Meta-analysis: Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke

Emerson et a (LANCET, 2014)

Within 9hrs* of symptom onset – Consider IV thrombolysis (Alteplase) for patients with:

- potentially disabling ischaemic stroke (NIHSS 4-26)

- who meet standard eligibility criteria

AND

- salvageable regions on CTP

defined as:

· vol. hypoperfusion/vol. of ischemic core ratio >1.2

AND

· absolute difference > 10 ml

AND

· ischemic-core < 70 ml.

* If wake-up stroke 9hrs from mid-point of sleep.

Alteplase within 9 hrs vs. placebo:

Adj RR 1.44, 95% CI 1.01-2.06, p value 0.04

EXTEND study (NEJM 2019)

Primary outcome of mRS scale 0-1 at 90 days assessed after receiving Alteplase between 4.5-9 hours post stroke onset on awakening with stroke (if within 9 hours from the midpoint of sleep). Perfusion lesion–ischemic core mismatch was

defined as:

- ratio > 1.2 between the volume of hypoperfusion/volume of ischemic core

AND

- absolute difference > 10 ml

AND

- ischemic-core < 70 ml.

Alteplase for unknown timeframe of stroke and selected MRI findings vs. placebo:

Adj OR 1.61, 95% CI 1.09-2.36, p value 0.02

WAKE-UP study (NEJM 2018)

Primary outcome of mRS scale 0-1 at 90 days after receiving Alteplase for unknown time of onset of stroke with MRI DWI evidence of ischaemic stroke but no parenchymal hypointensity on FLAIR.

(Large >1/3 MCA DWI excluded)

Endovascular clot retrieval

Within 6 hours of onset

ECR should be considered for all patients with ischaemic stroke who:

- Procedure can commence within 6 hours of onset

AND

- Have large artery occlusion of anterior circulation (ICA/M1)

** This is not available in Cairns in this timeframe**

ECR reduced mRS disability at 90 days. adj cOR 2·49, 95% CI 1·76–3·53, p<0·0001. NNT 2·6

HERMES collaboration pooled date from 5 trials between 2010-2014 MRCLEAN, ESCAPE, REVASCAT, SWIFT PRIME, EXTEND IA. Trials assessed proximal anterior circulation ischaemic strokes - ECR within 12hrs vs. control. Primary outcome - mRS at 90 days.

6-24 hours from onset

ECR should be considered for all patients with ischaemic stroke who:

- Procedure can commence within 6-24 hours of onset

AND

- Have large artery occlusion of anterior circulation (ICA/M1)

AND

- Have salvageable tissue on perfusion imaging

o Core <50ml

o Penumbra >15ml

o Mismatch ratio >1.8

Possible exclusion:

Premorbid MRS >2

ASPECTS <6 or >1/3 MCA affected on CT* (*see RESCUE-Japan)

ECR 6-16hrs:

Better mRS score, OR 2.77,

p < 0.001 and functional independence 45% compared to control 17%, p < 0.001

Trend to greater benefit with later, more severe strokes. No difference based on age or ASPECTS

DIFFUSE 3 Study (NEJM 2017)

ECR within 6-16hrs for occluded ICA (cervical or intracranial) or proximal MCA with findings on CTP:

- Core <70ml

- Ratio penumbra/core > 1.8

- Penumbra >15ml

NIHSS >/= 6

Premorbid MRS </= 2

Exclusion – ASPECTS <6

Primary outcome - mRS at 90 days

ECR 6-24hrs:

mRS in ECR group 5.5 vs. 3.4 in control.

FI at 90 days 49% ECR, 13% control

No significant difference in benefit b/n subgroups, age, NIHSS, time (<12 vs >12hrs)

DAWN Study (NEJM 2018)

ECR 6-24hrs for occluded intracranial ICA/proximal MCA stroke + mismatch on CTP.

