The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website www.eso-stroke.org

I. Karolinska Stroke Update Consensus Statement

Reperfusion Therapy - Intravenous Thrombolysis

The following Consensus Statement was adopted by the 8th Karolinska Stroke Update meeting on November 16th 2010.
The consensus statement was proposed by the chairman of the session, Professor Markku Kaste, Helsinki, Finland, and the session secretary Dr. Nikolaos Kostulas, Stockholm, Sweden, together with the speakers of the session. The statement was then finally approved by the participants of the meeting after listening to the other presentations.
The speakers in this session were Professor Risto O. Roine, Turku, Finland, Professor Kennedy R. Lees, Glasgow, UK, Professor Jan Sobesky, Berlin, Germany, Dr. Michael Mazya, Stockholm, Sweden. Professor Danilo Toni, Rome, Italy, took part in updating the consensus statement and recommendation to the ESO but could not attend the meeting.

Controversy to discuss at the 2010 consensus session:

• Is there sufficient evidence to support the conclusion that routine use of intravenous thrombolysis is effective and safe from 3 to 4.5 hours after the onset of stroke symptoms?
• Is there sufficient evidence that octogenarians and those with diabetes and prior stroke should be treated with thrombolysis?
• What, if any, is the role of multimodal imaging for patient selection for thrombolysis beyond 4.5 hours?
• Can intracerebral haemorrhage after thrombolysis be predicted?

Background

The second pooled analysis of eight randomised trials[1], confirmed the results of the first pooled analysis[2].

The second pooled analysis included also the EPITHET (100 patients) and ECASS III (821 patients) trials[1,3,4]. The treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as onset to treatment time (OTT) decreased (p=0.0269), and no benefit of alteplase treatment was seen after 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44–4.52) for 0–90 min, 1.64 (1.12–2.40) for 91–180 min, 1.34 (1.06–1.68) for 181–270 min, and 1.22 (0.92–1.61) for 271–360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41–1.48) for 0–90 min, 1.13 (0.70–1.82) for 91–180 min, 1.22 (0.87–1.71) for 181–270 min, and 1.49 (1.00–2.21) for 271–360 min[1].

Interpretation of the investigators:

Patients with ischaemic stroke selected by clinical symptoms and noncontrast CT (nCT) benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten the delay in initiation of treatment[1].

The essential points of the second pooled analysis compared to the first one are:

–     favourable outcome present also for treatment given up to 4.5 hrs, but the odds ratio (OR) for 3 to 4.5 hrs is 1.34 compared to 1.4 in the first pooled analysis.
–     “the sooner the better” is strongly confirmed by the OR for good outcome in the 0-90 min interval, with a number needed to treat (NNT) 4.5, as compared to the NNT 14.1 in the 181-270 min interval.
–     mortality is associated with the increase of OTT becoming statistically significant after 270 min indicating significant harm for some patients treated in the final OTT interval. However, mortality is not related to symptomatic intracerebral haemorrhage (SICH). In fact, the OR for parenchymal hematoma type 2 (PH2) is always >1 in all time intervals, but with similar absolute rates in all intervals. We consider PH2 instead of SICH as written in the first analysis, since there is not an unequivocal definition of SICH in the different papers, while PH2 is available in all the papers and is the type of ICH more likely to be related to clinical impairment. Hence the adjusted model does not confirm a relation to OTT (and in particular not associated with the 3 to 4.5 h interval), although the low rate of PH2 in some strata limits reliability of the estimation, and the small numbers of PH2 in the placebo group do not allow a statistical adjustment by prognostic factors.
–     the “shift analysis”, that is the distribution of alteplase and placebo patients within each category of mRS, confirms the significantly better outcome for patients treated up to 4.5 hrs, but not after 4.5 hrs.
–     net benefit is diminishing with time (OR for good outcome decreasing, OR for mortality increasing) and is undetectable beyond 4.5 hrs.

