Reperfusion in acute occlusive stroke - Karolinska Stroke Update

Consensus Statement 2004


The following Consensus Statement was adopted by the 5th Karolinska Stroke Update meeting on November 15, 2004.

The consensus statement  was proposed by the chairpersons in the session, Professor Markku Kaste, Helsinki, and Professor Kennedy R Lees, Glasgow, together with the speakers in the 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 Cesare Fieschi, Rome, Dr Geert Vanhooren, Brügge, Associate Professor Nils Wahlgren, Stockholm and Professor Heinrich Mattle, Bern


Reperfusion in acute occlusive stroke

1.         Intravenous rt-PA within 3 hours after the onset of symptoms in patients with acute ischaemic stroke is a highly effective treatment in selected patients (grade A evidence). The use of rt-PA is supported by results from randomized controlled trials, pooled analysis of six randomized rt-PA trials, meta-analyses and post-approval data.  According to meta-analyses, for patients given rt-PA within 3 hours of ischemic stroke at most 1 out of 22 may suffer some form of symptomatic haemorrhage, and 1 out of 100 more will survive as a result of the treatment (grade A evidence). In spite of haemorrhages approximately 1 out of 8 more will be independent according to the pooled analysis (grade A evidence).

2.         The pooled analysis of the 2775 patients of the ATLANTIS, ECASS and NINDS rt-PA trials suggests benefit up to 4 ½ hours after the onset of an ischemic stroke but the treatment benefit decreases with the time elapsed before treatment commences. Odds ratios for favourable outcomes with rt-PA in the pooled analysis were 2.8 (95%CI 1.8-4.5) in the 0-90, 1.6 (95%CI 1.1-2.2) in the 91-180, 1.4 (95%CI 1.1-1.9) in the 181-270 and 1.2 (95%CI 0.9-1.5) in the 271-360 minute time windows. Further randomized trials will be required to determine the latest useful time window (grade A evidence).

3.         Outside randomized controlled trials, it is recommended that the therapeutic use of intravenous rt-PA should follow published guidelines (with local modifications as appropriate), and the labelling approved by Health Authorities and should be subject to continuous quality control such as SITS collaboration.

4.         In most open studies the safety and efficacy of intravenous rt-PA in routine clinical practice is comparable to randomized studies. A meta-analysis of 12 post-approval open series with 2639 patients treated within 3 hours revealed comparable rates of symptomatic haemorrhages (5.2 vs 6.4 % in the NINDS trial), of favourable outcome as defined by mRS 0-1 pts (37.1 vs 39% in the NINDS trial) and of initial stroke severity as defined by the baseline NIHSS (14 vs 14 in the NINDS trial).

 5.         Thrombolysis within 3 hours is now widely approved by Health Authorities. The evidence strongly supports that rt-PA is made available for routine clinical use to treat stroke patients in adequately resourced and experienced centres. However, there is an obvious need for continuous education and for trained stroke specialists to guarantee safe and efficient use of thrombolysis. The development of hospital services designed to deliver early thrombolysis 24 hours a day for acute ischemic stroke is encouraged. If the local hospital is not able to provide it there should be a referral system designated to deliver thrombolysis.

6.         The approval of rt-PA in ischemic stroke by the European Union Health Authorities in 2002 was conditional. The first condition was that all treated patients should be included in the Safe Implementation of Thrombolysis in Stroke - The Monitoring Study register (SITS-MOST). The second condition was a double-blind, randomized, placebo-controlled trial of IV rt-PA in ischemic stroke where thrombolysis is initiated between 3 and 4 hours after stroke onset (ECASS III).

 7.         The heterogeneity for good outcome in meta-analyses of treatment > 3 hours 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, stroke severity, stroke subtype, vascular lesions, stroke pathophysiology, concomitant disease, and drug treatments should be further evaluated in future trials, meta-analyses, phase IV studies and the SITS register.

 8.         It is recommended that some 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. Extended ischemic oedema as detected by CT should militate against the use of thrombolysis (grade B evidence). MR diffusion and perfusion weighted imaging may reveal brain tissue at risk that can be salvaged with thrombolysis in individual patients within a 3-hour time window and possibly rather longer (grade C evidence). Other imaging modalities including perfusion CT, MR angiography, SPECT and TCD may be useful in selecting patients, in assessing arterial pathology and in monitoring the effects of therapy (grade C evidence). However, further data from randomized trials incorporating these new imaging modalities are required as although each may provide extra prognostic information, they may also increase time to treatment and hence reduce the benefit of rt-PA.

