Definitions
and comments:
Strength
of evidence grading (A-C);
1. Combined dipyridamole and aspirin treatment
2. Clopidogrel
3. General consensus statement on secondary prevention
4. Thrombolysis
Statements:
5.
Brain plasticity after stroke - a relearning process
6.
Neuroprotective treatment of acute stroke
1. Combined
dipyridamole and aspirin treatment
This consensus statement was
prepared by Dr Hans-Göran Hårdemark, Uppsala, Sweden.The
discussion was chaired by Professor Gudrun Boysen, Copenhagen,
Denmark and by Dr Hans-Göran Hårdemark. Professor
Jan Tijssen, Amsterdam, and
Dr Peter
Sandercock, Edinburgh,
were speakers in this session.
The attached document was
accepted as a consensus statement by the Update meeting.
Combined dipyridamole and
aspirin treatment
Update consensus statement,
Stockholm, November 1998
This consensus statement is
based on statistical reviews of studies of secondary prevention of
stroke using aspirin alone or in combination with dipyridamole in
patients with TIA or ischaemic stroke. Studies of patients with
myocardial infarction or peripheral vascular disease as qualifying
event for inclusion have not been included. The chosen endpoint of
the studies is ‘vascular events’, i.e. stroke, myocardial
infarction or vascular death.
1.1.
Compared to placebo, aspirin
treatment in doses of 50-1500 mg daily will reduce the risk of
vascular events (grade A evidence) by 13% (relative risk reduction,
95% confidence interval 5-19%, 10 studies).
1.2.
Compared to placebo,
combined therapy of aspirin in doses of 50-900 mg and dipyridamole
in doses of 150-400 mg daily will reduce the risk of vascular
events (grade A evidence) by 30% (relative risk reduction, 95%
confidence interval 22-37%, 4 studies).
1.3.
Compared to aspirin alone,
combined therapy of aspirin in doses of 50-900 mg and dipyridamole
in doses of 150-400 mg daily will reduce the risk of vascular
events (grade A evidence) by 15% (relative risk reduction, 95%
confidence interval 4-26%, 4 studies).
1.4.
Scientific proof beyond all
reasonable doubt show that aspirin is more effective than placebo
for prevention of vascular events in various athero-thrombotic
diseases, i.e., after myocardial infarction, in peripheral
vascular disease and after TIA or stroke (grade A evidence). Also,
aspirin treatment is the only antiplatelet agent proven to be
effective in the acute phase of stroke.
1.5.
Whether combined therapy of
aspirin and dipyridamole in the broader group of patients with
various athero-thrombotic vascular disorders will enhance the
treatment effect of single aspirin treatment is still not
clarified. This uncertainty has caused concern among some
clinicians about the interpretation of the positive treatment
effect seen with combined therapy in the more specific group of
patients with TIA and stroke.
1.6.
Analysis of the group of
patients with previous TIA or ischaemic stroke show that the
combination therapy of dipyridamole and aspirin is more effective
than placebo or aspirin alone to prevent new vascular events.
Based on these results, combination therapy should be considered
as first choice therapy in patients with TIA or ischaemic stroke
unless a cardio-embolic source is suspected or there is another
indication for anticoagulation treatment.
1.7.
Uncertainty about the
improved effect of combined therapy versus aspirin alone for wider
indications than only cerebrovascular events justifies inclusion
of patients with TIA and stroke in aspirin-controlled randomised
trials. Single use of aspirin as first choice treatment in
clinical routine can, from this perspective, not be regarded as
unethical.
2. Clopidogrel
This consensus statement was prepared by Associate
Professor Andreas Terent, Uppsala, Sweden. The discussion was
chaired by Professor
Philip Bath, Nottingham, UK, and Associate
Professor Andreas Terent. Professor J Donald Easton, Rhode Island, USA, and Dr
Peter Sandercock, Edinburgh, UK, were speakers in
this session.
The
attached document was accepted as a consensus statement by the
Update conference.
2.1.
Long-term administration of
clopidogrel to patients with atherosclerotic vascular disease
i.e., any of recent myocardial infarction, recent ischaemic stroke
or symptomatic peripheral artery disease, is more effective than
aspirin in reducing the absolute risk of the composite endpoint
ischaemic stroke, myocardial infarction or vascular death (0,5%
absolute risk reduction; 9% relative risk reduction ; grade A
evidence. The relative risk reduction in the subgroup of patients
with ischaemic stroke is similar, 7%.)
