Articles

Recombinant tissue plasminogen activator for acute ischaemic

stroke: an updated systematic review and meta-analysis
Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory del Zoppo, Peter Sandercock, Richard L Lindley, Geoff Cohen

Summary
Lancet 2012; 379: 2364–72 Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated
Published Online soon after acute ischaemic stroke in randomised trials, but licensing is restrictive and use varies widely. The IST-3 trial
May 23, 2012 adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic
DOI:10.1016/S0140-
stroke in an updated systematic review and meta-analysis.
6736(12)60738-7
See Comment page 2320
Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute
See Articles page 2352
ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for
Division of Clinical
Neurosciences, University of
prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke.
Edinburgh, Western General
Hospital, Edinburgh, UK Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being
(Prof J M Wardlaw MD, alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 [46·3%] vs 1434/3404 [42·1%],
Prof P Sandercock DM,
G Cohen PhD); Karolinska
OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable
Institute, Danderyd Hospital, outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients
Stockholm, Sweden treated within 3 h (mRS 0–2, 365/896 [40·7%] vs 280/883 [31·7%], 1·53, 1·26–1·86, p<0·0001), absolute benefit of
(Prof V Murray MD); 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 [31·6%] vs 202/883 [22·9%], 1·61, 1·30–1·90; p<0·0001),
Department of Internal
Medicine, Oslo University
absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 [8·9%] vs
Hospital, Oslo, Norway 174/2728 [6·4%], 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant
(Prof E Berge MD); School (679/3548 [19·1%] vs 640/3464 [18·5%], 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage
of Medicine, University of (272/3548 [7·7%] vs 63/3463 [1·8%], 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths.
Washington, Seattle, WA, USA
(Prof G del Zoppo MD); and
Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.
Sydney Medical
School-Westmead Hospital, Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with
and George Institute for Global favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients
Health, University of Sydney,
NSW, Australia
as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke.
(Prof R Lindley MD)
Correspondence to: Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health
Prof Joanna M Wardlaw, Division Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens
of Clinical Neurosciences, Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of
University of Edinburgh, Western
General Hospital, Crewe Road,
Norway, Oslo University Hospital.
Edinburgh EH4 2XU, UK
joanna.wardlaw@ed.ac.uk Introduction from a randomised trial for a wide range of patients,
Recombinant tissue plasminogen activator (rt-PA, including those older than 80 years, treated between
alteplase) was licensed in North America in 1996 for 3–6 h, and with comorbid disorders such as previous
intravenous use within 3 h of stroke in selected patients stroke. Meanwhile, a meta-analysis of individual patient
after the publication of the results of the trials undertaken data from completed trials undertaken in 2004 suggested
by the National Institute of Neurological Disorders and that intravenous rt-PA might be of benefit up to
Stroke (NINDS), Bethesda, MD, USA, in 624 patients.1 A 4·5 h after stroke,6 with the findings confirmed in 2008 in
restricted conditional licence for the use of rt-PA within the ECASS 3 trial of patients younger than 80 years who
3 h of ischaemic stroke was granted in Europe in were treated between 3·0–4·5 h after stroke.7,8 Despite this
2002 after publication of two further trials of intravenous increasing evidence from 11 trials of 3977 patients who
rt-PA administered up to 6 h after ischaemic stroke2,3 and were treated up to 6 h after stroke,9 substantial uncer-
a systematic review of 3156 patients.4,5 The European tainties10 have been caused by the lack of precision in the
approval allowed treatment, within 3 h, of patients overall estimates of treatment effects for the important
younger than 80 years who also met other strict criteria. outcomes of death and functional outcome, longest time
Although the licence restricted the use of rt-PA to within window for net benefit, effect of treatment in people older
3 h, the results of the trials6 suggested that rt-PA, given as than 80 years (only 94 patients in this age group were
late as 6 h after ischaemic stroke, might reduce the included in the completed trials), and the effect of factors
number of patients with poor functional outcomes.4,5 In such as stroke severity, stroke subtype, use of antiplatelet
that context, the Third International Stroke Trial (IST-3) drugs before stroke, and other comorbidities (eg, previous
was initiated in 2000, with the aim of providing evidence stroke, diabetes, or hypertension).

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Trial design Patients

Number Method of Dose Control Antithrombotic drug Age inclusion Stroke type Exclusion Time Final Follow-up
of randomisation use range criteria* for after follow-up method
patients CT-defined stroke (independent)
ischaemia
Mori et al,13 31 Seq Pack 0·6 mg/kg (34 mg) Placebo Avoid for 24 h 18–80 years Carotid Visible <6 h 4 weeks At clinic (not
1992 or 0·9 mg/kg territory; ICA or infarction stated)
(51 mg) MCA occlusion
on angiography
JTSG,14 1993 98 Seq Pack 0·6 mg/kg (34 mg) Placebo Avoid for 24 h 18–80 years Carotid Visible <6 h 4 weeks At clinic (not
territory; ICA or infarction stated)
MCA occlusion
on angiography
Haley et al,15 27 Seq Pack 0·85 mg/kg Placebo Avoid intravenous 18–80 years Any ischaemic None <3 h 3 months At clinic (not
1993 heparin for several stroke stated)
hours
ECASS,2 1995 620 Seq Pack 1·1 mg/kg Placebo Aspirin or intravenous 18–80 years Carotid Visible 6h 3 months At clinic (not
(maximum 100 mg) heparin not allowed; territory infarction stated)
subcutaneous heparin greater than
allowed for <24 h; a third of
thereafter, any MCA territory
antithrombotic
allowed
NINDS,1 624 Seq Pack 0·9 mg/kg Placebo Avoid for 24 h 18–80 years† Any except very None 3h 3 months At clinic
1995 (maximum 90 mg) mild and very (masked
severe independent
clinician)
ECASS II,3 800 Seq Pack 0·9 mg/kg Placebo Aspirin or intravenous 18–80 years Carotid Visible 6h 3 months At clinic (not
1998 (maximum 90 mg) heparin not allowed; territory infarction stated)
subcutaneous heparin greater than
allowed for <24 h a third of
MCA territory
ATLANTIS 142 Seq Pack 0·9 mg/kg Placebo Avoid for 24 h 18–80 years As for NINDS None 6h 3 months At clinic
A,16 2000 (maximum 90 mg) (masked
independent
clinician)
ATLANTIS 613 Seq Pack 0·9 mg/kg Placebo Avoid for 24 h 18–80 years As for NINDS Visible Most 3 months At clinic
B,17,18 1999 (maximum 90 mg) infarction within (masked
greater than 5 h independent
a third of clinician)
MCA territory
ECASS 3,7 821 Central 0·9 mg/kg Placebo Avoid for 24 h 18–80 years As for NINDS Visible 3·0–4·5 h 3 months At clinic
2008 telephone or (maximum 90 mg) infarction (masked
internet based greater than independent
a third of clinician)
MCA
territory
Wang et al,19 100 Seq Pack 0·9 mg/kg Open Avoid for 24 h 18–80 years As for NINDS Any visible 6h 3 months At clinic (not
2003 (maximum 90 mg) control infarction stated)
EPITHET,20 101 Seq Pack 0·9 mg/kg Placebo Avoid for 24 h 18–80 years† As for NINDS Visible 3–6 h 3 months At clinic (not
2008 (maximum 90 mg) infarction stated)
greater than
a third of
MCA territory
IST-3,21 2012 3035 Central 0·9 mg/kg Placebo Avoid for 24 h; start ≥18 years All subtypes Visible 6h 6 months Centralised
telephone or (maximum 90 mg) first 276 aspirin at 24 h unless infarct only if telephone or
internet based patients, contraindicated it appears postal
open >6 h after questionnaire
control stroke—ie, (yes)
thereafter incompatible
with stated
time after
stroke

