KAROLINSKA STROKE UPDATE
13-14 November 2006, Stockholm, Sweden

 


2000        

Consensus statements

1. Lipid lowering
2. Carotid Endarterectomy
3. Thrombolysis
4. Stroke prevention
5. Acute management of stroke
6. Antiplatelet treatment


Level of evidence:

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 one non-randomised controlled trials evidence.

 

 

1.          Lipid lowering

This consensus statement was proposed by the chairpersons, Professor Pierre Amarenco, Paris, France and Associate Professor Andreas Terent, Uppsala, Sweden, together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Professor Pierre Amarenco, Paris, France,  Dr Magnus von Arbin, Stockholm, Sweden and Professor Philip Bath, Nottingham, United Kingdom.

1.       A significant reduction of stroke by lipid lowering agents is found in patients with coronary artery disease (CAD; grade A evidence: pre-specified secondary endpoint in 2 randomised controlled trials and statistical reviews). The reduction is significant for statins in CAD, but not for any other drugs or interventions (grade B evidence: one statistical review). Data are largely restricted to middle-aged white men with CAD grade B evidence (statistical reviews).

2.       The progression of carotid wall thickness in patients with CAD is halted by statins (grade B evidence: randomised controlled trials). Statins reduce the number of clinical events in patients with carotid lesions (grade C evidence: small randomised controlled trials).

3.       Statin treatment is recommended for patients with stroke and CAD (myocardial infarction or angina with documentation of coronary atherosclerosis or myocardial ischaemia) (grade A evidence: pre-specified secondary endpoint in 2 randomised controlled trials and statistical reviews).

4.       The treatment should be started in the post-stroke period (3 months or later after the event) in patients with a total cholesterol above 5 mmol/l or a LDL cholesterol above 3 mmol/l. Blood samples for lipid analyses should be taken on arrival (within 48 hours) or 3 months after the event.

5.       Participation in randomised controlled trials are encouraged. Trials are ongoing with focus on:

·         Previous stroke or TIA: SPARCL, PROSPER, Heart Protection Study (>3,000 stroke patients)

·         CAD or PAD: Heart Protection Study 

·         Hypertension (high risk): ALLHAT, ASCOT

·         The elderly: PROSPER (70-82 years), RESPECT (65-80 years)

2.   Carotid Endarterectomy

This consensus statement was proposed by the chairpersons, Professor Jesper Swedenborg, Stockholm, Sweden and Dr Jan Malm, Umeå, Sweden together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Dr Peter Rothwell, Oxford, United Kingdom and Associate Professor Nils Gunnar Wahlgren, Stockholm, Sweden.

1.       Carotid endarterectomy (CEA) has been shown in two major trials (ECST and NASCET) to prevent stroke in patients with carotid territory TIA or non-disabling stroke during the last 6 months and a severe stenosis of the ipsilateral carotid artery. However, the trial results were not consistent for moderate stenosis, although this may have been due to differences between the trials in the method of measurement of the degree of stenosis and in the definition of outcomes. The individual patient data from these trials and a third trial (VA 309) have now been pooled normalising for these differences. The NASCET method of measuring stenosis was used in the pooled analysis and is used below.

 

2.       The benefit of CEA increases with the degree of stenosis, and is substantial for 70-99% stenosis of the symptomatic carotid artery (Grade A evidence): six patients were needed to treat to prevent one ipsilateral stroke (NNT=6; 95% CI 5-9) or any stroke or surgical death (NNT=6; 95% CI 5-10). However, patients with narrowing of the ICA distal to a severe stenosis (as shown by angiography) do not benefit from surgery.

3.       The benefit from CEA is lower in patients with 50-69% stenosis than for severe stenosis (grade A evidence); twenty-four patients were needed to treat to prevent one ipislateral ischaemic stroke (NNT=24; 95% CI 13-50), or fourteen to prevent one stroke of any origin or death (NNT=14; 95% CI 9-35). There is no benefit for patients with 30-49% stenosis and surgery is harmful for patients with <30% stenosis (grade A evidence).