- Group A - Age >80, NIHSS >10, Core <21ml

- Group B - Age <80, NIHSS >10, Core <31ml

- Group C - Age <80, NIHSS >20, Core 31-51ml

Premorbid MRS 0 or 1 (i.e.<2)

Exclusion – CT evidence of >1/3^rd MCA involved

Primary outcome – utility weighted mRS + functional independence (FI) at 90 days

Primary outcome: ECR 31% vs Medical 12.7%.

sICH: ECR 9% vs Medical 4.9%

RESCUE-Japan LIMIT (NEJM 2022)

ECR 6-12hours with large ischaemic area (ASPECT 3-5)

Used unusual mixture of CT and MRI criteria

Primary outcome: mRS 0-3 at 90 days

ECR for Basilar thrombosis

Consider for patients presenting up to 24 hours with:

- PC-ASPECTS score >6

- NIHSS >10 (may consider >6)

- Premorbid mRS <3

Good functional outcome (mRS 0-3) at 90 days - 46% vs 23%. ARR 23%, NNT 4.3

ATTENTION trial (NEJM 2022)

- 0-12 hours

Good functional outcome (mRS 0-3) at 90 days - 46% vs 24%. ARR 22%, NNT 4.5

BAOCHE trial (NEJM 2022)

- 60-24 hours

Acute Treatment - Continued
	Recommended intervention	Statistics	Evidence/Papers/Guidelines
Antiplatelet	Patients with acute ischaemic stroke should be given Aspirin as soon as possible (ideally within 48hrs of onset).	Fewer recurrent strokes in 14/7 (p < 0.001) In 14/7: 11 fewer deaths per 1000 treated In 6/12: 10 fewer deaths per 1000 treated Fewer recurrent strokes in 4/52 (p 0.01) In 4/52: 6.8 fewer deaths per 1000 treated On DC: 6.4 fewer deaths/dependency per 1000 treated In 3/52: 9 fewer cases of stroke or death in hospital per 1000 treated	IST study (LANCET 1997): Aspirin 300mg for 14 days vs. placebo. Primary outcomes assessed at 14 days and 6 months CAST study (LANCET 2007): Chinese population only. Aspirin 160mg for 4 weeks vs. placebo. Primary outcome – death from any cause in 4 weeks, death or disability on discharge IST+CAST pooled data
Blood pressure management	Patients for thrombolysis should have BP reduced to <185/110mmHg before treatment and in first 24 hours after treatment. Non-lysis patients with BP > 220/120 mmHg should have BP cautiously reduced (e.g. by no more than 20%) over the first 24 hours.	Mean SBP target in 3 separate groups did not alter outcome for patients. 51%, 52%, 39% (p value 0.27). Odds of good outcome greatest in group 2 (SBP 161-180mmHg) No difference in primary outcome in those given GTN vs. placebo. Adj OR poor outcomes 1.25, 95% CI 0.97-1.60, p = 0.08	MAPAS study (NeuroCrit Care 2019) Patients divided into 3 groups for SBP management in first 24hrs post ischaemic stroke. Group 1 140-160 mmHg, Group 2 161-180 mmHg, Group 3 181-200 mmHg RIGHT-2 study (STROKE 2019) Paramedic trial of stroke within 4hrs (using FAST) + SBP >120mmHg receiving GTN vs. placebo. Primary outcomes – mRS 90 days.
DVT prophylaxis	Chemical prophylaxis recommended - Enoxaparin is the preferred choice.	Unfractionated heparin vs. enoxaparin: Enoxaparin reduced VTE by 43% compared to heparin 28%, RR 0.57, 95% CI 0.44-0.76, p = 0.0001 Risk of bleed similar in both groups	PREVAIL Study (STROKE 2008) Unfractionated heparin vs. enoxaparin within 48hrs of ischaemic stroke. Primary outcomes – symptomatic/asymptomatic DVT, symptomatic or fatal PE.
	Intermittent Pneumatic Compression – is also effective	Use of IPC: VTE occurred in 8.5% compared to 12.1% in control. ARR 3.6%, RRR 0.69. No significant difference in skin breaks/falls. IPC patients had improved survival at 6 months	CLOTS 3 Study (LANCET 2013) Intermittent pneumonic compression (IPC – similar to SCUDS) applied to those with ischaemic stroke within 3 days. Primary outcome – silent/symptomatic DVT
	NOT RECOMMENDED - TED/Compression stockings	No significant improvement in DVT, increased risk of skin complications	CLOTS 1 Study (Lancet 2009)