rt-PA=recombinant tissue plasminogen activator. Seq Pack=randomised by taking the next of a sequentially numbered pack of active drug or placebo. ICA=internal carotid artery. MCA=middle cerebral artery.
*Haemorrhage and mimics were excluded in all studies. †NINDS included 69 patients and EPITHET included 25 patients older than 80 years.

Table 1: Randomised controlled trials of rt-PA in acute ischaemic stroke, design characteristics, and other key factors

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We updated the systematic review of rt-PA to assess the
overall effect of intravenous rt-PA when given up to 6 h
after stroke for important early and late outcomes, and to
address some of the previous key uncertainties.
Methods
We updated the systematic review of trials of rt-PA in
acute ischaemic stroke, first published in 1992,11 updated
periodically in the Cochrane Database of Systematic Reviews
since then.9 We searched using multiple overlapping
See Online for appendix search methods up to March, 2012 (appendix). We trans-
lated non-English language publications and obtained
additional information from principal investigators.
We included all randomised trials of rt-PA versus control
in patients with definite ischaemic stroke, after having
excluded intracerebral haemorrhage and other brain
disorders on imaging that might account for the
symptoms. Two reviewers independently assessed study
quality, applied the inclusion criteria, extracted the data,
and resolved discrepancies by discussion or asking the trial
investigators. We excluded trials that did not provide
relevant clinical outcomes or in which the latest follow-up
was less than 1 month after treatment. We aimed to use
intention-to-treat data, sought additional unpublished data
when necessary, and verified the extracted data with the
principal investigators of the trials when possible, avoiding
double counting of data when multiple publications arose
from the same trial.
We extracted data using a standard form for trial
characteristics including inclusion and exclusion criteria;
method of randomisation; latest time to treatment; rt-PA
dose and administration; other medical treatments;
methods and timing of follow-up assessments; and the
demographic details of patients. We extracted data for
the number of patients allocated rt-PA or control with
key early or late outcomes (detailed below) including
the numbers within prespecified categories of modified
Rankin Scale (mRS) score, Oxford Handicap Score
(OHS, a further modification of the mRS), or equivalent
by the end of follow-up. We treated mRS and OHS
scale points as being equivalent and translated Barthel
Index scores to mRS: Barthel scores greater than
60 are equivalent to mRS 0–2 and Barthel scores greater
than 90 are equivalent to mRS 0–1.8 We sought to extract
data for outcomes in key subgroups defined by delays to
treatment (0–3 h, 3–6 h); age (up to and including
80 years or >80 years); presence or absence of visible
infarction on imaging; baseline stroke severity; and
different antithrombotic regimens. Tabulations of IST-3
data were provided by the trial statistician.

Trials Events/patients Odds ratio (95% CI) Heterogeneity

rt-PA Control

Death
All trials before IST-3 7 87/1292 67/1208 1·23 (0·88–1·71)
χ21=1·44
IST-3 1 163/1515 107/1520 1·58 (1·23–2·03) (p=0·2)
All trials 8 250/2807 174/2728 1·44 (1·18–1·76)
p=0·0003
Fatal intracranial haemorrhage
All trials before IST-3 7 65/1844 14/1804 3·70 (2·36–5·79)
IST-3 1 55/1515 7/1520 4·87 (2·95–8·06) χ21=0·64
(p=0·4)
All trials 8 120/3359 21/3324 4·18 (2·99–5·84)
p<0·0001
Deaths (excluding fatal intracranial haemorrhage)
All trials before IST-3 4 33/1154 50/1114 0·63 (0·41–0·98)
χ21=4·23
IST-3 1 108/1515 100/1520 1·09 (0·82–1·44) (p=0·04)
All trials 5 141/2669 150/2634 0·93 (0·73–1·18)
p=0·54
Symptomatic intracranial haemorrhage
All trials before IST-3 11 168/2033 47/1944 3·28 (2·48–4·33)
χ21=2·13
IST-3 1 104/1515 16/1519 4·61 (3·20–6·65)
(p=0·1)
All trials 12 272/3548 63/3463 3·72 (2·98–4·64)
p<0·0001
Symptomatic oedema
All trials before IST-3 5 237/1475 268/1451 0·78 (0·62–1·00)
χ21=10·29
IST-3 1 68/1515 42/1520 1·64 (1·12–2·40)
(p=0·001)
All trials 6 305/2990 310/2971 0·97 (0·79–1·19)
p=0·75

0·1 0·5 1·0 5·0 10·0

Thrombolysis decreases Thrombolysis increases

Figure 1: Effects of rt-PA on early outcomes (7 days)

Data are numbers, unless otherwise indicated. Degrees of freedom is 1. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen
activator. IST-3=Third International Stroke Trial.