ECASS III enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. The results of ECASS III showed that 219 of 418 patients in the alteplase group (52.4%) had a favourable outcome, which was defined as a score of 0 or 1 on the modified Rankin Scale (mRS) compared with 182 of the 403 patients in the placebo group (45.2%) representing an absolute improvement of 7.2% (OR, 1.34; 95% CI, 1.02 -1.76). In the global analysis of ECASS III data based on the mRS, Barthel index and the National Institutes of Health Stroke Scale (NIHSS), the outcome was also improved with alteplase when compared with placebo (OR, 1.28; 95% CI, 1.00-1.65). In ECASS III with the extended time window, the NNT for one additional patient to achieve a favourable outcome (mRS 0-1) was 14 [4].
The incidence of intracranial haemorrhage was higher with alteplase than with placebo (for any intracranial haemorrhage, 27.0% vs. 17.6%; p=0.001; for symptomatic intracranial haemorrhage, 2.4% vs. 0.2%; p=0.008). Symptomatic haemorrhage was defined as any intracranial bleeding that was the predominant cause of clinical deterioration, as defined by an increase of 4 points or more in the NIHSS score, or death. In practice, only bleeds of type PH2 fell into this category. In both study groups 29 patients had symptomatic brain oedema. The rate did not differ significantly between the study groups. It was 6.9% in the alteplase group and 7.2% in the placebo group (OR, 0.96; 95% CI, 0.56-1.64). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; p=0.68). There was no significant difference in the rate of other serious adverse events[4].
In the post hoc intention to treat analysis adjusted for confounding baseline variables, treatment with alteplase remained significantly associated with a favourable outcome (odds ratio, 1.42; 95% CI, 1.02-1.98; p=0.04)[4].

Interpretation of the investigators:

Intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcome in patients with acute ischaemic stroke when compared with placebo; alteplase was more frequently associated with symptomatic intracranial haemorrhage[4].

SITS-ISTR is a part of SITS collaboration providing information about the safety of thrombolytic treatment in patients treated in a clinical routine setting in agreement with the European marketing licence for alteplase. SITS-ISTR also included off-label use, e.g. when treatment is provided beyond 3 hours. The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours. Outcome measures were SICH defined as PH2 associated with NIHSS > 4 points deterioration, mortality, and independence defined by mRS of 0-2 at 3 months[5].

The data from SITS-ISTR showed that in the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset (195 min (IQR 187-210) vs. 140 min (IQR 115-165); p< 0.0001), median age was 3 years younger (65 years (55-77) vs. 68 (58-74); p<0.001), and stroke severity was lower (NIHSS score 11 (7-16) vs. 12 (8-17); p<.00001) than in the 3-hour cohort. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures: SICH 2.2% (14 of 649) vs. 1.6% (183 of 11681), OR, 1.18; 95% CI, 0.89-1.55; adjusted OR, 1.32, 95% CI, 1.00-1.75, mortality 12.7% (70 of 551) vs. 12.2% (1263 of 10368), OR, 1.02; 95% CI, 0.90-1.17; adjusted OR, 1.15; 95% CI, 1.00-1.33, and independence 58.0% (314 of 541) vs. 56.3% (5757 of 10231), OR, 1.04; 95% CI, 0.95-1.13; adjusted OR, 0.93; 95% CI, 0.84-1.03)[5].

The updated analysis of the 3 to 4.5 hrs cohort of patients in the SITS-ISTR was published in September 2010 in Lancet Neurology. The aims were to assess the implementation of the wider time window and to evaluate its effect on the admission-to-treatment time, as well as safety and functional outcome in patients treated within 3 to 4.5 hrs[6].

23 942 patients were included in the SITS-ISTR registry between December 2002 and February 2010 of whom 2376 were treated within 3-4.5 h after symptom onset. By comparing patients treated before and after October 2008, when ECASS III was published, the proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs. 67 of 1023 [7%]). There was apparently an increase in delayed treatments. However, also patients treated within 3 hrs increased by 12% in the same period, and had increased by approximately 24% in first quarter of 2009 as compared to the last quarter of 2008.
The median admission-to-treatment time was 65 min both for patients registered before and after October 2008 (p=0.94). In the adjusted analysis there were significant differences as follows: 352 (2%) of 21204 patients treated within 3 h and 52 (2%) of 2317 treated within 3- 4.5 h of stroke had SICH at 3 months ([OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18583 patients who were treated within 3 h and 218 (12%) of 1817 who were treated within 3-4.5 h had died by the 3-months follow-up (OR 1.26, 95% CI 1.07-1.49;p=0.005). 10531 (57%) of 18317 patients treated within 3 h of stroke and 1075 (60%) of 1784 who were treated within 3-4.5 h were functionally independent at 3 months (OR 0.84, 95% CI 0.75-0.95; p=0.005)[6].

Interpretation of the investigators:
Since October 2008 thrombolysis within 3–4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes in SITS-ISTR are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier (see table below). Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset[6,7].

