Ghid ESO 2021 Tromboliza Intravenoasa

Guideline
European Stroke Journal

European Stroke Organisation (ESO) 0(0) 1–62
! European Stroke Organisation
guidelines on intravenous thrombolysis 2021

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for acute ischaemic stroke DOI: 10.1177/2396987321989865
journals.sagepub.com/home/eso
Eivind Berge1,*, William Whiteley2,*, Heinrich Audebert3,

Gian Marco De Marchis4, Ana Catarina Fonseca5 ,
Chiara Padiglioni6, Natalia P
erez de la Ossa7, Daniel Strbian8,
Georgios Tsivgoulis9,10 and Guillaume Turc11,12,13
Abstract
Intravenous thrombolysis is the only approved systemic reperfusion treatment for patients with acute ischaemic stroke.
These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in
their clinical decisions with regard to intravenous thrombolysis for acute ischaemic stroke. These guidelines were
developed based on the ESO standard operating procedure and followed the Grading of Recommendations,
Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical ques-
tions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence,
and wrote recommendations. Expert consensus statements were provided if not enough evidence was available to
provide recommendations based on the GRADE approach. We found high quality evidence to recommend intravenous
thrombolysis with alteplase to improve functional outcome in patients with acute ischemic stroke within 4.5 h after
symptom onset. We also found high quality evidence to recommend intravenous thrombolysis with alteplase in patients
with acute ischaemic stroke on awakening from sleep, who were last seen well more than 4.5 h earlier, who have MRI
DWI-FLAIR mismatch, and for whom mechanical thrombectomy is not planned. These guidelines provide further
recommendations regarding patient subgroups, late time windows, imaging selection strategies, relative and absolute
contraindications to alteplase, and tenecteplase. Intravenous thrombolysis remains a cornerstone of acute stroke man-
agement. Appropriate patient selection and timely treatment are crucial. Further randomized controlled clinical trials
are needed to inform clinical decision-making with regard to tenecteplase and the use of intravenous thrombolysis
before mechanical thrombectomy in patients with large vessel occlusion.
Keywords
Ischaemic stroke, thrombolysis, fibrinolysis, recommendations, thrombectomy
Date received: 30 October 2020; accepted: 27 December 2020
8
Department of Neurology, Helsinki University Hospital and University
1 of Helsinki, Helsinki, Finland
Department of Internal Medicine and Cardiology, Oslo University 9
Second Department of Neurology, Attikon University Hospital, School
Hospital, Oslo, Norway
2 of Medicine, National and Kapodistrian University of Athens, Athens,
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh,
Greece
UK 10
3 Department of Neurology, University of Tennessee Health Science
Klinik und Hochschulambulanz für Neurologie, Charite
Center, Memphis, TN, USA
Universit€atsmedizin Berlin & Center for Stroke Research Berlin, Berlin, 11
Department of Neurology, GHU Paris Psychiatrie et Neurosciences,
Germany
4 Hopital Sainte-Anne, Universite de Paris, Paris, France
University Hospital of Basel & University of Basel, Department for 12
INSERM U1266
Neurology & Stroke Center, Basel, Switzerland 13
5 FHU NeuroVasc
Department of Neurosciences and Mental Health (Neurology), Hospital
Santa Maria-CHLN, Faculdade de Medicina, Universidade de Lisboa, *These authors contributed equally to this work.
Lisboa, Portugal
6
Neurology Unit-Stroke Unit, Gubbio/Gualdo Tadino and Città di Corresponding author:
Castello Hospitals, USL Umbria 1, Perugia, Italy Guillaume Turc, GHU Paris Psychiatrie et Neurosciences, Site Sainte-
7
Stroke Unit, Department of Neurology, Germans Trias i Pujol Hospital, Anne, 1 Rue Cabanis, 75014 Paris, France.
Badalona, Spain Email: [email protected]
2 European Stroke Journal 0(0)
In memory of Professor Eivind Berge Therefore, we set out to provide guidelines on the
use of intravenous thrombolytics for stroke physicians
in Europe. We sought to update previous guidelines
from the European Stroke Organisation (ESO).1
Since 2008, new randomised controlled clinical trials
(RCTs) have added to our knowledge. Here we
review and make recommendations from randomized
and observational studies that support a wider use of
IVT, particularly about patient selection in late time
windows and in patients with relative contraindication
to alteplase.
In this document, we outline the current state of the
evidence on the effect of IVT in different patient sub-
groups and time windows, with different thrombolytic
agents, and with different imaging selection strategies.
This guideline was co-chaired and led by Professor We hope to facilitate decision-making in patients where
Eivind Berge, Consultant Cardiologist at the there is uncertainty about eligibility for IVT.
Department of Internal Medicine at Oslo University
Hospital. The ESO IVT guideline module working
group deeply felt the loss of his calm leadership,
Methods
thoughtfulness, and thoroughness after his death. This guideline was initiated by the ESO and prepared
Any mistakes or omissions are ours alone. according to the ESO standard operating procedure,4
which is based on the Grading of Recommendations,
Assessment, Development and Evaluations (GRADE)
Introduction system.5 The ESO Guideline Board and Executive
Intravenous thrombolysis (IVT) with alteplase is the Committee reviewed the intellectual and financial dis-
only approved systemic reperfusion treatment for closures of all module working group (MWG) mem-
patients with acute ischaemic stroke.1 The drive to bers (Supplemental Table 1) and approved the
reduce times to IVT has led to more rapid treatment composition of the group, which was chaired by
for stroke patients in some areas of Europe. It has Eivind Berge and William Whiteley up to January
blazed the trail for early stroke unit care, mechanical 2020. Following the sad death of Eivind Berge, the
thrombectomy, and reduced disability due to stroke MWG was chaired by Guillaume Turc and William
where this treatment is available. The widespread avail- Whiteley.
ability of IVT is a mark of success for researchers, The steps undertaken by the MWG are summarized
stroke physicians and health care planners. as follows:
However, the use of IVT varies across Europe, and
demonstrates the ‘inverse care law’2: in those areas of 1. A list of topics of clinical interest to Guidelines’
Europe where disability due to stroke in the mid-years users was produced and agreed by all MWG mem-
of life is the highest, IVT use is amongst the lowest. bers, avoiding: intra-arterial thrombolysis, mechan-
Those people who live in more rural areas, outside ical thrombectomy, early secondary prophylactic
University centres with large hospitals and in countries treatment after IVT, service provision or delivery
with more modest incomes have less access to IVT, a of treatment (e.g. thrombolysis in a spoke hospital
marker of access to acute stroke care.3 Another reason before transfer to stroke hub [‘drip and ship’], or
for the low IVT treatment rates in acute ischaemic thrombolysis in a hub hospital with rapid access to
stroke patients may be related to the strict inclusion a thrombectomy suite [‘mothership’]), drugs other
and exclusion criteria of pivotal randomized- than alteplase and tenecteplase (e.g. desmoteplase,
controlled clinical trials. streptokinase, urokinase), stroke in children, and
A well-functioning health care system is needed to stroke in pregnancy or in the peripartum period.
provide rapid IVT to patients with acute stroke: emer- 2. A list of relevant outcomes was produced and the
gency dispatch centres, primary care, ambulance serv- MWG used the Delphi method to score their impor-
ices, emergency departments, radiologists, and stroke tance (mean score from 10 respondents on a scale
teams coordinated by a vascular neurologist or a stroke from 1 to 10):
physician. A stroke physician needs to ensure optimal • Functional outcome including death (modified
patient selection, and rapid decision making because Rankin Scale [mRS] scores 0–6): 8.3
IVT is more effective when given sooner after stroke. • Symptomatic intracranial haemorrhage (sICH): 7.6
Berge et al. 3
• Death: 7.4 and each outcome, the risk of bias was assessed
• Quality of life: 6.2 and quality of evidence was rated as high, moderate,
• Imaging-measured recanalisation: 5.9 low or very low based on the type of available evi-
• Major extracranial bleeding: 5.7 dence (randomized or observational studies) and
• Neurological outcome (e.g. NIHSS score): 5.5 considerations on inconsistency of results, indirect-
• Imaging-measured final infarct size: 4.7 ness of evidence, imprecision of results, and risk of
bias.5 GRADE evidence profiles/summary of find-
Based on this vote, functional outcome was the out- ings tables were generated using GRADEPro.
come of highest priority and was considered first, fol- 9. Each PICO group addressed their respective PICO
lowed by sICH and death. Unless specified otherwise, question by writing up to three distinct paragraphs.
‘excellent’ and ‘good’ outcome were defined as three- First, a paragraph named ‘Analysis of current evi-
month mRS scores of 0–1 and 0–2, respectively. Unless dence’, in which the results of the dedicated RCTs
specified otherwise, ‘better functional outcome’ corre- were summarized and briefly discussed. Where no
sponded to a reduction of at least one point in the mRS RCT was available, this paragraph described results
score at three months. sICH was defined according to of systematic reviews of non-randomized studies. At
each study’s original criteria. In case of limited data for the end of the first paragraph, an evidence-based
the outcomes of highest importance, outcomes of lesser recommendation was provided, based on the
importance were also considered. GRADE methodology. The direction, the strength
and the formulation of the recommendation were
3. The MWG formulated a list of Population, determined according to the GRADE evidence pro-
Intervention, Comparator, Outcome (PICO) ques- files and the ESO standard operating procedure.
tions, which were reviewed and subsequently Second, an ‘Additional information’ paragraph
approved by the ESO Guideline Board and could be added to provide more details on random-
Executive Committee. ized trials mentioned in the first paragraph, to sum-
4. The main recommendations were based on a sys- marize results of observational studies, or to provide
tematic review of RCTs of IVT versus control. To information on ongoing or future trials. Third,
this aim, we have updated the results of a previously according to the first addendum to the ESO stan-
published systematic review that was conducted up dard operating procedure, an ‘Expert consensus
to March 2012.6 We have applied the same search statement’ paragraph was added whenever the
strategy6 for a period from March 2012 to May PICO group considered that insufficient evidence
2020. We have also included relevant literature pub- was available to provide evidence-based recommen-
lished afterwards in the final manuscript. dations for situations in which practical guidance is
5. The authors independently screened the titles and needed for the everyday clinical practice. In that
abstracts of the publications identified by the elec- particular case, a pragmatic suggestion was provid-
tronic search and assessed the full text of potentially ed, with the results of the votes of all MWG mem-
relevant RCTs. bers on this proposal. Importantly, the suggestions
6. For each PICO question, a PICO group consisting provided in this paragraph should not be mistaken
of two or three MWG members was formed. as evidence-based recommendations.
Whenever no RCT was available on a certain 10. The Guideline document was subsequently reviewed
topic, each PICO group conducted a literature several times by all MWG members and modified
search to identify systematic reviews of non- until a consensus was reached. Finally, the
randomized studies or key observational studies. Guideline document was reviewed and approved
7. Whenever appropriate, random-effects meta-analy- by external reviewers and members of the ESO
ses were conducted using Stata software version 11.0 Guideline Board and Executive Committee.
(Statacorp). Results were summarized as odds ratios
(ORs) or common odds ratio (cOR) and their 95%
confidence intervals (CIs). Heterogeneity across Results
studies was assessed using the I2 statistic.
Heterogeneity was classified as moderate (I2
1. Treatment within 4.5 h of onset
30%), substantial (I2 50%), or considerable (I2 PICO 1.1: In patients with acute ischaemic stroke of <4.5 h
75%).7 duration, does intravenous thrombolysis with alteplase lead to
8. The results of data analysis were imported into the better functional outcome than no intravenous thrombolysis?
GRADEpro Guideline Development Tool Analysis of current evidence. Two summaries provide
(McMaster University, 2015; developed by evidence for this question: a systematic review and
Evidence Prime, Inc.). For each PICO question meta-analysis of study-level data from 10 RCTs by
Figure 1. Pooled odds ratio for excellent outcome (mRS 0–1) in patients treated with IVT vs. control in the 0–4.5 h time window.
The numbers and the ORs for the two time subgroups are from the individual patient data meta-analysis of nine RCTs by
Emberson et al.
Wardlaw et al. (6887 patients)6 and an individual par- Additional information. The study-level systematic
ticipant data meta-analysis from 9 RCTs by Emberson review showed that alteplase increased the odds of
et al. (6756 patients).8 These reviews included patients sICH (OR 3.72, 95% CI: 2.98–4.64, P ¼ 0.00001,
with a wide range of ages and stroke severities. I2 ¼ 28%) and of fatal intracranial haemorrhage
The study level meta-analysis demonstrated that within 7–10 days (OR 4.18, 95% CI: 2.99–5.84,
alteplase within six hours of stroke onset reduced the p < 0.00001, I2 ¼ 0.0%).6 Although alteplase was asso-
risk of death or disability defined as a mRS score of ciated with an excess of early deaths, it had no clear
3–6 [odds ratio (OR) 0.84, 95% CI: 0.77–0.93, effect on death by the end of follow-up (OR 1.06, 95%
P ¼ 0.0006, I2 ¼ 63%], and that the effect was greatest CI: 0.94–1.20, P ¼ 0.34, I2 ¼ 38%).
within three hours (OR 0.68, 95% CI: 0.53–0.87, The meta-analysis of individual patient data showed
P ¼ 0.002, I2 ¼ 0.0%). that IVT with alteplase significantly increased the risk
The individual participant data meta-analysis was of sICH defined as parenchymal haemorrhage of type 2
consistent with these results. It showed that alteplase (OR 5.55, 95% CI: 4.01–7.70, p < 0.0001) or fatal hae-
significantly increased the odds of excellent outcome morrhage within seven days (OR 7.14, 95% CI: 3.98–
(no or non-disabling symptoms, mRS score 0–1) at 12.79, p < 0.0001).8 The absolute excess risk of intra-
three months (six months in the third International cranial haemorrhage increased with increasing stroke
Stroke Study [IST-3]9), with earlier treatment resulting severity, but the absolute risk of haemorrhage was
in greater proportional benefit (p for inter- less than the benefit from treatment with alteplase at
action ¼ 0.016). Alteplase significantly increased the all levels of stroke severity: for the average patient
odds of an excellent outcome when given within treated within 4.5 h the absolute increase in the propor-
three hours (OR 1.75, 95% CI: 1.35–2.27, p < 0.0001) tion of patients with a mRS score of 0 or 1 (6.8%, 95%
from 3 to 4.5 h (OR 1.26, 95% CI: 1.05–1.51, CI: 4.0–9.5) exceeded the absolute increase in risk
P ¼ 0.0132, Figure 1), but not after 4.5 h (OR 1.15, of fatal intracranial haemorrhage (2.2%, 95% CI:
95% CI: 0.95–1.40, P ¼ 0.15). 1.5–3.0).10
The overall quality of evidence was rated as high, The meta-analysis of individual patient data showed
with no serious risk of bias, inconsistency, indirectness, that the early excess case fatality caused by intracranial
or imprecision (Table 1). haemorrhage did not translate into a significant excess
case fatality at 90 days in patients treated in the 0–4.5 h
Recommendation time window (HR 1.08, 95% CI: 0.94–1.24, P ¼ 0.27,
Figure 2).8 With longer follow-up, there was no evi-
For patients with acute ischaemic stroke of <4.5 h dence of reduced survival in alteplase-treated patients
duration, we recommend intravenous thrombolysis
at 18 months,11 and at 3 years there was a non-
with alteplase.
significant risk difference in favour of alteplase (risk
Quality of evidence: High 丣丣丣丣
difference 3.6%, 95% CI: –0.8 to 8.1%).12
Strength of recommendation: Strong ""
It has been recently argued that the evidence sup-
porting the use of IVT 3–4.5 h after stroke is frail, and
Berge et al. 5
that imbalance in baseline NIHSS score may have been
Importance
CRITICAL
CRITICAL
solely responsible for the positive results of the
ECASS-3 trial.13 However, the individual participant
data meta-analysis by Emberson et al. does provide
support for this time window, and did adjust for
NIHSS score at baseline.8
Although IVT is currently recommended prior to
Certainty
mechanical thrombectomy,14 there is a debate about

⨁⨁⨁⨁
⨁⨁⨁⨁
HIGH
HIGH
whether IVT is necessary for patients directly arriving
at stroke centre with thrombectomy capability. The
(from 12 more
fewer to 38
recently published Direct Intraarterial Thrombectomy
82 more per
13 more per
in Order to Revascularize Acute Ischemic Stroke
to 159
more)
more)
Absolute
(95% CI)
(from 10
1 000
1 000
Patients with Large Vessel Occlusion Efficiently in
Chinese Tertiary Hospitals Multicenter Randomized
Clinical Trial (DIRECT-MT) suggested that direct
(1.06–2.02)
(0.94–1.24)
mechanical thrombectomy alone was non-inferior to

(95% CI)
OR 1.46
HR 1.08
Relative
mechanical thrombectomy preceded by IVT with alte-

Effect
plase (0.9 mg/kg) administered within 4.5 h after symp-

tom onset (n ¼ 656, adjusted cOR for better functional
608/2199
395/2199
outcome at three months 1.07, 95% CI: 0.81–1.40;

(27.6%)
(18.0%)
no IVT
P ¼ 0.04).15 However, the trial had a liberal non-

No of patients
inferiority margin (20%); a long onset-to-IVT time

(median approximately 184 min); and very short delay
744/2162
407/2162
Note: Results based on the individual patient data meta-analysis of nine RCTs by Emberson et al. and Figures 1 and 2.
alteplase
IVT with
(34.4%)
(18.8%)
from start of IVT to groin puncture (median approxi-

mately 29 min). In addition, alteplase was not reim-
bursed in the setting of DIRECT MT, which may
considerations
have resulted in delaying the allowed time for consent-

ing the patient and in further delaying the door to
Other
needle time (median 59 min). Moreover, 31 patients in

none
none
the bridging therapy (IVT plus mechanical thrombec-

tomy) group did not receive endovascular thrombec-
Imprecision
not serious
not serious
tomy, while another 30 patients from the same group

did not receive any or the full-dose of alteplase.16 The
proportion of patients with successful reperfusion after
thrombectomy (eTICI 2 b) was 79.4% vs. 84.5% (OR
Indirectness
not serious
not serious
0.70, 95% CI: 0.47–1.06) in the direct mechanical

thrombectomy and the bridging therapy groups,
respectively. sICH occurred in 4.3% and 6.1% of
patients in the direct thrombectomy and bridging ther-
Inconsistency
not serious
not serious
apy groups, respectively (OR 0.70, 95% CI: 0.36–1.37).

Table 1. GRADE evidence profile for PICO 1.1.
Other trials comparing direct mechanical thrombec-

mRS 0–1 at three months (six months in IST-3)
tomy and bridging therapy in mothership patients

with large vessel occlusion are ongoing
(NCT03192332, NCT03494920, ISRCTN80619088).
not serious
not serious
Whether IVT is effective in patients with lacunar

stroke has been debated. In the subgroup of patients
of bias
Risk
with clinically defined lacunar infarct in the National

Institute of Neurological Disorders and Stroke
Death at three months
(NINDS) tPA trial (13% of enrolled patients), the

randomised
randomised
Certainty assessment
OR for excellent outcome was 2.53 (95% CI: 1.00–

trials
trials
6.37; P ¼ 0.047).17 In patients with clinically defined

design
Study
lacunar infarct in IST-3 (11% of enrolled patients),

the adjusted OR for good functional outcome at
studies
No of
six months was 0.91 (0.48–1.72). However, there was

