Randomised controlled trial of streptokinase, aspirin, and
combination of both in treatment of acute ischaemic stroke
Multicentre Acute Stroke
Trial—Italy (MAST-I) Group*
Summary
Introduction
ischaemic stroke, thrombolytic drugs speed the
recanalisation of intracerebral arteries. The effects of
aspirin are not known. A trial was conducted to determine
whether, separately or together, streptokinase and aspirin
have clinical benefits in acute ischaemic stroke similar to
those in acute myocardial infarction. 622 patients with
acute ischaemic stroke within 6 hours of symptom onset
were randomised with a 2x2 factorial design to (i) a 1-hour
intravenous infusion of 1·5 MU streptokinase, (ii) 300
mg/day buffered aspirin for 10 days, (iii) both active
treatments, or (iv) neither. Early results raised a question
whether the trial should be continued.
Streptokinase (alone or with aspirin) was associated
with an excess of 10-day case fatality (odds ratio 2·7; 95%
Of the four
confidence interval 1&middot;7-4&middot;3; 2p<0&middot;00001).
allocated
to
randomised,
only patients
groups
streptokinase plus aspirin had a significantly higher risk of
early death than those given neither streptokinase nor
aspirin (odds ratio 3&middot;5; 95% Cl 1&middot;9-6&middot;5; 2p<0&middot;00001).
Streptokinase (alone or with aspirin) and aspirin (alone or
with streptokinase) reduced, albeit not significantly, the
incidence of combined six-month case fatality and severe
disability: odds ratio for streptokinase 0&middot;9 (95% Cl
0&middot;7-1&middot;3) and odds ratio for aspirin 0&middot;9 (95% Cl 0&middot;6-1&middot;3).
The risk of early death with thrombolytic treatments
should be weighed against the potential benefit of a
marginal reduction of severe disability after the first six
months.
Stroke, a severe disease in terms of both mortality and
disability, still lacks an effective treatment. In myocardial
infarction, thrombolytic treatments administered within 6
hours reduce mortality by about 30 per 1000 patients’
and increase the early recanalisation rate of coronary
vessels.2 In ischaemic stroke these drugs increase and
speed the recanalisation of intracerebral arteries, but their
In
1
clinical effectiveness remains uncertain.3 Controlled
clinical trials on stroke take a long time to start and to
conduct because patients are difficult to recruit within a
few hours of symptom onset and because the risk of
haemorrhagic transformation is higher than in myocardial
infarction. Haemorrhagic transformation and clinical
worsening was reported in 12% of patients receiving a
thrombolytic within 8 hours5 after stroke and in 4% of
patients treated within 90 minutes.6 What about aspirin?
Few data are available on the effectiveness of aspirin in
acute stroke whereas in acute myocardial infarction an
aspirin tablet given very early after symptom onset
reduces the mortality rate from 13% to 10%.8
A controlled multicentre clinical trial of streptokinase
and aspirin in acute stroke, MAST-1(Multicentre Acute
Stroke Trial-Italy), was planned in 1991. The aim was
to determine whether there is a favourable risk to benefit
ratio for streptokinase and/or aspirin. In January, 1995,
the data monitoring committee suggested that the steering
committee should examine the results, indicating that
there was an early hazard from thrombolytic therapy,
though after six months the proportion of patients who
were
dead or disabled was very similar in those
randomised to thrombolysis and those randomised to
control. The study was then interrupted and the data
were analysed to aid a decision about possible trial
closure. The results are presented and discussed here.
Patients and methods
MAST-1is a controlled, randomised, multicentre, open trial. The
protocol has been presented elsewhere.9 From May, 1991, to
February, 1995, a total of 14 083 patients were referred to the 70
participating centres in three countries of whom 622 (5%) were
randomised.
Eligibility
*Collaborators and
the report
participating
centres
are
listed at the end of
Correspondence to: Prof Livia Candelise, Istituto di Clinica
Neurologica, Via F Sforza 35, 20122 Milano, Italy
Patients were eligible if they were admitted to hospital after
sudden development of a focal neurological deficit attributable to
stroke, within 6 hours of symptom onset and with no clear
indication for or contraindication to streptokinase or aspirin.
Computed tomographic scanning was compulsory before
randomisation. Reasons for exclusion were intracerebral
haemorrhage, severe coma without any purposeful motor
response, rapid resolution of neurological symptoms, and any
medical disorders or exposure to drugs that might interfere with
the safety or efficacy evaluation. A register was kept of eligible
but non-randomised patients. The study was carried out in
accordance with the Declaration of Helsinki as amended in
Tokyo and Venice (1983), but written consent was not
1509
mandatory and was not always obtained. The policy regarding
requests for consent was left to the local investigators, who
respected the patient’s wishes as far as possible.