2.2.
The overall safety profile
of clopidogrel (75 mg once daily) is at least as good as that of
medium-dose aspirin (325 mg once daily). The number of patient
years is sufficient to confirm that the risk of neutropenia is
minimal.
2.3.
Clopidogrel, 75 mg once
daily, may be used as a first line drug for patients with TIA or
stroke, but the economic cost is high as compared to aspirin.
2.4.
Clopidogrel, 75mg once daily,
is a first line drug in patients with aspirin intolerance.
3. General
consensus statement on secondary prevention
This consensus statement was
prepared by Associate Professor Bo Norrving, Lund, Sweden. The
discussion was chaired by Professor John Bamford, Leeds, and
Associate Professor Bo Norrving. Professor
Charles Warlow, Edinburgh, UK, Professor
Gudrun Boysen, Copenhagen, Denmark, Dr Ale Algra,Utrecht, The Netherlands, and Associate
Professor Andreas Terent were speakers in this
session.
The attached document was
accepted as a consensus statement by the Update conference.
3.1.
Risk factor intervention:
Treatment
of risk factors has been shown to reduce the risk of stroke in the
setting of primary prevention, but has not been well documented in
secondary prevention after TIA or ischaemic stroke. Similar
general principles are likely to be applicable for both settings,
though in stroke patients blood pressure and cholesterol reduction
by drugs are both subjected to study in current large trials.
Risk factors should be carefully investigated and
treated, and a healthy life style should be promoted (grade C
evidence).
3.2.
Long term follow-up:
A well organised follow-up of secondary preventive measures is
needed for patients with TIA and stroke. Careful attention should
be paid to compliance with therapy, occurrence of adverse effects
and adherence to risk factor control (grade C evidence).
3.3.
General therapy:
A. Antiplatelet therapy.
Antiplatelet agents constitute baseline therapy in secondary
prevention after TIA and ischaemic stroke.
B. Anticoagulants.
Anticoagulants are not recommended as routine secondary prevention
therapy after cerebral ischaemic events in patients without atrial
fibrillation or a well established cardioembolic source (cf. below),
because this therapy has not been shown to be more effective than
aspirin in this setting and carries a higher risk of bleeding (grade
B evidence).
C. New ischaemic symptoms
during antiplatelet therapy. The possibility of non-ischaemic
causes should be considered, and a CT scan should be done in most
instances. Screening tests for large artery diseases and
cardioembolic sources should be performed (or repeated, if
performed earlier). If negative, single aspirin may be switched to
clopidogrel, or dipyridamole added. However, neither strategy has
been studied in randomised controlled trials in this specific
setting (grade C evidence).
3.4.
Atrial fibrillation and
other well established cardio-embolic sources. Anticoagulants are
recommended as first choice in patients with atrial fibrillation,
provided that there are no contra-indications (grade A evidence).
A target INR of 2,5 (interval 2.0 - 3.0) is recommended. As
secondary choice, medium dose aspirin could be used (grade B
evidence). There are no randomised controlled trials guiding
clinical practice in patients with acute myocardial infarction and
embolism to the brain, but anticoagulants for 3-6 months may be
used (grade C evidence).
3.5.
Carotid Endarterectomy
A. Carotid Endarterectomy
(CEA) has been shown to prevent stroke in patients with recent (within
6 months) carotid territory TIA and non-disabling stroke in
association with severe stenosis of the ipsilateral carotid artery,
and no contra-indications for surgery. The benefit of CEA
increases with the degree of stenosis, and is substantial if the
symptomatic carotid artery is stenosed 70% or more (NASCET method),
according to the NASCET study, or 80% or more (ECST method),
according to the ECST study (grade A evidence).
B. The benefit for CEA is
modest for patients with moderate stenoses (50-69% by the NASCET
method). In such patients, other prognostic factors (such as male
rather than female sex, cerebral rather than ocular symptoms,
ulcerated rather than smooth stenoses) may be taken into account
in the decision to perform a CEA, although these prognostic
factors are as yet imprecise. CEA is not warranted for most
patients with moderate stenosis, and patients with lesser degree
of stenosis should not be subjected to CEA (grade A evidence).