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We assessed early outcomes (within 7 days) including trials. Most trials included patients with different stroke
death from any cause; fatal intracranial haemorrhage severities and aetiological subtypes (eg, lacunar in
(death attributed to intracranial haemorrhage identified NINDS and IST-3), although the results were not
on scanning or at post mortem); death not attributable reported by subtype in most trials. Centralised random-
to intracranial haemorrhage; symptomatic intracranial isation, by telephone or through a secure webserver to
haemorrhage (as defined in individual trials, but usually ensure allocation concealment, was used in two trials.7,21
as worsening of neurological status contemporaneous The total rt-PA dose was about 0·6 mg/kg13,14 to
with the appearance of new haemorrhage on brain 1·1 mg/kg.2 An identical-looking placebo was used in all
imaging that was sufficient to cause neurological deteri- except two trials.19,21 Final follow-up was at 1 month in two
oration); and symptomatic infarct swelling (worsening of trials,13,14 6 months in the IST-3 trial, and 3 months in the
neurological status contemporaneous with major infarct other trials. In four trials, follow-up had to be done by a
swelling on imaging). We assessed outcomes at the end masked clinician who was not involved in the initial care
of follow-up including death between 7 days and the end of the patient;1,7,16–18 mostly postal or masked telephone
of follow-up; total number of deaths from all causes; alive follow-up was used in IST-3; follow-up masking was not
and favourable outcome (defined as mRS or OHS 0–1); specified in the remaining trials. Functional outcomes
alive and independent (defined as mRS or OHS 0–2); were not available for two trials.14,15 All trials included
and dependency (defined as mRS or OHS 3–5). patients who were taking aspirin before the stroke;
Statistical analyses were all prespecified in the review
protocol.9 The primary analysis was for all patients Effect per Heterogeneity
treated up to 6 h after stroke. We also assessed the effect 1000 patients
treated (95% CI)
of rt-PA given within 3 h and between 3–6 h of the stroke,
and in patients aged up to 80 years versus those older χ² Df p value
than 80 years; for analyses subdivided by time to Events within 7 days, treatment up to 6 h after stroke
treatment we have used time to randomisation in IST-3 Death (total) 25 (11 to 39) 7·34 7 0·39
because this provides an unbiased estimate of time to Fatal intracranial haemorrhage 29 (23 to 36) 6·29 7 0·51
treatment, which is applicable to patients allocated rt-PA Death (not due to intracranial haemorrhage) –4 (–16 to 8)* 5·73 4 0·22
and open control. We calculated odds ratios (ORs) and Symptomatic intracranial haemorrhage 58 (49 to 68) 15·24 11 0·17
95% CI for each outcome, unadjusted for baseline Symptomatic oedema –2 (–18 to 13)* 17·47 5 0·004
variables, using standard fixed-effects methods,12 and Events by end of follow-up, treatment up to 6 h after stroke
calculated statistical heterogeneity using the χ² statistic, Deaths between 7 days and end of follow–up –22 (–39 to –4) 4·88 5 0·43
mentioned when significant heterogeneity was present. Deaths by end of follow–up 7 (–11 to 25)* 17·70 11 0·09
We provided data for the comparison of the overall Alive and independent (mRS 0–2) 42 (19 to 66) 17·06 9 0·05
estimate from the 11 previous trials with IST-3 and with Alive and favourable outcome (mRS 0–1) 55 (33 to 77) 21·12 9 0·01
the updated overall estimate of effect. We calculated the Dependent (mRS 3–5) –50 (–73 to –27)* 19·08 9 0·02
absolute effects per 1000 patients treated. The figures Outcome by time to treatment
were prepared in R (version 2.11.1). Alive, favourable outcome (mRS 0–1), <3 h 87 (46 to 128) 7·90 5 0·16
Alive and independent (mRS 0–2), <3 h 90 (46 to 135) 1·87 5 0·87
Role of the funding source Alive and independent (mRS 0–2), 3–6 h 18 (–10 to 45)* 9·86 6 0·13
The sponsors and funding agencies were not involved in Dead by end of follow-up, <3 h –15 (–55 to 25)* 8·26 6 0·22
the design or execution of the review or interpretation
Dead by end of follow-up, 3–6 h 18 (–3 to 39)* 10·68 6 0·10
of the data. No drug manufacturing company was
Symptomatic intracranial haemorrhage, <3 h 68 (49 to 87) 3·12 5 0·68
involved in the study design, data collection, analysis,
Symptomatic intracranial haemorrhage, 3–6 h 58 (46 to 70) 3·55 6 0·74
and interpretation, writing of the report, or decision to
Outcome by age and time to treatment
submit this report for publication. All authors saw and
Treatment up to 6 h after stroke
approved the final version of the report. The
Alive and independent (mRS 0–2), ≤80 years 43 (16 to 70) 19·22 9 0·02
corresponding author had full access to all the data in the
Alive and independent (mRS 0–2), >80 years 38 (–3 to 79) 2·14 2 0·34
study and had final responsibility for the decision to
Treatment up to 3 h
submit for publication.
Alive and independent (mRS 0–2), ≤80 years 95 (35 to 155) 3·64 5 0·60
Alive and independent (mRS 0–2), >80 years 96 (35 to 157) 0·67 1 0·41
Results
12 trials of intravenous rt-PA versus control, with Treatment between 3–6 h

7012 patients (appendix p 4), were included in this Alive and independent (mRS 0–2), ≤80 years 23 (–8 to 54) 8·91 6 0·18

systematic review and meta-analysis.1–3,7,13–21 Key meth-
odological characteristics are identified in table 1 and
further details are reported elsewhere.9,21 Most data
(5276 patients [75%]) were from trials that were done in
Europe. We judged the risk of bias to be low across all
Alive and independent (mRS 0–2), >80 years –5 (–61 to 50) 0 1 0·95
rt-PA=recombinant tissue plasminogen activator. Df=degrees of freedom. mRS=modified Rankin Scale. *A minus
indicates fewer events per 1000 patients treated with rt-PA.
Table 2: Absolute effects of rt-PA per 1000 patients treated and between trial heterogeneity, all outcomes