no evidence of heterogeneity of the effect of IVT
9
9
Figure 2. Pooled hazard ratio for death at three months in patients treated with IVT vs. control in the 0–4.5 h time window.
The numbers and the HRs for the two time subgroups are from the individual patient data meta-analysis of nine RCTs by
Emberson et al.
across stroke clinical syndromes (P for inter- 90 days. Although there are ongoing discussions
action ¼ 0.46).9 In a post-hoc analysis of participants about the use of IVT in acute stroke in particular cir-
with MRI-defined lacunar stroke from the Efficacy and cumstances – before thrombectomy, in patients with
Safety of MRI-Based Thrombolysis in Wake-Up lacunar stroke, and in patients with no visible large
Stroke (WAKE-UP) trial (21% of included patients), artery occlusion – there is currently no strong evidence
the OR for excellent outcome was 1.68, 95% CI: 0.78– that it should be avoided.
3.69, without evidence of heterogeneity of the effect of
IVT in participants with lacunar stroke or other stroke 2. Treatment between 4.5 and 9 h after known onset
types (P for interaction ¼ 0.94).18 without use of advanced imaging
Vessel occlusion status was not available for the
majority of patients included in pivotal trials of IVT PICO 2.1 In patients with acute ischaemic stroke of 4.5–9 h
vs. no IVT, in which the imaging modality of choice duration (known onset time) selected with plain CT, does
was plain CT. In IST-3, there was a non-significant intravenous thrombolysis with alteplase lead to better
trend toward a better effect of IVT in patients with functional outcome than no intravenous thrombolysis?
obstructed (cOR for better functional outcome 1.86; Analysis of current evidence. The great majority
95% CI: 0.76–4.53) versus patent (OR, 0.72; 95% CI: (98.5%) of patients included in an individual partici-
0.42–1.25) arteries (P for interaction ¼ 0.075).19 pant meta-analysis of 9 RCTs were randomized after
However, the number of patients without arterial brain imaging with plain CT.8 In 6 RCTs, patient could
occlusion was modest (n ¼ 140). A study-level meta- be randomized beyond 4.5 h and up to 6 h after symp-
analysis suggested a significant interaction, but the tom onset (1229 patients treated with alteplase vs. 1166
thrombolytic used in 3 of the 5 included RCTs was receiving placebo).9,21–25 This individual participant
desmoteplase rather than alteplase.19 A post-hoc anal- data meta-analysis showed no evidence of significant
ysis of the WAKE-UP trial was presented at the ESO benefit of alteplase compared to placebo after 4.5 h of
Conference in 2019 but has not been published yet.20 stroke onset or when last seen well (OR for excellent
Among patients who underwent time-of-flight magnet- outcome at 3–6 months: 1.15, 95% CI: 0.95–1.40).8
ic resonance angiography (96% of the whole cohort), a Qualitatively similar results were obtained for good
total of 308 (63%) patients did not have visible arterial outcome (mRS 0–2), and with an ordinal logistic
occlusion after assessment by a core lab. There was no regression model (cOR for better functional outcome
evidence of modification of the effect of alteplase by beyond 4.5 h: 1.03, 95% CI: 0.90–1.18).26 The time at
the presence or absence of visible vessel occlusion (OR which the lower 95% CI for the estimated treatment
for mRS 0–1 at three months: 2.04, 95% CI: 1.00–4.18 benefit (mRS 0–1) crossed 1.0 was estimated to be
and 1.58, 95% CI: 0.97–2.56, respectively; P for 5.1 h.8
interaction ¼ 0.56). In a study level meta-analysis, the 4.5 h threshold
In summary, IVT increases the risk of intracranial was not examined specifically,6 but there was no signif-
haemorrhage and early death, but for those treated icant effect of alteplase in patients randomised more
within 0–4.5 h there are no clear excess of deaths by than three hours after stroke (OR 0.97, 95% CI:
Berge et al. 7
0.85–1.09; 5 trials, 1449 participants, I2 ¼ 45%), well >4.5 h).29,30 We decided to provide distinct recom-
although this estimate was not statistically different mendations for these two different clinical situations,
from patients randomised less than three hours after because the true stroke onset of patients awakening
stroke. from sleep may frequently be < 4.5 h before
The increase in risk of fatal ICH or type 2 paren- randomisation.31,32 This PICO question focuses on
chymal hemorrhage with alteplase in comparison with patients with known stroke onset 4.5–9 h before
placebo was similar irrespective of treatment delay.8 In presentation.
patients treated more than 4.5 h after stroke, the OR The Echoplanar Imaging Thrombolytic Evaluation
for parenchymal haemorrhage type 2 with alteplase Trial (EPITHET) randomised 101 patients with ischae-
was 6.89 (95% CI: 4.17–11.38), similar to what is mic stroke with 3–6 h duration to alteplase or placebo.
observed for patients treated within 4.5 h from symp- MRI was performed in all patients, but the imaging
tom onset (OR 5.58, 95% CI: 3.35–9.30).27 Using the results were not used for patient selection. Overall, 85
SITS-MOST definition of symptomatic intracranial patients (86%) had PWI-DWI mismatch, but the trial
haemorrhage, the absolute excess risk of intracerebral did not demonstrate a clinical benefit of alteplase.25 A
haemorrhage with alteplase was 3.1% within pooled analysis of the EPITHET trial and an observa-
three hours (95% CI: 1.7–5.2), 3.0% between 3 and tional study showed that, among patients with PWI-
4.5 h (95% CI: 1.6–5.0), and 3.6% (95% CI: 2.0–6.0) DWI mismatch within 3–6 h of symptom onset (101
beyond 4.5 h (p-value for interaction 0.73).10 In patients), those treated with alteplase (60 patients)
patients treated more than 4.5 h after stroke onset, had significantly smaller infarct growth and higher
IVT with alteplase led to a non-significant higher reperfusion rate, but clinical outcomes were not differ-
three-month mortality (HR: 1.22; 95% CI: 0.99–1.50).8 ent between the two groups.33
Other studies have found that patient selection using The fourth European Cooperative Acute Stroke
a prognostic score based on simple clinical variables Study (ECASS-4) compared alteplase with placebo in
and plain CT alone cannot identify a patient popula- 119 patients presenting between 4.5 and 9 h after stroke
tion for which alteplase given between 4.5 and 6 h of onset or after awakening with stroke, and used MRI
stroke is safe or effective.28 core/perfusion mismatch to select patients for treat-
Because the evidence in this chapter is from a sub- ment.30 Inclusion criteria were infarct core volume
group of high-quality RCTs, we have downgraded the <100 ml, absolute perfusion lesion volume 20 ml (at
quality of evidence from high to moderate. Tmax >6 s) and mismatch ratio between perfusion and
core >1.2. This RCT stopped early when recruitment
dropped after publication of the positive thrombec-
Recommendation
tomy trials. Of the 119 included patients, 37 (31%)
For patients with acute ischaemic stroke of 4.5–9 h had known stroke duration of 4.5–9 h (median time
duration (known onset time), and with no brain to treatment 6.9 h), and 82 (69%) had woken with
imaging other than plain CT, we recommend no stroke. There was no significant effect of alteplase on
intravenous thrombolysis. better functional outcome at three months (cOR 1.20,
Quality of evidence: Moderate 丣丣丣 95% CI: 0.63–2.27, P ¼ 0.57). The treatment effect was
Strength of recommendation: Strong ## similar in the dichotomized mRS analysis for excellent
outcome (mRS 0–1) which showed a 6.4% absolute
3. Treatment between 4.5 and 9 h after known onset difference in favour of alteplase that did not reach sta-
tistical significance (P ¼ 0.45). No analysis of the sub-
with the use of advanced imaging group of patients with known onset time has been
PICO 3.1 In patients with ischaemic stroke of 4.5–9 h duration presented.
(known onset time), and with CT or MRI core/perfusion The Extending the Time for Thrombolysis in
mismatch, does intravenous thrombolysis with alteplase lead Emergency Neurological Deficits (EXTEND) trial
to better functional outcome than no intravenous thrombolysis? compared alteplase with placebo in 225 patients pre-
Analysis of current evidence. Mismatch between non- senting between 4.5 and 9 h after stroke onset or after
contrast CT and CT Perfusion (CTP), or between awakening with stroke, using CT or MRI core/perfu-
diffusion-weighted and perfusion-weighted MRI sion mismatch to select patients.29 Inclusion criteria
(DWI and PWI) may quantify the penumbral cerebral were infarct core volume 70 ml, absolute perfusion
tissue and could identify patients who benefit of alte- lesion volume of >10 ml and mismatch ratio between
plase beyond 4.5 h. However, most RCTs of IVT in perfusion and core >1.2. Of the 225 included patients,
later time windows allowed not only the inclusion of 79 (35%) had stroke duration of 4.5–9 h, and 146
patients with known onset >4.5 h but also of patients (65%) had woken with stroke. The study showed that
with wake-up stroke (unknown onset, time last seen IVT with alteplase was associated with higher
Figure 3. Pooled odds ratio for excellent outcome (mRS 0–1), good outcome (mRS 0–2) and better functional outcome (common
OR across the whole range of the mRS) in patients with ischaemic stroke of 4.5–9 h duration (known onset time) treated with IVT vs.
control. This analysis comprises all patients enrolled in the EXTEND, ECASS 4 and EPITHET trials, stratified by time window (4.5–6 h
and 6–9 h).
The numbers and the ORs for the 4.5–6 h and 6–9 h time windows (adjusted on age and baseline NIHSS score) are taken from the
individual patient data meta-analysis of three RCTs (EXTEND, ECASS 4 and EPITHET) by Campbell et al.
proportion of patients with excellent outcome (mRS 0– results were observed for good outcome and better
1 at three months: 35.4% alteplase vs. 29.5% placebo, functional outcome (Figure 3).
adjusted RR 1.44, 95% CI: 1.01–2.06, P ¼ 0.04), and The authors conducted a sensitivity analysis restricted
there was no evidence that the effect was different in to the subgroup of 303 patients who met the mismatch
patients treated during different time intervals (4.5–6 h criteria of the EXTEND trial (see above). To this aim,
or 6–9 h), or in patients with wake-up stroke. A sec- imaging data for individual patients were reprocessed
ondary pre-specified ordinal analysis did not show a using an automated software. Alteplase remained
significant difference in functional outcome (cOR for associated with excellent outcome (OR 2.06, 95% CI:
better functional outcome, 1.55, 95% CI: 0.96–2.49). 1.17–3.62). However, after exclusion of patients with
The risk of sICH was higher in the alteplase group wake-up stroke, the associations between IVT and excel-
(adjusted RR 7.22, 95% CI: 0.97–53.5, P ¼ 0.05). lent outcome, good outcome or better functional out-
Campbell et al.34 conducted an individual partici- come failed to reach statistical significance (Figure 4).
pant data meta-analysis of EPITHET,25 ECASS-430 Of note, 62% of the patients analysed in the indi-
and EXTEND.29 The main analysis was based on all vidual participant data meta-analysis had large vessel
patients who met the inclusion criteria of the original occlusion but no thrombectomy was performed except
studies (n ¼ 414; 52% imaged with perfusion-diffusion for 1 protocol deviation procedure.14,34 Therefore, our
MRI, 48% with perfusion CT). IVT led to a higher rate evidence-based recommendation only applies to
patients who will not undergo mechanical thrombec-
of excellent outcome (36% alteplase vs. 29% placebo,
tomy; please see the expert consensus statement
OR 1.86, 95% CI: 1.15–2.99, P ¼ 0.01), higher rate of
below for patients eligible for both IVT and mechanical
symptomatic intracerebral hemorrhage (5% vs. < 1%;
thrombectomy.
OR 9.7, 95% CI: 1.23–76.55, P ¼ 0.03) with no signif-
Table 2 provides details regarding the assessment of
icant difference in mortality (14% vs. 9%; OR 1.55,
the quality of evidence, which was judged to be low.
95% CI: 0.81–2.96, P ¼ 0.19).34 However, 51% of
included patients had woken with stroke. There was
Recommendation
no evidence of a modification of the effect of alteplase
in an analysis across the 3 predefined time strata (4.5– For patients with ischaemic stroke of 4.5–9 h dura-
6 h, 6–9 h, wake-up stroke; P for interaction ¼ 0.87). In tion (known onset time) and with CT or MRI core/
the subgroups of patients with known onset treated perfusion mismatch*, and for whom mechanical
between 4.5–6 h and 6–9 h, the ORs for excellent out- thrombectomy is either not indicated or not
come (mRS score 0–1) were 2.19 (95% CI: 0.82–5.85) planned, we recommend intravenous thrombolysis
and 2.27 (95% CI: 0.83–6.24), respectively. Similar with alteplase.
Berge et al. 9
Figure 4. Pooled odds ratio for excellent outcome (mRS 0–1), good outcome (mRS 0–2) and better functional outcome (common
OR across the whole range of the mRS) in patients with ischaemic stroke of 4.5–9 h duration (known onset time) treated with IVT vs.
control. This analysis is restricted to the subgroup of patients enrolled in the EXTEND, ECASS 4 and EPITHET trials who meet the
EXTEND mismatch criteria detected by automated software.
The numbers and the ORs for the 4.5–6 h and 6–9 h time windows (adjusted on age and baseline NIHSS score) are taken from the
individual patient data meta-analysis by Campbell et al.
Quality of evidence: Low 丣丣 similar functional outcomes in patients treated within

4.5 h and patients selected with the use of DWI-FLAIR
Strength of recommendation: Strong "" mismatch and treated between 4.5 and 6 h after stroke
*In the individual participant data meta-analysis onset.36
by Campbell et al.,34 core/perfusion mismatch There is no current RCT assessing whether IVT is
was assessed with an automated processing soft- superior to no IVT in patients who undergo advanced
ware and defined as follows: imaging and display no core/perfusion mismatch. In
- Infarct core** volume < 70 ml the subgroup of patients who did not meet the
- and Critically hypoperfused† volume/Infarct EXTEND mismatch criteria after reprocessing imaging
core** volume > 1.2 data with an automated software in the individual par-
- and Mismatch volume > 10 ml ticipant data meta-analysis by Campbell et al. (see
above),34 no significant difference was observed in the
** rCBF < 30% (CT perfusion) or ADC < 620 mm2/s (Diffusion proportions of patients who achieved excellent func-
MRI) tional outcome between the alteplase and placebo
†
Tmax >6 s (perfusion CT or perfusion MRI) groups (adjusted OR 1.22, 95% CI: 0.48–3.10,
P ¼ 0.68), but there was no significant treatment by
For patients with no CT or MRI core/perfusion mismatch status interaction (P ¼ 0.43). These results
mismatch, please see the expert consensus state- should be interpreted with caution because those
ment below. patients were still considered to have a core/
perfusion mismatch according to an alternative defini-
Additional information. A recent prospective obser- tion of penumbral mismatch (i.e., they were deemed to
vational single-centre study reported that, among meet the inclusion criteria of the RCT in which they
were enrolled). Furthermore, the above-mentioned
acute ischemic stroke patients presenting in the 0–9 h
analysis also encompasses patients with wake-up
window, only 1.3% were eligible for IVT according to
stroke.
EXTEND neuroimaging and clinical eligibility
criteria.35
Expert consensus statement
The concept of DWI-FLAIR-mismatch, i.e., pres-
ence of an acute ischaemic lesion on DWI in the For patients with ischaemic stroke of 4.5–9 h dura-
absence of a hyperintense lesion on FLAIR in the tion (known onset), and with no CT or MRI core/
same area, has not been evaluated in RCTs of IVT perfusion mismatch, 9 of 9 group members suggest
for the selection of patients with known stroke dura- against IVT with alteplase.
tion of >4.5 h. One small observational study suggested
There is currently no randomized data to make a
three months) compared with control, with a similar OR in the 4.5–6 h and the 6–9 h time windows (pooled OR 2.23, 95% CI: 1.10–4.50, I2 ¼ 0%). However, when only considering those patients who
heterogeneity in these ORs (P for heterogeneity ¼ 0.09, I2 ¼ 66%), which might be due to a modest number of events. The pooled OR did not reach statistical significance and the confidence interval was
Importance
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Serious inconsistency and serious imprecision: when including all patients from EXTEND, ECASS 4 and EPITHET, IVT with alteplase was significantly associated with excellent outcome (mRS 0–1 at
actually had an automated perfusion mismatch, the point estimates for the 4.5–6 h and the 6–9 h time windows varied (OR 6.71 and 1.14, respectively), although there was no statistically significant
recommendation for patients who are scheduled to
undergo mechanical thrombectomy and are also eligi-
ble for IVT in the 4.5–9 h time window.
MODERATE
Certainty

LOW
LOW
LOW
⨁⨁⨁
For patients presenting directly to a thrombectomy
⨁⨁
⨁⨁
⨁⨁
centre with ischaemic stroke of 4.5–9 h duration
(known onset) with CT or MRI core/perfusion
mismatch and who are eligible for mechanical
Absolute
thrombectomy, the group members could not

(95% CI)
reach a consensus regarding whether intravenous

thrombolysis should be used before mechanical
thrombectomy.
(1.10–4.50)
(1.07–4.28)
(1.21–3.40)
(0.59–4.38)
cOR 2.02
OR 2.23
OR 2.14
OR 1.61
Relative
no IVT (95% CI)
For patients presenting to a non-thrombectomy

Effect
centre with ischaemic stroke of 4.5–9 h duration

(known onset) with CT or MRI core/perfusion
mismatch and who are eligible for mechanical
No of patients
thrombectomy, 6 of 9 group members suggest

intravenous thrombolysis before mechanical
alteplase
IVT with
thrombectomy.
4. Stroke on awakening from sleep/unknown onset

considerations
PICO 4.1 In patients with acute ischaemic stroke on awakening

from sleep/unknown onset, does intravenous thrombolysis with
Other
none
none
none
none
alteplase lead to better functional outcome than no intravenous

thrombolysis?
Analysis of current evidence. Up to one in five
Imprecision
strokes occur during sleep, but IVT is often withheld

serious
serious
serious
serious
in patients with new stroke symptom upon awakening

and who were last seen well more than 4.5 h earlier.37,38
Our literature search identified five randomised-
Indirectness
not serious
not serious
not serious
not serious
controlled trials of IVT with alteplase in patients with

wake-up stroke.29,30,39–42
MRI: DWI/FLAIR mismatch

Inconsistency
Improved mRS score at three months (shift analysis)
not serious
The WAKE-UP trial included 503 patients who woke

seriousa
serious
serious
up with a new stroke and were last known to be well

more than 4.5 h earlier, and had an acute ischaemic
wide (OR 2.46, 95% CI: 0.44–13.78, I2 ¼ 66%).
lesion on DWI but no marked parenchymal hyperin-

tensity on FLAIR (DWI-FLAIR mismatch).39,43 The
not serious
not serious
not serious
not serious
trial excluded patients for whom thrombectomy was

Risk of
planned. Patients were randomised to alteplase

bias
0.9 mg/kg or placebo, and the primary endpoint was

mRS 0–1 at three months
excellent outcome (mRS 0–1 at 90 days). The trial

was terminated prematurely owing to cessation of

randomised
randomised
randomised
randomised
funding after the enrolment of 503 of an anticipated

trials
trials
trials
trials
design
800 patients. Thirty-four percent of the patients had

Study
an intracranial vessel occlusion. The adjusted OR for

excellent outcome with alteplase was 1.61 (95% CI:
studies
1.09–2.36, P ¼ 0.02) and the cOR for better functional

No of
outcome was 1.62 (95% CI: 1.17–2.23, P ¼ 0.003).

3
a
Berge et al. 11
Alteplase was also associated with a non-significantly adjusted RR for excellent outcome was 1.53 (95% CI:
increased risk of sICH (2.0% vs. 0.4%, P ¼ 0.15) and a 0.97–2.43).
non-significantly higher mortality at 90 days (4.1% vs.
1.2%, P ¼ 0.07). Individual participant data Meta-analysis
The Thrombolysis for Acute Wake-Up and Unclear-
A systematic review and individual participant data
Onset Strokes With Alteplase at 0.6 mg/kg (THAWS)
meta-analysis of RCTs of IVT with alteplase for
trial used the same criteria for patient selection as the
patients with stroke of unknown time of onset guided
WAKE-UP trial, and patients with DWI-FLAIR mis-
by advanced imaging was recently conducted by the
match on MRI were randomised to low-dose alteplase
Evaluation of unknown Onset Stroke thrombolysis
(0.6 mg/kg) or placebo.44 The trial was terminated early
trials (EOS) investigators.46 A total of 843 patients
following the positive results of WAKE-UP with
enrolled in studies based on DWI-FLAIR mismatch
recruitment of 131 of the planned 300 patients, leading
(WAKE-UP39 and THAWS44) or core/perfusion mis-
to a low statistical power. This trial found no difference
match (EXTEND29 and ECASS-430) were included.
in excellent outcome (mRS score 0–1) at three months
Perfusion data was automatically reprocessed using
between the alteplase and control groups (RR 0.97,
the RAPID software, and the authors used the defini-
95% CI: 0.68–1.41, P ¼ 0.89). There was also no differ-
tion of penumbral mismatch from the EXTEND trial
ence for death (RR 0.85, 95% CI: 0.06–12.58,
for their analysis (infarct core volume 70 ml, absolute
P > 0.99). Only 1 patient in the alteplase group had
perfusion lesion volume of >10 ml and mismatch ratio
sICH versus 0 in the placebo group.
between perfusion and core >1.2). The median time
between last seen well and treatment initiation was
CT or MRI: core/perfusion mismatch 10.5 h and the imaging modality was MRI in 85% of
The EXTEND trial compared alteplase with placebo in cases. Compared to placebo or standard care, IVT was
225 patients presenting between 4.5 and 9 h after stroke significantly associated with excellent outcome (prima-
onset (or between 3 and 9 h, depending on national ry endpoint: adjusted OR 1.49, 95% CI: 1.10–2.03,
guidelines) or after awakening with stroke (if within P ¼ 0.01; I2 ¼ 27%) and better functional outcome
9 h from the midpoint of sleep),29 using CT or MRI (adjusted cOR 1.39, 95% CI: 1.05–1.80, P ¼ 0.02), at
core/perfusion mismatch to select patients. Inclusion the expense of a higher risk of sICH (3% vs. 0.5%,
criteria were infarct core volume 70 ml, absolute per- P ¼ 0.02) and mortality within three months (adjusted
fusion lesion volume of >10 ml and mismatch ratio OR 2.06, 95% CI: 1.03–4.09, P ¼ 0.04). The effect of
between perfusion and core >1.2. After 225 of the alteplase was consistent across predefined subgroups,
planned 310 patients had been enrolled, the study was including imaging modality (CT vs. MRI) and large
terminated because of a loss of equipoise after the pub- vessel occlusion status. Of note, mechanical thrombec-
lication of the WAKE-Up trial. The study found that tomy was not performed in the 25% of included
alteplase was associated with excellent outcome (mRS patients with large vessel occlusion.
0–1 at 90 days: adjusted RR 1.44, 95% CI: 1.01–2.06, Albeit based on the EOS meta-analysis, our recom-
P ¼ 0.04). Of note, the study would not have demon- mendation for patients with MRI DWI-FLAIR
strated superiority of alteplase had the investigators mismatch is mostly driven by the results of the
used another method of analysis than adjusted WAKE-UP trial, which used a standard dose of alte-
Poisson regression and a primary endpoint of mRS plase, unlike the small THAWS trial, in which the dose
0–1. However, the statistical analysis plan was deter- of 0.6 mg/kg was used. Both studies were terminated
mined before database lock and the results are there- early. We rated the quality of the evidence as high
fore valid. Intervention and control groups were (Table 3) because of the relatively large sample size,
generally well balanced, but alteplase-treated patients the fact that the WAKE-UP study was specifically
were slightly older, and with more severe strokes as focusing on patients with unknown symptom onset
measured by both core volume and NIHSS score and and that the superiority of IVT was consistently
this may account for the lack of statistical significance observed across secondary endpoints. For patients
for primary and secondary clinical endpoints in the with CT or MRI perfusion core/perfusion mismatch
unadjusted analyses.45 The risk of sICH was higher in and unknown time of onset, we rated the quality of
the alteplase group (adjusted RR 7.22, 95% CI: 0.97– evidence as moderate (Table 3) for several reasons.
53.5, P ¼ 0.05). The treatment effect was not signifi- First, no study based on perfusion mismatch was spe-
cantly different across the three time strata (4.5–6 h; cifically dedicated to patients with unknown time of
6–9 h; wake-up stroke: P for interaction ¼ 0.41). A onset and therefore the evidence comes from subgroups
total of 146 (65%) patients had woken with stroke. of patients in two relatively small RCTs that were
In the subgroup of patients with wake-up stroke, the stopped prematurely. Second, the positive association
Table 3. GRADE evidence profile for PICO 4.
Certainty assessment No of patients Effect
No of IVT with Relative Absolute

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations alteplase no IVT (95% CI) (95% CI) Certainty Importance
DWI-FLAIR mismatch (WAKE-UP trial39 & EOS Independent participant data meta-analysis46)
1 randomised not serious not serious not serious not serious none 131/246 102/244 OR 1.61 118 more ⨁⨁⨁⨁ CRITICAL
trials (53.3%) (41.8%) (1.09–2.36)* per 1 000 HIGH
(from 21
more to
211 more)
1 randomised not serious not serious not serious not serious none 10/251 3/244 OR 3.38 28 more ⨁⨁⨁⨁ CRITICAL
trials (4.0%) (1.2%) (0.92–12.52) per 1 000 HIGH
(from 1
fewer to
123 more)
sICH (ECASS 2 definition)
1 randomised not serious not serious not serious seriousa strong association 7/251 3/244 OR 2.40 17 more ⨁⨁⨁⨁ CRITICAL
trials (2.8%) (1.2%) (0.60–9.53) per 1 000 HIGH
(from 5
fewer to
94 more)
Core/Perfusion mismatch (EXTEND,29 ECASS-430 & EOS 46 & Campbell et al.34)
2 randomised not serious seriousb serious not serious none 45/112 29/109 Adjusted 171 more ⨁⨁⨁ CRITICAL
trials (40.2%) (26.6%) OR 2.14 per 1 000 MODERATE
(1.11–4.12) (from 21
more to
333 more)
2 randomised not serious not serious not seriousb seriousc none 14/112 9/109 OR 1.59 43 more ⨁⨁⨁ CRITICAL
trials (12.5) (8.3) (0.66–3.84) per 1 000 MODERATE
(from 26
fewer to
174 more)
*In the EOS meta-analysis of 4 RCTs of IVT vs. placebo/usual care in patients (n ¼ 843) with unknown stroke onset and either DWI-FLAIR mismatch or core/perfusion mismatch,46 the adjusted OR for mRS 0–1 at
three months was 1.49, 95% CI: 1.10–2.03 in favor of alteplase (P ¼ 0.01). In the subgroup of patients with DWI-FLAIR mismatch (n ¼ 641), the adjusted OR for mRS 0–1 was 1.45 (0.98–2.13). In the subgroup of patients with
core/perfusion mismatch (n ¼ 221), the OR for mRS 0–1 at three months was 2.14 (1.11–4.12).
a
Very large confidence interval. Although IVT with alteplase was not significantly associated with any definition of sICH, the point estimates where high (OR >4) for the ECASS 3 and SITS-MOST definitions, with very large
confidence intervals as well. Furthermore, IVT was significantly associated with Parenchymal Hemorrhage type 2.
b
These results are based on a reanalysis of individual patient imaging data, using the perfusion criteria of the EXTEND trial, which are slightly different from those of the ECASS 4 trial. Based on the perfusion mismatch
criteria of each original study, the association would not have been significant (OR 1.56; 0.81–3.02).34
c
Large confidence interval including 1.0.
Berge et al. 13
between IVT and excellent outcome was only demon- a wake-up stroke are ongoing (NCT03181360
strated after a reanalysis of individual patient imaging [TWIST], and NCT01455935 [WASSABI]).
data using the perfusion criteria of the EXTEND
trial,29 which slightly differ from those of the ECASS Expert consensus statement
4 trial.30 Based on the perfusion mismatch criteria of
For patients presenting directly to a thrombectomy
each original study, the association would not have
centre with acute ischaemic stroke on awakening
been significant (OR 1.56; 0.81–3.02).34 Of note, in
from sleep, who would be eligible for both IVT
the EOS individual participant data meta-analysis,
and mechanical thrombectomy, 6 of 9 group mem-
only 54% (n ¼ 221) of patients with available assess-
bers suggest IVT before MT.
ment for perfusion imaging had a penumbral mismatch
according to the EXTEND criteria46. However,
For patients presenting to a non-thrombectomy
because this analysis showed a clear benefit of IVT centre with acute ischaemic stroke on awakening
(adjusted OR for excellent outcome 2.14, 95% CI: from sleep, who would be eligible for both IVT
1.11–4.12), we provide a strong recommendation in and mechanical thrombectomy, 7 of 9 group mem-
favour of IVT in this situation. bers suggest IVT before MT.
There is currently no randomized data to make a
recommendation for wake-up stroke patients who are
scheduled to undergo mechanical thrombectomy and 5. Tenecteplase
are also eligible for IVT; please see the expert consensus PICO 5.1 In patients with acute ischaemic stroke of < 4.5 h
statement below for this situation. duration, does IVT with tenecteplase lead to better functional
outcome than IVT with alteplase?
Recommendation Analysis of current evidence. Tenecteplase has phar-
For patients with acute ischaemic stroke on awak- macological advantages over alteplase. It has a higher
ening from sleep, who were last seen well more than fibrin affinity, longer half-life, and can be administered
4.5 h earlier, who have MRI DWI-FLAIR mis- with a single intravenous bolus injection. We identified
match, and for whom mechanical thrombectomy 3 RCTs comparing tenecteplase with alteplase in ‘unse-
is either not indicated or not planned, we recom- lected’ patients with acute ischaemic stroke,47–49 which
mend intravenous thrombolysis with alteplase. are reviewed in the present section, and two trials com-
Quality of evidence: High 丣丣丣丣 paring tenecteplase with alteplase in selected patients
Strength of recommendation: Strong "" with acute ischaemic stroke due to large vessel occlu-
sion, which are discussed in the next section (PICO 5.2)
For patients with acute ischaemic stroke on awak-
in order to limit heterogeneity in meta-analyses.50,51
ening from sleep, who have CT or MRI core/per-
In the Phase IIB/III Trial of Tenecteplase in Acute
fusion mismatch* within 9 h from the midpoint of
sleep, and for whom mechanical thrombectomy is Ischemic Stroke (TNK-S2B), 112 patients were rando-
either not indicated or not planned, we recommend mised within three hours of stroke onset to tenecteplase
intravenous thrombolysis with alteplase. 0.1 mg/kg, 0.25 mg/kg, 0.4 mg/kg, or alteplase 0.9 mg/
Quality of evidence: Moderate 丣丣丣 kg. The first step of the trial aimed at finding the opti-
Strength of recommendation: Strong "" mal dose of tenecteplase using a composite outcome
measure, and the second step aimed at testing whether
*
In the EOS individual participant data meta-anal- this dose was superior to alteplase 0.9 mg/kg in improv-
ysis,46 core/perfusion mismatch was assessed with ing functional outcome at three months.47 The trial was
an automated processing software and defined as terminated prematurely because of slow recruitment.
follows: The adaptive dose selection procedure suggested that
- Infarct core** volume < 70 ml tenecteplase 0.4 mg/kg was inferior to the two other
- and Critically hypoperfused† volume/Infarct doses due to an excess of sICH (incidence rate
core** volume > 1.2 15.8%, 95% CI: 5.5–37.6%). The proportion of
- and Mismatch volume > 10 ml patients with good functional outcome (mRS 0–2) at
three months did not differ between the treatment
** rCBF <30% (CT perfusion) or ADC < 620 mm2/s (Diffusion
arms, but the study was underpowered for this analysis.
MRI)
In the Alteplase-Tenecteplase Trial Evaluation for
†
Tmax >6 s (perfusion CT or perfusion MRI)
Stroke Thrombolysis (ATTEST) trial, 104 patients
were randomised to tenecteplase 0.25 mg/kg or alte-
Additional information. As of September 2020, two trials plase 0.9 mg/kg within 4.5 h of stroke onset.48 The pri-
on intravenous thrombolytic treatment in patients with mary outcome measure was the percentage of
Figure 5. Pooled odds ratio for excellent outcome (mRS 0–1) in ‘unselected’ patients with ischaemic stroke of < 4.5 h duration,
treated with tenecteplase (0.25 or 0.4 mg/kg) vs. alteplase (0.9 mg/kg).
Figure 6. Pooled odds ratio for sICH in ‘unselected’ patients with ischaemic stroke of < 4.5 h duration, treated with tenecteplase
(0.25 or 0.4 mg/kg) vs. alteplase (0.9 mg/kg).
penumbra salvaged at 24–48 h, defined as CT stroke mimic. There was no difference in the proportion
perfusion-defined penumbra volume at baseline minus of patients with excellent outcome (OR 1.08, 95% CI:
plain CT infarct volume at 24–48 h. Three-quarters of 0.84–1.38, P ¼ 0.52), and there was no significant differ-
patients had an arterial occlusion on CT angiography. ence in the incidence of sICH.
Mechanical thrombectomy was not performed. There We performed a meta-analysis of study-level data,
were no significant differences for the primary outcome and found no significant difference between tenecte-
measure or for the secondary outcome measures of plase and alteplase in the proportion of patients with
mRS scores 0–1 at 90 days (OR 1.1, 95% CI: 0.3–3.5) excellent (Figure 5) or good outcome at three months
or sICH. (data not shown), irrespective of the tenecteplase dose.
In the Norwegian Tenecteplase Stroke Trial (NOR- There was no significant difference in the incidence of
TEST), 1100 patients were randomised to tenecteplase sICH (Figure 6). A published meta-analysis also found
0.4 mg/kg or alteplase 0.9 mg/kg within 4.5 h of stroke similar functional outcomes in the two treatment
onset or awakening with stroke.49 The trial aimed to groups.52
show superiority for tenecteplase, and the primary out- The quality of the evidence was deemed low (see
come measure was excellent outcome at three months Table 4 for justification). None of the trials were
(mRS score 0–1). The included patients had mild strokes designed to show non-inferiority of tenecteplase com-
(median NIHSS score 4) and 18% of the patients had a pared to alteplase.
IVT with IVT with

