The consensus statement  was proposed by the chairperson in the session, Associate professor Hans-Göran Hårdemark, Uppsala, and the session secretary dr Niaz Ahmed, Stockholm, 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 Antoni Davalos, Badalona, Professor Tom Skyhöj-Olsen, Copenhagen, Professor Wade S Smith, San Francisco, Professor Nils Wahlgren, Stockholm, and Professor Rüdiger von Kummer, Dresden

Is there sufficient evidence to support a conclusion that routine use of intravenous thrombolysis as evaluated by the SITS-MOST study has proven at least as efficacious and safe as in randomised controlled trials?

Which are the mail conclusions from DIAS and DEDAS trials?

Which conclusions can be made from studies of thrombectomy using the MERCI approach? Are further trials warranted?

Is the risk of haemorrhage after thrombolysis overestimated?

Is there sufficient evidence to support a conclusion that routine use of intravenous thrombolysis as evaluated by the SITS-MOST study has proven at least as efficacious and safe as in randomised controlled trials?

Intravenous thrombolysis is proven beneficial within 3 hours of stroke onset (Grade A). SITS-MOST has confirmed (1) that routine use of intravenous thrombolysis within the approved indications is at least as safe and as efficacious as in randomised controlled trials (Grade C). The recruitment of patients into SITS-MOST has exceeded expectations and the quality of data has been verified by systematic source data monitoring. The completeness of data entry was confirmed by participating centres when qualifying as a participating centre. Although the regulatory project in SITS is now terminated the continued use of the SITS registry for quality development purposes is still highly justified.

Still less than 2% of patients in Europe are treated with thrombolysis. Some centres treat 10% of patients or more indicating that there is serious undertreatment of thrombolysis in the stroke population. The broad implementation of this treatment should be given high priority in the next few years. The project SITS 2009 @ 5% is one initiative which should be widely used. Campaigns to raise public awareness are highly warranted

Which are the main conclusions  from DIAS and DEDAS trials?

Pooled analysis of DIAS and DEDAS trials (2,3) has shown that desmoteplase 125 µg/kg in a single IV bolus improves significantly reperfusion and clinical outcome compared to placebo in patients with ischaemic penumbra selected by MRI (Grade C). Desmoteplase were apparently safe, since it was associated with a low rate of SICH (1.7% SICH) and mortality rate was similar to placebo. Disability was significantly reduced with DSPA 125 µg/kg as measured by the mRS at day 90. The high rate of MRI protocol violators affected outcome with 90 µg/kg in ITT. The benefit of desmoteplase 125 µg/kg warrants confirmation in a further study (DIAS-2), and the potential benefit of 90 µg/kg to be verified.

What conclusions can be made considering the results of the MERCI and multi MERCI trials (4, 5) ?

1. Large vessel stroke is highly morbid if left untreated
2. Mechanical embolectomy with the MERCI device opens vessels 54% of the time, a rate superior to natural history
3. Adjuvant IA thrombolysis improves final recanalisation to 69%
4. Clinical outcome is significantly better if the vessel is recanalised
5. Mortality is significantly lower if the vessel is recanalised
6. Target vessel recanalisation is an independent predictor of good clinical outcome and mortality using multivariate modelling
7. Clinically significant procedure complications occur in 4.5-7.1% of cases
8. It is safe to treat patients with thrombectomy who have failed IV t-PA (defined as the vessel remaining closed after IV t-PA infusion)
9. The treatment is cleared by FDA for in acute  large vessel stroke and may also be used for failed i.v. thrombolysis (Grade C)
10. Randomised data is necessary before one can conclude that mechanical recanalisation mitigates stroke

Is the risk of haemorrhage after thrombolysis overestimated?

Brain haemorrhage after reperfusion therapy may be caused by ischaemic damage of artery wall, pre-existing arterial and brain tissue pathology, anticoagulation and thrombolysis, sudden increase in perfusion pressure, increased arterial blood pressure, arterial injury by devices, and even yet unknown factors.  Haemorrhagic transformation (HT) of ischaemic brain tissue is a common phenomenon (6). Not each haemorrhage will cause clinical symptoms and relevant deterioration. It is unlikely that HT within infarcted brain tissue may cause any symptoms. The assessment of HT that causes clinical deterioration, symptomatic intracerebral haemorrhage (SICH), requires, therefore, brain imaging and a careful analysis of brain pathology. We regard a brain haemorrhage as SICH, if the patient deteriorated by 4 or more points on NIHSS and CT or MRI at the time of clinical deterioration shows haemorrhage as the only pathology in the location relevant for the symptoms or a haemorrhage together with ischaemic damage that is more prominent than the volume of ischaemic injury and likely to have caused the symptoms (1). We are afraid, that such careful assessment of HT has not been performed and, consequently, the incidence of SICH was overestimated in RCTs.

References:

1. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G: Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.

2. Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, Sachara C, Soehngen M, Warach S, Hacke W; DEDAS Investigators. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006 May;37(5):1227-31.

3. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S; DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase.
Stroke. 2005 Jan;36(1):66-73

3. Wade S. Smith, Gene Sung, Sidney Starkman, Jeffrey L. Saver, Chelsea S. Kidwell, Y. Pierre Gobin, Helmi L. Lutsep, Gary M. Nesbit, Thomas Grobelny, Marilyn M. Rymer, Isaac E. Silverman, Randall T. Higashida, Ronald F. Budzik, Michael P. Marks for the MERCI Trial Investigators. Safety and Efficacy of Mechanical Embolectomy in Acute Ischemic Stroke: Results of the MERCI Trial. Stroke 2005 36: 1432 - 1438

4.Smith W. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol 2006 Jun-Jul;27(6):1177-82

5. Larrue V, von Kummer R, Müller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with rt-PA. Stroke. 2001;32:438-441.