Mednotes

L4 Clinical Pharmacology Drug treatment of stroke

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tagsclinicalpharmacology, lecture
aliasesL4 Clinical Pharmacology Drug treatment of stroke

28 min read

Overview

This lecture covers the pharmacological management of ischaemic stroke. It begins with the definition and causes of stroke, its epidemiology and its risk factors (including drug-induced risk), then explains the pathophysiology that makes reperfusion worthwhile: an infarct core surrounded by a salvageable penumbra threatened by the ischaemic cascade. The two mechanisms of ischaemic occlusion, platelet-rich thrombosis on a ruptured atherosclerotic plaque and cardiac embolism (chiefly from atrial fibrillation), dictate the two arms of secondary prevention: antiplatelets for atherosclerotic risk and anticoagulants for stasis-related risk. The second half deals with acute care: recognise, stabilise and reperfuse as fast as possible, using intravenous rt-PA within a defined time window (extendable on perfusion imaging) or mechanical clot retrieval. The closing message is that only rt-PA (alteplase and tenecteplase) and clot retrieval are approved for acute ischaemic stroke; every other intervention trialled has failed.

Guideline sources given: the Aus/NZ Living Clinical Guidelines for Stroke Management (Chapter 3, acute medical and surgical management) and the UK National Clinical Guidelines for Stroke 2023 (Chapter 3 acute, Chapter 5 long-term). Background reading: ELM2 Clinical Pharmacology cardiovascular drugs, and the ELM3 neuroimaging lecture on ischaemic versus haemorrhagic stroke pathophysiology.

Definition, causes and epidemiology

Stroke is a syndrome of rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin.

Four vascular causes:

  • Thrombotic occlusion (ischaemic)
  • Embolic occlusion (ischaemic)
  • Haemorrhage
  • Global hypoperfusion (ischaemic)

Epidemiology:

  • Ischaemic: around 80% of strokes, from occlusion by an embolus or a thrombus.
  • Haemorrhagic: under 15% of strokes.
  • A smaller percentage is caused by hypoperfusion.
  • Stroke numbers in New Zealand are projected to rise by 40% by 2028 (Ranta 2018, NZMJ).

Risk factors

A clear patient history, including a careful assessment of the patient’s prescription history, is needed to eliminate other potential causes.

Established modifiable lifestyle factors:

  • High fat diet
  • Excessive alcohol and/or other illicit drug abuse
  • Cigarette smoking
  • Socio-economic factors
  • Medication

Other co-morbidities:

  • Established hypertension
  • Elevated total cholesterol and TC/HDL ratio
  • Diabetes mellitus
  • AF, MI / heart disease (including altered anatomy)
  • Prior stroke (including TIA), renal disease history
  • High RBC count, atherosclerosis (CAD and PAD)
  • Cardiac anatomical anomalies (patent foramen ovale and similar)

Drug-induced stroke (raised BP and embolic risk)

  • Hormone replacement therapy: oral versus transdermal route matters (Marto et al 2021, Stroke).
  • Oral contraceptive pill (oestrogens).
  • Chemotherapy does appear to increase the risk (J Nat Cancer Inst 2004).
  • Atypical antipsychotics: risperidone increased the incidence of cerebrovascular events in dementia trials (Wooltorton 2004).
  • NSAIDs, comparing COX-2 with COX-1 inhibition: celecoxib, rofecoxib and diclofenac increase embolic risk. In the celecoxib colorectal adenoma prevention trial (Solomon et al 2005, NEJM) the estimated probability of the composite endpoint over 36 months was highest for celecoxib 400 mg, intermediate for celecoxib 200 mg and lowest for placebo, with the curves diverging early (P = 0.01), so the effect was dose-related.
  • Procoagulants: prothrombin complex concentrate (PCC) and fresh frozen plasma.

Ischaemic stroke pathophysiology

Ischaemic stroke is abrupt occlusion of arteries leading to or within the brain.

Infarction and penumbra:

  • Loss of blood supply causes brain cell death in the immediate area, usually within minutes to a few hours of onset, producing an infarct of dead brain cells.
  • The blood supply to the surrounding area, the penumbra, is compromised but not completely cut off. Collateral flow supplies it. This is the target for recovery intervention protocols.

The ischaemic cascade:

  1. Brain cells in the infarct die.
  2. Dead cells release excitotoxic and inflammatory mediators.
  3. This chain reaction endangers the penumbra.
  4. Without prompt reperfusion treatment the penumbral cells also die.