Treatment
Streptokinase (Kabi, Sweden) 1-5 MU was infused intravenously
1 hour in 1 dL physiological saline. Oral aspirin (300 mg
buffered tablets) was given daily, the first dose immediately after
randomisation and then every day until day 10. In patients
unable to swallow, crushed tablets via nasogastric tube,
intravenous aspirin (100 mg lysine salt of acetylsalicylic acid
dissolved in 1 dL saline), or aspirin rectal suppositories were
used instead. Physicians were free to use whatever additional
therapy they judged necessary; however, thrombolytics, heparin,
oral anticoagulants, and antiplatelet treatments were to be
avoided for the first 10 days. Subcutaneous calcium heparin was
allowed at a dose no higher than 15 000 U daily.
over
Randomisation
A 2x2factorial study design was used. Patients were randomly
assigned in equal proportion to four treatment groups:
streptokinase alone, aspirin alone, both, or neither. The
randomisation lists were generated by computer and stratified by
centre. Entry to the study was by a 24-hour telephone service,
based in Milan for Italy and in Oxford (UK) for the other
countries. Before randomisation some details were recorded
including patient identifiers, age, time of onset (when unknown it
was considered as the mid-point between the last time the patient
was seen in good condition and when he/she was discovered with
symptoms), severity (stupor, drowsiness, and paralysis or paresis
if motor deficit was present) and type of neurological deficit
(aphasia, sensory, visual, and vertebrobasilar symptoms),
electrocardiogram, and CT scan results. A standardised
definition of all clinical variables was provided with the protocol.
If any prerandomisation details were incomplete, the
randomisation code was not issued, thus the patient was not
included in the trial. After allocation to a specific treatment
group the patient was irrevocably in the trial. Whether or not the
treatment was actually given and/or the follow-up was completed,
patients remained in their originally allocated treatment group
for an "intention-to-treat" analysis.
Discharge
The
patients
were
observed
during
the
10
0
days
after
randomisation, and compliance with trial treatments, protocol
deviations, and the occurrence of major in-hospital events or
death were evaluated. A second CT scan was performed on all
patients during this period, preferably on day 5. CT was repeated
if a new stroke occurred. At discharge, copies of CT scans and a
simple two-page form were returned to the trial office as well as
the patient’s clinical record if major events or death had
occurred. Each CT scan was read by members of the
neuroradiological reviewing committee who were blind to
treatment allocation. If haemorrhagic transformation was present
this was classified as follows: (1) intracerebral haemorrhage
(homogeneous region of high attenuation exceeding the vascular
territory of the presumed infarction); (2) haemorrhagic infarction
type III (homogeneous region of high attenuation of total
presumed cerebral infarct area); (3) haemorrhagic infarction type
II (large homogeneous or heterogeneous region of high
attenuation within an infarct area); (4) haemorrhagic infarction
type I (small petechial and linear high attenuation region within
an infarct area).
The clinical record of any patient who died or had a major inhospital event was blindly reviewed by the clinical reviewing
committee. The events and causes of death were independently
adjudicated according to the protocol definition as follows: (1)
symptomatic cerebral haemorrhage (sudden neurological
worsening after a period of good recovery or stable condition,
with CT scan or necropsy documented intracranial haemorrhage
or haemorrhagic infarction); (2) cerebral infarction (sudden
neurological worsening after a period of good recovery or stable
1510
*2p<O.01; -j’2p<0’001. Fhree missing observations.
Tablel : Baseline characteristics according to treatment group
condition, without intracranial haemorrhage or haemorrhagic
infarction); (3) cardiac event (fatal or non-fatal myocardial
infarction, heart failure, or arrhythmia followed by death, sudden
death); (4) anaphylactic shock (severe respiratory distress with
urticaria or angioneurotic oedema followed by arterial
hypotension and oliguria, occurring within 12 hours of
treatment); (5) systemic haemorrhage (extracerebral severe
bleeding, requiring immediate treatment with at least one unit of
blood). In the event of discordance cases were rediscussed to
reach final agreement.
