Antithrombic therapy in stroke prevention

Kuldeep Paik

Stroke Services Pharmacist, St. George’s Hospital

Outline of presentation

The presentation of different types of stroke

Current treatment options used within secondary stroke prevention

Antiplatelets vs anticoagulants for various types of stroke

Which antiplatelets are used in practice

How does this fit in with national evidence?

Clinical trials in progress for use of antiplatelet drugs

Clinical features of stroke

Facial features

Arms (can the person keep their arms up?)

Slurred speech?

Time to call 999 if any of the above features are observed

Time is critical – thrombolysis is only effective < 3hr post presentation

Locations of common strokes and features of motor function affected

Location of stroke Part of brain affected Functions affected

Middle cerebral artery (MCA)

Frontal, temporal and parietal lobes (can be more extensive)

Facial features, speech, arms and legs, visual disorders (more features can be affected)

Anterior communicating artery (ACA)

Frontal lobes Visual field deficits, blurred vision

Posterior communicating artery (PCA)

Midbrain region, surrounding lobes/nuclei

Loss of motor coordination, memory, reading, visual field loss

Basilar artery Midbrain, temporal lobes Some degree of paralysis, speech, reduced GCS

Common types of stroke

Type of stroke Mechanism of blood flow deprivation

Treatment options

TIA Thrombus or embolism in artery blocking blood flow to brain for < 5 minutes

Antiplatelet + high intensity statin

Thrombotic stroke Plaque formation in artery blocking flow to brain

Antiplatelet + high intensity statin

Embolic stroke Emboli lodged in artery blocking flow to brain

Antiplatelet + high intensity statin

Any ischaemic stroke with AF and CHADS2VASC score >1 and low bleed risk

As thrombotic and embolic stroke

Antiplatelet (first 2 weeks) then anticoagulation + statin

Ischaemic stroke with AF and high bleed risk

As above Antiplatelet + statin

Haemorrhagic stroke Blood escapes from artery into the brain – depriving brain of oxygen

None – reverse INR if previously on anticoagulants, stop antiplatelets

Antiplatelets vs anticoagulants In practice – antiplatelets form the mainstay of most types of arterial strokes

where there is no indication for anticoagulation.

Clopidogrel monotherapy tends to be sufficient for most types of ischaemic stroke (300mg load, then 75mg once daily), NB must not be within 24 hours of thrombolysis if given. Aspirin/dipyridamole MR is used if clopidogrel resistance (aspirin PR 300mg od load, then 150mg PR od is used if NBM)

Dual antiplatelets may be indicated if CTA/MRA scans reveal over 90% occlusion of carotid arteries if patient unwilling or unfit to have carotid endardectomy, or for some dissecting strokes in younger patients.

Anticoagulation is reserved for venous sinus thrombus strokes or for secondary prevention of AF (SPAF)

How does this compare with national evidence?

NICE guidelines for acute stroke recommends 300mg PR/PO aspirin for 14 days, then 75mg once daily thereafter.

Clopidogrel is considered a treatment option for patients who have had ischaemic strokes to prevent occlusive events.

Dipyridamole MR is considered if patients are allergic to both aspirin and clopidogrel.

For occlusive vascular events where clopidogrel is not tolerated, aspirin and dipyridamole MR may be considered.

Why the difference? Clopidogrel was deemed to be clinically superior to aspirin in preventing ischaemic stroke

in the Clopidogrel vs Aspirin at Risk of Ischaemic Stroke (CAPRIE) study in 1998.

The study compared 75mg clopidogrel to 325mg aspirin in 19,185 patients, over 6,300 patients were randomised to each arm.

Safety profile of clopidogrel was found to be similar to aspirin

However – back in 1998, Plavix (trade name of clopidogrel) was around £25-30 per month vs aspirin (< £1 per month). Furthermore some centres disputed the clinical significance of the results.

However, now clopidogrel is off patent, costs have decreased significantly

Also – expert opinions of consultants have swayed clinical practice

TARDIS trial Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS).

Multicenter trial run via the University of Nottingham

The aim of this study is to determine if hyper-aggressive antiplatelet therapy in the first month abolishes further events, using the hypothesis that if dual therapy is similar to monotherapy, then triple therapy will be even better.

Study compared aspirin/dipyridamole/clopidogrel therapy to clopidogrel monotherapy for first month.

Primary outcomes – ‘breakthrough’ ischaemic events at 90 days

Secondary outcomes – bleeding, MI, vascular events, function, platelet function

ENCHANTED trial Enhanced Control of Hypertension and Thrombolysis Stroke Study

Co-ordinators – George Institute in collaboration with NHMRC, Australia, four arms of study

Low dose 0.6mg/kg rtPA vs standard dose 0.9mg/kg rtPA – aim equivalence in ischaemic stroke in terms of efficacy

Does intensive BP lowering (130-140mmHg systolic) vs 180 mmHg systolic improve patient outcome in ischaemic stroke?

Does low dose (0.6mg/kg) rtPA reduce the risk of symptomatic intracerebral haemmorhage?

Does adding intensive BP control (as above) to thrombolysis reduce the risk of ICH?

RESTART trial Restart or Stop Antithrombotics Randomised Trial

Aimed at patients surviving intracerebral haemmorhage (non-traumatic) who had previously been on antiplatelets or anticoagulants.

The start aims to compare whether starting antiplatelet drugs (either aspirin, dipyridamole, clopidogrel, or a combination of two antiplatelets) as dictated by the physician, decreases risk of future vascular events over 2 years vs no treatment.

Primary outcome – recurrent symptomatic ICH

Secondary outcomes – extracranial/non-fatal extracerebral haemmorhage, vaso-occlusive effects, adherence to antiplatelet drugs

TICH-2 Tranexamic acid (TXA) for hyperacute primary intracerebral haemorrhage

A study to see if tranexamic acid is safe and reduces death and dependency after hyperacute primary intracerebral haemorrhage.

1g of TXA given as 100ml infusion over 10 minutes, followed by a second infusion of 1g of TXA given as a 8 hourly infusion in 250ml of fluid.

Placebo controlled trial (placebo = 0.9% saline)

Primary outcome – death and/or dependency

Secondary outcomes – NIHSS score at day 7 or discharge, quality of life studies, radiological assessment of changes in haematoma and any new infarcts.