4.       Other variables in addition to the degree of stenosis may be useful in the selection of patients for surgery. This is particularly important for patients with 50-69% stenosis. In patients with 70-99% stenosis without an ICA narrowing, benefit is present for all subgroups. In patients with 50-69% stenosis the following variables may influence the benefit of surgery: sex, age, time since last event, stroke vs. cerebral TIA and angiographic plaque surface morphology. (grade A evidence). Additional studies are needed to identify other possible variables that may influence the outcome e.g. ultrasonographic appearance of the plaque and recording microemboli with TCD.

5.       Patients with carotid TIA or non disabling stroke require urgent investigation. This should include history, neurological and cardiovascular examination and imaging of the carotid arteries. CT and or MR brain imaging should be done at least in cases with symptoms of cerebral ischaemia. Delay of treatment reduces the benefit of surgery. Ideally surgery should be performed within 2 months of last symptoms.

6.       Surgery should be restricted to 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. Monitoring should be prospective and independent and should take account of case mix.

7.       Although trial evidence is based on angiography, most centers now use non-invasive methods in the diagnosis of carotid artery stenosis. Since it is unlikely that trials will be repeated with non invasive methods, individual centers should ideally compare their method with angiography. However, if this is not done it should at least be ensured that the method is reproducible.

8.       Carotid angioplasty with or without stenting has not been properly compared with CEA in terms of safety, effectiveness and durability. The results of ongoing studies are awaited.

9.       Surgery is also effective for severe asymptomatic stenosis (Grade A evidence), but the benefit is much less than for severe symptomatic stenosis (NNT = 20 for any stroke or surgical death; 95% CI=14-50). A large trial is currently ongoing in order to determine which patient groups benefit most. Ideally surgery for asymptomatic carotid stenosis should be performed within such a trial.

Abbreviations:

CEA, carotid endarterectomy

TIA, transitory ischaemic attack

ECST, European Carotid Surgery Trial

NASCET, North American Surgery Carotid Endarterectomy Trial

NNT, number necessary to treat

CI, confidence interval

ICA, internal carotid artery

TCD, transcranial doppler

CT,computer tomography

MR, magnetic resonance

3.             Thrombolysis

This consensus statement  was proposed by the chairpersons, Professor Markku Kaste, Helsinki, Finland and Dr Lars Thomassen, Bergen, Norway together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Professor Werner Hacke, Heidelberg, Germany,  Dr Joanna Wardlow, Edinburgh, United Kingdom, Dr Martin Grond, Cologne, Germany, Professor Stig Holtås, Lund, Sweden,  Associate Professor Nils Gunnar Wahlgren, Stockholm, Sweden,  Dr Risto Roine, Helsinki, Finland and Dr Richard Lindley, Edinburgh, United Kingdom

1.       Intravenous r-tPA within 3 hours after the onset of symptoms in patients with acute ischaemic stroke is a highly effective evidence-based treatment (grade A evidence). The use of r-tPA is supported by results from randomised controlled trials and meta-analyses. The risk of early fatal and symptomatic intracranial haemorrhage is increased, but these hazards are offset by reduction in the proportion of patients being dead or dependent. According to meta-analyses, for patients given r-tPA within 3 hours of ischaemic stroke approximately 1 out of 10 more will be independent, 1 of 14 will suffer symptomatic haemorrhage and 1 in 100 fewer may die as a result of the treatment (grade A evidence). Overall, the net benefit of r-tPA given within 3 hours of onset will result in one more independent survivor for every 10 patients treated.

2.       Intravenous r-tPA within 6 hours after the onset of an ischaemic stroke seems to be beneficial, but the benefit is smaller while the risks are higher. The use of r-tPA up to 6 hours is supported by the results of meta-analyses (grade B evidence).

3.       The therapeutic use of intravenous r-tPA is recommended within 3 hours in selected patients in acute ischaemic stroke (grade A evidence), but may also be beneficial up to 6 hours (grade B evidence) and possibly even longer in certain subgroups of stroke patients such as basilar artery occlusion (grade C evidence).