Follow-up
Patients
assessed six months after randomisation by
use of the telephone to evaluate the
outcome of acute stroke had been validated previously.lo The
evaluation was performed by a single rater for each country,
"blind" to treatment allocation. In surviving patients, disability
was assessed on a modified Rankin scale with five levels: (1) not
were
telephone interview. The
significant (able to carry out all previous activities); (2) slight
(unable to carry out some previous usual activities but able to
attend to own bodily needs without assistance); (3) moderate
(requiring some help for bodily needs and/or unable to walk
without some assistance or physical device); (4) severe (unable to
attend to bodily needs and/or to walk without assistance); (5)
very severe (bedridden, incontinent, and requiring constant
nursing care and attention). In the present report the first two
categories are merged as favourable outcome, whereas death or
survival with Rankin score of three or higher was judged an
unfavourable
outcome.
fibrillation, and basal CT scan (absence or presence of focal
hypodense lesion). The type of stroke was classified according to
the type of neurological deficit as lacunar (presence of unilateral
pure motor, sensory, or sensory motor deficit for more than 24
hours), or non-lacunar syndrome.
Comparisons of in-hospital events and six-month outcomes are
presented in terms of odds ratios with 95% confidence intervals
Table 2: Effect of allocated treatment
and 6-month outcomes
on
10-day case fatality
(CI).
During recruitment, interim data on in-hospital events and
follow-up outcomes were to be reviewed on four occasions, after
enrolment of 100, 300, 500, and 600 patients. The data
monitoring committee were to advise the steering and organising
committee to suspend at least one arm of the trial if a difference
of over three standard deviations was shown in favour
disfavour of streptokinase or aspirin therapy.
follow-up
None of the 622 patients was lost to follow-up. In 29 of them
interviews were conducted earlier-between three and
six months after stroke onset in 20 and before three months in 9.
Results
Sample size
to
A conservative sample size of 1500 cases was calculated, on the
assumption that about 50% of patients in a control group would
have an unfavourable outcome at six months and that the
reduction achieved with streptokinase or aspirin would be 20%,
with an alpha and beta error of 5 % in a two-sided comparison.
Statistical method
protocol specified two main analyses. These involved
of (i) the effects of intravenous streptokinase (alone
or in combination with aspirin) versus no streptokinase (aspirin
alone or neither drug) and (ii) the effects of aspirin (alone or in
combination with streptokinase) versus no aspirin (streptokinase
alone or neither drug) on the combined endpoint of death and
severe disability at six months. It also specified three secondary
analyses-on the effect of the three active treatments separately
neither drug (streptokinase alone, aspirin alone,
versus
streptokinase plus aspirin); the risk of in-hospital mortality or
cerebral haemorrhages; and subgroup analyses according to age,
hours from onset, severity of neurological deficit (severe if the
patient presented problems of alertness or at least one paralysed
limb, slight no more than one paretic limb or only non-motor
deficit), type of stroke, systolic and diastolic blood pressure, atrial
The
assessment
or
patients were randomised-157 to streptokinase, 153
aspirin, 156 to streptokinase plus aspirin, and 156 to
neither. The treatment groups were comparable for the
main pre-randomisation prognostic features except for
hours from onset and type of stroke (table 1).
Streptokinase infusion was interrupted in 31 of the 313
cases and compliance was complete in 90% of patients.
Systemic bleeding was observed in 2 patients, persistent
hypotension in 6, and allergic reaction in 12. In 14 cases
there were other reasons for interruption. In the 309
patients given aspirin, 95% of those discharged alive had
continued their trial tablets for 10 days. Systemic bleeding
(7 cases) and allergic reaction (3) were the most frequent
causes of interruption. Severe systemic haemorrhages
requiring transfusion of at least one unit of blood
occurred in 2 patients, one receiving streptokinase and
one aspirin. Non-fatal anaphylactic shock developed in
one patient treated with streptokinase.
622
Main streptokinase and aspirin results (table 2)
There were 313 patients allocated to streptokinase
treatment (alone or with aspirin) and 309 allocated to the
V’:J
-L
L
Figure: 10-day case-fatality in various subgroups treated with streptokinase compared with controls
1511
in
both
the
streptokinase-plus-aspirin and the
streptokinase-alone groups (7% and 6%, respectively, vs
0-6%) and showed also an excess of haemorrhagic
infarctions in these groups (20% and 18% vs 10%). In the
aspirin-alone group the rates of symptomatic cerebral
haemorrhage (2%), CT scan intracerebral haemorrhage
(0-7%), and haemorrhagic infarction (7%) were similar to
or lower than those in the group given neither study drug.