C. Attempts to confirm a
diagnosis of suspected symptomatic carotid stenosis should be
urgently started and include history, neurological and
cardiovascular examination and ultrasonography of the carotid
arteries. CT and or MR investigation should be done at least in
cases with symptoms of cerebral ischaemia.
D. Surgery should be
restricted to specialist centres at which the practice and
complication rates are regularly monitored, and at which
complication rates of surgery are comparable to those found in the
clinical trials demonstrating efficacy.
E. The effectiveness of CEA
based solely on ultrasonographic diagnosis of carotid artery
stenosis is not well documented (grade C evidence). Comparisons of
non-invasive studies with angiography must be carried out at
individual centres and the use validated before angiography is
discarded.
F. Carotid angioplasty with or without stenting has not
been shown to be superior to carotid endarterectomy in terms of
safety, effectiveness and durability (grade C evidence). Further
studies are necessary before this technique comes into routine use.
4. Thrombolysis
This consensus statement was
prepared by Associate Professor Nils Gunnar Wahlgren, Stockholm,
Sweden. The discussion was chaired by Professor J Donald Easton,
Rhode Island, USA, and Associate Professor Nils Gunnar Wahlgren. Professor Werner Hacke, Heidelberg, Germany, Dr
Peter Sandercock, Edinburgh, UK and Professor
Markku Kaste, Helsinki, Finland, were speakers in
this session.
The attached document was
accepted as a consensus statement by the Update conference.
The following statement
should be read in the abscence of approval of tPA for acute
ischaemic stroke in Europe and with the knowledge that a
registration application has been submitted. General
recommendations of use of tPA in acute ischaemic stroke will await
approval of this registration.
4.1.
Results from randomised
controlled trials and statistical reviews support, under specified
conditions, the therapeutic use of intravenous tPA (0.9 mg/kg, max
90 mg) with 10% of the dose given as a bolus followed by an
infusion lasting 60 minutes within 3 hours of onset of an
ischaemic stroke (Grade A evidence).
4.2.
Treatment within a time
limit of 6 hours may be beneficial for long term outcome after
ischaemic stroke. The available documentation in support for use
within the six hour interval is less than for treatment of
patients within a three hour time limit (grade B evidence).
Treatment is not recommended if early changes of a recent cerebral
infarction involve more than one third of the vascular territory.
4.3.
This treatment is not
recommended unless given within a strict quality control protocol
demonstrating a low complication rate in centers with expertise in
neurological and neuroradiological evaluation and general
management of stroke patients. The organisational implications of
this need clarification before general treatment recommendations
are given.
4.4.
Intravenous tPA is not
recommended when the time of onset of stroke cannot be ascertained
reliably, including stroke recognised upon awakening.
4.5.
Patients should be excluded
from treatment according to the criteria used in the large
randomised trials of tPA in acute stroke.
4.6.
Further trials of the use of
tPA in acute ischaemic stroke are warranted, in particular for
documentation of treatment effect beyond three hours after onset
of stroke and for new compounds. Patients should give informed
consent, but may require that treatment with active tPA will be
considered with regard to inclusion- and exclusion criteria.
5. Brain
plasticity after stroke - a relearning process
This statement was prepared
by participants in the session chaired by Dr Veronica Murray,
Danderyd, and Dr Magnus
Thorén, Stockholm, Sweden. Professor
Barbro Johansson, Lund, Sweden, Doctoral
student Louise Martinsson, Stockholm, Sweden, Dr Peter Eriksson, Gothenburgh, Sweden and Professor
Jean-Marc Orgogozo, Bordeaux, France, were
speakers in this session.
The attached document was
accepted as a statement by the Update conference.
Brain plasticity after
stroke - a relearning process
Update consensus statement,
Stockholm, November 1998
The central nervous system
is more sophisticated than a most powerful computer. It has an
inherent capacity to modify itself including its cellular
organisation and mobilisation of new connections. Neurons can
increase their dendritic tree and synaptic connections. Possibly
the brain also has a capacity to recruit stem cells in vulnerable
regions such as the hippocampus.
