Acute Stroke Slide Kit August 2017.

Acute Stroke Slide Kit August 2017

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Studies and Registries

Studies and registries
ECASS 3 Imaging studies (MRI-based patient selection) Meta- and pooled analyses SITS ▪ SITS-MOST ▪ SITS-ISTR ▪ SITS-NEW ▪ SITS-UTMOST ▪ SITS-WATCH VISTA IST-3 ENCHANTED

ECASS 3

ECASS 3: background & rationale
Worldwide, <5% of acute ischaemic stroke patients are treated with rt-PA within 3 hours of stroke symptom onset Efficacy is highest if thrombolysis is initiated within 90 min of symptom onset The pooled analysis of individual patient data (N=2,775) from 6 trials of IV rt-PA vs. placebo showed that the effective treatment window may extend to 4.5 hours rt-PA was approved by EMEA in 2002 for use within 3 h of ischaemic stroke with two post-approval requirements: Registration with the SITS internet database and entry into an observational safety study, SITS-MOST Randomised trial of rt-PA versus placebo, with an extended therapeutic window greater than 3 hours Alteplase was licensed for use in the USA in 1996, and in Canada in In 2002, it was granted a conditional license in the European Union (EU), based on 2 conditions: that it was used in within the realms of an observational safety study (SITS-MOST); and a new, randomised trial, the European Cooperative Acute Stroke Study (ECASS) 3 was set up with an extended therapeutic window beyond 3 h. Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008; 359: NINDS Trialists N Engl J Med 1995;333: ; Hacke et al. Lancet 2004;363: ; Ingall. Stroke 2009;40: ; Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3: overview Objective Primary Endpoint: Disability at day 90
To assess efficacy and safety of rt-PA between 3 and 4.5 hours after stroke onset in the European setting Primary Endpoint: Disability at day 90 Favourable (mRS ≤1) vs. unfavourable outcome (mRS 2-6) Secondary Endpoint Global outcome analysis at day 90, combining mRS (0-1), Barthel Index ≥95, NIHSS (0-1), Glasgow Outcome Scale (1) Safety Endpoints Included mortality at 90 days, any ICH, sICH Alteplase was licensed for use in the USA in 1996, and in Canada in In 2002, it was granted a conditional license in the European Union (EU), based on 2 conditions: that it was used in within the realms of an observational safety study (SITS-MOST); and a new, randomised trial, the European Cooperative Acute Stroke Study (ECASS) 3 was set up with an extended therapeutic window beyond 3 h. Study design: Randomised, placebo-controlled, double-blind, clinical trial CT pre-randomisation to exclude ICH or major ischaemic infarction 1:1 randomisation by IVRS to IV alteplase (rt-PA) 0.9mg/kg bodyweight, or placebo Alteplase (rt-PA) administration: bolus (10% of total dose) in 1-2 min, remaining 90% infused IV over 60 min Inclusion criteria: Age years Acute ischaemic stroke, after excluding ICH Onset of stroke symptoms h prior to initiation of study drug Identical to the European Summary of Product Characteristics (ESPC) of alteplase (rt-PA) for ischaemic stroke, except for treatment time window Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008; 359: Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3: primary endpoint (ITT)
Disability at Day 90, mRS ≤1 Analysis rt-PA n/N (%) Placebo OR (95% CI) p Unadjusted 219/418 (52.4%) 182/403 (45.2%) 1.34 (1.02−1.76) 0.04‡ Adjusted* − 1.42 (1.02−1.98) 0.04§ Favours placebo Favours rt-PA A post-hoc adjusted ITT analysis (logistic regression) for the primary endpoint was undertaken for sensitivity purposes. This was conducted by including all baseline variables in the model and retaining those that were significant at P<0.1. Thus treatment, baseline NIHSS, stroke onset to treatment time, smoking history and prior hypertension were retained. Treatment with rt-PA in this final prognostic model remains significant (P=0.037) with an OR of 1.42 and a 95% CI of ( ). Age, prior stroke and diabetes were not prognostic at p<0.1 and their inclusion inevitably introduces more variability; nevertheless, after also forcing these variables into the prognostic model, treatment with rt-PA remains significant (P=0.0495) with an OR of 1.40 and a 95% CI of ( ). We have reported the formal adjusted analysis as a non-prespecified endpoint in the manuscript. ITT, intent-to-treat *Adjusted for NIHSS score at presentation and the time to start of treatment ‡ p value was obtained by the Pearson chi-square test of proportions §p value was obtained by stepwise logistic regression Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3: secondary endpoint (ITT)
Day 90: NINDS global endpoint statistic (mRS 0-1; BI ≥95; NIHSS ≤1 or >8 point improvement; GOS 1) rt-PA (N=418) Placebo (N=403) OR (95% CI) p Global outcome n/a 1.28 (1.00–1.65) 0.05 mRS score ≤1 219 (52.4%) 182 (45.2%) 1.34 (1.02–1.76) 0.04‡ BI score ≥95 265 (63.4%) 236 (58.6%) 1.23 (0.93–1.62) 0.16‡ NIHSS score ≤1 210 (50.2%) 174 (43.2%) 1.33 (1.01–1.75) GOS score 1 213 ( 51.0%) 183 (45.4%) 1.25 (0.95–1.64) 0.11‡ Favours placebo Favours rt-PA ITT, intent-to-treat; ‡ p value was obtained by the Pearson chi-square test of proportions Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3: functional efficacy endpoints at 90 days (PP population)
730 patients (out of 821 randomised) Endpoint day 90 rt-PA (N=375) Placebo (N=355) OR (95% CI) p mRS score 0-1 206 (54.9%) 161 (45.4%) 1.47 (1.10−1.97) 0.01‡ Global outcome statistic (unadjusted) n/a 1.39 (1.07−1.80) 0.02 The PP results, that show an even greater effect are relevant, because they reflect the observed benefit of patients who received alteplase and did not have any contraindication to its approved use Favours placebo Favours rt-PA mRS, modified Rankin Scale PP, per protocol ‡ p value was obtained by the Pearson chi-square test of proportions Bluhmki et al. Lancet Neurol 2009;8:

ECASS 3: distribution of mRS scores at 90 days for the PP population
Per-protocol (PP) population Patients Distribution of the Modified Rankin Scale Scores: Per-Protocol Populations at the 3-Month Visit. Cochran–Mantel–Haenszel test on the stratified outcome distribution analysis of the modified Rankin scale at day 90, adjusted for baseline National Institutes of Health Stroke Scale scores and time-to-treatment onset. The mortality rate at the 3-month visit (n=59) was different from the overall mortality rate (n=66), as 7 deaths occurred after 90 days. p=0.016 ‡stratified on Cochran–Mantel–Haenszel test, adjusted for baseline NIHSS scores and time-to-treatment onset Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3 - efficacy: summary
rt-PA administered hours after stroke symptom onset is effective Significantly more patients benefitted vs. placebo in terms of: Disability at day 90, mRS 0-1 Overall greater functionality/independence (global outcome statistic) at day 90 Improved neurological functioning (NIHSS 0-1 or >8 point improvement) at day 30 Independence (mRS 1-2) at day 30 in the PP population Efficacy For the primary end point, 219 of the 418 patients in the alteplase group (52.4%) had a favorable outcome (defined as a score of 0 or 1 on the modified Rankin scale), as compared with 182 of the 403 patients in the placebo group (45.2%), representing an absolute improvement of 7.2 percentage points (odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; relative risk, 1.16; 95% CI, 1.01 to 1.34; P = 0.04). In the post hoc intention-to-treat analysis, adjusted for confounding baseline variables (logistic regression), study-group assignment, baseline NIHSS score, smoking status, time from the onset of stroke to treatment, and presence or absence of prior hypertension were identified as significant at P<0.10. In the adjusted analysis, treatment with alteplase remained significantly associated with a favorable outcome (odds ratio, 1.42; 95% CI, 1.02 to 1.98; P = 0.04). Treatment with alteplase also resulted in a more favorable outcome than that with placebo for the secondary end point, as indicated by the global odds ratio. (Since the global odds-ratio test was based on a linear logistic-regression model, with generalized estimation equations used to perform a Wald-type test, only probabilities, and not absolute numbers, for each treatment group can be provided.) The global odds ratio for a favorable outcome was 1.28 (95% CI, 1.00 to 1.65; P<0.05), indicating that the odds for a favorable outcome (the ability to return to an independent lifestyle) after stroke were 28% higher with alteplase than with placebo. The post hoc stratified analysis of scores on the modified Rankin scale at day 90 (performed with the use of the Cochran–Mantel–Haenszel test, with adjustment for the baseline NIHSS score and time to the start of treatment) also showed a favorable outcome with alteplase as compared with placebo (P = 0.02). In the intention-to-treat analysis, the odds ratios for a score of 0 or 1 on the modified Rankin scale, an NIHSS score of 0 or 1, and more than an 8-point improvement in the NIHSS score at day 30 showed a significant advantage of alteplase treatment, whereas there were no significant differences between the groups with respect to the other functional end points. Neurologic status up to day 30 did not differ significantly between the two groups. Reference: Hacke et al. the ECASS 3 Investigators. N Engl J Med 2008; 359: mRS, modified Rankin Scale PP, per protocol NIHSS, National Institute of Health Stroke Scale Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359: 12

ECASS 3 – safety endpoints: mortality (ITT)
Mortality by time interval 10% After day 90 (7 deaths) Days 8–90 (34 deaths) 0.7% 8% Days 1–7 (25 deaths) 1.0% 6% Death (%) 4.5% 3.8% 4% 2% 3.2% 2.9% 0% rt-PA Placebo rt-PA (N=418) Placebo (N=403) OR (95% CI) p Overall mortality 32 (7.7%) 34 (8.4%) 0.90 (0.54–1.49) 0.68 Safety A total of 66 patients died — 32 of the 418 patients in the alteplase group (7.7%) and 34 of the 403 in the placebo group (8.4%). Of these 66 patients, 25 died between days 1 and 7 (12 [2.9%] in the alteplase group and 13 [3.2%] in the placebo group), 18 between days 8 and 30 (10 [2.4%] and 8 [2.0%], respectively), and 16 between days 31 and 90 (6 [1.4%] and 10 [2.5%], respectively). Seven patients died after day 90 (four [1.0%] and three [0.7%], respectively). There were more cases of intracranial hemorrhage in the alteplase group than in the placebo group (27.0% vs. 17.6%, P = 0.001). The incidence of symptomatic intracranial hemorrhage with alteplase was less than 3 cases per 100 patients (10 of 418 patients [2.4%]), but that incidence was significantly higher than the incidence with placebo (1 of 403 [0.3%]; odds ratio, 9.85; 95% CI, 1.26 to 77.32; P = 0.008). All symptomatic intra cranial hemorrhages occurred within the first 22 to 36 hours after initiation of treatment. The rate of symptomatic edema did not differ significantly between the study groups: 6.9% in the alteplase group and 7.2% in the placebo group (29 patients in each group; odds ratio, 0.96; 95% CI, 0.56 to 1.64; P = 0.88). Other serious adverse events categorized according to organ system did not differ significantly between the two groups. Reference: Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008; 359: Favours rt-PA Favours placebo ITT, intent-to-treat Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:

ECASS 3 – safety endpoints: summary
sICH (symptomatic intracranial haemorrhage) Significant difference in sICH rates (2.14% absolute difference), although the incidence of sICH among rt-PA-treated patients was low (2.4%) Mortality Low overall mortality rate (approximately 8%), not different between treatment arms Probably due to the mild to moderate initial stroke severity Consistent with results from other randomised controlled trials of thrombolysis in acute ischaemic stroke No safety concerns in the longer time window Thrombolysis in patients with acute ischaemic stroke is associated with an increased risk of symptomatic intracranial haemorrhage, which is the most feared complication. It is difficult, however, to compare the incidence of symptomatic intracranial haemorrhage across studies because of the varying definitions used. In ECASS 3, the ECASS definition of symptomatic intracranial haemorrhage was modified by specifying that the haemorrhage had to have been identified as the predominant cause of the neurologic deterioration. With the use of this definition, the difference in rates of symptomatic intracranial haemorrhage between the two study groups was significant (a difference of 2.14 percentage points), although the incidence of symptomatic intracranial haemorrhage among alteplase-treated patients was low. Safety A total of 66 patients died — 32 of the 418 patients in the alteplase group (7.7%) and 34 of the 403 in the placebo group (8.4%). Of these 66 patients, 25 died between days 1 and 7 (12 [2.9%] in the alteplase group and 13 [3.2%] in the placebo group), 18 between days 8 and 30 (10 [2.4%] and 8 [2.0%], respectively), and 16 between days 31 and 90 (6 [1.4%] and 10 [2.5%], respectively). Seven patients died after day 90 (four [1.0%] and three [0.7%], respectively). There were more cases of intracranial haemorrhage in the alteplase group than in the placebo group (27.0% vs. 17.6%, P=0.001). The incidence of symptomatic intracranial hemorrhage with alteplase was less than 3 cases per 100 patients (10 of 418 patients [2.4%]), but that incidence was significantly higher than the incidence with placebo (1 of 403 [0.3%]; odds ratio, 9.85; 95% CI, 1.26 to 77.32; P=0.008). The incidence of symptomatic intracranial haemorrhage according to definitions used in other studies followed a similar. All symptomatic intracranial haemorrhages occurred within the first 22 to 36 hours after initiation of treatment. The rate of symptomatic oedema did not differ significantly between the study groups: 6.9% in the alteplase group and 7.2% in the placebo group (29 patients in each group; odds ratio, 0.96; 95% CI, 0.56 to 1.64; P=0.88). Other serious adverse events categorised according to organ system did not differ significantly between the two groups. Reference: Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359: Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359: 14