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subcutaneous heparin was allowed within 24 h of rt-PA
in three trials;2,3,7 and antithrombotic drugs were not
allowed until 24 h after rt-PA in the other trials. Data for
all outcomes were not provided in all trials but all
available data were used.
The effects of rt-PA on the early outcomes are shown in
figure 1 and the absolute event rates per 1000 patients
treated with estimates of heterogeneity are provided in
table 2. Data for deaths within 7 days, available from eight
trials,2,3,7,13,15,19–21 showed that 8·9% of patients allocated
rt-PA and 6·4% allocated control died within 7 days
(figure 1), an absolute increase of 25 deaths per
1000 individuals treated (table 2).
Data for fatal intracranial haemorrhage within 7 days,
available from eight trials,1–3,7,15–18,21 showed that 3·6%
of patients allocated rt-PA and 0·6% of those allocated the
control died from intracranial haemorrhage (figure 1), an
absolute increase of 29 deaths per 1000 patients.
There was no evidence that rt-PA increased the
number of deaths within 7 days from causes other than
intracranial haemorrhage (figure 1), implying that the
excess of early deaths with rt-PA is mostly from fatal
intracranial haemorrhage, although it should be noted
that data were only available from five trials.2,3,7,15,21
Although no between-trial heterogeneity was noted
(table 2), there was marginal heterogeneity between pre-
vious trials as a group and IST-3 (p=0·04; figure 1).
Data for symptomatic intracranial haemorrhage within
7 days, available from all 12 trials, showed that 7·7% of
patients allocated rt-PA and 1·8% allocated control
developed this haemorrhage (figure 1; appendix p 5).
The crude estimate of the absolute excess of symptom-
atic intracranial haemorrhage with rt-PA was 58 per
1000 patients treated (table 2).
Data for symptomatic infarct swelling within 7 days
was available from six trials;1–3,7,17,18,21 10·2% allocated rt-PA
and 10·4% allocated control developed infarct swelling
(figure 1), with substantial between-trial heterogeneity
(table 2) mostly due to differences between IST-3 and
previous trials (p=0·001 figure 1).
The effects on outcomes at final follow-up are shown in
figure 2 and the absolute event rates in table 2. Data for
deaths between 7 days and the end of follow-up, available
from eight trials,2,3,7,13,15,19–21 showed that 11·5% of patients
allocated rt-PA and 13·6% allocated control died in this
period (figure 2), a reduction of 22 deaths per
1000 individuals treated with rt-PA (table 2).
Data for total number of deaths from all causes by the
end of follow-up, available from all 12 trials, showed that
19·1% allocated rt-PA and 18·5% allocated control died
(figure 2; appendix p 5), equivalent to a non-significant
increase in deaths of seven per 1000 patients treated
with rt-PA.
Data for patients who were alive and indepen-
dent (mRS 0–2) were available from ten trials
(appendix p 6).1–3,7,13,16–21 46·3% of patients allocated rt-PA
and 42·1% allocated control were alive and independent
(mRS 0–2) at the end of follow-up (figure 2), an absolute
increase of 42 per 1000 people treated with rt-PA
(table 2).

Trials Events/patients Odds ratio (95% CI) Heterogeneity

rt-PA Control

All deaths between 7 days and final follow-up

All trials before IST-3 7 78/1292 72/1208 1·04 (0·75–1·45)
χ21=2·11
IST-3 1 245/1515 300/1520 0·79 (0·65–0·95) (p=0·1)
All trials 8 323/2807 372/2728 0·84 (0·71–0·99)
p=0·03
All deaths
All trials before IST-3 11 271/2033 233/1944 1·14 (0·95–1·38)
χ21=1·00
IST-3 1 408/1515 407/1520 1·01 (0·86–1·18)
(p=0·3)
All trials 12 679/3548 640/3464 1·06 (0·94–1·20)
p=0·33
Alive and independent (mRS 0–2) dd
All trials before IST-3 9 1057/1968 900/1884 1·27 (1·12–1·45)
χ21=3·08
IST-3 1 554/1515 534/1520 1·06 (0·92–1·23)
(p=0·08)
All trials 10 1611/3483 1434/3404 1·17 (1·06–1·29)
p=0·001
Favourable outcome (mRS 0–1)
All trials before IST-3 9 848/1968 678/1884 1·35 (1·19–1·55)
χ21=1·18
IST-3 1 363/1515 320/1520 1·18 (1·00–1·40)
(p=0·3)
All trials 10 1211/3483 998/3404 1·29 (1·16–1·43)
p<0·0001

0·5 1·0 2·0

Thrombolysis decreases Thrombolysis increases

Figure 2: Effects of rt-PA on outcomes at final follow-up

Data are numbers, unless otherwise indicated. Treatment was administered up to 6 h after the stroke. rt-PA=recombinant tissue plasminogen activator. IST-3=Third
International Stroke Trial. mRS=modified Rankin Scale.

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Data for patients who were alive with favourable
outcome (mRS 0–1) were available in the same ten trials
(appendix p 6). 34·8% of patients allocated rt-PA and
29·3% allocated control had mRS 0–1 at the end of
follow-up (figure 2), equivalent to 55 more patients alive
and almost symptom free per 1000 treated (table 2).
Heterogeneity was noted between all trials (table 2)
but not between previous trials combined and IST-3
(figure 2).
Data for patients treated within 3 h and between 3–6 h
after stroke were available for three key outcomes
(figure 3, table 2). Among patients treated within 3 h of
stroke, using a cutoff of mRS 0–1 (six trials1–3,16,18,21),
283 (31·6%) of 896 allocated rt-PA and 202 (22·9%) of
883 allocated control achieved a favourable outcome
(OR 1·61, 95% CI 1·30–1·99, p<0·0001), an absolute
increase of 87 per 1000 individuals given rt-PA. Among
patients treated within 3 h of stroke (six trials1–3,16,18,21),
40·7% allocated rt-PA and 31·7% allocated control
achieved mRS 0–2 (figure 3), an absolute increase of
90 per 1000 patients treated (table 2). Of the patients
treated between 3–6 h after stroke (seven trials2,3,7,16,17,20,21),
47·5% allocated rt-PA and 45·7% allocated control
achieved mRS 0–2 (figure 2), an absolute increase of
18 per 1000 patients treated. The difference in ORs
between the subgroups treated within 3 h and between
3–6 h was significant (χ²=9·49, 2 degrees of freedom (df),
p=0·002). There were slightly fewer deaths by the end of
follow-up in people treated within 3 h (seven trials;1–3,15,16,18,21
figure 3), equivalent to 15 fewer deaths per 1000 (table 2),
but slightly more deaths in those treated between 3–6 h
(seven trials;2,3,7,16,17,20,21 figure 3), equivalent to an excess of
18 per 1000 individuals who were treated with rt-PA.
However, the difference in ORs between the subgroups
treated within 3 h and between 3–6 h was not significant
(χ²=3·20, df 2, p=0·07). No difference was noted in the

