the over 80s.

Contraindications for thrombolytic treatment²

The following suggest haemorrhagic stroke or other reasons to avoid thrombolysis:

• Seizure at onset of stroke
• Symptoms suggestive of subarachnoid haemorrhage
• Stroke or serious head injury in last 3 months
• Major surgery or serious trauma within 2 weeks
• Previous intracranial haemorrhage
• Intracranial neoplasm
• Arteriovenous malformation or aneurysm
• GI or urinary tract haemorrhage in last 3 weeks
• Lumbar puncture in last week
• Current anticoagulation (INR>1.7)

Physical examination²

• Rapidly improving neurological signs. There is no benefit from thrombolysis in a transient ischaemic attack.
• Marked hypertension with systolic BP>185 mmHg or diastolic BP>110 mmHg or aggressive (continuous intravenous) treatment required to lower BP to this range
• Suspected acute pericarditis

Laboratory results

• Platelets <100 x 10⁹/L
• INR >1.7
• Glucose <2.7 mmol/l (50 mg/dL) or > 22 mmol/l (400 mg/dL)
• Positive pregnancy test (very unusual in this group)

Blood should be sent for group and cross-match in case transfusion is required.

Differential diagnosis²

The important differential diagnoses are haemorrhagic stroke, including intracranial haemorrhage and subarachnoid haemorrhage, and transient ischaemic attack.

Investigations

• It is essential to have a CT or MRI scan to differentiate the type of stroke before commencing treatment. MRI is as accurate as CT to detect acute haemorrhage in patients with focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral haemorrhage.³
• Access to these investigations must be available 24 hours a day. Interpreting the scan requires experience but it is possible to train people to an acceptable level of competence in a short time.⁴
• Even if the window for thrombolysis has been missed, the Royal College of Physicians states that all patients should have CT or MRI within 24 hours.
• An ECG is useful in diagnosing pericarditis and possible causes of stroke including myocardial infarction and atrial fibrillation. An ECG is not required before starting alteplase.

The interpretation of a CT or MRI scan to exclude haemorrhage is not easy and usually requires a senior radiologist or an experienced geriatrician. It should not be delegated to a junior doctor in the small hours of the morning. The availability of such expertise 24 hours a day, 7 days a week, adds further to the requirements of a stroke service.

Evidence

There have been a number of RCTs published from North America, Europe and Australia examining the role of thrombolysis in stroke. Many have used intravenous alteplase but some have used intra-arterial infusion, especially for vertebro-basilar strokes. Studies include:

• MAST-E Multicentre Acute Stroke Trial-Europe
• MAST-I Multicentre Acute Stroke Trial - Italy
• ASK Australian Streptokinase
• NINDS National Institute of Neurological Disorders and Stroke (USA)⁵
• ECASS European Cooperative Acute Stroke Study
• ECASSS II European and Australian Cooperative Acute Stroke Study II
• ATLANTIS Alteplase Thrombolysis for Acute Noninterventional Treatment in Ischaemic Stroke
• STAT Stroke Treatment with Ancrod Trial

NICE considered the results of all these trials as well as the results of a large pan-European post-marketing study UK Safe Implementation for Thrombolysis in Stroke - Monitoring Study (SITS-MOST).Their opinion is that alteplase is both clinically effective and cost effective when delivered within the framework of a specialist setting.¹

Figures and interpretation

• When alteplase was given within 3 hours of onset of symptoms, the number needed to treat for 1 more patient to have a normal or near normal outcome was 8, and the number needed to treat for 1 more patient to have an improved outcome was 3. These NNT are very impressive.
• The single most important factor excluding patients from thrombolytic therapy is presentation after the 3 hours "golden window" had passed. Only 4% of the patients in the NINDS study met the criteria for alteplase therapy.
• If a stroke did not wake up a sleeping person, alteplase cannot be given.
• As cerebral infarction progresses it can undergo haemorrhagic transformation and this would account for the unfavourable outcome in those treated later.
• Cochrane is uncertain as to whether lower doses of thrombolytics are safer or if there is any advantage to intra-arterial over intravenous routes of administration.⁶ Intra-arterial treatment tends to be used for posterior stroke but it is still uncertain if it is superior.⁷ The important point is early recovery of flow and the vertebro-basilar system appears to take longer to recover.
• Meta-analysis does suggest that there may be some benefit from treatment up to 6 hours along with gains in quality of life.⁸ Between 3 and 6 hours the intra-arterial route may be preferable.⁹
• Only oral aspirin within 48 hours and tissue plasminogen activator within 3 hours of ischaemic stroke have been shown to have clinical benefit.¹⁰ Other "neuroprotectors" have been disappointing.