The adjusted results of SITS-ISTR with 23 942 patients data were almost identical with those of the SITS analysis 2008[5,6].

Extension of thrombolysis beyond a time window of 4,5 h: the role of multimodal imaging

The statement is based on four major data sources: the EPITHET data, the DEFUSE data, the DIAS2 data, and the recent meta-analysis of delayed thrombolysis [3,8-10].

Background:

The current evidence for the time dependent benefit of IV thrombolysis is based on randomised clinical trials (RCTs) using noncontrast Computed Tomography (nCT) as the imaging modality of choice. Accordingly, the guidelines recommend IV thrombolysis up to 4,5 hours after symptom onset by the use of nCT. In the pooled analysis, IV thrombolysis beyond 4,5 h was associated with a higher shown significant increased risk of mortality, with a lower chance of clinical recovery after 3 months and showed a trend to higher rates of treatment related bleeding[1].

However, several studies suggest that multimodal imaging techniques yield a valuable pathophysiological characterisation of ischaemic stroke[3,8,9]. The presence of irreversibly damaged tissue (“infarct core”) and of hypoperfused but still viable tissue (“penumbra”) in the first hours after ischaemic stroke has been demonstrated by case series using positron emission tomography (PET). In the clinical setting this concept has been translated to the concept of “mismatch” using DW/PW-MRI and perfusion-CT. Mismatch defines the volumetric ratio of at least 1,2 between the hypoperfusion (defined by PWI) and the infarct core (defined by DWI). Alternatively, perfusion CT can be used for mismatch definition keeping in mind several methodological differences.

Current data:
The assessment of mismatch in acute stroke bears the promise to identify the subgroup of patients that might benefit from reperfusion/recanalisation beyond 4,5 h after symptom onset. Observational studies suggest, that IV thrombolysis beyond 4,5 h using the mismatch criteria might be comparable to nCT based thrombolysis within 3 h with respect to safety and efficacy. However, evidence from RCT is still scant, and the mismatch criteria need to be standardised.

Two clinical trials of multimodal MR imaging using alteplase for IV thrombolysis 3 to 6 hours after stroke are available. In both studies, however, the therapeutic decision for IV thrombolysis was drawn by noncontrast CT. The DEFUSE trial suggested that MRI might identify mismatch patterns that respond favourably to thrombolysis. However, this study included only 74 patients and had no control group[8]. The EPITHET trial included 101 patients in a prospective placebo controlled randomised design. It found a significantly increased reperfusion rate in mismatch patients and better outcome in patients with reperfusion[3]. However, the reduction of infarct growth was not significant. The only RCT in which patients for thrombolysis were selected according to mismatch criteria, the DIAS II trial[9], used desmoteplase and included 193 patients (n=122 stroke MRI; n=64 perfusion CT). Although specific issues of the trial are currently under discussion, a benefit of thrombolysis beyond 4,5 h according mismatch criteria could not be shown. Accordingly, a recent meta-analysis, including 502 patients from DEFUSE, EPITHET and DIAS (as well as the precursor studies DIAS and DEDAS) with IV thrombolysis beyond 3 hours, summarizes that the imaging based mismatch selection of patients for IV thrombolysis beyond 4,5 h can at present not be recommended as a part of routine care[10]. Even though delayed thrombolysis in mismatch patients was associated with an increased rate of reperfusion and even though reperfusion was associated with improved outcome, the mismatch based selection of patients for delayed thrombolysis did not significantly improve outcome.

Conclusions:

Although the current data suggest that multimodal imaging might help to identify patients that benefit from IV thrombolysis beyond 4,5 h, the current evidence is not strong enough to recommend reliance on this patient-selection for routine care. Nevertheless, the data are in favour of further investigations in RCT. The correct definition of the “tissue at risk” seems crucial to apply this concept to acute stroke patients.

Main issues needing to be clarified include:
–     the choice of the adequate perfusion imaging parameters [11]
–     the performance of mismatch imaging with respect to the tissue at risk [12]
–     the adequate definition of mismatch [13,14]
–     the problem of DWI reversibility [15]
–     the comparison of multimodal CT and MRI in imaging the tissue at risk [16]
–     the additional value of FLAIR imaging for patient selection [17]

The ongoing studies EXTEND, DIAS-3 and -4, and ITAIS-2 will shed more light on this multimodal imaging approach.

