ISCHEMIC STROKE / ACUTE THERAPY

Intravenous thrombolysis in acute stroke

Created 22/10/2021, last revision 21/04/2023

All patients with suspected acute stroke or TIA must require immediate clinical evaluation to establish a diagnosis and to determine eligibility for intravenous thrombolysis or/and endovascular thrombectomy (EVT).

intravenous thrombolysis (IVT) is the standard therapy for acute ischemic stroke → fibrinolytic drugs
- a clear benefit of treatment, NNT to achieve mRS 0-1 varies in different publications
  - 0-3h window – NNT 10, 3-4.5h time window – NNT 19 [Brunström, 2015]
  - 0-3h window – NNT 8, 3-4.5h time window – NNT 12 [Tsivgoulis, 2021]

start IVT ASAP in eligible patients! – the earlier thrombolysis is started, the greater the chance of achieving recanalization and the lower the risk of ICH, mortality, and dependency [Emberson, 2014]
- mortality: <3 h HR 1, 3-4.5 h HR 1.14, >4.5 h HR 1.22
- mRS 0-1: <3 h OR 1.68, 3-4.5h OR 1.26, >4.5 h OR 1.07
- every 15-minute delay in IVT administration reduces the chance of achieving mRS 0-1 by 16%

Patients eligible for both IVT and thrombectomy

IVT is also indicated in patients scheduled for endovascular treatment
- results of SWIFT-DIRECT and DIRECT-SAFE trials do not support omitting IVT before thrombectomy in eligible patients
- mechanical thrombectomy should not prevent the initiation of IVT, and IVT should not delay mechanical thrombectomy (do not wait for potential clinical/radiological/neurosonological improvement)
- IVT can be performed concomitantly with EVT, and there is insufficient evidence for premature termination of IVT before initiation of EVT
- transport from the Stroke Center to the Comprehensive Stroke Center should happen immediately after the initiation of IVT
the benefit of IVT before MT in patients with ASPECTS < 6 is uncertain (Broocks, 2022)

WUS patients within 4.5 hours of symptom recognition after wakeup

wake-up stroke (WUS) within 4.5 hours after symptom recognition after wakeup ⇒ IVT + MT (ESO guidelines 2022)
the selection criteria for IVT and MT in patients with WUS (ESO guidelines 2021)
- core < 70 ml (rCBF <30% on CTP or ADC < 620 μm²/s)
- mismatch ratio (penumbra/core) > 1.2 – penumbra defined as Tmax > 6s
- mismatch volume > 10 ml

Where should patients be thrombolysed?

the thrombolysis-eligible patient should preferably be treated at the Stroke Center or Comprehensive Stroke Center (CSC) and should be admitted to the ICU for at least the first 24h after IVT initiation
in the stroke center, the availability of emergency transport to the CSC (to perform endovascular treatment) should be arranged before starting IVT in patients with LVO

Thrombolytics

alteplase and more recently tenecteplase are the only fibrinolytic drugs recommended for intravenous thrombolysis (IVT) in stroke patients (ESO guidelines 2021)
- the risk of complications is comparable between those treated with tenecteplase versus alteplase for acute stroke (Rose, 2023)
based on the results of the ACT trial, a switch from tPA to TNK can be expected

Alteplase (ACTILYSE)

alteplase (ACTILYSE) is a tissue plasminogen activator and has long been the standard treatment for acute ischemic stroke
planned mechanical thrombectomy is not a reason to avoid IVT !!! → more
- non-randomized studies suggest better outcomes with combination therapy [Mistry, 2017] [Goyal, 2018]
- on the other hand, if the indication criteria for EVT are met, do not wait for the possible effect of IVT
in a 0-4.5 hour window prefer the standard dose (0.9 mg/kg) to a reduced dose (ESO guidelines 2021)