Trials Events/patients Odds ratio (95% CI) Heterogeneity

rt-PA Control

Alive and independent

Treated within 3 h
All trials before IST-3 5 233/465 185/465 1·56 (1·20–2·02)
χ21=0·04
IST-3 1 132/431 95/418 1·50 (1·10–2·03) (p=0·8)
All trials 6 365/896 280/883 1·53 (1·26–1·86)
p<0·0001
Treated between 3–6 h
All trials before IST-3 6 760/1407 694/1380 1·17 (1·00–1·36)
χ21=2·76
IST-3 1 422/1084 439/1100 0·96 (0·81–1·14) (p=0·10)
All trials 7 1182/2491 1133/2480 1·07 (0·96–1·20)
p=0·24
Death by the end of follow-up
Treated within 3 h
All trials before IST-3 6 83/479 83/478 0·97 (0·69–1·36)
χ21=0·25
IST-3 1 141/431 150/418 0·87 (0·65–1·15) (p=0·6)
All trials 7 224/910 233/896 0·91 (0·73–1·13)
p=0·39
Treated between 3–6 h
All trials before IST-3 6 177/1404 140/1378 1·29 (1·02–1·63)
χ21=1·27
IST-3 1 267/1084 256/1100 1·08 (0·89–1·31)
(p=0·3)
All trials 7 444/2488 396/2478 1·16 (1·00–1·35)
p=0·06
Symptomatic intracranial haemorrhage
Treated within 3 h
All trials before IST-3 5 40/465 7/465 4·28 (2·36–7·77)
χ21=0·09
IST-3 1 32/431 4/418 4·91 (2·52–9·57) (p=0·8)
All trials 6 72/896 11/883 4·55 (2·92–7·09)
p<0·0001
Treated between 3–6 h
All trials before IST-3 6 119/1404 33/1347 3·35 (2·40–4·67)
χ21=1·08
IST-3 1 72/1084 12/1100 4·48 (2·90–6·93)
(p=0·3)
All trials 7 191/2488 45/2447 3·73 (2·86–4·86)
p<0·0001

0·5 1·0 5·0 10·0

Thrombolysis decreases Thrombolysis increases

Figure 3: Effects of rt-PA on alive and independent (mRS 0–2) and death by the end of follow-up and on symptomatic intracranial haemorrhage within the
first 7 days, by time to treatment
Data are numbers, unless otherwise indicated. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial. mRS=modified Rankin Scale.

www.thelancet.com Vol 379 June 23, 2012 2369

 Articles

Trials Events/patients Odds ratio (95% CI) Heterogeneity

rt-PA Control

Treated up to 6 h
≤80 years 10 1372/2612 1237/2562 1·16 (1·04–1·29)
χ21=0·42
>80 years 3 237/870 197/841 1·22 (0·98–1·53)
(p=0·5)
All trials 10 1609/3482 1434/3403 1·18 (1·07–1·30)
p=0·001
Treated up to 3 h
≤80 years 6 254/512 211/526 1·51 (1·18–1·93)
>80 years 2 111/384 69/357 1·68 (1·20–2·34) χ21=0·67
(p=0·4)
All trials 6 365/896 280/883 1·56 (1·28–1·90)
p<0·0001
Treated between 3–6 h
≤80 years 7 1054/2004 1005/1997 1·09 (0·96–1·24)
>80 years 2 126/486 128/484 0·97 (0·73–1·30) χ21=0·53
All trials 7 1180/2490 1133/2481 1·07 (0·96–1·21) (p=0·5)
p=0·23

0·5 1·0 2·5

Thrombolysis decreases Thrombolysis increases

Figure 4: Effect of rt-PA on alive and independent at the end of follow-up, subgrouped by age and time to treatment
Data are numbers, unless otherwise indicated. rt-PA=recombinant tissue plasminogen activator. IST-3=Third International Stroke Trial.

summary ORs for symptomatic intracranial haemor-
rhage for those treated within 3 h (six trials;1–3,16,18,21
figure 3), equivalent to 68 more such haemorrhages per
1000 treated individuals (table 2), and for those treated
between 3–6 h (seven trials;2,3,7,16,17,20,21 figure 3), equivalent
to 58 more per 1000 treated patients (table 2; test for
difference between subgroups χ²=0·57, df 2, p=0·45).
The results were the same when the analysis was
restricted to the trials of treatment in both time windows
(data not shown). No heterogeneity was noted between
trials, or between previous trials combined and IST-3, for
any of the outcomes within 3 h and between 3–6 h.
Three trials included a total of 1711 patients older than
80 years (25 from EPITHET, 69 from NINDS, the rest
from IST-3).1,20,21 Among patients older than 80 years who
were treated within 6 h, 27·2% allocated rt-PA and 23·4%
allocated control were mRS 0–2 (p=0·07; figure 4), an
increase of 38 per 1000 individuals were alive and
independent (table 2). Among patients aged 80 years and
younger, 52·5% allocated rt-PA and 48·3% allocated
control were alive and independent (mRS 0–2) at the end
of follow-up (p=0·009), an increase of 43 per 1000 people
(table 2). For patients older than 80 years treated within
3 h, 28·9% allocated rt-PA and 19·3% allocated control
were alive and independent (figure 4; p=0·003), an
increase of 96 per 1000 people (table 2). Among those
80 years and younger treated within 3 h, 49·6% allocated
rt-PA and 40·1% allocated control were alive and
independent (figure 4; p=0·001), an increase of 95 per
1000 people (table 2). Among people treated between
3–6 h after stroke, of those aged 80 years and younger
52·6% allocated rt-PA and 50·3% allocated control
achieved mRS 0–2 at the end of follow-up compared with
25·9% allocated rt-PA and 26·4% allocated control who
were older than 80 years (figure 4).
Tabular data were too few to provide reliable evidence
about the effects of antithrombotic drugs in addition to
rt-PA, and were not available to assess the effect of
presence or absence of visible infarction on imaging or
by baseline stroke severity on main outcomes.
Discussion
The data reported in this systematic review and meta-
analysis for 7012 patients showed that for every
1000 patients allocated intravenous rt-PA up to 6 h after
stroke, 42 more patients were alive and independent
(mRS 0–2); 55 more were alive with a favourable
outcome (mRS 0–1) at the end of follow-up. This benefit
occurred despite an increase in the number of early
symptomatic intracranial haemorrhages and early
deaths. These early hazards were offset by a reduction
in the number of deaths between 7 days and the end of
follow-up, and so, by the end of follow-up, no effect on
deaths from all causes was apparent, and the number
who were dependent (mRS 3–5) was reduced. Earlier
treatment is better, leading to an increase in the number
of patients who were alive with favourable outcomes
(mRS 0–1) and alive and independent (mRS 0–2) with
treatment within 3 h of stroke. Among the 1711 patients
older than 80 years, the absolute benefits from rt-PA
were at least as large as for the younger patients,
especially with early treatment.
Do the effects of rt-PA in the 3035 patients in IST-3
(95% of whom did not meet contemporaneous
European licence criteria) differ materially from the
effects in the 3977 patients from 11 previous trials (who
largely did meet these criteria)? The characteristics of
patients in IST-3 that excluded them from the licence
criteria were chiefly age and time: 53% were older than
80 years, 72% were treated more than 3 h after stroke