Data on the safety and efficacy of thrombolysis in octogenarians and those with diabetes and earlier stroke
Data on the safety and efficacy of thrombolysis in octogenarians, those with diabetes and earlier stroke i.e. the off-label use of alteplase is based on SITS and SITS-ISTR registries, on controlled comparisons within and against VISTA, and on open non-randomised case series[5,6,18,19,20,389] with only limited data from randomised trials.
Adjusted analysis of the limited randomised data in patients above 80 years is consistent with similar benefit and risk as in patients under 80 years. While some registries have found poorer outcomes in octogenarians than in younger patients treated with IV alteplase[21-23] other registries[20,24] and controlled studies have shown that the treatment benefit of IV alteplase in patients aged over 80 years is similar to that in younger patients[19,25] and registries have not shown significant increased risk of symptomatic hemorrhage[26].
A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes[18,24].

In due course, the ongoing IST-3 and the TESPI trial will supplement these data.

Discussion
The results of ECASS III and the SITS-ISTR registry study showed that intravenous alteplase given between 3 and 4.5 hours (median 3 hours 59 minutes in ECASS III and 3 hours 15 minutes in SITS-ISTR registry) after stroke onset is associated with an improvement in clinical outcome (absolute difference 7.2% and NNT up to 14 in ECASS III), in patients who otherwise meet the licensing criteria, without a higher rate of SICH than reported previously among patients treated within 3 hours. The effect size of thrombolysis is time-dependent. The shift analysis of the distribution of alteplase and placebo patients within each category of mRS showed the significant better outcome for patients treated up to 4.5 hrs, but not after 4.5 hrs[4,5].
The results of the second pooled analysis confirmed that intravenous alteplase started between 3 and 4.5 hours after stroke onset is effective, although the net benefit decreases with time due to decrease of odds for good outcome and increase of odds for mortality which becomes significant after 270 minutes. The risk of symptomatic intracranial hemorrhage does not significantly increase with time[1].
The results of the SITS-ISTR registry showed that the extension of the time window to 4.5 hours led to an increase of treatments in the time interval 3 to 4.5 hours but also of treatments within 3 hours, and that admission to treatment times did not increase. Rates of symptomatic intracranial hemorrhage and mortality were higher and good outcome less frequent in the later cohort, but these outcomes have remained constant for several years[6].
The effect size of thrombolysis is time-dependent. The NNT to get one more favourable outcome drops from 4.5 during the first 90 minutes, through 9 within 3 hours and towards 14 between 3 and 4.5 hours[1]. Early treatment remains essential but a longer time window offers an opportunity for patients who cannot be treated within the previously approved 3-hour time window. The results of ECASS III, of the second pooled analysis and SITS-ISTR registry should not slow down the efforts to facilitate early treatment. Patients should be treated as early as possible to maximize the benefit.
The value of multimodal imaging for thrombolysis beyond 4.5 hours is still under investigation. The possibility of imaging based patient stratification has been described in various non randomised studies and has shown promising results. However, the current evidence from clinical trials[3,8,9]  is not strong enough to imply multimodal imaging in routine care and ongoing studies have to be awaited[10].
Although some registries have found poorer outcomes in octogenarians than in younger patients[21-23], other registries[20] and controlled comparisons have suggested that treatment benefit in octogenarians is similar to that in younger patients[19,25] and registries have not shown significant increased risk of symptomatic hemorrhage[26]. Treatment of very elderly is reasonable and may be offered unless the patient is prepared to enter an RCT, or unless the marketing approval restrictions prevent this locally.
A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes[18,24].

Conclusions
The results of ECASS III, the second pooled, analysis and the SITS-ISTR registry confirm the conclusion drawn from the pooled data from prior RCTs, that intravenous alteplase started between 3 and 4.5 hours after symptom onset is effective, and that although the risk of intracranial haemorrhage is increased compared to placebo, this treatment from 3 up to 4.5 hours remains safe and effective.
The current evidence supports the use of IV thrombolysis in patients aged over 80 years as well as in diabetic patients with prior stroke if they otherwise fulfill treatment criteria.
Multimodal imaging might be helpful in the identification of patients that can benefit from IV thrombolysis beyond 4.5 h but the current evidence is not sufficient to implement imaging based selection for delayed thrombolysis in routine care.