Tenecteplase (METALYSE)

tenecteplase (METALYSE) is an alternative to alteplase in 4.5h time window
- genetically modified tPA with enhanced fibrin specificity and longer half-life, allowing bolus administration
- according to registry data, TNK is associated with a lower risk of sICH compared to tPA → see here; in the ACT trial, however, the risk of bleeding was similar
at a dose of 0.25 mg/kg administered as a bolus, TNK is an alternative to tPA:
- in patients indicated for EVT – ESO guidelines 2021 prefer TNK in patients scheduled for MT (at a dose of 0.25 mg/kg)
  - the EXTEND-IA TNK trial showed a higher incidence of reperfusion and better functional outcome with TNK compared to tPA in patients with large artery occlusion (LVO) followed by MT (complete reperfusion 22% with TNK vs. 10% with alteplase)
  - a meta-analysis of 4 RCTs showed greater efficacy of TNK versus IVT in patients with LVO [Katsanos, 2020]
  - in ExTEND-IA trial part 2, a dose of 0.40 mg/kg versus 0.25 mg/kg did not significantly improve reperfusion before MT (Cambell, 2020)
- standard acute stroke patients eligible for IVT
  - randomized ACT trial (2022) showed non-inferiority of TNK at a dose of 0.25 mg/kg compared to tPA in the standard indication
  - a meta-analysis of 5 trials demonstrated the non-inferiority of TNK versus tPA [Burgos, 2019]
NOR-TEST 2 trial part A with TNK dose of 0,4 mg/kg was stopped prematurely for safety reasons (TNK did worse than tPA)

Relevant clinical trials

ALTEPLASE

NINDS – effect of tPA was demonstrated within 3h after stroke onset – mRS 0-1/3months.: 39% vs 26% (placebo)
ECASS 3 – tPA effect demonstrated within 4.5h window after stroke onset
SITS-MOST – effect of tPA within a 4.5 hours window
- analysis of SITS online registry data
- comparable results from routine clinical practice with results of randomized trials
EXTEND (2018)
- time window 4.5-9h, CTP mismatch ratio >1.2 + mismatch ≥ 10 ml
- mRS 0-1 /3m RR 1.44 (35.4% vs 29.5%)
the efficacy and safety of IVT indicated by CTP were also demonstrated in a meta-analysis of the EXTEND, ECASS-4/EXTEND, and EPITHET (mRS 0-1, OR 1.86) [Campbell, 2020].
WAKE-UP
- MR DWI/FLAIR mismatch
- OR 1.61 (mRS 0-1 53.3 vs 41.8)
- the effect also present with lacunar infarcts
MR WITNESS

TENECTEPLASE

NOR-TEST (bolus 0.4 mg/kg, maximum 40mg vs. tPA 0.9 mg/kg)
- n=1100, time window 4.5 h, median NIHSS 4
- similar results as tPA
EXTEND-IA TNK
- TNK 0.25 mg/kg versus tPA within 4.5 h
- large artery occlusion (LVO); TNK administered before subsequent mechanical thrombectomy
- better results than tPA
meta-analysis of 4 RCTs in patients with LVO [Katsanos, 2020]
- TNK vs tPA – mRS 0-2 OR 2.06, recanalization 3.05
NOR-TEST 2 part A (Norwegian Tenecteplase Stroke Trial 2)
- prematurely terminated
- TNK 0.4 mg/kg vs. TPA in moderate/severe ischemic stroke
- tenecteplase resulted in worse safety- and functional outcomes than alteplase did

ongoing studies comparing the effect of tPA and TNK:
- TASTE (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation)
- TEMPO-2 (Multicentre, Prospective Randomized Open Label, Blinded-End Point (PROBE)
- ACT (Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke: QuICR & OPTIMISE Registry Based Pragmatic Randomized Controlled Trial],
- TWIST (Tenecteplase in Wake-up Ischaemic Stroke Trial)

Advantages and disadvantages of IVT

no special equipment required
quick initiation of therapy
low costs

short therapeutic window
low efficacy in larger thrombosis (Clot Burden Score)
- larger artery occlusion = lower efficacy
- complete recanalization in terminal occlusion ICA ~10%, M1~20-30%
- recanalization (TIBI 2b/3) in m¨Medium-sized Vessel Occlusion (MeVO – mostly M2 segment) in approx. 42% [Ospel, 2020]
- according to the INTERRSECT study, recanalization of intracranial ICA and MCA occlusions is achieved in 27% of patients [Ohara, 2020]
bleeding risk (intracranial, but also systemic bleeding)
- various definitions of symptomatic IC bleeding. ~ 6-7% according to the NINDS definition
- risk is lower in the posterior circulation [Keselman, 2020]
numerous contraindications (many of which have become relative over time) [Tsivgoulis, 2021]

Indications for intravenous thrombolysis

Time from stroke onset (AHA/ASA 2018 and ESO guidelines 2021)

