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A systematic review of
the effectiveness, cost-
effectiveness and barriers to
implementation of thrombolytic
and neuroprotective therapy
for acute ischaemic stroke
in the NHS
P Sandercock1*
E Berge3
M Dennis1
J Forbes2
P Hand1
J Kwan1
S Lewis1
R Lindley1
A Neilson4
B Thomas1
J Wardlaw1
Departments of
1Clinical Neurosciences and
2Public Health, University of Edinburgh,Western General Hospital,
Edinburgh, Scotland;
3Department of Internal Medicine, Ullevål Hospital, Oslo, Norway;
4HealthEcon, Basel, Switzerland
* Corresponding author
HTA
Health Technology Assessment
NHS R&D HTA Programme
Health Technology Assessment 2002; Vol. 6: No. 26
Executive summary
Thrombolytic and neuroprotective therapy for acute
ischaemic stroke
Background
There is strong evidence that, for patients with
acute stroke, admission to a stroke unit providing
organised stroke care and rehabilitation saves lives
and reduces disability. Medical treatments such
as thrombolysis or neuroprotective agents, given
within the first few hours of onset of ischaemic
stroke, offer the prospect of at least moderate
additional benefit. Most of the evidence of
benefit of thrombolysis came from trials per-
formed in healthcare systems that are rather
different to the NHS. This review therefore
aims to assess whether, when used in the NHS,
these new agents are likely to be effective and
cost-effective.
Objectives
The objectives of the current report are:
•to assess the effectiveness of thrombolytic drugs
•to assess the effectiveness of neuroprotective
drugs
•to map current pathways of acute stroke
care, identify barriers to implementation of
emergency drug treatments for acute stroke
in the NHS, and to suggest solutions to
overcome these barriers
•to model the health economic impact of
thrombolytic therapy.
Methods
Data sources and study selection
Multiple bibliographic sources were searched
to identify: all unconfounded randomised trials
comparing either a thrombolytic or a neuro-
protective agent with placebo (or open control)
in patients with acute stroke; and all published
reports of studies identifying barriers to effective
acute stroke care. A panel developed an
economic model of acute stroke care from
the Lothian Stroke Register, and by consensus
discussion between the research team members
supplemented by data on outcome after
stroke derived from relevant publications
where necessary.
Data extraction
For the review of thrombolysis, the data included
in the analyses were checked where possible
with the original trialists. For the review of
neuroprotection completed systematic reviews
were sought. For the review of barriers to acute
care and interventions to overcome them, two
reviewers independently selected studies meeting
the inclusion criteria and extracted the data;
differences were resolved by discussion.
Data synthesis
Standard Cochrane quantitative systematic
review methods were used (Cochrane Revman
4.1 software); a fixed-effect model was used and
results were expressed as odds ratios (ORs).
For the economic analyses, a Markov model was
created to estimate the number of life-years and
quality-adjusted life-years (QALYs) gained with
thrombolytic therapy. Sensitivity analyses were
used to test the robustness of the estimates.
Results
Efficacy of thrombolysis
Seventeen trials (5216 patients) of urokinase,
streptokinase, recombinant tissue plasminogen
activator (rt-PA) or recombinant pro-urokinase
were included. About 50% of the data came
from trials testing intravenous rt-PA, mostly given
within 6 hours of stroke onset. Thrombolytic
therapy significantly increased the odds of fatal
intracranial haemorrhage (OR = 4.15; 95%
confidence interval (CI), 2.96 to 5.84). Thrombo-
lytic therapy also increased the odds of death at
the end of follow-up (OR = 1.31; 95% CI, 1.13 to
1.52). However, despite the increase in deaths,
(because it markedly reduced the degree of
disability in survivors), thrombolytic therapy within
6 hours significantly reduced the proportion of
patients who were dead or dependent at the end
of follow-up (OR = 0.83; 95% CI, 0.73 to 0.94).
There was heterogeneity between the trials that
could have been due to: the thrombolytic drug
used, variation in the concomitant use of aspirin
and heparin, severity of the stroke, and time to
treatment. The most widely tested agent, rt-PA,
may be associated with slightly less hazard and
more benefit than other agents.
Executive summary: Thrombolytic and neuroprotective therapy for acute ischaemic stroke
Executive summary
Health Technology Assessment 2002; Vol. 6 No. 26 (Executive summary)
Efficacy of neuroprotective drugs
No agent has yet been proven to be sufficiently effec-
tive in man to be granted a product licence. Useful
economic analyses were therefore not possible.
Barriers to acute stroke treatments
The key barriers identified were:
•the patient’s or family’s inability to recognise
stroke symptoms or failure to seek urgent help
•patient or family calls general practitioner
instead of an ambulance
•inefficient process of emergency stroke care in
hospital, and
•delay in neuroimaging.
Some interventions to overcome specific barriers
had been evaluated:
•education programme for the public and
healthcare workers
•training programme for paramedical staff to
improve the accuracy of diagnosis, and
•reorganisation of in-hospital systems to
streamline acute stroke care.
None of the evaluation studies provided reliable
estimates of effect.
Cost-effectiveness of thrombolysis
with rt-PA
The model suggested that if eligible patients were
treated with rt-PA there was a 78% probability of a
gain in quality-adjusted survival during the first
year, at a cost of £13,581 per QALY gained. Over a
lifetime, rt-PA was associated with a cost-saving of
£96,565 per QALY. However, the estimates were
imprecise and highly susceptible to the assump-
tions employed in the economic model; under
several plausible assumptions, rt-PA was much
less cost-effective than standard care and under
others, a great deal more cost-effective.
Conclusions
Implications for healthcare
Thrombolytic drugs
The data available are limited and the estimates of
effectiveness and cost-effectiveness are imprecise.
The data were judged to be insufficient to provide
reliable estimates of the cost of modifying NHS
services for patients with acute stroke to enable
rt-PA to be delivered safely and effectively within
the NHS. In the authors’ opinion, the data do
not, therefore, support the widespread use of
thrombolytic therapy in routine clinical practice
in the NHS.
Neuroprotective drugs
An agent associated with even modest benefit is
likely to be cost-effective, but none is available yet.
Barriers
The cost of overcoming the known barriers to
acute stroke treatment is likely to vary from centre
to centre and will depend chiefly on the baseline
level of stroke service provision.
Recommendations for research
There is a case for further research to:
•determine reliably the effects of rt-PA on short-
and long-term survival and to identify which
patients are most likely to benefit (and which to
be harmed); this would require new large-scale
randomised trials comparing thrombolytic
therapy with control
•determine the nature (and costs of) the changes
in NHS services that would be needed to deliver
rt-PA therapy safely and effectively to patients
with acute stroke (if rt-PA is licensed in the UK);
this would include the costs of service changes
that would be necessary to ensure that patients
with suspected acute ischaemic stroke are
admitted to hospital much more quickly
than is currently the norm.
Publication
Sandercock P, Berge E, Dennis M, Forbes J,
Hand P, Kwan J, et al. A systematic review of the
effectiveness, cost-effectiveness and barriers to
implementation of thrombolytic and neuro-
protective therapy for acute ischaemic stroke
in the NHS. Health Technol Assess 2002;6(26).
NHS R&D HTA Programme
The NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure that
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The research reported in this monograph was funded as project number 98/02/02.
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Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search,
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HTA Programme Director: Professor Kent Woods
Series Editors: Professor Andrew Stevens, Dr Ken Stein, Professor John Gabbay,
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