References

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9. Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S, Ringleb PA, Rowley HA, Schneider D, Schwamm LH, Leal JS, Söhngen M, Teal PA, Wilhelm-Ogunbiyi K, Wintermark M, Warach S. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141-50.
10. Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W, Lees KR. Mismatch-based delayed thrombolysis: a meta-analysis. Stroke 2010;41:e25-33. Erratum in: Stroke 2010;41:e399.
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24. Meretoja A, Putaala J, Tatlisumak T, Atula S, Artto V, Curtze S, Häppölä O, Lindsberg PJ, Mustanoja S, Piironen K, Pitkäniemi J, Rantanen K, Sairanen T, Salonen O, Silvennoinen H, Soinne L, Strbian D, Tiainen M, Kaste M. Off-label thrombolysis is not associated with poor outcome in patients with stroke. Stroke 2010;41:1450-8.
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II. Recommendation by Karolinska Stroke Update participants to ESO Guidelines Committee to revise ESO guidelines

Specific treatment: thrombolysis

Recommendations

1. Intravenous rtPA (0.9 mg/kg body weight, maximum 90 mg), with 10% of the dose given as a bolus followed by a 60-minute infusion, is recommended within 3 hours of onset of ischaemic stroke (Class I, Level A)
2. There is clear evidence that intravenous rtPA is beneficial if given between 3 and 4.5 hours after stroke onset (Class I, Level A). It is recommended that treatment is considered in patients who otherwise meet the licence criteria.
3. The use of multimodal imaging criteria may be useful for patient selection for thrombolysis (Class III, Level C) but is not recommended for routine clinical practice (Class II, Level B)
4. It is recommended that blood pressures of 185/110 mmHg or higher is lowered before thrombolysis (Class IV, GCP)
5. It is recommended that intravenous rtPA may be used in patients with seizures at stroke onset, if the neurological deficit is related to acute cerebral ischaemia (Class IV, GCP)
6. It is recommended that intravenous rtPA may also be administered in selected patients under 18 years and over 80 years of age, although this is outside the current European labeling (Class III, Level C)
7. It is recommended that intravenous rtPA may also be administered in selected patients who have diabetes mellitus and have suffered prior stroke, although this is outside the current European labeling (Class III, Level C)
8. Intra-arterial treatment of acute MCA occlusion within a 6-hour time window is recommended as an option (Class II, Level B)
9. Intra-arterial thrombolysis is recommended for acute basilar occlusion in selected patients (Class III, Level B). Intravenous thrombolysis for basilar occlusion is an acceptable alternative even after 3 hours (Class III, Level B) 
10. It is recommended that aspirin (160–325 mg loading dose) be given within 48 hours after ischaemic stroke (Class I, Level A) 
11. It is recommended that if thrombolytic therapy is planned or given, aspirin or other antithrombotic therapy should not be initiated within 24 hours (Class IV, GCP)
12. The use of other antiplatelet agents (single or combined) is not recommended in the setting of acute ischaemic stroke (Class III, Level C) 
13. The administration of glycoprotein-IIb-IIIa inhibitors is not recommended (Class I, Level A)
14. Early administration of unfractionated heparin, low molecular weight heparin or heparinoids is not reommended for the treatment of patients with acute ischaemic stroke (Class I, Level A)
15. Currently, there is no recommendation to treat ischaemic stroke patients with neuroprotective substances (Class I, Level A)

Addition to text:

Thrombolytic therapy:

The European Cooperative Acute Stroke Study III (ECASS III) showed that intravenous alteplase administered between 3 and 4.5 hours (median 3 h 59 min) after the onset of symptoms significantly improves clinical outcomes in patients with acute ischemic stroke compared to placebo[1]; the absolute improvement was 7.2% and the adjusted OR of favourable outcome (mRS 0-1) was 1.42, 1.02-1.98. Mortality did not differ significantly (7.7% versus 8.4%), but alteplase increased the risk of SICH (2.4% vs. 0.2%). Treatment benefit is time-dependent. The number needed to treat to get one more favourable outcome drops from 4.5 during the first 90 minutes through 9 within 3 hours and towards 14 between 3 and 4.5 hours[5]. 

The SITS investigators compared 664 patients with ischaemic stroke treated between 3 and 4.5 hours otherwise compliant with the European summary of the product characteristics criteria with 11 865 patients treated within 3 hours. In the 3-4.5-hour cohort, treatment was started on average 55 minutes later after symptom onset. There were no significant differences between the 3-4.5-hour cohort and the 3-hour cohort for any outcome measures, confirming that alteplase remains safe when given between 3 and 4.5 hours after the onset of symptoms in ischaemic stroke patients who otherwise fulfil the European summary of product characteristics criteria[2].