< 4.5 h

age ≥ 16 years
- the risk/benefit of treatment in individuals < 16 years of age is unknown
- since 2019, Actilyse is approved in patients aged 16-17 years based on SITS-ISTR registry data
the upper age limit of 80 years has been removed (ESO guidelines 2021)
- according to metanalysis, IVT is safe in patients > 80 years of age [Bluhmki, 2020]
- age alone should not be a limiting factor for IVT (even in wake-up stroke, an ischemic stroke of 4.5–9 h duration with CT or MRI mismatch, minor stroke with disabling symptoms, etc.)
ESO guidelines from 2021 recommend ACTILYSE 0.9 mg/kg for patients without subsequent EVT and METALYSE 0.25 mg/kg for patients with planned EVT
- tPA dose reduction is not recommended
initial non-contrast brain CT is normal or shows early ischemic changes of small or moderate extent (<1/3 MCA territory or ASPECTS ≥7)
- even in the presence of extensive early ischemic changes, IVT may be performed after careful risk-benefit consideration, but a worse outcome and higher risk of bleeding should be expected (ESO Guidelines 2021)
- IVT should not be performed in the presence of extensive marked hypodensities

> 4.5 h non-selected

IVT is accepted for basilar artery occlusion (BAO) outside the 4.5h window without the use of advanced imaging (perfusion, DWI/FLAIR mismatch)
absence of complete brainstem ischemia is required

4.5-9 h

advanced brain imaging should be used to select patients for treatment with alteplase if they present between 4.5 and 9 h after the symptom onset or if a stroke is detected on awaking from sleep (ESO guidelines 2021)
CT/MRI perfusion mismatch – EXTEND (2018) criteria (SO guidelines 2021)
- ≥ 18 years, premorbid mRS < 2, NIHSS 4-26
- time:
  - 4.5-9 h after onset (if the time of onset is known)
  - stroke present on awakening – IVT initiated within 9h of mid-sleep interval
- radiological parameters:
  - mismatch >1.2 , absolute >10 ml (Tmax >6 s on perfusion)
  - core < 70 ml – rCBF < 30% (CTP) or ADC < 620 mm²/s (DWI)
- results: mRS 0-1 /3m RR 1.44 (35.4% vs 29.5%)
- efficacy and safety were also demonstrated in a meta-analysis of the EXTEND, ECASS-4/EXTEND, and EPITHET trials (mRS 0-1, OR 1.86) [Campbell, 2020]
MR DWI/FLAIR mismatch (according to WAKE-UP trial criteria)
for patients without CT or MRI core/perfusion mismatch, the ESO 2021 guidelines suggest against IVT with alteplase
if the patient is a candidate for both IVT and MT in the 4.5-9 h window (according to the above criteria), then:
- initiate IVT before transport from the stroke center to the Comprehensive Stroke Center (CSC) (ESO guidelines 2021)
- if the patient is in a CSC, there is no consensus on whether to start IVT before MT (ESO guidelines 2021)

Wake Up Stroke (WUS) / Stroke of Unknown Time of Onset

according to a meta-analysis of the WAKE-UP, EXTEND, THAWS, and ECASS-4 studies, IVT is safe and effective in patients with persisting salvageable brain tissue (determined by advanced CT/MR techniques) [Thomalla, 2020]
- therapy with tPA resulted in a higher percentage of patients with no or minor neurological deficit than the use of placebo
MR DWI/FLAIR mismatch – DWI lesion without a correlate on FLAIR, with a DWI lesion < 1/3 of the MCA territory (AHA/ASA 2019 IIa/B-R) (ESO guidelines 2021)
- in the absence of changes on FLAIR, the predicted stroke duration is < 4.5h – see positive results of the WAKE-UP trial
CT/MR perfusion (perfusion mismatch on CT or MR – see EXTEND study criteria above) (ESO guidelines 2021)
- IVT administered within 9 hours of mid-sleep interval
if the patient is a candidate for both IVT and EVT, then IVT is likely to be administered before EVT (ESO Guidelines 2021, expert consensus)

indication for IVT based on ASPECTS score on NCCT – ESO guidelines 2021 recommend advanced imaging in the time window of > 4.5h or WUS
- however, it appears safe to thrombolyse patients with wake-up stroke and a normal NCCT; similar results have been reported in patients with witnessed-onset and wake-up strokes and normal CT (Armon, 2019)
  - patients with WUS < 4.5h after awakening or patients with an unclear stroke onset time
  - NCCT: normal findings or early ischemic changes in < 1/3 of the MCA territory and/or ASPECTS > 7
- non-randomized TRUST-CT trial showed benefit in patients with ASPECTS ≥ 7 (OR 1.94 ) – RCTs are needed