No of Other tenecteplase alteplase Relative Absolute
Berge et al.
studies Study design Risk of bias Inconsistency Indirectness Imprecision considerations 0.25 mg/kg 0.9 mg/kg (95% CI) (95% CI) Certainty Importance
Tenecteplase 0.25 mg/kg vs. Alteplase 0.9 mg/kg (‘unselected’ patients)

2 randomised seriousa not serious seriousb not serious none 28/78 23/80 OR 1.40 73 more per ⨁⨁ CRITICAL
trials (35.9%) (28.7%) (0.70–2.78) 1 000 LOW
(from 67
fewer to
241 more)
2 randomised seriousa not serious seriousb not serious none 15/78 14/80 OR 0.97 4 fewer per ⨁⨁ CRITICAL
trials (19.2%) (17.5%) (0.45–2.09) 1 000 LOW
(from 88
fewer to
132 more)
sICH
a c
2 randomised serious not serious serious not serious none 5/83 5/82 OR 1.12 7 more per ⨁⨁ CRITICAL
trials (6.0%) (6.1%) (0.49–2.52) 1 000 LOW
(from 30
fewer to 80
more)
Tenecteplase 0.40 mg/kg vs. Alteplase 0.9 mg/kg (‘unselected’ patients)
2 randomised very serious a,d not serious not serious not serious none 361/568 358/582 OR 1.07 16 more per ⨁⨁ CRITICAL
trials (63.6%) (61.5%) (0.84–1.36) 1 000 LOW
(from 42
fewer to 70
more)
d
2 randomised serious not serious not serious not serious none 32/568 34/582 OR 1.03 2 more per ⨁⨁⨁ CRITICAL
trials (5.6%) (5.8%) (0.62–1.72) 1 000 MODERATE
(from 21
fewer to 38
more)
sICH
d e
2 randomised serious not serious not serious serious none 18/568 14/582 OR 1.70 16 more per ⨁⨁ CRITICAL
trials (3.2%) (2.4%) (0.45–6.42) 1 000 LOW
(from 13
fewer to
113 more)
a
The TNK-S2B trial was terminated prematurely – in the dose finding phase – because of slow recruitment. The following phase would have investigated the superiority of Tenecteplase over Alteplase 0.9 mg/kg.
b
Differences in populations
c
Different definitions of sICH were used across studies.
d
In NOR-TEST, 18% of included patients had a stroke mimic and were distributed similarly between the Tenecteplase and Alteplase arm.
15
e
Clinical recommendation (tenecteplase or alteplase) would markedly differ if the upper versus the lower boundary of the 95% CI of the OR represents the truth.
thrombectomy was not performed. The two

Recommendation co-primary outcome measures were the percentage of
the perfusion lesion that was reperfused at 24 h after
For patients with acute ischaemic stroke of <4.5 h treatment (as assessed by perfusion MRI) and the
duration and not eligible for thrombectomy, we change on the NIHSS score between baseline and
suggest intravenous thrombolysis with alteplase 24 h. Tenecteplase was superior to alteplase for both
over intravenous thrombolysis with tenecteplase. co-primary outcome measures. At three months, good
Please see paragraph 5.2 for patients eligible for outcome (mRS 0–2) was observed in 72% of patients in
mechanical thrombectomy. the pooled tenecteplase groups vs. 44% in the alteplase
Quality of evidence: Low 丣丣 group (P ¼ 0.02). The rate of symptomatic intracerebral
Strength of recommendation: Weak "? haemorrhage did not differ significantly between the
groups. In the dose-tier analysis, tenecteplase
Additional information. A meta-analysis of 5 ran- 0.25 mg/kg was associated with clinical improvement
domized trials (TNK-S2B, Tenecteplase versus during the first 24 h and a non-significant increase in
Alteplase for Acute Ischemic Stroke [TAAIS], the proportion of patients with good outcome at
ATTEST, NOR-TEST, Tenecteplase versus Alteplase three months (P ¼ 0.11). The frequency of sICH was
before Endovascular Therapy for Ischemic Stroke similar in the two tenecteplase groups (4%).
[EXTEND-IA TNK]) suggested that there is enough The EXTEND-IA TNK trial compared tenecteplase
evidence to conclude that tenecteplase is non-inferior 0.25 mg/kg with alteplase 0.9 mg/kg within 4.5 h of
to alteplase for acute ischemic stroke (risk difference symptom onset in 202 patients with large vessel occlu-
for mRS 0–1: 4%, 95% CI: –1% to 8%).53 However, sion (internal carotid artery, first and second segments
this result was mostly driven by the inclusion of of the middle cerebral artery, or the basilar artery) who
EXTEND-IA TNK and TAAIS in the meta-analysis, were candidates for mechanical thrombectomy.51 The
which enrolled only patients with large vessel occlusion trial was designed to demonstrate non-inferiority, but
as opposed to the other trials. Furthermore, the high after testing for non-inferiority, superiority testing was
proportion of stroke mimics in NOR-TEST could have performed as pre-specified. The primary outcome mea-
sure was reperfusion greater than 50% of the involved
biased results towards non-inferiority. Of note, the
ischaemic territory or absence of retrievable thrombus
non-inferiority margin was selected using data from a
at the time of the initial angiographic assessment, and
RCT comparing two doses of alteplase (0.9 mg/kg vs.
was found in 22% of the patients treated with tenecte-
0.6 mg/kg).54
plase versus 10% of those treated with alteplase (p for
There are ongoing trials of tenecteplase for acute
non-inferiority ¼ 0.002; p for superiority ¼ 0.03).
ischemic stroke (ATTEST-2 [NCT02814409],
Tenecteplase was borderline associated with better 90-
Tenecteplase versus Alteplase for Stroke Thrombolysis
day functional outcome than alteplase (cOR 1.7, 95%
Evaluation (TASTE; ACTRN12613000243718), CI: 1.0–2.8, P ¼ 0.04 – adjusted on age and baseline
A Randomized Controlled Trial of TNK-tPA Versus NIHSS score). There were no significant differences
Standard of Care for Minor Ischemic Stroke With in the proportions of patients with good (P ¼ 0.06),
Proven Occlusion (TEMPO-2; NCT02398656). We excellent outcome (P ¼ 0.23) or early neurological
encourage enrolment into ongoing trials. improvement (P ¼ 0.70). Symptomatic intracerebral
haemorrhage occurred in 1% of the patients in each
group.
PICO 5.2 In patients with acute ischaemic stroke of < 4.5 h A meta-analysis of patients with large vessel occlu-
duration and with large vessel occlusion, who are candidates sion in EXTEND-IA TNK and TAAIS showed that
for mechanical thrombectomy, and for whom intravenous tenecteplase was associated with a higher likelihood
thrombolysis is considered before thrombectomy, does IVT of complete recanalisation (OR 2.01, 95% CI: 1.04–
with tenecteplase lead to better functional outcome than IVT 3.87, P ¼ 0.04).52 Furthermore, Bivard et al. conducted
with alteplase? a pooled patient subgroup analysis of TAAIS and
Analysis of current evidence. In the TAAIS trial, 75 ATTEST suggesting that tenecteplase compared to
patients were randomised to tenecteplase 0.1 mg/kg or alteplase was associated with higher complete recanali-
0.25 mg/kg or alteplase 0.9 mg/kg within 6 h of stroke zation rates at 24 h (71% vs. 43%; p < 0.001) and
onset.50 Patient selection was based on the finding of higher rates of three-month excellent outcome (mRS-
occlusion of the anterior, middle, or posterior cerebral scores of 0–1; OR 4.82, 95% CI: 1.02–7.84, P ¼ 0.05) in
artery on CT angiography and a CT perfusion lesion 69 patients with baseline intracranial occlusion
volume that was at least 20 ml and at least 20% greater [Thrombolysis in Cerebral Infarction (TICI) grades
than the infarct core on CT perfusion. Mechanical 0–1].55 This study also suggested that vessel occlusion
Berge et al. 17
Figure 7. Pooled odds ratio for excellent outcome (mRS 0–1) and better functional outcome (common OR across the whole range
of the mRS) in patients with ischaemic stroke of < 4.5 h duration who have documented vessel occlusion and were randomized to IVT
with tenecteplase 0.25 mg/kg vs. IVT with Alteplase 0.9 mg/kg.
The study by Bivard et al.55 is a pooled patient subgroup analysis of the TAAIS50 and ATTEST48 randomized trials. The ORs from
EXTEND IA TNK51 were adjusted on age and baseline NIHSS score.
status (complete vs. partial or no occlusion) was a post-hoc pooled subgroup analysis of 2 other small
modifier of the effect of tenecteplase – compared with RCTs (Figure 7). The quality of the evidence is
alteplase – regarding three-month functional outcome graded as low (see Table 5 for justification).
(P for interaction ¼0.01). Some of the included patients
had distal vessel occlusion and would therefore not Recommendation
currently be eligible for mechanical thrombectomy.14 For patients with acute ischaemic stroke of < 4.5 h
We have conducted a study-level meta-analysis of duration and with large vessel occlusion who are
EXTEND-IA TNK and the subgroup of patients candidates for mechanical thrombectomy and for
with complete vessel occlusion in the pooled analysis whom intravenous thrombolysis is considered
by Bivard et al. (Figure 7).55 The pooled OR for excel- before thrombectomy, we suggest intravenous
lent outcome and better functional outcome were 2.42 thrombolysis with tenecteplase 0.25 mg/kg over
(95% CI: 0.73–8.04) and 2.09 (1.16–3.76), respectively. intravenous thrombolysis with alteplase 0.9 mg/kg.
EXTEND-IA TNK 2 was a randomised trial com- Quality of evidence: Low 丣丣
paring two different doses of intravenous tenecteplase Strength of recommendation: Weak "?
(0.25 mg/kg vs. 0.4 mg/kg) within 4.5 h of stroke onset
in 300 patients who subsequently underwent mechani-
cal thrombectomy.56 The proportion of patients with Additional information. Tenecteplase in Stroke
greater than 50% reperfusion of the previously occlud- Patients Between 4.5 and 24 h (TIMELESS;
ed vascular territory (eTICI 2b50,57 primary end- NCT03785678) is an ongoing trial of tenecteplase
point) before thrombectomy was 19% in the two versus placebo for acute ischemic stroke patients
arms. There was not difference between treatment with large vessel occlusion presenting in late time
groups regarding functional outcome at three months windows.
(adjusted common OR for better functional outcome
0.96, 95% CI: 0.74–1.24, P ¼ 0.73) and mortality. The 6. Alternative doses
rate of sICH according to the SITS-MOST definition PICO 6.1 In patients with acute ischaemic stroke of < 4.5 h
was non-significantly higher in the 0.4 mg/kg arm: duration, does intravenous thrombolysis with low-dose alteplase
4.7% vs. 1.3%, RR 3.50 (95% CI: 0.74–16.62, lead to non-inferior (not worse) functional outcome compared
P ¼ 0.12). to standard-dose alteplase?
Our recommendation is based on one small RCT, Analysis of current evidence. The literature search
with a non-clinical primary outcome measure and a identified one RCT comparing low dose (0.6 mg/kg)
18

Other IVT with IVT with Relative Absolute

No of studies Study design Risk of bias Inconsistency Indirectness Imprecision considerations tenecteplase alteplase (95% CI) (95% CI) Certainty Importance

3 randomised not serious seriousa seriousb not serious none 52/101 43/101 OR 2.42 216 more ⨁⨁ CRITICAL
trials (51.5%) (42.6%) (0.73–8.04) per 1 000 LOW
(from 75
fewer to
431 more)
Improved mRS score at three months (shift analysis)
3 randomised not serious seriousa seriousb not serious none cOR 2.09 – per 1 000 ⨁⨁ CRITICAL
trials (1.16–3.76) (from – to –) LOW
1 randomised not serious not serious seriousc not serious none 10/101 18/101 OR 0.4 98 fewer per ⨁⨁⨁ CRITICAL
trials (9.9%) (17.8%) (0.2–1.1) 1 000 MODERATE
(from 137
fewer to 14
more)
sICH
1 randomised not serious not serious not serious very seriousd none 1/101 1/101 OR 1.0 – per 1 000 ⨁⨁ CRITICAL
trials (1.0%) (1.0%) (0.1–16.2) (from – to 0 LOW
fewer)
The results regarding functional outcome are based on Bivard et al.55 (pooled analysis of the TAAIS50 and ATTEST48 trials) and the EXTEND IA TNK trial51 (Figure 7). The results about death and sICH are
solely based on the EXTEND IA TNK trial.
a
In EXTEND IA TNK, tenecteplase was only significantly associated with better functional outcome in shift analysis of the mRS. Furthermore, other RCTs in unselected patients did not suggest superiority of
tenecteplase over alterplase.
b
This result is based on a secondary outcome of the EXTEND IA TNK trial and subgroup analyses of TAAIS and ATTEST. In those last 2 trials, some patients had distal vessel occlusion (M2, M3, ACA, PCA).
c
The primary endpoint was radiological, not clinical.
d
Only one event in each treatment group.
European Stroke Journal 0(0)
Berge et al. 19
with standard dose (0.9 mg/kg) of alteplase in 3310 7. Adjunctive therapies (i.e. antithrombotic agents,
patients treated with IVT within 4.5 h of stroke onset, ultrasound)
the Enhanced Control of Hypertension and
PICO 7.1 In patients with acute ischaemic stroke of < 4.5 h
Thrombolysis Stroke Study (ENCHANTED).54 The
duration, does antithrombotic agents in addition to IVT lead
trial aimed to show non-inferiority of the lower dose.
to better functional outcome than IVT alone?
About two-thirds of patients were from Asia.
Analysis of current evidence. Re-occlusion of a cere-
Unfavourable functional outcome (mRS scores 2–6)
bral artery occurs in 14%–34% of patients who have
was seen in 53.2% in the low-dose and 51.1% in the
achieved recanalisation after IVT with alteplase, and is
standard-dose group, which did not demonstrate non-
associated with clinical deterioration and poor out-
inferiority (OR 1.09, 95% CI: 0.95–1.25, P for non-infe-
come.73,74 It has been suggested that the use of antith-
riority ¼ 0.51).58 The rate of sICH was lower in the low-
rombotic agents (aspirin, glycoprotein IIb/IIIa
dose group (1.0% vs. 2.1%, P ¼ 0.01). Mortality at
inhibitors or thrombin inhibitors) during or after alte-
three months did not differ significantly between the plase infusion might reduce the risk of re-occlusion and
groups (8.5% and 10.3%, respectively, P ¼ 0.07). The improve functional outcome.75,76
pre-specified subgroup analyses did not identify patients The effect of intravenous aspirin as an adjunct ther-
who benefitted from the low-dose therapy.59–61 but apy to alteplase was tested in the Antiplatelet therapy
patients using antiplatelet drugs before their strokes had in combination with Rt-PA Thrombolysis in Ischemic
non-significantly better functional outcomes after low- Stroke (ARTIS) trial.77 A total of 642 patients treated
dose alteplase than other patients (OR 0.84, 95% CI: with alteplase were randomly assigned to 300 mg intra-
0.62–1.12 versus OR 1.16, 95% CI: 0.99–1.36, p for inter- venous aspirin within 90 min of alteplase bolus or to no
action ¼ 0.053).62,63 This association was further attenu- additional treatment. Oral antiplatelet therapy was
ated in analyses adjusted for potential confounders.62,63 given 24 h following alteplase treatment in both
The evidence for this recommendation is limited to groups. The trial was terminated prematurely because
one trial. However, the trial was adequately powered to of an excess of sICH (assessed in a non-blinded fash-
address its scientific question and we could not identify ion) and no evidence of benefit in the aspirin group.
reason that would lead to downgrade the quality of The OR for good outcome (mRS 0–2 at three months)
evidence regarding risk of bias, inconsistency, indirect- with intravenous aspirin was 0.91 (95% CI: 0.66–1.26,
ness, or imprecision. The quality of evidence was there- P ¼ 0.58), and the relative risk for sICH, defined as in
fore rated as high. The trial did not show non- the third European Cooperative Acute Stroke Study
inferiority of low-dose alteplase, and the recommenda- (ECASS-3) trial,78 was 2.78 (95% CI: 1.01–7.63,
tion is therefore strong. P ¼ 0.04). Of note, follow-up imaging was not system-
atically performed in patients without neurological
Recommendation deterioration.
For patients with acute ischaemic stroke of < 4.5 h Eptifibatide is a glycoprotein IIb/IIIa inhibitor that
duration who are eligible for intravenous throm- is being investigated as an adjunct to intravenous
bolysis, we recommend standard-dose alteplase thrombolysis. One randomised-controlled trial of 94
(0.9 mg/kg) over low-dose alteplase. patients compared low-dose alteplase (0.3 mg/kg and
Quality of evidence: High 丣丣丣丣 0.45 mg/kg) combined with eptifibatide to standard-
Strength of recommendation: Strong "" dose alteplase alone, and did not raise major safety
concerns (OR for any ICH with combination therapy
compared to alteplase alone: 0.28, 95% CI: 0.06–
1.23).79 Another trial randomised 126 patients 4:1 to
Additional information. The ENCHANTED trial did low-dose alteplase (0.6 mg/kg) plus eptifibatide or
not show non-inferiority of low-dose alteplase, despite standard-dose alteplase alone, and found a non-
the fact that almost two-thirds of the patients were significantly lower risk of sICH in the combination
from Asia (who have presumed higher risk of sICH). group (OR 0.15, 95% CI: 0.01–1.40, P ¼ 0.053).80
There was also no imbalance in the baseline character- The safety of eptifibatide as an adjunct to alteplase
istics that could explain the results. For example, the low-dose or standard-dose has also been reported in
percentage of large-artery occlusions and successful observational studies.81,82
recanalisation were similar in the two groups. We identified no RCTs of the glycoprotein IIb/IIIa
There are several older Asian registry studies that inhibitor tirofiban as an adjunctive therapy to alte-
have inconsistent results regarding the optimal dose plase, but there are observational data hinting that tir-
of alteplase in Asian populations.64–72 ofiban might be safe (no sICH in 14 patients treated
with tirofiban þ standard-dose alteplase), although potentiate fibrinolytic activity.86,87 Moreover, intrave-
uncertainties remain.83 nous gaseous microspheres have been introduced with
Argatroban is a direct thrombin inhibitor that has ultrasound as an alternative to fibrinolytic agents to
been given as adjunct therapy to alteplase. One small recanalise discrete peripheral thrombotic arterial occlu-
observational study of 65 patients showed that combi- sions or acute arteriovenous graft thromboses.86,87
nation therapy compared to alteplase alone had a sICH Small RCTs of high-frequency ultrasound in combina-
rate of 4.6% in patients with proximal cerebral artery tion with thrombolytic treatment (sometimes referred
occlusion.84 A RCT of 90 patients treated with alte- to as ‘sonothrombolysis’) have shown promising results
plase randomised patients to no argatroban, argatro- in patients who did not receive mechanical thrombec-
ban bolus followed by low-dose infusion of argatroban, tomy.88,89 The Combined Lysis of Thrombus in Brain
or to argotroban bolus followed by standard-dose infu- Ischemia Using Transcranial Ultrasound and Systemic
sion of argatroban for 48 h.85 No difference in the rates t-PA (CLOTBUST) trial of transcranial ultrasound
of sICH was observed across the three groups (10, 13 and meta-analyses of other similar studies have
and 7%, respectively; RR (low-dose argatrobran vs reported that ultrasound could at least double the
alteplase alone:1.27; 95% CI: 0.32–5.05; RR (high- chance of early recanalisation.90–92 In the
dose argatrobran vs alteplase alone:0.60; 95% CI: CLOTBUST trial of 126 patients, sonothrombolysis
0.11–3.41), as were the proportions of patients with was also associated with a higher likelihood of excellent
mRS scores 0–1 at 90 days (21, 30 and 32%, respective- outcome (secondary endpoint, mRS 0–1 at
ly; RR (low-dose argatrobran vs alteplase alone:1.50; three months) in the subgroup of patients with pre-
95% CI: 0.64–3.49; RR (high-dose argatrobran vs alte- treatment NIHSS scores 10 points.93
plase alone:1.63; 95% CI: 0.72–3.72). However, the These findings were not reproduced in two larger
small sample of this trial should be taken into account RCTs. The Norwegian Sonothrombolysis in Acute
in the interpretation of these findings. Stroke Study (NOR-SASS) randomised 183 patients
The recommendation is based on the ARTIS trial with or without evidence of proximal cerebral artery
and very small randomized trials assessing safety rather occlusion and without a lower cut-off for baseline
than efficacy. The quality of evidence is therefore NIHSS score to contrast-enhanced high-frequency
graded as low.
sonothrombolysis or IVT with alteplase alone (with
sham ultrasound monitoring).94,95 The primary end-
Recommendation points were neurological improvement at 24 h defined
For patients with acute ischaemic stroke of < 4.5 h as a NIHSS score of 0 or a reduction of 4 points
duration, we recommend no antithrombotic drugs compared with baseline NIHSS, and excellent func-
within 24 h of intravenous thrombolysis over tional outcome. The trial was prematurely terminated
antithrombotic drugs as an adjunct therapy to because of a lack of funding. The rates of neurological
intravenous thrombolysis with alteplase. improvement at 24 h, excellent outcome at 90 days and
Quality of evidence: Low 丣丣 sICH were similar in the two groups. Only 113 out of
Strength of recommendation: Strong ## 183 enrolled patients (61%) were treated according to
study protocol in NOR-SASS.
Additional information. The effects of eptifibatide The Combined Lysis of Thrombus using Ultrasound
and argatroban as adjuncts to alteplase will be further and Systemic Tissue Plasminogen Activator for
investigated in the ongoing phase Multi-arm Emergent Revascularization (CLOTBUST-ER) trial
Optimization of Stroke Thrombolysis (MOST) trial enrolled 676 patients with NIHSS scores of 10 points
(NCT03735979). In this trial, 1200 patients treated who received IVT with alteplase within 4.5 h (3 h in
with standard-dose alteplase within three hours of North America) and were randomised to ultrasound
stroke onset will be randomised to intravenous arga- enhancement of IVT or sham.96,97 Vascular imaging
troban, eptifibatide or placebo, and the primary effect was not mandatory and mechanical thrombectomy
variable is functional outcome at 90 days. Patients may was not performed. The primary endpoint was improve-
also receive mechanical thrombectomy per usual care. ment in the mRS-score at 90 days. The trial was stopped
early because of futility. The adjusted cOR for better
PICO 7.2 In patients with acute ischaemic stroke of < 4.5 h functional outcome was 1.05 (95% CI: 0.77–1.45,
duration, does ultrasound augmentation of IVT lead to better P ¼ 0.74) for patients treated within three hours and
functional outcome than IVT alone? 1.06 (95% CI: 0.80–1.42, P ¼ 0.67) for patients treated
Analysis of current evidence. Ultrasound delivers within 4.5 h. There was no difference in three-month
mechanical pressure waves to the clot, exposing more mortality (OR 1.19, 95% CI: 0.74–1.92, P ¼ 0.48) or
thrombus surface to circulating alteplase, which may sICH (OR 1.39, 95% CI: 0.51–3.95, P ¼ 0.52).
Berge et al. 21
Figure 8. Pooled odds ratio for excellent outcome (mRS 0–1) in patients randomized to ultrasound augmentation of IVT vs. IVT
alone.
All patients received IVT with alteplase.
We performed a meta-analysis of the five largest In the meta-analysis of individual participant data
RCTs88–90,95,97 and found no benefit in terms of excel- by Emberson et al., the OR for excellent outcome
lent outcome (mRS score 0–1 at three months) with (mRS score 0–1) in patients >80 years treated with alte-
high-frequency ultrasound in combination with alteplase was 1.56 (95% CI: 1.17–2.08), compared to 1.25
plase versus alteplase alone (OR 1.07, 95% CI: 0.77– (95% CI: 1.10–1.42) in patients 80 years of age, with-
1.50, P ¼ 0.68, I2 ¼ 12%, Figure 8). out evidence of difference in efficacy between the
The recommendation is based on the results of the groups (P for interaction ¼ 0.53).26 There was also no
meta-analysis including two phase 3 and three phase 2 evidence in the pooled analysis that patients aged
RCTs. The quality of evidence was judged to be low >80 years were at any greater risk of ICH than younger
(see Table 6 for justification). patients. Furthermore, age was not associated with
increased risk of sICH in the ENCHANTED trial.59
The Thrombolysis in Elderly Stroke Patients in Italy
Recommendation
(TESPI) trial, which investigated IVT with alteplase
For patients with acute ischaemic stroke of < 4.5 h within three hours of stroke onset in 191 patients over
duration, we recommend against ultrasound aug- the age of 80 years, was terminated early because the
mentation in patients receiving intravenous IST-3 trial provided evidence of treatment benefit in in
thrombolysis. this age group.99 The trial was underpowered and
Quality of evidence: Low 丣丣 showed a non-significant effect on the proportion of
Strength of recommendation: Strong ## good outcome (mRS score 0–2: 29% versus 23%).
The recommendation for patients who are over
80 years of age is based on an individual patient data
meta-analysis of high quality.8,98
8. Higher age, multimorbidity, frailty or prior
disability Recommendation
PICO 8.1 In patients with acute ischaemic stroke of < 4.5 h For patients with acute ischaemic stroke of <4.5 h
duration, who are over 80 years of age, does IVT with duration, who are over 80 years of age, we recom-
alteplase lead to better functional outcome than no IVT? mend intravenous thrombolysis with alteplase.
Analysis of current evidence. Most trials of IVT for Quality of evidence: High 丣丣丣丣
ischaemic stroke have excluded patients who were over Strength of recommendation: Strong ""
80 years old or who had multimorbidity/frailty or pre-
stroke disability. IST-3 included patients over 80 years
of age and added substantial information on this
patient group.9 Information about the effect of alte-
plase in elderly patients can also be found in meta- Nine of nine group members believe that age alone
analyses of RCTs, either with individual patient should not be a limiting factor for IVT, even in
data8,26,98 or on study-level.6 other situations covered in the present guidelines
In the CLOTBUST trial, 19% of the randomized patients were not eligible for the analysis of functional outcome at three months, which was a secondary endpoint. The two trials by Eggers et al. were very
Certainty Importance
(e.g. wake-up stroke; ischaemic stroke of 4.5–9 h
CRITICAL
duration (known onset time) with CT or MRI
core/perfusion mismatch; minor stroke with dis-
abling symptoms).
⨁⨁
per 1 000 LOW
Two small trials by the same group (Eggers et al., 2003, 2008) and one larger study (CLOTBUST) suggested a strong benefit of sonothrombolysis, whereas two large trials did not.
duration, who have multimorbidity, frailty or prior disability,
does intravenous thrombolysis with alteplase lead to better
96 more)
(from 56
fewer to
15 more
(95% CI)
functional outcome than no IVT?
Absolute
Analysis of current evidence. The literature search
identified no trials that targeted patients with multi-
morbidity/frailty or those with pre-stroke disability.
(0.77–1.50)
Some trials only included patients with proven arterial occlusion (Eggers et al., CLOTBUST), whereas other studies did not (NOR-SASS, CLOTBUST-ER).
An analysis of observational data from 3017 patients
OR 1.07
(95% CI)
in IST-3 used brain imaging findings before treatment
alteplase Relative
Effect
with alteplase to identify patients with pre-existing
‘brain frailty’, such as old lesions, brain atrophy or
leukoaraiosis. The risk of sICH was higher in patients
augmentation IVT with
158/463
(34.1%)
with old infarct (OR 1.72, 95% CI: 1.18–2.51), and the
alone
chance of excellent functional outcome was lower
No of patients
(severe leukoaraiosis: OR 0.62, 95% CI: 0.50–0.78;
of IVT with
severe brain atrophy: OR 0.75, 95% CI: 0.57–0.99;
ultrasound
Inconsistency Indirectness Imprecision considerations alteplase