If intervening late, the size of the salvageable region must be determined (CT perfusion).

Thrombotic occlusion

  1. Rupture of the atherosclerotic plaque exposes sub-endothelial collagen to the bloodstream.
  2. On contact with collagen, platelets become activated and aggregate at the site of injury.
  3. The resulting platelet-rich thrombus can occlude major vessels, or dislodge (embolise) to occlude smaller vessels.

The pharmacological answer to a platelet-rich thrombus is antiplatelet therapy.

Embolic occlusion

Dislodged thrombi can arise from stasis of heart tissue or blood:

  • As a result of AF
  • At the site of artificial heart valves
  • As a result of valve disorders
  • After a heart attack
  • In congestive heart failure

Emboli can also form from fat particles, tumour cells, or air/gas bubbles. The pharmacological answer to stasis-related thrombus is anticoagulation.

Atrial fibrillation as a stroke risk

Stroke is the most common and devastating complication of AF.

  • All-cause stroke incidence in patients with AF is around 5% per year.
  • AF is a major independent risk factor: AF patients are around 5-fold more likely to have a stroke.
  • 15% of all people who have a stroke have AF.
  • Stroke risk increases with age, and is present even in asymptomatic AF.

Priorities in the AF patient care pathway, depicted as stages along a path from nearest to furthest: rate control (most immediate), prevention of thromboembolism, then rhythm control (most distant).

AF treatment pathways:

ArmPharmacologicalNon-pharmacological
Rate controlBeta-blockers, Ca2+ blockers, digoxin, amiodaroneAblate and pace
Sinus rhythm maintenanceClass IA, class IB, class III, beta-blockers, amiodaroneCatheter ablation, pacing, surgery, implantable devices
Stroke prevention (high risk, CHA2DS2-VASc score >= 2)Direct thrombin inhibitors: dabigatran; rivaroxaban; vitamin K antagonists: warfarinSurgical isolation of the left atrium

Oral anticoagulants

Mechanisms

  • Warfarin: a coumarin, vitamin K epoxide reductase inhibitor, inhibiting factors II, VII, IX and X.
  • Dabigatran etexilate (Pradaxa): oral direct thrombin (IIa) inhibitor, reducing fibrin formation.

Warfarin: efficacy, safety and reversal

The INR-versus-odds-ratio data (Fang 2004; Hylek 1996) show two opposing curves. Ischaemic stroke risk is very high at low INR (odds ratio around 17 to 18 at INR 1.0) and falls steeply to near 1 by INR 2 to 3. Intracranial bleeding risk stays near 1 until about INR 3 to 4 then rises steadily to around 10 by INR 7 to 8. The therapeutic window sits around INR 2 to 3 where both risks are near their minimum.

Emergency reversal, if haemorrhage develops or thrombolysis is intended:

  • Prothrombinex-VF (PCC), containing vitamin K cofactors, 500 IU vial for iv infusion. Small concentrated volume means faster delivery and action. Preferred option.
  • Fresh frozen plasma given with vitamin K, 15 to 20 mL/kg (around 2 litres per patient). Requires blood type matching. Much slower.
  • Intravenous vitamin K. INR normalisation takes more than 6 to 24 hours. Much slower.

Dabigatran: pharmacology

  • Direct thrombin inhibitor, half-life 12 to 14 hours.
  • Produces an isolated elevated thrombin time (>60 s; normal range <21 s).
  • Absorption: dabigatran etexilate is absorbed from the gut as a P-glycoprotein transporter substrate, then rapidly converted to the active form by serum esterases in the portal vein or by hepatic glucuronide conjugation.
  • The dose to anticoagulant effect relationship is virtually linear, giving a predictable therapeutic response and reducing the need for monitoring.
  • Clearance: around 80% renally excreted, so half-life is prolonged in renal impairment. Creatinine clearance must be >30 mL/min.
  • P-gp transport in enterocytes, hepatocytes and renal epithelia can be affected by other P-gp inhibitors and inducers.

Important

Dabigatran should be initiated in preference to warfarin for patients with non-valvular AF and adequate renal function.