A neurological deficit

Mild deficit → see comments on IVT contraindications

mild disabling deficit (mild stroke – NIHSS 0-5, e.g., homonymous hemianopsia, mild aphasia or dysarthria in an actor, mild paresis in a pianist, etc.) ⇒ IVT is recommended (ESO guidelines 2021) (AHA/ASA 2019 I/B-R)
mild non-disabling deficit: IVT is not recommended (ESO guidelines 2021) (AHA/ASA 2019 III/B-R)
mild non-disabling deficit + LVO ⇒ IVT is suggested, but an individualized approach is required (ESO 2021 – expert consensus)
- neurological deficits may fluctuate; many patients with acute arterial occlusion will eventually progress if recanalization is not achieved (END – Early Neurological Deterioration)
- CT perfusion with the RAPID system is a valuable tool in the detection of peripheral occlusions
rapidly improving but still disabling deficit ⇒ IVT is suggested (ESO 2021 – expert consensus)
thrombolysis for central retinal artery occlusion (CRAO) → see separate chapter here

A severe stroke

the benefit of IVT in patients with NIHSS > 25 is unclear; IVT may be considered a life-saving procedure (ESO guidelines 2021)
the extent of early ischemic changes that could be considered futile for thrombolytic therapy is not clear
- however, ASPECTS < 7 has been shown to increase the risk of sICH [Singer, 2009]
- according to ESO guidelines 2021 (expert consensus), patients with NIHSS > 25 and/or ASPECTS < 7 should probably be treated with IVT
- selection criteria may include results of advanced imaging (especially core/perfusion mismatch), the extent of white matter lesions, other contraindications to IVT, and pre-stroke disability
direct mechanical thrombectomy (dMT) is recommended

Contraindications

→ see a separate chapter

Administration of thrombolytic therapy

Start thrombolysis as soon as possible after the patient arrives at the hospital. No investigation should delay its initiation.
The Door-To-Needle Time (DTN) should be less than 45-60 minutes; in uncomplicated patients, the bolus can usually be injected within 10-15 minutes.
Urgently consult with a stroke specialist within the institution or through telestroke services if needed.

Initial patient assessment and monitoring

focus on ultra-fast administration of the IVT bolus (less than 10-15 minutes in an uncomplicated patient!)
- the procedure requires logistical arrangements within the stroke center
- many centers no longer insert a urinary catheter, second IV cannula, or perform an ECG before IVT administration
- it is a good idea to check contraindications by phone or in the documentation before the patient arrives
- pre-hospital mobile stroke units are also being tested to expedite treatment. The cost-benefit is still uncertain; one analysis showed no better mRS 0 and 1 compared to standard care; however, there was no higher incidence of hematoma [Kunz, 2016]
perform rapid clinical examination including assessment of NIHSS and vital signs, verify the time of onset and contraindications → initial examination of an acute stroke patient
perform non-contrast CT (NCCT) of the brain (sufficient for IVT indication)
- there is no known threshold for the extent of early CT signs of ischemia that should lead to withholding IVT unless there is a known contraindication
- hyperdense media sign is not a contraindication to IVT (AHA/ASA 2019 IIa/B-NR)
- routine use of MRI to exclude microbleeds is not recommended (AHA/ASA 2019 I/B-NR)
always consider the risk-benefit of IVT (AHA/ASA 2019 I/C-EO)
minimize the risk of stroke mimics (especially exclude hypoglycemia); imaging is helpful (especially CTA/CTP)
do not wait for coagulation test results unless:
- there is reasonable suspicion of thrombocytopenia or a bleeding disorder (from patient history)
- anticoagulant use is uncertain but possible
- the patient is taking anticoagulants ⇒ follow a specific protocol for IVT in anticoagulated patients
if no contraindication is found, administer tPA/TNK bolus
proceed with CTA/CTP and consider thrombectomy

Infusion preparation, dose

Actilyse

vials with alteplase (10mg, 20mg, or 50mg) are diluted with the supplied solution
infusion dilution: 1mg/1mL
do not dilute this solution further and do not administer it with other drugs (use separate IV cannula)

ACTILYSE 0.9 mg/kg
- 10% as an initial intravenous bolus over 2 minutes
- the rest (90%) is given as an intravenous infusion over 60 minutes
- the maximum dose for stroke is 90 mg
if laboratory results show INR > 1.7, aPTT values above the Upper Limit of Normal (ULN), or platelet count < 100 000/μL, IVT must be discontinued immediately