old infarct: OR 0.79, 95% CI: 0.64–0.96).100
167/472
(35.4%)
However, no imaging findings, individually or com-
bined, modified the effect of alteplase on functional
outcome or sICH.100 Renal dysfunction, which is
another marker of multimorbidity, was not associated
with increased risk of sICH in the ENCHANTED
Other
not seriousc not serious none

trial,60 but was associated with increased risk of other
haemorrhagic complications, death and poor function-
al outcome before and after adjustment for potential
confounders in meta-analyses of observational stud-
ies.101–104 Finally, one observational study of patients
with non-metastatic cancer, found that functional out-
come after IVT with alteplase was comparable to that
of other patients.105 These findings suggest that cancer
should not be an absolute contraindication against
thrombolytic treatment, although caution seems
small. Furthermore, two phase III trials were stopped early.
appropriate.
Patients with pre-existing disability are often not

seriousb
treated with alteplase.106 Despite high mortality rates,

observational studies of patients with pre-existing dis-
ability have indicated that IVT may prevent further
functional deterioration and that treatment is more
beneficial the earlier it is given.107,108 Observational
randomised seriousa
of bias
studies have not found evidence that pre-stroke disabil-

Risk
ity is associated with an increased risk of ICH after

thrombolytic treatment.107,109,110
The recommendations for patients with multimor-

trials
bidity, frailty or pre-stroke disability is based on

studies design
No of Study
small observational studies, corresponding to a very

low quality of evidence.
5
b
c
a
Berge et al. 23
performing basic activities of daily living (i.e., bathing,

Recommendation ambulating, toileting, hygiene, and eating) or return-
ing to work’.114
For patients with acute ischaemic stroke of < 4.5 h The quality of evidence for the recommendation is
duration, and with multimorbidity, frailty or pre- moderate (see Table 7 for justification).
stroke disability, we suggest intravenous thrombol-
ysis with alteplase.
Recommendation
Quality of evidence: Very low 丣
Strength of recommendation: Weak "? For patients with acute minor, disabling ischaemic
stroke of < 4.5 h duration, we recommend intrave-
nous thrombolysis with alteplase.
Additional information. The weak recommendations Quality of evidence: Moderate 丣丣丣
given above imply that the decision to treat must be Strength of recommendation: Strong ""
made on an individual basis and that it must consider
the patient’s values and preferences.
A single-centre observational study suggested that PICO 9.2 In patients with acute minor, non-disabling ischaemic
the outcome of patients with cognitive impairment stroke of < 4.5 h duration, does IVT with alteplase lead to
no-dementia who are treated with IVT does not signif- better functional outcome than no IVT?
icantly differ from that of cognitively normal Analysis of current evidence. Patients with minor
patients.111 neurological deficits (NIHSS score 0–5) judged to not
be clearly disabling within three hours of stroke onset
9. Minor stroke and stroke with rapidly improving were assessed in the PRISMS trial of IVT with alte-
plase vs. aspirin.114 A disabling deficit was defined as ‘a
neurological signs
deficit that, if unchanged, would prevent the patient
PICO 9.1 In patients with acute minor, disabling ischaemic from performing basic activities of daily living (ie,
stroke of < 4.5 h duration, does IVT with alteplase lead to bathing/dressing, ambulating, toileting, hygiene, and
better functional outcome than no IVT? eating) or returning to work’. Due to slow recruitment
Analysis of current evidence. About half of all ischae- and insufficient funding, the trial was terminated after
mic strokes are initially minor (defined typically as inclusion of 313 patients, while the calculated sample
NIHSS score < 5), but up to one third of patients size was 948. The adjusted risk difference for excellent
with minor stroke are disabled or dead three months outcome (mRS 0–1 at three months) with alteplase
after the index event.112,113 Emberson et al. conducted was –1.1% (95% CI: –9.4 to 7.3%) and the cOR for
an individual participant data meta-analysis of 9 RCTs better functional outcome was 0.81 (95% CI: 0.5–1.2).
of IVT with alteplase vs. placebo or open control, The risk of sICH (defined as any neurological wors-
which included 666 patients (10%) with a baseline ening within 36 h attributed to ICH by local investi-
NIHSS score 0–4.8 All trials included in this meta- gators) was significantly higher in the alteplase group
analysis excluded patients with non-disabling neurolog- (risk difference 3.3%, 95% CI: 0.8–7.4), and there
ical deficits, except IST-3.9 The meta-analysis showed were more patients with serious adverse events
that the proportional benefit of alteplase was not sta- (mostly intracranial/intracerebral hemorrhage) in the
tistically different in patients with mild, moderate and alteplase group (risk difference 12.9%, 95% CI: 4.1–
severe strokes (P for interaction ¼ 0.06). In patients 21.7%). A limitation of this trial was missing three-
with baseline NIHSS score of 0–4, the OR for excellent month mRS score evaluations in 10% of enrolled
outcome (mRS score 0–1 at three months) was 1.48 patients.
(95% CI: 1.07–2.06). These data support the use of Because IST-3 had not explicitly excluded patients
alteplase in patients with minor disabling stroke. with non-disabling neurological deficits, we also used
One critical question is how ‘minor disabling data from that trial.9 Among the subgroup of patients
stroke’ should be defined in clinical practice. No stan- with NIHSS 0–5 in IST-3, the adjusted OR for good
dardized definition has been used across trials includ- functional outcome (Oxford Handicap Scale score 0–2)
ed in the present meta-analysis, which relied on the with alteplase was 0.85 (95% CI: 0.52–1.38).
subjective judgment of each investigator. An opera- The recommendation is based on one relatively
tional definition of a disabling deficit has since been small RCT that was stopped early and one trial that
proposed in the Potential of Rt-PA for Ischemic did not explicitly exclude patients with non-disabling
Strokes with Mild Symptoms (PRISMS) trial: ‘a def- ischaemic stroke. The quality of the evidence is there-
icit that, if unchanged, would prevent the patient from fore graded as moderate.
Importance
CRITICAL
Recommendation
For patients with acute minor non-disabling
ischaemic stroke of < 4.5 h duration, we suggest
This result is based on an analysis of subgroups of patients included in RCTs with various inclusion criteria. There was no clear definition of disabling stroke in patients with NIHSS 0–4.
MODERATE no intravenous thrombolysis. For patients with
Certainty
⨁⨁
⨁⨁⨁
minor stroke and large-vessel occlusion, please
LOW
refer to the section below (PICO 9.3).
Quality of evidence: Moderate 丣丣丣
9 more per 1
to 25 more)
(from 16 more
91 more per
Strength of recommendation: Weak #?
(from 4 more
to 158
1 000
more)
Absolute
(95% CI)
000
Additional information. A list of examples of non-
disabling symptoms was provided to each participating
(1.46–10.44)
centre in the PRISMS trial and in the published proto-

(1.07–2.06)
col115: isolated mild aphasia (patient still able to com-

(95% CI)
OR 1.48
OR 3.90
Relative
Effect
municate meaningfully), isolated facial droop, mild

cortical hand (especially non-dominant: NIHSS score-
¼ 0), mild hemimotor loss, hemisensory loss, mild
189/321
(58.9%)
no IVT
(0.0%)
0/321
hemisensorimotor loss and mild hemiataxia (patient

No of patients
still able to ambulate). Importantly, the two most

common neurological deficits of patients enrolled in
alteplase
IVT with
237/345
(68.7%)
(0.9%)
3/345
PRISMS were mild sensory loss (46%) and facial

palsy (39%).
strong association
PICO 9.3 In patients with acute minor, non-disabling ischaemic

considerations
stroke of < 4.5 h duration, and with proven large vessel occlu-
sion, does IVT with alteplase lead to better functional outcome
Other
none
than no IVT?
Analysis of current evidence. Patients with large
very seriousb
vessel occlusion have a higher risk of stroke progres-

Note: All results are based on the individual patient data meta-analysis by Emberson et al.
Imprecision
not serious
sion and poor prognosis than other patients.116 The

literature search identified no RCT of IVT with alte-
plase in patients with NIHSS scores of 0–5 with non-
disabling neurologic deficits and with proven intracra-
Indirectness
nial large artery occlusion. TEMPO-1 was a case series

seriousa
seriousa
of 50 patients with NIHSS sores 0–5 (disabling or non-

disabling symptoms) who were given tenecteplase 0.1
or 0.25 mg/kg for acute ischaemic stroke due to any
Inconsistency
not serious
not serious
proven and relevant intracranial occlusion.117 The

mRS 0–1 at three months (six months in IST-3)
TEMPO-2 trial (NCT02398656) is an ongoing RCT

that compares tenecteplase with standard care in a sim-
ilar population.
The number of events was extremely low.
not serious
not serious
Recommendation
Risk of
For patients with acute minor non-disabling

bias
Fatal ICH within seven days
ischaemic stroke of < 4.5 h duration, and with

proven large-vessel occlusion, there is insufficient
randomised
randomised
evidence to make an evidence-based recommenda-

trials
trials
tion. Please see the Expert consensus statement

design
Study
below.
studies
Strength of recommendation: -
No of
b
a
Berge et al. 25
Additional information. Recommendations for man- trial.17 The original intent was to avoid inclusion of
agement of patients with large artery occlusions are transient ischaemic attack (TIA) patients, who recover
also provided in the European Guidelines for mechan- completely without treatment.121 A working group of
ical thrombectomy.14 Trials are underway to test the investigators from the pivotal NINDS trial that
effectiveness of thrombectomy in patients with large- reviewed this exclusion criterion concluded that
artery occlusion and NIHSS scores 0–5 (In Extremis/ patients with improvement of any degree, but with a
Minor Stroke Therapy Evaluation [MOSTE; NCT persisting neurological deficit that is potentially dis-
03796468], Endovascular Therapy for low NIHSS abling, should be treated with alteplase.121 The authors
Ischemic Strokes [ENDOLOW; NCT 04167527]). In performed structured interviews of the original NINDS
addition, two recent multicentre observational studies clinical trialists to form this conclusion.
suggest a potential beneficial effect of IVT118 and
bridging therapy119 in acute ischaemic stroke patients Expert consensus statement
with minor stroke (NIHSS-scores < 6) and large vessel
For patients with acute ischaemic stroke of < 4.5 h
occlusion.
duration, and rapidly improving neurological
signs, which are still disabling, 8 of 9 group mem-
Expert consensus statement bers suggest intravenous thrombolysis with
For patients with acute minor, non-disabling alteplase.
ischaemic stroke of < 4.5 h duration, and with The group agreed that the treatment decision
large-vessel occlusion, 6 of 8 group members sug- should be based on the clinical status at presenta-
gest intravenous thrombolysis with alteplase. tion, and that it is not justifiable to wait for reso-
lution of symptoms.
One group member (WW) did not vote or comment on this
chapter because he has been involved in the data monitoring
committee of a trial related to this topic (TEMPO-2).
10. Severe stroke
PICO 10.1 In patients with severe acute ischaemic stroke
PICO 9.4 In patients with acute ischaemic stroke of < 4.5 h of < 4.5 h duration, does IVT with alteplase lead to better
duration, and with rapidly improving neurological signs, does functional outcome than no IVT?
IVT with alteplase lead to better functional outcome than no Analysis of current evidence. Severe stroke can be
IVT? defined clinically (e.g. NIHSS score >25), or with CT
Analysis of current evidence. We found no evidence or other brain imaging prior to IVT, e.g. visible infarc-
of direct relevance for this question. The literature tion in more than 1/3 of the middle cerebral artery
search did not identify any RCT of IVT in patients territory or an Alberta Stroke Program Early CT
with rapidly improving symptoms, although the
Score (ASPECTS) of < 7.122
PRISMS trial included about 5% of such patients.114
One large observational study of 29,200 patients with Clinically severe stroke. A study-level meta-analysis
mild or rapidly improving symptoms, who did not classified RCTs recruiting patient with ‘more severe
receive IVT, showed that unfavourable outcomes stroke’ as trials with a case fatality of 20% in the
were common (28.3% were not discharged to home,
control group.6 There was no evidence of heterogeneity
and 28.5% were unable to ambulate without assistance
in the effect of IVT with alteplase on death or disability
at hospital discharge), and strongly associated with
between trials with different levels of average stroke
baseline NIHSS score.120
severity, but this study did not use the threshold of
NIHSS score 25 to define severe stroke.
Recommendation In the individual participant data meta-analysis by
For patients with acute ischaemic stroke of < 4.5 h Emberson et al,8 there was no clear evidence of hetero-
duration, and rapidly improving neurological geneity in the effect of alteplase on excellent outcome
signs, which are still disabling, there is insufficient (mRS 0–1) between groups of patients with different
evidence to make a recommendation. Please see the baseline NIHSS scores, after controlling for age and
Expert consensus statement below. time to treatment (p for interaction ¼ 0.06). In the
Quality of evidence: Very low 丣 622 participants with the highest level of stroke severity
Strength of recommendation: - (NIHSS score 22) alteplase improved the odds of
excellent outcome (OR 3.25, 95% CI: 1.42–7.47;
Additional information. Rapidly improving stroke Table 8).8 Regarding for better functional outcome),
symptoms were a contraindication in the NINDS there was no evidence of an interaction (P for
interaction ¼ 0.72) between higher NIHSS score and
This result is based on an independent patient data meta-analysis of subgroups of 9 trials, and was restricted to patients with NIHSS 22. It is uncertain whether those results would also apply to patients
Importance
CRITICAL
CRITICAL
lesser benefit from alteplase.26
radiologically severe stroke (e.g. attenuation of >1/3 of the MCA in ECASS 2 and ATLANTIS B) were excluded. Therefore, a selection bias is likely: patients with clinically severe stroke were not
Although the 9 RCTs included in the individual patient data meta-analysis had patients with NIHSS 22, in many trials, patients with clinically very severe stroke (e.g. NIHSS >25 in ECASS-3) or
In IST-3, where the subgroup of patients with
NIHSS score 25 was reported specifically, there was
evidence of an interaction (P ¼ 0.003) between stroke
MODERATE
MODERATE
Certainty
severity and the effect alteplase on good outcome (mRS
⨁⨁⨁
⨁⨁⨁
score 0–2), with greater relative benefit in patients with
more severe stroke. In the small subgroup of 146
patients with the most severe strokes (NIHSS scores
(from 10 more
(from 10 more
53 more per
59 more per
25) alteplase-treated patients were non-significantly
to 138
to 226
1 000
1 000
more)
more)
Absolute
(95% CI)
more likely to have a good outcome than patients in
the control group (OR 7.43, 95% CI: 0.43–129.0).9
The individual participant data meta-analysis
showed that the absolute risk of fatal ICH due to
(2.54–47.15)
(1.42–7.47)
OR 10.94
(95% CI)
IVT with alteplase was highest in those participants
OR 3.25
Relative
with the highest stroke severity (NIHSS scores 22,
Effect
6.8% vs 0.6%; Table 8),8 although the odds of fatal
ICH with alteplase was similar in patients with high or
no IVT
(2.6%)
(0.6%)
8/313
2/313
low stroke severity. Altogether, these studies do not
No of patients
provide evidence that patients with the highest level
of stroke severity have a lesser proportional benefit
alteplase
IVT with
22/309
21/309
(7.1%)
(6.8%)
from alteplase.
Extensive ischaemic change on baseline imaging.
very strong association

Studies have also used brain imaging to define severe
strong association
stroke. A Cochrane review did not demonstrate any
considerations
important statistical difference between the effect of

alteplase in those with more and in those with less
Other
extensive ischaemic change on baseline CT scan.6 We
Note: All results are based on the individual participant data meta-analysis by Emberson et al.8
found no individual participant data meta-analysis of
baseline brain imaging findings in patients in the large
Imprecision
not serious
trials of alteplase. Although the presence of a greater

Table 8. GRADE evidence profile for PICO 10.1 – Clinically severe stroke.
seriousc
degree of low attenuation on brain CT is associated

with a much poorer outcome after ischaemic
stroke,123,124 there is no evidence that patients with
Indirectness
larger lesion or with more tissue attenuation benefit

seriousb
seriousb
less from alteplase in analyses from 3 individual

trials, after adjustment for time to randomisa-
tion.100,125,126 However, there is no trial specifically
Inconsistency
not serious
not serious
addressing this question, and extensive baseline ische-

mia was an exclusion criteria in the major IVT trials.
with very severe stroke (e.g., NIHSS >25 or coma).
We have conducted a study-level meta-analysis of 3

trials in which inclusion of patients in spite of an early
indiscriminately randomized in those trials.
ischemic change of more than 1/3 of the middle cere-

bral artery territory was permitted (IST-3, NINDS and
The confidence interval is very wide
seriousa
seriousa
ECASS I).100,125,127 The unadjusted pooled ORs for