2370 www.thelancet.com Vol 379 June 23, 2012


onset. A large proportion had severe strokes and
146 (5%) had National Institutes of Health Stroke Scale
greater than 25, hence the fairly high numbers of deaths
in both the rt-PA and control groups. There was no
evidence to suggest that any of the beneficial or adverse
effects of rt-PA were qualitatively different in these
outside-licence patients from individuals in earlier
trials, except for non-intracranial-haemorrhage early
deaths and symptomatic infarct swelling. The propor-
tion of patients with symptomatic infarct swelling in
IST-3 (3·6%) was less than that of previous trials
(17·3%) but the results of IST-3 showed an increase in
symptomatic infarct swelling with rt-PA, whereas those
of previous trials had suggested a reduction (p=0·06).
These differences could be attributable to several
factors: the analysis of symptomatic oedema and its
definition were prespecified in IST-3 but not in five of
11 previous trials that provided relevant data; patients in
IST-3 were older, had more severe strokes (hence larger
infarcts), and were treated later than in previous trials.
These and other possibly aggregate characteristics
could have changed the effect of rt-PA on symptomatic
infarct swelling and in turn the effect on non-
intracranial-haemorrhage early deaths; these points
merit further analysis.
The updated review provides additional insights. First,
the finding that fewer deaths occurred with rt-PA
between 7 days and late follow-up in IST-3 confirms a
pattern suspected in previous trials, and indicates that
the excess hazard with rt-PA is largely attributable to
symptomatic intracranial haemorrhage and occurs early,
so that patients who survive the acute phase without
intracranial haemorrhage benefit. One explanation for
this might be that more disabled stroke survivors have
an ongoing higher risk of death;22 rt-PA, by shifting the
balance towards better functional outcome, reduces the
risk of death in the long term. The longer follow-up in
IST-3 (6 months vs 3 months in previous trials), might
have allowed this net balance of early hazard versus later
benefit to emerge more clearly. Second, the benefits of
rt-PA occur in severe and milder strokes. Third, as
suggested by the results of non-randomised studies,23,24
the relative and absolute benefits of rt-PA are at least as
large in older as in younger people (figure 4, table 2).
Fourth, the new data reinforce the evidence that benefit
is greatest when rt-PA is given within 3 h. Therefore,
efforts to reduce treatment delays should continue,
particularly for older people.
The latest time window for benefit remains unclear.
Although benefit from thrombolysis clearly declines with
increasing delay to treatment,8 these data suggest that
benefit probably extends beyond 4·5 h, possibly as late as
6 h in some patients, though the time probably varies
with key individual or combined patients’ characteristics,
which were not possible to identify with just summary
unadjusted data. Patients presenting later are different
(eg, less severe stroke) than those presenting earlier. The
www.thelancet.com Vol 379 June 23, 2012
Articles
lower benefit with later treatment is not due to more
symptomatic intracranial haemorrhage because the odds
of this haemorrhage with rt-PA are actually slightly lower
in patients treated between 3–6 h than within 3 h
(figure 3, table 2). Thus, non-significantly more deaths
and the reduction in the OR for alive and independent at
the end of follow-up for treatment between 3–6 h might
indicate less benefit with later treatment—ie, less tissue
to salvage, rather than simply more hazard.
An analysis of individual patient data from all 12 trials is
essential to find out the effect of rt-PA in patients with
different severities and subtypes of stroke (particularly
lacunar stroke), by appearance of the ischaemic lesion
or rest of the brain on imaging, in key subgroups of
patients—eg, those in atrial fibrillation, on aspirin
before stroke, with high blood pressure or diabetes—with
narrow time windows and functional outcome strata, and
by different doses of rt-PA, and to define the latest time for
benefit. Identifying how to avoid symptomatic intra-
cranial haemorrhage is critical, because it is the single
largest hazard. Ongoing trials, Thrombolysis in Elderly
Stroke Patients in Italy (TESPI),25 Enhanced Control
of Hypertension and Thrombolysis Stroke Study
(ENCHANTED), or EXtending the time for Thrombolysis
in Emergency Neurological Deficits (EXTEND26) are
addressing treatment in the elderly or at later times and
ways to reduce the risk of haemorrhage—eg, whether a
lower dose of rt-PA or blood pressure lowering can reduce
symptomatic intracranial haemorrhage. Trials to invest-
igate alternative doses, routes of thrombolytic drug admin-
istration, different thrombolytic drugs, and mechanical
thrombectomy and advanced imaging could help identify
patients for whom these alternative therapies might be
more effective than is intravenous rt-PA. Information
about the effect of thrombolysis on long-term survival free
of dependence is sparse (with NINDS1 being the only trial
so far in which outcomes at 12 months have been reported;
for IST-3 the intention is to report functional outcome up
to 18 months and overall survival thereafter21) but this
study will be important for understanding the true health
economic effect of thrombolytic treatment. If small gains
in functional ability by 3–6 months translate into greater
long-term survival free of disability,22 this is likely to
reduce health-care costs and increase quality of life and
cost-effectiveness.
Contributors
JMW wrote the protocol, undertook the searching, data extraction, and
verification, sought additional information and verified information with
trialists, analysed, drafted, and edited the report for the first published
version and all the subsequent updates. VM and EB undertook searching,
trial evaluation, data extraction, and verification in previous updates. GC
provided data from IST-3. VM, EB, GdZ, PS, RIL, and GC did the data
verification in this update and edited the report. All authors approved the
report for submission.
Conflicts of interest
JMW, VM, EB, PS, RIL, and GC are all investigators in the IST-3 trial.
JMW was a member of the expert neuroradiological adjudication
committee for IST-3 and ECASS 3. GdZ was on the data and safety
monitoring committees of the ECASS and ECASS II trials funded by
2371
 Articles
Boehringer Ingelheim. JMW has received reimbursement for expenses for
speaking at and attending meetings arranged by Boehringer Ingelheim, is
not or has not been on any industry expert panels but did provide
independent information to Boehringer Ingelheim to assist with the
European license application for rt-PA. RIL has received payment in his
role as conference Scientific Committee member and for occasional
lectures from Boehringer Ingelheim; he has attended national stroke
meetings that were organised and funded by Boehringer Ingelheim; and
he is not a member of any industry advisory boards. EB and PS have
received payment for lectures at meetings arranged by Boehringer
Ingelheim, and reimbursement for costs for attending these meetings.
