Background
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Cover sheet - Background - Methods - Results - Discussion - References - Tables & Graphs
This information is taken from a regularly updated, systematic review prepared and maintained by the Cochrane Collaboration. A substantive amendment to this systematic review was last made on 5 July 1999. The full review is available in The Cochrane Library. See http://www.update-software.com/cochrane.htm for further information.
This review should be cited as : Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software.
Background and objectives:
The majority of strokes are due to blockage of an artery in the
brain by a blood clot. Clot dissolving (or thrombolytic) drugs may reduce brain damage from
the stroke, but may also cause serious bleeding in the brain. Thrombolytic therapy has now
been evaluated in several randomised trials in acute ischaemic stroke. The objective of this
review was to assess the safety and efficacy of thrombolytic agents in patients with acute
ischaemic stroke.
Search strategy:
Cochrane Stroke Review Group search strategy plus ongoing contact with
researchers and pharmaceutical companies. Last search conducted March 1999.
Selection criteria:
Randomised trials of any thrombolytic agent compared with control in
patients with definite ischaemic stroke.
Data collection and analysis:
One reviewer applied the inclusion criteria and extracted the
data. Trial quality was assessed. The extracted data were verified by the principal
investigators of all major trials.
Main results:
Seventeen trials including 5216 patients were included. Fifteen trials were
double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen
activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the
rest used the intravenous route. About 50% of the data come from trials testing intravenous
tissue Plasminogen Activator. Thrombolytic therapy significantly increased the odds of death
within the first ten days (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.48 to 2.32).
The main cause of the increase in deaths was fatal intracranial haemorrhage following
thrombolysis (OR 4.15, 95% CI 2.96 to 5.84). Symptomatic intracranial haemorrhage is also
increased following thrombolysis (OR 3.53, 95% CI 2.79 to 4.45). Thrombolytic therapy also
increased the odds of death at the end of follow-up (OR 1.31, 95% CI 1.13 to 1.52).
Despite this, thrombolytic therapy, administered up to six hours after ischaemic stroke,
significantly reduced the proportion of patients who were dead or dependent (modified
Rankin 3 to 6) at the end of follow-up (OR 0.83, 95% CI 0.73 to 0.94). For patients treated
within three hours of stroke, thrombolytic therapy appeared more effective in reducing death
or dependency (OR 0.58, 95% CI 0.46 to 0.74) with less adverse effect on death (OR 1.11,
95% CI 0.84 to 1.47). There was heterogeneity between the trials that could have been due
to : thrombolytic drug used, variation in the concomitant use of aspirin and heparin, severity of
the stroke, and time to treatment. Trials testing intravenous recombinant tissue Plasminogen
Activator suggest that it may be associated with slightly less hazard and more benefit when
given up to six hours after stroke - death within the first ten days OR 1.24, 95% CI 0.85 to
1.81, death at the end of follow-up OR 1.16, 95% CI 0.94 to 1.44, dead or dependent at the
end of follow-up OR 0.79, 95% CI 0.68 to 0.92. One trial that tested thrombolysis plus
aspirin showed an increase in deaths of patients given both drugs in combination compared
with thrombolysis alone.
Reviewers' conclusions:
Thrombolytic therapy increases deaths within the first seven to ten
days, and deaths at final follow-up. Thrombolytic therapy also significantly increases
symptomatic and fatal intracranial haemorrhage. These risks are offset by a reduction in
disability in survivors, so that there is, overall, a significant net reduction in the proportion of
patients dead or dependent in activities of daily living. The data from trials using intravenous
recombinant tissue Plasminogen Activator, from which there is the most evidence on
thrombolytic therapy so far, suggest that it may be associated with less hazard and more
benefit. There was heterogeneity between the trials and the optimum criteria to identify the
patients most likely to benefit and least likely to be harmed, the agent, dose, and route of
administration, are not clear. The data are promising and may justify the use of thrombolytic
therapy with intravenous recombinant tissue Plasminogen Activator in experienced centres in
selected patients. However, the widespread use of thrombolytic therapy in routine clinical
practice at this time cannot be supported. Further trials will be needed to identify which
patients are most likely to benefit from treatment and the environment in which it may best be
given, before thrombolytic therapy should be adopted on a wider scale.
Background |
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To determine whether (and in what circumstances) thrombolytic therapy might be an effective
and safe treatment for acute ischaemic stroke.
We wished to test three main hypotheses :
1. That thrombolytic therapy
a) increases the risk of death within the first two weeks, and
b) reduces the risk of death at long term follow-up.
2. That thrombolytic therapy increases the risk of early symptomatic or fatal intracranial haemorrhage.
3. That, at long term follow-up, the reduction in the proportion of patients alive but dependent more than offsets any early hazard, so that there is an overall net benefit and a reduction in the proportion with a poor outcome (ie dead or dependent).
4. We wished to undertake exploratory analyses to examine whether:
a) thrombolytic therapy interacts with antithrombotic therapy to increase the hazard;
b) that the balance of risk and benefit with thrombolytic therapy may vary with the severity of the stroke;
c) a therapeutic time window for effective treatment beyond which there is either no net benefit, or unacceptable hazard, could be defined on the available data.
Criteria for considering studies for this review
Trials which included patients of any age or sex with a definite (confirmed by CT scanning
to exclude cerebral haemorrhage prior to randomisation) acute ischaemic stroke were eligible.
Agent and dose : All types of thrombolytic drug : urokinase (UK, also known as u-PA),
recombinant pro-urokinase (rpro-UK), streptokinase (SK), recombinant tissue plasminogen
activator (rt-PA), or lumbrokinase (LK), given in any dose, by the intravenous or
intra-arterial route, were included.
Trials which were confounded by the treatment or control group receiving another active
therapy which had not been factored in to the randomisation (eg thrombolytic drug plus
another agent vs placebo, or thrombolytic drug vs another agent), were excluded.
1. Deaths from all causes within the scheduled treatment period (usually the first seven to
ten days after treatment).
2. Symptomatic intracranial haemorrhage : either symptomatic (ie associated with a
deterioration in the patient's neurological state), or fatal (ie leading directly to death).
Note that "symptomatic intracranial haemorrhage" includes haemorrhagic transformation of the
infarct, haemorrhage elsewhere in the brain, and haemorrhage into the spaces surrounding the
brain.
3. Deaths from all causes during the whole trial follow-up period.
4. "Poor functional outcome" at the end of follow-up. This was defined as death or dependency, measured by the Rankin or Barthel scales, at the end of the trial follow-up period. Poor functional outcome is the most clinically relevant and important measure of outcome since the aim of treatment should be not merely to avoid death but to increase the proportion of independent survivors and conversely reduce the risk of survival with serious disability. Dependency in the present analysis was defined as a score of between three and five inclusive on the Modified Rankin Scale. Some would prefer a definition of "good outcome" (independence) including Rankin zero and one only, therefore wherever possible we sought data on the number of patients in each individual Rankin category.
We sought to identify all truly randomised trials of thrombolytic therapy compared with
placebo or open control in patients with acute ischaemic stroke. Trials which were not truly
random (eg dose range finding studies) were not included. Trials in which the exact method
of randomisation was unknown, even after correspondence with the authors, were included for
the present. Trials which were not originally analysed on an intention-to-treat basis were
included if information on outcome could be obtained on all randomised patients thus allowing
an intention-to-treat analysis to be performed.
Search strategy for identification of studies
See: Colloborative Review Group search strategy
This review has drawn on the search strategy developed for the Stroke Group as a whole. All
possibly relevant trials were identified in the Specialised Register of Controlled Trials (see
Review Group Details for more information). The Register was last searched by the Review Group
Co-ordinator for this review in March 1999 using a search strategy designed to identify all
trials relevant to this review.
In addition, all publications describing (or which might describe) relevant trials were sought through:
1. Embase (Ovid) was searched through the Bath Information Database Service (BIDS) between 1980 and Feb 1997 using the following strategy:
001 exp cerebrovascular disease/
002 stroke$.tw
003 cerebrovasc$.tw
004 1 or 2 or 3
005 urokinase/
006 prourokinase/
007 streptokinase/
008 tissue plasminogen activator/
009 lumbrokinase/
010 thrombol$.tw
011 (urokinase or pro?urokinase or streptokinase).tw
012 (tissue plasminogen activator or lumbrokinase).tw
013 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
014 4 and 13
2. The following journals were hand-searched from 1979 to April 1994: Japanese Journal of
Stroke; Clinical Evaluation; Japanese Journal of Pharmacology & Therapeutics; Rinsho Ketsueki.
Translations of the non-English language publications were obtained from people in whose native language the paper was published.
3. Pharmaceutical companies (n = 321) were contacted for more information about trials
known to exist from the above efforts, and for information on any trials which were so far
unknown to the reviewers (last systematic contact December 1997). All companies except one (who was known to be doing a trial in any case) responded, and no trials were identified that were not already known about.
4. References quoted in thrombolytic therapy papers were examined;
5. Direct contact with principal investigators of trials in Europe, the USA, Japan and China;
6. Attendance at the 1st and 2nd International Conferences on Acute Stroke (Geneva 1991 and 1993), the 2nd to 8th European Stroke Conferences (Lausanne 1992, Stockholm 1994, Bordeaux 1995, Munich 1996, Amsterdam 1997, Edinburgh 1998, Venice 1999), the 2nd, 3rd, 4th and 5th International Symposia on Thrombolysis in Acute Ischaemic Stroke (La Jolla, USA 1992; Nara, Japan 1994; Copenhagen, Denmark 1996, Bethesda Maryland 1998), and the 1st and 3rd Annual Advances in Stroke Management Meetings (Barcelona, March 1995 and Crete, Oct 1998 respectively).
Methods of the review |
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We aimed to extract from each trial the number of patients originally allocated to each treatment group to allow an intention-to-treat analysis, if the trial had not already been presented in this way.
For each included trial we collected information about :
We extracted the number of patients in the treated and control groups who had :
a) died within the first seven to ten days,
b) developed symptomatic or fatal intracranial haemorrhage early after the stroke (within
the first seven to ten days),
c) died by the end of the trial follow up, and
d) were dependent on others in activities of daily living by the end of the trial follow up period.
We also extracted data to allow a number of exploratory subgroup analyses as follows :
e) the proportion of patients given aspirin or heparin within the treatment period,
f) the number of patients who died or were dependent at the end of follow-up according to
whether they had been treated within three hours of the stroke or later than three hours (in
trials which randomised patients beyond three hours after the stroke).
A tabulation of the extracted data was cross-checked and then verified with the principal
investigator or each trial and any errors were corrected. In Haley 1993 and
Morris 1995 , the outcomes were very clearly described in the original texts
and verification with the principal investigators was not necessary. The results of Atlantis
A and B (1999) and PROACT 2 (1999) were obtained from
the presentation at the 21st American Heart Association meeting, Nashville, Tenn. Febuary
1999, and at the 8th European Stroke Conference in Venice, April 1999 and on discussion with
the study investigators. Paper publication is yet to appear, but we did not wish to delay the
release of other important information in this version of the review. Therefore the Atlantis
and PROACT 2 data must be regarded as preliminary, and additionally, data on about
seventy-two patients in Atlantis B were not included in the presentations.
Our definition of symptomatic intracranial haemorrhage included patients who died or
deteriorated clinically as a result of intracranial haemorrhage. This could be either
secondary bleeding into the infarct or new bleeding at an anatomically separate site
elsewhere in the brain or its surrounding spaces after randomisation, confirmed by CT
scanning or post mortem. We have defined "early after the stroke" as within the first seven
to ten days, as the trials each tended to use a slightly different time point, but all had
collected information on intracranial haemorrhage certainly within the first ten days. Many
symptomatic haemorrhages actually occurred within the first few days of the stroke. It is
difficult to estimate the exact number of symptomatic intracranial haemorrhages because some
patients died without a CT scan or post mortem. Thus the true number with symptomatic
intracranial haemorrhage may be higher than that suggested by these data. The ECASS 1995
trial did not report the number with symptomatic ICH, but whether the radiological appearance
of the haemorrhage suggested haemorrhagic transformation of an infarct or parenchymatous
haematoma (and its size). Most parenchymatous haemorrhages were associated with symptoms,
so we used the number of patients with parenchymatous haematoma as the number with
symptomatic haemorrhages.