Risk of
bias
‘favourable’ outcome (mRS 0–1 at three months in

Fatal ICH with seven days
NINDS and ECASS I, Oxford Handicap Score 0–2

at six months) were 1.65 (0.38–7.20) and 1.55 (1.05–
randomised
randomised
2.28) in patients with and without early ischemic

trials
trials
change of more than 1/3 of the middle cerebral artery

design
Study
territory (Figure 9). We found no evidence that the

presence of an early ischemic change of more than 1/
studies
No of
3 of middle cerebral artery territory significantly modi-

fies the effect of IVT on favourable outcome (P for
9
c
a
Berge et al. 27
Figure 9. Pooled odds ratio for favourable outcome* in patients with ischaemic stroke of < 4.5 h duration randomised to with IVT
vs. control, stratified by the extent of early ischaemic change on baseline CT (> 1/3 vs. < 1/3 of middle cerebral artery territory).
Random effects meta-analysis, based on data from von Kummer et al.,127 Patel et al.125 and IST-3 subgroup analyses.100
*Favourable outcome at 3–6 months refers here to Oxford Handicap Scale 0–2 at six months in IST-3 and mRS 0–1 at three months in
NINDS and ECASS 1. EIC denotes early ischaemic changes on baseline CT scan. There was no significant interaction between the
extent of early ischemic changes (> 1/3 vs. < 1/3 of the MCA territory) and the effect of IVT on favourable outcome (P for
interaction ¼ 0.67).
Figure 10. Pooled odds ratio for death at three months in patients with ischaemic stroke of < 4.5 h duration randomised to IVT vs.
control, stratified by the extent of early ischaemic change on baseline CT (> 1/3 vs. < 1/3 of middle cerebral artery territory).
Random effects meta-analysis, based on data from von Kummer et al.127 and Patel et al.125 EIC denotes early ischaemic changes on
baseline CT scan. There was a significant interaction between the extent of early ischemic changes (> 1/3 vs. < 1/3 of the MCA
territory) and the effect of IVT on death at three months (P for interaction ¼ 0.005).
interaction ¼ 0.67). However, we observed a significant An ASPECTS of < 7 has also been used to define
interaction of the presence of early ischemic changes severe stroke.128
on baseline CT on the association of IVT with The recommendation for patients with clinically
three-month mortality (P for interaction ¼ 0.005). severe acute ischaemic stroke is based on meta-
Patients treated with alteplase were at higher odds of analyses of a number of RCTs. The quality of the evi-
three-month mortality compared with patients not dence is moderate (Table 8). For severe stroke defined
treated with IVT (OR 3.90, 95% CI: 1.42–10.68; by the extent of ischaemic change on CT the recom-
Figure 10). mendation is based on fewer data from fewer trials.
The quality of the evidence is rated as very low (see increase the risk of sICH after IVT. The majority of
Table 9 for details). the RCTs of IVT with alteplase therefore excluded
patients with systolic blood pressure >185 mmHg or
Recommendation diastolic blood pressure >110 mmHg, and aimed to
maintain blood pressure below these values during
For patients with clinically severe acute ischaemic
the first 24 h.
stroke of < 4.5 h duration, we recommend intrave-
In IST-3, an analysis by subgroups of baseline sys-
nous thrombolysis with alteplase.
tolic (< 143, 144–164, >164 mmHg) or diastolic blood
Quality of evidence: Moderate 丣丣丣 pressure did not show a modification in the effect of
Strength of recommendation: Strong "" alteplase on sICH, death at seven days, or functional
outcome at six months.129 However, results for patients
with systolic blood pressure >185 mmHg have not been
duration, and with severe stroke, defined by the
published.
extent of early ischaemic changes on CT, we sug-
While analyses of RCTs have not shown an effect
gest that intravenous thrombolysis with alteplase
modification of IVT by high blood pressure, a number
be considered in selected cases (see the Expert con-
of analyses of observational data have shown that high
sensus statement below).
blood pressure is associated with poorer prognosis. In
Quality of evidence: Very Low 丣 patients treated with alteplase in the ECASS-2 trial,
Strength of recommendation: Weak "? higher baseline, maximum, mean (per 10 mmHg
increase), and variability of systolic blood pressure
were all inversely associated with excellent outcome
Additional information. The European Medicine
(mRS score 0–1) at three months (OR 0.84, 95% CI:
Agency stipulates in the product insert for Actilyse
0.74–0.94; OR ¼ 0.82, 95% CI: 0.73–0.91; OR ¼ 0.81,
that ‘Patients with severe stroke (as assessed clinically
95% CI: 0.71–0.93; OR 0.57, 95% CI: 0.35–0.92,
[NIHSS score >25] and/or by appropriate imaging
respectively) and associated with an increased risk of
techniques) . . . at baseline should not be treated with
parenchymal haemorrhage within the first seven days
Actilyse’ because ‘patients with very severe stroke are
(OR 1.27, 95% CI: 1.07–1.51; OR 1.49, 95% CI:
at higher risk for intracerebral haemorrhage and death’.
1.27–1.75; OR 1.52, 95% CI: 1.23–1.87; OR 2.62,
95% CI: 1.40–4.87, respectively) after adjusting for
Expert consensus statement age, sex, time from stroke onset to treatment, stroke
Seven of nine group members voted for intrave- severity, history of hypertension, medication with aspi-
nous thrombolysis with alteplase in selected rin and the extent of hypodensity on initial CT.130
patients with severe stroke associated with extend- Likewise, in an analysis of observational data from
ed radiological signs of infarction (e.g., early ische- IST-3, the odds of sICH increased by 10% (95% CI:
mic change of more than 1/3 of the middle cerebral 2–19) for each 10 mmHg increase in baseline systolic
artery territory or ASPECTS < 7 on plain CT). blood pressure, after adjustment for baseline stroke
Patient selection criteria might include eligibility severity.131 In addition, a single-centre observational
for an alternative reperfusion strategy (mechanical study reported that pretreatment blood pressure limit
thrombectomy), results of advanced imaging (nota- violations (systolic blood pressure >185 mmHg and/or
bly core/perfusion mismatch), time since symptom diastolic blood pressure >110 mmHg) occurred frequent-
onset, extent of white matter lesions, other contra- ly (12%) in everyday clinical practice and were indepen-
indications for IVT, and pre-stroke disability. dently associated with higher likelihood of sICH (OR
2.59, 95% CI: 1.07–6.25).132 Also, in a recent retrospec-
tive analysis of the Safe Implementation of Treatments
11. High blood pressure and high blood glucose level in Stroke (SITS) thrombolysis registry with regard to 11
PICO 11.1 In patients with acute ischaemic stroke of < 4.5 h off-label criteria according to the European licence for
duration, and with persistently increased blood pressure above alteplase, elevated pretreatment blood pressure levels rep-
185/110 mmHg, even after blood pressure lowering treatment, resented the only off-label criterion that was independent-
does IVT with alteplase lead to better functional outcome than ly associated with a higher odds of sICH (OR 1.39; 95%
no IVT? CI: 1.08–1.80).133
Analysis of current evidence. Increased blood pres- A systematic review and meta-analysis of observa-
sure is a common finding during the first hours of tional data from 56,513 patients found that higher pre-
ischaemic stroke, and may be considered an adaptive treatment systolic blood pressure (OR 1.08, 95% CI:
physiological response aiming to improve cerebral per- 1.01–1.16 per 10 mm Hg increase, I2 ¼ 82%) and higher
fusion. However, increased blood pressure may also post-treatment systolic blood pressure (OR 1.13 95%
Berge et al.
Table 9. GRADE evidence profile for PICO 10.1 – Extensive ischaemic change on baseline imaging.
No of Study Risk of Other IVT with Relative Absolute

studies design bias Inconsistency Indirectness Imprecision considerations alteplase no IVT (95% CI) (95% CI) Certainty Importance
Favourable outcome: mRS 0–1 at three months in ECASS-1 & NINDS; OHS 0–2 at six months in IST-3
3 randomised seriousa seriousb seriousc seriousd none 36/207 27/179 OR 1.65 76 more per ⨁ CRITICAL
trials (17.4%) (15.1%) (0.38–7.20) 1 000 VERY LOW
(from 88
fewer to
410 more)
sICH
1 randomised seriousa not serious seriousc seriousd none 15/138 4/112 OR 3.24 71 more per ⨁ CRITICAL
trials (10.9%) (3.6%) (0.72–14.60) 1 000 VERY LOW
(from 10
fewer to
315 more)
2 randomised seriousa not serious seriousc not seriousd strong association 49/69 32/67 OR 3.90 303 more ⨁⨁ CRITICAL
trials other consideratione (71.0%) (47.8%) (1.42–10.68) per 1 000 LOW
(from 87 more
to 429
more)
Note: These results are based on the ECASS-1, NINDS and IST-3 studies.
a
Selection bias: it is plausible that all patients with very extensive signs of brain infarction on baseline imaging were not systematically randomized. Besides, because advanced imaging was not used, it is likely
that the included population is heterogeneous, consisting of patients with and without residual salvageable (penumbral) tissue despite extensive infarction.
b
A strong benefit of IVT was observed in the NINDS trial (OR for favourable outcome 6.8; 95% CI: 1.30–36.2), whereas a trend towards deleterious effect was observed in ECASS-1 (OR for favourable
outcome 0.4; 95% CI: 0.10–2.70).
c
In IST-3 and ECASS-1, patients could be treated up to six hours after symptom onset. In IST-3, to our knowledge extent of early ischemic change was not specifically reported as less or more than 1/3 of the
MCA territory but according to 4 categories, of which the authors considered ‘large or very large’ to correspond to more than 1/3 of the MCA territory.100 Conversely, in NINDS and ECASS-1, all baseline
images were centrally reviewed and classified as less or more than 1/3 of the MCA territory.125
d
The confidence interval is wide. However, in our meta-analysis we found evidence that presence of early ischaemic changes >1/3 of the middle cerebral artery territory modifies the effect of IVT on
mortality at three months (P for interaction ¼ 0.005).
e
Regarding IST-3, we could not find published data on the raw numbers or ORs for the association between IVT and death at six months, stratified by the extend of early ischaemic changes.
29
CI: 1.01–1.25 per 10 mm Hg increase, I2 ¼ 63%) were group. Functional outcome at 90 days did not differ
associated with an increased risk of sICH.134 Higher between groups (unadjusted cOR for better functional
systolic blood pressure was also associated with lower outcome 1.01, 95% CI: 0.87–1.17, P ¼ 0.87). Fewer
odds of good outcome (mRS 0–2) at three months: OR patients in the intensive group (14.8%) than in the con-
0.91, 95% CI: 0.84–0.98 per 10 mmHg increase in pre- trol group (18.7%) had any ICH (OR 0.75, 0.60–0.94,
treatment pressure, I2 ¼ 29%, and OR 0.70, 95% CI: P ¼ 0.01). Blood pressure reduction was also related to a
0.57–0.87 per 10 mm Hg increase in post-treatment non-significant decrease in type 2 parenchymal haemor-
pressure, I2 ¼ 0%). rhage (OR 0.71, 95% CI: 0.50–1.01).
An analysis of observational data from IST-3 indi-
Recommendation cated that the use of blood pressure lowering treatment
For patients with acute ischaemic stroke of < 4.5 h during the first 24 h were associated with a reduced risk
duration, and with persistently increased systolic of poor outcome (Oxford handicap scale 3–6) at
blood pressure >185 mmHg or diastolic blood six months (OR 0.78, 95% CI: 0.65–0.93, P ¼ 0.007),
pressure >110 mm Hg even after blood pressure irrespective of whether the patient was given alteplase
lowering treatment, we suggest no intravenous or not (p for interaction > 0.05).131 However, analyses
thrombolysis. of the effect of blood pressure lowering treatment using
Quality of evidence: Very low 丣 observational data from the NINDS trial did not pro-
Strength of recommendation: Strong ## vide conclusive results.137
Recommendation
Additional information. It should be noted that,
based on current acute antihypertensive treatment For patients with acute ischaemic stroke of < 4.5 h
options, persistent elevated blood pressure of >185/ duration, and with systolic blood pressure
110 excluding patients from treatment is uncommon. >185 mm Hg or diastolic blood pressure
There is evidence suggesting that it is also important >110 mm Hg, which has subsequently been low-
to monitor blood pressure after treatment with alte- ered to < 185 and < 110 mm Hg, we recommend
plase. In a cohort of 1868 patients treated with alte- intravenous thrombolysis with alteplase.
plase, patients with sICH had significantly higher Quality of evidence: Low 丣丣
systolic blood pressure at several time-points after Strength of recommendation: Strong ""
IVT compared with those without sICH (P < 0.01 at
2 and 4 h; P < 0.05 at 12 and 48 h). The odds ratios for PICO 11.3 In patients with acute ischaemic stroke of < 4.5 h
development of sICH per 10 mmHg increase in blood duration, and with known pre-stroke hypertension, does IVT
pressure at 2, 4, 12 and 48 h were 1.14 (95% CI: 1.03– with alteplase lead to better functional outcome than no IVT?
1.25), 1.14 (95% CI: 1.03–1.25), 1.12 (95% CI: 1.01– Analysis of current evidence. Only two of the RCTs
1.23) and 1.12 (95% CI: 1.01–1.23), respectively.135 (ECASS-3 and IST-3) that were included in the indi-
vidual participant data meta-analysis8 presented the
PICO 11.2 In patients with acute ischaemic stroke of < 4.5 h effect of IVT with alteplase for patients with or without
duration, and with increased blood pressure above 185/ known pre-stroke hypertension. There was no evidence
110 mm Hg, which has subsequently been lowered to below that known hypertension modifies the effect of IVT
185/110 mm Hg, does IVT with alteplase lead to better with alteplase on excellent outcome in ECASS-3 (P
functional outcome than no IVT? for interaction ¼ 0.19), or better functional outcome
Analysis of current evidence. Blood pressure lowering at six months in IST-3 (P for interaction ¼ 0.79).129,138
treatment to values below 185/110 mmHg was allowed There was also no evidence that known hypertension
in all completed RCTs of IVT with alteplase versus modifies the effect of IVT with alteplase on mortality
control, and so the results of these trials apply to or sICH in these two trials.
these patients.
In the ENCHANTED trial, 2196 patients with sys- Recommendation
tolic blood pressure >150 mmHg and < 185/110 mmHg
who were eligible for IVT with alteplase were rando- For patients with acute ischaemic stroke of < 4.5 h
mised to intensive blood pressure lowering (target sys- duration, and with known pre-stroke hypertension,
tolic blood pressure 130–140 mm Hg within 1 h) or to a we recommend intravenous thrombolysis with
target systolic blood pressure < 180 mm Hg, and to keep alteplase.
blood pressure in that range over 72 h.136 Mean systolic Quality of evidence: Moderate 丣丣丣
blood pressure over 24 h was 144 10 mmHg in the Strength of recommendation: Strong ""
intensive group and 150 12 mmHg in the control
Berge et al. 31

duration, and with blood glucose level above >22.2 mmol/L Recommendation
(>400 mg/dL), does IVT with alteplase lead to better
functional outcome than no IVT? For patients with acute ischaemic stroke of < 4.5 h
Analysis of current evidence. Hyperglycaemia in the duration, and with blood glucose levels above
acute phase may represent stress, underlying impaired 22.2 mmol/L (400 mg/dL), we suggest intravenous
glucose tolerance or unrecognised diabetes mellitus. thrombolysis with alteplase.
Higher blood glucose level at admission has been con- Quality of evidence: Very Low 丣
sistently associated with poorer functional outcome Strength of recommendation: Weak "?
and sICH in acute ischemic stroke patients treated Intravenous thrombolysis should not prevent the
with or without IVT.139,140 However, blood glucose administration of insulin therapy in acute ischae-
level was not a modifier of the effect of alteplase on mic stroke patients with high blood glucose
functional outcome in RCTs.9,129 It is uncertain wheth- levels.144
er this also holds true for patients with very high blood
glucose levels (>22.2 mmol/L, >400 mg/dL) because
Additional information. In an analysis of 16,049
they were not included in RCTs, owing to concerns
patients treated with alteplase and included in the
of an increased risk of sICH,122 but also because hyper-
SITS registry,145 blood glucose as a continuous vari-
glycaemia can present with focal neurological deficits
able was independently associated with a higher case
that mimic acute stroke.141
fatality (p < 0.001), poorer functional outcome
We identified only one observational study allowing
(p < 0.001) and increased risk of sICH (P ¼ 0.005).
the comparison of IVT and no IVT in acute ischaemic
stroke patients with blood glucose levels >22.2 mmol/ Compared to patients with blood glucose level 80–
L. In this analysis of 9613 patients from the Virtual 120 mg/dL, patients with blood glucose from 181 to
International Stroke Trials Registry (VISTA), only 23 200 mg/dL had an increased risk of sICH (OR 2.86,
patients had blood glucose levels >22.2 mmol/L. Of 95% CI: 1.69–4.83, p < 0.001). The associations
these, 6 had been treated with alteplase, and in this between blood glucose and outcomes were similar in
very small group no cases of sICH were observed.142 patients with or without diabetes mellitus, except for
Compared with patients not treated with IVT, those case fatality (p for interaction < 0.001) and sICH (p for
who received IVT had a cOR for better functional out- interaction ¼ 0.02), for which the associations were not
come of 1.06 (95% CI: 0.19–5.91) and an OR for excel- statistically significant in patients with diabetes
lent functional outcome of 1.31 (0.08–20.61). mellitus.
Large observational registries of patients treated In the SITS-EAST registry, 14 of 5461 patients
with IVT provide some insight on the risk of sICH in (0.3%) had blood glucose levels >22.2 mmol/L, and
patients with very high blood glucose levels. Out of these patients had an increased rate of sICH (unad-
56,258 patients treated with IVT in the SITS registry, justed OR 5.91, 95% CI: 1.18–12.5, P ¼ 0.03) and
baseline blood glucose levels >22.2 mmol/L were docu- unfavourable functional outcome (adjusted OR 8.59,
mented in 91 patients and independently associated 95% CI: 0.88–83.9 P ¼ 0.06).146
with a higher risk of sICH according to ECASS-2 cri- Intravenous thrombolysis should not prevent the
teria (OR 1.99, 95% CI: 1.01–3.92).133 The incidence administration of insulin therapy in acute ischaemic
rate of sICH was 9.9% (95% CI: 5.3%–17.7%) and stroke patients with high blood glucose levels. More
3.3% (95% CI: 1.1–9.4%) according to the ECASS-2 information about management of hyperglycaemia in
and SITS definitions, respectively. patients with acute ischaemic stroke can be found in
Of note, persistent hyperglycemia may be a more the ESO guideline on glycaemia management in acute
important predictor of poor functional outcome than stroke.144
baseline hyperglycemia in patients with acute ischaemic The Stroke Hyperglycemia Insulin Network Effort
stroke.143 (SHINE) randomized clinical trial included adult
Given the lack of evidence of an heterogeneity in the patients with hyperglycemia (glucose concentration of
effect of alteplase in patients with higher blood glucose >110 mg/dL in case of diabetes or 150 mg/dL in
levels, and the available data regarding the risk of sICH patients without diabetes) and acute ischemic stroke
in patients with glucose level >22.2 mmol/L, we believe who were enrolled within 12 h from stroke onset.147
that alteplase should not be withheld in these patients, Patients were randomized to receive continuous intra-
even though they have a substantial risk of poor func- venous insulin (target blood glucose concentration of
tional outcome. 80–130 mg/dL, intensive treatment group: n ¼ 581) or
subcutaneous insulin (target blood glucose concentra- before stroke onset. A secondary analysis of IST-3
tion of 80–179 mg/d, standard treatment group: showed that the proportion of sICH in patients treated
n ¼ 570) for up to 72 h. A total of 725 enrolled patients with antiplatelet therapy within the previous 48 h
(63%) received IVT. The proportion of patients with before stroke onset was 9% for those allocated alte-
favourable outcome at 90 days did not differ in the two plase versus 1% in control, compared with 5% for
arms of the trial (20.5% vs. 21.6%) and in the sub- alteplase and 1% control for those with no recent anti-
group of patients receiving IVT (23.0% vs. 24.9%). platelet therapy (P ¼ 0.019 for interaction).129 A sec-
The number of patients who received blood glucose ondary analysis of the ENCHANTED trial indicated
lowering therapy prior to alteplase bolus was not an association between standard-dose alteplase and
reported. risk of sICH in patients receiving antiplatelets before
the stroke,62 but antiplatelet pre-treatment was not
PICO 11.5 In patients with acute ischaemic stroke of < 4.5 h associated with worse functional outcome after adjust-
duration, and with known diabetes mellitus, does IVT with ment for potential confounders.63
alteplase lead to better functional outcome than no IVT? Meta-analyses of observational data from RCTs or
Analysis of current evidence. Only two of the RCTs from a combination of RCTs and observational studies
(ECASS-3 and IST-3) that were included in the indi- indicated that antiplatelet agents increased the risk of
vidual participant data meta-analysis8 presented the sICH in unadjusted analyses (absolute increase 6.5%,
effect of IVT with alteplase for patients with or without 95% CI: 5.8–7.6%),63 but not after adjustment for con-
known diabetes mellitus. There was no evidence that founders.150–152 Another analysis of observational data,
known diabetes mellitus modified the effect of IVT from VISTA, indicated that alteplase compared to no
with alteplase on excellent outcome in ECASS-3 (P alteplase improved functional outcome in patients who
for interaction ¼ 0.17), or better functional outcome had received pre-treatment with a single antiplatelet
at six months in IST-3 (P for interaction ¼ 0.91).129,138 agent (common OR 1.42, 95% CI: 1.19–1.70).142
There was also no evidence that known diabetes melli- The literature search identified no RCT of IVT in
tus modified the effect of IVT with alteplase on mor- patients using dual antiplatelet therapy (DAPT) before
tality or sICH in these two trials. Amongst 54,206 acute the stroke. The VISTA analysis showed a relatively high
ischemic stroke patients included in the SITS registry risk of sICH in patients receiving DAPT (8.5%, 95%
and treated with IVT, there was no interaction of the CI: 3.9–17.2%), but the analysis was unadjusted and the
history of diabetes mellitus on the association of admis- increase in sICH was statistically non-significant.142
sion hyperglycemia (144 mg/dL) with sICH according Similarly, an analysis of patients given IVT within the
to the SITS definition (P for interaction ¼ 0.27), three- Stroke–Acute Ischemic–NXY Treatment (SAINT) I and
month good functional outcome (P for inter- II trials indicated that DAPT was associated with a
action ¼ 0.92) and three-month mortality (P for higher risk of sICH but not with a higher risk of poor
interaction ¼ 0.63).148 functional outcome (mRS score 3–6) at three months.153
Other studies have used propensity score matching to
Recommendation attempt to account for imbalances between patients
For patients with acute ischaemic stroke of < 4.5 h with and without DAPT. These studies indicate that
duration, and with known diabetes mellitus, we patients who use DAPT before IVT with alteplase
recommend intravenous thrombolysis with have comparable sICH rates and comparable functional
alteplase. outcome and survival at three months compared with
Quality of evidence: Moderate 丣丣丣 patients who don’t use antiplatelet drugs.154,155
Strength of recommendation: Strong "" Finally, a recent meta-analysis of 9 observational
studies comprising 66,675 acute ischaemic stroke
patients treated with IVT failed to document any asso-
12. Use of antithrombotic drugs before the stroke ciation between DAPT and the likelihood of sICH,
PICO 12.1 In patients with acute ischaemic stroke of < 4.5 h three-month good functional outcome (mRS 0–2),
duration, who use antiplatelet agents, does IVT with alteplase three-month excellent functional outcome (mRS 0–1),
lead to better functional outcome than no IVT? and three-month mortality in adjusted analyses con-
Analysis of current evidence. Treatment with antipla- trolling for potential confounders.156
telet agents before an ischaemic stroke may increase the In summary, analyses of observational data indicate
risk of sICH in patients given alteplase,149 but antipla- that single or dual antiplatelet pre-treatment is not
telet treatment was not an exclusion criterion in the independently associated with poorer functional out-
completed RCTs. Some of those trials have analysed come and higher risk of sICH. Use of antiplatelet
separately patients who used an antiplatelet agent agents should therefore not be used as a reason to
Berge et al. 33
withhold IVT with alteplase in patients with acute highly variable (0% in 14 patients,142 3% in 33
ischaemic stroke, although more research is needed. patients159 and 30% in 10 patients162).
Recommendation Recommendation
For patients with acute ischaemic stroke of < 4.5 h For patients with acute ischaemic stroke of < 4.5 h
duration, who used single or dual antiplatelet duration, who use vitamin K antagonists and have
agents prior to the stroke, we suggest intravenous INR 1.7 we recommend intravenous thromboly-
thrombolysis with alteplase. sis with alteplase.
Quality of evidence: Low 丣丣 Quality of evidence: Low 丣丣
Strength of recommendation: Strong "" Strength of recommendation: Strong ""
PICO 12.2 In patients with acute ischaemic stroke of < 4.5 h duration, who use vitamin K antagonists and have
duration, who use vitamin K antagonists, does IVT with INR >1.7 we recommend no intravenous
alteplase lead to better functional outcome than no IVT? thrombolysis.
Analysis of current evidence. Patients given vitamin Quality of evidence: Very Low 丣
K antagonists (VKA) and with International Strength of recommendation: Strong ##
Normalized Ratio (INR) >1.7 were excluded from For patients with acute ischaemic stroke of < 4.5 h
the RCTs of IVT, and the European license for alte- duration, who use vitamin K antagonists, and for
plase precludes treatment in all patients taking VKA. whom the results of coagulation testing is
In a systematic review and meta-analysis of observa- unknown, we recommend no intravenous
tional studies,157 25 of 240 patients (10.4%) who used thrombolysis.
VKA (median INR 1.14–1.5) experienced an sICH, Quality of evidence: Very low 丣
compared with 184 of 3391 patients (5.4%) without Strength of recommendation: Strong ##
VKA medication (OR 2.58, 95% CI: 1.13–5.89,
P ¼ 0.02; I2 ¼ 56%). However, VKA use was not asso-
ciated with poor functional outcome (mRS 3, OR Additional information. Case series indicate that pro-
thrombin complex concentrates can be used to reverse
1.18, 95% CI: 0.85–1.61, P ¼ 0.32; I2 ¼ 15%) or death
the effect of VKAs in patients who are eligible for
(OR 1.22, 95% CI: 0.85–1.75, P ¼ 0.28; I2 ¼ 0%).
thrombolytic treatment and have INR >1.7.163,164
Among 45,074 patients from the SITS registry
However, prothrombin complex concentrates might
treated with alteplase, 768 (1.7%) used warfarin and
enhance coagulation, which can lead to a worsening
had INR 1.7.158 After adjustment for potential con-
of patients’ neurological deficits.165 Mechanical throm-
founders, warfarin use was not significantly associated
bectomy appears to be safe in patients with large vessel
with sICH (adjusted OR 1.26, 95% CI: 0.82–1.70), and
occlusion who have been pre-treated with a VKA and
no increase in poor functional outcome or death at
with INR >1.7.166–168
three months was observed. Among 23,437 patients
treated with alteplase in the U.S. Get With The PICO 12.3 In patients with acute ischaemic stroke of < 4.5 h
Guidelines Registry, 1802 (7.7%) were treated with duration, who use NOACs, does IVT with alteplase lead to
warfarin with an INR 1.7 (median 1.20; IQR 1.07– better functional outcome than no IVT?
1.40). After adjustment for potential confounders, war- Analysis of current evidence. The use of non-VKA
farin use was not significantly associated with sICH oral anticoagulants (NOACs, i.e. direct thrombin
(adjusted OR 1.01, 95% CI: 0.82–1.25), serious system- inhibitors and factor Xa inhibitors) may increase the
ic haemorrhage, or in-hospital death.159 risk of sICH after IVT with alteplase, and alteplase is
In patients with INR 1.7, other large registries159–161 contraindicated if NOAC has been used during the last
have also indicated that IVT with alteplase is associated 48 h before stroke onset, according to the labels for
with a low risk of sICH and poor outcomes, both in the these drugs.
0–3 and in the 3–4.5 h time windows, although this may In an observational study of 51 patients taking
have been due to confounding.160 Moreover, data from DOACs and 390 patients treated with VKA, sICH
VISTA showed that alteplase was associated with after intravenous alteplase occurred in 4.0% of patients
improved functional outcome in patients given VKA taking NOACs and 3.6% of patients taking VKA (no
and with INR 1.7 (cOR for better functional outcome significant difference).169 Out of 42,887 patients treated
2.20, 95% CI: 1.12–4.32; Table 10).142 with alteplase in the Get With The Guidelines Registry,
There is little data on the rates of sICH in patients 251 (0.6%) were treated with NOACs and 1,500 (3.5%)
using VKA and INR >1.7, and the reported rates are with warfarin.170 Compared with patients without
anticoagulants, the adjusted OR for sICH was 0.92