Idarucizumab (Praxbind): dabigatran reversal

  • Monoclonal antibody given intravenously.
  • Binds dabigatran 350-fold more avidly than dabigatran binds thrombin.
  • Completely reverses dabigatran’s anticoagulant effect within 10 minutes, with full effect within 4 hours, in nearly 90% of participants.
  • Dose: 5 g IV as 2 consecutive 50 mL infusions over 5 to 10 minutes each, or as a bolus injection.

RE-LY: dabigatran versus warfarin

Randomized Evaluation of Long-Term Anticoagulation Therapy (Connolly et al 2009, NEJM), rates in %/year:

OutcomeDabigatran 110 mg bdDabigatran 150 mg bdWarfarin
Stroke/embolic primary outcome1.53 (similar)1.11 (lower)1.69
Major bleeding2.71 (lower)3.11 (similar)3.36
Haemorrhagic stroke0.12*0.10*0.38
Mortality3.753.644.13

*P < 0.001 versus warfarin.

Summary: 110 mg twice daily gives a similar rate of ischaemic stroke and systemic embolism with a lower rate of major haemorrhage; 150 mg twice daily gives a lower rate of ischaemic stroke and systemic embolism with a similar rate of major haemorrhage. There is an excess risk of gastrointestinal bleeding with dabigatran relative to age (Romanelli 2016, Circulation).

Coagulation cascade and where the drugs act

Intrinsic pathway, initiated by exposed endothelium and exposure to a negatively charged surface:
XII to XIIa, then XI to XIa, then IX with VIIIa (plus phospholipid and Ca2+) forming the factor X activating complex.

Extrinsic pathway, initiated by tissue factor (factor III) after vascular injury or trauma:
VII to VIIa with Ca2+ and tissue factor, forming the tissue factor / factor VIIa complex. Inhibited by tissue factor pathway inhibitor and by andexanet alfa.

Common pathway:

  1. X to Xa, which with Va, phospholipid and Ca2+ forms the prothrombinase complex. Inhibited by antithrombin III, by the factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and by fondaparinux (indirect factor Xa inhibitor).
  2. Prothrombinase complex converts II (prothrombin) to IIa (thrombin). Inhibited by antithrombin III, by heparin and LMWH (indirect thrombin inhibitors), by the direct thrombin inhibitors (argatroban, bivalirudin, desirudin, dabigatran), and, specific to dabigatran, by idarucizumab.
  3. Thrombin converts I (fibrinogen) to Ia (fibrin) and XIII to XIIIa.
  4. Cross-linking of fibrin gives thrombus formation.

Fibrinolysis, from the second pathway diagram: plasminogen converts to plasmin, and rt-PA drives this activation. Plasmin acts on fibrin to give fibrin degradation products. Factor Xa and thrombin are each also inactivated by antithrombin III into inactive complexes, and the vitamin K reduced/oxidised cycle feeds prothrombin synthesis (warfarin’s site of action).

Transient ischaemic attack

TIA has the same symptom presentation as ischaemic stroke but with a short duration.

Definition: an acute episode of temporary neurologic dysfunction that typically lasts less than an hour, results from focal cerebral, spinal cord or retinal ischaemia, and is not associated with acute tissue infarction.

Immediate treatment of a confirmed TIA, started immediately:

  • Clopidogrel 300 mg loading dose, then 75 mg daily
  • Aspirin 75 mg
  • Atorvastatin 20 to 80 mg daily

Patients with non-disabling acute ischaemic stroke or TIA should receive treatment for secondary prevention. Antiplatelets should not be used for stroke prevention in patients with AF (Connolly et al 2011).

ABCD3-I risk stratification

Clinical featurePoints
Age >= 60 years1
BP systolic >139 or diastolic >89 mmHg1
Speech impairment without weakness1
Unilateral weakness2
Duration <= 59 minutes1
Duration > 59 minutes2
Diabetes present1
Dual TIA (second TIA within 7 days)2
Same-sided > 49% stenosis of the ICA2
MRI showing hyperintensity on diffusion weighted images2
Total range0 to 13
ScoreRisk for strokeRecurrence within 90 days
0 to 3Low2 to 3%
4 to 7Intermediate<6%
8 to 13High>18%

(Lancet Neurol 2010;9:1060-69.) The accompanying bar chart of stroke recurrence rate at 2, 7, 28 and 90 days shows recurrence rising with both score category and length of follow-up, consistent with the table.