Both proportional and absolute risk reductions were calculated for each outcome.
Heterogeneity between trial results was tested for using a standard Chi squared test. The
results reported in the text are odds ratios (ie the ratio of the odds of an unfavourable
outcome among treatment-allocated patients to the corresponding odds amongst controls) which
were calculated using the Peto fixed-effects method (APT 1994).
Description of studies
See: Table of included studies, Table of excluded studies
Seventeen trials including 5216 patients are included, though data are not yet available for
the seventy two patients in the ATLANTIS B trial (see the "Included Trials"
table). Note that the NINDS trial (1995) was conducted in two consecutive parts, A
and B, but published in one paper, so is included as one trial in this review.
The trials performed in the 1980s (Ohtomo 1985, Atarashi 1985, Abe 1981) were methodologically
very different to the trials performed in the 1990's (all the rest). The 1980s' trials used
very low doses of thrombolytic drug, given daily intravenously for several days, and started
up to five or fourteen days after the stroke. The 1990s' trials used a single large dose of
thrombolytic drug (in the region of 80 to 100 mg rt-PA or equivalent), given intravenously
in most trials, within three, or at most six, hours of the stroke. The 1980s' trials did not
collect data on functional outcome and therefore only the 1990s' trials contribute to the
analysis of death or dependency. All trials however contribute to analyses of intracranial
haemorrhage and death by the end of follow-up (although very few deaths or intracranial
haemorrhages occurred in the trials in the 1980s).
The MAST-I trial (MAST-I 1995), which tested intravenous streptokinase and oral aspirin given
within six hours of stroke onset, in a two-by-two factorial design, was the only trial so far
to test for an interaction between thrombolytic and antithrombotic drugs in a randomised trial
- the comparison of SK plus aspirin versus aspirin from MAST-I is included in this review
(separated from the MAST-I data in the absence of aspirin) because it represents the only
available randomised evidence on this important interaction. As there was a significant
adverse interaction between SK and aspirin which we felt was important to highlight, the data
for the patients receiving SK in the presence or absence of aspirin are presented separately
(ie SK versus control separate to SK with aspirin versus aspirin).
Methodological quality
See: Table of included studies
Seventeen trials have been included : eight recent trials from 1995 to 1999, seven earlier trials
all using intravenous thrombolytic therapy, and two trials using intra-arterial thrombolytic
therapy. A trial by Naito (Naito 1984) was excluded after discussion with Professor T Abe
(co-investigator) as it was not possible to account for 11/101 randomised patients (most of
whom were in the control group). Another trial (Edinburgh 1991) was excluded because it
stopped prematurely after randomisation of only four patients. Three trials conducted in
China were excluded, two because of confounding (Don-Cai Yuan 1995, Zhang Yuan Xiang 1995)
and one because the duration of follow-up was only three weeks (Pang Shi-Qi 1993).
Types of stroke patient included:
The selection of patients was based initially on clinical criteria to diagnose the stroke sub-type (cortical vs lacunar vs posterior circulation):
- five trials randomised all types of ischaemic stroke (cortical, lacunar and posterior circulation) MAST-I 1995, NINDS 1995, Haley 1993, ATLANTIS A 1999, ATLANTIS B 1999;
- one trial included cortical and lacunar strokes - ASK 1996;
- four trials included only patients with symptoms of hemispheric cortical ischaemia (see below for additional CT scan criteria) - ECASS 1995, ECASS II 1998, MAST-E 1996, Morris 1995;
- four trials included patients with angiographically proven occlusion of the internal carotid or middle cerebral artery - Mori 1992, JTSG 1993, PROACT 1998, PROACT 2 1999;
- three trials included presumed "thrombotic" stroke of most severities and excluded presumed cardio-embolic strokes (though it is not clear whether artery-to-artery embolism counted as "embolic" in this context) - Atarashi 1985, Abe 1981, Ohtomo 1985.
Most trials used a stroke severity scale, such as the National Institutes of Health Stroke
Scale (NIHSS) or Scandinavian Stroke Scale (SSS) or developed their own neurological stroke
severity scale, to measure the severity of the stroke at baseline.
Patients who were drowsy or in coma as a result of the stroke:
- All trials excluded patients in coma (ie unconscious); most trials did not randomise many patients who were drowsy except MAST-E 1996 in which 50% of the patients were drowsy or stuporose at randomisation.
Age :
- Only five trials had no upper age limit and included very elderly patients - MAST-E 1996, MAST-I 1995, Ohtomo 1985, Atarashi 1985, Abe 1981;
- three trials had an upper age limit of 85 years - ASK 1996, PROACT 1998, PROACT 2 1999;
- the NINDS 1995 trial protocol stated an upper age limit of 80 years, although patients over the age of 80 were randomised (the actual age of oldest patient was not stated in the primary publication, but a patient of 87 years is referred to in the subsidiary paper on intracranial haemorrhage by the NINDS Stroke Study Group, Stroke 1997).
- all the rest had an upper age limit of 80 years.
Visible infarction on the CT scan at randomisation:
- two trials specified that the prerandomisation CT had to be normal - Mori 1992, JTSG 1993;
- three trials specified that the prerandomisation CT scan had to be normal or only show ischaemic changes in less than one third of the middle cerebral artery supply territory - ECASS 1995, ECASS II 1998, ATLANTIS B 1999;
- two trials excluded patients with mass effect and midline shift on CT - PROACT 1998, PROACT 2 1999;
- none of the other trials specified that patients with a CT scan which showed an infarct (which was likely to be symptomatic) should be excluded, though individual doctors may have excluded these patients in some centres depending on local opinion.
Time to randomisation:
The maximum time interval allowed between the onset of the stroke and the start of the treatment administration varied from within three hours to up to two weeks.
- two trials randomised patients within three hours - NINDS 1995 and Haley 1993;
- one trial randomised patients within four hours - ASK 1996;
- one trial randomised patients within three to five hours - part of ATLANTIS B 1999;
- ten trials randomised patients within six hours - Mori 1992, JTSG 1993, ECASS 1995, MAST-I 1995, MAST-E 1996, Morris 1995, ECASS II 1998 ATLANTIS A 1999, PROACT 1998, PROACT 2 1999;
- two trials randomised patients within five days - Ohtomo 1985, Atarashi 1985;
- and one trial randomised patients within two weeks - Abe 1981.
[Note that the latter three trials (Ohtomo 1985, Atarashi 1985, Abe 1981) do not contribute data to the analysis of early deaths or of death and dependency as early deaths were not recorded and a functional outcome measure was not used in these trials. They do contribute data to the analyses of intracranial haemorrhages and deaths by the end of follow up].
Randomisation method:
- five trials used central telephone randomisation - MAST-I 1995, MAST-E 1996, ASK 1996, PROACT 1998, PROACT 2 1999. In MAST-I and PROACT 2, the allocated treatment was then given unblinded without a placebo. In MAST-E and ASK, sealed prepacks of SK or identical-appearing placebo were selected according to the randomisation instructions.
- in three trials randomisation was at the participating hospital by selection of a sealed, sequentially-numbered, prepack (of active drug or identical appearing placebo) followed within two hours by a telephone call to the Central Trial Co-ordinating Office to notify them of the patient and the number of the drug pack - NINDS 1995, ATLANTIS A 1999, ATLANTIS B 1999.
- in two trials, randomisation was by selection of a sequentially numbered, sealed drug prepack at the participating centre provided by the sponsor from a randomisation schedule drawn up centrally - ECASS 1995, ECASS II 1998.
Of the remaining trials:
- five trials used sealed drug prepacks of active drug or identical-appearing placebo - Abe 1981, Atarashi 1985, Ohtomo 1985, JTSG 1993, Mori 1992;
- one used sealed envelopes - Haley 1993,
- and the method was not stated in one - Morris 1995.
It should be noted that thrombolysis, due to its effects on the coagulation system at high doses, is difficult to blind completely due to the obvious signs of bleeding (prolonged bleeding at venepuncture sites, easy bruising, gingival or conjunctival haemorrhages, etc). Thus, provision of an identical-appearing placebo (in the syringe) may not fully blind investigators to treatment allocation.
Drug and dosage :
- Four trials used streptokinase (SK) - MAST-I 1995, MAST-E 1996, ASK 1996, Morris 1995;
- eight used recombinant tissue Plasminogen Activator (rt-PA) - ATLANTIS A 1999, ATLANTIS B 1999, ECASS 1995, ECASS II 1998, NINDS 1995, Mori 1992, JTSG 1993, Haley 1993;
- three used urokinase (UK) - Abe 1981, Ohtomo 1985, Atarashi 1985;
- and two used recombinant Pro-Urokinase (rpro-UK) - PROACT 1998, PROACT 2 1999.
Thus trials using iv rt-PA contribute 2889/5144 patients, 56% of the data to this review.
The SK dose was 1.5 MU (as used to treat acute myocardial infarction) in MAST-I 1995, MAST-E
1996, ASK 1996, Morris 1995.
The rt-PA dose was similar to that used to treat acute myocardial infarction at 1.1 mg/kg to
a maximum of 100 mg in ECASS 1995, about 20% less at 0.9 mg/kg to a maximum of 90 mg in the
NINDS 1995, Haley 1993, ECASS II 1998, ATLANTIS A 1999, ATLANTIS B 1999, and about one third
of that in Mori 1992 and JTSG 1993. All SK and rt-PA doses were administered by intravenous
infusion through a peripheral arm vein, over one hour.
The UK dose in Abe 1981, Atarashi 1985 and Ohtomo 1985 was much lower than the equivalent for
acute myocardial infarction and was administered intravenously once daily for seven days.
The rpro-UK dose was 6 mg in PROACT 1998 and 9mg in PROACT 2 1999, in both trials given
intra- arterially, through a catheter with its tip embedded in the occluding thrombus.
Concomitant use of antithrombotic treatment :
One trial (MAST-I 1995) compared aspirin with SK and control, started within six hours of
stroke onset, in a factorial randomisation (in the groups randomised to receive aspirin,
it was continued for ten days). Antithrombotic use was not randomly assigned in any other
trials and its permitted use varied : in ASK 1996 all patients were to receive 300 mg
aspirin starting within four hours of the SK infusion and continued daily therafter; in
PROACT 1998 all patients received 1000 u/hour intravenous heparin during the trial
angiogram, reduced to 500 u/hour halfway through the trial; in PROACT 2 1999 all patients
received intravenous heparin 500 u/hr for four hours starting at the time of the angiogram
infusion; in MAST-E 1996 aspirin and intravenous heparin were allowed to start at any time
and continue for any time (about 25% of patients received aspirin or heparin within 24 hours
and 75% within the first week of the stroke); in ECASS 1995 and ECASS II 1998 subcutaneous
heparin was allowed within 24 hours of the stroke (and thereafter) and aspirin after 24
hours (in ECASS II, about 20% of patients were taking aspirin at the time of their stroke
and 54% of rt-PA treated patients received subcutaneous heparin within the first 24 hours,
but we are unsure of the corresponding numbers for ECASS 1995, nor how many patients in
either trial received aspirin or heparin after 24 hours); in Haley 1993 a few patients
received antithrombotic drugs within 24 hours and thereafter; in NINDS 1995, Mori 1992,
ATLANTIS A 1999 and ATLANTIS B 1999 no antithrombotic drugs were allowed within 24 hours but
aspirin was allowed thereafter; in Ohtomo 1985, Abe 1981 and Atarashi 1985 antithrombotic
drugs were not allowed during the seven days of treatment infusion, but could be used
thereafter. The antithrombotic drug use is not stated clearly in JTSG 1993 or Morris 1995.
Follow-up :
Early outcome assessments were made at around seven to ten days in most trials. Some trials
also performed more frequent assessments in the first few hours and days after the trial
treatment. In the present review, outcome events occuring within the first seven to ten days
(whichever was the later date at which data were collected) have been used to determine the
effect of thrombolytic therapy on early outcome.