The incidence rate of the combined six-month case
fatality and disability was lower in the streptokinase-alone
(62%), streptokinase-plus-aspirin (63%), and aspirin(61 %) groups with respect to the patients not given
treatments
(68%). However, none of these
between
treated groups and their control
comparisons
showed a statistically significant difference. The aspirinalone group had the lowest six-month fatality rate (20%)
and the highest disability rate (42%) and the
streptokinase-plus-aspirin group had the highest fatality
rate (44%) and the lowest disability rate (20%).
alone
these
*2p<001; t2p<0’001. All other differences with neither-drug group not statistically
significant.
Table 3: Distribution of in-hospital events, CT scan findings,
and 6-month outcomes by treatment group
Discussion
of the data collected so far in the MAST-1trial
indicate that streptokinase increases the risk of early death
in acute stroke patients-significantly if combined with
aspirin and not significantly if given alone. Moreover,
although thrombolytic and antithrombotic treatments
both seem to reduce six-month case fatality and disability,
no statistically significant evidence for effectiveness or
ineffectiveness of the two types of drugs could be
obtained, perhaps because of the low power of the study.
Analyses
control groups
alone
neither
The
drug).
(aspirin
primary outcome measure (sixmonth case fatality and disability) was 63% in the
streptokinase and 65% in the control group (OR 0&deg;9;
95% CI 0-7-1-3). However, patients allocated to
streptokinase had a higher 10-day case fatality than
controls (27% vs 12%, OR 2’7, 95% CI 1’7-4’3). Of the
83 deaths in the streptokinase-treated patients, 63 were
incidence
rate
or
of the
attributed to cerebral causes, 9 to cardiac causes, and 11
to other causes. There were 36 deaths in the control
group-20 cerebral, 6 cardiac, and 10 other causes. A
total of 309 patients received aspirin (alone or with
streptokinase) and were compared with 313 controls
(streptokinase alone or neither treatment). Aspirin did not
significantly increase the risk of early death (OR 1-5, 95%
CI 0-9-2-3). The effect of aspirin on six-month case
fatality and disability was in favour of this treatment but
the difference with respect to the control group was not
statistically significant (OR 0-9; 95% CI 0-6-1-3).
Subgroup analysis
identify the patients for whom thrombolytic treatment
was a particularly high risk, subgroups analyses on the
major basal clinical characteristics were performed
(figure). We found little evidence of heterogeneity among
subgroups except for hours from onset. There was a lack
of apparent risk in patients treated with streptokinase
To
within 3 hours from symptom onset, but this should be
viewed with caution since false negative results must be
expected in some subgroups only by chance, particularly
if the number of cases is very small.
Four-way comparison (table 3)
streptokinase and aspirin had a
significantly higher 10-day case fatality than those given
neither (34% vs 13%; OR 3&deg;5; 95% CI 1-9-6-5;
whereas the increase in early fatality in
2p<0’00001),
those allocated to streptokinase alone (19% vs 13%; OR
1-6; ; 95% CI 0-8-3-1; 2p=0-12) was not significant.
Symptomatic cerebral haemorrhages were more
and
in
the
frequent
streptokinase-plus-aspirin
in
the
than
streptokinase-alone groups
group given
neither drug (10% and 6%, respectively, vs 0&deg;6%). CT
scan confirmed the excess of intracerebral haemorrhages
Patients receiving both
1512
Streptokinase
study showed a 9% reduction in odds of death and
disability at six months for the 313 patients allocated to
streptokinase versus aspirin alone or neither drug and a
24% reduction for the 157 patients allocated to
streptokinase alone versus neither streptokinase nor
aspirin. These marginal results are consistent with an
This
overview of six randomised trials that revealed a 30%
reduction in the odds of death or deterioration for 350
patients allocated to thrombolytic treatment."11 The
potential benefit associated with the use of thrombolytics
should be contrasted with an increased risk of dying in the
acute phase. Two recent communications reported a
significant increase of early case fatality for acute stroke
treated with the same dose (1-5 MU) of streptokinase as
in the present study. The absolute increase of risk of 15%
in MAST-E (270 cases treated within 6 hours)12 and 22%
in the ASK study (228 cases treated between 3 and 4
hours) 13 is very near to the 15% found by us. An early
hazard of dying was observed also in acute myocardial
infarction’ during the 24 hours after therapy although this
was outweighed by a much larger benefit during the
subsequent period. The subgroup analyses of the present
study suggest that the risk of in-hospital mortality may be
lower in patients receiving thrombolytic therapy within 3
hours than in those receiving it within 6 hours of
symptom onset. A reduction has also been described in
acute myocardial infarction patients when the magnitude
of early hazard was linked to the interval between
symptom onset and subsequent treatment.2
Aspirin
Aspirin reduced the short-term and the long-term case
fatality although statistical significance was not reached.