Secondary prevention

Antiplatelets reduce platelet aggregation associated with atherosclerosis. Use in secondary prevention if a high-risk TIA is established (ABCD2 > 3) or following a minor ischaemic stroke, if rtPA is excluded.

  • Dual antiplatelet therapy (aspirin plus clopidogrel), used in acute ischaemic stroke and high-risk TIA as 3 weeks of therapy. The combination is more effective but carries greater haemorrhagic risk.
  • Clopidogrel is subsidised and most effective, but around 5 to 10% of patients are non-responders.
  • Aspirin: the Lancet (May 2009) questioned the validity of prophylactic use in some patients.

Anticoagulants (dabigatran, rivaroxaban, warfarin) reduce blood coagulation and fibrin formation, and are used where there is stasis (concurrent treatment in AF).

  • Concurrent antiplatelet therapy should not be used in patients anticoagulated for AF unless there is a clear indication otherwise.
  • For patients with TIA, anticoagulant therapy should begin once CT or MRI has excluded intracranial haemorrhage.

Antihypertensives, antidyslipidaemics and antiarrhythmics are used if indicated.

Clopidogrel bioactivation and non-response

Clopidogrel is absorbed from the intestine in an inactive form and bioactivated in the liver in two steps:

  1. Clopidogrel (inactive) is converted by CYP1A2, CYP2B6 and CYP2C19 to 2-oxo-clopidogrel (still inactive).
  2. 2-oxo-clopidogrel is converted by CYP2B6, CYP2C19 and CYP3A4 to Clopi-H4, the active metabolite, which acts on the platelet P2Y12 receptor (the same receptor ADP acts on).

CYP2C19 phenotype, determined by allele combinations (*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, *3/*3), divides patients into normal metabolisers (n = 142), intermediate metabolisers (n = 147) and poor metabolisers (n = 56). Clopidogrel resistance (CR) was assessed with the VerifyNow P2Y12 platelet test, defined as PRU > 208, giving 174 patients without CR and 171 patients with CR. The study population was patients undergoing revascularisation (surgical or endovascular) for peripheral artery disease, with a composite endpoint of major or minor amputation, major or minor re-intervention, heart attack, ischaemic stroke and all-cause death.

Non-pharmacological

Carotid stenting (deployment of a stent across the narrowed segment) versus carotid endarterectomy (open surgical removal).

Acute stroke care

Time is brain. The goal is to recognise, stabilise and reperfuse as soon as possible, across TIA, ischaemic stroke and haemorrhagic stroke. Severity is quantified with the NIH Stroke Scale/Score (NIHSS).

Tests at hospital:

  • Bedside: vitals, ECG, bloods (cTnI, INR if warranted)
  • Level of consciousness, neurological examination, symptom scoring (NIHSS)
  • CT scan to exclude haemorrhagic stroke if thrombolysing
  • MRI or CT-based imaging to quantify infarct core to perfusion mismatch as an indicator of salvageable tissue in selected patients

Management steps:

  1. Establish the clinical history, an accurate definition and diagnosis of stroke type (discount haemorrhagic), the last known-well time, and the stroke severity score.
  2. Provide acute general medical care: treat highly elevated blood glucose (moderate control, discount hyperglycaemia) and body temperature if needed, since both are positively associated with neurotoxicity, greater mortality and poor functional outcome. Revisit after reperfusion.
  3. Intervene with reperfusion: pharmacological rt-PA (either alteplase or tenecteplase, which are not to be confused), stroke clot retrieval (mechanical thrombectomy), or neuroprotection (still questionable).

Rationale from the guidelines: restoration or improvement of perfusion to the ischaemic area is the key therapeutic strategy; the existence of an ischaemic penumbra is fundamental to the current approach; although the infarcted core may not be salvageable, adjacent dysfunctional tissue might be saved; blood flow to the ischaemic region should be improved as quickly as possible. To date, only intravenous administration of rt-PA has been proven to be effective.

Thrombolysis with rt-PA

Alteplase mechanism

  • Manufactured using recombinant DNA technology (human sequence, so less antigenic); recombinant tissue plasminogen activator.
  • A serine protease, normally synthesised by endothelial cells in the body, which binds to fibrin in the thrombus.
  • It increases cleavage of plasminogen to release plasmin.
  • Plasmin digests fibrin, circulating fibrinogen and other proteins involved in fibrin formation.
  • Structure: kringle 1, kringle 2, EGF domain, fibronectin finger and protease domains along the chain from NH2 to COOH.