The final outcome assessment was at :
- about one month after the stroke in Abe 1981, Atarashi 1985, Ohtomo 1985, Mori 1992, JTSG 1993 and Morris 1995;
- three months in Haley 1993, ECASS 1995, ASK 1996, NINDS 1995, ECASS II 1998, ATLANTIS A 1999, ATLANTIS B 1999, PROACT 1998, and PROACT 2 1999;
- and six months in MAST-I 1995 and MAST-E 1996.
Note that follow-up at six months and one year have recently been reported for NINDS 1995 -
see References to Studies - but the three month outcome, the primary outcome originally
reported, is used in the present review.
Note that because of the difficulty of blinding the biological effect of thrombolytic
therapy, follow-up by an individual who had not been involved at all in the administration
of the trial treatment, or in the care of the patient during at least the first few days,
and was unaware of treatment allocation, is important to ensure objective outcome assessment. In MAST-I 1995 the six month follow-up was by telephone by a trained observer blind to the treatment allocation. The MAST-E 1996 and ASK 1996 trials did not specify who performed the follow up or that they should not have been involved in the trial treatment administration or patient care in the first 24 hours. In NINDS 1995, ATLANTIS A 1999 and ATLANTIS B 1999, follow-up at all stages was to be by a doctor (blinded) who had not been involved in the randomisation or care of the patient in the first 24 hours. In ECASS 1995, ECASS II 1998, PROACT 1998 and PROACT 2 1999, follow-up was by a mixture of individuals - where possible by someone who had not been involved in the patient's care within the first 24 hours but this may not always have been the case.
Assessment of functional outcome :
The assessment of functional outcome was by :
- the Barthel Scale in Mori 1992, JTSG 1993, Morris 1995 and ASK 1996;
- an undefined scale (no, mild, moderate or severe "limitation") in Haley 1993;
- the Rankin Scale in MAST-I 1995 and MAST-E 1996;
- the modified Rankin Scale in ECASS 1995, NINDS 1995, ECASS II 1998, ATLANTIS A 1999, ATLANTIS B 1999, PROACT 1998 and PROACT 2 1999;
- and was not assessed in Abe 1981, Ohtomo 1985 and Atarashi 1985.
Some trials used more than one scale to measure outcome. The trials by Abe (Abe 1981),
Ohtomo (Ohtomo 1985) and Atarashi (Atarashi 1985) used the "Global Improvement Rating" which
measures change in neurological status and safety outcome as a composite surrogate for
functional outcome.
There are differences in the primary outcome measure used between trials, in that some used
a poor functional outcome and some used a good outcome. The following trials sought
"dependency" as a measure of poor functional outcome: MAST-I 1995 and MAST-E 1996, which
defined dependancy as Rankin 3 or worse, and Morris 1995 and ASK 1996 which defined
dependency as Barthel 60 or worse. The following trials sought "good functional outcome" :
ECASS 1995, ECASS II 1998, NINDS 1995, ATLANTIS A 1999 and ATLANTIS B 1999, which defined
"good outcome" as modified Rankin 0 or 1. For most trials, it has been possible to obtain
data on patients in each individual Rankin (or Barthel) group, or data dichotomised on
Rankin 0 to 2 versus 3 to 6, or 0 and 1 versus 2 to 6, so that dependency in this review
refers to Rankin (or Modified Rankin) 3 to 5 (6 being dead) unless otherwise stated. The
only trials for which the number of patients in individual Rankin groups were not so far
available (and therefore the data shown are for Rankin 2 or worse) are ATLANTIS A 1999 and
PROACT 1998.
Analysis :
Only the intention-to-treat results are included here. In any trials where there have been exclusions, these were made prior to the breaking of the randomisation code.
A strict "intention-to-treat analysis" was used in MAST-I 1995, MAST-E 1996, ASK 1996, ECASS 1995, NINDS 1995, ECASS II 1998, PROACT 1998, PROACT 2 1999, ATLANTIS A 1999 and ATLANTIS B 1999 but not in any of the earlier trials. However, for the earlier trials, with additional information from the principal investigators where necessary, we have attempted to find a final outcome for all randomised patients, rather than simply relying on the published data from which some randomised patients may have been excluded. Note the ECASS 1995 trial was published as intention-to-treat and as a "target population" after about 20% of the randomised patients had been excluded.
Premature closure of recruitment : Randomisation in MAST-E 1996 (all) and ASK 1996 (in the over three hour group) stopped on the advice of their respective data monitoring committees after only about half of the originally intended number of patients had been randomised. MAST-I 1995 was suspended by its steering committee (in view of the adverse climate for continuing thrombolytic trials at the time due to the stopping of MAST-E and ASK) to examine its interim results after randomising about one third of its originally intended number. ECASS 1995, NINDS 1995, ECASS II 1998, and PROACT 2 1999 all reached their planned targets. PROACT 1998 stopped after completing two of its planned three dosage arms. ATLANTIS A 1999 was stopped on publication of the NINDS trial (NINDS 1995), and continued in modified form as ATLANTIS B, which in turn stopped in 1998 following a "futility analysis" prompted by results from ECASS II 1998.
Results |
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The results figures can be accessed in the list of comparisons. Note that in each figure, trials are grouped according to which thrombolytic
drug was used, with a subtotal odds ratio for that agent. The overall odds ratio for all
trials appears at the bottom of each figure.
Death from all causes within the first seven to ten days
Data on deaths occurring within the first seven to ten days were available for six trials.
There was a significant excess of early deaths with thrombolysis. 16.6% of those allocated
to thrombolytic therapy died compared to 9.8% of those allocated to control (odds ratio (OR)
1.85, 95% confidence interval (CI) 1.48 to 2.32, 2p<0.000001). In absolute terms, if
confirmed, this is an increase of 68 (95% CI 44 to 93) early deaths per 1000 patients treated
with thrombolysis. There was borderline significant heterogeneity (Chi squared 15.05, (df=7)
p<0.05).
Data on early deaths were available for four trials using iv rt-PA. The numerical (tabular)
data on early deaths for the NINDS trial (NINDS 1995) have not been published, but the NINDS
trial did publish a survival curve which suggested that fewer deaths occurred in the
rt-PA-treated patients from 24 hours after treatment onwards. The tabular data available from
the other rt-PA trials showed a non-significant excess of early deaths: the odds ratio was
1.24 (95% CI 0.85 to 1.81, 2p=NS) with no significant heterogeneity. In the trials using SK,
there was a significant excess of early deaths (OR 1.9, 95% CI 1.37 to 2.63).
Fatal intracranial haemorrhage
Data are available from eleven trials on fatal intracranial haemorrhage. This outcome may
underestimate the frequency of intracranial haemorrhage since some of the patients who died
without a post mortem or CT scan may have died of intracranial haemorrhage. There was a
significant five-fold increase in the rate of fatal intracranial haemorrhage with
thrombolysis (5.4% of patients allocated to thrombolysis compared to 1.0% of those allocated
to control, OR 4.15, 95% CI 2.96 to 5.84, 2p<0.000001). There was no heterogeneity (Chi
squared for heterogeneity 8.99, p=NS). In trials using rt-PA, there were 29 (95% CI 17 to
41) extra fatal intracranial haemorrhages per 1000 patients treated (OR 3.2, 95% CI 2.0 to
5.2, 2p<0.000001) with no heterogeneity between trials (Chi squared 3.7, 4df, p=NS).
In trials using streptokinase, there were 92 (95% CI 65 to 120) extra fatal intracranial
haemorrhages per 1000 treated (OR 6.03, 95% CI 3.47 to 10.47).
The combination of streptokinase with aspirin in MAST-I 1995 significantly increased total
deaths from cerebral causes (OR 2.0, 95% CI 1.1 to 3.7), fatal intracranial haemorrhage (OR
2.2, 95% CI 1.0 to 5.0), and more patients died of cerebral causes without a CT scan or
autopsy who may therefore also have had intracranial haemorrhage, than in the group who
received streptokinase alone.
Symptomatic (including fatal) intracranial haemorrhage
All trials provided data on intracranial haemorrhage and most provided them in a form which
made it clear how many patients had suffered a neurological deterioration associated with the
appearance of new haemorrhage in the brain on a CT brain scan or at post mortem. There was a
highly significant four-fold increase in symptomatic intracranial haemorrhage with
thrombolysis in 9.4% of those allocated to thrombolysis versus 2.5% of those allocated to
control (OR 3.5, 95% CI 2.8 to 4.5, 2p<0.000001). This represents an extra 70 (95% CI 58 to
83) symptomatic intracranial haemorrhages per 1000 patients treated. In trials using rt-PA,
there were 73 (95% CI 55 to 90) extra symptomatic intracranial haemorrhages per 1000 patients
treated (OR 3.2, 95% CI 2.4 to 4.3, 2p<0.000001) with no heterogeneity between trials (Chi
squared 12.9, 7df, p=NS).
Deaths from all causes within the scheduled follow-up (including the early deaths)
Data were available for all seventeen trials (5144 patients).
There was a modest but significant increase in deaths within scheduled follow-up, from
15.9% in controls to 19% in the patients allocated to thrombolysis (OR 1.31, 95% CI 1.13 to
1.52, 2p=0.0008). In absolute terms, this represented an extra 36 (95% CI 17 to 56) deaths
at the end of follow-up per 1000 patients treated with thrombolysis. There was considerable
heterogeneity between the trials (Chi squared 38.7 (df=17), p<0.01); two trials (NINDS 1995
and MAST-I 1995 patients allocated to SK alone) showing a non-significant reduction and
others (ASK 1996, MAST-E 1996 and MAST-I 1995 patients allocated to SK + aspirin) showing a
significant increase in case fatality with thrombolysis. In the trials using intravenous
rt-PA there was a non-significant increase in deaths (OR 1.16, 95% CI 0.94 to 1.44)
equivalent overall to 18 more deaths per 1000 patients treated. There was significant
heterogeneity of treatment effect among the trials of rt-PA (Chi squared 14.16 (df=7) p<0.05).
Death or dependency at the end of trial follow-up
Analysable data from twelve trials on functional outcome were available for 4476 patients.
A further two trials also assessed functional outcome but the data from one, Haley 1993,
were incomplete (3/27 patients were alive but lost to follow up), and in the other, JTSG 1993,
the Barthel Scores have not been published (but are still being sought).
There was a significant reduction in death or dependency with thrombolysis; 55.2% of those
allocated to thrombolytic therapy compared to 59.7% of those allocated to control (OR 0.83, 95% CI 0.73 to 0.94, 2p=0.003). This would be clinically important if confirmed as it is equivalent to 44 (95% CI 15 to 73) fewer dead or dependent patients per 1000 treated. There was no significant heterogeneity of treatment effect between the trials (Chi squared 19.96 (df=12) p=NS), ie broadly speaking, the treatment effect in all trials was in the same direction.
For the six trials using intravenous rt-PA (2764 patients), the odds ratio was 0.79 (95% CI 0.68 to 0.92, 2p=0.002), equivalent to 57 (95% CI 20 to 93) fewer patients being dead or dependent. There was significant heterogeneity of treatment effect among the trials using rt-PA (Chi squared 12.82 (df=5), p<0.05).
If an alternative definition of "poor outcome" (Rankin two to six) is used in this analysis,
the effect of thrombolysis is unchanged, with a significant reduction in the number of
patients with a "poor outcome" (OR 0.79, 95% CI 0.69 to 0.90), with no significant
heterogeneity. For the six trials using rt-PA, the odds ratio was 0.76 (95% CI 0.65 to 0.89),
with significant heterogeneity (Chi squared 14.84 (df=5) p<0.05).