The magnitude of reduction is similar to that found in
infarction. The possible benefit of
ischaemic
in
stroke is currently being tested
acute
aspirin
in the International Stroke Trial, a study of approximately
20 000 patients with acute ischaemic stroke who are being
treated with aspirin, heparin, both drugs, or neither
within 48 hours of the onset of symptoms.14 Our results
demonstrated only a slightly higher risk of symptomatic
intracerebral haemorrhage in patients treated with aspirin
(2%) than in those given neither of the study drugs
(0-6%). The systematic assessment with CT scan at 5
days showed fewer haemorrhagic transformations in
patients given aspirin (8%) than in those who received
neither aspirin nor streptokinase (10%). Thus although
acute
myocardial
aspirin induces a long-lasting platelet function defect and
prolongs the bleeding time it does not increase the risk of
intracranial haemorrhage.
Streptokinase plus aspirin
study provides evidence of a higher risk of
10-day case fatality with streptokinase plus aspirin than
with streptokinase alone. There are several possible
explanations. The combination of the two agents might
reduce haemostatic activity, favouring intracranial
bleeding. Experimental data suggest that aspirin
increases the risk of haemorrhagic infarction in animals
treated with alteplase,l&oacute; but in the present clinical study
no significant difference emerged between streptokinase
alone and streptokinase plus aspirin (6% vs 10%; OR 0-6;
95% CI 0-3-1-6; 2p=0-39); bleeding complications were
not the only cause of death in patients treated with
streptokinase plus aspirin. Other factors may account for
the excess of early case fatality in this treatment group.
For example, delayed reperfusion could worsen cellular
The present
15
metabolic function and increase oedema formation." This
hypothesis is supported by the observation that the early
hazard of dying was lower in patients treated very early.
Other workers have found that the more rapid the
recanalisation, the smaller the extent of cerebral
infarction. 18
Research implications
Identification of a subgroup of patients whose risk of
death in hospital will be reduced by treatment with
streptokinase (or streptokinase plus aspirin) is one of the
major issues in thrombolytic treatment for stroke. The
number of patients included up to now in each trial is far
too small to allow such analysis. These studies should be
continued in order to strengthen the power of subgroup
analyses in single trials. At the moment it is possible to
identify groups at high and low risk only by meta-analysis
of all published trials, which is urgently required. The
development of new thrombolytic agents, new drug
combinations, and new methods of administration could
create a window of opportunity to enhance the quality of
regional perfusion and to reduce side-effects in acute
cerebral infarction. Meanwhile, more stroke patients
should be assessed in the acute phase. 19
Clinical
implications
Thrombolysis and
aspirin both remain potentially
beneficial treatments for acute stroke but evidence of their
efficacy is still not available and their use in routine
practice should be avoided. However, if the absolute risk
reduction of 50-70 dead and disabled patients per 1000
patients treated, as suggested in this study, is confirmed in
larger trials, then these drugs could represent a clinically
useful treatment for acute stroke. Meanwhile all the
clinical and ethical implications of early risk (short-term
mortality) and potential benefit (survival free of severe
disability) from thrombolytic drugs should be evaluated
from the patient’s point of view. We need to clarify the
priority to be attached to the different outcome measures.
We should, however, emphasise that in the design of our
study the decision to establish the combined endpoint of
death and severe disability as a primary outcome measure
was taken explicitly on the basis of a value judgment that
for stroke patients (and their families) severe and
permanent disability could be considered as an event
closely resembling death .20 From the results of this study
and others already terminated but not yet published
(MAST-E, ASK, and ECASS), the medical community
must now decide whether clinical experimentation with
thrombolytic treatment in acute stroke ought to be
continued.
Tnal
organisation
Writing committee : L Candelise, E Aritzu, A Ciccone, S Ricci,
J Wardlaw.
Steering and organising committee: L Candelise, G Tognoni,
E Aritzu, A Ciccone, S Ricci, M C Roncaglioni,J Wardlaw (Istituto di
Clinica Neurologica, Universita degli Studi, Milano; Istituto di Ricerche
Famacologiche "Mario Negri", Milano (IRFMN); Clinica Neurologica,
Perugia; Institute of Neurological Sciences, Glasgow.
Data management office: E Negri, F Colombo (IRFMN).
Neuroradiological review committee: E Boccardi C De Grandi,
G Scialfa (Ospedale "Niguarda-Ca Granda", Milano).
Clinical reviewing committee: C Argentino (Umversita "La Sapienza",
Roma); V Bertele (Consorzio Mario Negri Sud, S Maria Imbaro);
A P Maggioni (IRFMN); P Perrone (Ospedale di Legnano).