Importance
An important risk of bias, notably of selection bias and confounding, exists in this pooled analysis based on RCTs of neuroprotectants. However, we consider that those limitations are already taken into
CRITICAL
CRITICAL
CRITICAL
(95% CI: 0.51–1.65) for those on NOACs and 0.85
(95% CI: 0.66–1.10) for those on warfarin. There
were also no significant differences across the three
groups in the risk for serious systemic haemorrhage
VERY LOW
Certainty
⨁
or in-hospital deaths.
⨁⨁
⨁⨁
LOW
LOW
A recent meta-analysis of cohort studies reported no
additional risk of sICH following IVT among selected
patients taking NOACs within 48 h compared to
to 0 fewer)
(from 2 fewer
1 fewer per patients treated with warfarin (ECASS-2 criteria: OR
0.77, 95% CI: 0.28–2.16) and compared to patients
Absolute
account in mentioning in GRADEpro that this analysis corresponds to an observantional study and have therefore not further downgraded the quality of evidence.
(95% CI)
1 000
without anticoagulation pretreatment (OR, 0.87, 95%
CI: 0.32–2.41).171 Patient selection was based on vari-
ous coagulation assays.
not estimable
A number of decision algorithms have been pro-

(1.12–4.32)
(0.25–1.86)
cOR 2.20
OR 0.68
(95% CI)
posed to identify patients treated with NOACs who

Relative
Effect
can be given IVT.165,172–175 According to these algo-

rithms, thrombolytic treatment can be given (i) in
patients using dabigatran if thrombin time is
no IVT
(3.4%)
–/119
4/119
normal172 or below 60 seconds,173 (ii) in patients

No of patients
using rivaroxaban if the drug plasma level is < 20 ng/

ml174 or < 50 ng/ml,173 or if anti-Xa activity is < 0.5 U/
alteplase
IVT with
(5.3%)
ml,173 (iii) in patients using apixaban if anti-Xa activity

–/38
2/38
is < 0.5 U/ml,173 (iv) in patients using edoxaban if anti-

Xa activity < 0.5 U/ml.173 The safety of these treatment
considerations
decision algorithms has not been tested in clinical prac-

tice, with the exception of the cut-off plasma level of
Other
rivaroxaban (<20ng/ml).174 The coagulation parame-

none
none
none
ters used to select patients for IVT in these studies

were different, and global coagulation tests, such as
Imprecision
not serious
not serious
prothrombin time (PT), activated partial thromboplas-

seriousb
tin time (aPTT) and INR are not specific for NOACs.
Further research is therefore needed to identify the
Better functional outcome (shift analysis of the mRS at three months)
optimal coagulation parameters (e.g. thrombin time

Indirectness
not serious
not serious
not serious
for dabigatran, direct factor Xa activity for rivaroxa-

ban, apixaban and edoxaban, or individual NOAC
plasma levels). Until such data are available, we believe
that IVT with alteplase should not be used indiscrimi-
Inconsistency
nately in patients who have received a NOAC dose

not serious
not serious
not serious
within the last 48 h in patients with normal renal

function.
Others have proposed the use of agents to reverse
the anticoagulant effects of NOACs.172–174 For exam-
ple, idarucizumab has been used to reverse dabigatran
not seriousa
not seriousa
not seriousa
activity before alteplase treatment, and this treatment

Risk of
algorithm has been tested in small studies in the pre-

bias
hospital and hospital settings.176–178 However, there

Note: Results from VISTA.142
are theoretical concerns that idarucizumab may poten-

tiate the prothrombotic activity in the acute phase of

observational
observational
observational
ischaemic stroke, and increase the risk of ischaemic

studies
studies
studies
events.172 Nevertheless, such complications were not

Very few events.
design
Study
documented in two national cohorts from Germany

and New Zealand reporting the experience of IVT for
studies
No of
acute ischaemic stroke patients pretreated with idaru-

sICH
cizumab for dabigatran reversal.177,179

1
b
a
Berge et al. 35
acute ischaemic stroke patients otherwise eligible for

Recommendation IVT who have been pretreated with apixaban or rivar-
oxaban. However, there is only anecdotal published
For patients with acute ischaemic stroke of < 4.5 h evidence about acute ischaemic stroke patients treated
duration, who used a NOAC during the last 48 h with IVT following rivaroxaban or apixaban reversal
before stroke onset, and for whom there is no spe- with andexanet alfa. Importantly, the infusion of
cific coagulation tests available (i.e. calibrated anti-
andexanet alfa requires two hours, which may have
Xa-activity for factor Xa inhibitors, thrombin time
implications for the eligibility of patients to receive
for dabigatran, or the NOAC blood concentra-
alteplase with regard to the approved time window of
tions), we suggest no intravenous thrombolysis.
4.5 h.182 Furthermore, a rebound effect of anti-Xa
Quality of evidence: Very Low 丣
activity may occur. In contrast to idarucizumab in
Strength of recommendation: Strong ##
patients treated with dabigatran, andexanet alpha has
For patients with acute ischaemic stroke of < 4.5 h not been approved for reversing Factor Xa inhibitor
duration, who used a NOAC during the last 48 h activity in patients who require emergency surgery/
before stroke onset, and who have an anti-Xa urgent procedures.183,184 Besides, the cost of andexanet
activity < 0.5 U/ml (for factor Xa inhibitors) or alfa, which has not been approved for edoxaban rever-
thrombin time < 60 s (for direct thrombin inhibi- sal,184 is considerable.182 Finally, a safety analysis con-
tors), there is insufficient evidence to make an evi- ducted in the overall ANNEXA-4 study population has
dence-based recommendation. Please see the documented 40 thrombotic events (7 myocardial infarc-
Expert consensus statement below. tions, 15 transient ischemic attacks or ischaemic
Quality of evidence: Very low 丣 strokes, 18 venous thromboembolic events) occurring
Strength of recommendation: - in 34 (10%) patients at 30 days.181 Eleven patients had
a thromboembolic event within five days of receiving
andexanet alfa and 8 patients had an event after
duration, who used dabigatran during the last 48 h
before stroke onset, there is insufficient evidence to restarting anticoagulation.181 Therefore, the U.S.
make a recommendation for or against the use of FDA prescribing information for andexanet alfa
the combination of idarucizumab and intravenous includes a black box warning regarding the risk of
thrombolysis with alteplase over no intravenous venous and arterial thromboembolic events.185
thrombolysis. Please see the Expert consensus In summary, we caution against the off-label use of
statement below. andexanet alfa for reversal of anticoagulant activity of
Quality of evidence: Very low 丣 apixaban or rivaroxaban in acute ischaemic stroke
Strength of recommendation: - patients who are otherwise eligible for IVT.

Additional information. Measurement of anti-Xa
For patients with acute ischaemic stroke of <4.5 h
activity has been proposed to select acute ischaemic
duration, who used a NOAC during the last 48 h
stroke patients pretreated with factor Xa inhibitors before stroke onset, and who have an anti-Xa activ-
for IVT, particularly where NOAC drug levels are ity <0.5 U/ml (for factor Xa inhibitors) or thrombin
not readily available.173 Of note, mechanical thrombec- time <60 s (for direct thrombin inhibitors) 7 of 9
tomy appears to be safe in patients with large vessel group members suggest IVT with alteplase.
occlusion who have used a NOAC within last 48 h of
symptom onset.168,172–174,180 For patients with acute ischaemic stroke of < 4.5 h
Andexanet alfa is a modified recombinant factor Xa. duration, who used dabigatran during the last 48 h
It is catalytically inactive and cannot participate in before stroke onset, 8 of 9 group members suggest
coagulation, but it retains the ability to bind to and the combination of idarucizumab and intravenous
thrombolysis with alteplase over no intravenous
sequester factor Xa inhibitors. It has been conditionally
thrombolysis.
approved by US FDA (Food and Drug
Administration) in 2018 and European Medicines For patients with acute ischaemic stroke of < 4.5 h
Agency in 2019 for the reversal of the anticoagulant duration, who used factor Xa inhibitors during the
effects of the Factor Xa inhibitors (apixaban or rivar- last 48 h before stroke onset, 9 of 9 group members
oxaban) in patients experiencing uncontrolled or life- suggest against the combination of andexanet and
threatening bleeding based on the results of the intravenous thrombolysis with alteplase over no
ANNEXA-4 study.181 Andexanet alfa could reverse intravenous thrombolysis.
the anticoagulant effects of Factor Xa inhibitors in
13. Potential risk factors for bleeding the harm of bleeding from inadvertently treating
patients with a low platelet count.
An increased risk of bleeding after IVT can be sus-
pected in many clinical situations, but the literature
Recommendation
search identified no RCT to guide treatment in such
situations. Many observational studies have focused on For patients with acute ischaemic stroke of < 4.5 h
this topic, often comparing outcomes after IVT in duration, and with known platelet
patients with and without a bleeding-prone condition. count < 100 109/L, we suggest no intravenous
Although this might identify risk factors for ICH, thrombolysis.
RCTs would be needed to formally demonstrate or dis- Quality of evidence: Very low 丣
card a greater harm with IVT in patients with these Strength of recommendation: Weak #?
factors. For patients with acute ischaemic stroke of < 4.5 h
duration, and with unknown platelet count before
PICO 13.1 In patients with acute ischaemic stroke of < 4.5 h initiation of intravenous thrombolysis and no
duration, who have low platelet count, does IVT with alteplase reason to expect abnormal values, we recommend
lead to better functional outcome than no IVT? starting intravenous thrombolysis with alteplase
Analysis of current evidence. Patients with a platelet while waiting for lab tests results.
count below 100,000/mm3. A platelet count below Quality of evidence: Very low 丣
100 109/L (100,000/mm3) was an exclusion criterion Strength of recommendation: Strong ""
in all RCTs of IVT with alteplase except ECASS I and
IST-3. We could not find a subgroup analysis of
patients with a platelet count below 100 109/L in
duration, who have a history of recent trauma, surgery, or
these two trials. In an observational study from ten
biopsy, does IVT with alteplase lead to better functional
European centres including 7,533 patients given alte-
outcome than no IVT?
plase, 595 (7.9%) had thrombocytopenia (<150 109/
Analysis of current evidence. Significant trauma
L) and 44 (0.6%) a platelet count below 100 109/L.157
within the last three months is a contraindication for
Thrombocytopenia was not associated with poor func-
IVT with alteplase according to the European
tional outcome (mRS score 3–6) at three months
license.192 The outcome of IVT in patients with this
(adjusted OR 0.92, 95% CI: 0.73–1.17, P ¼ 0.50) or
death, but was significantly associated with a higher contraindication has been reported in small case
risk of sICH (adjusted OR 1.68, 95% CI: 1.21–2.36, series.193,194 A relatively high number of patients had
P ¼ 0.002). Compared with other patients, those with serious intracranial or systemic haemorrhage, although
a platelet count below 100 109/L more often had poor there is a possibility of publication bias.
outcome (59.1% vs. 43.1%, P ¼ 0.03), but this associ- Major surgery, which can be defined as surgery of
ation did not reach significance in a multivariable anal- the abdomen, chest, skull or well-vascularized tissues
ysis (adjusted OR 1.63, 95% CI: 0.82–3.24, P ¼ 0.16). or of any large artery,195 has also been an exclusion
Similar point estimates were observed for death criteria in all RCTs if performed within 14 days
(adjusted OR 1.42, 95% CI: 0.66–3.07, P ¼ 0.37) and before stroke onset and is therefore also listed as a
sICH (adjusted OR 1.60, 95% CI: 0.49–5.21, P ¼ 0.43). contraindication on the drug label. Among 4,848
patients treated with alteplase in the Telemedical
Patients with unknown platelet count before initiation Project for Integrative Stroke Care (TEMPiS) registry,
of IVT. In our review of the literature, excluding case 49 and 85 patients had undergone surgery within the 10
series, we found that, among 12,701 patients treated and 11–90 days preceding stroke onset, respectively.195
with alteplase for acute ischaemic stroke, a total of 66 In 86 (64%) patients, surgery was classified as major
(0.5%) patients had a platelet count below 100 109/L, and in 48 (36%) as minor. A total of 9 (7%) patients
of which 4 had sICH (incidence rate 6.1%, 95% CI: developed surgical site haemorrhage after IVT, more
2.4–14.6).142,157,186–189 Amongst patients with < 100 often after recent than after non-recent surgery. sICH
109 platelets/L in the study by Gensicke et al., occurred in 9.7% of patients. No information on three-
median platelet count was 90 109/L (IQR 71–96).157 month functional outcome was provided. Other small
Other observational studies have indicated that the observational studies of patients treated with alteplase
proportion of stroke patients with a platelet count in spite of recent surgery also suggest that surgical site
<100 109/L is below 0.5%.190,191 It is therefore haemorrhage is the main hazard, without evidence of
likely that the benefit of earlier IVT would outweigh poor neurological outcome.194,196
Berge et al. 37

Recommendation duration, who have cerebral microbleeds, does IVT with
alteplase lead to better functional outcome than no IVT?
For patients with acute ischaemic stroke of < 4.5 h Analysis of current evidence. Most patients enrolled
duration and with major surgery on a in the RCTs of IVT did not undergo MRI before ran-
non-compressible site where bleeding is likely to
domisation and therefore their cerebral microbleed
lead to significant haemorrhage (e.g., abdomen,
(CMB) burden is unknown. In a meta-analysis of 9
chest, skull, well-vascularized tissues, or large
observational studies, CMB was observed on pre-
artery) during the preceding 14 days, we recom-
treatment MRI in 581 (23.4%) patients, and was asso-
mend no intravenous thrombolysis.
ciated with an increased risk of sICH (RR 2.36, 95%
CI: 1.21–4.61, P ¼ 0.01; I2 ¼ 46%), but the incidence
rate of sICH remained relatively low (6.5%, 95% CI:
4.8–8.9 in patients with 1 CMB, and 4.4%, 95% CI:
PICO 13.3 In patients with acute ischaemic stroke of < 4.5 h 3.5–5.4% in patients without CMB).199 However, in
duration, who have a history of intracranial haemorrhage, does the very small subgroup of 15 patients (0.8%) with
IVT with alteplase lead to better functional outcome than no more than 10 CMBs, the incidence rate of sICH was
IVT? 46.9% (95% CI: 22.8–72.5). In an individual partici-
Analysis of current evidence. Patients with history of pant data meta-analysis of 1973 patients, presence of
ICH were excluded from RCTs of IVT with alteplase, 1 and >10 CMBs were observed in 526 (26.7%) and
and our literature search identified very few observa- 35 (1.8%) patients, respectively.200 The association
tional studies on this topic. In one observational study between CMB presence and sICH did not reach statis-
of 1,212 patients treated with alteplase, only 7 (0.6%) tical significance (adjusted OR 1.42, 95% CI: 0.86–
had a history of ICH (hematoma volume: 1–21 cm,3 2.35, P ¼ 0,17), but a count of more than 10 CMBs
elapsed time between previous ICH and ischemic was associated with sICH (adjusted OR 3.65, 95%
stroke: 1.5–12 years), none of whom developed sICH CI: 1.17–11.42), remote parenchymal haemorrhage
or died after IVT.197 There are also case (adjusted OR 9.09, 95% CI: 3.25–25.40) and poor func-
reports.189,196,198 A key question is the time elapsed tional outcome (adjusted OR 3.99, 95% CI: 1.55–
since the intracranial haemorrhage, but unfortunately 10.22). Increasing CMB burden, defined as a continu-
this information is not provided in most reports. ous variable, was also independently associated with
both sICH and poor functional outcome (mRS score
Recommendation >2) at three months.
duration, and a history of intracranial haemor- Recommendation
rhage, there is insufficient evidence to make an For patients with acute ischaemic stroke of < 4.5 h
evidence-based recommendation. Please see the duration, for whom cerebral microbleed burden is
Expert consensus statement below. unknown or known to be low (e.g. < 10), we sug-
Quality of evidence: Very low 丣 gest intravenous thrombolysis with alteplase.
Strength of recommendation: - Quality of evidence: Low 丣丣
Strength of recommendation: Weak "?
Expert consensus statement duration, for whom cerebral microbleed burden
For patients with acute ischaemic stroke of < 4.5 h has been previously reported to be high (e.g.
duration and with a history of intracranial haemor- >10), we suggest no intravenous thrombolysis.
rhage, 8 of 9 members suggest intravenous throm- Quality of evidence: Low 丣丣
bolysis with alteplase in selected cases. For exam- Strength of recommendation: Weak #?
ple, intravenous thrombolysis may be considered if
a long time has elapsed since the haemorrhage, or if Additional information. Susceptibility-weighted
there was a non-recurrent or treated underlying imaging (SWI) is more sensitive than T2* for detecting
cause for the haemorrhage (e.g. trauma, subarach- cerebral microbleeds.201 Therefore, it is not certain how
noid haemorrhage with subsequent endovascular generalisable recommendations based on T2* detected
or surgical aneurysm removal, or use of specific microbleeds are to SWI detected microbleeds, notably
antithrombotic medication). regarding the threshold that should be used to define
high microbleed burden. However, a systematic review
and individual participant data meta-analysis did not
Importance
CRITICAL
CRITICAL
find that the type of MRI sequence (SWI vs. T2*) was
associated with the risk of sICH following IVT
(P ¼ 0.74 for the whole sample; P ¼ 0.34 in the sub-
group of patients with at least one microbleed).199
MODERATE
Certainty
A recent study devised a multistep algorithm to
⨁⨁⨁
⨁⨁⨁⨁
model three-month mRS scores in patients with 10
HIGH
versus >10 CMBs who do or do not receive IVT.202
Parameters were extracted from recently published
(from 10 more
(from 19 more
62 more per
56 more per
meta-analyses and included pairwise relationships
to 115
to 127
between CMBs. IVT in patients with >10 CMBs sig-
1 000
1 000
more)
more)
Absolute
(95% CI)
nificantly increased the odds of mortality, while the
This result corresponds to presence or absence of leukoaraiosis. It therefore does not directly address the situation of patients with extensive leukoaraiosis.
beneficial treatment effect of IVT on clinical outcome
was attenuated in patients with >10 CMBs as com-
(2.49–12.13)
(1.05–1.67)
pared with patients with 10 CMBs. However, because
(95% CI)
OR 1.33
OR 5.50
Relative
Of note, there was no evidence that presence of leukoaraiosis modifies the effect of IVT on functional outcome in IST-3 (P for interaction ¼ 0.24).
the general pretest probability of >10 CMBs is low
Effect
(0.6%–2.7%), the authors hypothesized that pretreat-
ment MRI to quantify CMB burden would be justified
323/1129
15/1129
(28.6%)
There was no evidence in IST-3 that presence of leukoaraiosis significantly modifies the effect of IVT on siCH (P for interaction ¼ 0.14)
no IVT
only if it delayed IVT by < 10 min.
(1.3%)
Expert consensus statement No of patients
376/1105
alteplase
IVT with
87/1105
(34.0%)
(7.9%)
For patients with acute ischaemic stroke within
4.5 h of stroke onset, 9 of 9 members suggest
against systematic screening with MRI to assess
very strong association

cerebral microbleed burden before making a treat-
ment decision regarding intravenous thrombolysis.
considerations

Other
none
duration, who have cerebral white matter lesions, does IVT with
not seriousb
not seriousc
Analysis of current evidence. In IST-3 there was no
Imprecision
evidence for heterogeneity of treatment effect regarding

good functional outcome between patients with and
without white matter lesions (P for inter-
action ¼ 0.24).100 However, in an analysis of patients
Indirectness
enrolled in 4 RCTs (IST-3, NINDS, ECASS-1, Note: Results based on data from NINDS, ECASS 1 and 2 and IST-3.
seriousa
seriousa
ECASS-2; n ¼ 2234), IVT with alteplase was associated

with a higher incidence rate of sICH in patients with
white matter lesions (7.9%, 95% CI: 6.4–9.6) than in

Inconsistency
not serious
not serious
patients without (1.3%, 95% CI: 0.8–2.2; Table 11).