4.       Outside randomised controlled trials, the therapeutic use of intravenous r-tPA must be subject to continuous quality control. It is recommended that the use of intravenous  r-tPA follows the recommendations of published guidelines, with local modifications as appropriate. In most open studies the safety and efficacy of intravenous r-tPA in routine clinical practice is comparable to randomised studies. However, there is an obvious need for continuous education and for trained local stroke specialists to be responsible for a safe stroke thrombolysis service.

5.       The evidence strongly supports that r-tPA is made available for routine clinical use to treat stroke patients in adequately qualified centers. The development of hospital services designed to deliver early thrombolysis 24 hours a day for acute ischaemic stroke is encouraged. Continuous auditing of the routine use of thrombolytic therapy in stroke is advisable. For example, the International Stroke Thrombolysis Register (SITS) is an on-line monitoring system designed for auditing safety and efficacy of routine therapeutic use of r-tPA in acute ischaemic stroke, and could be used for such a purpose.

6.       The heterogeneity for good outcome in meta-analyses implies that more data are needed on how to identify the patients most likely to benefit and least likely to be harmed by thrombolysis. The role of patient characteristics including age, sex, stroke severity, stroke subtype, concomitant disease, drug treatments, strategies for blood pressure control, prior antiplatelet therapy and antiplatelet and anticoagulation therapy after thrombolysis should be further evaluated in future trials, meta-analyses, phase IV studies and SITS.

7.       It is recommended that future trials of safety and efficacy of thrombolysis should assess modern imaging techniques as a part of the protocol to help in patient selection and in monitoring of the effects of therapy. For example, MR diffusion and perfusion weighted imaging may reveal in individual patients brain tissue at risk but salvageable with thrombolysis within a 3 hour time window and possibly even longer (grade C evidence). Other imaging modalities including perfusion CT, MR angiography, SPECT and TCD may also help in selecting patients, in verifying recanalization of the occluded artery and in detecting change of infarct size (grade C evidence).

8.       It is strongly recommended that one of the main targets in future randomised trials should be to try to extend the time window beyond 3 hours after stroke onset as this would increase the proportion of patients who may benefit from therapy. This would have an important public health impact in Europe. It is also recommended that new thrombolytic agents, and thrombolysis together with neuroprotective agents, should be evaluated in future randomised trials to try to increase the effectiveness and to decrease the risks involved in thrombolysis.

  1. Future studies should include collection of data to allow the assessment of the impact on health economics and on quality of life of r-tPA in acute is haemic stroke. The public should be educated of the value of early expert assessment and treatment.

4.          Stroke prevention

This consensus statement was proposed by the chairpersons, Associate Professor Kenneth Pehrsson, Stockholm, Sweden  and Dr Christian Carlström, Stockholm, Sweden together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Associate Professor Hans Johnsson, Stockholm, Sweden Professor Michael Brown, Cambridge, United Kingdom, Professor Peter Sleight, Oxford, United Kingdom and Associate Professor Jesper Petersson, Malmö, Sweden.

 

1.       Thrombin inhibitors are currently being compared with warfarin in studies of secondary prevention after venous thrombosis and pulmonary embolism and in atrial fibrillation.

2.       Further trials are necessary before thrombin inhibitors can be recommended for stroke prevention.

3.       Today thrombin inhibitors offer no alternative to warfarin.

4.       ACE inhibitors and calcium antagonists prevent stroke in patients with hypertension (Grade A evidence).

5.       For patients with hypertension beta-blockers and diuretics are well established as a first line of treatment (Grade A evidence).

6.       ACE inhibitors prevent stroke in patients with heart failure (Grade A evidence), vascular diseases and/or diabetes (Grade B evidence).

7.       ACE inhibitors may be effective in a subgroup of stroke patients with coronary heart disease and heart failure (grade B evidence).

Further trials in this area are warranted.

5.          Acute management of stroke

This consensus statement was proposed by the chairpersons, Professor László Csiba, Debrecen, Hungary and Associate Professor Per Wester, Umeå, Sweden together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Associate Professor Nils Gunnar Wahlgren, Stockholm, Sweden, Professor Kennedy Lees, Glasgow, United Kingdom, Dr Niaz Ahmed, Stockholm, Sweden, Professor Angel Chamorro, Barcelona, Spain, Professor Philip Bath, Nottingham, United Kingdom and Associate Professor Bo Norrving, Lund, Sweden.

