Thrombolytic treatment of acute ischaemic stroke

The enormous initial success of treating coronary thrombosis with thrombolytic therapy made the thrombolytic treatment of ischaemic stroke the obvious next step. Although coronary thrombolysis has now been superseded by primary angioplasty, thrombolysis is the standard of care for stroke if it can be done within 4.5 hours of the known onset of a stroke. ¹

How common is ischaemic stroke? (Epidemiology)²³⁴

• As of 2022, stroke was the fourth biggest single cause of death in England and Wales.

• There are around 100,000 strokes every year in the UK, with around 1.3 million people living with the consequences of stroke.

• Stroke incidence fell by 30% between 1999 and 2011, probably due to better management of cardiovascular risk factors in primary care.

• Whilst the incidence rises with age, the average age has fallen by 1-2 years between 2007 and 2016, when it was 68 for men and 73 for women. In Scotland, the equivalent ages are 71 and 76 respectively.

• There is no age limit to the use of thrombolytic therapy.

Diagnosing ischaemic stroke (investigations)⁵⁶

It is essential to have a CT or MRI scan to differentiate the type of stroke before commencing treatment. The use of MRI as a first-line tool has the potential to reduce thrombolysis of stroke mimics, but this must not be at a cost of delay. Access to these investigations, and to staff trained to interpret them, must be immediately available 24 hours a day.

Differential diagnosis

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

Management of ischaemic stroke ⁵⁷

The 2023 National Clinical Guidelines for Stroke is endorsed by the National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN) and the Royal College of Physicians. NICE also have a separate guideline on stroke, updated in 2022.

Recommendations include the following:

• Thrombolysis with alteplase - also known as tissue plasminogen activator (tPA) - should be the thrombolysis of choice when thrombolysis is being considered. 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.

  • It is administered within a well-organised stroke service.

• Acute stroke services must link with the ambulance service; as well as being able to provide emergency care, they must also have facilities to deal with swallowing assessment, hydration and nutrition, palliative care, secondary prevention and rehabilitation. They must also provide education for all staff who give acute stroke care, including those in the emergency department.

• Every patient treated with alteplase should be started an antiplatelet agent within 24 hours unless contraindicated.

• Patients who are eligible for mechanical thrombectomy should also receive thrombolysis as soon as possible.

As of 2023, only 10.7% of patients who have a stroke are treated with thrombolysis, and 3.1% are treated with thrombectomy. This is a slight improvement compared to 10.4% and 2.5% respectively in the previous year. Only 40% are admitted to a stroke unit within four hours and only 76.5% spend at least 90% of their inpatient stay on a stroke unit.

A new NICE guidance published in July 2024 authorised the use of a second thrombolytic agent, tenecteplase, on the same basis (for thrombolysis up to 4.5 hours after presentation, when intracranial haemorrhage has been excluded). The guidance says that the less expensive of the two agents should be used. ⁸

Contraindications for thrombolytic treatment⁹

Absolute contraindications include a recent intracranial haemorrhage or structural cerebral vascular lesion or neoplasm, possible aortic dissection, active bleeding (excluding menstruation), recent intracranial or spinal surgery and current severe uncontrolled hypertension.

Relative contraindications include a history of severe and poorly controlled hypertension, prolonged cardiopulmonary resuscitation (over 10 minutes), major surgery in the last three weeks, dementia, pregnancy, non-compressible vascular punctures and an active peptic ulcer.

Complications¹⁰

The most serious complication is intracranial haemorrhage - a 2023 systematic review gave the likelihood of this as 1.7 - 8.8%. Risk factors for intracranial haemorrhage include age, hypertension, atrial fibrillation and the use of antiplatelet or anticoagulant therapy; however, a haemorrhage can only be confirmed or excluded after appropriate imaging. The Stroke Association patient leaflet gives an intracranial haemorrhage rate of 4% within seven days of thrombolysis and advises that 2.5% of these will be fatal.

Prognosis¹¹

A 2018 study followed over 2000 patients who had received thrombolysis between 2005 and 2015. They found that the number needed to treat to prevent one death was 12 at five years and 20 at 10 years. Thrombolysis reduced mortality by 37% at 10 years (slightly more for those who arrived at hospital within three hours of symptom onset) and on average, by 10 years, treated patients had lived one year longer than controls. At five years, thrombolysis was associated with higher independence scores with an odds ratio of 3.76.

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 being that the speed of getting a patient to a thrombolysis unit is critical. A nationwide cohort study in Denmark found that symptom to thrombolysis time of over 90 minutes was associated with a higher risk of death or recurrent ischaemic stroke. ¹²

Even if the 4.5 hour cut-off for thrombolysis 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 TIA³⁷

• Offer aspirin (300 mg daily), unless contra-indicated, to people who have had a suspected TIA, to be started immediately. Those who are already taking low-dose aspirin should continue with this and not have a 300mg dose.

• Refer immediately people who have had a suspected TIA for specialist assessment and investigation, to be seen within 24 hours of onset of symptoms. If someone presents having had a suspected TIA more than seven days ago, they should be referred as soon as possible and definitely within another seven days.

• 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.

• Patients with a suspected TIA should not drive until they have seen a specialist, who will give definitive advice.

Secondary prevention

This is discussed in the separate Stroke prevention article.