To attempt to identify possible causes for the heterogeneity of the data on death (amongst
all trials), we have ordered the trials by (a) thrombolytic drug used; (b) concomitant
antithrombotic drug usage; and (c) "severity" of stroke patient randomised based on the case
fatality in the control group. We have also examined the effect of time to treatment on (d)
death or dependency, and (e) death, by the end of follow-up.
a) Thrombolytic drug used : Although trends were observed, there were no statistically significant differences in treatment effect (on case fatality at the end of follow-up) between trials using urokinase (OR 0.71), streptokinase (OR 1.43) and rt-PA (OR 1.16), because the confidence intervals were wide reflecting the relatively small sample sizes. It is possible that the heterogeneity is due to factors other than thrombolytic drug used as there are numerous other important methodological differences between these trials. For example, the dose and drug administration regimens differed, mainly between trials using UK and those using SK and rt-PA, but this precluded the analysis of the effect of dose. Direct randomised comparisons would be required to decide which drug at which dose has least hazard (and most benefit). Alternatively, an integrated comparison based on individual patient data might help.
b) Concomitant antithrombotic drug use : It is not possible to comment on the effect of
aspirin use prior to the stroke; though some trials recorded prior aspirin use, data could
not be extracted from the publications. The interaction between thrombolytic drugs and
antithrombotic drugs given simultaneously (or the latter very soon after the former) was
only tested by random allocation in MAST-I 1995 which therefore provides the only reliable
evidence. In MAST-I 1995, there was a clinically important adverse interaction between
aspirin and SK when given simultaneously resulting in a substantial increase in case
fatality (early and late), which was not offset by a reduction in the number of dead or
dependent patients by the end of follow-up (28% of those allocated to SK alone versus 43% of
those allocated to SK plus aspirin were dead by the end of follow-up (p<0.001), and 62% and
63% were dead or dependent respectively (versus 68% in the control group)). The actual cause
of the increase in early and total deaths with SK and aspirin appears largely to be due to
neurological events. Aspirin with streptokinase significantly increased the number of deaths
in hospital from all causes (OR 2.2, 95% CI 1.3 to 3.8), from cerebral causes (OR 2.0, 95%
CI 1.1 to 3.7), and intracranial haemorrhage on CT scan or at autopsy (OR 2.2, 95% CI 1.0 to
5.0) when compared with the group who received streptokinase alone. There was no difference
in deaths from cerebral causes without intracranial haemorrhage, but note also that more
patients in the SK plus aspirin group died of cerebral causes without a CT scan or autopsy,
so could also have had an intracranial haemorrhage, ie the increase in intracranial
haemorrhage with aspirin and SK may be even greater (Ciccone et al 1998).
Reasonably reliable data are available on antithrombotic drug use in eleven other trials
(Mori 1992, Haley 1993, ECASS 1995, NINDS 1995, ASK 1996, MAST-E 1996, ECASS II 1998, PROACT
1998, PROACT 2 1999, ATLANTIS A 1999 and ATLANTIS B 1999), and some further data in three
other trials (Abe 1981, Atarashi 1985, Ohtomo 1985). There is a trend towards increased case
fatality the more frequent and nearer to the administration of thrombolysis the concomitant
antithrombotic drug use (OR 1.93 when all patients received antithrombotic drugs within 24
hours of thrombolysis; 1.27 when some patients received antithrombotic drugs within 24 hours;
1.14 when no patients received antithrombotic drugs within 24 hours but some thereafter; and
0.89 for no antithrombotic drugs within the first 10 to 14 days). Although these data are
based mainly on non-randomised comparisons, they do support the evidence of a clinically
significant adverse interaction between thrombolysis and antithrombotic drugs given
concurrently found in MAST-I 1995 and may go some way towards explaining the heterogeneity
between the trials for case fatality.
c) "Severity" of stroke randomised : There was no obvious statistically significant
difference in the effect of thrombolysis on case fatality between trials with a case
fatality rate less than 19% in the control group (OR 1.3) and those with a case fatality rate
greater than 20% in the control group (OR 1.13). However this may mask an important
relationship between stroke severity and hazard with thrombolysis as the risk of
thrombolytic treatment was much greater in the trials which randomised the most "severe"
strokes (MAST-E 1996, OR 1.41) compared to the most "mild" (Abe 1981, OR 0.98). The
relationship with stroke severity requires individual patient data for proper analysis. See
also sections d and e below.
d) Death or dependency at the end of follow-up in patients treated (randomised) within three hours of the stroke
Two trials included only patients who could be randomised and start treatment within three
hours of the stroke (Haley 1993, NINDS 1995). Data are available from five other trials on
the subgroup of patients randomised within three hours (MAST-I 1995, MAST-E 1996, ASK 1996,
ECASS 1995, ECASS II 1998). The data are limited and strongly influenced by the NINDS trial
which contributed more patients to the analysis of treatment within three hours of stroke
than the other trials combined. There are also likely to be imbalances in baseline variables
between the thrombolysis and control patients as evidenced by the small and uneven numbers
of patients. These data should therefore be regarded with EXTREME CAUTION and require
confirmation in future trials. There was a significant reduction in the number of patients
dead or dependent with thrombolysis (55.2% of those allocated to thrombolysis were dead or
dependent compared to 68.3% of those allocated to control, OR 0.58, 95% CI 0.5 to 0.7,
2p=0.00002). In absolute terms, if confirmed, this would be equivalent to 126 (95% CI 71
to 181) fewer dead or dependent patients per 1000 treated with thrombolysis, and would be
highly important clinically.
To compare these data on the effects of treatment given within three hours with the effects
when given after three hours, we examined only those trials which reported data for both time
windows (MAST-I 1995, ECASS 1995, MAST-E 1996, ASK 1996, ECASS II 1998). There was no
significant difference in the proportion dead or dependent with thrombolytic treatment given
within three hours (OR 0.7, 95% CI 0.49 to 0.99) and between three and six hours (OR 0.93,
95% CI 0.78 to 1.10), although there is a trend towards better outcome with earlier
treatment. In trials using rt-PA alone, the effect of treatment was similar whether given
within three hours (OR 0.7, 95% CI 0.4 to 1.2), or more than three hours after stroke (OR
0.76, 95% CI 0.6 to 0.96). This should not be interpreted to mean that time to treatment is
unimportant, but rather that some third factor interacts with the effect of thrombolytic
treatment and with time.
e) Death during follow-up in patients treated (randomised) within three hours of the stroke.
Data are available for seven trials. The NINDS 1995 trial contributes more than 50% of the
data. There was a very modest, non-significant excess of deaths during follow-up with
thrombolysis, of 22.3% of patients allocated to thrombolysis versus 20.7% of those
allocated to control (OR 1.11, 95% CI 0.84 to 1.47). If confirmed in future trials, this
would be equivalent to 17 extra deaths per 1000 patients treated with thrombolysis (95% CI
28 less to 62 more). In trials using rt-PA, the equivalent figure was 12 fewer deaths per
1000 (95% CI 61 fewer to 38 more).
To compare treatment within, with treatment after, three hours, a similar analysis to (d)
above was performed. There was no difference in treatment effect between those treated
within three hours (OR 1.59, 95% CI 1.06 to 2.38) and between three and six hours (OR 1.51,
95% CI 1.23 to 1.87) after the stroke. For trials testing intravenous rt-PA, the relative
excess of deaths was similar for patients treated within three hours (OR 1.56, 95% CI 0.77
to 3.15) and between three and six hours (OR 1.24, 95% CI 0.92 to 1.68). The same comment
as in above applies to the interpretation of these data.
Discussion |
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The excess of early deaths with thrombolytic therapy appears to be due mainly to intracranial
haemorrhage. Fatal intracranial haemorrhage was increased by thrombolytic therapy about
five-fold and symptomatic intracranial haemorrhage about four-fold.
The effects of thrombolysis on death at the end of follow-up were less clearly consistent
between trials. Early case fatality was increased about two-fold in trials for which the
data were available. But, at the end of follow-up, in eleven trials (including the MAST-I
patients allocated to SK alone) thrombolysis was associated with a (non significant)
reduction in case fatality, and in six (including the MAST-I patients allocated to SK +
aspirin) with an increase (some significant) in case fatality. Overall thrombolysis
significantly increased case fatality (about an extra 36 deaths per 1000 patients treated).
The data were rather scanty, but the excess with intravenous rt-PA or intra-arterial
rpro-UK was rather smaller, and with intravenous SK plus aspirin somewhat larger. The limited
exploration of reasons for this heterogeneity, which has been possible with the data
available so far, suggest that (i) concomitant use of antithrombotic drugs within 24 hours of
thrombolysis and (ii) randomisation of mainly "severe" strokes with a high case fatality in
the control group both increase case fatality (the hazard) with thrombolytic treatment.
Although the data on death in patients treated within three hours from other trials support
the NINDS conclusion, the sample size is tiny and there are imbalances such that the data
must at present be regarded with caution. Note that most of the trials (all of the recent
rt-PA trials) performed the follow-up at three months. The NINDS trial recently published
data on functional outcome at six months and one year which indicate that the effect of
rt-PA was sustained beyond three months, but there are no other data on whether the benefit
of thrombolysis is sustained (or even increases) at one year. This information would be
important for understanding the impact of thrombolytic treatment on health economics.
The interaction between aspirin and thrombolytic therapy (streptokinase) was only tested by
random allocation in the MAST-I trial. Although the number of patients was small (about 155
patients in each treatment group), there was a highly statistically and clinically
significant adverse interaction between aspirin and SK which increased case fatality at all
stages. Although it appears that aspirin and SK given within a short time of each other are
hazardous, there is no information on the effect of thrombolysis if patients are taking
aspirin at the time of their stroke, or on when it might be safe to start aspirin after the
stroke.
The "time window" beyond which there is unlikely to be any benefit (or too much hazard) with
thrombolytic therapy is unclear. The NINDS rt-PA trial, which randomised patients within
three hours of the stroke, showed a significant reduction in the number of patients dead or
dependent and a non-significant reduction in case fatality during follow-up (but the data on
early case fatality have not been published). rt-PA has been licenced by the United States
Food and Drug Administration (and in countries which follow the US FDA guidelines) and recently
in Canada (with application under consideration in Europe) for treatment of acute ischaemic
stroke if given within three hours and only in patients similar to those included in the
NINDS trial. However, the three hour time window is only one possible factor to explain the
NINDS trial result. Other possibilities being considered are : minor imbalances in baseline
stroke severity between the treatment groups, strict avoidance of antithrombotic drugs within
24 hours of rt-PA, use of a slightly lower dose of rt-PA than the dose of thrombolytic drugs
used in the other recent trials, rigorous control of the patient's blood pressure during the
treatment infusion, the particular type of hospital setting in which the trial was conducted,
or simply the play of chance. There is no way of knowing what the trial result might have
been if patients had been randomised between three and six hours using the same protocol. The
subgroup of patients randomised within three hours of the stroke in the MAST-I trial
(patients allocated to SK alone), ASK 1996, ECASS 1995 and ECASS II 1998, showed a similar
reduction in the proportion of dead or dependent patients to the NINDS trial. In these trials,
patients randomised between three and six hours after stroke showed some reduction in the
number of dead or dependent patients (albeit non-significant). Thus the time window for
benefit might extend to, or even beyond six hours in selected patients.
There is little information on which thrombolytic drug might have most benefit and least
hazard. There is little information on which dose of drug has least hazard and most benefit.
Direct randomised comparisons would be required.
There is little information yet on the effect of thrombolytic therapy in the elderly, in whom
stroke is most common. Of the recent trials, only MAST-I 1995, MAST-E 1996 and NINDS 1995
did not have an upper age limit. All the other rt-PA trials had an upper age limit of 80
years, and the NINDS trial included very few patients older than 80 years.
There is a suggestion that the presence of a visible recent infarct on the CT scan prior to
randomisation may be related to increased hazard (risk of intracranial haemorrhage and death)
but this was based on a post hoc analysis of the CT scans in ECASS 1995 in which the baseline
CT scans were not read blind to follow-up CT scans. Some trials had CT visible infarction
exclusion criteria and some, including NINDS 1995, did not. The reported rate of CT visible
infarction varied between trials, either reflecting differences in patient selection,
observer sensitivity, or definition of visible infarction signs. There is no information on
other possible risk factors on the CT scan for intracranial haemorrhage with thrombolytic
therapy (such as evidence of "small vessel disease") which should be addressed in future
trials.
