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Thrombolytic therapy for acute stroke in the UnitedKingdom:
experience from the safe implementation ofthrombolysis in stroke
(SITS) register
K.R. LEES1, G.A. FORD2, K.W. MUIR3, N. AHMED4, A.G. DYKER5, S.
ATULA1, L. KALRA6,E.A. WARBURTON7, J.-C. BARON7, D.F. JENKINSON8,
N.G. WAHLGREN4
and M.R. WALTERS1 for the SITS-UK Group
From the1Division of Cardiovascular and Medical Sciences,
University of Glasgow, 2Institute for
Ageing and Health University of Newcastle, 3Division of Clinical
Neurosciences, University of
Glasgow, UK, 4Department of Neurology, Karolinska University
Hospital, Karolinska Institutet, SE-171
76 Stockholm, Sweden, 5The Newcastle upon Tyne Hospitals NHS
Foundation Trust, Newcastle,6Kings College Schools of Medicine,
London, 7Department of Clinical Neurosciences, University of
Cambridge and 8The Royal Bournemouth & Christchurch
Hospitals NHS Trust, Christchurch, UK
Received 20 June 2008 and in revised form 14 July 2008
Summary
Aim: To describe the United Kingdom (UK) experi-ence with
thrombolytic therapy with intravenousalteplase (rt-PA) for stroke,
as captured by theImplementation of Thrombolysis in Stroke
(SITS)project.Methods: The multinational Safe Implementationof
Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an
observational study to assess thesafety and efficacy of
thrombolytic therapy, whenadministered within the first 3 h after
onset ofischaemic stroke. SITS-MOST was embeddedwithin the Safe
Implementation of Thrombolysis inStroke-International Stroke
Thrombolysis Register(SITS-ISTR), an internet-based, international
moni-toring registry for auditing the safety and efficacy ofroutine
therapeutic use of thrombolysis in acuteischaemic stroke. We
performed an analysis of datacontributed to SITS-MOST and SITS-ISTR
from UKcentres.Results: A total of 614 patients received
thrombo-lysis for stroke between December 2002 and April2006, 327
were registered to SITS-MOST and 287 toSITS-ISTR. Thirty-one
centres treated patients inthe UK, of which 23 registered patients
in both
SITS-MOST and SITS-ISTR and eight solely toSITS-ISTR. The median
age from the UK SITS-MOST was identical to the non-UK
SITS-MOSTregister: 68 years (IQR 5975). The majority (96.1%)of
patients from the UK were treated between8.00a.m. and 9.00p.m., and
only 18.4% were
treated on weekend days, reflecting the difficultiesof
maintaining provision of a thrombolytic serviceout of hours. Median
onset-to-treatment-time was155min (IQR 130170 min) for the UK,
comparedto 140 min (IQR 114165 min) for the non-UK SITS-MOST group
(P
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Conclusion: Thrombolytic therapy for stroke hasbeen implemented
successfully at a small number ofUK stroke centres, with patchy
provision throughoutthe country. The low frequency of treatment
outwithoffice hours suggests deficient infrastructure to
support delivery. UK patients tended to be moreseverely affected
at baseline and to be treated later.Outcomes are comparable to
those seen at the non-UK SITS centres.
IntroductionThe Safe Implementation of Thrombolysis in
Stroke-Monitoring Study (SITS-MOST) has confirmed thesafety and
effectiveness of recombinant tissueplasminogen activator (rt-PA)
when used for thetreatment of acute ischaemic stroke within
Europe.1
The United Kingdom (UK) in general2 and Scotlandin particular3
have generous time windows forroutine brain imaging written into
national guide-lines produced by expert groups. Fewer than half
ofall UK stroke patients undergo brain imaging within24 h of
symptom onset.4 The UK has poor outcomesfor stroke in comparison to
other countries.5
Deficiencies in the recognition of the symptoms ofstroke,
coordination between ambulance servicesand stroke teams,
availability of specialised acutestroke care and imaging in the UK
have beenacknowledged,6 and the initial slow uptake ofthrombolytic
therapy for stroke within the UK7
raises the question of whether widespread imple-mentation of
thrombolysis in the UK will be feasible,sustainable and safe. This
question is made morepressing by the recent favourable
cost-effectivenessassessment of thrombolysis of ischaemic
strokeperformed by the National Institute for Health andClinical
Excellence.8
We report the UK experience of thrombolysis forstroke between
December 2002 and April 2006 asrecorded in the SITS-MOST register.