ECASS 3: Further analyses

ECASS 3: further analyses
Additional outcome analyses included functional endpoints at day 90 or day 30 mRS 0-1 [day 30], mRS 0-2, Barthel Index ≥85, and global outcome statistic [day 30] and treatment response (8-point improvement from baseline or 0-1 score on NIHSS) A stratified responder analysis by baseline NIHSS The subgroup analyses were based on the mRS 0-1 at day 90, sICH, and death mRS, modified Rankin Scale sICH, symptomatic intracranial haemorrhage NIHSS, National Institutes of Health Stroke Scale Bluhmki et al. Lancet Neurol 2009;8:

Favours placebo Favours rt-PA
ECASS 3 – subgroup analysis of favourable outcome (mRS 0-1): demographics (ITT) rt-PA % (n/N) Placebo OR (95% CI) p NIHSS at baseline 0-9 10-19 ≥20 73% (156/215) 34% (57/166) 16% (6/37) 67% (128/190) 31% (50/161) 8% (4/52) 1.28 ( ) 1.16 ( ) 2.32 ( ) 0.631 Age <65 ≥65 57% (105/184) 49% (144/234) 45% (70/155) 45% (112/247) 1.61 ( ) 1.15 ( ) 0.230 Gender Male Female 53% (139/264) 52% (80/154) 42% (97/231) 50% (85/171) 1.54 ( ) 1.09 ( ) 0.237 Time to treatment min min min 58% (23/40) 49% (93/191) 56% (98/174) 40% (17/42) 47% (91/193) 43% (64/148) 1.99 ( ) 1.06 ( ) 1.69 ( ) 0.212 Results of the ITT subgroup analyses With the exception of the presence or not of previous stroke, no significant subgroup-by-treatment interactions were noted (p<0.05) for the primary endpoint (mRS 0–1) at day 90. Both subgroups benefited from alteplase treatment, but patients who previously had a stroke seemed to benefit significantly more than those who had not had a previous stroke. In nearly all subgroups, there was a clear uniform pattern favouring alteplase, indicated by the fact that the OR was greater than 1 but p values for interaction (based on logistic regression with treatment, subgroup, and the interaction term) were non-significant. Reference: Bluhmki E et al. Lancet Neurol 2009;8: 1 mRS, modified Rankin scale ITT, intent-to-treat Favours placebo Favours rt-PA Bluhmki et al. Lancet Neurol 2009;8:

Favours placebo Favours rt-PA
ECASS 3 – subgroup analysis of favourable outcome (mRS 0-1): risk factors (ITT) rt-PA % (n/N) Placebo OR (95% CI) p Diabetes No Yes 54% (191/356) 45% (28/62) 44% (149/335) 49% (33/67) 1.45 ( ) 0.85 ( ) 0.167 Prior stroke 52% (199/387) 63% (20/32) 47% (163/345) 33% (19/57) 1.19 ( ) 3.33 ( ) 0.033 Hypertension 57% (90/157) 49% (129/261) 44% (66/149) 46% (116/253) 1.69 ( ) 1.15 ( ) 0.190 Atrial flutter/ fibrillation 56% (205/365) 26% (14/53) 47% (163/347) 35% (19/55) 1.45 ( ) 1.69 ( ) 0.092 Results of the ITT subgroup analyses With the exception of the presence or not of previous stroke, no significant subgroup-by-treatment interactions were noted (p<0.05) for the primary endpoint (mRS 0–1) at day 90. Both subgroups benefited from alteplase treatment, but patients who previously had a stroke seemed to benefit significantly more than those who had not had a previous stroke. In nearly all subgroups, there was a clear uniform pattern favouring alteplase, indicated by the fact that the OR was greater than 1 but p values for interaction (based on logistic regression with treatment, subgroup, and the interaction term) were non-significant. Reference: Bluhmki E et al. Lancet Neurol 2009;8: 1 mRs, modified Rankin scale ITT, intent-to-treat Favours placebo Favours rt-PA Bluhmki et al. Lancet Neurol 2009;8:

ECASS 3 – further analyses: summary
Subgroup results For mRS 0-1 all subgroups were in favour of rt-PA; most notably no interaction by age and stroke severity was established Additional endpoints mRS 0-1, 0-2, Barthel index ≥85 and global outcome statistic and treatment response (8 point improvement from baseline or 0-1 on the NIHSS) stratified responder analysis mRS, modified Rankin scale NIHSS, National Institutes of Health Stroke Scale Bluhmki et al. Lancet Neurol 2009;8:

ECASS 3: Conclusions

ECASS 3: conclusions Intravenous rt-PA initiated h after onset of stroke symptoms is: An effective treatment for patients with AIS, who cannot be thrombolysed within 3 h, with no relevant increase in intracranial bleeding compared with treatment within 3 h A viable therapeutic option for the many patients previously excluded from thrombolysis by missing the narrow treatment time- frame Favourable across a broad range of subgroups of patients This finding opens a window of opportunity for later-arriving stroke patients However … In this study, intravenous alteplase given 3 to 4.5 hours (median, 3 hours 59 minutes) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of symptomatic intracranial hemorrhage than that reported previously among patients treated within 3 hours. Although our findings suggest that treatment with alteplase may be effective in patients who present 3 to 4.5 hours after the onset of stroke symptoms, patients should be treated with alteplase as early as possible to maximize the benefit. Having more time does not mean we should be allowed to take more time. Reference: Hacke et al. the ECASS 3 Investigators. N Engl J Med 2008; 359: AIS, acute ischaemic stroke Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359: Bluhmki et al. Lancet Neurol 2009;8: 21

ECASS 3: conclusions (cont)
… having more time does not mean we should take more time Patients need to be treated as early as possible with rt-PA to maximise the benefit, therefore networks have to work fast! There may be more time for the patients, but not for the treating physicians In this study, intravenous alteplase given 3 to 4.5 hours (median, 3 hours 59 minutes) after the onset of stroke symptoms was associated with a modest but significant improvement in the clinical outcome, without a higher rate of symptomatic intracranial hemorrhage than that reported previously among patients treated within 3 hours. Although our findings suggest that treatment with alteplase may be effective in patients who present 3 to 4.5 hours after the onset of stroke symptoms, patients should be treated with alteplase as early as possible to maximize the benefit. Having more time does not mean we should be allowed to take more time. Reference: Hacke et al. the ECASS 3 Investigators. N Engl J Med 2008; 359: Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359: Bluhmki et al. Lancet Neurol 2009;8: 22

Clinical implications of ECASS 3
Provides a better understanding of stroke systems of care for patients with acute ischaemic stroke A multidisciplinary team is required to implement changes, including healthcare professionals and professional organisations Extension of the treatment window to 4.5 hours will impact all stages of stroke networks from dispatchers and emergency medicine services to acute stroke units and imaging facilities The balance of costs and benefits (in terms of gain in QALYs) favours treatment with rt-PA in the hour time window after stroke onset vs. non-thrombolytic therapy Tung et al. Stroke 2011;42: Ingall. Stroke 2009;40:

Impact of ECASS 3 on time to thrombolysis
Following confirmation by ECASS 3 of the extended time window to 4.5 hours for the administration of rt-PA to patients with an acute ischaemic stroke, concerns of increased delays in administration due to the extended time window proved unfounded: the proportion of patients with a DTN <60 min increased Guideline publication ECASS 3 publication ECASS 3 offers an extended time window to patients with an acute ischaemic stroke, who are unable to receive rt-PA within 3 hours of symptom onset. The earlier treatment is given, the greater the benefit for the patient. Initially, there were concerns that this would cause delays in administration of rt-PA. But just because doctors had more time, does not mean they could take more time. A prospective database study of 93 hospitals in Northwestern Germany included 91,805 patients with an acute ischaemic stroke admitted between Jan 2007 and Dec 2009. Overall, 10.1% (N=9,262) were treated with rt-PA, with the proportion increasing from 8.6% in 2007 to 11.7% in 2009. After the publication of ECASS 3, the number of patients with a door-to-needle time <60 min increased (OR 1.49; 95% CI, 1.37 to 1.63) but there was no significant increase in the number of patients with a door-to-needle time of 3 to 4.5 hours. Conclusion: The extension of the time window following ECASS 3 did not lead to delays in the administration of rt-PA. Minnerup et al. Impact of the extended thrombolysis time window on the proportion of recombinant tissue-type plasminogen activator-treated stroke patients and on door-to-needle time. Stroke 2011;42: Minnerup et al. Stroke 2011;42:

(MRI-based patient selection)
Imaging studies (MRI-based patient selection)

What is mismatch? Historically defined on MRI as the difference in volume of DWI lesion and PWI lesion PWI > DWI by at least 20% Uncorrected / unthresholded time-based perfusion parameter map (TTP, MTT) Isotropic DWI Limitations DWI lesion reversibility in a minority of patients Therefore, DWI lesion is an approximation of infarct PWI without any thresholding identifies all brain tissue with hypoperfusion MRI, magnetic resonance imaging; DWI, diffusion weighted imaging; PWI, perfusion weighted imaging TTP, time to peak; MTT, mean transit time

Mismatch: MRI-based patient selection
Mismatch* decreases over time, but may be found in individual patients as late as 24 hours or more, depending on individual symptoms This may help to increase the time window and also allow treatment in patients without known onset of stroke Practical issues 15-20 minutes scan time Some patients do not tolerate MR study Overall feasibility in experienced centres >90% In recent years, much emphasis has been put on the development of better imaging strategies in the identification of patients suitable for thrombolytic therapy. Although diffusion-weighted and perfusion MRI is not yet available everywhere, the number of centres that can provide this technology to their patients is ever increasing. The mismatch concept, on which this method of patient selection is based, is explained in the next slide. Warach et al. Ann. Neurol 2000; 48 (5): Kidwell et al. Stroke 2002; 33 (1): Jansen et al. Der Nervenarzt 1998; 69 (6): Schellinger, Fiebach. In Fiebach, Schellinger 2003; 6: *Mismatch refers to the difference in the region identified on diffusion-weighted imaging (DWI) and that seen on perfusion weighted imaging (PWI), and is considered to be “tissue at risk”. Warach et al. Ann. Neurol 2000;48: Kidwell et al. Stroke 2002;33:95-98. Jansen et al. Der Nervenarzt 1998;69: Schellinger, Fiebach. In Fiebach, Schellinger 2003;6:31-34.

Paradigm: MRI-based studies and individual therapeutic approach
Baseline Acute ischaemic stroke Acute tissue at risk 4-8h after rt-PA Reperfusion No reperfusion Interim lesion 30 days Final lesion Tissue at risk (penumbra) Dead brain (ischaemic core) Healthy brain Higher chance for better outcome Higher chance for poorer outcome

Example: imaging on presentation of acute ischaemic stroke and after rt-PA

Rationale for (MRI-) mismatch-based thrombolysis
Time from symptom onset and (more or less) normal CT is an excellent tool to screen for patients likely responsive to rt-PA The earlier the time, the smaller the core The earlier the time, the likelier no demarcation as also seen on normal CT The earlier the time, the larger the tissue at risk Note: After 3-4.5h patients still have a reduced benefit Unselected treatment (CT, NIHSS, time 4.5-9h) leads to low or no benefit with higher risk of bleeding and mortality (pooled analyses) Therefore, selection of suitable patients beyond established time windows is a worthwhile target This includes patients with unknown time window

DEFUSE study Objective
To determine whether MRI profiles can help to predict clinical response in patients with ischaemic stroke treated with IV thrombolysis at 3-6 hours after onset Key Results Target Mismatch pattern was associated with substantial benefit from early reperfusion in 67% of patients Malignant MRI pattern was associated with high risk of fatal sICH following reperfusion Small DWI and PWI lesions are associated with favourable outcomes “Malignant profile” was defined as a large DWI and / or PWI lesion volume (>100 ml), with a prolonged Tmax (≥8 secs). This was associated with a high rate of sICH and a low rate of favourable outcomes. Patients with a mismatch, who did not fall into the malignant profile, were classified as “target mismatch”. 74 patients were enrolled and received an MRI scan. In 45 patients the data were complete and could be analysed fully. A PI/DWI mismatch was found in 54% of patients, and of these, 56% had a favourable clinical response on early reperfusion vs. 19% in those who did not have early reperfusion (p=0.039). Patients with “No mismatch” did not have a favourable clinical response on early reperfusion vs. 5 of 7 (71%) of those who did not have early reperfusion. In patients with a small lesion profile, 74% had a 30-day mRS ≤2. Target mismatch was associated with favourable clinical outcomes in 67% of patients with early reperfusion vs. 19% without early reperfusion (p=0.011). Patients with the malignant profile generally had a poor clinical outcome and all 3 patients with early reperfusion and the malignant profile has a sICH and died. Conclusions: Acute MRI scans are feasible in patients with acute ischaemic stroke Certain profiles on MRI may help to identify those patients most likely to benefit from early reperfusion following an acute ischaemic stroke. Albers et al; for the DEFUSE Investigators. Ann Neurol 2006; 60: Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60:

DEFUSE: MRI profile and clinical outcome
Mean age (y) Median baseline NIHSS score Favourable clinical response* Target mismatch with early reperfusion 15 78.3 14 67%** (42-84) Target mismatch without early reperfusion 16 68.0 13 19% (7-43) Malignant profile 6 68.3 18.5 17% (3-56) * Improvement of 8 points or more in the NIHSS score between baseline and 30 days or a score of 0-1 at 30 days ** p≤0.01, compared with target mismatch without early reperfusion Target mismatch excludes patients with malignant mismatch Albers et al. Ann Neurol 2006;60:

Take 5: multicentre study
Large dataset (N=1,210 patients) More than 500 MRI-based rt-PA-treated patients Comparison Standard CT based rt-PA <3 hours MRI-based rt-PA <3 hours MRI-based rt-PA >3 hours (<17 hours) Schellinger et al. Stroke 2007;38:

Take 5: safety and efficacy multivariate
Symptomatic ICH Age OR=1.033, 95% CI , p=0.016 NIHSS OR=1.057, 95% CI , p=0.016 Use of MRI OR=0.520, 95% CI , p=0.05 Good outcome Age and NIHSS OR=0.973 and 0.862, for both, p<0.001 Use of MRI >3h OR=1.467, 95% CI , p=0.040 Use of MRI <3h OR=1.36, 95% CI , p=NS Conclusion MRI-based thrombolysis within and beyond the 3-h time window is at least as safe and possibly more effective than CT-based thrombolysis A multicenter study with 5 European stroke centres assessed the safety and efficacy of CT-based thrombolysis compared to MRI-based thrombolysis within and beyond the 3-hour time window. Predefined safety outcomes were symptomatic intracranial haemorrhage (sICH) and mortality. The primary efficacy outcome was a favourable outcome according to the modified Rankin Scale (mRS 0-1). Secondary efficacy outcomes were independent outcome (mRS 0-2) and responder analysis (NIHSS 0-7: mRS 0; NIHSS 8-14: mRS 0-1; NIHSS>14 mRS 0-2). Univariate and multivariate analyses were performed for all endpoints including age, NIHSS, treatment group (CT <3h, MRI <3h and >3h) and onset to treatment time (OTT) as variables. Results: 1210 patients were included into the study (55.5% male, 53% left). Groups contained N=714 (CT<3h), N=322 (MRI<3h), N=174 (MRI>3h) patients. Mean age was 66.8, 65.2, and 66.7 years (P=NS), median NIHSS was 12, 13, and 14 (2-sided p=0.024). Mean OTT was 130, 136 and 279 minutes (P<0.001). sICH rates were 5.3%, 3.1%, and 4.0%, mortality was 13.7%, 12.4%, and 12.1% (both P=NS). Favourable outcomes were seen in 35.6%, 38.8%, and 42% (independent: 49.6%, 52.2%, 49.4%; responder: 32.4%, 35.7%, 34.5%). All differences were non-significant in univariate analysis. Univariate safety and efficacy outcomes were not different when the CT group was compared to the combined MRI groups. In multivariate analysis (CT versus all MRI), age and NIHSS entered the model as highly significant predictors for all safety and efficacy outcomes. Only for the primary efficacy endpoint (mRS 0-1 vs. 2-6) an additional variable entered the model: The use of MRI instead of CT increased the odds for a favourable outcome by 34.9%: OR= ( , P=0.023). For MRI <3h the OR was and >3h it was Conclusion: This is the largest study comparing MRI- and CT-based thrombolysis to date. Despite significantly longer time windows and significantly higher baseline NIHSS scores, MRI-based thrombolysis is at least as safe as and possibly more effective than standard CT-based thrombolysis. Therefore, if available, within and especially beyond the 3-hour time window, MRI-based decision making should be the standard of care in thrombolysis for acute stroke. Reference: Schellinger et al. Stroke 2007;38: Schellinger et al. Stroke 2007;38:

EPITHET study Hypotheses Objective Design
PI/DWI mismatch represents potentially salvageable tissue in the ischaemic penumbra rt-PA will attenuate infarct growth by increased perfusion of the penumbra Objective To determine whether rt-PA administered 3-6 hours after stroke onset decreases infarct growth in patients with a known PI/DWI mismatch Design Randomised, double-blind, placebo-controlled trial Davis et al. Lancet Neurol 2008;7:

EPITHET outcomes: infarct growth
Primary measure p Ratio of geometric means (rt-PA/placebo) 0.24 Secondary growth measures Median relative growth 0.05 Growth >0% 0.03 Geometric mean growth (baseline lesion >5 ml) 0.01 Davis et al. Lancet Neurol 2008;7:

EPITHET functional outcome: mRS Day 90 in mismatch patients
rt-PA (N=42) Placebo (N=43) p mRS 0-2 45% (19/42) 40% (17/43) 0.60 mRS 0-1 36% (15/42) 21% (9/43) 0.13 NIHSS improvement ≥8 or NIHSS ≤1 50% (21/42) 37% (16/43) 0.23 EPITHET was not powered to achieve significance for a clinical endpoint. rt-PA increases the likelihood of reperfusion in some of the treated patients, which increases the likelihood of reducing infarct size in the patients that reperfused, which again increases the likelihood for a better clinical outcome. The causal link in between these pathophysiological processes is not guaranteed. This means that a study to show an increased rate of reperfusion will need less patients than a study that aims to show reduced infarct size. Again, a study that aims to show that reduced infarct size translates into better clinical results needs more patients than the latter. While patients per arm would suffice for differences in infarct size, 200 patients per arm will be needed to demonstrate clinical efficacy. Results suggest, in mismatch patients a Phase III trial of rt-PA vs. placebo 3-6 hours could be powered with <200 patients per arm mRS, modified Rankin Scale Davis et al. Lancet Neurol 2008;7:

Reperfusion and mismatch
EPITHET study confirms the results of DEFUSE Reperfusion is associated with a better outcome and a reduced infarct growth Reperfusion No reperfusion p Infarct growth N=30 N=47 Median relative growth 0.86 (0.34 to 1.75) 2.07 (1.19 to 3.65) <0.0001 Median absolute growth -1.0 (-9.0 to 11.2) 43.6 (4.0 to 92.3) Clinical outcomes Good neurological outcome 22 (73%) 13 (27%) Good functional outcome 19 (63%) 15 (32%) 0.007 Davis et al. Lancet Neurol 2008;7:

Imaging studies: conclusions
CT is sufficient for exclusion of intracranial haemorrhage and therefore decision making for or against thrombolysis Infarct detection <3h is achieved in only a third of ischaemic strokes MRI is more sensitive than CT Perfusion/diffusion MRI can add more information about the penumbra and potentially salvageable tissue after acute ischaemic stroke Specific patient profiles on MRI can help to identify subgroups of patients that may benefit from early reperfusion with thrombolytic therapy outside of approved time windows Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60: Davis et al. Lancet Neurol 2008;7: Schellinger et al. Neurology 2010;75:

Meta- and pooled analyses

Cochrane meta-analysis of IV rt-PA versus control (including ECASS 3)
Mori 1992 13/19 10/12 0.4% 0.43 [0.07, 2.62] ECASS 1995 201/313 217/307 11.3% 0.74 [0.53, 0.68] NINDS 1995 179/312 229/312 0.49 [0.35, 0.68] ECASS II 1998 244/409 248/391 15.8% 0.85 [0.64, 1.13] ATLANTIS B 1999 161/307 162/306 12.8% 0.98 [0.71, 1.35] ATLANTIS A 2000 64/71 56/71 1.4% 2.45 [0.93, 6.44] Wang 2003 29/67 26/33 0.21 [0.08, 0.54] EPITHET 2008 34/52 37/49 1.7% 0.61 [0.26, 1.46] ECASS 140/418 155/403 15.7% 0.81 [0.61, 1.07] Subtotal (95% Cl) 1968 1884 71.7% 0.76 [0.66, 0.87] Total events: 1065 (Thrombolysis), 1140 (Control) Heterogeneity: Chi2=23.25, df=8 (p=0.003); I2=66% Test for overall effect: Z=4.03 (p= ) Favours thrombolysis Favours control 0.1 1.0 10 In the 2009 Cochrane analysis, 9 trials using intravenous rt-PA versus control were compared for the outcomes of death and dependency (mRS 2-6) during follow-up. Results were significantly in favour of thrombolysis: 0.76 (95% CI 0.66 to 0.87, P = ), with significant between-trial heterogeneity (I2 = 66%, P = 0.003). Reference: Wardlaw et al. Cochrane Database of Systematic Reviews 2009;4: CD DOI: / CD pub2. Wardlaw et al. Cochrane Database of Systematic Reviews 2009;4: CD DOI: / CD pub2.

Updated pooled analysis (including ECASS 3 and EPITHET)
Data from ECASS 3 and EPITHET were added to the pool of common data elements from the 6 previous trials of rt-PA for acute ischaemic stroke (N=3,670 patients) Time Window Adjusted OR (95% CI) 0-90 2.81 ( ) 91-180 1.55 ) Pooled 1.40 ( ) ECASS 3 1.42 ( ) 1.15 ( ) 0.1 1.0 10.0 Odds Ratio (95% CI) This updated analysis included data from eight trials and 3670 patients randomly allocated to alteplase (N=1850) or to placebo (N=1820). The investigators used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0–1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The trials analysed represent the major randomised placebo-controlled trials of rt-PA (alteplase) for acute stroke. These trials are the two NINDS trials (parts I and II), the first two ECASS trials, two Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trials, and the ECASS 3 trial. Initially, the investigators intended not to include the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET), but while preparing to publish their findings they learned that all variables needed for the analysis had been gathered by the EPITHET investigators. Consequently, they reanalysed the data from all eight trials. The update pooled analysis included: 1,850 patients treated with rt-PA;1,820 patients given placebo Men: 60% Median age: 68 years (IQR 59-74) Median NIHSS: 11 (IQR 7-16) Median time-window: 240 min (IQR ) Separate analyses at four OTT intervals (0-90 min, min, min, min) were undertaken. Reference: Lees et al. Lancet 2010;375: Pooled data analysis of NINDS, ATLANTIS and ECASS I and II trials (green) showing odds ratios and 95% confidence intervals for favourable outcome in different time windows from onset, adjusted for prognostic confounders, with ECASS 3 outcome superimposed (blue) Hacke et al. Lancet 2004;363: Lees et al. Lancet 2010;375:

Updated pooled analysis: favourable outcome (mRS 0-1) vs. time
5 Odds ratio (OR) 4 OR 2.55 OR 1.64 OR 1.34 OR 1.22 3 Odds ratio and 95% CI 2 1 Modified Rankin scores by OTT interval 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 OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 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. The numbers needed to be treated to achieve one additional favourable outcome rose as OTT increased. Reference: Lees et al. Lancet 2010;375: 60 90 120 150 180 210 240 270 300 330 360 OTT (min) NNT 4-5 NNT 9 NNT 14 NNT 21 NNT, Number needed to treat OTT, Time from stroke onset to start of treatment mRS, modified Rankin Scale Lees et al. Lancet 2010;375:

Updated pooled analysis: mortality
Placebo n/N (%) rt-PA n/N (%) OR* (95%CI) p 0-90 min 31/151 (20.5%) 3/161 (18.6%) 0.78 ( ) 0.440 min 49/315 (15.6%) 51/303 (16.8%) 1.13 ( ) 0.608 min 82/811 (10.0%) 89/809 (10.6%) 1.22 ( ) 0.252 min 55/542 (10.2%) 86/757 (15.0%) 1.49 ( ) 0.050 0-360 min 217/1820 (11.9%) 257/1849 (13.9%) 1.19 ( ) 0.108 Overall mortality in the 3669 patients in the final analysis (a patient in EPITHET who declined assessment at day 90 was excluded from the survival analysis) was 474 (12.9%), 13.9% in the alteplase group and 11.9% in the control group. The full analysis found an association between OTT and mortality (P=0.0444), and a significant increase in deaths at OTT beyond 4.5 h. Lees et al. Stroke 2010;375: *OR adjusted for NIHSS, age, diastolic blood pressure Lees et al. Lancet 2010;375:

Time delay (odds ratio (95% CI) for alteplase vs. control)
Patient-based meta-analysis on the effects of treatment delay and age on the efficacy of alteplase A patient-based meta-analysis which included data on more than 6,750 patients from 9 clinical trials investigated whether patient factors (time delay, age, and stroke severity) impact the treatment effects of rt-PA The results show time as the most important factor with regard to good stroke outcome (defined as mRS 0-1), regardless of age Time delay (odds ratio (95% CI) for alteplase vs. control) ≤3 h >3 - ≤4.5 h >4.5 h Good stroke outcome (mRS 0-1) All patients 1.75 ( ) 1.26 ( ) 1.15 ( ) ≤80 years 1.68 ( ) 1.26 ( ) 1.07 ( ) >80 years 1.86 ( ) 1.36 ( ) 1.55 ( ) Fatal intracranial haemorrhage within 7 days 10.86 ( ) 5.63 ( ) 8.16 ( ) 90-day mortality 1.00 ( ) 1.14 ( ) 1.22 ( ) Emberson et al. Lancet 2014;384:

Meta-analysis on the effects of age and stroke severity on the efficacy of alteplase
Age and stroke severity alone did not significantly alter the effects of rt-PA Age (odds ratio (95% CI) for alteplase vs. control) ≤80 years >80 years Good stroke outcome (mRS 0-1) 1.25 ( ) 1.56 ( ) Fatal intracranial haemorrhage within 7 days 6.93 ( ) 7.95 ( ) Stroke severity* (odds ratio (95% CI) for alteplase vs. control) 0-4 5-10 11-15 16-21 ≥22 Good stroke outcome (mRS 0-1) 1.48 ( ) 1.22 ( ) 1.24 ( ) 1.50 ( ) 3.25 ( ) Fatal intracranial haemorrhage within 7 days NE 3.90 ( ) 24.14 ( ) 5.00 ( ) 10.94 ( ) *By baseline NIHSS score; NE, not estimable Emberson et al. Lancet 2014;384:

Alteplase and risk of ICH
Secondary analyses shows treatment with rt-PA is associated with an absolute risk ranging from 1.5% to 3.7%, which varies significantly depending on baseline stroke severity Stroke severity† (modelled absolute risk (95% CI) for alteplase vs. control) 0-4 5-10 11-15 16-21 ≥22 SITS-MOST definition of h by stroke severity 1.5% ( ) 2.4% ( ) 3.3% ( ) 3.4% ( ) 3.7% ( ) Trend p value = No significant differences in absolute risk for ICH were shown within the rt-PA group with respect to treatment delay* or age** Although there is an increase the risk of fatal ICH by an average of 2- 3% during the first week after stroke, the risk is offset by the 5-10%‡ increase in the likelihood of a good stroke outcome (mRS 0-1) associated with rt-PA treatment ≤3 h vs. >3 - ≤4.5 h vs. >4.5 h; ** ≤80yrs vs. >80 yrs; †By baseline NIHSS score; ‡ 5% increase if treated >3-≤4.5 h, 10% increase if treated in ≤3 h Emberson et al. Lancet 2014;384: Whiteley et al. Lancet Neurol 2016;15(9):

Favourable outcome (mRS 0-1) vs. time
5 4 OR (≤3h) 1.75 OR (>3h, ≤4.5h) 1.26 OR (>4.5h) 1.15 3 Odds ratio and 95% CI 2 1 Modified Rankin scores by OTT interval 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 OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 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. The numbers needed to be treated to achieve one additional favourable outcome rose as OTT increased. Reference: Lees et al. Lancet 2010;375: 60 90 120 150 180 210 240 270 300 330 360 390 OTT (min) OR, Odds ratio OTT, Time from stroke onset to start of treatment mRS, modified Rankin Scale Emberson et al. Lancet 2014;384:

Updated pooled analysis: interpretation
Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous rt-PA when treated up to 4.5 h – regardless of age or stroke severity No increase in mortality with rt-PA use up to 4.5 h The earlier treatment with rt-PA is administered, the greater the benefit To maximise benefit, every effort should be taken to shorten delay in initiation of treatment Beyond 4.5 h, risk might outweigh benefit This updated pooled analysis shows that treatment with thrombolysis until 4.5 h from stroke onset enhances the chance of favourable outcome. Serious haemorrhage rates are independent of OTT, but mortality increases with OTT longer than 4.5 h. However, across the time window studied, the analysis showed that the greatest benefit comes from earlier treatment, since net benefit is diminishing and is undetectable in the sample beyond 4.5 h. Reference: Lees et al. Lancet 2010;375: Emberson et al. Lancet 2014;384: Lees et al. Lancet 2010;375: Whiteley et al. Lancet Neurol 2016;15(9):

Safe Implementation of Treatments in Stroke (SITS)

SITS overview SITS (Safe Implementation of Treatments in Stroke) is an internet-based interactive thrombolysis register SITS is a global academic and clinical collaboration 60 countries 1,300 centres 78,000 patients Presentation by Nils Wahlgren at Karolinska Stroke Update Meeting in Stockholm, 2012.

SITS structure SITS Clinical Trials Platform
SITS-OPEN Thrombectomy I-Stroke New Randomised Trials SITS Registry Core Structure IVTP (standard) + SITS UTMOST + SITS-WATCH APP (standard) + Atrial fibrillation + ICH registry IA/Thrombectomy registry IVTP (minimal) APP (minimal)

Currently active SITS registries Future SITS registries
SITS-IVT (IV-thrombolysis) SITS-TBY (thrombectomy) SITS-IVT+TBY bridge (IV-thrombolysis + thrombectomy) SITS-AP (all stroke patients) SITS-AF (atrial fibrillation) Future SITS registries SITS-ICH (intracerebral haemorrhage) Each registry is linked with a protocol for treatment and data collection

SITS studies: SITS-MOST

SITS-MOST: overview Objective
To assess whether iv rt-PA, when given as thrombolytic therapy within 3 hours of the onset of ischaemic stroke is as safe and effective in routine clinical practice as reported in rcts Primary outcome sICH* or death within 3 months Secondary outcomes Functional independence (mRS ≤2 at 3 months); sICH according to NINDS and Cochrane reviews§; sICH according to ECASS (I + II)#; complete recovery (mRS ≤1 at 3 months) Stroke is one of the leading causes of death and disability in developed countries. Although considerable progress has been made in the prevention and treatment of strokes, the quality of care still needs to be improved further. The two most important factors are: the time to initiation of thrombolytic therapy. This leads to an early reperfusion and avoidance of extensive tissue damage due to ischaemia. The earlier thrombolysis is initiated, the better the outcome. the early prevention of secondary stroke. A high proportion of secondary strokes occur within 3 months of the initial stroke or transient ischaemic attack (TIA). The aim of SITS-MOST was to investigate whether treatment with intravenous alteplase within 3 h of ischaemic stroke symptoms is as safe as is reported in RCTs. SITS-MOST is an observational safety monitoring study within the EU, plus Norway, Iceland, and Switzerland (a cohort of SITS-ISTR) Wahlgren et al; the SITS-MOST Investigators. Lancet 2007; 369: Giles MF & Rothwell PM. Expert Rev Neurother 2005; 5(2): 203–210. *Defined as local or remote parenchymal haemorrhage type 2 on the 22–36 hour post-treatment imaging scan; plus deterioration of NIHSS by ≥4 points; or leading to death; § Any haemorrhage + deterioration of NIHSS ≥1; # Any haemorrhage + deterioration of NIHSS ≥4; rcts, randomised controlled trials Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:

Modified Rankin Scores (mRS) at 3 months
Pooled placebo 0–3 h (N=465) Pooled rt-PA 0–3 h (N=463) SITS-MOST (N=6,136) mRS The effect of treatment on modified Rankin scores at 3 months was compared with pooled data from randomised controlled trials (RCTs). Complete recovery (mRS 0–1) at 3 months was seen in 38.9% (95% CI 37.7 – 40.1) of SITS-MOST patients compared with 42.3% (37.8 – 47.0) in RCTs. Wahlgren et al; the SITS-MOST Investigators. Lancet 2007; 369: Functional independence (mRS 0-2) at 3 months was higher in SITS-MOST (54.8%) than in RCTs (50.1%) Mortality rates within the first 3 months were lower in SITS-MOST (11.3%) than in RCTs (17.3%) RCT, randomised controlled trial Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:

SITS-MOST: summary & conclusions
Confirms that routine use of rt-PA within 3 hours of onset of symptoms of acute ischaemic stroke is as safe and effective as in randomised controlled clinical trials Shows that safety can be maintained across centres, regardless of experience in acute stroke thrombolysis Demonstrates the advantage of establishing stroke centres for treating stroke patients and the need for a multidisciplinary approach to ensure recognition of symptoms, rapid transportation, accurate diagnosis, and effective treatment The incidence of intracerebral haemorrhage with alteplase was comparable between SITS-MOST and the alteplase arm of randomised controlled trials (RCTs) when similar definitions for symptomatic intracerebral haemorrhage (sICH) were applied. Although there was a reduced incidence of sICH in SITS-MOST, confidence intervals overlapped. Mortality was substantially lower in SITS-MOST (11.3%; CI ) compared to RCTs (17.3%, CI ). This may be caused by several things, such as a lower average age and baseline stroke severity in SITS-MOST compared to other studies and registries. Also, improved care within a specialised stroke unit has been shown to reduce mortality and accounts for a reduction in SITS-MOST compared to older RCTs. In CASES, the median age was 73 years (vs. 68 years in SITS-MOST), and the median NIHSS score was 14 (vs. 12 in SITS-MOST). Strokes were therefore less severe, and the population was younger in SITS-MOST. RCTs have shown an improvement of approximately 10% in functional independence at 3 months following treatment with alteplase, compared with placebo. Although complete recovery was similar in SITS-MOST and RCTs (39% vs. 42%), independent outcomes (mRS 0-2) were more frequent in SITS-MOST at 3 months compared with RCTs [54.8% ( ) versus 50.1%( )]. Wahlgren et al; the SITS-MOST Investigators. Lancet 2007; 369: Wahlgren et al. Lancet 2007; 369: 826. Albers & Olivot. Lancet 2007; 369: 249–250. The ATLANTIS, ECASS, and NINDS Study Group Investigators. Lancet 2004; 363: 768–774. Hill et al. CMAJ 2005; 172: 1307–1312. Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369: Wahlgren et al. Lancet 2007;369:826.

SITS studies: SITS-ISTR

Updated analysis of SITS-ISTR
Centres participating in the SITS database are required to enter all patients into SITS-ISTR (International stroke treatment register), regardless of whether they fulfil the SITS-MOST criteria or not Between December 2002 and February 2010, SITS-ISTR looked at a cohort of patients (N=2,376) treated with rt-PA within hours after the onset of ischaemic stroke and compared the outcome with that of patients treated within the 3-hour time window (N=21,566) Outcome measures were: sICH within 24 hours Mortality Independence (mRS 0-2) at 3 months From December, 2002, to February, 2010, data on 23,942 patients from 650 centres were recorded in SITS-ISTR. Up to the end of September, 2008, 15,789 (94.3%) of 16,750 patients from 566 centres were treated within 3 h and 961 (5.7%) of patients from 255 centres were treated within 3–4∙5 h of stroke onset. Between October, 2008, and February, 2,010, 5,777 (80.3%) of 7,192 patients from 371 centres were treated within 3 h and 1,415 (19.7%) of 7,192 patients from 242 centres were treated within 3–4.5 h of stroke onset. 306 centres were actively recording patients in the registry before and after October, 2008, and contributed 17,532 (73.2%) of the 23,942 patients; of these, 15,511 patients (8.5%) were treated within 3 h and 2,021 patients (11.5%) were treated within 3–4.5 h. 71 centres started recording patients in the SITS registry from October 2008, contributing data on 644 (2.7%) of 23,942 patients; of these, 541 within 3 h and 103 within 3–4.5 h. 22,702 (94.8%) of 23,942 patients were from centres in Europe, 492 (2.1%) from centres in Australia, 740 (3.1%) from centres in Asia, and eight (0.03%) from Latin America. The proportion of patients treated within 3–4.5 h in the last quarter of 2009 was three times higher than in the first quarter of 2008 (282 of 1293 [22%] vs. 67 of 1023 [7%]). The median time between stroke onset and alteplase treatment was 140 min (IQR 114–165) in patients who were treated within 3 h and 205 min (IQR 190–229) in patients treated within 3–4.5 h after symptom onset. The median time between hospital admission and treatment was 65 min (IQR 46–88) in patients treated within 3 h and 77 min (50–116) in patients treated within 3–4.5 h after symptom onset (difference 12 min; P<0.0001). The median age of patients treated within 3 h of symptom onset was 68 years (IQR 58–74) and for patients treated within 3–4.5 h after symptom onset the median age was 67 years (57–74; P<0.0007). 8,546 of 21,566 patients who were treated within 3 h and 1,020 of 2,376 patients who were treated within 3–4.5 h of symptom onset were women (P=0·002), The median NIHSS score was 12 (IQR 7–17) in patients treated within 3 h and 10 (6–15) in those treated within 3–4.5 h (P<0.0001). 4,179 of 21,369 patients treated within 3 h and 575 of 2,345 patients treated within 3–4.5 h had evidence of a present infarct on baseline imaging (P<0.0001). All other factors were similar between the groups. Reference: Ahmed et al; for the SITS Investigators. Lancet Neurol 2010; 9: Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:

SITS-ISTR: results No significant difference for any outcome measure between patients treated within 0-3 hours or at hours after stroke onset 0 - 3 h h Unadjusted results Adjusted results n/N (%) Odds ratio (95% CI) p value sICH (SITS-MOST definition) 352/21204 (1.7%) 52/2317 (2.2%) 1.36 ( ) 0.04 1.44 ( ) 0.02 sICH (ECASS II definition) 1020/21206 (4.8%) 121/2304 (5.3%) 1.10 ( ) 0.35 1.27 ( ) sICH (NINDS definition) 1515/21245 (7.1%) 171/2317 (7.4%) 1.04 ( ) 0.66 1.18 ( ) 0.06 Mortality at 3 months 2287/18583 (12.3%) 218/1817 (12.0%) 0.97 ( ) 0.70 1.26 ( ) 0.005 Mortality at 7 days 1307/20956 (6.2%) 132/2259 (5.8%) 0.93 ( ) 0.46 1.22 ( ) 0.052 Functionally independent at 3 months (mRS 0-2) 10531/18317 (57.5%) 1075/1784 (60.3%) 1.12 ( ) 0.84 ( ) Minimal or no disability at 3 months (mRS 0-1) 7467/18317 (40.8%) 793/1784 (44.5%) 1.16 ( ) 0.003 0.92 ( ) 0.17 sICH = symptomatic intracerebral haemorrhage SITS-MOST = Safe Implementation of Thrombolysis in Stroke Monitoring Study ECASS = European-Australasian Acute Stroke Study NINDS = National Institute of Neurological Disorders and Stroke mRS = modified Rankin scale The unadjusted rate of symptomatic intracerebral haemorrhage according to the SITS-MOST definition was significantly higher in patients treated within 3–4.5 h than those treated within 3 h (P=0.04), but the rate of symptomatic intracerebral haemorrhage according to the ECASS II and NINDS definitions did not differ significantly between the groups (ECASS II P=0.35; NINDS P=0.6). 10,531 (58%) of 18,317 patients treated within 3 h and 1,075 (60%) of 1,784 patients treated within 3–4.5 h were functionally independent at 3 months (P=0.02), and 7,467 (41%) of 18,317 patients treated within 3 h and 793 (44%) of 1,784 patients treated within 3–4.5 h had minimal or no disability at 3 months (P=0.003). There was no substantial difference in mortality between the groups at 7 days (P=0·46) or at 3 months (P=0.70). When adjusted for the baseline imbalances in the multivariate analysis, the rate of symptomatic intracerebral haemorrhage was higher in patients treated within 3–4.5 h than in those treated within 3 h according to the SITS-MOST (P=0.02) and ECASS II (P=0.02) definitions but not according to the NINDS definition (P=0.06). In the adjusted analysis, the odds ratio for mortality at 3 months was higher in patients treated within 3–4.5 h compared with those treated within 3 h (1.26, 95% CI 1.07–1.49; P=0.005), whereas the odds ratio for functional independence (mRS 0–2) at 3 months was lower (0.84, 0.75–0.95; P=0.005). 57 (0.27%) of 21,204 patients treated within 3 h and eight (0.35%) of 2,317 patients treated within 3–4.5 h had died of symptomatic intracerebral haemorrhage according to the SITS-MOST definition (P=0.51). The corresponding proportion of patients who died according to the ECASS II definition was 518 (2%) of 21,206 and 64 (3%) of 2,304 (P=0.33), and according to the NINDS definition was 528 (2%) of 21,245 and 64 (3%) of 2,317 (P=0.42). Reference: Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9: mRS, modified Rankin Scale Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:

SITS-ISTR: mRS at 3 months
Outcomes for patients in the h and <3 h cohorts according to the modified Rankin scale (mRS) score at 3 months mRS Functional independence at 3 months was almost identical in the 2 treatment groups Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:

SITS-ISTR: conclusions
Early treatment with thrombolysis has been confirmed and leads to better outcomes SITS-ISTR confirms the safety and efficacy of rt-PA for the thrombolysis of ischaemic stroke within the approved 3-hour time window as well as in the hour time window SITS-ISTR confirms the results of SITS-MOST and reinforces the results of ECASS 3 These results should provide more patients with access to thrombolysis which should be administered as early as possible However, “time is brain” and patients should be treated as early as possible after stroke In conclusion, our study shows that rapid implementation of thrombolysis with alteplase beyond the 3 h time window into clinical routine occurred after the publication of the ECASS 3 trial and the SITS-ISTR study. There was no reduction in the number of patients treated in the earlier interval; rather the publications were followed by an increase in treatments within the entire widened time window. This has not been at the expense of increased delay from admission-to-treatment time. Increases in the risk of symptomatic intracerebral haemorrhage and mortality in the later time window are minor and are outweighed by the benefit of the treatment. Our follow-up safety analysis confirms our previous finding that, in patients who otherwise fulfill European Summary of Product Characteristics criteria for intravenous thrombolysis, alteplase remains safe when given with short treatment delays beyond 3 h. Nevertheless, our results emphasise that patients should be treated as early as possible after stroke. Reference: Ahmed et al; for the SITS Investigators. Lancet Neurol 2010; 9: Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9: Wahlgren et al. SITS Investigators. Lancet 2008;372:

SITS studies: SITS-NEW

SITS-NEW: overview Prospective, open, monitored, observational study focussing on Asian patients (48 stroke centres in Korea, China, India and Singapore) Objective To evaluate if the results for the use of iv rt-PA within 3 hours of AIS symptom onset are consistent with SITS-MOST and RCTs Primary outcome sICH* or death within 3 months Secondary outcome Functional independence (mRS ≤2 at 3 months) Additional outcomes include: sICH according to NINDS§ sICH according to ECASS II# Minimal or no disability (mRS ≤1 at 3 months) Reference Rha et al. Int J Stroke 2012 [epub ahead of print]. *symptomatic intracerebral haemorrhage with deterioration of ≥4 points on the NIHSS at h or death within 24 h AIS, acute ischaemic stroke mRS, modified Rankin Scale RCTs, randomised controlled trials Rha et al. Int J Stroke 2012 [epub ahead of print].

SITS-NEW: results SITS-NEW SITS-MOST Unadjusted results
n/N (%) Odds ratio (95% CI) p value sICH (SITS-MOST definition) 11/587 (1.87%) 107/6444 (1.66%) 1.13 0.7046 1.83 0.1156 Mortality at 3 months 59/579 (10.19) 701/6218 (11.27%) 0.89 0.4231 0.90 0.5092 Functionally independent at 3 months (mRS 0-2) 362/579 (62.52%) 3362/6136 (54.79%) 1.38 0.0003 1.57 <0.0001 sICH (ECASS 3 definition) 33/585 (5.64%) 296/6442 (4.59%) 1.24 0.2645 1.33 0.2084 sICH (NINDS definition) 51/586 (8.70%) 468/6438 (7.27%) 1.22 0.2146 1.30 0.1471 Minimal or no disability at 3 months (mRS 0-1) 247/579 (42.66%) 2386/6136 (38.89%) 1.17 0.0766 0.0728 mRS, modified Rankin Scale sICH, symptomatic intracerebral haemorrhage Rha et al. Int J Stroke 2014;9:Suppl A100: doi: /j x. Epub 2012 Sep 18.

SITS-NEW: summary & conclusions
Similar levels of sICH and mortality were seen in SITS-NEW as in SITS-MOST, and better functional outcomes were seen in SITS-NEW SITS-NEW confirms the safety and efficacy of intravenous rt-PA within 3 hours of stroke onset in an Asian population These findings should encourage wider use of thrombolysis of ischaemic stroke for suitable patients in Asian countries Rha et al. Int J Stroke 2014;9:Suppl A100: doi: /j x. Epub 2012 Sep 18.

SITS studies: SITS-UTMOST

SITS-UTMOST: overview
Design SITS-UTMOST (Safe Implementation of Thrombolysis in Upper Time window Monitoring Study) – registry-based, prospective, observational study Objective To evaluate whether the extended time window (up to 4.5 hours) for treatment with Actilyse® has an impact on routine clinical practice Primary outcomes (measured at 3 months) sICH Death and independency (mRS 0-2) Favourable outcome (mRS 0-1) Secondary outcome Time delays in the management of stroke Additional outcomes include: sICH according to NINDS§ sICH according to ECASS II# Minimal or no disability (mRS ≤1 at 3 months) Reference Rha et al. Int J Stroke 2012 [epub ahead of print]. sICH, symptomatic intracerebral haemorrhage mRS, modified Rankin Scale Ahmed et al. Eur Stroke J 2016;1(3) 213–221.

SITS-UTMOST: results Primary outcomes (clinical 3 months, h vs. <3 h) sICH – No statistically significant differences between the two groups Death and independency (mRS 0-2) – 0.81( )*; p=0.044 Favourable outcome (mRS 0-1) – 0.87( )*; p=0.159 Secondary outcome (time delays) In-hospital time delays were longer for patients treated within the h time window vs. those treated <3 h However, when stratified by onset-to-door time, the in-hospital time delays tended to be shorter at each management interval as the onset-to-door time increased mRS, modified Rankin Scale sICH, symptomatic intracerebral haemorrhage *Adjusted odds ratio (95% confidence interval) Ahmed et al. Eur Stroke J 2016;1(3) 213–221.

SITS-UTMOST: summary & conclusions
The extended time window 4.5 h did not have an impact on clinical safety or functional outcomes at 3 months compared to <3 h The extended time window up to 4.5 h did not negatively impact the patient hospital management logistics However, hospitals need to shorten the time delays that fall under their scope Improvement in the time management of acute ischaemic stroke treatment should be prioritised due to the overwhelming evidence that the quicker treatment is initiated, the better the patient’s outcomes Ahmed et al. Eur Stroke J 2016;1(3) 213–221.

SITS studies: SITS-WATCH

SITS-WATCH: background and rationale
“Time is brain” Onset-to-alarm time Alarm-to-door time Door-to-needle time (DNT) DNT is the only component that is entirely within hospitals Aim of SITS-WATCH is to reduce DNT from a median of 65 min to 40 min (in some cases = 10–15% reduction) Presentation by Daniel Strbian at the Karolinska Stroke Update meeting in Stockholm, 2012.

SITS-WATCH: approach Survey distributed to participating centres:
Education (FAST) Transport (EMS) Hospital procedures Free comments Specific programme of change identified and implemented in each centre DNT improvements reported every 6 or 12 months and results analysed anonymously No results published yet Presentation by Daniel Strbian at the Karolinska Stroke Update meeting in Stockholm, 2012.

The Virtual International Stroke Trials Archive
(VISTA)

VISTA: rationale and objective
Datasets from many studies investigating risk factors, aetiology, prevalence, ethnic disparity and potential benefits of stroke treatment regimens reside in industry and academic archives long after the studies have been published The importance of this stored information is often underestimated By collating these datasets, a large and rich pool of information can be utilised for novel analyses of the natural history of homogeneous subgroups of stroke patients Objective To establish a comprehensive resource comprising patient data from acute stroke clinical trials, on which novel analyses to inform clinical trial design could be performed Many studies worldwide have investigated the risk factors, etiology, geographic occurrence, ethnic disparity, and potential benefits of treatment regimens for stroke. The data sets from such studies reside in industry and academic archives long after the studies were published, but the importance of the information contained within them is often underestimated. By collating these data sets, a large and rich pool of information can be used for novel analysis of the natural history of homogeneous subgroups of stroke patients. This wealth of valuable information could inform the design of future randomized clinical trials. It could also allow testing of specific hypotheses. The Virtual International Stroke Trials Archive (VISTA) was set up in the spirit of contributing to mutually beneficial ventures to aid progress and breakthroughs in stroke clinical trials. Ali et al. Stroke 2007;38: Ali et al. Stroke 2007;38:

VISTA: overview VISTA contains 29 anonymised acute stroke clinical trials and one acute stroke registry >27,500 patients with either ischaemic or haemorrhagic stroke Patients aged years Medical history and onset-to-treatment time are readily available, and CT lesion data are available for selected trials Outcome measures include Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale Ali et al. Stroke 2007;38: Weimar et al. Int J Stroke 2010;5:

VISTA: baseline stroke severity predicts outcome with thrombolysis
In a non-randomised comparison of 5,817 patients from the VISTA database, outcomes with thrombolysis were significantly better across baseline NIHSS levels 5 to 24 NIHSS at baseline Forest plot OR (95%Cl) CMH p Sample size rt-PA/Control 1-4 1.14 (0.30, 4.35) 0.82 8/161 5-8 1.25 (0.98, 1.59) 0.04 278/934 9-12 1.32 (1.07, 1.62) 0.01 404/942 13-16 1.63 (1.30, 2.05) < 0.05 342/814 17-20 1.67 (1.32, 2.12) 311/736 21-24 1.56 (1.14, 2.14) 178/466 ≥ 25 1.12 (0.66, 1.90) 0.08 64/179 0.2 0.5 1 2 5 Favours control Favours alteplase The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrolment, or both. Data from 5,817 stroke patients (1,585 thrombolysed and 4,232 non-thrombolysed) from neuroprotection trials ( ) entered into the VISTA database were analysed to assess whether baseline NIHSS scores were predictive of outcomes with or without thrombolysis. Baseline severity was greater among thrombolysed than non-thrombolysed (median baseline NIHSS, 14 vs. 13; P<0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0–1.6; N=278/934 thrombolysed/non-thrombolysed), 9 to 12 (P=0.01; OR, 1.3; 95% CI, 1.1–1.6; N=404/942), 13 to 16 (P<0.05; OR, 1.6; 95% CI, 1.3–2.1; N=342/814), 17 to 20 (P<0.05; OR, 1.7; 95% CI, 1.3–2.1; N=311/736), and 21 to 24 (P<0.05; OR, 1.6; 95% CI, 1.1–2.1; N=178/466). No association was observed within baseline NIHSS categories 1 to 4 (P=0.8; OR, 1.1; 95% CI, 0.3–4.4; N=8/161) or ≥25 (P=0.08; OR, 1.1; 95% CI, 0.7–1.9; N=64/179). Outcomes after thrombolysis were significantly better than in non-thrombolysed patients across baseline NIHSS scores from 5 to 24. At the extremes, sample sizes were small and confidence limits wide so that the significance was lost in these groups. The lack of data in thrombolysis trials for patients at the extremes of the NIHSS scores presents a problem for treating physicians. In SITS-ISTR, however, 4% of patients had a NIHSS score of ≥25 and 12% had NIHSS score of 0-4. Several reports suggest that patients with a mild stroke (NIHSS <5) are denied treatment with thrombolysis. However, the risk of a recurrent stroke remains and in an American study, 32% of patients denied treatment due to “mild” stroke scores had either died or were disabled at 90 days. References: Mishra et al; VISTA Collaborators. Stroke 2010;41: Brown et al. Neurology 2009;72: Mishra et al; VISTA Collaborators. Stroke 2010;41:

VISTA: outcomes by age group
Odds ratios (OR) with 95% confidence intervals for better outcome are estimated from ordinal logistic regression, adjusted for age and NIHSS Age group Forest plot OR (95%Cl) CMH p Sample size rt-PA/Control 21-30 0.14 (0.02, 0.87) 0.24 10/10 31-40 1.60 (0.80, 3.20) 0.63 33/88 41-50 1.49 (1.03, 2.16) 0.43 143/256 51-60 1.46 (1.11, 1.92) < 0.05 233/543 61-70 1.53 (1.23, 1.91) 335/970 71-80 1.39 (1.17, 1.67) 525/1472 81-90 1.33 (1.03, 1.70) 275/835 91-100 1.50 (0.61, 3.69) 0.55 26/57 0.01 0.1 1 2 5 Favours control Favours rt-PA The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrolment, or both. Data from 5,817 stroke patients (1,585 thrombolysed and 4,232 non-thrombolysed) from neuroprotection trials ( ) entered into the VISTA database were analysed to assess whether baseline NIHSS scores were predictive of outcomes with or without thrombolysis. Baseline severity was greater among thrombolysed than non-thrombolysed (median baseline NIHSS, 14 vs. 13; P<0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0–1.6; N=278/934 thrombolysed/non-thrombolysed), 9 to 12 (P=0.01; OR, 1.3; 95% CI, 1.1–1.6; N=404/942), 13 to 16 (P<0.05; OR, 1.6; 95% CI, 1.3–2.1; N=342/814), 17 to 20 (P<0.05; OR, 1.7; 95% CI, 1.3–2.1; N=311/736), and 21 to 24 (P<0.05; OR, 1.6; 95% CI, 1.1–2.1; N=178/466). No association was observed within baseline NIHSS categories 1 to 4 (P=0.8; OR, 1.1; 95% CI, 0.3–4.4; N=8/161) or ≥25 (P=0.08; OR, 1.1; 95% CI, 0.7–1.9; N=64/179). Outcomes after thrombolysis were significantly better than in non-thrombolysed patients across baseline NIHSS scores from 5 to 24. At the extremes, sample sizes were small and confidence limits wide so that the significance was lost in these groups. The lack of data in thrombolysis trials for patients at the extremes of the NIHSS scores presents a problem for treating physicians. In SITS-ISTR, however, 4% of patients had a NIHSS score of ≥25 and 12% had NIHSS score of 0-4. Several reports suggest that patients with a mild stroke (NIHSS <5) are denied treatment with thrombolysis. However, the risk of a recurrent stroke remains and in an American study, 32% of patients denied treatment due to “mild” stroke scores had either died or were disabled at 90 days. References: Mishra et al; VISTA Collaborators. Stroke 2010;41: Brown et al. Neurology 2009;72: Mishra et al. Stroke 2010;41:

VISTA: diabetes and prior stroke
0.5 1 2 5 Diabetes & prior stroke NIHSS mRS Previous stroke Diabetes SITS recorded only Rankin Favours Thrombolysis Favours Control No diabetes/stroke interaction: p=0.9 No diabetes/stroke interaction: p=0.5 Mishra et al, for VISTA & SITS Collaborators. Cerebrovascular Diseases 2010 [abstract from ESC]; Mishra et al, for VISTA Collaborators. Diabetes Care 2010 PMID

VISTA: summary rt-PA is an approved* and recommended treatment
Age restriction Age >80 years does not appear to influence response to rt-PA No loss of benefit or enhanced ICH with age <90 years Severity restriction Efficacy extends across NIHSS up to 24 Diabetes and prior stroke restriction No interaction between diabetes and prior stroke * Marketing approval does not extend to >25 NIHSS; diabetes with prior stroke; or in some countries, >80 years (e.g. EU, although relaxed to a warning in others, e.g. Australia)

The Third International Stroke Trial
(IST-3)

IST-3: overview Thrombolysis with rt-PA is of net benefit in patients with acute ischaemic stroke <80 years old, treated within 4.5 hours of symptom onset Aim of IST-3 was to determine if a wider range of patients might benefit from treatment up to 6 hours following symptom onset IST-3 was a multicentre, international, open study in which patients were randomised to rt-PA or control Patients screened for eligibility and excluded if either a clear reason to treat with rt-PA or a clear contra-indication to rt-PA; therefore, patients included in study only if a promising but unproven benefit The primary endpoint was the proportion of patients alive and independent (OHS* 0-2) at 6 months *OHS, Oxford Handicap Score: a variant of the modified Rankin Scale, mRS The IST-3 collaborative group. Lancet 2012;379: Presentation by Peter Sandercock at the Karolinska Stroke Update meeting in Stockholm, 2012.

IST-3: results, time to randomisation
Number of patients 0-3 4.5-6 Time to randomisation (hours) 3,035 patients enrolled in 156 centres in 12 countries Presentation by Peter Sandercock at the Karolinska Stroke Update meeting in Stockholm, 2012.

IST-3: results, mortality
rt-PA (N=1515) Control (N=1520) Unadjusted results Adjusted results n (%) Odds ratio (95% CI) p value Died within 7 days 163 (11%) 107 (7%) 1.60 (1.22 to 2.08) 0.001 1.59 (1.23 to 2.07) 0.0004 Died 7 days to 6 months 245 (16%) 300 (20%) 0.73 (0.59 to 0.89) 0.002 0.78 (0.65 to 0.95) 0.011 Died before 6 months 408 (27%) 407 0.96 (0.80 to 1.15) 0.672 1.01 (0.86 to 1.19) 0.924 The primary endpoint was the proportion of patients alive and independent (OHS* 0-2) at 6 months Reference The IST-3 collaborative group. Lancet 2012;379: More deaths occurred before 7 days in the rt-PA group, but fewer occurred between 7 days and 6 months, so that by 6 months, similar numbers had died in total .The IST-3 collaborative group. Lancet 2012;379:

IST-3: results Oxford Handicap Scale (OHS*) 0-6
% % % % % % % % % % % % % % The primary endpoint was the proportion of patients alive and independent (OHS* 0-2) at 6 month. OHS is a variant of the modified Rankin score, where OHS 0, 1, or 2 indicated independence. Reference The IST-3 collaborative group. Lancet 2012;379: According to the pre-specified statistical plan, in which OHS levels 4, 5, and 6 were grouped and levels 0–3 remained discrete, common odds ratio (OR) = 1.27 (95% CI 1.10–1.47; p=0.001) *OHS, Oxford Handicap Score, is a variant of the modified Rankin Scale, mRS . The IST-3 collaborative group. Lancet 2012;379:

IST-3: summary and conclusions
Despite early hazards, IST-3 showed that thrombolysis within 6 h improved functional outcome for the patients in this study Clinicians may consider thrombolytic treatment for a wider variety of patients, particularly those aged >80 years or with more severe strokes More effort has to be made to increase the proportion of ischaemic strokes treated within 3 hours of symptom onset Clinicians can be reassured that mortality is not increased by thrombolysis The IST-3 collaborative group Lancet 2012; 379: Presentation by Peter Sandercock at the Karolinska Stroke Update meeting in Stockholm, 2012.

ENchanted Control of Hypertension ANd Thrombolysis strokE stuDy

ENCHANTED: Overview The ENchanted Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) enrolled patients with an acute ischaemic stroke and a SBP ≤185 mmHg who are eligible for thrombolysis Primary Outcomes Combined outcome of death or disability (mRS 2-6) at 90 days to determine: Part A: non-inferiority of low-dose rt-PA vs. standard-dose rt-PA Part B: superiority of early intensive blood pressure lowering over standard, guideline-recommended blood pressure management Huang et al. Int J Stroke 2015;10(5): Anderson et al. N Engl J Med 2016; 374:

ENCHANTED: study design
Part A investigates the efficacy of low-dose intravenous rt-PA (0.6 mg/kg) compared to standard dose rt-PA (0.9 mg/kg), as well as the risk of symptomatic intracerebral haemorrhage (sICH) with either dose Part B compares early intensive systolic blood pressure (SBP) lowering (target mmHg) with guideline-recommended BP lowering (<180 mmHg) with respect to the risk of any ICH Randomisation arm A Randomisation arm B Low-dose rt-PA (0.6 mg/kg) Early intensive BP control (target SBP mmHg) Standard dose rt-PA (0.9 mg/kg) Standard BP control (target SBP <180 mmHg) Patients with acute ischaemic stroke, within 4.5 h of symptom onset, with SBP ≤185 mmHg SBP ≥150 mmHg and no contraindication to rapid SBP lowering to mmHg Adapted from Huang et al. Int J Stroke 2015;10(5):

ENCHANTED Part A - rt-PA dose Rationale & objective
Intravenous rt-PA is currently approved for use in most countries at a dose of 0.9 mg/kg body weight In Japan, the approved dose of rt-PA is 0.6 mg/kg body weight. This is partly due an increased risk of sICH associated with the 0.9 mg/kg dose in Asian patients. Objective To assess the non-inferior efficacy and safety of low-dose (0.6 mg/kg) rt-PA with the current standard dose (0.9 mg/kg) rt-PA in patients with an acute ischaemic stroke, randomised within 4.5 hours of onset of symptoms Chao AC, et al. Stroke 2014;45(8): Yamaguchi T, et al. Stroke 2006;37(7): Mori E, et al. Stroke 2010;41(3): Nakagawara J, et al. Stroke 2010;41(3): Toyoda K, et al. Stroke 2009;40: Chao AC, et al. Stroke 2014;45(8): Huang Y, et al. Int J Stroke 2015;10(5): Mori E, et al. Stroke 2010;41(3): Nakagawara J, et al. Stroke 2010;41(3): Toyoda K, et al. Stroke 2009;40: Yamaguchi T, et al. Stroke 2006;37(7):

ENCHANTED Part A - rt-PA dose Primary outcome results
53.2% of patients who received low dose rt-PA met the primary outcome of death or disability, compared to 51.1% on standard dose (OR 1.09; 95% CI 0.95 – 1.25) Forest plot for the primary outcome, death or disability (mRS 2-6) at 90 days Adapted from Anderson C, et al. N Engl J Med 2016;374(24): Suppl. DOI: /NEJMoa Presented by Craig Anderson at ESOC 2016, Barcelona, Spain.