Investigations/ Interventions
	*Recommended investigation*	*Statistics*	*Evidence*
Imaging - Acute	CT Brain (non-contrast) For all patients suspected of acute stroke.	Primarily to determine haemorrhagic cause or established infarct.
	Acute CT Angiogram (arch – cerebral vertex) For all patients who are potential candidates for ECR. MR Angiogram Consider if CI to CTA	To assess intracranial large vessel occlusion and state of proximal vessels for access. Can also be considered – however harder to do and le
	CT Perfusion Brain Patients who are candidates for ECR or delayed (>4.5hrs) IVTPA should have CTP to guide eligibility.
	MRI
Imaging - subacute	CTA/Carotid Doppler/MRA For patients with carotid territory symptoms who are candidates for carotid revascularisation	CTA/MRA allow imaging of rest of vascular tree to assess for alternative aetiology Carotid Doppler may be more accurate for quantification of significant stenosis MRA can be combined with Fat sat T1 imaging to confirm arterial dissection
Heart Rate Monitoring	24 hours Telemetry/Holter Consider in all stroke patients		Australian Stroke Guidelines 2017
Heart Rate Monitoring	Loop Recorder Consider in ESUS/Cryptogenic stroke	Long-term monitoring: AF detected 8.9% vs. 1.4% control. HR 6.4, 95% CI 1.9-21.7, p < 0.001. Long-term monitoring: AF detected 16% vs. 3.2% control. 95% CI, 8.0-17.6, p<0.001. AF >2.5mins 9.9% vs 2.5% control	CRYSTAL AF study (NEJM 2014) Long-term cardiac monitoring vs. conventional measures in those with cryptogenic stroke. Primary outcome – time to first detecting AF (>30sec) 6 months EMBRACE study (NEJM 2014) Long-term cardiac monitoring vs. control in those with cyptogenic stroke/TIA in last 6 months. Primary outcome – time to first detect AF (>30sec) in 90 days
Echo-cardiography	TTE should be considered in cryptogenic strokes and TIA as most cost effective option. TOE remains gold standard.	Sensitivity to detect LA thrombus with TTE 0.79 and specificity 1 compared to TOE.	Systemic Review – Routine echocardiography in the management of stroke and TIA. Economic analysis of both TTE + TOE for stroke work up assessed. (Holmes et al, 2014).
Echo-cardiography	TTE with bubble study should be performed to detect PFO in young patients (<60yrs) without alternative aetiology
Bloods	Routine bloods: FBC, electrolytes, renal function, cholesterol and glucose levels. Consider HbA1c if lacunar stroke/vascular risk factors/high blood sugar levels “Young stroke bloods” – looking for vaculitis/thrombotic causes should be considered in those < 50 years old with minimal risk factors		Australian Stroke Guidelines 2017

Secondary prevention

Recommended intervention

Statistics

Evidence/Papers

Antiplatelets

Acute ischaemic strokes not thrombolysed should receive antiplatelet therapy in first 24hrs – once haemorrhage excluded. Different antiplatelet options/trials below.

Australian Stroke Guidelines 2017

Aspirin alone

Aspirin lifelong after ischaemic stroke/TIA

Reduced recurrent stroke 60%, HR 0·42, 95% CI 0·32–0·55, p<0·0001 and disabling/fatal stroke 70%

HR 0·29, 95% CI 0·20–0·42, p<0·0001. Greatest benefit in TIA/minor stroke patients.

Meta-analysis: Effect of aspirin on risk and severity of early recurrent stroke after TIA and ischaemic stroke: time course analysis of randomised trials

- 12 trials of aspirin vs control data pooled

- Outcomes regardless of dose, aetiology of stroke

- Rothwell et al (LANCET 2016)

Clopidogrel vs. Aspirin

Clopidogrel slightly better than aspirin in long term secondary prevention

(more evidence to use DAPT in first 3/52 – see below trials)

Clopidogrel vs. Aspirin

Relative RR 7% with clopidogrel (p 0.043). No major differences in safety.

CAPRIE study (LANCET 1996)

Clopidogrel vs. aspirin to reduce risk of clinical thrombotic events (patients followed for 3yrs). Primary outcome – Ischaemic stroke, MI and vascular death.

Aspirin + Dipyrimadole (Asasantin)

Asasantin may be alternate to Aspirin.

Risk of headache with this combination. Requires slow up-titration.