Neuroprotective treatment and metabolic control

Neuroprotective treatment

As yet, no drug has shown convincing neuroprotective effects in the setting of clinical acute ischemic stroke. No neuroprotective agent can be recommended at present for routine use in acute stroke patients. There are numerous possible  reasons for the lack of effect on outcome of several relatively large randomised clinical trials. Further trials of potential neuroprotectants are required.

1.      In animal experiments with carefully controlled blood pressure, temperature and oxygenation a standardised amount of ischaemia is induced by a reproducible intervention. In contrast, aetiology, location and severity of stroke in patients is very heterogeneous. The following strategies may be considered for future studies:

1.1. The animal models should be regarded as a method to screen whether a particular compound has the ability to save the ischaemic penumbra when administered after the insult.

1.2. Data on neuroprotection should be based on a range of animal stroke models, e.g., with and without reperfusion and also from models of thrombotic and thromboembolic origin .

1.3. Data should be critically explored and be derived from several independent laboratories. Neutral results should be also published.

1.4. It might be rewarding to explore treatments using a combination of induced reperfusion with neuroprotection or various combinations of neuroprotectants.

1.5. From these data one should know

a)     whether the drug penetrates the blood-brain barrier (if it ought to do);

b)     a detailed dose-response relationship for efficacy and safety;

c)     time window and duration for efficacy;

d)     major side effects.

2.       The following strategies may be considered for future clinical trials:

·         The drug should generally be tested within the time window and duration that has been shown to be effective from animal data although different time windows may be present in humans.

·         The optimal dose-response and duration of treatment should be determined in phase IIb trials. 

·         Diffusion-perfusion MR, Xe-CT or SPECT may be used to delineate treatable region/penumbra in individual patients and thereby identify more rationally appropriate candidates for neuroprotective therapy. These data may be used as co-variables to explain the effects. 

·         Unless very large trials are conducted, stratification or adaptive randomisation of patients at baseline should be done taking into account factors of known prognostic importance (age, stroke subtype, stroke severity) in order to balance groups at baseline.

·         Choose a realistic (but also meaningful) primary endpoint with a realistic magnitude of effect.

Blood pressure

3.       Blood pressure higher than 160/90 mm Hg is common  in acute stroke patients on admission to hospital. Increased blood pressure values typically normalise gradually during the first hours and days after hospital admission. There is uncertainty whether systemic blood pressure should be manipulated in the acute phase of stroke and if so, in what subgroups of stroke, at which blood pressure levels and at what duration after ictus intervention should start.

4.       Treatment of hypertension in the acute phase of stroke should be avoided, except within randomised controlled trials, and in cases of hypertensive encephalopathy, dissecting aortic aneurysm, acute heart failure and unstable angina pectoris/ myocardial ischaemia (grade C evidence). In patients eligible to thrombolysis, blood pressure may be reduced to levels below 180/110 mm Hg before treatment (grade B evidence). Trials of altering blood pressure are urgently required.

Metabolic control

5.       Hyperthermia consistently increases brain injury in experimental models, acting through several mechanisms. Observational studies in humans have demonstrated that hyperthermia is independently associated with a worse outcome. No randomised clinical trials of the treatment of hyperthermia have been performed. Trials of treating hyperthermia and inducing hypothermia are urgently required.

·         It is recommended that prompt antipyretic therapy (e.g. paracetamol) should be part of routine care in patients with acute stroke and body temperature greater than 37.5 o C (grade C evidence).

6.       Hyperglycemia consistently aggravates brain injury in ischaemic reperfusion models, acting through accumulation of lactate with acidosis and glutamate increase. Clinical observational findings support the concept of hyperglycemia-induced cerebral damage, irrespective of whether the patient has previously diagnosed or latent diabetes, or stress hyperglycemia. Hyperglycemia is also a predictor of intracerebral haemorrhage during thrombolysis therapy. An ongoing multicentre study is assessing the effect of  lowering  blood glucose in patients with hyperglycemia.