We also presentthe data from those patients treated outwith
therestrictions imposed by the SITS-MOST study andcaptured in the
Safe Implementation of Thrombo-lysis in Stroke-International Stroke
ThrombolysisRegister (SITS-ISTR)9 between May 2002 andOctober
2006.
Methods
Detailed descriptions of the SITS-MOST studydesign, methodology,
data management10 andresults1 exist elsewhere. Briefly, SITS-MOST
wasan open, multinational, prospective observationalstudy, which
collected data from centres performingthrombolysis for acute
ischaemic stroke in EUcountries, Norway and Iceland. Patients from
thesecentres treated within the terms of the conditionalproduct
licence for alteplase11 were registered inSITS-MOST. The SITS-MOST
protocol required the
availability of an acute stroke unit with adequate
monitoring, early mobilisation and rehabilitationfacilities; and
availability of a clinician trained in
provision of thrombolytic therapy to monitorprogress.
The SITS-ISTR is an internet-based interactiveregistry of stroke
patients treated with thrombolysis
which includes reports from the clinical strokecentres which did
not participate in SITS-MOST,
and also includes data from patients who did notmeet the
inclusion and exclusion criteria of the
licence and who were therefore not included in theSITS-MOST
study. SITS-ISTR participation simplyrequired a commitment to
register all patients
treated with thrombolysis, to provide source datafor monitoring
and to provide clarification of
potential adverse events when requested. Therewas no requirement
to attend training in order to
contribute to the SITS-ISTR. UK stroke physicianswere required
by conditions of the EuropeanMedicines Evaluation Agency (EMEA)
licence and
by their professional body, the British Association ofStroke
Physicians (BASP), to register patients in SITS
unless these patients were treated within anotherapproved
clinical trial of thrombolysis.
The SITS-MOST study protocol was reviewed by a
UK multicentre research ethics committee (MREC Afor Scotland)
concluding that the study should beconducted as an anonymised
audit. Within the UK,
clinicians from the participating centres attended
one-day thrombolysis training sessions organisedjointly by SITS
and BASP, at which instruction onthe thrombolysis evidence base,
the SITS-MOST
protocol, outcome scales and logistical serviceissues were
provided, together with an opportunityto discuss local difficulties
with provision of
thrombolytic therapy. Following these training
days, participants were able to contribute data tothe monitoring
study.
In the UK, monitoring against the source data wasperformed by an
experienced clinical research
associate from an academic department, indepen-dent of the
sponsor.
Complications from intracerebral haemorrhage
were independently evaluated. To facilitate com-parison with
other reported series, two commonly
used criteria were employed. According toEuropean Cooperative
Acute Stroke Study (ECASS)Group criteria,12 a haemorrhagic
complication was
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defined as any ICH combined with a neurologicaldeterioration of
more than 4 points on the NationalInstitutes of Health Stroke Scale
(NIHSS) score frombaseline, or from the lowest NIHSS value or
deathdue to ICH within 7 days. According to the SITS-MOST criteria,
a haemorrhagic complication wasdefined as local or remote
parenchymal haemor-rhage type 2 (defined as dense haematoma >30%
ofthe infarcted area with substantial space-occupyingeffect or as
any haemorrhagic lesion outside theinfarcted area) on the 2236 h
post-treatment CT scancombined with neurological deterioration of 4
ormore NIHSS points from baseline, or from the lowestNIHSS value
between baseline and 24 h, or leadingto death because of the
intracerebral haemorrhage.
Experienced centres were defined as centres,which had
participated in either of the Europeancooperative studies of
thrombolysis12,13 or treated atleast 5 patients before joining
SITS-MOST. Highvolume centres were defined as those who regis-
tered more than 20 patients into the SITS registry.