** N.B. Asasantin no longer available in Australia**

Risk stroke or death reduced: 13% aspirin (p = 0.016), 15% dipyridamole (p = 0.015),

24% combination therapy

(p < 0.001).

ESPS-2 (J Neurol Sci 1998)

Patients with prior stroke/TIA randomized to aspirin alone (50 mg daily), modified-release dipyridamole alone (400 mg daily), the two agents in combination, or placebo. Primary outcomes – stroke or death.

Clopidogrel vs. Asasantin

Clopidogrel is similar to but not better than Asasantin in preventing recurrent strokes.

** N.B. Asasantin no longer available in Australia**

Clopidogrel vs. Asasantin

Recurrent strokes 9% Asasantin, 8.8% - Clopidogrel. Secondary outcome 13% each group.

PRoFESS study (NEJM 2008)

Clopidogrel vs. Asasantin in those with recent ischaemic stroke. Primary outcome – first recurrent stroke. Secondary outcome – stroke/MI/death from vascular causes. Patients followed for mean 2.5yrs

Clopidogrel + Aspirin

Give aspirin plus clopidogrel within 24hrs of ischaemic stroke and use:

- short term (3/52)

- in minor ischaemic stroke (NIHSS</=3)

- high-risk TIA (ABCD >/=4)

Long term use of combination should NOT be routine in stroke secondary prevention (may be used in selected cases or if co-morbid IHD/stents)

Australian Stroke Guidelines 2017

Clopidogrel + aspirin:

Major ischaemic events 5% vs. aspirin alone 6.5% HR 0.75, 95% CI 0.59-0.95, p = 0.02

Clopidogrel + aspirin:

Major bleed 0.9% vs aspirin 0.4% HR 2.32, CI 1.10-4.87, p = 0.02 Risk of haemorrhage increased after 30 days with minimal further benefit.

POINT study (NEJM 2018)

Clopidogrel and Aspirin given for for minor acute ischaemic stroke (NIHSS </=3) or high risk TIA (ABCD2 >/= 4). Primary outcome – risk of major recurrent stroke, MI, death from vascular event at 90 days.

Clopidogrel + aspirin:

Stroke 8.2% vs aspirin alone 11.7%

HR 0.68, 95%CI 0.57-0.81, p < 0.001

Mod-severe haemorrhage 0.3% both groups

CHANCE study (NEJM 2013)

Chinese population only. Clopidogrel and Aspirin given for minor acute ischaemic stroke (NIHSS </=3) or high risk TIA (ABCD2 >/= 4). Primary outcome – stroke (ischaemic or haemorrhagic) during 90 days

Clopidogrel + aspirin:

Stroke 15.7% vs. clopidogrel alone 16.7%. RRR 6.4% (95% CI -4·6- 16·3), ARR 1% (95% CI −0·6-2.7)

Non-significant difference.

Clopidogrel + aspirin: Increased risk of major bleeds, no difference in mortality

MATCH study (LANCET 2004)

Clopidogrel and Aspirin for up to 18 months in those with recent ischaemic stroke vs. Clopidogrel only. Primary outcome – recurrent stroke, MI, vascular death, rehospitalisation for ischaemia.

Clopidogrel + aspirin:

Reduced recurrent stroke by 20 in 1000. Increased mod-severe bleeding by 2 in 1000.

Meta-analysis: pooled data from all three trials – Clopidogrel + aspirin for minor stroke and high risk TIA most beneficial with minimal harm in first 21days

Blood pressure management

Patients with recent stroke or TIA and ongoing BP of > 140/90mmHg should have long term BP lowering therapy initiated.

Ideal long-term BP aim not well established.

Target SBP < 130mmHg may achieve greater benefit especially in strokes due to small vessel disease.

Higher BP target vs. lower target:

No significant reduction in all strokes HR 0.81, 95% CI 0.64-1.03, p = 0.08. Rate of ICH reduced in lower target group p = 0.03

Intense BP lowering significantly reduced risk of stroke [RR 0.71 (0.60-0.84)], major cardiovascular events [0.75 (0.68-0.85)]

Australian Stroke Guidelines

SPS 3 study (LANCET 2013)

Patients with recent lacunar strokes assigned to SBP targets of 130-149mmHg or less than 130mmHg. Primary outcome – reduction in all strokes (ischaemic and haemorrhagic). Assessed at 1 year.