·         It is recommended that blood glucose should be monitored and hyperglycemia (>10 mmol/l) treated with insulin (grade C evidence).

7.       Hypoxia: No favourable effect was observed from oxygen supplementation in a quasi randomised trial.

·         It is recommended that in all patients, oxygen tension should be monitored in the acute phase. Supplemental oxygen should not be used unless the patients are hypoxic (grade C evidence).

·         Further trials of oxygen supplementation (and also hyperbaric oxygen supplementation) are required. 

 

8.       Fluid and electrolyte management: Dehydration may worsen ischaemic injury because of increased blood viscosity and hypotension. Hyper-osmolar dehydration is usually due to decreased fluid intake (or diabetes). Hypo-osmolar dehydration due to inappropriate secretion of antidiuretic hormone is rare and usually transient.

·         Monitoring and correction of electrolyte and osmotic disturbance is recommended (grade C evidence). Trials of fluid replacement are required.

6.   Antiplatelet treatment for secondary stroke prevention

This consensus statement was proposed by the chairpersons, Dr Karsten Overgaard, Copenhagen, Denmark and Dr Hans-Göran Hårdemark, Uppsala, Sweden together with the speakers in this session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Professor Michael Gent, Hamilton, Canada,  Professor Jaques De Keyser, Groningen, the Netherlands, Associate Professor Arne Lindgren, Lund, Sweden and Dr Georgios Kaponides, Stockholm, Sweden.

1.       Since the 1998 consensus statement was published no new studies of secondary prevention of stroke using antiplatelet drugs have been published. Therefore it was not considered necessary to revise this text. However, the role of antiplatelet therapy in the acute phase of stroke was not considered in the 1998 document. This issue was addressed in the present statement. Some aspects on dipyridamole related headache were also added.

2.       Antiplatelet treatment in the acute phase of ischaemic stroke: In the acute setting of ischaemic stroke aspirin in a dose of 160-300 mg daily will reduce the risk of non-fatal stroke or death by 10% per 2-4 weeks as compared to placebo (relative risk reduction, 3 studies, grade A evidence).

3.       Results regarding the use of dipyridamole alone or in combination with aspirin or clopidogrel in the acute phase of stroke have not been published.

4.       Dipyridamole treatment: Dipyridamole induced headache appears often to be of vasodilatory type. No published study has yet systematically addressed the question of how to manage dipyridamole associated headache but several methods may be worth considering e.g. starting with a lower dose of dipyridamole or provide concomitant treatment with analgetics during a short initiation period. A study addressing the management of dipyridamole related headache is needed.

5.       Clopidogrel treatment: The combined use of aspirin and clopidogrel in TIA and stroke patients is presently under investigation in several studies, but results have not been published.

  1. In conclusion (addendum to 1998 statement): In the acute phase of ischaemic stroke, i.e. during the first 2-4 weeks, aspirin treatment is the only antiplatelet drug proven to reduce the risk of recurrent non-fatal stroke or death compared to placebo (grade A evidence)

Unchanged statement from 1998:

Consensus statements on combined dipyridamol and aspirin treatment (A) and on clopidogrel (B):

 The consensus statement on combined dipyridamol and aspirin treatment was based on studies of secondary prevention of stroke. The consensus statement on clopidogrel was based on studies using a wider range of vascular inclusion criteria, including secondary prevention of stroke.

A.  Combined dipyridamol and aspirin treatment:

The 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, Uppsala, Sweden, Professor Jan Tijssen, Amsterdam, the Netherlands and Professor Peter Sandercock, Edinburgh, United Kingdom were speakers in this session.

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.       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).

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).

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).

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.

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.

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.

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.


B. Clopidogrel

This consensus statement was prepared by Associate Professor Andreas Terent, Uppsala, Sweden. The discussion was chaired by Professor Philip Bath, Nottingham, United Kingdom, and Associate Professor Andreas Terent, Upssala, Sweden, Professor J Donald Easton, Rhode Island, USA, and Professor Peter Sandercock, Edinburgh, United Kingdom, were speakers in this session.

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.       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.

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.

Clopidogrel, 75mg once daily, is a first line drug in patients with aspirin intolerance.