Statistical testingDescriptive statistics for baseline and
demographicdata were presented according to UK compared toother
SITS-MOST patients excluding UK patients.Multivariate analyses were
performed to examine ifthere was any difference in outcomes between
UKSITS-MOST compared to the non-UK SITS-MOSTpatients excluding UK
after adjusting for age,gender, hypertension, diabetes mellitus,
hyperlipi-
daemia, atrial fibrillation, congestive heart failure,previous
stroke, independence before current stroke(defined as modified
Rankin score14 01), smoking,aspirin treatment at stroke onset,
signs of currentinfarction in the baseline imaging study,
patientstreated in centres with previous thrombolysisexperience,
baseline NIHSS, blood pressure andblood glucose and stroke onset to
treatment time.
Analyses presented were performed using MINITABsoftware (version
14, Minitab Inc. PA, USA).Multivariate analysis was performed by
generalizedlinear or non-linear model using the STATISTICA(version
7.1, Statsoft Inc., OK, USA).
ResultsDemography and logisticsA total of 614 patients treated
in the UK wereincluded in the SITS-MOST and SITS-ISTR registersover
the period May 2002 to October 2006. Of thetotal 6483 patients and
285 centres in SITS-MOST,327 patients (5.0%) were treated in 23 UK
centres(8.1% of all the centres). The UK contributed 287patients
from 27 centres to the SITS-ISTR database.A total of 31 UK centres
participated in the registers.The age, NIHSS15 and delay to
treatment (onset-to-treatment-time, OTTT) for UK patients in
SITS-MOST
and SITS-ISTR with corresponding data for the non-UK SITS-MOST
cohort are given in Table 1. A higherproportion of patients in the
non-UK SITS-MOSTregistry had premorbid mRS scores of 0-1,
indicativeof minimal or no disability (93.3% vs. 90.2%,P= 0.023).
NIHSS score on admission was higherin the UK cohort compared to the
non-UK cohort,and median OTTT was greater.
Provision of thrombolytic therapy was not uniformacross the UK
and the wide variation was unrelatedto the population density
(Figure 1). Centre activity(1135) and assignment between SITS-MOST
andSITS-ISTR both varied widely. Four centres did not
attend the SITS-MOST training during the observa-tion period
thus all patients from these centres couldbe added only to
SITS-ISTR. As all patients >80years of age were automatically
entered into SITS-ISTR and not SITS-MOST, the cohort of UK
patientstreated outwith SITS-MOST had a higher proportionof very
old [66 (23%) SITS-ISTR patients were >80years of age] patients.
Overall, UK SITS-ISTR
Table 1 Baseline characteristics of patients in UK SITS-MOST, UK
SITS-ISTR and non-UK SITS-MOST registries
UK SITS-MOST(n = 327)
UK SITS-ISTR(n = 287)
Non-UK SITS-MOST(n = 6483)
UK SITS-MOST vs.non-UK SITS
MOST (P-value)
Median age (IQR) 68 years (5975) 72 years (6080) 68 years (5975)
0.87Male gender (%) 196 (60) 158 (55) 3706 (60) 0.92Median NIHSS
(IQR) 14.5 (919) 15 (1020) 12 (817)
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UK: 8 (2.5%, 95% CI 1.34.8%) of the SITS-MOSTpatients and 2
(0.7%, 95% CI 0.22.5%) of theSITS-ISTR patients. The corresponding
ICH rate inthe non-UK SITS-MOST cohort was 1.7% (95% CI1.42.0%, P=
0.28 for the comparison of UK SITS-MOST vs. the non-UK SITS-MOST
cohort).
A smaller proportion of UK patients were treatedin experienced
centres the UK compared to thenon-UK SITS cohort (57% vs. 78%). In
the UK therewas no significant difference in mortality
followingtreatment in an experienced centre in comparisonwith a new
centre (14.4% vs. 18.7%, P= 0.32).
Similarly, no difference in outcome was seen inhigh-throughput
centres compared to outcomes inlow-throughput centres (Figure
5).
In the multivariate analysis there was no statisti-cally
significant difference in any outcome betweenUK SITS-MOST compared
to non-UK SITS-MOSTexcluding UK (P= 0.39 for SICH per
SITS-MOSTdefinition, P= 0.96 for SICH per RCT/Cochranedefinition,
P=0.11 for mortality at 3 months andP= 0.35 for functional
independence at months).