Meta Analysis: Effect of BP lowering on outcome incidence in hypertension: effects of more vs. less intensive BP lowering and different achieved BP levels (Thomopoulos et al, 2016) – multiple RCTs assessed

Lipid management

Patients with ischaemic stroke and possible atherosclerotic contribution should have high dose statin if there is reasonable life expectancy.

New evidence to aim LDL < 1.8.

Fibrates are not routinely recommended for stroke prevention

Statins are not routinely recommended for haemorrhagic strokes

Atorvastatin vs placebo:

11% on atorvastatin vs. 13.1% on placebo had fatal/non-fatal stroke. ARR 2.2%, adj HR 0.84, 95% CI 0.71-0.99, p = 0.03.

LDL target of 1.8mmol/L vs. 2.3-2.8mmol/L vascular events 8.5% in lower target and 10.9% in higher target. Adj HR 0.78, 95% CI 0.61-0.98, p = 0.04

Australian Stroke Guidelines

SPARCL study (NEJM 2006)

Patients with stroke/TIA in last 6/12 and LDL 2.6-4.1mmol/L assigned to atorvastatin vs. placebo. Primary outcome - first non-fatal/fatal stroke. Median follow up 4.9 years.

Comparison of two LDL Cholesterol targets after ischaemic stroke (NEJM 2020)

France + South Korea population. Patients with ischaemic stroke/TIA in last 3/12 had LDL targets of 1.8mmol/L vs. 2.3-2.8mmol/L. Primary outcome – major vascular event (stroke, MI, CVS death)

Carotid surgery

Carotid endarterectomy recommended for recent (<3 months) non-disabling carotid artery territory ischaemic stroke/TIA if ipsilateral carotid stenosis measures 70-99%

Carotid endarterectomy should be preformed as soon as possible (ideally within 2/52) after ischaemic stroke/TIA

- Based on subgroup analysis

Carotid surgery vs. control:

Stroke/death 37% surgery vs. 36.5% control. Stenosis >80%, stroke/death at 3yrs 14.9% surgery vs. 26.5% in control.

CEA vs. control: reduced 5-year risk of death or stroke by 29% for symptomatic high-mod (50-69%) carotid stenosis

ECST study (LANCET 1998)

Patients with some degree of carotid stenosis and transient of minor strokes in distribution of carotid arteries in the last 6/12, had surgery vs. control. Primary outcome – major stroke or death.

NASCET study (STROKE 1999)

Patients with symptomatic carotid stenosis: low-moderate (<50%), high-moderate (50-69%) and severe (>70%) given CEA vs. control.

CEA can be considered in selected patients with recent (<3 months) non-disabling ischaemic stroke or TIA patients with symptomatic carotid stenosis of 50–69%

Carotid Endarterectomy preferred over Carotid Stenting in general

Stenting vs. CEA: increased peri-procedural outcomes (MI, stroke, death) with stenting, OR 1.31, 95% Ci 1.08-1.59

Meta-analysis - Carotid Artery Stenting vs. Carotid Endarterectomy, 13 RCTs (2011). Peri-procedural outcomes, intermediate and long term outcomes assessed.

Anticoagulation for AF

Anticoagulation recommended for patients with ischaemic stroke/TIA with AF (paroxysmal or permanent)

- DOAC over warfarin in non-valvular AF

- No preferences between DOACs

Indirect comparison Apixaban, Dabigatran, Rivaroxaban: similar efficacy with all three in stroke prevention. Reduced haemorrhagic stroke dabigatran vs. rivaroxaban HR 0.15, 95% CI 0.03-0.66

Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in AF: indirect comparison analysis. Primary outcome – secondary prevention of stroke.

- Rasmussen et al (BMJ 2012)

(Trial of each DOAC vs. warfarin for stroke prevention: RELY, ARISTOTLE, ROCKET-AF)

Restarting after ICH

See ICH section below

PFO closure

Recommended in patients

- aged < 60

- non-lacunar stroke

- no other aetiology for stroke found.

AF risk slightly increased with PFO closure

Summary: Overall benefit of closure with long term follow-up. All trials demonstrated low risk of recurrence in young patients with cryptogenic stroke. Risk of recurrence is late (c.f. carotid disease). All except DEFENCE-PFO use age limit for 60yrs.