The trials included in this review are small in comparison with the thrombolytic therapy in
myocardial infarction trials. The data published so far suggest that there may be imbalances
between the treatment groups (particularly as three of the trials stopped early and well
short of their planned sample size targets) in baseline variables which might contribute to
the apparent treatment effect and overall trial result. For example in MAST-E more patients
allocated to SK treatment received antithrombotic drugs than those allocated to control
(MAST-E 1996). Individual patient data are required to examine the interaction of these and
other baseline variables with the effect of thrombolytic therapy which may help to overcome
some of the problems with imbalances between the treatment groups.
A more detailed individual patient data meta-analysis of the SK trials using data from
MAST-E, MAST-I and ASK is now underway (the Thrombolysis in Acute Stroke Pooling Project
(TAS-PP 1999)) and is being co-ordinated by Professor Jean Pierre Boissel in Lyon, France,
and a meta-analysis is planned of data from the rt-PA trials by the ECASS, NINDS and ATLANTIS
investigators.
This review is based on data from just over 5000 patients - a very small number in relation
to the global burden of the disorder (perhaps six million ischaemic strokes per year world
wide). The centres which took part in the trials reviewed were specially interested in, and
familiar with, the investigation and management of acute stroke. To extrapolate these results
to thrombolysis when used more widely in "routine" clinical practice in less specialist
centres could result in much greater hazard and thereby reduce or completely negate any
potential benefit. Much more information is needed on : how to select patients (to maximise
benefit and minimise hazard), the influence of stroke severity, stroke subtype, age, time
from onset, concomitant use of antithrombotic drugs, choice of thrombolytic drug, dose and
route of administration, and CT scan appearances before thrombolytic drugs should be used
outside very strict licence regulations. Randomised trials to specifically examine the
effect of age, stroke severity, prior aspirin use, CT scan appearance, the interaction with
time from stroke, and in different care delivery environments are the best means of
providing such data.
This review is the result of an ongoing process involving the collaborative effort of many researchers worldwide and the principal investigators of many of the thrombolysis trials. It should be noted that it has not been possible to achieve a consensus among all of the reviewers on the inclusion of the earlier thrombolysis studies (Abe 1981; Atarashi 1985; Ohtomo 1985) because of their methodological differences (they tended to use lower doses of thrombolytic drug and randomised up to two weeks after stroke onset). At present this review represents all of the evidence from the randomised controlled studies on the effects of thrombolytic therapy on acute ischaemic stroke.
Reviewers' conclusions
a) The data available are limited. However, with tested thrombolytic agents in recent trials
there is, overall, proof beyond all reasonable doubt of a substantial excess risk of fatal
intracranial haemorrhage and death from all causes with thrombolytic therapy. This hazard may
be increased if antithrombotic drugs are given concurrently.
b) Taken overall, the risks are offset by reductions in dependent survival, so that there is
a net benefit of a significant reduction in the proportion of patients who are dead or
dependent at the end of follow-up, ie significantly more patients are alive and independent.
c) Despite the substantial net benefit, the available data do not provide sufficient
evidence to determine the magnitude of treatment effect for the individual patient, including
: the duration of the therapeutic time window, the optimum agent (or dose or route of
administration) or the clinical or radiological features which identify the patients most
likely to be benefited (or harmed).
d) the greatest amount of data are available for intravenous rt-PA, which was associated with
fewer deaths and more patients avoiding death or dependent survival than was intravenous SK
(intravenous UK was used in low doses and given late after the stroke so cannot be
extrapolated to a regime of high doses given within a few hours of the stroke, and the
rpro-UK data were from intra-arterial trials).
e) In the light of these considerations, some clinicians may wish to use thrombolytic therapy
in highly selected patients; others who are concerned about the definite risks may choose not
to use the treatment at all.
These uncertainties suggest that further large-scale randomised trials comparing
thrombolytic therapy with control in patients with acute ischaemic stroke are needed :
a) To confirm whether the advantage to thrombolytic therapy in terms of the reduction in death and dependency at three months does indeed persist to six months and beyond, as suggested by one trial.
b) To determine reliably the effects on survival.
c) To identify which categories of patient are most likely to benefit (and which are harmed).
d) To identify means of minimising the hazard without reducing the benefit.
e) To provide clearer evidence that when used in a wider range of hospitals, thrombolytic therapy is associated with a definite net benefit.
Potential conflict of interest
The Department of Clinical Neurosciences at the University of Edinburgh has a collaborative
project with Boehringer Ingelheim (UK) to establish a research magnetic resonance scanner,
through the UK Research Councils Joint Research Equipment Initiative. For this, the
Department received a grant from Boehringer Ingelheim towards the purchase of the scanner.
The Department of Clinical Neurosciences at the University of Edinburgh are co-ordinating the
Third International Stroke Trial (IST3) of intravenous tissue Plasminogen Activator within
six hours of acute ischaemic stroke, main trial to start in 2000. The start-up phase of about
200 patients, to start in Autumn 1999, is funded by the UK Stroke Association, with supply
of drug and placebo from Boehringer Ingelheim.
The review was assembled, analysed and reported independent of any sponsor or pharmaceutical company.
Prof Hacke, previously listed as an author of this review prior to 1996, asked that his name be removed forthwith as he disagreed with the methods and interpretation of the results in this review. We are very grateful to the principal investigators of all the trials who provided additional unpublished information, particularly Professor E Mori, Professor T Abe, Professor E Ohtomo, Professor T Yamaguchi, Professor L Candelise, Professor W Hacke, Professor M Kaste, Dr D Meier, Professor G Donnan, Dr M Hommel, Professor T Furlan, Dr G Albers, and Dr W Clarke. We would also like to thank Dr Kyoshi Miyagawa for translating the Japanese language papers, and Dr Kazuo Minematsu and Dr Masahiro Yasaka of the National Cardiovascular Centre, Osaka, Japan for assistance in journal searching and translation, Dr David Moher of the Ottawa Stroke Trials Registry, Dr Ming Liu for the information on the Chinese trials, and Ms Hazel Fraser and Mrs Brenda Thomas of the Cochrane Stroke Review Group for trial lists. We would also like to thank the Cochrane Stroke Review Group external referees, Dr J Van der Meulen, of the Academisch Medisch Centrum, Amsterdam, The Netherlands, for comments on the manuscript of version 1 (1996), and Dr Richard Lindley, Consultant Geriatrician, Western General Hospital, Edinburgh, for comments on the manuscript of the present version, and Dr Peter Sandercock, the co-ordinator of the Cochrane Stroke Group. We would also like to thank the Stroke Association of the United Kingdom for previous financial support for this review. Anyone aware of any thrombolysis trials not mentioned herein or inaccuracies should please contact us with the relevant information.
References |
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ABE 1981 (published and unpublished data)
Abe T, Kazama M, Naito I, et al. Clinical evaluation for efficacy of tissue cultured urokinase (TCUK) on cerebral
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ECASS randomised and treated patients. A post-hoc analysis. Stroke 1998;29:288 (abst)Von Kummer R, Allen
KL, Holle R, Bozzao L, Bastianello S, Manelfe C, Bluhmki E, Ringleb P, Meier DH, Hacke W: Acute stroke -
usefulness of early CT findings before thrombolytic therapy. Radiology 1997;205:327-333Steiner T, Bluhmki E,
Kaste M, Toni D, Trouillas P, Von Kummer R, Hacke W, for the Ecass Study Group: The ECASS 3-hour cohort.
Secondary analysis of ECASS data by time stratification. Cerebrovasc Dis 1998;8:198-203.Fiorelli M, Busse O,
Mau J, Bozzao L, Bastianello S, Fieschi C, Hacke W, Kaste M, Von Kummer R, for the ECASS 1 Study Group.
Cortical extension of the infarction at 24 hours in patients with isolated hypodensity of the lentiform nucleus on 1 -
6 hour CT : Incidence, predictors and outcome in the ECASS 1 Cohort. Cerebrovasc Dis 1998;8(Suppl 4): 19
(Abstract).
ECASS II 1998 (unpublished data only)
ECASS 2: Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S,
DOnnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second European-Australasian Acute Stroke Study
Investigators: Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase
in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-51Schaefer E, Hacke W, Davalos A, Donnan GA,
Fieschi C, Kaste M, Von Kummer R, Larrue V , Bluhmki E, Meier D, for the ECASS II Investigators:
European-Australian cooperative acute stroke study II (ECASS II) - interim demographics and baseline
characteristics. Cerebrovasc Dis 1998;8(Suppl 4):82 (Abstract).Ford G, Freemantle N; Lees KR; Raha S; Barer
D; Jenkinson D; Hacke W, Davalos A, von Kummer R, Kaste M, Larrue V, for the Steering Committee and
authors of the ECASS II study group:ECASS II: Intravenous alteplase in acute ischaemic stroke. Lancet
1999;353:65-68.
(Correspondence on original publication of study results and authors' reply).Berrouschot J, Barthel H, von Kummer
R, Hesse S, Schneider D: Reperfusion after focal cerebral ischaemia does not increase the rate and severity of
secondary haemorrhage. Cerebrovasc Dis 1999;9(Suppl 1):95 (abstract).
HALEY 1993 (published data only)
Haley EC, Brott TG, Sheppard GL, et al. Pilot Randomized Trial of Tissue Plasminogen Activator in Acute
Iscemic Stroke. Stroke 1993; 24:1000-1004.
JTSG 1993 (published and unpublished data)
Yamaguchi T, Japanese Thrombolysis Study Group. Intravenous tissue plasminogen activator in acute
thromboembolic stroke: A placebo controlled, double blind trial. In: del Zoppo GJ, Mori E, Hacke W, eds.
Thrombolytic Therapy in Acute Ischemic Stroke II. New York: Springer Verlag, 1993:59-65.Yamaguchi T,
Hayakawa T, Kiuchi H, Japanese Thrombolysis Study Group. Intravenous Tissue Plasminogen Activator
Ameliorates the Outcome of Hyperacute Embolic Stroke. Cerebrovasc Dis 1993; 3:269-272.
MAST-E 1996 (published and unpublished data)
Hommel M, Boissel JP, Cornu C, Boutitie F, Lees KR, Besson G, Leys D, Amarenco P, Bogaert M, for the
MAST Study Group: Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet 1995:345:57.
This describes the interim results at the point when the trial was prematurely stopped on the advice of the Data
Monitoring Committee.The Multicentre Acute Stroke Trial - Europe Study Group (Hommel M, Cornu C, Boutitie
F, Boissel JP): Thrombolytic therapy with streptokinase in acute ischaemic stroke. The New England Journal of
Medicine 1996;335:145-150.
MAST-I 1995 (published and unpublished data)
Multicentre Acute Stroke Trial - Italy (MAST-I) Group (Candelise L, Aritzu E,Ciccone A, Ricci S, Wardlaw J):
Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic
stroke. Lancet 1995;346:1509-1514.
This paper contains the full results on the first 622 patients randomised up to the point when randomisation was
suspended to look at the results by the Steering Committee in view of the difficulties in continuing with
randomisation in the light of adverse results from the ASK and MAST-E.Ciccone A, Motto C, Aritzu E, Piana A,
Candelise L on behalf of the MAST-I Collaborative Group: Risk of aspirin use plus thrombolysis after acute
ischaemic stroke: a further MAST-I analysis. Lancet 1998;352:880Candelise L, Aritzu E, Ciccone A, Ricci S,
Wardlaw J: Multicentre Acute Stroke Trial - Italy. Authors' Reply. Lancet 1996;347:393The MAST-I
Collaborative Group: Is thrombolysis useful for acute stroke patients? The experience of the MAST-I Study. in
Yamaguchi T, Mori E, Minematsu K, Del Zoppo GJ (eds). Thrombolytic Therapy in Acute Ischaemic Stroke, Publ
Springer-Verlag Tokyo 1995, pp198-205.