DiscussionThe UK contains 15% of the pooled populationsof the
countries participating in SITS-MOST16 butcontributed only 5% of
cases to the SITS-MOSTregistry. Therefore a smaller proportion of
patientsare thrombolysed within the terms of the productlicence in
the UK as compared with other European
countries. Relatively few stroke centres were activein provision
of thrombolysis and there was signifi-cant geographic variability
in UK registrationirrespective of population density. This echoes
therecent English national stroke audit,4 which identi-fied
substantial deficiencies in availability andquality of acute stroke
care in the UK. That auditreported that 218 patients were
thrombolysed inEngland, Wales and Northern Ireland in 1
year,suggesting that hospitals exaggerated their truefigures,
treated within clinical trials or failed tocomply fully with
professional and EMEA guidancein reporting to SITS; even the higher
figurerepresents under 0.2% of acute stroke patients.Stroke
services in Wales were especially weak, afinding underlined by the
lack of any participatingcentre from that country in the SITS
registry. Furtherreorganisation of stroke services is required
toaddress this inequity of access to thrombolytictreatment for
stroke in the UK.
The main rate-limiting step in provision ofthrombolytic therapy
is the three-hour timewindow. The ASSIST study17 showed that
withinthe UK, 37% of stroke patients were already presentin
hospital within 3 h of onset of stroke. This suggests
that changes to patient pathways within as well asoutwith
hospital are required before thrombolytictherapy for stroke will be
more widely applied.For example, the median time from stroke to
firstbrain imaging is 27h in the UK, and only 15%of patients are
admitted to a specialist strokeunit on the same day as their stroke
occurs.4 Inareas where the emergency services treat strokewith the
same priority as acute myocardialinfarction and are often the
initial point of patientcontact, admission to hospital is more
rapid.18
A European study19 found that extensive reorganisa-tion of
out-of-hospital stroke services on use of
rt-PA substantially improved the proportion ofpatients
thrombolysed.
The successful introduction of a streamlinedreferral triage
protocol in Newcastle20 suggests thatonce suitable centres of
expertise have becomeestablished in the UK, relatively simple
measureswill increase numbers of potentially treatablepatients
rapidly brought to appropriate facilities.However, there remains
the potential for transport ofpatients ineligible for thrombolytic
treatment to
19
10
8
20
15
14
15
24
14
14
18
17
14
12
10
5
6
10
11
16
27
0% 20% 40% 60% 80% 100%
Non-UK SITS-
MOST (n=5816)
UK SITS-MOST(n=320)
UK SITS-ISTR(n=223)
mRs0 mRs1 mRs2 mRs3 mRs4 mRs5 Death
Figure 4. Outcome at 3 months by modified Rankinscale for the UK
SITS-MOST, UK SITS-ISTR and non-UKEuropean SITS-MOST patients.
10
10
16
12
24
24
18
18
11
12
6
6
15
18
0% 20% 40% 60% 80% 100%
High Vol (n=220)
Low Vol (n=100)
mRs0 mRs1 mRs2 mRs3 mRs4 mRs5 Death
Figure 5. Outcome at low volume (120 patientstreated) and high
volume (>20 patients treated) UKSITS-MOST centres.
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centres that may be remote from their local hospital,without
sufficient resources for comprehensivestroke care, as well as
increasing the use of scarceambulance resources. Major changes to
the acutecare pathway in stroke need to be part of anintegrated
whole system approach, with carefulimplementation of local
guidelines and monitoringof service utilization.
Although outcomes in those UK centres withlimited experience of
rt-PA use were comparable tobusier centres, (an observation
previously reportedin other phase 4 studies21), provision of
out-of-hourstreatment in smaller centres represents a
particularchallenge, with only about half of all
participatingcentres able to maintain such a service.
Experienceelsewhere suggests that teleradiology may have arole in
improving access to thrombolysis in centreswith access to
out-of-hours computed tomographybut with limited on-site
expertise.22,23 UK experi-ence with telemedicine and teleradiology
is scant
but the data presented suggest an unmet need forfurther
exploration of initiatives which may improveaccess to thrombolytic
therapy.