Sites of action: circulating rt-PA exists in both free and bound forms with plasma proteins such as alpha2-antiplasmin, plasminogen activator inhibitor 1 (PAI-1), C1-esterase inhibitor and alpha1-antitrypsin, which may influence volume of distribution, plasma clearance and metabolism. At the clot, free t-PA converts fibrin-bound plasminogen to plasmin, which lyses the fibrin clot and releases fibrin degradation products; t-PA bound to PAI forms an inactive t-PA/PAI complex, and plasmin bound by alpha2-antiplasmin forms an inactive plasmin/alpha2-antiplasmin complex.

Alteplase delivery and PK

  • Route and dose: intravenous 0.9 mg/kg body weight, maximum 90 mg, infused over 60 minutes, with 10% of the total dose given as an initial bolus.
  • Not indicated in patients under 18 years.
  • More than 50% of alteplase is cleared from plasma within 5 minutes of stopping an IV infusion, and approximately 80% within 10 minutes.
  • Clearance is by hepatic metabolic degradation (endocytosis), with endocytosed peptides cleared renally. Hepatic perfusion and cardiac output are critically important in clearance.

Time window and evidence

  • ECASS III (2008) found intravenous rtPA effective when given up to 4.5 hours post stroke onset. There was a significant increase in symptomatic intracranial haemorrhage (2.7% versus 0.3%, p = 0.008) but no significant effect on deaths (6.7% versus 8.2%).
  • Benefit falls with delay: adjusted odds ratios for mRS 0 to 1 at day 90 decline from roughly 2 to 3 at an onset-to-treatment time of 60 minutes toward about 1.0 by 360 minutes. The bands are <3 h (SITS-MOST), 3 to 4.5 h (NIND-2, ECASS-3), and >4.5 h, which is excluded except in selected patients.

Administration requirements:

  • Thrombolysis should only be given in specialist stroke units, or in a setting with appropriate infrastructure, facilities and network support (for example via telemedicine), by physicians with expertise in acute stroke assessment and management, and where protocols for thrombolysis are in place.
  • Intravenous rtPA is the recommended thrombolytic: alteplase is used mainly, and tenecteplase can now be used in large vessel occlusions.
  • Patients should not receive rtPA if they have any of the exclusion criteria used in the NINDS trial. Age over 80 is no longer a barrier.

Criteria for giving intravenous alteplase 0.9 mg/kg (max 90 mg) to carefully selected people with acute ischaemic stroke:

  1. There is a clear history of the time of onset of symptoms.
  2. Treatment is given within 4.5 hours of onset of symptoms.
  3. Intracerebral haemorrhage has been excluded by imaging.

No other pharmacological agent is recommended apart from tenecteplase (New Zealand guideline).

Extended intravenous window

Strong recommendation: for patients with potentially disabling ischaemic stroke who meet perfusion mismatch criteria in addition to the standard clinical criteria, intravenous alteplase (0.9 mg/kg, maximum 90 mg) should be administered up to 9 hours after the time the patient was last known to be well, or from the midpoint of sleep for patients who wake with stroke symptoms, unless immediate endovascular thrombectomy is planned (Ma et al 2019, Campbell et al 2019).

Antiplatelet therapy in acute ischaemic stroke:

  • Aspirin and/or clopidogrel in patients with NIHSS < 4 only, and only if intracerebral haemorrhage is excluded and thrombolysis is not advocated.
  • Administration of aspirin within 24 hours before or after a thrombolytic agent is not recommended.

Other acute treatments:

  • No agents with putative neuroprotective effect can be recommended for the treatment of acute ischaemic stroke.
  • Drugs with a sedative effect should be avoided if possible.
  • There is no evidence to support an intensive approach to tight glycaemic control (4.0 to 7.5 mmol/L). Treatment is only acceptable above 10 mmol/L.

Brain oedema and raised intracranial pressure (no therapeutic benefit as yet):

  • Corticosteroids are not recommended for cerebral oedema and raised intracranial pressure after ischaemic stroke; adverse effects outweigh benefit.
  • Diuretics such as intravenous frusemide decrease intracranial pressure, but the evidence is sparse and they are not recommended. Frusemide can drop pressure abruptly.

Punchline: only rtPA (alteplase and tenecteplase) and clot retrieval are approved for acute ischaemic stroke. All other trials have failed, despite the number of stroke reviews and trials registered by the Cochrane Stroke Group rising from near zero in 1965 to around 11,000 by 2015 to 2016.