Data monitonng committee: H J M Barnett (John Robarts Research
Institute, London, Ontario);J Bogousslavsky (CHU Vaudois, Lausanne);
A Del Favero (Policlinico, Perugia); U Lol (Corte d’Appello, Palazzo di
Giustizia, Milano); R Peto (Clinical Trial Service Unit, Oxford);
C Warlow (Western General Hospital, Edinburgh).
Orgamsational staff. S Canzi, S Comparetti (Istituto di Clinica
Neurologica, Universita degli Studi, Milano); F Clerici, A Palumbo,
G Sgaroni (IRFMN).
The following Centres participated (number of cases in parentheses):
Italy: Ancona-Ospedale di Torrette, Clinica Neurologica (S Polonara,
R Regmelli); Istituto Malattie del Sistema Nervoso (M G Ceravolo,
L Provinciali, R Regmelli); Ospedale INRCA, Divisione di Neurologia
(M Del Gobbo, 0 Scarpino) (12); Aosta-Ospedale Regionale, Divisione
Neurologica (E Bottacchi, G D’Alessandro, M Di Giovanni), Divisione
Radiologica (S Blanc), Divisione Geriatria (L Roveyaz) (11): ArezzoOspedale USL 23, Divisione Medicina la (L Ralli, D Vanni), Divisione
Radiologica (C Refi) (3); Bari-Ospedale Policlinico, Clinica Neurologica
I (F Federico, C Conte, V Inchingolo, R Insabato) (5); Bassano del
Grappa (VI)-Ospedale, USL 5, Divisione N eurologica (F Salsa,
A Lonzio) (11); Bergamo-Ospedali Riuniti, Divisione N eurologica I
(M R Rottoli, L Bruni, C A Defanti, L Fera) (31); Bergamo-Ospedali
Riuniti, Divisione Neurologica 2a (M Camerlingo, L Casto, B Censori,
A Mamoli) (24): Busto Arsizio (VA)-Ospedale Generale Provinciale,
Divisione Neurologica (D Porazzi, G Grampa, I La Spina) (13);
Caltanissetta-Ospedale "S Elia", Divisione Neurologica (L Giglia,
V Avenia, S Gueli) (2); Carpi (MO)-Ospedale "B Ramazzini", USL 14,
Divisione Neurologica (V Lolli, V Miele, M Santangelo) (23); Casarano
(LE)-Ospedale Civile "F Carrano", Divisione di Neurologia
(G Coppola, G Trianni, M Marra, E Greco) (18); Cesena (FO)Ospedale "M Bufalini", USL 39, Divisione Medicina, Divisione
Neurofisiopatologica (D Tonti, E Pretolani) (3); Como-Ospedale "S
Anna", Divisione Neurologica (M Stellio, M Arnaboldi, R Ciola,
G Danieli, M Rezzonico) (6); Como-Ospedale "Valduce", Divisione
Neurologica (M Guidotti, G Pellegnni, F Raudino), Divisione Radiologica
(C Del Favero, T Frattini) (17); Crema (CR)-Ospedale Maggiore,
Divisione Neurologica (T Riccardi, C Levi-Minzi, F Locatelli, F Passeri)
(10); Empoli (FI)-Ospedale "S Giuseppe", Divisione di Medicina
(G Lombardo, F Cocco, M Pratesi, S Santini) (21); Firenze (Antella)Ospedale "S M Annunziata", Medicina Interna la (F Cardopatri,
0 Tafani); Medicina Interna 2a (G C Landini, E Pieragnoli); Medicina
Interna 3a (R Bellesi, L Bagnoli, A Ghetti, 0 B Marrazza, P Menegazzo)
(22); Firenze-Ospedale "S Giovanni di Dio", Divisione di Medicina
Interna (S Spolveri, C Cappelletti) (17): Foggia-Ospedale Riumti,
Divisione di Neurologia (G Candeliere, G Costantino, F D’Acuno,
T Lo Muzio, F P R-izzitelli); Radiologia Maternita (G Bovio, G P Grilli)
(20); Grosseto-Ospedale "Misericordia", USL 28, Divisione Neurologica
1513
(M Zocchi, I Mazzanti) (5); Grottaglie (TA)-Ospedale "S Marco",
Divisione di Medicma Rep Donne (G Pisapia, R Nuzzi, G Russo) (11);
Imola (BO)-Ospedale Nuovo, Divisione Medicina Generale (G Lama,
G Baldassarri, R Bettini, E Cani, E Cerioli, M De Giorgi, A Garagnani,
S Pasquali) (7): Imola (BO)-Ospedale Nuovo, Divisione di Genatria