The median age of UK SITS-MOST participantsmatched that of the
non-UK SITS-MOST cohort.Patients in the UK SITS-ISTR were older,
howeverreflecting the absence of an upper age limit
forregistration. The median baseline NIHSS score in theUK SITS-MOST
register was higher than for the non-UK SITS-MOST data (14.5 vs.
12), demonstratingthat patients treated in the UK were more
severelyaffected at baseline than their counterparts.
Thisdifference in severity is likely to be associated with a
1520% absolute increase in the proportion ofpatients with poor
outcome24 and could readilyaccount for the outcome difference
between UKSITS and non-UK SITS-MOST data. Our multivariatemodelling
supports this hypothesis. Further, therewas a longer OTTT in the UK
compared with thewhole SITS-MOST register. These trends were
alsoapparent prior to the inception of the SITS project,7
and a number of factors may be contributory.Selective
recognition and transport of more severestroke patients in the UK
may play a role; however,an ongoing reluctance to treat mildly
affectedpatients with an agent that also carries potential for
harm may also have contributed. Our data from theSITS register
suggest that these issues have yet to beaddressed in the UK.
The outcome results for the patients in the UKSITS-MOST cohort
were comparable to non-UKSITS-MOST data following correction for
baselinedisparities. It is worth noting that both the mortalityand
rate of symptomatic ICH observed amongstthrombolysed stroke
patients in the UK remainconsistent with those seen in the
randomised trials
of thrombolysis for stroke.12,13,2527 Less clear is
theunderlying cause of the disparity in symptomaticICH rate between
UK SITS-MOST and SITS-ISTRcases. This observation differs from a
previousstudy28,29 which suggested that protocol violationsare
strongly associated with haemorrhagic compli-cations. Higher NIHSS
scores and delayed treatmentmay predispose to increased symptomatic
haemor-rhagic transformation; however the numbers ofpatients with
ICH according to either definition ofsymptomatic ICH are small,
precluding definitiveinferences. There were 11% more deaths in
theSITS-ISTR-UK than in the SITS-MOST-UK cohort(P= 0.002). It is
possible that some patients diedfrom an intracranial haemorrhage
without under-going a second CT scan, hence some of death
rateexcess in SITS-ISTR-UK could be explained by anexcess of
intracranial haemorrhagic complications.Such a hypothesis could
explain the discrepancy inhaemorrhage rates between SITS-ISTR and
SITS-
MOST in UK.In conclusion, thrombolytic treatment in the UKhas
been implemented successfully but only in arelatively small number
of centres and significantinequity of access exists across the
country.Outcome data and complication rates are consistentwith
clinical trial experience but unfavourabledifferences in baseline
patient characteristics andOTTT between the UK and the other
participatingcountries are apparent. Although it is encouragingthat
access to thrombolysis in some areas of the UKmatches that of major
European and NorthAmerican centres, it is clear that the challenge
of
equitable provision throughout the country has yetto be met.
AcknowledgementsWe thank all the SITS investigators and their
centresin the UK for their participation. The SITS-MOSTregister was
funded by an unrestricted grant fromBoehringer-Ingelheim GmbH
(Ingelheim, Germany).Uppsala Clinical Research (Uppsala,
Sweden)develops, maintains and upgrades the software forthe SITS
register. The study protocol for the Safe
Implementation of Thrombolysis in Stroke-Monitoring Study
(SITS-MOST) was drafted by SITSand developed in collaboration
between SITS,Boehringer-Ingelheim and the European
MedicinesEvaluation Agency (EMEA). All data collection andanalysis
was performed independent of the sponsor.Biannual reports to the
EMEA were written inparallel by SITS and Boehringer-Ingelheim
indepen-dent of each other. In the UK, source dataverification was
performed by independent clinical
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staff under the direction of K.R.L. and
G.A.F.Boehringer-Ingelheim was responsible for reportingof serious
adverse drug reactions to regulatoryauthorities. Training meeting
venues and speakerstravel costs were paid by Boehringer-Ingelheim
butno payments were made to speakers.
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