Metalyse

the vial of tenecteplase (10 000 units/50 mg) is diluted with the supplied solution (10 mL); the solvent is added to the powder
final dilution: 1mL/1000 IU/5mg → more
do not further dilute the solution or administer it with other medications (use a separate cannula)
discontinue IVT immediately if INR > 1.7, aPTT above the ULN, or platelet count < 100 000/μL is detected in the blood sample

dosage
- thrombolysis alone (according to the NOR-TEST study) – bolus 0.4 mg/kg (0.08 mL/kg), maximum 40mg
- thrombolysis preceding MT (according to the EXTEND-IA TNK study) – bolus 0.25 mg/kg (0.05 mL/kg)

TCCD monitoring during intravenous thrombolysis - complete recanalization of occluded MCA was achieved

Basilar artery occlusion on NCCT (dense artery sign)

Care during thrombolysis

monitor vital signs
blood pressure (BP) should be lowered and maintained below 180/105 mmHg before, during, and 24 hours after IVT administration (BP > 185/110 mmHg is a contraindication to thrombolytic treatment) (AHA/ASA 2022)
- check BP every 15 minutes in the first 2h, then every 30 min for the next 22 hours
- in decompensated hypertension and on parenteral antihypertensive therapy, measure more frequently (every 3-5 min) → protocol for BP correction during IV
- aggressive BP correction in the first 72 h (BPs < 130140 mmHg) leads to a reduction in ICH risk (14.8% vs. 18.7%) according to the ENCHANTED study, but therapy did not affect the outcome (mRS/3m). Patients with mild and moderate deficits were included in the study [Anderson, 2019])
- avoid abrupt drops in blood pressure because this might worsen or induce ischemia, particularly in the setting of intracranial or extracranial arterial occlusion/stenosis
monitor for bleeding complications (injection sites, oral cavity, GIT, genitourinary tract, site of injury) and allergic reactions, including angioedema (→ more here)
monitor NIHSS / GCS
- if NIHSS increases by ≥ 4 points (which can not be attributed to, e.g., TCCD-demonstrated reocclusion) and in case of new-onset severe headache, consider stopping IVT and order CT scan
TCD/TCCD monitoring
- repeat quick examinations with TIBI assessment only; continuous monitoring (sonothrombolysis) is not recommended beyond clinical trials

in patients with large-artery occlusion (LVO), arrange endovascular intervention at the start of IVT and do not wait for the completition of IVT (the chance of LVO recanalization with IVT alone is low; <10% for terminal ICA occlusion)
- transport the patient to the center performing EVT immediately after the initiation of IVT
criteria of probable persistent occlusion:
- no clinical improvement (<40% NIHSS reduction)
- TCD/TCCD TIBI ≤ 3

Post-thrombolysis monitoring

check blood samples
- CBC and coagulation (aPTT, INR, fibrinogen) at 6 and 24 h post-IVT
- basic metabolic panel at 12-24 h
follow-up NCCT of the brain at 22-36 h
continue strict BP control for the first 24h (< 180/105 mm Hg)
insert urinary catheter either before thrombolysis or > 60 minutes after completion of IVT
do not insert a nasogastric tube or central venous catheter (CVC), and do not perform arterial puncture in the first 24 h
- in an emergency, wait at least 30 minutes after infusion; APTT and INR must be normal
- prefer puncture of the femoral vein rather than the subclavian vein
avoid IM injections during thrombolysis and 60 minutes after completion of IVT
avoid anticoagulation therapy in the first 24h after IVT
- even prophylactic doses of LMWH should be delayed for 24h ⇒ use mechanical prevention of DVT (IPC) instead
antiplatelet therapy in the first 24h:
- do not administer IV aspirin within 90 minutes after starting IVT (ARTIS study) (AHA/ASA 2019 III/B-R)
- do not administer abciximab concomitantly with IVT
- standard antiplatelet therapy should be started after 24h if a hemorrhagic complication has been excluded by follow-up CT
- antiplatelet therapy may be given within 24h after IVT if there is evidence of benefit in comorbidities (e.g., in a patient after acute stenting, with concomitant acute MI, etc.) (AHA/ASA 2019 IIb/B-NR)

→ antiplatelet therapy in the acute phase of stroke see here

Complications

→ see separate chapter