ENCHANTED Part A - rt-PA dose Death and disability results
Patients treated with low-dose rt-PA had significantly reduced mortality than with standard-dose rt-PA at 7 days (3.6% vs. 5.3%, p=0.02); and at 90 days, (8.5% vs %, p=0.07) However, fewer patients in the standard-dose group had mRS scores ≥2 compared to the low-dose group (51.1% vs. 53.2%, respectively; OR:1.09, 95% CI: , one-sided p=0.51 for non-inferiority) Secondary outcome: unadjusted ordinal shift mRS scores CI: confidence interval; mRS, modified Rankin Scale; OR: odds ratio Adapted from Anderson et al. N Engl J Med 2016; 374(24):

ENCHANTED Part A - rt-PA dose Clinical implications
ENCHANTED did not achieve its primary objective of showing non-inferiority of low-dose compared to standard-dose rt-PA with respect to death and disability at 90 days Standard-dose rt-PA is equally appropriate for Caucasians and Asians Low-dose rt-PA was associated with fewer sICH; however, mortality was not significantly different in the two groups at 90 days Adapted from Anderson CS, et al. N Engl J Med 2016;374(24):

ENCHANTED Part B - blood pressure (BP) control Rationale & objective
BP is typically elevated after intracerebral haemorrhage (ICH), and an elevated baseline systolic BP is associated with worse outcomes and an elevated risk of sICH following rt-PA administration The benefit of intensive lowering of BP in the hyperacute phase of acute ischaemic stroke remains to be definitively determined Objective To test whether early, intensive lowering of BP (systolic target mmHg) is superior to current guideline recommended management of elevated systolic BP (target of <180 mmHg), and whether intensive lowering of systolic BP reduces the risk of any ICH Part B of ENCHANTED is expected to be completed in 2018 Huang et al. Int J Stroke 2015;10(5):

Endovascular therapy Meta-Analyses SWIFT-PRIME MR CLEAN REVASCAT EXTEND-IA THRACE ESCAPE Registry Data

Endovascular therapy (EVT)
EVT is an inter-arterial method that uses catheter-guided devices to assist restoration of blood flow in an occluded vessel. Recently, researchers have had a great deal of success in combining EVT with IV rt-PA in the treatment of acute ischaemic stroke, and it is now recommended in several guidelines Recent development of retrievable stent technology has improved the speed and efficacy of recanalisation - and patient outcomes “Observing patients after intravenous rt-PA to assess for clinical response before pursuing endovascular therapy is not required to achieve beneficial outcomes and is not recommended. (Class III; Level of Evidence B-R).” American Heart Association/American Stroke Association (AHA/ASA) 2015 Guidelines “Mechanical thrombectomy, in addition to intravenous thrombolysis within 4.5 h when eligible, is recommended to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 h after symptom onset (Grade A, Level 1a, KSU Grade A).” ESO-Karolinska Guidelines Powers et al. Stroke 2015;46(10):3020–3035. Saver et al. N Engl J Med 2015;372: Wahlgren et al. Int J Stroke 2016;11(1):

AHA/ASA criteria for use of endovascular therapy
Prestroke mRS score 0 to 1 Acute ischaemic stroke receiving intravenous rt-PA within 4.5 hours of onset according to guidelines from professional medical societies Causative occlusion of the internal carotid artery or proximal MCA (M1) Age ≥18 years NIHSS score of ≥6 ASPECTS of ≥6 Treatment can be initiated (groin puncture) within 6 hours of symptom onset NEW recommendation: If the patient meets all of the criteria, endovascular therapy with a stent retriever is recommended (Class I; Level of Evidence A) Powers et al. Stroke 2015;46(10):3020–3035. .

Common Odds Ratio [95% CI] Absolute Risk Difference
Absolute risk difference for patient outcomes according to time delay to reperfusion Absolute risk difference in patient outcomes for each 1-hour delay to reperfusion Patient Outcome Common Odds Ratio [95% CI] Absolute Risk Difference Degree of disability 0.84 [0.76, 0.93] -6.7% Functional independence 0.81 [0.71, 0.92] -5.5% Mortality 1.12 [0.93, 1.34] 1.5% Adapted from Saver et al. JAMA. 2016;316(12):

Meta-analyses – endovascular therapy Functional independence
All the meta-analyses show a significant increase in rate of independence at 90 days (mRS 0-2) with EVT over standard care Meta-analysis Studies mRS 0-2 (Day 90) Odds ratio [95% CI] Badhiwala et al. JAMA 2015 All studies 1.71 [1.18, 2.49] Sardar et al. Eur Heart J 2015 1.73 [1.18, 2.53] 2015 studies 2.42 [1.91, 3.08] Steiner et al. (Wahlgren et al. Int J Stroke 2016) 1.68 [1.14, 2.48] 2.39 [1.88, 3.04] Goyal et al. Lancet 2016 2015 studies (unadjusted) 2.35 [1.85, 2.98] 2015 studies (adjusted*) 2.71 [2.07, 3.55] *Adjusted for age, sex, baseline stroke severity, site of occlusion, intravenous rt-PA, baseline Alberta Stroke Program Early CT Score (ASPECTS), and time from stroke onset to randomisation Badhiwala et al. JAMA 2015;314: Goyal et al. Lancet 2016;387: Sardar et al. Eur Heart J 2015;36(35): Wahlgren et al. Int J Stroke 2016;11(1):

Meta-analyses – endovascular therapy sICH
No significant differences in mortality at 90 days and in risk of symptomatic intracranial haemorrhage (sICH) in any of the analyses Mortality (Day 90) sICH Odds ratio [95% CI] Badhiwala et al. JAMA 2015 All studies 0.87 [0.68, 1.12] 1.12 [0.77, 1.63] Sardar et al. Eur Heart J 2015 0.89 [0.68, 1.15] 1.07 [0.73, 1.56] 2015 studies 0.80 [0.54, 1.18] 1.08 [0.62, 1.88] Steiner et al. (Wahlgren et al. Int J Stroke 2016) 0.91 [0.70, 1.19] 1.19 [0.71, 2.00] 0.78 [0.55, 1.12] 1.12 [0.78, 1.60] Goyal et al. Lancet 2016 2015 studies (unadjusted) 0.77 [0.54, 1.10] 1.07 [0.62, 1.83] 2015 studies (adjusted*) 0.73 [0.47, 1.13] 1.07 [0.62, 1.84] *Adjusted for age, sex, baseline stroke severity, site of occlusion, intravenous rt-PA, baseline Alberta Stroke Program Early CT Score (ASPECTS), and time from stroke onset to randomisation Badhiwala et al. JAMA 2015;314: Goyal et al. Lancet 2016;387: Sardar et al. Eur Heart J 2015;36(35): Wahlgren et al. Int J Stroke 2016;11(1):

MR CLEAN Objective: To assess intra-arterial treatment* against ‘usual care alone’ following ischaemic stroke caused by an intracranial arterial occlusion within 6 hours after onset of symptoms 89% of patients included in MR CLEAN received IV rt-PA 32.6% of IA-treated patients had mRS 0-2 at 3 months, vs.19.1% for ‘usual care alone’ (absolute difference,13.5%; adjusted OR: 2.16; 95% CI: 1.39 to 3.38) mRS at 3 months Conclusion: Intra-arterial treatment provided within 6h of symptom onset of ischaemic stroke is safe and effective *Defined as: Arterial catheterisation with a microcatheter (MERCI stent retriever) to the level of occlusion and delivery of a thrombolytic agent, mechanical thrombectomy, or both MR CLEAN, Multicentre Randomised Clinical trial of Endovascular treatment for Acute ischaemic stroke in the Netherlands Berkhemer et al. N Engl J Med 2015;372:11-20.

EXTEND-IA Objective: To assess the effectiveness* of early endovascular therapy (EVT)§ after IV rt-PA vs. IV rt-PA alone in anterior circulation ischaemic stroke patients with vessel occlusion and evidence of salvageable tissue upon perfusion imaging, within 4.5 hours of symptom onset mRS results at 3 months EVT in conjunction with rt-PA vs. rt-PA therapy alone showed: Significantly greater reperfusion rates (>90% vs. 40%, respectively) Significantly improved early neurologic recovery at 3 days Significant improvement in mRS at 90 days Lower mortality; p=0.18 Conclusion: With very strict patient selection criteria via imaging, ischaemic stroke patients with proximal cerebral arterial occlusion and salvageable tissue benefit significantly from early EVT after treatment with IV rt-PA *Defined as: improved reperfusion and early neurologic improvement §Using the Solitaire Flow Restoration stent retriever EXTEND-IA, EXtending the Time for thrombolysis in Emergency Neurological Deficits – Intra-Arterial trial Campbell et al. N Engl J Med 2015;372:

ESCAPE Objective: To assess the efficacy of rapid endovascular treatment (EVT) plus guideline-based care (IV rt-PA within 4.5 hours of symptom onset) in patients with acute ischaemic stroke, selected via CT and CT angiography compared to guideline-based care alone. mRS results at 3 months Overall results were favourable for combined EVT plus guideline-based care vs. guideline-based care alone Mortality (mRS=6) was significantly reduced with combined treatment vs. guideline-based care alone (10.4% vs. 19%; p=0.04) Conclusion: The primary emphasis of the ESCAPE study was to achieve early reperfusion and patients in the intervention group underwent groin puncture whilst rt-PA was being infused. The investigators concluded that “The trial confirms the benefit of endovascular treatment reported recently in the MR CLEAN trial.” ESCAPE, Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimising CT to recanalisation times Adapted from Goyal et al. N Engl J Med 2015;372:

SWIFT-PRIME Objective: To assess the efficacy and safety of rapid EVT in combination with IV rt-PA vs. IV rt-PA alone to treat acute ischaemic stroke (AIS)* Higher proportion of functional independence (mRS score <2) at Day 90 with EVT plus iv rt-PA than with rt-PA alone (60% vs. 35%) Higher proportion of patients with successful reperfusion at 27 with EVT plus iv rt-PA (83%) than with rt-PA alone (40%), (RR: 2.05; 95% CI: ) Conclusion: Treatment of AIS* with a stent retriever after IV rt-PA resulted in significantly improved functional outcomes at 90 days *Patients with acute ischaemic stroke were included if they had an imaging-confirmed occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery or both, and in the absence of large ischaemic-core lesions SWIFT-PRIME, Solitaire With the Intention For Thrombectomy as PRIMary Endovascular treatment Saver et al. N Engl J Med 2015;372:

REVASCAT Objective: To assess efficacy and safety of neurovascular thrombectomy* in addition to medical therapy (which may entail rt-PA) vs. medical therapy alone in the treatment of eligible ischaemic stroke cases within 8 hours of symptom onset Note: 68% of patients in the thrombectomy group received rt-PA as standard medical therapy Significantly improved efficacy outcomes with IAT plus rt-PA versus standard medical therapy mRS <2 at 90 days: 43.7% vs. 28.1% (adjusted OR 2.1; 95% CI, 1.1 to 4.0) Improvement in neurologic function at 24 h Similar safety profiles Conclusion: The results support the use of IAT plus medical therapy in patients with an image-confirmed anterior circulation stroke, treated within 8 hours of symptom onset *using the Solitaire stent retriever; REVASCAT, Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset Jovin et al. N Engl J Med 2015;372:

THRACE Objective: To assess the effect of mechanical thrombolysis in addition to IV thrombolysis (IVTMT) on clinical outcomes versus IV thrombolysis alone (IVT) in patients with AIS, treated within 4 hours of onset mRS at 3 months Functional dependence (mRS 0-2) significantly favoured IVTMT vs. IVT (OR: 1.55, 95% CI: ; p=0.028) No significant difference in mortality Mean NIHSS score 4 points lower for IVTMT over IVT at Day 7 (p=0.001) Barthel index significantly favoured IVMT (OR: 1.59, 95% CI: ; p=0.04) Conclusion: IVMT is associated with a significantly higher rate of functional independence at 3 months, and does not increase mortality versus IVT alone THRACE, Mechanical Thrombectomy after intravenous alteplase versus alteplase alone after stroke Bracard et al. Lancet Neurol 2016;15(11):

North American Solitaire Acute Stroke (NASA) registry Real world applicability of clinical studies
Are trials supporting endovascular treatment (with retrievable stents) plus intravenous thrombolysis applicable in the real world? Significantly better outcomes with IA-IV treatment mRS scores at 90 days versus all IV rt-PA control groups IA-IV group had greater stroke severity, longer time from stoke onset to groin puncture, and more proximal location of arterial occlusions, yet improved outcomes NASA registry data was used to compare outcomes for endovascular treatment (Solitaire FR stent retriever) plus IV thrombolysis (IA-IV) to IV rt-PA alone* Controls were taken from both registry patients and the MR CLEAN, ESCAPE, SWIFT Prime, and REVASCAT trial control groups Real-world registry data support recent thrombectomy trials on the use of a combined IA-IV approach over IV rt-PA *Inclusion criteria reflected the IMS-III trial, which found no benefit for an IA-IV approach over IV rt-PA, but used devices lacking stent receiver technology Nogueira et al. Intervent Neurol 2016;5: Broderick et al. N Engl J Med Mar 7; 368(10): 893–903.