Acknowledgments
UK Medical Research Council, Stroke Association, University of
Edinburgh, National Health Service Health Technology Assessment
Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm
(Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute,
Marianne and Marcus Wallenberg Foundation, Research Council of
Norway, Oslo University Hospital funded this study. The authors of the
Cochrane Review have not received financial support from any
pharmaceutical company to undertake the review. We are extremely
grateful to Lisa Blackwell, Clinical Trial Service Unit, Oxford, for
preparing all the figures and Colin Baigent for very helpful comments
during the preparation of this and the previous version of the Cochrane
Review. We also thank Charles Warlow and Martin Dennis for helpful
comments. We sincerely thank the principal investigators of previous
trials for additional data during previous updates of the Cochrane Review
and Steve Davis for data for patients older than 80 years in this update.
We also thank the IST-3 Trial Steering Committee including the national
coordinators and the data monitoring committee who commented on the
draft report (details in reference 22).
References
1 The National Institute of Neurological Disorders and Stroke (NINDS)
rt-PA Stroke Study Group. Tissue plasminogen activator for acute
ischaemic stroke. N Engl J Med 1995; 333: 1581–87.
2 Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with
recombinant tissue plasminogen activator for acute hemispheric
stroke. The European Cooperative Acute Stroke Study (ECASS).
JAMA 1995; 274: 1017–25.
3 Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind
placebo-controlled trial of thrombolytic therapy with intravenous
alteplase in acute ischaemic stroke (ECASS II). Lancet 1998;
352: 1245–51.
4 Wardlaw JM, Sandercock PAG, Berge E. Thrombolytic therapy with
recombinant tissue plasminogen activator for acute ischemic stroke.
Where do we go from here? A cumulative meta-analysis. Stroke 2003;
34: 1437–42.
5 Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for
acute ischaemic stroke. Cochrane Database Syst Rev 2003; CD000213.
6 Hacke W, Donnan G, Fieschi C, et al. Association of outcome with
early stroke treatment: pooled analysis of ATLANTIS, ECASS, and
NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74.
7 Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase
3 to 4·5 hours after acute ischemic stroke. N Engl J Med 2008;
359: 1317–29.
8 Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with
intravenous alteplase and outcome in stroke: an updated pooled
analysis of ECASS, ATLANTIS, NINDS and EPITHET trials. Lancet
2010; 375: 1695–703.
9 Wardlaw JM, Murray VE, Berge E, del Zoppo GJ. Thrombolysis
in acute ischaemic stroke. Cochrane Database Syst Rev 2009;
4: CD000213.
10 Wardlaw JM, Sandercock PA, Murray V. Should more patients with
acute ischaemic stroke receive thrombolytic treatment? BMJ 2009;
339: b4584.
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11 Wardlaw JM, Warlow CP. Thrombolysis in acute ischaemic stroke:
does it work? Stroke 1992; 23: 1826–39.
12 Antiplatelet Trialists’ Collaboration. Collaborative overview of
randomised trials of antiplatelet therapy— I: Prevention of death,
myocardial infarction, and stroke by prolonged antiplatelet therapy
in various categories of patients. Antiplatelet Trialists’ Collaboration.
BMJ 1994; 308: 81–106.
13 Mori E, Yoneda Y, Tabuchi M, et al. Intravenous recombinant tissue
plasminogen activator in acute carotid artery territory stroke.
Neurology 1992; 42: 976–82.
14 Yamaguchi T, Hayakawa T, Kiuchi H, for the Japanese Thrombolysis
Study Group. Intravenous tissue plasminogen activator ameliorates
the outcome of hyperacute embolic stroke. Cerebrovasc Dis 1993;
3: 269–72.
15 Haley EC Jr, Brott TG, Sheppard GL, et al. Pilot randomized trial of
tissue plasminogen activator in acute ischemic stroke. The TPA
Bridging Study Group. Stroke 1993; 24: 1000–04.
16 Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase)
0– to 6–hour acute stroke trial, part A (A0276g): results of a
double-blind, placebo-controlled, multicenter study. Thrombolytic
therapy in acute ischemic stroke study investigators. Stroke 2000;
31: 811–16.
17 Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP,
Hamilton S. Recombinant tissue-type plasminogen activator
(Alteplase) for ischemic stroke 3 to 5 hours after symptom onset.
The ATLANTIS Study: a randomized controlled trial. Alteplase
Thrombolysis for Acute Noninterventional Therapy in Ischemic
Stroke. JAMA 1999; 282: 2019–26.
18 Albers GW, Clark WM, Madden KP, Hamilton SA. ATLANTIS trial:
results for patients treated within 3 hours of stroke onset. Alteplase
Thrombolysis for Acute Noninterventional Therapy in Ischemic
Stroke. Stroke 2002; 33: 493–95.
19 Wang SY, Wang XL, Zeng H, et al. Early intravenous thrombolysis
with recombinant tissue plasminogen activator for acute cerebral
infarction. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2003; 15: 542–45.
20 Davis SM, Donnan G, Parsons MW, et al. Effects of alteplase beyond
3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation
Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol
2008; 7: 299–309.
21 The IST-3 collaborative group. The benefits and harms of intravenous
thrombolysis with recombinant tissue plasminogen activator within
6 h of acute ischaemic stroke (the third international stroke trial
[IST-3]): a randomised controlled trial. Lancet 2012; published online
May 23. DOI:10.1016/S0140-6736(12)60768-5.
22 Bruins Slot K, Berge E, Dorman P, et al. Impact of functional status
at six months on long term survival in patients with ischaemic stroke:
prospective cohort studies. BMJ 2008; 336: 376–79.
23 Mishra NK, Ahmed N, Andersen G, et al. Thrombolysis in very
elderly people: controlled comparison of SITS International Stroke
Thrombolysis Registry and Virtual International Stroke Trials
Archive. BMJ 2010; 341: c6046.
24 Bhatnagar P, Sinha D, Parker RA, Guyler P, O’Brien A. Intravenous
thrombolysis in acute ischaemic stroke: a systematic review and
meta-analysis to aid decision making in patients over 80 years of age.
J Neurol Neurosurg Psychiatry 2011; 82: 712–17.
25 Lorenzano S, Toni D, for the TESPI trial Investigators. TESPI
(Thrombolysis in Elderly Stroke Patients in Italy): a randomized
controlled trial of alteplase (rt-PA) versus standard treatment in acute
ischaemic stroke in patients aged more than 80 years where
thrombolysis is initiated within three hours after stroke onset.
Int J Stroke 2012; 7: 250–57.
26 Ma H, Parsons MW, Christensen S, et al. A multicentre, randomized,
double-blinded, placebo-controlled Phase III study to investigate
EXtending the time for Thrombolysis in Emergency Neurological
Deficits (EXTEND). Int J Stroke 2012; 7: 74–80.
www.thelancet.com Vol 379 June 23, 2012
Supplementary appendix
This appendix formed part of the original submission and has been peer reviewed.
We post it as supplied by the authors.
Supplement to: Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen
activator for acute ischaemic stroke: an updated systematic review and meta-analysis.
Lancet 2012; published online May 23. DOI:10.1016/S0140-6736(12)60738-7.
Web Appendices

