Treatment in acute stroke

Question 1

Stroke Unit Care

Answer 1

• Reduce mortality unlike the small percentage of ischaemic stroke receiving thrombolysis and mechanical thrombectomy
• Reduced dependency
• Reduced need for institutional care
• NNT = 20, 20 admissions for 1 patient to benefit from reduced mortality and dependency
• Early mobilisation, equipped to provide rapid diagnostic imaging, such as CT scans and MRIs. Receive faster access to treatments such as thrombolysis and evaluated for mechanical thrombectomy
• Rehabilitation from day 1 (MDT). mobility exercises, speech therapy and occupational therapy. Enhance functional recovery and promote independence
• Secondary prevention from admission, pneumonia, deep vein thrombosis, UTI, swallowing difficulties, high blood pressure and sugar
• VTE prevention - IPC’s
• Early treatment of complications

Question 2

Thrombolysis for acute ischaemic stroke

Answer 2

Alteplase (Recombinant Plasminogen Activator)

• Primary thrombolytic agent used in the treatment of acute ischaemic stroke
• Catalyses the conversion of plasminogen to plasmin, the enzyme responsible for clot breakdown.
• 10% of dose administered as an initial bolus over one minute, followed by 90% infused over 60 minutes
• Up to 4.5 hours from the onset of stroke symptoms

Tenecteplase in Ischemic Stroke Thrombolysis

• Greater fibrin specificity and longer half-life, allowing for a single bolus injection.
• Simplifies administration logistics and may enhance the clot dissolution process
• Not yet licensed but shown similar or better efficacy and safety profile compared to Alteplase

Thrombolysis Trials

• GISSI 1& 2: Examined the use of streptokinase in stroke patients and found that it led to an increase in mortality, indicating streptokinase is not a suitable agent for stroke thrombolysis
• NINDS 1995: Established efficacy of alteplase within 3 hours of stroke onset compared to placebo
• ECASS-3 2008: Alteplase works within 4.5 hours but decrease slightly compared to 3 hour window (from 1 in 3 improvement to 1 in 7)
• IST-3 2012: Aspirin vs alteplase up to 6 hours, not favourable beyond 4.5 hours but help broaden alteplase to different clinical scenarios

Wake-Up Stroke Trial (2018)

• Using diffusion-FLAIR mismatch to estimate stroke window of less than 4.5 hours for thrombolysis
• No significant increase in cerebral haemorrhages, suggesting MRI could guide thrombolysis in patients waking up with stroke symptoms

Ma et al., 2019 extended trial

• Treatable within 4.5 to 9 hours of onset or waking up stroke, with salvageable brain tissue identified on perfusion imaging.
• Stopped early because of Wake-Up trial
• Looking for small core and big penumbra
• Increased the likelihood of a favourable outcome at 90 days compared to placebo with a noted 6% bleeding risk with alteplase (1% in placebo)

Question 3

Mechanical Thrombectomy for Acute Ischaemic Stroke

Answer 3

Overview:

• MT is a treatment for acute ischaemic stroke which is caused by large artery occlusions (blockage). Specifically the internal carotid artery and the proximal middle cerebral artery
• Mechanical removal of a clot using a stent retriever or an aspiration system (suction at the tip of the catheter). most effective ASAP, ideally within 6 hours

Clinical Application and Efficacy:

• MT is indicated for patients with signficant neurological deficits (NIHSS > 6) and minimal ischaemic damage (infarct) visible on brain imaging
• Considered for MCA, internal carotid artery and basilar artery
• Thrombolysis first but if large clots, unlikely to recanalize with tPA (tissue plasminogen activator) so MT in addition
• Recent trial suggests tPA first before MT improves outcome in large clots
• MR-CLEAN, ESCPAE, SWIFT PRIME, EXTEND-IA, REVASCAT trials
• HERMES meta-analysis of all - Functional indepence at 90d significantly increase with MT, significantly reduced disability with MT, NNT for favourable 90d outcome = 3-7.5
• DAWN Trial: Efficacy of MT up to 24 hours from the last known normal in patients with favourable perfusion imaging profiles (Diffusion-FLAIR MRI or perfusion CT). 49% 90d functional independence vs 13% in control. NNT = 3
• DEFUSE 3 Trial: 6-16 hours, <70ml infarct size and ratio of ischaemic tissue volume to infarct volume > 1.8. Increased 90d functional independence, NNT = 3.6