The Royal College of Physicians, along with other organisations, have produced evidence-based reviews of the management of stroke.¹¹ They recommend that:

• Alteplase should only be administered within a well organised stroke service.
• Staff in such a service should be trained in delivering thrombolysis and in monitoring for any associated complications.
• Care should be provided by level 1 and 2 nursing staff trained in acute stroke and thrombolysis.
• There should be immediate access to imaging and re-imaging and staff appropriately trained to interpret the images.
• Protocols should be instituted for the delivery and management of thrombolysis, including post-thrombolysis complications.
• Staff in A&E departments, if appropriately trained and supported, can administer alteplase for the treatment of acute ischaemic stroke provided that patients can be managed within an acute stroke service with appropriate neuroradiological and stroke physician support.
• Every patient treated with alteplase should be started on aspirin 300 mg daily after 24 hours, unless aspirin is contraindicated.
• Any person with acute ischaemic stroke for whom previous dyspepsia associated with aspirin is reported should be given a proton pump inhibitor in addition to aspirin.
• Any person with acute ischaemic stroke who is allergic to or genuinely intolerant of aspirin should be given an alternative antiplatelet agent.

Complications⁵

In the NINDS trials, the rate of clinical deterioration from new intracranial haemorrhage, 24 to 36 hours after treatment, was 6.4% with alteplase versus 0.6% with placebo. Mortality at three months was 17% in the alteplase group and 21% in the placebo group (P = 0.30).

Prognosis

A good outcome 24 hours after thrombolysis tends to predict a good outcome at 3 months.¹²

Neurological deficits

Three months after alteplase therapy:

• Approximately 30% of patients are neurologically normal or near normal
• 30% have mild to moderate neurological deficits
• 20% have moderate to severe neurological deficits
• 20% have died

Functional disability

Three months after alteplase therapy:

• Approximately 50% of patients are completely or almost completely independent in activities of daily living
• 15% are moderately dependent on others
• 15% are completely dependent on others
• 20% have died

Implications for Primary Care

Rapid admission

Although the high technology of scanning and thrombolysis is delivered within a hospital system, there are still implications for primary care. The most obvious is that if there is reason to suspect a stroke the patient must be admitted to a suitable unit with the utmost speed. Simply being in hospital within 3 hours is not good enough. The scan has to have been taken, read and the infusion started within 3 hours of the onset of symptoms. Hospitals also need to look to their systems to reduce delay¹³ as has been done with acute myocardial infarction.

A study from Spain¹⁴ showed a thrombolysis rate of 7.5% for acute ischaemic stroke. This is most commendable compared with more usual figures of 4 or 5%. 16% arrived in hospital on time but more than half of these were excluded.
They concluded that reducing the "door to needle" time was the most important aim in improving numbers treated. Their own figures ranged from 33 to 122 minutes with a mean of 51 minutes. This includes time for admission, history, examination, blood tests, scan and interpretation.

Even if the deadline has passed, patients should still be admitted to hospital as all should have a scan within 24 hours and the outcome for all is better in a stroke unit.

Not only do doctors and hospitals have to examine their systems to prevent delay in the process, but patients also need to be able to recognise what is happening and know that a rapid response is required.

Prophylactic admission¹⁵

The RCP recommend the following:

• Any patient who presents with transient neurological symptoms suggestive of cerebrovascular event should be considered to have had a transient ischaemic attack (TIA).
• People who have had a suspected TIA, that is, they have no neurological symptoms at the time of assessment (within 24 hours), should be assessed as soon as possible for their risk of subsequent stroke using a validated scoring system, such as ABCD-2.
  