Favourable functional outcome at 3–6 months
Still, IVT was associated with a lower risk of poor

functional outcome in patients with white matter
lesions, compared with no IVT (OR 0.75, 95% CI:
0.60–0.95, P ¼ 0.015; I2 ¼ 23%).203
not serious
not serious
In a study-level meta-analysis of observational data

Risk of
from 5910 patients treated with alteplase, presence of

bias
white matter lesions on CT was associated with sICH

(OR 1.55, 95% CI: 1.17–2.06, P ¼ 0.002; 7 studies;
I2 ¼ 21%).203 Severe white matter lesion burden,
randomised
randomised
mostly defined as a score >2 on the Van Swieten

trials
trials
design
Study
scale, was strongly associated with sICH after treat-

ment (OR 2.53, 95% CI: 1.92–3.34, p < 0.001;
I2 ¼ 0%). In the 818 patients with severe white matter
studies
No of
sICH
lesions, the incidence rate of sICH was 9.9% (95% CI:

4
b
c
a
Berge et al. 39
8.0–12.1). Presence of white matter lesions was associ- aneurysms (RR 1.60; 95% CI: 0.54–4.77, P ¼ 0.40;
ated with poor functional outcome after IVT (OR 2.02, I2 ¼ 22%). No case of cerebral artery aneurysm rupture
95% CI: 1.54–2.65, p < 0.001; I2 ¼ 74%), but this asso- was reported in this study.
ciation may have been caused by confounding, as
larger white matter lesions volumes on MRI are inde- Recommendation
pendently associated with worse three-month function-
al outcome.204
duration, who have an unruptured cerebral artery
aneurysm, we suggest IVT with alteplase.
Recommendation Quality of evidence: Very low 丣
For patients with acute ischaemic stroke of < 4.5 h Strength of recommendation: Weak "?
duration, and small to moderate burden of white
matter lesions, we recommend intravenous throm-
bolysis with alteplase. 14. Other co-existing conditions
duration, who have a history of ischaemic stroke during the last
For patients with acute ischaemic stroke of < 4.5 h three months, does IVT with alteplase lead to better functional
duration, and high burden of white matter lesions, outcome than no IVT?
we suggest intravenous thrombolysis with Analysis of current evidence. Patients with co-
alteplase. existing conditions thought to increase the risk of
Quality of evidence: Low 丣丣 sICH or worse outcome were excluded from the
Strength of recommendation: Weak "? RCTs of IVT with alteplase. One such example is ‘his-
tory of ischaemic stroke during the last three months’,
Additional information. In an observational study of which was also used as an exclusion criterion in trials of
2,485 patients treated with alteplase, severe white alteplase for acute myocardial infarction.122 In an
matter lesions on CT, defined as a Blennow rating observational study of alteplase for acute ischaemic
scale score of 5 or 6, was independently associated stroke, 14(1.5%) of 946 patients had had a prior
with remote parenchymal hemorrhage (adjusted OR stroke within three months.146 The risk of poor out-
6.79, 95% CI: 2.57–17.94), but not with parenchymal come (mRS 3–6 at three months) was non-
hemorrhage strictly within the ischemic area (adjusted significantly increased in these patients (adjusted OR
OR 1.45, 95% CI: 0.83–2.53).205 Another study, based 4.07, 95% CI: 0.97–17.1). In an analysis of the SITS-
on MRI volumetric evaluations of white matter lesions, EAST registry, 249(2%) of 13,007 patients had a stroke
confirmed that larger whole brain corrected white in the preceding three months, but it was not indepen-
matter lesion volume was associated with remote dently associated with poor functional outcome defined
ICH, irrespective of the deep or periventricular loca- as an mRS score 3–6 at three months (adjusted OR
tion of white matter lesions.206 0.74, 95% CI: 0.35–1.56) or sICH (adjusted OR 0.74,
95% CI: 0.35–1.56).208 Other observational studies
have shown similar results.196,209–211 In addition, a
duration, who have an unruptured cerebral aneurysm, does IVT
large study using administrative data from 36,599
with alteplase lead to better functional outcome than no IVT?
patients treated with alteplase found that ischaemic
Analysis of current evidence. The discovery of unrup-
tured aneurysms in the acute phase of stroke is becom- stroke during the last three months was not associated
ing more frequent with the increasing use of cerebral with an increased risk of ICH (adjusted OR 0.9, 95%
artery imaging. Data on IVT in patients with unrup- CI: 0.6–1.4, P ¼ 0.62), but was related to an increased
tured aneurysms is scarce. In a systematic review and risk of death (OR 1.5, 95% CI: 1.2–1.9, P ¼ 0.001) and
meta-analysis of observational data, the incidence of unfavourable discharge disposition (OR 1.3, 95% CI:
sICH among 120 patients treated with alteplase for 1.0–1.7, P ¼ 0.04).212 Finally, a meta-analysis of obser-
acute ischaemic stroke and having unruptured intracra- vational studies including 52,631 patients treated with
nial aneurysms was 6.7% (95% CI: 3.1–13.7%).207 The alteplase found no evidence of increased risk of sICH,
mean maximum diameter of the aneurysms was 4.3 death or poor functional outcome or mortality in the
2.7 mm. The risk of sICH did not significantly differ 1.7% of patients who had a history of ischaemic stroke
between patients with and without unruptured during the last three months.213
from stroke registries have also provided reassurance

Recommendation that inadvertent administration of alteplase to patients
with seizures at onset of stroke-like symptoms does not
increase the risk of sICH.214 However, the possibility of
duration, and with a history of ischaemic stroke
a head trauma as a consequence of the seizure must
during the last three months, there is insufficient
always be considered.
evidence to make an evidence-based recommenda-
tion recommendation. Please see the Expert con-
sensus statement below. Recommendation
Quality of evidence: Very low 丣 For patients with acute ischaemic stroke of <4.5 h
Strength of recommendation: - duration who have seizures at time of stroke onset,
and for whom there is no suspicion of a stroke
mimic or significant head trauma, we suggest intra-
Additional information. These observational studies
venous thrombolysis with alteplase.
have a number of limitations. Relatively few patients
had had an ischaemic stroke within the previous
three months, and many studies did not provide data
on the baseline characteristics of these patients.
Importantly, most studies did not report the time Additional information. Advanced imaging methods
since the previous ischaemic stroke, precluding defini- like MRI with DWI and apparent diffusion coefficient
tive conclusions about the minimal time interval that (ADC) sequences and perfusion CT although not used
should be respected before using IVT in such patients. in RCTs may be useful to distinguish between post-
ictal deficits and stroke.217,218 Seizures may be associ-
Expert consensus statement ated with transient peri-ictal MRI abnormalities: a) dif-
fusion abnormalities with mixed appearance with
simultaneous acute cytotoxic cortical oedema and
duration, and a history of ischemic stroke within
vasogenic subcortical oedema without a vascular terri-
the last three months, nine of nine members voted
tory lesion distribution; b) gyral enhancement occur-
for intravenous thrombolysis with alteplase in
ring earlier than expected for acute ischemic stroke,
selected cases, for example in case of a small
c) perfusion studies with normal or increased cerebral
infarct, stroke occurring more than one month ear-
blood volume (hyperperfusion) at the epileptogenic
lier, or good clinical recovery.
area during the ictal phase and hypoperfusion in the
postictal phase.
duration, who had a seizure at time of stroke onset, does IVT PICO 14.3 In patients with acute ischaemic stroke of <4.5 h
with alteplase lead to better functional outcome than no IVT? duration, who have dissection in the aortic arch, in a carotid
Analysis of current evidence. A seizure can be the artery or in an intracerebral artery, does IVT with alteplase lead
initial manifestation of a stroke, but patients with seiz- to better functional outcome than no IVT?
ures at the time of stroke have been excluded from the Analysis of current evidence. Most cases of aortic
RCTs of IVT, for several reasons. First, post-ictal state arch dissection receiving IVT with alteplase are patients
can mimic a stroke. Second, seizures can also be caused with acute myocardial infarction. Some of these
by conditions other than stroke, like structural brain patients have suffered extension of dissection into the
lesions or metabolic/infectious states. Third, a seizure pericardium, leading to cardiac tamponade and
can lead to – sometimes unobserved – head trauma that death.219 There are only anecdotal case reports in the
may increase the risk of secondary ICH. literature of patients with acute ischaemic stroke who
Data from several observational studies suggests had an aortic arch dissection and were treated with
that the risk of sICH is low in patients with stroke alteplase. Reported complications include cardiac tam-
mimics214,215 and also in patients with suspected acute ponade and intrapleural haemorrhage.220,221 IVT in
ischaemic stroke with seizure at stroke onset.216 In an these patients could also reduce the possibility of sur-
observational study of 5,581 patients treated with alte- vival by leading to the postponement of an emergency
plase, 100 patients had stroke mimics (1.8%). The rate operation to treat thoracic aortic dissection.222
of sICH in patients with stroke mimics was 1.0% (95% Extracranial artery dissection was a not specific
CI: 0.0–5.0) compared with 7.9% (95% CI: 7.2–8.7) in exclusion criterion in RCTs of IVT versus placebo,
patients with ischaemic strokes.214 Analysis of data but because dissection is a rare event the number of
Berge et al. 41
randomised patients is likely to be very low and no observational studies with important risk of selection
specific subgroup analysis has been published. Few bias and confounding by indication. We decided not to
observational studies provide a direct comparison of perform a meta-analysis of these studies due to notable
IVT versus no IVT in patients with artery dissection. differences in study design.
The Cervical Artery Dissection and Ischemic Stroke
Patients (CADISP) group published an observational Recommendation
study of 616 patients with extracranial artery dissec-
tion, of which 68 (11.0%) received alteplase (81%
duration and with aortic arch dissection we recom-
treated with IVT and 19% with intra-arterial alte-
mend no intravenous thrombolysis.
plase).223 After adjustment for stroke severity and
large vessel occlusion status, the likelihood of good
outcome (mRS 0–2) did not differ between patients
treated with alteplase and controls (adjusted OR 0.95, For patients with acute ischaemic stroke of < 4.5 h
95% CI: 0.45–2.00). ICH occurred in 4 (5.9%) of the duration and with isolated cervical artery dissec-
patients who received alteplase (all of which were tions, we suggest intravenous thrombolysis with
asymptomatic) and 3 (0.6%) of patients who did not alteplase.
receive alteplase (two of which were asymptomatic). In Quality of evidence: Low 丣丣
a small single-centre study of 46 patients with ischae- Strength of recommendation: Weak "?
mic stroke due to artery dissection, of which 19 (41%) For patients with acute ischaemic stroke of < 4.5 h
were treated with IVT, the proportion of good outcome duration and with intracerebral artery dissections,
(mRS 0–2) did not significantly differ between patients there is insufficient evidence to make a recommen-
treated with or without IVT (95% vs. 82%; adjusted dation. Please see the Expert consensus statement
OR 5.49; 95% CI: 0.77–39.11).224 In an unpublished below.
subgroup analysis (n ¼ 49) of patients with dissection Quality of evidence: Very low 丣
and internal carotid occlusion from the Systemic Strength of recommendation: -
thrombolysis in patients with acute ischemic stroke
and Internal Carotid ARtery Occlusion (ICARO)
observational study,225 IVT (n ¼ 26) was not signifi- Additional information. The presence of intracranial
cantly associated with excellent (mRS score 0–1) or arterial dissection may result in subadventitial exten-
good (mRS score 0–2) outcome compared with no sion of the hematoma and increase the risk of sub-
IVT (unadjusted ORs 2.11, 95% CI: 0.54–8.25 and arachnoid haemorrhage (especially when located in
1.96, 95% CI: 0.60–6.35, respectively). the posterior circulation) or intracranial bleeding in
Other observational studies provide a comparison of acute ischaemic stroke patients receiving antithrom-
IVT-treated patients with and without dissection. An botic and thrombolytic treatments.228
individual participant data meta-analysis of observa-
tional studies including 180 patients with cervical Expert consensus statement
carotid artery dissection indicated that case fatality at For patients with acute ischaemic stroke of < 4.5 h
three months and risk of sICH was similar in patients duration and with an intracerebral artery dissec-
with dissection and matched controls (fatality rate tion, 6 of 9 group members suggest against intra-
7.3%, 95% CI: 3.7–13.9% vs. 8.8%, 95% CI: 5.1– venous thrombolysis with alteplase.
14.5%, and sICH rate 3.3% 95% CI: 1.2–8.5% vs.
rate 5.9% 95% CI: 3.0–10.9%).226 Similar findings
were reported in a meta-analysis of 234 patients with PICO 14.4 In patients with acute ischaemic stroke of < 4.5 h
co-existent extra- or intracranial dissections who duration, who have had myocardial infarction during the last
received alteplase.227 The respective rates of sICH three months, does IVT with alteplase lead to better functional
and death were 2% (0–5%) and 4% (0–8%), under- outcome than no IVT?
scoring the safety of alteplase in dissection-related Analysis of current evidence. Myocardial infarction
acute ischaemic stroke. during the last three months was not an exclusion cri-
The quality of evidence for IVT in patients with iso- terion in the completed RCTs, so the results from these
lated cervical artery dissection was rated as low because trials apply to these patients.
although extracranial dissection was not a formal However, there are case reports describing myocar-
exclusion criterion in pivotal RCTs, direct comparison dial rupture, cardiac tamponade or embolisation of
of IVT vs. no IVT in this population relies only on ventricular thrombus after IVT for acute ischaemic
stroke in patients who have had a recent acute myocar- Mechanical thrombectomy may be a therapeutic
dial infarction.229–231 Conversely, other case reports alternative to bridging therapy in patients with large-
describe successful administration of IVT with alte- vessel occlusion and recent myocardial infarction.
plase in patients with acute ischaemic stroke and
recent myocardial infarction. In a systematic review Expert consensus statement
of case series that included 102 patients, four (8.5%) For patients with acute ischaemic stroke of < 4.5 h
of the 47 IVT-treated patients died from confirmed or duration and with history of ST-elevation myocar-
presumed cardiac rupture/tamponade, all with sub- dial infarction of more than a week to
acute (>6 h) ST-elevation Myocardial Infarction three months, nine of nine group members suggest
(STEMI) in the week preceding stroke.232 This compli- IVT with alteplase in specific situations. Variables
cation occurred in 1 (1.8%) patients in the non-treated to take into account are the size of the myocardial
group (P ¼ 0.18). No non-STEMI patients receiving infarction, whether recanalisation therapy was
IVT with alteplase had cardiac complications. given for the myocardial infarction, and echocar-
Non-STEMI patients have a lower risk of complica- diographic findings.
tions than transmural STEMI patients, and among ST-
elevation infarctions, infarctions in the anterior wall
have the highest cardiac complication rates.233
Cardiac complications tend to peak 2–14 days after
duration, who have infective endocarditis, does IVT with
myocardial infarction.234
Analysis of current evidence. Stroke is the most
Recommendation
common neurological complication of infective endo-
For patients with acute ischaemic stroke of < 4.5 h carditis, affecting up to 35% of all patients.235
duration and with history of subacute (>6 h) ST- Histopathological studies also suggest that cerebral
elevation myocardial infarction during the last sev- infarcts caused by septic emboli are particularly
en days, we suggest no IVT. prone to haemorrhagic transformation as a result of
Quality of evidence: Very low 丣 septic arteritis with erosion of the arterial wall in the
recipient vessel, with or without the formation of
For patients with acute ischaemic stroke of < 4.5 h mycotic aneurysms.236 Consequently, there are theoret-
duration and with history of ST-elevation myocar- ical reasons to expect that IVT for acute ischaemic
dial infarction of more than a week to stroke due to infective endocarditis will be associated
three months, there is insufficient evidence to with a higher risk of sICH.222 In a large study based on
make a recommendation. Please see the Expert administrative data, the outcome of patients treated
consensus statement below. with IVT for acute ischaemic stroke with (n ¼ 222)
Quality of evidence: Very low 丣 and without (n ¼ 134,048) infective endocarditis was
Strength of recommendation: - compared. The rate of post-thrombolytic ICH was sig-
For patients with acute ischaemic stroke of < 4.5 h nificantly higher in patients with infective endocarditis
duration and with a history of non-ST-elevation than in those without (20% versus 6.5%, P ¼ 0.006),
myocardial infarction during the last three months, and the proportion of patients with discharge disposi-
we suggest intravenous thrombolysis with tion of home/self-care was significantly lower in the
alteplase. infective endocarditis group (10% versus 37%,
Quality of evidence: Very low 丣 P ¼ 0.01).237 Some studies have also shown that alte-
Strength of recommendation: Weak "? plase in patients with co-existing infective endocarditis
may be complicated with multifocal ICH.238,239
Additional information. IVT with alteplase at a dose
of 1.1 mg/kg is indicated in patients with acute (< 6 h) Recommendation
myocardial infarction. Consequently, in the uncom- For patients with acute ischaemic stroke of < 4.5 h
mon case scenario of an acute ischaemic stroke com- duration and with a clear or suspected diagnosis of
plicating an acute myocardial infarction alteplase may infective endocarditis, we suggest no intravenous
be administered if there are no other contraindications thrombolysis.
to IVT. The dose and the time window should conform Quality of evidence: Low 丣丣
to the recommendations of IVT for acute ischaemic Strength of recommendation: Strong ##
stroke to minimize the risk of sICH.
Berge et al. 43
Discussion suggest tenecteplase over alteplase in patients with

large vessel occlusion who are candidates for mechan-
This guideline document was developed following the
ical thrombectomy.
GRADE methodology and aims to assist physicians in
The strengths of this guideline are its systematic
decision-making regarding IVT for acute ischaemic
approach to searching the literature and guidance by
stroke. It includes up-to-date scientific evidence that
the GRADE recommendations. However, many ques-
supersedes the previously published ESO guidelines
tions posed to the guideline module working group
and Karolinska Stroke Update recommendations.1,240
were about particular subgroups of patients with dif-
All recommendations and Expert consensus statements
ferent clinical characteristics, or who were taking par-
are summarized in Table 12.
ticular drugs at baseline. In many of these patients
Whenever possible, we based our recommendations
on RCTs or individual participant data meta-analyses there are clinical uncertainties about the balance of
of RCTs rather than observational studies, which are benefit and harm of IVT. However, in the absence of
more prone to selection bias and confounding. We studies randomly allocating participants in these sub-
found that there is high quality evidence for recommen- groups to IVT or control, the precise effects of treat-
dations on time to treatment, patients with different ments are unknown. It would be a mistake to interpret
ages and stroke severity, based on individual partici- a modestly higher risk of post-IVT sICH as a reason
pant data analyses of all trials of IVT with alteplase to not to treat such patients, because the benefit of alte-
date. plase has not been similarly quantified. Therefore, for
We decided to provide separate recommendations almost all patients the best prediction of effect of IVT is
for patients with unknown symptom onset and patients that of the average patient treated at that time point in
with known stroke onset of more than 4.5 hrs, because a randomised trial rather than patient with very similar
we believe that they correspond to two distinct clinical characteristics from an observational study. However,
scenarios. Indeed, many patients with wake-up stroke for practical reasons not all remaining questions
may have a ‘true’ stroke onset of < 4.5 hrs.31,32 regarding IVT can be answered by RCTs. Multicentre
Therefore, from a pathophysiological standpoint, this registries offer observational evidence that could con-
situation notably differs from strokes of more than tribute to our knowledge on IVT, particular when they
4.5hrs’ duration. Furthermore, in our experience the are representative of all treated patients.
information on whether the symptom onset is known To support physicians in their practical decision-
or unknown is generally available when the patient making, expert consensus statements are given in a
arrives in the hospital. Based on the result of an indi- dedicated paragraph. Whenever appropriate, these
vidual participant data meta-analysis of RCTs,46 we opinions were systematically collected as polls. About
recommend IVT in patients with unknown stroke three out of four of these polls (13/17) led to a good
onset selected with advanced imaging (DWI-FLAIR agreement of 7–9 of the 9 group members. In the
mismatch or core/perfusion mismatch). An extension remaining questions, the group members’ opinions
of the time window beyond 4.5 h of known onset time varied considerably. The recommendations with very
is also possible if perfusion-diffusion MRI or CT per- low evidence and poor agreement among experts were
fusion shows potentially salvageable brain tissue. on the subjects of IVT before thrombectomy in wake-
However, urgent advanced brain imaging is not up stroke or ischaemic stroke of 4.5–9 h duration, espe-
always available, which may limit the immediate appli- cially in those patients directly admitted to a
cability of these recommendations. Moreover, the thrombectomy-capable centre.
recent trials on the extended time window –EXTEND A next priority of research into thrombolysis is how
and ECASS-4– excluded patients for whom mechanical to implement it widely in populations with the greatest
thrombectomy was planned, which may further reduce need – that is patients in those areas with the highest
the number of patients qualifying of IVT beyond 4.5 h. stroke incidence and lowest use of thrombolysis. This
Although there are several high-quality trials to guide will need methods to make decisions about IVT as
practice, 29 out of 40 recommendations are based on rapid and as simple as possible and remove certain bar-
low or very low quality of evidence. These recommen- riers related to initial exclusion criteria that are not sup-
dations came from meta-analyses of small trials, single ported by current randomised or observational evidence.
modest-sized randomised trials, or observational stud- Implementation studies, training, further improvement
ies. Although tenecteplase has a number of potential in safety of IVT, reducing the cost of thrombolytics and
advantages, it is remains uncertain whether it is non- resource allocation to stroke in the areas of Europe with
inferior to alteplase for all patients with acute ischae- the highest stroke incidence are most likely to give the
mic stroke. Still, we found low quality evidence to greatest return on investment.
Table 12. Summary of PICO questions, evidence based recommendations, and expert consensus statements.
Topic/PICO Question Recommendations Expert consensus statement
0–4.5 h time window

1.1: In patients with acute For patients with acute ischaemic stroke of
ischaemic stroke of <4.5 h <4.5 h duration, we recommend intra-
duration, does intravenous venous thrombolysis with alteplase.
thrombolysis with alteplase Quality of evidence: High 丣丣丣丣
lead to better functional out- Strength of recommendation: Strong ""
come than no intravenous
thrombolysis?
4.5–9 h time window (known onset), plain CT

ischaemic stroke of 4.5–9 h 4.5–9 h duration (known onset time),
duration (known onset time) and with no brain imaging other than
selected with plain CT, does plain CT, we recommend no intravenous
intravenous thrombolysis with thrombolysis.
alteplase lead to better func- Quality of evidence: Moderate 丣丣丣
tional outcome than no intra- Strength of recommendation: Strong ##
venous thrombolysis?
4.5–9 h time window (known onset), perfusion mismatch

3.1: In patients with ischaemic For patients with ischaemic stroke of 4.5– For patients with ischaemic stroke of
stroke of 4.5–9 h duration 9 h duration (known onset time) and 4.5–9 h duration (known onset), and
(known onset time), and with with CT or MRI core/perfusion mis- with no CT or MRI core/perfusion
CT or MRI core/perfusion match*, and for whom mechanical mismatch, 9 of 9 group members
mismatch, does intravenous thrombectomy is either not indicated or suggest against IVT with alteplase.
thrombolysis with alteplase not planned, we recommend intrave-
lead to better functional out- nous thrombolysis with alteplase. For patients presenting directly to a
come than no intravenous Quality of evidence: Low 丣丣 thrombectomy centre with ischaemic
thrombolysis? Strength of recommendation: Strong "" stroke of 4.5–9 h duration (known
onset) with CT or MRI core/ perfu-
*In the individual participant data meta- sion mismatch and who are eligible
analysis by Campbell et al.,34 core/per- for mechanical thrombectomy, the
fusion mismatch was assessed with an group members could not reach a
automated processing software and consensus regarding whether intra-
defined as follows: venous thrombolysis should be used
- Infarct core** volume < 70 ml before mechanical thrombectomy.
- and Critically hypoperfused† volume/ Infarct
core** volume > 1.2 For patients presenting to a non-
- and Mismatch volume > 10 ml thrombectomy centre with ischaemic
** rCBF <30% (CT perfusion) or ADC < 620 stroke of 4.5–9 h duration (known
mm2/s (Diffusion MRI) onset) with CT or MRI core/perfu-
† Tmax >6 s (perfusion CT or perfusion MRI) sion mismatch and who are eligible
for mechanical thrombectomy, 6/9
group members suggest intravenous
thrombolysis before mechanical
thrombectomy.
Wake-up stroke/Unknown onset

4.1: In patients with acute For patients with acute ischaemic stroke For patients presenting directly to a
ischaemic stroke on awakening on awakening from sleep, who were last thrombectomy centre with acute
from sleep / unknown onset, seen well more than 4.5 h earlier, who ischaemic stroke on awakening from
does intravenous thrombolysis have MRI DWI-FLAIR mismatch, and for sleep, who would be eligible for both
(continued)
Berge et al. 45
Table 12. Continued.

with alteplase lead to better whom mechanical thrombectomy is IVT and mechanical thrombectomy,
functional outcome than no either not indicated or not planned, we 6/9 group members suggest IVT
intravenous thrombolysis? recommend intravenous thrombolysis before MT.
with alteplase.
Quality of evidence: High 丣丣丣丣 For patients presenting to a non-
Strength of recommendation: Strong "" thrombectomy centre with acute
ischaemic stroke on awakening from
For patients with acute ischaemic stroke sleep, who would be eligible for both
on awakening from sleep, who have CT IVT and mechanical thrombectomy,
or MRI core/perfusion mismatch* within 7/9 group members suggest IVT
nine hours from the midpoint of sleep, before MT.
and for whom mechanical thrombec-
tomy is either not indicated or not
planned, we recommend intravenous
thrombolysis with alteplase.
*In the EOS individual participant data

meta-analysis,46 core/perfusion mis-
match was assessed with an automated
processing software and defined as fol-
lows:
- Infarct core** volume < 70 ml
- and Critically hypoperfused† volume / Infarct
core** volume > 1.2
- and Mismatch volume > 10 ml
** rCBF <30% (CT perfusion) or ADC < 620
mm2/s (Diffusion MRI)
† Tmax >6 s (perfusion CT or perfusion MRI)
Tenecteplase – no large vessel occlusion

ischaemic stroke of <4.5 h <4.5 h duration and not eligible for
duration, does IVT with ten- thrombectomy, we suggest intravenous
ecteplase lead to better func- thrombolysis with alteplase over intra-
tional outcome than IVT with venous thrombolysis with tenecteplase.
alteplase? Please see paragraph 5.2 for patients
eligible for mechanical thrombectomy.
Quality of evidence: Low 丣丣
Tenecteplase – large vessel occlusion