More recently the SITS investigators extended the analysis by comparing 2376 patients treated between 3 and 4.5 hours with 21 566 patients treated within 3 hours, of whom those reported in the previous analysis are a part. In the updated analysis 23 942 patients were included in the SITS-ISTR registry between December 2002 and February 2010 of whom 2 376 were treated within 3-4.5 h after symptom onset. The proportion of patients treated within 3-4.5 h by the end of 2009 was three times higher than in the first three quarters of 2008 (282 of 1293 [22%] vs. 67 of 1023 [7%]). The median admission-to-treatment time was 65 min both for patients registered before and after October 2008 (p=0.94). In the adjusted analysis there were significant differences as follows: 352 (2%) of 21 204 patients treated within 3 h and 52 (2%) of 2 317 treated within 3- 4.5 h of stroke had SICH at 3 months ([OR] 1.44, 95% CI 1.05-1.97; p=0.02). 2287 (12%) of 18 583 patients who were treated within 3 h and 218 (12%) of 1 817 who were treated within 3-4.5 h had died by the 3-month follow-up (OR 1.26, 95% CI 1.07-1.49;p=0.005); 10 531 (57%) of 18 317 patients treated within 3 h of stroke and 1 075 (60%) of 1 784 who were treated within 3-4.5 h were functionally independent at 3 months (OR 0.84, 95% CI 0.75-0.95; p=0.005)[3].

The updated cohort studied in this new analysis made the differences between patients treated within 3 hours and those treated between 3 and 4.5 hours statistically significant in favour of earlier treatment, although the absolute rates of symptomatic intracranial haemorrhages, mortality and functional independence in the two time intervals were similar and quite overlapping to those of the previous report. Admission to treatment times were not increased after the implementation of the 3 to 4.5 hour time window[3]. Interpretation of the investigators: Since October 2008 thrombolysis within 3–4.5 h after stroke has been implemented rapidly, with a simultaneous increase in the number of patients treated within 3 h; admission-to-treatment time has not increased. Safety and functional outcomes are less favourable after 3 h, but the wider time window now offers an opportunity for treatment of those patients who cannot be treated earlier. Thrombolysis should be initiated within 4.5 h after onset of ischaemic stroke, although every effort should be made to treat patients as early as possible after symptom onset[3,4].

Pooled analysis of individual patient data from the randomised trials of intravenous alteplase of acute ischaemic stroke confirms a favourable risk-benefit profile until 4.5 hours after stroke onset, but later initiation of treatment is associated with increased 3-month mortality and no significant benefit[5]. Treatment benefit is time-dependent. The net benefit decreases with time due to decrease of odds for good outcome and increase of odds for mortality, which becomes significant after 270 minutes. The risk of symptomatic intracranial haemorrhage does not increase with time. The number needed to treat to get one more favourable outcome drops from 4.5 during the first 90 minutes, through 9 within 3 hours and towards 14 between 3 and 4.5 hours[5].
The value of multimodal imaging for thrombolysis beyond 4.5 hours is still under investigation. The possibility of imaging based patient stratification for delayed thrombolysis has been shown in non randomised studies with promising results[400, 401]. However, the adequate definition of the tissue at risk using multimodal MRI or CT is still lacking[6-12]. The current evidence from clinical trials of delayed thrombolysis[13,14,15] is promising but not strong enough  to implement multimodal imaging in routine care[16] and ongoing studies have to be awaited.
Although some registries have found poorer outcomes in octogenarians than in younger patients[17-19], other registries[20] and controlled comparisons have suggested that treatment benefit in the octogenarians is similar to that in younger patients[21,22] and registries have not shown significant increased risk of symptomatic haemorrhage[23]. Treatment of patients aged over 80 years is reasonable and may be offered unless the patient is prepared to enter an RCT, or unless the marketing approval restrictions prevent this locally.

A non-randomised controlled comparison and a registry in patients with diabetes and prior stroke found similar benefit as in patients without stroke or diabetes [24,25].

References:
New references:

1. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, for the ECASS Investigators. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. New Engl J Med 2008;359:1317-29.
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17. Alshekhlee A, Mohammadi A, Mehta S, Edgell RC, Vora N, Feen E, Kale S, Shakir ZA, Cruz-Flores S. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke 2010;41:2259-64.
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