Haemorrhagic stroke

Bleeding into the brain occurs when a blood vessel bursts. No effective targeted therapy for haemorrhagic stroke exists, and treatment of acute intracerebral haemorrhage depends on the cause and severity of bleeding.

Acute management:

  • Emergency: evacuation of the haematoma is promising (craniotomy and similar) but is rarely done; care is mostly palliative. Surgical options also include clipping or coiling an aneurysm.
  • Conservative: basic life support (ABCs), including control of bleeding, seizures, blood pressure and intracranial pressure, all critical.
  • Pharmacological: recombinant factor VIIa gave disappointing trial results, reducing haematoma but not improving survival or functional outcome after intracerebral haemorrhage.

Ongoing pharmacological treatment and secondary prevention:

  • Antihypertensives to carefully reduce elevated BP (to under 140) and intracranial pressure
  • Anticonvulsants in the event of seizure recurrence
  • Vasoselective calcium channel blocker (nimodipine), oral or intravenous, to reduce reactive vasospasm; it may also prevent Ca2+ overload in ischaemic neurones, a neuroprotective effect
  • Osmotic diuretics to decrease intracranial pressure in the subarachnoid space, as a last resort
  • Antidyslipidaemics and glycaemic control

Self-test

  1. Define stroke as given in the lecture, including the duration criterion.
  2. List the four vascular causes of stroke and state which of them are ischaemic.
  3. Give the approximate proportions of ischaemic and haemorrhagic stroke, and the projected change in New Zealand stroke numbers.
  4. List the drug classes that increase stroke risk, giving the mechanism or trial evidence where the lecture supplies it.
  5. Distinguish the infarct core from the penumbra, and explain why the penumbra determines treatment strategy.
  6. Describe the steps of the ischaemic cascade and predict what happens to the penumbra if reperfusion is delayed.
  7. Describe the sequence of events by which a platelet-rich thrombus forms on an atherosclerotic plaque, and name the drug class that targets it.
  8. List the cardiac sources of emboli, and name the drug class that targets stasis-related thrombus.
  9. Quantify the stroke risk conferred by AF using the figures given.
  10. Describe the three priorities of the AF care pathway in order of proximity, and list the pharmacological stroke prevention options with the risk threshold that triggers them.
  11. Distinguish the mechanisms of warfarin and dabigatran.
  12. Explain what the graph of odds ratio against INR shows, and why the therapeutic window sits where it does.
  13. Describe the options for emergency reversal of warfarin, ranking them by speed.
  14. Describe dabigatran’s pharmacokinetics from absorption to clearance, and predict the consequence of co-administering a P-gp inhibitor.
  15. What creatinine clearance threshold applies to dabigatran, and why does renal function matter for this drug?
  16. Describe idarucizumab: mechanism, binding avidity, speed of effect and dose.
  17. Summarise the RE-LY findings for dabigatran 110 mg and 150 mg twice daily against warfarin.
  18. Define TIA and distinguish it from ischaemic stroke.
  19. State the immediate drug regimen, with doses, for a patient with a confirmed TIA, and explain why this regimen would be wrong in a patient with AF.
  20. List the ABCD3-I components worth 2 points, and give the three risk bands with their 90-day recurrence rates.
  21. Explain why around 5 to 10% of patients do not respond to clopidogrel, describing the activation pathway.
  22. Describe the mechanism of action of alteplase, from binding to clot lysis.
  23. State the intravenous alteplase regimen for acute ischaemic stroke, including dose ceiling, bolus fraction and infusion time.
  24. What is the cut-off time window for intravenous rtPA in standard practice, and what did ECASS III report for haemorrhage and death?
  25. Describe the criteria that permit the extended intravenous alteplase window, including how the clock is started in a patient who wakes with symptoms.
  26. State the rules governing aspirin and clopidogrel use in acute ischaemic stroke.
  27. List the acute interventions the guidelines explicitly do not recommend, with the reason given for each.
  28. Describe the pharmacological management of haemorrhagic stroke.
  29. Integrative: a 72 year old with known AF and adequate renal function, on dabigatran, presents 2 hours after sudden onset of right-sided weakness and dysphasia. Describe the assessment and treatment sequence, explaining the pharmacological decisions at each step.

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