Question 4

Antiplatelet therapy in acute ischaemic stroke

Answer 4

• Initial antiplatelet therapy typically involves aspirin administered within 48 hours after stroke onset to reduce the risk of early recurrence. Aspirin works by inhibiting platelet aggregation, thereby preventing new clot formation (IST, CAST trials)
• CHANCE (2013) and POINT (2018) benefit of both aspirin and clopidogrel for minor strokes (NIHSS < 3) or TIA (transient ischaemic attack) however suggests increased bleeding risks
• THALES trial (2020) showed aspirin and Ticagrelor in mild to moderate non-cardioembolic ischaemic stroke (NIHSS < 5) prevent recurrence at 30d with similar bleeding risks to CHANCE and POINT

Question 5

Blood Pressure Management in acute ischaemic stroke

Answer 5

Overview

- Autoregulation of Cerebral Blood Flow: Disrupted in acute ischaemic stroke, making cerebral blood flow more dependant on systemic blood pressure. This disruption means both excessively high and low BP can reduce perfusion to penumbra, the salvageable areas around the ischaemic core

• Risk of Haemodynamic Instability: High BP may increase the risk of haemorrhagic transformation of the infarct, particularly in patients who have received thrombolytic therapy but low BP may lead to further ischaemic damage due to decreased perfusion pressure

Guidelines

Before Thrombolysis: control BP, systolic below 185 mmHg and diastolic below 110 mmHg before IV thrombolysis

After Thrombolysis: maintain BP below 180/105 mmHg for at least 24 hours to minimise risk of haemorrhagic complications

No Thrombolysis: Do not lower BP unless above 220/120 mmHg, gradual reduction with continuous monitoring

INTERACT2 and ATACH-2 Trials: for haemorrhagic stroke, intense BP lowering shows beneficial outcomes

SCAST Trial: BP reduction did not lower mortality or disability in acute ischaemic stroke; emphasise on individualised management

IV antihypertensives e.g. nicardipine

Question 6

Neurosurgery for acute ischaemic stroke

Answer 6

For Maligant MCA syndrome and Large cerebellar infarction (pressure on brainstem resulting in drop in GCS)

Decompressive Hemicraniectomy

Indications:

• Indicated in cases of malignant middle cerebral artery (MCA) syndrome, where extensive ischaemic stroke leads to significant cerebral oedema (10% of ischaemic strokes)
• Most often recommended for younger patients
• Ideal candidates are those who show signs of rapid neurological deterioration despite maximum medical therapy and signs of brain herniation

Procedure:

• Removal of a large section of the skull (hemicraniectomy) to allow the swollen brain tissue room to expand without being compressed against the skill or other brain structures, can prevent transtentorial herniation
• The dura mater is open opened as well to provide additional space for the swollen brain

RCP guidelines:

• NIHSS > 15

Surgical Embolectomy

Indication:

• direct surgical removal of a clot (embolectomy) considered if endovascular thrombectomy is not available / feasible or if the clot is in a location that is accessible for direct surgical intervention
• More common in larger blood vessels such as the carotid artery

Procedure

• Craniotomy to access the affected artery then mechanical extraction of the clot, invasive; open brain

Posterior fossa decompression

Indication:

• Large cerebellar infarct, swelling of the posterior skull, increases intracranial pressure dramatically, compressing the brainstem and the fourth ventricle

Procedure:

• Removal of the skull in the back of the head to allow swollen brain tissue room to expand, relief pressure on the brainstem and lower cranial nerves and preventing herniation
• Dura mater also opened

Outcomes:

• Life saving but depends on extent of the cerebellar damage and timing of surgery
• No RCT because not ethical, compressed brain stem = death

Question 7

Management of acute primary intracerebral haemorrhage

Answer 7

Emergency Management of Primary Intracerebral Haemorrhage (PICH)

• Resuscitation
• Urgent brain imaging: non-contrast CT scan is typically first to confirm the diagnosis of PICH, delineating the size and location of the haematoma
• Reverse anticoagulation: If Warfarin, Vitamin K and Prothrombin Complex Concentrate (PCC), If DOAC, idarucizumab
• Surgical referral: for decompressive craniectomy

Medical Management of PICH

Hypertension Management:

• ATACH-2 showed BP lowering reduced haematoma but not INTERACT-2
• But ATACH-2 BP lower had worse renal function
• RCP stroke guidelines (2016) recommend lowering BP in PICH patients
• Prevention of Complications:
• immobility, DVT with compression, nutrition and preventing aspiration

Haemostatic Therapy

• Human factor 7a and tranexamic acid have been explored to promote extrinsic pathway of coagulation cascade
• FAST trial investigated recombinant factor 7a but showed no significant benefit for primary outcomes
• The TICH-2 trial with tranexamic acid showed no difference in clinical outcomes despite reducing hematoma expansion

Role of Surgery

Indication for Neurosurgery:

• Posterior fossa bleeds leading to hydrocephalus, where interventions like external ventricular drains or decompressive surgeries can be life-saving
• For supratentorial (upper parts of the brain) haemorrhages STICH 1 and 2 found no benefit with surgical intervention