  ABCD and ABCD-2 Score Prognostic score to identify people at high risk of stroke after a TIA. It is calculated based on: Age (≥60 years, 1 point) Blood pressure at presentation (≥140/90 mmHg, 1 point) Clinical features (unilateral weakness, 2 points or speech disturbance without weakness, 1 point) Duration of symptoms (≥ minutes, 2 points or 10-59 minutes, 1 point). The calculation of ABCD-2 also includes the presence of diabetes (1 point). Total scores range from 0 (low risk) to 7 (high risk).

• People who have had a suspected TIA who are at high risk of stroke (that is, with an ABCD-2 score of 4 or above) should have:
  • Aspirin (300 mg daily) started immediately
  • Specialist assessment and investigation within 24 hours of onset of symptoms
  • Measures for secondary prevention introduced as soon as the diagnosis is confirmed, including discussion of individual risk factors.
• People with crescendo TIA (two or more TIAs in a week) should be treated as being at high risk of stroke even though they may have an ABCD-2 score of 3 or below.
• People who have had a suspected TIA who are at lower risk of stroke (that is, an ABCD-2 score of 3 or below) should have:
  • Aspirin (300 mg daily) started immediately
  • Specialist assessment and investigation as soon as possible, but definitely within one week
    of onset of symptoms
  • Measures for secondary prevention introduced as soon as the diagnosis is confirmed,
    including discussion of individual risk factors.
• People who have had a TIA but who present late (more than one week after their last symptom
  has resolved) should be treated as though they are at lower risk of stroke

Secondary prevention

The RCP is also very enthusiastic about the role of primary care in the secondary prevention of stroke.¹⁵ This also has its own article and will be discussed no further here.

Document references

1. Ischaemic stroke (acute) - alteplase, NICE Technology Appraisal Guidance (2007)
2. Saver JL, Kalafut M; Thrombolytic Therapy in Stroke. eMedicine, November 2007.
3. Kidwell CS, Chalela JA, Saver JL, et al; Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA. 2004 Oct 20;292(15):1823-30. [abstract]
4. Fiebach JB, Schellinger PD, Gass A, et al; Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke. 2004 Feb;35(2):502-6. Epub 2004 Jan 22. [abstract]
5. No authors listed; Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec 14;333(24):1581-7. [abstract]
6. Mielke O, Wardlaw J, Liu M; Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD000514. [abstract]
7. Macleod M; Current issues in the treatment of acute posterior circulation stroke. CNS Drugs. 2006;20(8):611-21. [abstract]
8. Sandercock P, Berge E, Dennis M, et al; Cost-effectiveness of thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke assessed by a model based on UK NHS costs. Stroke. 2004 Jun;35(6):1490-7. Epub 2004 Apr 22. [abstract]
9. Schellinger PD, Kaste M, Hacke W; An update on thrombolytic therapy for acute stroke. Curr Opin Neurol. 2004 Feb;17(1):69-77. [abstract]
10. Ly JV, Zavala JA, Donnan GA; Neuroprotection and thrombolysis: combination therapy in acute ischaemic stroke. Expert Opin Pharmacother. 2006 Aug;7(12):1571-81. [abstract]
11. Royal College of Physicians; National clinical guideline for diagnosis and initial management of acute stroke and transient ischaemic attack (2008).
12. Saposnik G, Di Legge S, Webster F, et al; Predictors of major neurologic improvement after thrombolysis in acute stroke. Neurology. 2005 Oct 25;65(8):1169-74. [abstract]
13. Lindsberg PJ, Happola O, Kallela M, et al; Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology. 2006 Jul 25;67(2):334-6. [abstract]
14. Garcia-Monco JC, Pinedo A, Escalza I, et al; Analysis of the reasons for exclusion from tPA therapy after early arrival in acute stroke patients. Clin Neurol Neurosurg. 2006 Aug 1;. [abstract]
15. National clinical guideline for stroke (third edition), Royal College of Physicians (July 2008); Prepared by the Intercollegiate Stroke Working Party, incorporating the recommendations from NICE stroke guideline.

Internet and further reading

• Stroke: The diagnosis and acute management of stroke and transient ischaemic attacks, NICE Clinical Guideline (July 2008)
• Stroke and Transient Ischaemic Attack, Clinical Knowledge Summaries (February 2009)

Acknowledgements