MORI 1992 (published and unpublished data)
Mori E, Yoneda Y, Tabuchi M, et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery
territory stroke. Neurology 1992; 42:976-982.
MORRIS 1995 (published data only)
Morris AD, Ritchie C, Grosset DG, Adams FG, Lees KR: A pilot study of streptokinase for acute cerebral
infarction. Q J Med 1995;88:727-731.
NINDS 1995 (published data only)
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue Plasminogen
Activator for Acute Ischaemic Stroke. The New England Journal of Medicine 1995;333:1581-1587.Fagan SC,
Morgenstern LB, Petitta A, Ward RE, Tilley BC, Marler JR, Levine SR, Broderick JP, Kwiatkowski TG, Frankel
M, Brott TG, Walker MD, and the NINDS rt-PA Stroke Study Group: Cost-effectiveness of tissue plasminogen
activator for acute ischaemic stroke. Neurology 1998;50:883-890.Brott T, Kothari R, Fagan S, Frankel M, Grotta
JC, Broderick J, Kwiatkowski T, Lewandowski C, Haley EC, Marler JR, Tilley BC, for the NINDS rt-PA Stroke
Study Group: Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke 1998;29:1504-1509.Haley
EC, Lewandowski C, Tilley BC, NINDS rt_PA Stroke Study Group: Myths regarding the NINDS rt-PA Stroke
Trial: Setting the record straight. Ann Emerg Med 1997;30:676-682.The NINDS rt_PA Stroke Study Group: Effect
of rt-PA on ischaemic stroke lesion size by computed tomography: preliminary results from the NINDS rt-PA
Stroke Trial. 23rd International Joint Conference on Stroke and Cerebral Circulation.The NINDS t-PA Stroke
Study Group: Generalised efficacy of t-PA for Acute Stroke. Subgroup analysis of the NINDS t-PA Stroke Trial.
Stroke 1997;28:2119-2125.The NINDS t-PA Stroke Study Group: Intracerebral haemorrhage after intravenous
t-PA therapy for ischaemic stroke. Stroke 1997;28:2109-2118.Kwiatkowski TG, Libman R, Frankel M, Tilley B,
Morganstern L, Lu M, Broderick J, Marler J, Brott T, and the NINDS RT-PA Stroke Study Group: The NINDS
RT-PA stroke study - sustained benefit at one year. Stroke 1998;29:288 (abst).Kwiatkowski TG, Libman RB,
Frankel M, Tilley BC, Morgenstern LB, Lu M, Broderick JP, Lewandowski CA, Marler JR, Levine SR, Brott T,
for the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke
Study Group: Effects of tissue Plasminogen Activator for acute ischaemic stroke at one year. New Eng J Med
1999;340:1781-1787.
OHTOMO 1985 (published data only)
Ohtomo E, Araki G, Itoh E, Toghi H, Matsuda T, Atarashi J. Clinical efficacy of urokinase in the treatment of
cerebral thrombosis. Multi-center double-blind study in comparison with placebo. Clin-Eval 1985;15(3):711-731
(translated from Japanese).Ohtomo E, Araki G, Itoh E, Toghi H, Matsuda T, Atarashi J. Clinical efficacy of
urokinase in patients with cerebral thrombosis: multicentre double blind study. Kiso-to-Rinshyo (Basic and Clinical)
1985;19:445-478 (translation from Japanese awaited)
PROACT 1998 (published and unpublished data)
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT Investigators:
PROACT: A phase II randomised trial of recombinant pro-urokinase by direct arterial delivery in acute middle
cerebral artery stroke. Stroke 1998;29:4-11.
PROACT 2 1999 (unpublished data only)
Furlan A, Higashida R, Wechsler L, Schulz G on behalf of the PROACT II Investigators: PROACT II:
Recombinant prourokinase (r-ProUK) in acute cerebral thromboembolism. 23rd Joint International Conference on
Stroke and Cerebral Circulation, Feb 5-7 1998, Orlando, Florida (Publ in Feb or March edition of Stroke).Furlan
AJ, Higashida R, Wechsler L, Schulz G, for the PROACT 2 Investigators: PROACT II: Recombinant
prourokinase (r-ProUK) in acute cerebral thromboembolism. Initial trial results. Stroke 1999;30:234.
Also presented at the 24th American Heart Association International Conference on Stroke and Cerebral
Circulation, Nashville, Tennessee, Feb 4-6 1999, p36 in Book of Abstracts.
* indicates the major publication for the study
DON-CAI YUAN 1995
Don-Cai Yuan, et al: High dose urokinase in the treatment of acute ischaemic stroke. J of Brain and Neurological
Diseases 1995;3(2):111. (Chinese - abstracted by Dr Ming Liu).
EDINBURGH 1991
Edinburgh Stroke Trial. Wardlaw JM, Lindley RI, Warlow CP, Sandercock PAG. A pilot study of intra-arterial
thrombolysis for acute ischaemic stroke. J Neurol Neurosurg Psychiatry 1994;57:251.
This study terminated prematurely because of the impracticality of intraarterial thrombolytic treatment. Four
patients were randomised between streptokinase (250000 MU into the occluded cerebral artery) or placebo during
the year that the trial ran (1991). It had been intended to randomise at least 10 patients. 3 received SK, 1 placebo.
1 (SK) died within a week of the stroke of a massive cerebral infarct; 6 month outcome in the other three was : 1
(SK) Rankin 2; 1 (SK) Rankin 3; 1 (placebo) Rankin 4. These results have not been included because the number
is so small and the randomisation (because of the premature termination) so imbalanced.
HONG KONG 1994
Kumana C: Hong Kong trial of streptokinase v placebo
Participants: unknown
Interventions: streptokinase or placebo iv
Outcome measures: unknown
Date started: 1994
Completion date: randomisation stopped March 1995
Additional centres sought: no
Funding: unknown
Principal Investigator: Prof C Kumana
Contact : Prof C Kumana
Dept of Medicine
University of Hong Kong
MEYER 1963
Meyer JS, Gilroy J, Barnhart MI, Johnson JF. Therapeutic thrombolysis in cerebral thromboembolism. Neurology
1963; 13:927-937.
MEYER 1964
Meyer JS, Gilroy J, Barnhart MI, et al. Anticoagulants plus streptokinase therapy in progressing stroke. Journal of
the American Medical Association 1963;189:373.
NAITO 1984
Naito I, Abe T. Oral urokinase: absorption, mechanisms of fibrinolytic enhancement and clinical effect on cerebral
thrombosis. Folia-Haematol-(Leipz) 1986; 113:122-136.
This trial was excluded because many patients were lost to follow up and it was not possible to find out what
happened to them as the principal investigator has died (see excluded trials table).
PANG SHI-QI 1993
Pang Shi-qu, et al: Clinical study of therapeutic effectiveness in treating ischaemic cerebrovascular disease with
lumbrokinase. Chinese Journal of Neurology and Psychiatry 1993;26(4):229-231.
ZHANG YUAN XIANG1995
Zhang Yuan Xiang et al: Thrombolytic therapy and external counterpulsation in acute cerebral infarction.
Proceedings of the Fourth Chinese Stroke Conference, Chengdu, Oct 1995, p44 (abstract)
AUST
Davis SM, Donnan GA, Gerraty RP, Mitchell PJ, Fitt G, et al: Australian Urokinase Stroke Trial. Cerebrovascular
Diseases 1996;6:188.
AUST - The Australian Urokinase Stroke Trial trial of intraarterial urokinase plus heparin versus intraarterial
heparin alone in patients with angiographically proven vertebrobasilar occlusion within 24 hours of stroke onset.
200 patients will be enrolled in 12 centres in Australia starting spring 1996, over three years,
Principal Investigator: Prof G Donnan
CHEN ET AL
Chen Q et al: Acute Occlusive CVA Early Intervention Clinically Controlled Trial. Protocol only available so far.
Believed to be an ongoing study in China, which started randomising in August 1998, run by Professor Qintang
Chen and colleagues, of urokinase or placebo within six hours of onset in patients aged 35 to 75 years.
Progress unknown.
Manufacturer QuandDong Pharmaceuticals Ltd.
Believed to be planned in two phases: in Phase 1, 300 patients will be randomised to intravenous thrombolysis or
placebo and 80 to intraarterial thrombolysis or placebo, in escalating dose regimen to a maximum amount; in Phase
2, 1200 patients will be randomised to intravenous and 120 to intraarterial thrombolysis vs placebo, in two dose
regimens. It appears that the randomisation will be two active for every one placebo allocation, at least in the
intravenous arms. It appears that patients will all also be treated with intravenous heparin in the intraarterial arms
of the trial, and low molecular weight dextran or heparin (translation uncertain) in the intravenous arms.
Number of centres unknown.
Method of randomisation unclear - would appear to be by selection of pre-labled sequential bottles of trial
treatment, but this may be incorrect.
Outcome assessment will be at 90 days using the Rankin Scale and Barthel Score. Early symptomatic intracranial
haemorrhage, early deaths, and total deaths by the end of follow-up will also be assessed.
EMPHATAS
Fieschi C, Sacchetti ML: The EMPHATAS project: a four-arm safety and efficacy European trial.
Cerebrovascular Diseases 1996;6:192
patients within 6 hours of acute ischaemic stroke
intervention: intravenous tPA vs neuroprotection (agent not specified) vs both vs neither
outcome: Rankin at 3 months; death
start date: not known
principal investigator: Dr C Fieschi, Rome
it is believed that this trial has not yet started.
APT 1994
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. BMJ 1994;308:81-106.
TAS-PP 1999
Cornu C, Boutitie F on behalf of the TAS-PP Group: Thrombolysis in acute stroke pooling project: a metaanalysis
on individual patient data. J Clinical Neuroscience 1999;6:20-23.
WARDLAW ET AL 1992
Wardlaw JM, Warlow CP. Thrombolysis in acute ischaemic stroke - Does it work? Stroke 1992;23:1826-39.
WARDLAW ET AL 1997
Wardlaw JM, Warlow CP, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. The Lancet, 1997; 350:607-614
Cover Sheet |
|
|
| Thrombolysis in acute stroke | ||
|---|---|---|
| Reviewer(s) | Wardlaw JM, del Zoppo G, Yamaguchi T | |
| Date of most recent amendment | 13 July 1999 | |
| Date of most recent substantive amendment | 05 July 1999 | |
| Contact address | Dr Joanna Wardlaw
Reader and Honourary Consultant in Neuroradiology Neurosciences Trials Unit, Department of Clinical Neurosciences Western General Hospital Crewe Road Edinburgh UK EH4 2XU Telephone: ++44 (0) 131 537 3110 Facsimile: ++44 (0) 131 332 5150 E-mail: jmw@skull.dcn.ed.ac.uk |
|
| Cochrane Library number | CD000213 | |
| Editorial group | Cochrane Stroke Group | |
| Editorial group code | HM-STROKE |
Tables & Graphs |
|
|
List of comparisons |
|
|
|
Fig 01 Any thrombolytic agent versus control
01.01.00 Deaths from all causes within seven to ten days
01.02.00 Fatal intracranial haemorrhage within seven to ten days
01.03.00 Symptomatic (including fatal) intracranial haemorrhage within seven to ten days
01.04.00 Deaths from all causes during follow up
01.05.00 Death or dependency at the end of follow-up
01.06.00 Deaths from all causes ordered by antithrombotic drug use
01.07.00 Deaths from all causes ordered by stroke "severity"
01.08.00 Death or dependency at the end of follow up - patients randomised within 3 hrs
01.09.00 Death or dependency by time to treatment up to six hours
01.10.00 Deaths from all causes during follow-up - patients randomised within 3 hrs
01.11.00 Deaths by time to treatment up to six hours
Table of included studies |
|
|
|
| Study | Methods | Participants | Interventions | Outcomes | Notes |
| ABE 1981 | Sealed drug prepacks. Double blind. Not intention to treat. |
All grades of presumed thrombotic stroke <2 weeks, pre-entry CT, age 18 years and up. Excluded presumed embolic stroke, severe neurological deficit. | Tissue cultured urokinase (Abbott Labs, USA) 60000U/day IV for 7 days versus identically appearing placebo. | Global Improvement Rating and safety assessment at 4 weeks after treatment start (including follow-up CT if neurologically deteriorated). | Further information from Prof Abe. Eleven patients who received non-trial drugs outside the trial protocol were excluded from analysis prior to breaking the randomisation code (6 treatment and 5 placebo) plus 2 who underwent STA-MCA bypass surgery. Published in Japanese. |
| ASK 1996 | Double-blind, central telephone randomisation, sealed drug prepacks of SK or identical-looking placebo; intention to treat. | Any acute ischaemic stroke (though not very mild or rapidly recovering) who could be randomised and start treatment within 4 hours of clearly defined symptom onset; age <18 and <85 years; CT scan mandatory to exclude cerebral haemorrhage pre-randomisation. Patients with recent traums or surgery, stroke within the last three months or at any time if in the same hemisphere as the presenting stroke, pregnancy, any anticoagulants given within the previous 48 hours (axcept aspirin), uncontrolled hypertension (systolic BP >200 mmHg, diastolic >120 mmHg), etc, were excluded. | Streptokinase (Hoechst, Australia) 1.5 MU in 100 mls of normal saline IV over 1 hour vs identical-looking placebo (prepared by Berhingwerke, Germany, in association with Heochst). Infusion to be stopped and IV Haemaccel given (plasma expander) should the BP fall below 100mmHg systolic (or by more than 20mmHg from the initial systolic BP) during the infusion. This procedure to be repeated should hypotension occur again, but the infusion to be completed within three hours or abandonned.