Summary major trials:

Patent Foramen Ovale - story closed

(Kohrmann et al, 2019)

(GORE-REDUCE, CLOSE, DEFENSE-PFO, RESPECT)

ICH

Acute blood pressure management

Acute reduction of BP to around 140 (but not significantly below):

- is safe

- reduces haematoma expansion

- has no effect on mortality

- trend to reduced disability

No benefit.

Death or disability 38.7% vs 37.7% (RR 1.04, CI 0.85-1.27)

ATACH-2 Trial (NEJM 2016)

ICH (<60mm) and GCS >5 randomised to BP 110-139 vs BP 140-179. Within 4.5 hours of onset. Achieved mean BP was 129 vs 141.

Trend to benefit.

Death or disability 52% vs 55.6% (HR 0.87 CI 0.75-1.01).

Analysis of mRS outcomes showed slight shift to improved outcomes.

INTERACT2 NEJM 2013

ICH randomised to BP <140 within 1 hour vs std care with targe <180. Within 4.5 hours of onset. Achieved mean BP was ~140 vs 150.

3 month mortality OR 0.99 (CI: 0.82-1.2)

3 month death or dependency OR 0.91 (CI: 0.8-1.02)

ICH expansion OR0.82 (CI:0.68-1.00)

Meta-analysis (Boulouis JNNP 2017)

Caution if initial BP >220mmHg, consider less aggressive target.

Patients with initial BP >220mmHg treated with intensive BP management (vs standard BP control) had higher rate of neurological deterioration (15.5 vs6.8%) and renal AE 13.6% vs 4.2%) with no difference in disability or death.

ATACH-2 subgroup (JAMA Neurol 2020)

Restarting antiplatelets after ICH

Recurrent sICH

- 4% (antiplatelet) vs 9% (avoid) – after 2 years

- 8.2% vs 9.3% - after 3 years

Ischaemic stroke 7% vs 10% - after 2 years

Major vascular event – 26.8% vs 32.5%

Overall no significant differences – trends to improved outcomes with restarting.

RESTART trial Lancet 2019

Patients taking antiplatelet or anticoagulant who had ICH

Restart antiplatelet vs avoid

268pts each group. Started at median ~70-80 days post event.

Median F/U 2 years

RESTART trial 3yr F/U JAMA Neurol 2021

Restarting Anticoagulation after ICH

No clear recommendation

Low rate of recurrent ICH 8% (AC) vs 4% (no-AC) – NS

Any recurrent stroke (ICH or ischaemic) 11% vs 22%

SoSTART trial (Lancet Neurology 2021)

ICH, history of AF, CA2DS2-VASc at least 2

DOAC/Warfain vs Avoid anticoagulation

~100 patients in each group

Median retart time 115 days post ICH

Rapid Assessment

Recommended intervention

Statistics

Evidence/Papers/Guidelines

History

ROSIER Scale (score from -2 to 5)

Scale contains pertinent history and examination findings with negative/positive scores. Useful scale to suspect stroke/TIA

Consider Stroke if score ≥ 1

Sensitivity 93%

Specificity 83%

PPV 90%

NHMRC guidelines

*APPENDIX 1

Clinical Assessment

ACT-FAST Scale

Scale contains pertinent examination findings to prompt suspicion of large vessel occlusion

Designed for pre-hospital/paramedic assessment however useful to triage patients needing urgent CTA/CTP in ED

Sensitivity 85%

Specificity 88%

PPV 96%

(ACT-FAST) algorithmic pre-hospital triage tool for endovascular thrombectomy: ongoing paramedic validation – Zhao et al, BMJ 2018

*APPENDIX 2

NIHSS Score

Rapid assessment to identify deficits due to stroke.

- Small stroke (NIHSS < 4)

- Moderate stroke (NIHSS 5-15)

- Moderate-Severe stroke (NIHSS 16-20)

Australian Stroke Guidelines 2017

Strengths:

Reliable tool to rapidly assess stroke deficits

Limitations:

Heavily weighted towards Left Stroke

- 5 points for language

Less weight on Posterior Circulation Strokes

- Diplopia, vertigo, unsteady gait not assessed

APPENDIX 1: ROSIER scale

APPENDIX 2: ACT-FAST scale