(V Chioma, C Fini, G Marzara, A Balotta, D Bertuzzi, M Masina,
C Matacena, M Michelim, G Pirazzoli, C Sacchet) (2); Lecco-Ospedale,
USL 16, Divisione Neurologica (P Marotta, L Calvi, C Scaccabarozzi)
(1); Melegnano (MI)-Ospedale "Predabissi", USL 57, Divisione
Neurologica (C Menozzi, F Sasanelli, C Bascelli, V Pontrelli) (13); Merate
(CO)-Ospedale "S Leopoldo Mandic", USL 14, Divisione Neurologica
(F Schieroni, D Belvedere, E De Capitani, M Di Costanzo, M Rascaroli),
Servizio Radiodiagnostica (0 Citterio, R Milani, R Capialbi) (20);
Messini-Policlinico Universitario, la Clinica Neurologica (G Arena,
R Musolino, R Di Perri) (10); Milano-Ospedale "Fatebenefratelli’,
Divisione Neurochirurgica (C Bonaventi, F Finzi, A Messina,
V Romanazzi) (1); Milano-Ospedale Maggiore Niguarda Ca’Granda,
Divisione Neurologica (R Sterzi, G Bottini, I Santilli), Divisione Medicina
Generale 2a "Brera" (A Brucato, E De Juli, G Palmieri), Divisione
Medicina Generale 5a "Rizzi" (S Ragaini, G Thiella) (9); MilanoOspedale Maggiore Niguarda Ca’Granda, "Medicina Vergani", (C Alli,
L Carosella, G Rizzato) (2); Milano-Ospedale Maggiore Policlino,
Clinica Neurologica "Padiglione Ponti" (L Candelise, E Aritzu,
M Bianchi, A Ciccone, C Motto, G Pinardi, G Scarlato); Divisione di
Neuroradiologia (A Bettinelli) (21); Milano-Ospedale Maggiore
Policlinico, Medicina d’Urgenza (F Porro, A Randazzo) (!); MilanoOspedale "S Carlo Borromeo’, Divisione Medicina, 6&deg; piano (U Marini),
Divisione di Neurologia (P Lattuada, A Pietra) (3); Milano-Ospedale "S
Raffaele", Divisione Neurologica (M Franceschi, M A Voloute) (1);
Modena-Ospedale Civile, Divisione Medicina Generale I (G Malferrari,
M Bondi, W Garuti, L Melini) (1); Modena-Ospedale Policlinico,
Clinica Neurologica (A Colombo, G Alborini, P Panzetti, M Scarpa,
P Sorgato); Servizio Neuroradiologia (G Crisi) (1); Palermo-Ospedale
Civico, Divisione Neurologica (N Bonasera, F Basso, E Natali) (2);
Palermo-Villa Sofia, USL 61, Divisione Neurologica (P Monaco,
A M Gasparro, F Triolo) (22); Parma-Ospedali Riuniti, Istituto di
Neurologia, USL 8 (A Lechi, F Colonna, I D’Ascola, C Giorgi,
U Scoditti), Cattedra di Neuroradiologia (P Bassi, R Menozzi, P Piazza),
Medicina d’Urgenza (G Degliantoni, M Desimoni, A Giannini) (2);
Pavia-Fondazione Istituto Neurologico "C Mondino", Divisione III
(G Micili, D Bosone, A Cavallim, A Martelli); Policlinico S Matteo,
Presidio di Belgioioso (F Barzizza); Casorate Primo (PV)-Ospedale
C Mira (M Poli) (4); Perugia-Ospedale, USL 3, Clinica Neurologica
(S Ricci, S Biagini, G Capocchi, M G Celani, A Picchiarelli, E Righetti,
M Zampolini); Divisione Neuroradiologia (N Caputo) (19); PistoiaPresidio Ospedali Riuniti, USL 8, Divisione Neurologica (S Bartolini,
M Santoni, D Sita’, M Taglioli, G Volpi) (4); Pozzilli (IS)-Istituto
Scientifico "Sanatrix", Divisione Neurologica (F Rossi, F Aloy,
A E Castellano, F Minotta); Reparto di Anestesiologia e Terapia Intensiva
(A Gatta) (10); Prato-Ospedale, USL 9, Divisione Neurologica
(A Vinattieri, A Cantini) (2); Ravenna-Ospedale "S Maria delle Croci",
Divisione Nerologica (G G Rebucci, G Bissi) (4); Reggio CalabriaPresidio Ospedali Riuniti, USL 31, Divisione di Neurochirurgia e
Medicina (F De Blasi, E Pascarelli, F Turiamo) (3); Reggio EmiliaArcispedale "S Maria Nuova", Divisione Neurologica (D Guidetti,