Aspirin 100 mg to be given orally within 4 hours of the trial treatment infusion and thereafter daily for the duration of the study. No other anticoagulants to be given within 48 hours of the trial treatment. |
Death and dependency at 3 months assessed by the Barthel Index, ie favourable outcome = alive and Barthel Score > 60, unfavourable = dead or Barthel Score < 60; CT scan at 7 - 10 days (or sooner if clinically indicated) to look for cerebral haemorrhage. | Terminated prematurely after randomisation of 340 (of the intended 600) patients, initially just the 3-4 hour randomisation (because of significant excess early mortality in the streptokinase group) and then all randomisation because the randomisation rate within 3 hours was too slow to be viable. Apparent excess of problems with hypotension during the SK infusion compared with MAST-I and MAST-E (20% in ASK vs only a few % in the two MAST trials), and note routine use of aspirin within 4 hours of trial treatment. |
| ATARASHI 1985 | Sealed prepacked drug or placebo Double-blind Not intention-to-treat |
Presumed cerebral arterial thrombosis (angiography where possible), < 5 days, aged 18 years and up, entry CT. Excluded presumed embolic stroke, severe neurological deficit. | High dose urokinase (240000 u/day iv for 7 days) versus low dose (60000 u/day iv for 7 days) versus identically appearing placebo. The high and low dose patients were analysed as one group for the purpose of this review, ie the comparison is "any urokinase treatment versus placebo". | Clinical improvement (Final Global Improvement Rating) at 4 weeks from start of treatment, safety (absence of side effects), including follow up CT if neurological deterioration | Further information provided by Prof Ohtomo, co-investigator. Six patients were excluded from analysis prior to breaking the randomisation code as the diagnosis thought not to be stroke (four treated low dose, two placebo). |
| ATLANTIS A 1999 | Double blind, placebo controlled. Randomisation was by selection of a numbered treatment pack held in the participating centre (of tPA or identical-appearing placebo). The numbered pack had been identified by telephoning the Trial co-ordinating centre in advance of the arrival of the next patient to be randomised. Once administered, the trial co-ordinating centre was phoned to inform them of the patient's details and identify the next treatment pack to be given to the next patient to be randomised. | Aug 1991 to Nov 1993. Any acute ischaemic stroke who could be randomised and start treatment within 6 hours of clearly defined stroke onset. Patient selection criteria believed to be otherwise similar to those in the NINDS trial. CT scan mandatory prior to randomisation to exclude cerebral haemorrhage, but NO exclusion criteria based on visible infarction. Age > 18 years, ? upper age limit | Alteplase (tPA - Activase, Genentech, South San Francisco) 0.9 mg/kg body weight to a maximum of 90 mg, in 100 ml normal saline, the initial 10% given as a bolus and the rest over an hour intravenously. Blood pressure control as for NINDS. Aspirin and anticoagulants to be avoided for the first 24 hours, but could be used thereafter. | NIH Stroke Scale improvement at 30 days. Death and dependency at 90 days (modified Rankin 2-6), Barthel, NIH Stroke Scale. Cerebral haemorrhage on repeat CT.
The final follow-up assessment was performed by a neurologist who had not cared for the patient at randomisation or during the first few days after treatment |
Stopped in November 1993, protocol modified and continued as ATLANTIS B in the same centres. 42 active centres, 142 patients randomised. |
| ATLANTIS B 1999 | Double blind, placebo controlled. Randomisation was by selection of a numbered treatment pack held in the participating centre (of tPA or identical-appearing placebo). The numbered pack had been identified by telephoning the Trial co-ordinating centre in advance of the arrival of the next patient to be randomised. Once administered, the trial co-ordinating centre was phoned to inform them of the patient's details and identify the next treatment pack to be given to the next patient to be randomised. | Dec 1993 to Jan 1996, 0 - 5 hour time window; Feb 1996 to end of trial 3 - 5 hour time window and CT exclusion criteria introduced (visible infarction in > 1/3 of the MCA territory excluded). Within the above time periods, any acute ischaemic stroke with clearly defined symptom onset who could be treated within the specified time period. Age >18, ? upper limit. CT prerandomisation mandatory to exclude cerebral haemorrhage only until Feb 1996, but thereafter also to exclude visible infarction in more than a third of the MCA territory. 120 centres active. | Alteplase (tPA - Activase, Genentech, South San Francisco) 0.9 mg/kg to max dose of 90 mg in 100 ml normal saline or identical appearing placebo, the first 10% as a blous and the rest infused over an hour intravenously. Aspirin to be avoided within the first 24 hours, but could be used thereafter. | NIH Stroke Scale, modified Rankin (death or dependency = 2 - 6, Barthel Index at 90 days. Death. Cerebral haemorrhage (symptomatic and fatal).
The final follow-up assessment was performed by a neurologist who had not cared for the patient at randomisation or during the first few days after treatment. |
Stopped in mid 1998 following a "futility analysis", prior to the publication of ECASS 2. Data on all 619 patients randomised has not yet been presented, only on 547 randomised between 3 and 5 hours. |
| ECASS 1995 | Sealed drug prepacks (no central telephone randomisation). Double blind. Only intention-to-treat data used in this review. | Acute MCA territory ischaemic stroke who could be randomised and start treatment within 6 hours of symptom onset.
Pre entry CT to exclude cerebral haemorrhage and patients whose infarct was already visible; age >18 and <80 years. Exclude patients with mild strokes or whose symptoms were rapidly improving, in coma, BP >110 diastolic and >200 systolic; recent trauma or surgery, pregnancy, weight > 100 kg (because of dose limit), etc. |
Actilyse (recombinant tissue Plasminogen Activator, tPA) 1.1 mg/kg body weight up to a max of 100 mg (Boehringer Ingelheim, Germany), or identical-appearing placebo, intravenously. The first 10% of the total dose was given as a bolus followed by infusion of the remainder over 60 minutes.
All anticoagulants and aspirin to be avoided in the first 24 hours (subcutaneous heparin allowed); thereafter the use of these drugs was at the discretion of the attending physician. |
Primary: Barthel Index and Modified Rankin scores at 90 days. Secondary: mortality at 30 days; various combined stroke scores at 90 days; duration of hospital stay. Rankin 2 or worse = disabled on this modified scale: 0 = no symptoms, 6 = dead. | Trial sponsored by Boehringer-Ingelheim. Results presented as ITT analysis and "Target Population" ie after exclusion of protocol violations most of which were due to visability of early signs of cerebral infarction on the randomisation CT on review by the central CT monitoring committee. In this review, only the ITT data have been used. The published data were supplemented by additional information from the principal investigators, and with data presented at the meeting organised by the sponsors to present the results held in Barcelona in March 1995. |
| ECASS II 1998 | Double-blind, placebo controlled, randomisation by sequential numbered packs at each centre (the allocation having been generated randomly centrally) | Acute hemispheric ischaemic stroke, patients aged 18 to 80 years, within six hours of onset, CT having excluded intracranial haemorrhage AND visible infarction in more than a third of the MCA territory. | Actilyse (recombinant tissue Plasminogen Activator, t-PA) 0.9 mg/kg to a maximum dose of 90 mg (Boehringer Ingelheim Germany), or identical appearing placebo, 10% given as a bolus and the rest infused over one hour, to be started within six hours of stroke onset.
Aspirin and anticoagulants (apart from subcutaneous heparin) to be avoided in the first 24 hours ; thereafter the use of these drugs was at the discretion of the attending physician. |
Death or Dependency at 90 days defined as Modified Rankin 2 - 6, intracranial haemorrhage, death. Various other scores at 90 days. | |
| HALEY 1993 | Randomised blinded placebo controlled. Sealed envelope treatment allocation, opened by pharmacist at randomisation and appropriate infusion made up. Other study personnel remained blinded. Not intention-to-treat. | Ischaemic stroke <90 or <180 minutes from onset, 18-80 years, pre entry CT. Excluded TIA, very mild and very severe neurological deficits. | tPA (Alteplase, Genentech) 0.85 mg/kg or identically appearing placebo IV over 60 minutes. Early (0-90 min) versus late (91- 180 min) treatment versus placebo, although in this review the early and late groups have been analysed together, ie the comparison is "any tPA versus placebo".. | Clinical improvement using NIH Stroke Scale at 24 hrs, 2+7 days, and 3 months. Follow up CT at 24 hrs, 7 days and 3 months for infarct volume and haemorrhagic transformation. | Pilot for larger NINDS tPA trial. |
| JTSG 1993 | Sealed identical prepacks of drug or placebo. Double-blind. Not intention-to-treat. |
Thromboembolic stroke < 6 hrs, aged 18-80 years, pre entry CT and angiography. Excluded haemorrhagic stroke or patent cerebral arteries at angiography. | 20 MIU duteplase v identically appearing placebo, IV over 60 mins. duteplase supplied by the Sumimoto Corporation, Japan. | Reperfusion (immediate post infusion angiography), clinical improvement using Hemispheric Stroke Scale (HSS) at 4 weeks after stroke; haemorrhagic transformation on follow up CT; death. | 112 pts recruited, 14 excluded for protocol violations before breaking the randomisation code, analysis is of 98 patients who completed the study. Further information provided by Prof Yamaguchi. |
| MAST-E 1996 | Double blind, randomised controlled trial; central telephone randomisation; sealed prepacks of drug (SK) or identical placebo; intention-to-treat. | Patients with symptoms of large acute ischaemic stroke in the middle cerebral artery territory who could be randomised and start treatment within 6 hours of symptom onset; age > 18yrs, but no upper limit; CT scan mandatory prior to randomisation to exclude cerebral haemorrhage. Exclusions : patients with mild neurological deficit (MAST Unified Scale >55), or who were improving rapidly when assessed; previous disabling stroke; pregnancy; systolic BP >220, diastolic BP >110; oral anticoagulants (not aspirin); recent trauma, surgery, peptic ulcer disease, etc. | Streptokinase 1.5 MU in 100 ml normal saline intravenously over one hour versus identically appearing placebo. Heparin and aspirin use were allowed in the first 24 hours (as well as later) at the discretion of the attending physician provided that the dose, route and time of administration were recorded. | Death and disability (MAST unified scale, Rankin and Barthel scales) at ten days and six months after randomisation (disability = Rankin 3 or worse); cerebral haemorrhage within the first ten days; other adverse events (hypotension, systemic haemorrhage). Death and disability at one year is being collected. | Trial terminated in September 1994 after 310 patients had been randomised on the advice of the Data Monitoring Committee due to an excess of cerebral haemorrhages and associated early mortality in the streptokinase treated group. Original sample size was to have been 600 patients.