5.2: In patients with acute For patients with acute ischaemic stroke
ischaemic stroke of <4.5 h of < 4.5 h duration and with large vessel
duration and with large occlusion who are candidates for
vessel occlusion, who are mechanical thrombectomy and for
candidates for mechanical whom intravenous thrombolysis is con-
thrombectomy, and for whom sidered before thrombectomy, we sug-
intravenous thrombolysis is gest intravenous thrombolysis with
considered before thrombec- tenecteplase 0.25 mg/kg over intrave-
tomy, does IVT with tenecte- nous thrombolysis with alteplase
plase lead to better functional 0.9 mg/kg.
(continued)

outcome than IVT with Quality of evidence: Low 丣丣

alteplase? Strength of recommendation: Weak "?
Low-dose alteplase
ischaemic stroke of <4.5 h <4.5 h duration who are eligible for
duration, does intravenous intravenous thrombolysis, we recom-
thrombolysis with low-dose mend standard-dose alteplase
alteplase lead to non-inferior (0.9 mg/kg) over low-dose alteplase.
(not worse) functional out- Quality of evidence: High 丣丣丣丣
come compared to standard- Strength of recommendation: Strong ""
dose alteplase?
Adjunct antithrombotic therapy

ischaemic stroke of <4.5 h <4.5 h duration, we recommend no
duration, does antithrombotic antithrombotic drugs within 24 h of
agents in addition to IVT lead intravenous thrombolysis over antith-
to better functional outcome rombotic drugs as an adjunct therapy to
than IVT alone? intravenous thrombolysis with alteplase.
Sonothrombolysis
ischaemic stroke of <4.5 h <4.5 h duration, we recommend against
duration, does ultrasound ultrasound augmentation in patients
augmentation of IVT lead to receiving intravenous thrombolysis.
better functional outcome Quality of evidence: Low 丣丣
than IVT alone? Strength of recommendation: Strong ##
Higher age, multimorbidity, prior disability

8.1: In patients with acute For patients with acute ischaemic stroke of 9/9 group members believe that age
ischaemic stroke of <4.5 h <4.5 h duration, who are over 80 years alone should not be a limiting factor
duration, who are over of age, we recommend intravenous for IVT, even in other situations
80 years of age, does intrave- thrombolysis with alteplase. covered in the present guidelines
nous thrombolysis with alte- Quality of evidence: High 丣丣丣丣 (e.g. wake-up stroke; ischaemic
plase lead to better functional Strength of recommendation: Strong "" stroke of 4.5–9 h duration (known
outcome than no IVT? onset time) with CT or MRI core/
perfusion mismatch; minor stroke
8.2: In patients with acute For patients with acute ischaemic stroke of with disabling symptoms).
ischaemic stroke of <4.5 h <4.5 h duration, and with multimorbid-
duration, who have multimor- ity, frailty or pre-stroke disability, we
bidity, frailty, or prior disability, suggest intravenous thrombolysis with
does intravenous thrombolysis alteplase.
with alteplase lead to better Quality of evidence: Very low 丣
functional outcome than no Strength of recommendation: Weak "?
IVT?
(continued)
Berge et al. 47

Minor stroke (disabling)

9.1: In patients with acute minor, For patients with acute minor, disabling
disabling ischaemic stroke of ischaemic stroke of <4.5 h duration, we
<4.5 h duration, does IVT with recommend intravenous thrombolysis
alteplase lead to better func- with alteplase.
tional outcome than no IVT? Quality of evidence: Moderate 丣丣丣
Minor stroke (non-disabling)

9.2: In patients with acute minor, For patients with acute minor non-dis-
non-disabling ischaemic stroke abling ischaemic stroke of <4.5 h dura-
of <4.5 h duration, does IVT tion, we suggest no intravenous
with alteplase lead to better thrombolysis. For patients with minor
functional outcome than no stroke and large-vessel occlusion, please
IVT? refer to the section below (PICO 9.3).
9.3: In patients with acute minor, For patients with acute minor, non-
non-disabling ischaemic stroke disabling ischaemic stroke of <4.5 h
of <4.5 h duration, and with duration, and with large-vessel
proven large vessel occlusion, occlusion, 6 of 8 group members
does IVT with alteplase lead to suggest intravenous thrombolysis
better functional outcome with alteplase.
than no IVT?
Rapidly improving symptoms

9.4: In patients with acute For patients with acute ischaemic
ischaemic stroke of <4.5 h stroke with < 4.5 h duration, and
duration, and with rapidly rapidly improving neurological signs,
improving neurological signs, which are still disabling, 8 of 9 group
does IVT with alteplase lead to members suggest intravenous
better functional outcome thrombolysis with alteplase. The
than no IVT? group agreed that the treatment
decision should be based on the
clinical status at presentation, and
that it is not justifiable to wait for
resolution of symptoms.
Severe stroke
10.1: In patients with severe For patients with clinically severe acute 7 of 9 group members voted for intra-
acute ischaemic stroke of ischaemic stroke of <4.5 h duration, we venous thrombolysis with alteplase in
<4.5 h duration, does IVT with recommend intravenous thrombolysis selected patients with severe stroke
alteplase lead to better func- with alteplase. associated with extended radiologi-
tional outcome than no IVT? Quality of evidence: Moderate 丣丣丣 cal signs of infarction (e.g., early
Strength of recommendation: Strong "" ischemic change of more than 1/3 of
the middle cerebral artery territory
For patients with acute ischaemic stroke of or ASPECTS <7 on plain CT).
<4.5 h duration, and with severe stroke, Patient selection criteria might
defined by the extent of early ischaemic include eligibility for an alternative
changes on CT, we suggest that intrave- reperfusion strategy (mechanical
nous thrombolysis with alteplase be thrombectomy), results of advanced
considered in selected cases (see the imaging (notably perfusion/core
(continued)

Expert consensus statement). mismatch), time since symptom

Quality of evidence: Very Low 丣 onset, and pre-stroke disability.
High Blood pressure on admission

ischaemic stroke of <4.5 h <4.5 h duration, and with persistently
duration, and with persistently increased systolic blood pressure
increased blood pressure >185 mmHg or diastolic blood pressure
above 185/110 mmHg, even >110 mm Hg even after blood pressure
after blood pressure lowering lowering treatment, we suggest no
treatment, does IVT with intravenous thrombolysis.
alteplase lead to better func- Quality of evidence: Very low 丣
tional outcome than no IVT? Strength of recommendation: Strong ##
ischaemic stroke of <4.5 h <4.5 h duration, and with systolic blood
duration, and with increased pressure >185 mm Hg or diastolic
blood pressure above 185/ blood pressure >110 mm Hg, which has
110 mm Hg, which has subse- subsequently been lowered to <185 and
quently been lowered to <110 mm Hg, we recommend intrave-
below 185/110 mm Hg, does nous thrombolysis with alteplase.
IVT with alteplase lead to Quality of evidence: Low 丣丣
better functional outcome Strength of recommendation: Strong ""
than no IVT?
Pre-stroke hypertension
ischaemic stroke of <4.5 h <4.5 h duration, and with known pre-
duration, and with known pre- stroke hypertension, we recommend
stroke hypertension, does IVT intravenous thrombolysis with alteplase.
with alteplase lead to better Quality of evidence: Moderate 丣丣丣
functional outcome than no Strength of recommendation: Strong ""
IVT?
High glucose level on admission

ischaemic stroke of <4.5 h <4.5 h duration, and with blood glucose
duration, and with blood glu- levels above >22.2 mmol/L (400 mg/dL),
cose level above 22.2 mmol/L we suggest intravenous thrombolysis
(>400 mg/dL), does IVT with with alteplase.
alteplase lead to better func- Quality of evidence: Very Low 丣
tional outcome than no IVT? Strength of recommendation: Weak "?
Intravenous thrombolysis should not pre-
vent the administration of insulin thera-
py in acute ischaemic stroke patients
with high blood glucose levels.144
Diabetes mellitus
ischaemic stroke of <4.5 h <4.5 h duration, and with known diabe-
duration, and with known tes mellitus, we recommend intravenous
(continued)
Berge et al. 49

diabetes mellitus, does IVT thrombolysis with alteplase.

with alteplase lead to better Quality of evidence: Moderate 丣丣丣
functional outcome than no Strength of recommendation: Strong ""
IVT?
Antiplatelet agents prior to stroke

ischaemic stroke of <4.5 h <4.5 h duration, who used single or dual
duration, who use antiplatelet antiplatelet agents prior to the stroke,
agents, does IVT with alteplase we suggest intravenous thrombolysis
lead to better functional out- with alteplase.
come than no IVT? Quality of evidence: Low 丣丣
Anticoagulants before stroke (VKA)

ischaemic stroke of <4.5 h <4.5 h duration, who use vitamin K
duration, who use vitamin K antagonists and have INR 1.7 we rec-
antagonists, does IVT with ommend intravenous thrombolysis with
alteplase lead to better func- alteplase.
tional outcome than no IVT? Quality of evidence: Low 丣丣
For patients with acute ischaemic stroke of

<4.5 h duration, who use vitamin K
antagonists and have INR >1.7 we rec-
ommend no intravenous thrombolysis.

<4.5 h duration, who use vitamin K
antagonists, and for whom the results of
coagulation testing is unknown, we rec-
ommend no intravenous thrombolysis.
Anticoagulants before stroke (NOACs)

12.3: In patients with acute For patients with acute ischaemic stroke of For patients with acute ischaemic
ischaemic stroke of <4.5 h <4.5 h duration, who used a NOAC stroke of <4.5 h duration, who used
duration, who use NOACs, during the last 48 h before stroke onset, a NOAC during the last 48 h before
does IVT with alteplase lead to and for whom there is no specific stroke onset, and who have an anti-
better functional outcome coagulation tests available (i.e. calibrated Xa activity <0.5 U/ml (for factor Xa
than no IVT? anti-Xa-activity for factor Xa inhibitors, inhibitors) or thrombin time <60 s
thrombin time for dabigatran, or the (for direct thrombin inhibitors) 7 of 9
NOAC blood concentrations), we sug- group members suggest IVT with
gest no intravenous thrombolysis. alteplase.
Strength of recommendation: Strong ## For patients with acute ischaemic
stroke of <4.5 h duration, who used
dabigatran during the last 48 h before
(continued)

stroke onset, 8/9 group members

suggest the combination of idaruci-
zumab and intravenous thrombolysis
with alteplase over no intravenous
thrombolysis.
For patients with acute ischaemic

stroke of <4.5 h duration, who used
factor Xa inhibitors during the last
48 h before stroke onset, 9/9 group
members suggest against the combi-
nation of andexanet and intravenous
thrombolysis with alteplase over no
intravenous thrombolysis.
Low platelet count

ischaemic stroke of <4.5 h <4.5 h duration, and with known plate-
duration, who have low platelet count <100 109/L, we suggest no
let count, does IVT with alte- intravenous thrombolysis.
plase lead to better functional Quality of evidence: Very low 丣
outcome than no IVT? Strength of recommendation: Weak #?

<4.5 h duration, and with unknown
platelet count before initiation of intra-
venous thrombolysis and no reason to
expect abnormal values, we recommend
starting intravenous thrombolysis with
alteplase while waiting for lab tests
results.
Recent trauma or surgery

ischaemic stroke of <4.5 h <4.5 h duration and with major surgery
duration, who have a history on a non-compressible site where
of recent trauma, surgery or bleeding is likely to lead to significant
biopsy, does IVT with alteplase haemorrhage (e.g., abdomen, chest,
lead to better functional out- skull, well-vascularized tissues, or large
come than no IVT? artery) during the preceding 14 days, we
recommend no intravenous thromboly-
sis.
History of intracranial hemorrhage

ischaemic stroke of < 4.5 h stroke of <4.5 h duration and with a
duration, who have a history history of intracranial haemorrhage,
of intracranial haemorrhage, 8/9 members suggest intravenous
(continued)
Berge et al. 51

does IVT with alteplase lead to thrombolysis with alteplase in

better functional outcome selected cases. For example, intra-
than no IVT? venous thrombolysis may be consid-
ered if a long time has elapsed since
the haemorrhage, if there was a
specific underlying cause for the
haemorrhage (e.g. trauma, subarach-
noid haemorrhage with subsequent
endovascular or surgical aneurysm
removal, or use of specific antith-
rombotic medication).
Microbleeds
ischaemic stroke of <4.5 h <4.5 h duration, for whom cerebral stroke within 4.5 h of stroke onset, 9
duration, who have cerebral microbleed burden is unknown or of 9 members suggest against
microbleeds, does IVT with known to be low (e.g. <10), we suggest screening with MRI to assess cere-
alteplase lead to better func- intravenous thrombolysis with alteplase. bral microbleed burden before
tional outcome than no IVT? Quality of evidence: Low 丣丣 making a treatment decision regard-
Strength of recommendation: Weak "? ing intravenous thrombolysis.

<4.5 h duration, for whom cerebral
microbleed burden has been previously
reported to be high (e.g. >10), we sug-
gest no intravenous thrombolysis.
White matter lesions

ischaemic stroke of <4.5 h <4.5 h duration, and small to moderate
duration, who have cerebral burden of white matter lesions, we
white matter lesions, does IVT recommend intravenous thrombolysis
with alteplase lead to better with alteplase.
functional outcome than no Quality of evidence: Moderate 丣丣丣
IVT? Strength of recommendation: Strong ""

<4.5 h duration, and high burden of
white matter lesions, we suggest intra-
venous thrombolysis with alteplase.
Cerebral aneurysm
ischaemic stroke of <4.5 h <4.5 h duration, who have an unrup-
duration, who have an unruptured cerebral artery aneurysm, we
tured cerebral aneurysm, does suggest IVT with alteplase.
IVT with alteplase lead to Quality of evidence: Very low 丣
(continued)

better functional outcome

than no IVT?
History of ischaemic stroke

ischaemic stroke of <4.5 h stroke of <4.5 h duration, and a his-
duration, who have a history tory of ischemic stroke within the
of ischaemic stroke during the last three months, nine of nine
last three months, does IVT members voted for intravenous
with alteplase lead to better thrombolysis with alteplase in
functional outcome than no selected cases, for example in case of
IVT? a small infarct, stroke occurring more
than one month earlier, or good
clinical recovery.
Seizure
ischaemic stroke of <4.5 h <4.5 h duration who have seizures at
duration, who had a seizure at time of stroke onset, and for whom
time of stroke onset, does IVT there is no suspicion of a stroke mimic
with alteplase lead to better or significant head trauma, we suggest
functional outcome than no intravenous thrombolysis with alteplase.
IVT? Quality of evidence: Very low 丣
Dissection
ischaemic stroke of <4.5 h <4.5 h duration and with aortic arch stroke of <4.5 h duration and with
duration, who have dissection dissection we recommend no intrave- an intracerebral artery dissection, 6/
in the aortic arch, in a carotid nous thrombolysis. 9 group members suggest against
artery or in an intracerebral Quality of evidence: Very low 丣 intravenous thrombolysis with
artery, does IVT with alteplase Strength of recommendation: Strong ## alteplase.
lead to better functional out- For patients with acute ischaemic stroke of
come than no IVT? <4.5 h duration and with isolated cer-
vical artery dissections, we suggest
intravenous thrombolysis with alteplase.
Myocardial infarction
ischaemic stroke of <4.5 h <4.5 h duration and with history of stroke of <4.5 h duration and with
duration, who have had myo- subacute (>6 h) ST-elevation myocardial history of ST-elevation myocardial
cardial infarction during the infarction during the last seven days, we infarction of more than a week to
last three months, does IVT suggest no IVT. three months, 9/9 group members
with alteplase lead to better Quality of evidence: Very low 丣 suggest IVT with alteplase in specific
functional outcome than no Strength of recommendation: Weak #? situations. Variables to take into
IVT? For patients with acute ischaemic stroke of account are the size of the myocar-
<4.5 h duration and with a history of dial infarction, whether recanalisa-
non-ST-elevation myocardial infarction tion therapy was given for the
during the last three months, we suggest myocardial infarction, and echocar-
intravenous thrombolysis with alteplase. diographic findings.
(continued)
Berge et al. 53


Infective endocarditis
ischaemic stroke of <4.5 h <4.5 h duration and with a clear or
duration, who have infective suspected diagnosis of infective endo-
endocarditis, does IVT with carditis, we suggest no intravenous
alteplase lead to better func- thrombolysis.
tional outcome than no IVT? Quality of evidence: Low 丣丣
Plain language summary bleeds (microbleeds), or damage to the brain

‘white matter’
Patients with stroke due to blood clots in brain arteries
• has had a brain bleed because of a cause unlikely
(‘ischaemic stroke’) can be treated with clot-dissolving
to re-occur
drugs called ‘thrombolytics’. By dissolving blood clots,
5. Generally, to avoid treatment with alteplase if the
thrombolytic drugs improve brain blood supply and ischaemic patient is taking blood thinning drugs
lead to better recovery. However, thrombolytic drugs such as a ‘direct oral anticoagulants’ or warfarin,
may cause bleeding in the brain which can lead to unless:
worse disability or death. The most commonly used • The patient is taking warfarin and the INR (a
thrombolytic drug for ischemic stroke is called alte- measure of blood clotting) is known to be < 1.7.
plase. The guideline authors make recommendations • The patient had been prescribed a ‘direct oral
about the use of thrombolytic drugs given into a vein anticoagulant’ (such as apixaban, dabigatran,
for patients with acute ischaemic stroke. rivaroxaban, edoxaban) but has not taken the
The guideline makes forty recommendations. The drug in the 48 h before stroke.
most important recommendations are: 6. Generally to avoid treatment with alteplase if the
patient has recently had major surgery, major
1. To treat ischaemic stroke patients with alteplase if it trauma, infection of the heart valves (endocarditis),
can be started within 4.5 h of symptoms beginning. or dissection of the aorta. If the patient is known to
The stroke symptoms should be disabling at the time have more than ten tiny bleeds of the brain (micro-
of treatment. The age of the patient does not matter. bleeds) or very low levels of blood platelets, treat-
2. Advanced brain imaging (magnetic resonance or CT ment should be avoided, but looking for these with
perfusion) should be used to select patients for treat- blood tests or extra brain scans should not delay
ment with alteplase, if they present between 4.5 and treatment.
9 h after the start of symptoms, or if a stroke is 7. An alternative thrombolytic drug, tenecteplase, may
noticed at waking from sleep. be favored over alteplase before clot pulling treat-
3. To avoid treatment with low dose alteplase, or to ment (thrombectomy), but its place to treat all
add ultrasound or immediate antiplatelet drugs to patients is uncertain.
alteplase because they do not give a better chance 8. Once blood pressure is lower than 185 mmHg sys-
of surviving with no disability. tolic or 110 mmHg diastolic, alteplase can be given
4. If an ischaemic stroke patient could be treated with safely.
alteplase, do not avoid treatment if the patient:
• has a diagnosis of high blood pressure, diabetes, The major recommendations were supported by
previous stroke, or a heart attack high to moderate quality evidence. Other than for age
• takes antiplatelet drugs like aspirin and stroke severity, there was weaker evidence to sup-
• At the time of stroke has a high blood glucose port when to use alteplase in very particular situations.
level, or an epileptic seizure (if the diagnosis of
stroke is certain) or dissection of the carotid Declaration of conflicting interests
artery The author(s) disclosed receipt of the following financial sup-
• Has had a brain scan that shows a brain port for the research, authorship, and/or publication of this
aneurysm that has not burst, or < 10 tiny brain article: All disclosures are listed in Supplemental Table 1
Funding 6. Wardlaw JM, Murray V, Berge E, et al. Thrombolysis

This research received no specific grant from any funding for acute ischaemic stroke. Cochrane Database Syst Rev
agency in the public, commercial, or not-for-profit sectors. 2014: CD000213
7. Higgins JPT, Thomas J, Chandler J, et al. Cochrane
handbook for systematic reviews of interventions ver-
Ethical approval
sion 6.0 (updated July 2019), www.training.cochrane.
No ethical approval was needed for this manuscript, which is org/handbook (accessed 21 August 2020).
an ESO Guideline. 8. Emberson J, Lees KR, Lyden P, et al. Effect of treat-
ment delay, age, and stroke severity on the effects of
Informed consent intravenous thrombolysis with alteplase for acute
Not relevant for this type of manuscript. ischaemic stroke: a meta-analysis of individual patient
data from randomised trials. Lancet 2014; 384:
Guarantor 1929–1935.
9. IST-3 collaborative group. The benefits and harms of
G Turc
intravenous thrombolysis with recombinant tissue plas-
minogen activator within 6 h of acute ischaemic stroke
Contributorship (the third international stroke trial [IST-3]): a rando-
EB, WW and G Turc conceived the study. All authors mised controlled trial. Lancet 2012; 379: 2352–2363.
searched the literature. G Turc, GMDM and G Tsivgoulis 10. Whiteley WN, Emberson J, Lees KR, et al; Stroke
conducted the statistical analysis. All authors contributed to Thrombolysis Trialists’ Collaboration. Risk of intrace-
writing the first draft of the manuscript, under the supervi- rebral haemorrhage with alteplase after acute ischaemic
sion of EB, WW and G Turc. All authors reviewed and edited stroke: a secondary analysis of an individual patient
the manuscript several times and approved the final version data meta-analysis. Lancet Neurol 2016; 15: 925–933.
of the manuscript. 11. IST-3 Collaborative Group. Effect of thrombolysis with
alteplase within 6 h of acute ischaemic stroke on long-
ORCID iDs term outcomes (the third international stroke trial [IST-
Ana Catarina Fonseca https://orcid.org/0000-0001-6913- 3]): 18-month follow-up of a randomised controlled
trial. Lancet Neurol 2013; 12: 768–776.
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12. Berge E, Cohen G, Roaldsen MB, et al.; IST-3
Guillaume Turc https://orcid.org/0000-0001-5059-4095
Collaborative Group. Effects of alteplase on survival
after ischaemic stroke (IST-3): 3 year follow-up of a
randomised, controlled, open-label trial. Lancet Neurol
Supplemental material
2016; 15: 1028–1034.
Supplemental material for this article is available online. 13. Alper BS, Foster G, Thabane L, et al. Thrombolysis
with alteplase 3–4.5 hours after acute ischaemic stroke:
trial reanalysis adjusted for baseline imbalances. BMJ
Acknowledgments Evid Based Med 2020; 25: 168–171.
We thank Joshua Cheyne for his help with the systematic 14. Turc G, Bhogal P, Fischer U, et al. European Stroke
review of the literature. Organisation (ESO) – European society for minimally
invasive neurological therapy (ESMINT) guidelines on
mechanical thrombectomy in acute ischaemic stroke.
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Guideline

European Stroke Journal

guidelines on intravenous thrombolysis 2021

Eivind Berge1,*, William Whiteley2,*, Heinrich Audebert3,

that imbalance in baseline NIHSS score may have been

mechanical thrombectomy,14 there is a debate about

mechanical thrombectomy alone was non-inferior to

mechanical thrombectomy preceded by IVT with alte-

plase (0.9 mg/kg) administered within 4.5 h after symp-

outcome at three months 1.07, 95% CI: 0.81–1.40;

P ¼ 0.04).15 However, the trial had a liberal non-

inferiority margin (20%); a long onset-to-IVT time

from start of IVT to groin puncture (median approxi-

have resulted in delaying the allowed time for consent-

needle time (median 59 min). Moreover, 31 patients in

the bridging therapy (IVT plus mechanical thrombec-

tomy, while another 30 patients from the same group

0.70, 95% CI: 0.47–1.06) in the direct mechanical

apy groups, respectively (OR 0.70, 95% CI: 0.36–1.37).

Other trials comparing direct mechanical thrombec-

tomy and bridging therapy in mothership patients

Whether IVT is effective in patients with lacunar

with clinically defined lacunar infarct in the National

(NINDS) tPA trial (13% of enrolled patients), the

OR for excellent outcome was 2.53 (95% CI: 1.00–

6.37; P ¼ 0.047).17 In patients with clinically defined

lacunar infarct in IST-3 (11% of enrolled patients),

six months was 0.91 (0.48–1.72). However, there was

Quality of evidence: Low 丣丣 similar functional outcomes in patients treated within

There is currently no randomized data to make a

Expert consensus statement

thrombectomy, the group members could not

reach a consensus regarding whether intravenous

For patients presenting to a non-thrombectomy

centre with ischaemic stroke of 4.5–9 h duration

thrombectomy, 6 of 9 group members suggest

4. Stroke on awakening from sleep/unknown onset

PICO 4.1 In patients with acute ischaemic stroke on awakening

alteplase lead to better functional outcome than no intravenous

strokes occur during sleep, but IVT is often withheld

in patients with new stroke symptom upon awakening

controlled trials of IVT with alteplase in patients with

MRI: DWI/FLAIR mismatch

Improved mRS score at three months (shift analysis)

The WAKE-UP trial included 503 patients who woke

up with a new stroke and were last known to be well

lesion on DWI but no marked parenchymal hyperin-

trial excluded patients for whom thrombectomy was

planned. Patients were randomised to alteplase

0.9 mg/kg or placebo, and the primary endpoint was

mRS 0–2 at three months

excellent outcome (mRS 0–1 at 90 days). The trial

was terminated prematurely owing to cessation of

funding after the enrolment of 503 of an anticipated

800 patients. Thirty-four percent of the patients had

an intracranial vessel occlusion. The adjusted OR for

1.09–2.36, P ¼ 0.02) and the cOR for better functional

outcome was 1.62 (95% CI: 1.17–2.23, P ¼ 0.003).

Certainty assessment No of patients Effect

Eivind Berge1,, William Whiteley2,, Heinrich Audebert3,