 9.         The limitation of the 3-hour time window and age limits are the major  factors which prevent wider application of thrombolysis in ischemic stroke.  ECASS III, IST-3, EPITHET and DIAS II aim at extending the time window. This may have an important public health impact in Europe. It is recommended that new thrombolytic agents, wider time windows and age limits, and thrombolysis together with ultrasound and/or neuroprotective  agents, should be evaluated in future randomized trials to try to extend  the effectiveness and to limit the risks of thrombolysis.

 10.     Another factor that prevented the wider application of thrombolysis in ischemic stroke is the concern that brain haemorrhage may harm the patient. In the pooled analysis (ATLANTIS, ECASS and NINDS), the rate of large space occupying haematoma (PH) was 1.1% in the placebo group and 5.9% in the rt-PA group. Despite this 5.4 fold risk, rt-PA significantly increased the overall chance of not being disabled or dead after stroke. From meta-analysis, the true increase in risk is probably lower, at under 4-fold.  In addition, closer examination of the data shows that not all of these haemorrhages were symptomatic. Many were incidental findings with no impact on clinical status of the patients. Accordingly, the definition of symptomatic brain haemorrhage should fulfil the following criteria: 'Clinical deterioration by > 4 points on NIHSS (or equivalent) combined with brain haemorrhage without other pathology, or clinical deterioration by > 4 points on NIHSS (or equivalent) combined with cerebral haemorrhage within an ischemic lesion where any mass effect is largely attributable to the haemorrhage. A small haemorrhage within a large space-occupying infarction should not be considered as “symptomatic haemorrhage” but rather “ischemic edema”, and data should be collected on ischemic edema in future trials.'

11.     IA thrombolysis is experimental and has not been approved in any country. Intra-arterial thrombolysis with r-proUK reduced disability in patients with occluded M1 or M2 segments of the middle cerebral artery within 6-hour time window in PROACT I and II (grade B evidence). The drug is not available in Europe. Open series have suggested that urokinase may be equally effective and safe as r-proUK. IA thrombolysis has also been used in basilar artery occlusions although IV thrombolysis may be equally effective due to faster delivery of the drug.  Large trials to assess IA treatment beyond 3 h and trials to compare IV and IA thrombolysis and their combination are needed.

 12.     Various mechanical means of clot removal and angioplasty are under investigation.  The safety and efficacy of these endovascular techniques including stent protected angioplasty in acute stroke need further assessment.

 13.     Thrombolysis for stroke in children, in patients older than 80 years, in carotid dissections, and in those with basilar artery occlusions needs further studies although case series suggest that it may have similar utility in those over 80 years of age as in younger patients, in basilar artery occlusions as in anterior circulation strokes, and in carotid dissections.

 14.     The present guidelines may need updating in many aspects of acute stroke care during thrombolysis. In the pooled analysis (ATLANTIS, ECASS and NINDS) every 10 mg/dl increase of blood sugar reduced odds ratios of good outcome (modified Rankin scale 0-1) by 0.98 and increased odds ratios for a bad outcome (modified Rankin scale 5-6) by 1.04 (grade B evidence). Open studies have revealed similar relationships between admission hyperglycemia and outcome in patients treated with thrombolytics. Accordingly, more active blood glucose control seems indicated in connection with thrombolysis.

 15.     Neither the pooled analysis (ATLANTIS, ECASS and NINDS) nor the reanalysis of the NINDS t-PA trial allowed assessment of the effect of blood pressure or its management on outcome but there are several case series which strongly suggest that it may not be desirable to reduce blood pressure without good clinical reason such as heart failure or hypertensive encephalopathy. When the occluded artery reopens the blood pressure declines, but if it does not recanalize, the blood pressure remains elevated to ensure perfusion in ischemic penumbra, and then an aggressive reduction of blood pressure may reduce the chances of good outcome. The SITS-MOST register may give an answer to some of these open questions but ongoing randomized trials may also contribute in this respect.

 16.     The impact of antiplatelet treatment prior to stroke on the risk of symptomatic haemorrhage following stroke needs to be studied further. Existing data do not indicate an increased risk of symptomatic haemorrhage (grade B evidence). Furthermore, the safety and efficacy of post-thrombolytic antithrombotic treatment and anticoagulation to prevent reocclusion need to be analysed in randomized trials.

 17.     The public should be educated of the value of early expert assessment and treatment

 18.     Thrombolysis in stroke should be widely available. Our task is now to increase rapid response to stroke. It is equally important to develop a well-functioning stroke triage and an in-hospital stroke care pathway.