The results included here are only for the first 270 patients which appeared in the Lancet in Jan 1995 - the full results on the 310 patients cannot be included until the trial has been published in full. Note the frequent use of heparin (25%) and aspirin (13.5%) within 24 hours of trial treatment and during the first two weeks (65% and 25% respectively). |
| MAST-I 1995 | Randomised controlled trial with 2 x 2 factorial design; central telephone randomisation; intention-to-treat; control group did not receive a placebo but six month follow-up was by blinded investigators. | All acute ischaemic stroke who could be randomised and start treatment within 6 hours from symptom onset; age > 18yrs, but no upper limit; pre-entry CT mandatory to exclude cerebral haemorrhage.
Exclusions : rapidly improving symptoms likely to be a TIA; recent trauma or surgery; oral anticoagulant treatment (not aspirin); aspirin or SK not either definitely indicated or definitely contraindicated; SK in the past year, etc. |
Streptokinase 1.5 MU iv over one hour immediately after randomisation, or aspirin 300 mg oral started immediately and continued for 10 days (or via nasogastric tube, per rectum, or IV in Italy), or both, or neither. Other anticoagulants to be avoided within the first 24 hours, but could be used therafter. Aspirin use encouraged after 10 days or at hospital discharge (whichever came first). | Death within the first 10 days; cerebral haemorrhage; death and disability at 6 months (Rankin scale : disabled = Rankin 3 or more). One year follow up is also being performed. | Trial suspended after 622 patients randomised because of slow randomisation rate partly due to increasing confusion about thrombolysis in stroke from MAST-E and ASK. |
| MORI 1992 | Identical coded drug prepacks Double-blind Not intention-to-treat |
Ischaemic stroke in carotid territory < 6 hrs from onset, aged <80 yrs, pre entry CT (to exclude haemorrhage) and angiography (to confirm arterial occlusion). Excluded patients in deep coma. | Duteplase (Sumitomo Pharmaceuticals, Tokyo) 20 or 30 MIU versus identical placebo IV over 1 hr. The 20 and 30 MIU groups were analysed as one group in this review, ie the comparison is "any duteplase versus placebo". | Reperfusion at 60 mins after start of infusion, clinical status at 30 days using modified Hemispheric Stroke Scale (HSS). CT at 1, 2, 7 and 30 days for haemorrhagic transformation. | Additional information from Prof Mori. Unbalanced numbers due to accidental loss of a 20 MIU dose pack and substitution with placebo. No patients excluded therefore an ITT analysis was possible. |
| MORRIS 1995 | Randomised, double blind trial of streptokinase 1.5MU or placebo. Randomisation method not stated (sequentially number drug prepacks probably). Intention-to-treat. Note saline is not an identical placebo for SK. | Anterior circulation acute ischaemic stroke who could be randomised and start treatment within six hours of onset, (CT mandatory to exclude any haemorrhage), aged 40 to 80 years, no previous stroke. | streptokinase 1.5MU iv over one hour versus saline placebo | death at three months, neurological improvement at three months, intracranial haemorrhage. | No additional information forthcoming from the authors. |
| NINDS 1995 | Randomised, placebo controlled, blinded trial. Intention-to-treat. Randomisation was at the participating hospital by sequentially numbered drug (or identically appearing placebo) prepacks, followed within two hours by a telephone call to the Trial Co-ordinating centre to notify them that a patient had been randomised. | Patients with ischaemic stroke (CT mandatory to exclude intracerebral haemorrhage) with a clearly defined time of symptom onset who could receive the trial treatment within 180 minutes of symptom onset; age >18 and <80 years; a neurological deficit measurable on the NIH stroke scale (ie not very mild and not improving rapidly at the time of assessment) - thus cortical and lacunar strokes were eligible. Patients with previous stroke or head trauma within 3 months, pregnancy/lactation, abdominal surgery, heparin within 48 hours or deranged clotting factors/platelets, systolic BP >180 or diastolic BP >110 (+ various other features) were excluded. | Alteplase (Activase, Genentech, South San Francisco - a recombinant tissue-type plasminogen activator) in a dose of 0.9 mg per kg body weight (max dose 90mg) or identical-appearing placebo (prepared by Genentech) given intravenously. The first 10% of the dose was given as a bolus followed by the remainder as a constant infusion over 60 minutes.
No antiplatelet or anticoagulants were to be given during the first 24 hours after randomisation, and the blood pressure had to be kept within prespecified limits ( <180 systolic and <110 diastolic). The patients randomised within the first 90 minutes after the stroke were analysed separately to those randomised between 91 and 180 minutes after the stroke in the publication but have been put together in this review. |
Assessment was by a physician who had not been involved in the randomisation or treatment administration using the following : NIH stroke scale at 2 hours after start of treatment, and at 24 hours, 7-10 days and 3 months after onset of the stroke. Glasgow outcome score at 3 months; Barthel Index at 7-10 days and 3 months; modified Rankin score (0 = no symptoms, 5 = severe disability) at 7-10 days and 3 months; CT scan at 24 hours, 7-10 days and 3 months. Rankin 2 or worse was the cut off for disability in the analysis. The data cannot be subdivided further at this point as the results have not yet been published by individual Rankin group. | The trial was conducted in two phases : the first (291 patients) was to assess the effect of tPA on outcome at 24 hours after the stroke; the second (333 patients) was to assess the effect of tPA on outcome at 3 months. The investigators remained blinded to the results of part 1 until the end of part 2. The protocols were identical for the two parts except for their primary hypotheses, ie patients in part 1 were followed up at the same time points as in part 2. Additional information to that published is being sought from the principal investigators, but has not yet been received. |
| OHTOMO 1985 | Randomised, double-blind. Identical prepacked drugs. Not intention to treat. | Presumed "non-embolic" ischaemic stroke < 5 days, no age limit, pre-entry CT. | Urokinase 60000 U/day IV over 1 hour for 7 days versus identically appearing placebo. Urokinase supplied by Abbott Labs, USA. | Clinical status (Global Improvement and Severity Ratings) and safety (absence of side effects) at 4 weeks from start of treatment. Follow-up CT to assess haemorrhagic transformation. | Additional information from Prof Ohtotmo. All cases accounted for including those who "dropped out", therefore an intention to treat analysis possible. |
| PROACT 1998 | Double blind, placebo controlled; centralised randomisation; follow-up blinded to treatment allocation by an independent neurologist who was blinded to the angiogram findings and in-hospital course. | Subjects aged 18-85 without prior stroke, within six hours of onset of symptoms indicative of an MCA occlusion, NIHSS score >4 and <30, and who had an MCA occlusion (complete or major branch) on conventional intraarterial angiography. | Recombinant prourokinase 6mg or saline placebo intraarterially through the angiogram catheter with the tip in the thrombus. Heparin was also administered in a high dose to the first 16 subjects, and thereafter in a lower dose, so the study was confounded. Funding and drug supplied by Abbott Laboratories. | Recanalisation of the MCA at 120 mins after treatment infusion; NIHSS, Barthel, Rankin, at 7, 30 and 90 days after treatment; haemorrhagic transformation of the infarct, extracranial bleeding, deaths. | This trial was confounded by heparin (the dose of which was altered half way through the trial, and was testing intraarterial not intravenous thrombolysis. It has been included in the present data tables, though in a separate subgroup, until further information on intraarterial thrombolysis becomes available to make a separate review worthwhile. |
| PROACT 2 1999 | Randomised, controlled trial with central telephone randomisation. No placebo. Follow-up assessment by a neurologist blinded to the angiogram result, treatment allocation, and to the in-hospital course, who was not involved in the care of the patient during the acute treatment phase. Analysis was by intention to treat. | Acute ischaemic stroke, aged 18-85 years, with NIH stroke scale > /= 4 but < 30, without visible infarction in > 1/3 of the MCA territory on baseline CT scan, with angiography-proven MCA main stem (M1) or major branch (M2) occlusion, within six hours of onset of stroke symptoms. Randomisation stratified by stroke severity according to the baseline NIH Stroke Scale, and two patients allocated to active treatment for every one allocated placebo. | Intraarterial pro-urokinase (Abbott Laboratories) 9 mg given intra-arterially through the angiography catheter with the tip embedded in the thrombus. No placebo. Intravenous heparin 2000 IU bolus IV at time of angiography followed by 500 IU/hour IV for four hours, to both treatment groups. | Rankin | During the trial, 12323 patients were screened, of whom 476 underwent angiography and only 180 were randomised. |
Table of excluded studies |
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| Study | Reason for exclusion |
| DON-CAI YUAN 1995 | Don-Cai Yuan, et al: High dose urokinase in the treatment of acute ischaemic stroke. J of Brain and Neurological Diseases 1995;3(2):111. (Chinese - abstracted by Dr Ming Liu).
A randomised trial of intravenous urokinase 8000-10000 u/kg (total 600,000-900,000 ) plus Nimodipine, Vit E and C, Aspirin, mannitol, dexamethasone, nidocain and snake venom, versus "conventional treatment" (ie everything except urokinase) given over 40 minutes within two days of onset of ischaemic stroke; UK 10,000 - 15,000 repeated the following day if no improvement. Follow up was using the Chinese Neurological Scale at only two weeks after treatment. No long term follow up. This scale does not appear to measure dependency. A total of 80 patients were randomised, 40 per treatment arm. There is no mention of the number who died or had symptomatic intracranial haemorrhage. The trial was excluded because of the short follow-up period. |
| EDINBURGH 1991 | This trial stopped after randomisation of four patients. |
| HONG KONG 1994 | This trial of iv streptokinase, stopped prematurely after randomisation of only a few patients because of concerns about use of streptokinase arising from termination of MAST-E, ASK and MAST-I. |
| MEYER 1963 | Although randomised and controlled, this trial was conducted in the pre-CT era. Thus there was no way of being sure that only ischaemic stroke patients were included. |
| MEYER 1964 | Although randomised and controlled, this trial was conducted in the pre-CT era and therefore there was no way of being sure that only ischaemic strokes were included. |
| NAITO 1984 | The data are presented in two, possibly three, different publications. Many patients were lost to follow-up during the four week trial period. Dr Naito has died and Professor Abe is unable to supply further information on those lost to follow-up. Although there were no deaths or cerebral haemorrhages among the patients who completed the four week trial period, the data are incomplete and may be badly skewed by lack of information on what happened to the patients who "dropped out". |
| PANG SHI-QI 1993 | Pang Shi-qu, et al: Clinical study of therapeutic effectiveness in treating ischaemic cerebrovascular disease with lumbrokinase. Chinese Journal of Neurology and Psychiatry 1993;26(4):229-231. Data extracted by Dr Ming Liu.
Appears to be a randomised trial (method uncertain) of lumbrokinase two tablets daily for 21 days versus placebo. 303 received lumbrokinase and 150 placebo, both groups received dextran. Very little known about outcome. Follow up was at three weeks only, therefore this trial was excluded. No information on deaths or intracranial haemorrhages. There is thought to have been conflict between the authors and the pharmaceutical sponsor so no further details have been published (Ming Liu, personal communication). |
| ZHANG YUAN XIANG1995 | Zhang Yuan Xiang et al: Thrombolytic therapy and external counterpulsation in acute cerebral infarction. Proceedings of the Fourth Chinese Stroke Conference, Chengdu, Oct 1995, p44 (abstract). Data extracted by Dr Ming Liu.
Randomised trial (method unknown) of intraarterial urokinase 300,000-1,000,000 units for one hour plus heparin, plus a "physical therapy" (nature uncertain) plus "conventional treatment" versus "conventional treatment" (nature uncertain) started within six hours of onset of acute ischaemic carotid territory stroke. 67 patients were included, 32 in the active and 35 in the placebo arms. Follow-up was at three months using a neurological deficit score. The number of deaths and intracranial haemorrhages was not mentioned. The trial was excluded because of the confounding of treatment allocation. |