Web Appendix: Search strategy

Web figure 1: PRISMA diagram

Web figure 2: Effect of rt-PA on SICH within 7 days, by trial. Treatment up to six
hours
Web-figure 3: Effects on all deaths by the end of follow-up, by trial. Treatment up to
six hours
Web-figure 4: Effects on Alive and Independent (mRS 0-2) at the end of follow-up,
by trial. Treatment up to six hours.
Web-figure 5: Effects on favourable outcome (mRS 0-1) at the end of follow-up, by
trial, treatment up to six hours.

1
Web Appendix 1, Search Strategy
Search included: Cochrane Stroke Trials Registry to November 2011
Internet Stroke Trials Centre: in March 2011
References in Review Articles, Conference abstracts
Full details of historical searches are in The Cochrane Library

MEDLINE 1966 to March 2012 (similar search run in EMBASE)

1 Cerebrovascular disorders/
2 exp Brain ischemia/
3 Carotid artery diseases/ or Carotid artery thrombosis/
4 stroke/ or exp brain infarction/
5 exp Hypoxia-ischemia, brain/
6 Cerebral arterial diseases/ or Intracranial arterial diseases/
7 exp "Intracranial embolism and thrombosis"/
8 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or transient isch?emic
attack$ or tia$).tw.
9 (brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or
intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior
circulation).tw.
10 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$).tw.
11 9 and 10
12 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 11
13 Thrombolytic therapy/
14 Fibrinolysis/
15 exp plasminogen activators/
16 Fibrinolytic agents/ or Plasmin/ or Plasminogen/
17 (thromboly$ or fibrinoly$ or clot lysis).tw.
18 (plasminogen or plasmin or tPA or t-PA or rtPA or rt-PA).tw.
19 (anistreplase or streptodornase or streptokinase or urokinase or pro?urokinase or
rpro?uk or lumbrokinase or duteplase or lanoteplase or pamiteplase or reteplase or
saruplase or staphylokinase or streptase or alteplase).tw.
20 exp "intracranial embolism and thrombosis"/dt or Thromboembolism/dt
21 Thrombosis/dt [Drug Therapy]
22 or/13-21
23 12 and 22
24 randomized controlled trial.pt.
25 randomized controlled trials/
26 controlled clinical trial.pt.
27 controlled clinical trials/
28 random allocation/
29 double-blind method/
30 single-blind method/
31 clinical trial.pt.
32 exp clinical trials/
33 (clin$ adj25 trial$).tw.
34 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.
35 placebos/
36 placebo$.tw.
37 random$.tw.
38 research design/

2
39 clinical trial phase ii.pt.
40 clinical trial phase iii.pt.
41 clinical trial phase iv.pt.
42 multicenter study.pt.
43 intervention studies/
44 control$.tw.
45 latin square.tw.
46 "comparative study"/
47 exp evaluation studies/
48 Follow-up studies/
49 Prospective studies/
50 prospective.tw.
51 (versus or allocat$).tw.
52 experimental group$.tw.
53 or/24-52
54 23 and 53
55 limit 54 to human

3
Web figure 1: PRISMA diagram
Note the search for randomised trials of thrombolysis versus control has been ongoing
since 1989, repeated every few years and by continuous monitoring of the relevant
literature, conferences, contact with investigators, etc. The following is a distillate of
the most recent searches and does not represent the full search volume back to 1989.
Further details are available in the Cochrane Library.

Records identified through database Additional records identified

searching through other sources
(n = 349) (n = 51)

Duplicates removed
(n = 30)

Records excluded
Records screened (n = 250)
(reviews, not a trial,
(n = 370)
irrelevant, etc)

Full-text articles assessed Full-text articles excluded,

for eligibility Not RCT of rt-PA 40
(n = 120) RCT, confounded 40
Dose comparison only 8
No clinical outcomes 10
Follow-up too short 10
Studies included in
analysis
(n = 12 )

4
Web figure 2

Web figure 3

5
Web figure 4 mRS 0-2

Web figure 5 mRS 0-1

6
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.