Early rehabilitation is
often claimed to be a key factor for recovery and brain plasticity.
Systematic studies of different components in rehabilitative
methods are insufficient to give detailed knowledge about effects
of different strategies. Stroke unit care is clearly better than
general medical ward care. This advantage can be a summary effect
of better medical management in general, more appropriate nursing
and better specific management of the acute brain damage. A more
stimulating environment as well as the effect of early
rehabilitation could also contribute to the benefit yielded by
stroke units.
Pharmacological treatment to
enhance restitution and substitution, which both contribute to
recovery, is a field of increasing interest. More studies are
indicated to confirm or reject hypotheses generated from animal
experiments and clinical studies. It is further important to
elucidate possible conflicting mechanisms with respect to acute
neuroprotective effects and long-term effects on plasticity.
Further in an intermediate early phase after ictus, the damaged
brain is sensitive to secondary effects such as brain edema, blood
brain barrier damage, loss of autoregulation etc., which can all
be affected by a variety of pharmacological agents.
In addition to further
animal experiments specific targeted clinical trials are necessary
before there can be a firm basis for clinical recommendations.
6. Neuroprotective
treatment of acute stroke
This statement was prepared
by Professor Christian Blomstrand, Gothenburgh, Sweden. The
discussion was chaired by Dr Milita Crisby, Huddinge, Sweden, and
Professor Christian Blomstrand. Associate
Professor Nils Gunnar Wahlgren, Stockholm, Sweden,
Professor Hans-Christoph
Diener, Essen, Germany, Professor
Jean-Marc Orgogozo, Bordeaux, France and Associate Professor Tommy Olsson, Umeå, were speakers
in this session.
The attached document was
accepted as a statement by the Update conference.
There is a growing body of
evidence about early neuroprotective drug treatment in
experimental focal brain ischaemia. Accordingly, many different
principles of treatment might be expected to work in a clinical
situation. In animal models, different pathophysiological
components in the complicated cascade of changes in the brain
after the ictus can be pharmacologically counteracted, separately
and under carefully controlled conditions. This have given rise to
an optimism in acute neuroprotective treatment in stroke patients.
However, a series of large randomised studies have failed to show
any significant effects of the drugs tested so far. Heterogeneity
in stroke populations, combined illnesses in elderly individuals,
narrow time windows and blunt methods of treatment effects could
be possible reasons for discrepancies between experimental
situations n animals and in stroke patients.
The three studies discussed
at this meeting concerning lubeluzole, clomethiazole and piracetam
did not show significantly favourable treatment effects with
respect to the chosen primary outcome variables.
For clomethiazole, post hoc
analysis showed that there may be an effect on large
supratentorial infarctions and for piracetam post hoc subgroup
analysis indicated a possible effect for treatment within 7 hours,
particularly for large infarctions. This has motivated further
studies targeted to elucidate the role for these drugs in future
acute stroke treatment.
Early inflammatory
mechanisms including cytokine effects on blood-brain barrier, on
cellular functions and on apoptosis comprise a field of intense
scientific interest. However, for the moment no recommendation can
be given except for competent early care in a stroke unit.
In conclusion, no
neuroprotective drug can be recommended at present for use in
routine acute stroke care.
Strength
of evidence grading
The grade of evidence
strength has been defined at this meeting as follows:
GRADE A EVIDENCE:
Strong
support from randomised controlled trials and statistical reviews
(at least one randomised controlled trial plus one statistical
review)
GRADE B EVIDENCE:
Support
from randomised controlled trials and statistical reviews (one
randomised controlled trial or one statistical review)
GRADE C EVIDENCE:
No
reasonable support from randomised controlled trials,
recommendations based on small randomised and/or non-randomised
controlled trials evidence.
Comment: What is consensus?
At this meeting, with almost
250 participants, 'consensus' does not imply a total unity in
their view on the various issues under discussion. The consensus
statements will necessarily be a compromise. It was stated at the
opening of the conference that the consensus statements should be
'acceptable for most' in the audience and that individuals should
not be bound for future discussions.
The Stroke Update meeting is
independent of any authority or professional organisation.
The
strength of its statements and recommendations is that it is based
on a free discussion and evaluation of available evidence by a
representative group of international experts, active researchers
and stroke carers.