M Baratti, G Ferrarini, E Ghidoni, G Greco, N Marcello, L Motti,
F Sohme’, S Terenziani, R Zucco); Divisione Radiologica (A Troiso);
Servizio Pronto Soccorso (M Veneziani, I Iori) (15); S Benedetto del
Tronto (AP)-Ospedale, USL 22, Divisione Neurologica (L Curatola,
G Bollettini, T Carboni, R Gobbato); Divisione Geriatrica 312
(P Infriccioli, D Sabatini, M Sfrappini) (18); Sassari-Ospedale, USL 1,
III Divisione di Medicina (A Fancellu, G Casu, M G Deledda, M A
Spanu); Universita di Sassari, Clinica Neurologica (A Pirisi, F A Marras,
G Rosati) (2); Seriate (BG)-Presidio Ospedaliero Bolognini, USL 30,
Divisione Neurologica (A Brambilla, G C Erli, B Felice, R Grandi,
D Mirabile, M Zadra) (25); Sesto S Giovanni (MI)-Presidio
Ospedaliero, USL 65, Divisione Medica "Campari" (R Cavestri, D Gori,
E Longhini) (21); Spoleto (PG)-Ospedale Civile "S Matteo degli
Infermi", Divisione Neurofisiopatologia-Medicina Generale Geriatria
(N Miele, G Divizia, S Grasselli, F Pezzella, F Zuccari) (9); TarantoOspedale Civile, Divisione Neurologica (L Sallusto, F Lincesso; Divisione
Radiologia (C Scarpati) (1); Terni-Ospedale "Santa Maria", Divisione
Neurologica (G Iannone, A Bartocci, F Costantini, L De Santis,
G Lancia, E Moschini, A Paci, A Sensidoni, A Trenta); Divisione
Neuroradiologica (N Bartolini, P Ottaviano) (18); Todi (PG)-Ospedale
Civile, Divisione di Medicina (B Biscottini, G Alunni, I Bartolini,
D Belladonna, A Boccali, M Cruciani, R Ibba, R Luccioli, A Marceca,
M Pacini, M Pallone) (2); Trento-Ospedale "S Chiara", Divisione
Neurologica (P Girardi, D Ornco) (1); Treviglio (BG)-Ospedale
Generale Provinciale, USL 32, Divisione Medicina 2a (E Lanza, A Ballini)
(4); Trieste-Ospedale Maggiore, Divisione Neurologica (F Chiodo
Grandi, G Musco) (2); Varese-Ospedale Multizonale, USL 3, Divisione
Medicina Generale (L Steidl, G Santoro, A Vemco) (5); VicenzaOspedale "S Bortolo", Divisione Neurologica (P Dudine, F Ferro Milone)
1514
(9); Zingonia (BG)-Policlinico "S Marco", Divisione Neurologica (L
Munari, A Perretti, M Porta); Servizio Terapia Intensiva (C Longoni, R
Ferani) (23).
UK: Belfast-Institute of Neurological Sciences, Department of
Neurology (M Watt) (1); Edinburgh-Western General Hospital,
University Department of Clinical Sciences (P Sandercock) (3);
Glasgow-Institute of Neurological Sciences, Department of
Neuroradiology (J Wardlaw) (2); Glasgow-Southern General Hospital,
Medical Unit A (A Fennetry) (1); Greater Manchester-Barnes Hospital,
The Robert Barnes Medical Unit (P Bannister) (1); Hull-Hull Royal
Infirmary, Department of Neurology (C E Clarke) (6); Leeds-St James
University Hospital, Department of Neurology (J Bamford) (2);
Sheffield-Royal Hallamshire Hospital, Department of Neurology
(G Venables) (9).
Portugal: Porto-Hospital Geral de Santo Antonio, Servicio de
Neurologia (M Correia) (12).
Acknowledgments
The study was partly supported by Pierrel SpA, Italy and Pharmacia
Therapeutics, Sweden. Pharmacia provided streptokinase and RhonePoulenc Rorer and Sanofi-Winthrop supplied aspirin.
We thank the Stroke Association for their support to the UK centres,
and the Ospedale di Sesto San Giovanni (Milano) and the Clinical Trials
Centre Service (Oxford) for the 24-hour randomisation.
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