Thrombolytic Treatment of Acute Ischaemic Stroke

The enormous success of treating coronary thrombosis with thrombolytic therapy makes the treatment of ischaemic stroke the obvious next step. Several large trials have confirmed the benefits of thrombolysis in acute stroke within three hours of development of symptoms - eg, National Institute of Neurological Disorders and Stroke (NINDS) in the USA^[1] .

In 2014, a Cochrane review recommended that thrombolysis was beneficial up to six hours following acute ischaemic stroke^[2] . In 2015, concerns were raised that thrombolysis may not be safe at 3-4.5 hours following an acute ischaemic stroke^[3] .

The National Institute for Health and Care Excellence (NICE) recommends that thrombolysis with alteplase - also known as tissue plasminogen activator (tPA) - should be the thrombolysis of choice when thrombolysis is being considered^[4] . Its use should be limited to the following circumstances:

• Haemorrhagic stroke has been excluded.
• The patient presents within four and a half hours of having the event.
• Access to specialised services is available.

Epidemiology^[5]

• Stroke is the third biggest single cause of death in Scotland and the fourth most common in the UK.
• Stroke incidence fell by 19% between 1990 and 2010 in the UK.
• The incidence rises with age, doubling every decade after the age of 45.
• The average age of stroke has decreased in recent years.
• In England, Wales and Northern Ireland the average age of stroke is 74 for men and 80 for women.
• In Scotland, the equivalent ages are 71 and 76 respectively.
• There is no age limit to the use of thrombolytic therapy.

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^[6] .
• 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^[7] .
• The Royal College of Physicians (RCP) states that maximise the potential benefit from revascularisation treatments and the acute management of intracerebral haemorrhage, all patients should have imaging urgently and at most within 1 hour of arrival at hospital^[8] .
• 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, seven days a week, adds further to the requirements of a stroke service.

Differential diagnosis

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

Management

The RCP and NICE have produced evidence-based reviews of the management of stroke^{[8, 4]} . 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 48 hours, unless contra-indicated. This should be continued for 14 days^[9] .

The situation is more complex for acute ischaemic stroke than for coronary thrombosis:

• 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 four and a half 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.

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^[10] . Intra-arterial treatment tends to be used for posterior stroke but it is still uncertain if it is superior^[11] . The important point is early recovery of flow and the vertebrobasilar system appears to take longer to recover. In the majority of its recommendations for stroke thrombolysis, NICE cites intravenous administration - there are no circumstances in which they specifically recommend intra-arterial administration.

The 2019 NICE guidelines have recommended several circumstances where thrombectomy should be offered, together with intravenous thrombolysis (where not contra-indicated and within the licensed time window).

Contra-indications for thrombolytic treatment

The following suggest haemorrhagic stroke or other reasons to avoid thrombolysis^[12] :

• Seizure at onset of stroke.
• Symptoms suggestive of subarachnoid haemorrhage.
• Stroke or serious head injury in the preceding three months.
• Major surgery or serious trauma within three months.
• Previous intracranial haemorrhage.
• Intracranial neoplasm or surgery.
• Arteriovenous malformation or aneurysm.
• Gastrointestinal or urinary tract haemorrhage in the preceding three weeks.
• Lumbar puncture in the preceding week.
• Current anticoagulation (INR >1.7).
• Acute pericarditis.
• Significant bleeding, bleeding disorder or anticoagulant treatment.
• Severe uncontrolled arterial hypertension.
• Severe liver disease.
• Bacterial endocarditis, pericarditis, acute pancreatitis.
• Prior stroke within three months, or any stroke with concomitant diabetes.

Physical examination

• Neurological signs improving suggesting a TIA.
• Marked hypertension - systolic BP >185 mm Hg or diastolic BP >110 mm Hg, or need for aggressive antihypertensive therapy to reach below these levels.

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.

Complications^[13]

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 but did not reach statistical significance.

Prognosis

A good outcome 24 hours after thrombolysis tends to predict a good outcome at three months^[14] .

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 three hours is not good enough. The scan has to have been taken and read, and the infusion started, within three hours of the onset of symptoms. Hospitals also need to look to their systems to reduce delay, as has been done with acute myocardial infarction^[15] . 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.

Initial management of suspected and confirmed TIA^[4]

• Offer aspirin (300 mg daily), unless contra-indicated, to people who have had a suspected TIA, to be started immediately.
• Refer immediately people who have had a suspected TIA for specialist assessment and investigation, to be seen within 24 hours of onset of symptoms.
• Do not use scoring systems, such as ABCD², to assess risk of subsequent stroke or to inform urgency of referral for people who have had a suspected or confirmed TIA.
• Offer secondary prevention, in addition to aspirin, as soon as possible after the diagnosis of TIA is confirmed.

Secondary prevention

The RCP is also very enthusiastic about the role of primary care in the secondary prevention of stroke and this is discussed in the separate Stroke Prevention article^[8] .