Endovascular therapy – overall conclusions
Results of 6 recent clinical trials demonstrated that combination of guideline-based care (including rt-PA within 4.5 hours of onset of stroke symptoms in eligible patients) plus endovascular therapy can be highly beneficial, as compared with standard stroke care alone ESO-Karolinska , EROICAS, and AHA/ASA updated their recommendations based on these results However, only a small proportion of carefully selected ischaemic stroke patients (those with large proximal arterial occlusions) benefit from timely endovascular treatment Bracard et al. Lancet Neurol 2016;15(11): Berkhemer et al. N Engl J Med 2015;372:11-20. Campbell et al. N Engl J Med 2015;372: Fiehler et al. Int J Stroke 2016;11(6): Goyal et al. N Engl J Med 2015;372: Jovin et al. N Engl J Med 2015;372: Powers et al. Stroke 2015;46(10):3020–3035. Saver et al. N Engl J Med 2015;372: Wahlgren et al. Int J Stroke 2016;11(1):

Prescribing information
Actilyse® Summary of Product Characteristics (SPCs)

Summary of Product Characteristics
This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 1. NAME OF THE MEDICINAL PRODUCT Actilyse 10 mg powder and solvent for solution for injection and infusion Actilyse 20 mg powder and solvent for solution for injection and infusion Actilyse 50 mg powder and solvent for solution for injection and infusion [Disclaimer: List of strengths according to national registration. To be completed nationally.] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 vial with powder contains: 10 mg alteplase (corresponding to 5,800,000 IU) or 20 mg alteplase (corresponding to 11,600,000 IU) or 50 mg alteplase (corresponding to 29,000,000 IU), respectively Alteplase is produced by recombinant DNA technique using a Chinese hamster ovary cell-line. The specific activity of alteplase in-house reference material is 580,000 IU/mg. This has been confirmed by comparison with the second international WHO standard for t-PA. The specification for the specific activity of alteplase is 522,000 to 696,000 IU/mg. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder and solvent for solution for injection and infusion. The powder is presented as a colourless to pale yellow lyophilizate cake. The reconstituted preparation is a clear and colourless to pale yellow solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications: Thrombolytic treatment in acute myocardial infarction 90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 h after symptom onset 3 h dose regimen (see section 4.2): for patients in whom treatment can be started between h after symptom onset provided that the diagnosis has been clearly confirmed. Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction. Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning. There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism. Fibrinolytic treatment of acute ischaemic stroke Treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the presence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.2 Posology and method of administration Actilyse should be given as soon as possible after symptom onset. The following dose guidelines apply. Acute Myocardial infarction Posology a) 90 minutes (accelerated) dose regimen for patients with acute myocardial infarction, in whom treatment can be started within 6 hours after symptom onset: Concentration of alteplase 1 mg/ml 2 mg/ml ml 15 mg as an intravenous bolus 15 7.5 50 mg as an infusion over 30 minutes 50 25 followed by an infusion of 35 mg over 60 minutes until the maximal dose of 100 mg 35 17.5 In patients with a body weight below 65 kg the dose should be weight adjusted according to the following table: Concentration of alteplase 1 mg/ml 2 mg/ml ml 15 mg as an intravenous bolus 15 7.5 ml/kg bw and 0.75 mg/kg body weight (bw) over 30 minutes (maximum 50 mg) 0.75 0.375 followed by an infusion of 0.5 mg/kg body weight (bw) over 60 minutes (maximum 35 mg) 0.5 0.25

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. b) 3 h dose regimen for patients, in whom treatment can be started between 6 and 12 hours after symptom onset: Concentration of alteplase 1 mg/ml 2 mg/ml ml 10 mg as an intravenous bolus 10 5 50 mg as an infusion over the first hour 50 25 ml/30 min followed by infusions of 10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours In patients with a body weight below 65 kg the total dose should not exceed 1.5 mg/kg. The maximum dose of alteplase is 100 mg. Adjunctive therapy: Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with ST-elevation myocardial infarction. Method of administration The reconstituted solution should be administered intravenously. 2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Pulmonary embolism A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen: Concentration of alteplase 1 mg/ml 2 mg/ml ml 10 mg as an intravenous bolus over minutes 10 5 followed by an intravenous infusion of 90 mg over 2 hours 90 45 The total dose should not exceed 1.5 mg/kg in patients with a body weight below 65 kg. Adjunctive therapy: After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal. The infusion should be adjusted to maintain aPTT between seconds (1.5 to 2.5 fold of the reference value). Method of administration The reconstituted solution should be administered intravenously. 2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Acute ischaemic stroke Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4. Posology The recommended dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10% of the total dose administered as an initial intravenous bolus. Adjunctive therapy: The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid within the first 24 hours of onset of the symptoms have not been sufficiently investigated. Administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24 hours after treatment with Actilyse. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU per day, administered subcutaneously. Method of administration The reconstituted solution should be administered intravenously. 2 mg vials of alteplase are not indicated for use in this indication. For instructions prior to reconstitution / administration, see section 6.6. Paediatric population The safety and efficacy of Actilyse in children and adolescents has not yet been established. Actilyse is contraindicated for the treatment of acute stroke in children and adolescents (see section 4.3). Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of symptoms. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with Actilyse administration and so it should not be administered (see section 5.1).

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.3 Contraindications Generally, in all indications Actilyse should not be administered to patients with known hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients listed in section 6.1. Additional contraindications in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke: Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as: significant bleeding disorder at present or within the past 6 months known haemorrhagic diathesis patients receiving effective oral anticoagulant treatment, e.g. warfarin sodium (see section 4.4) manifest or recent severe or dangerous bleeding known history of or suspected intracranial haemorrhage suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery) recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture) severe uncontrolled arterial hypertension bacterial endocarditis, pericarditis acute pancreatitis documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial-aneurysm, arterial/venous malformations neoplasm with increased bleeding risk severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis major surgery or significant trauma in past 3 months. Additional contraindications in acute myocardial infarction: any known history of haemorrhagic stroke or stroke of unknown origin known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months except current acute ischaemic stroke within 4.5 hours.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Additional contraindications in acute pulmonary embolism: any known history of haemorrhagic stroke or stroke of unknown origin known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months except current acute ischaemic stroke within 4.5 hours. Additional contraindications in acute ischaemic stroke: symptoms of ischaemic attack beginning more than 4.5 hours prior to infusion start or symptoms for which the onset time is unknown and could potentially be more than 4.5 hours ago (see section 5.1) minor neurological deficit or symptoms rapidly improving before start of infusion severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques seizure at onset of stroke evidence of intracranial haemorrhage (ICH) on the CT-scan symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory patients with any history of prior stroke and concomitant diabetes prior stroke within the last 3 months platelet count of below 100,000/mm3 systolic blood pressure > 185 or diastolic BP > 110 mm Hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce BP to these limits blood glucose < 50 or > 400 mg/dl. Use in children and adolescents Actilyse is not indicated for the treatment of acute stroke in paediatric patients under 18 years. Use in elderly patients Actilyse is not indicated for the treatment of acute stroke in adults over 80 years of age.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.4 Special warnings and precautions for use The appropriate presentation of alteplase product should be chosen carefully and in accordance with the intended use. The 2 mg presentation of alteplase is not indicated for use in acute myocardial infarction, acute pulmonary embolism or acute ischaemic stroke (due to risk of massive under dosing). Only 10, 20 or 50 mg presentations are indicated for use in these indications. Thrombolytic/fibrinolytic treatment requires adequate monitoring. Actilyse should only be used under the responsibility and follow-up of physicians trained and experienced in the use of thrombolytic treatments and with the facilities to monitor that use. It is recommended that when Actilyse is administered standard resuscitation equipment and pharmacotherapy is available in all circumstances. Hypersensitivity No sustained antibody formation to the recombinant human tissue-type plasminogen activator molecule has been observed after treatment. There is no systematic experience with re-administration of Actilyse. Anaphylactoid reactions associated with the administration of Actilyse are rare and can be caused by hypersensitivity to the active substance alteplase, gentamicin (a trace residue from the manufacturing process) or to any of the excipients. The stopper of the glass vial with Actilyse powder contains natural rubber (a derivative of latex) which may cause allergic reactions. If an anaphylactoid reaction occurs, the infusion should be discontinued and appropriate treatment initiated. Haemorrhages If a potentially dangerous haemorrhage occurs, in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued. In general, however, it is not necessary to replace the coagulation factors because of the short half-life and the minimal effect on the systemic coagulation factors. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Haemorrhages (continued from previous slide) As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections, cardiac massage for resuscitation conditions with an increased risk of haemorrhage which are not mentioned in section 4.3. The use of rigid catheters should be avoided. Patients receiving oral anticoagulant treatment: The use of Actilyse may be considered when dosing or time since the last intake of anticoagulant treatment makes residual efficacy unlikely confirmed by appropriate test(s) of anticoagulant activity for the product(s) concerned showing no clinically relevant activity on the coagulation system (e.g. INR≤ 1.3 for vitamin K antagonists or other relevant test(s) for other oral anticoagulants are within the respective upper limit of normal). Paediatric population As yet, there is only limited experience with the use of Actilyse in children and adolescents. Additional special warnings and precautions in acute myocardial infarction and acute pulmonary embolism: A dose exceeding 100 mg of alteplase must not be given because it has been associated with an additional increase in intracranial bleeding. Therefore special care must be taken to ensure that the dose of alteplase infused is as described in section 4.2. The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with systolic blood pressure > 160 mm Hg. GPIIb/IIIa antagonists: Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Additional special warnings and precautions in acute ischaemic stroke: Special precautions for use: Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care. For the verification of treatment indication remote diagnostic measures may be considered as appropriate (see section 4.1). Special warnings / conditions with a decreased benefit/risk ratio: Compared to other indications patients with acute ischaemic stroke treated with Actilyse have a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area. This applies in particular in the following cases: all situations listed in section 4.3. and in general all situations involving a high risk of haemorrhage small asymptomatic aneurysms of the cerebral vessels with later time-to-treatment from onset of stroke symptoms the net clinical benefit is reduced and may be associated with a higher risk of ICH and death compared to patients treated earlier. Therefore, the administration of Actilyse should not be delayed. patients pre-treated with acetyl salicylic acid (ASA) may have a greater risk of intracerebral haemorrhage, particularly if Actilyse treatment is delayed. Blood pressure (BP) monitoring during treatment administration and up to 24 hours seems justified; an intravenous antihypertensive therapy is also recommended if systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg. The therapeutic benefit is reduced in patients that had a prior stroke or in those with known uncontrolled diabetes, thus the benefit/risk ratio is considered less favourable, but still positive in these patients. In patients with very mild stroke, the risks outweigh the expected benefit (see section 4.3). Patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and should not be treated (see section 4.3). Patients with extensive infarctions are at greater risk of poor outcome including severe haemorrhage and death. In such patients, the benefit/risk ratio should be thoroughly considered.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Additional special warnings and precautions in acute ischaemic stroke (continued from previous slide): In stroke patients the likelihood of good outcomes decreases with increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or relevant intracranial bleedings increases, independently from treatment. Patients over 80, patients with severe stroke (as assessed clinically and/or by appropriate imaging techniques) and patients with blood glucose levels < 50 mg/dl or > 400 mg/dl at baseline should not be treated with Actilyse (see section 4.3). Data available from ECASS III and the pooled analysis indicate that the net clinical benefit becomes smaller in elderly with increasing age compared to younger patients as benefit from treatment with Actilyse appears to decrease and the risk of mortality appears to increase with increasing age. Other special warnings: Reperfusion of the ischaemic area may induce cerebral oedema in the infarcted zone. Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase. 4.5 Interaction with other medicinal products and other forms of interaction No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed. The risk of haemorrhage is increased if coumarine derivatives, oral anticoagulants, platelet aggregation inhibitors, unfractionated heparin or LMWH or active substances which interfere with coagulation are administered (before, during or within the first 24 hours after treatment with Actilyse) (see section 4.3). Concomitant treatment with ACE inhibitors may enhance the risk of suffering an anaphylactoid reaction, as in the cases describing such reactions a relatively larger proportion of patients were receiving ACE inhibitors concomitantly. Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.6 Fertility, pregnancy and lactation Pregnancy There is limited amount of data from the use of Actilyse in pregnant women. Nonclinical studies performed with alteplase in doses higher than human doses exhibited fetal immaturity and/or embryotoxicity, secondary to the known pharmacological activity of the drug. Alteplase is not considered to be teratogenic (see section 5.3). In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk. Breast-feeding It is not known if alteplase is excreted into human milk. Fertility Clinical data on fertility are not available for Actilyse. Nonclinical studies performed with alteplase showed no adverse effect on fertility (see section 5.3) 4.7 Effects on ability to drive and use machines Not relevant. 4.8 Undesirable effects The most frequent adverse reaction associated with Actilyse is bleeding in different forms resulting in a fall in haematocrit and/or haemoglobin values. Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data). Except for intracerebral/intracranial haemorrhage as adverse reaction in the indication stroke as well as for reperfusion arrhythmias in the indication myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications pulmonary embolism and acute ischaemic stroke is different from the profile in the indication myocardial infarction.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.8 Undesirable effects (continued from previous slide) Table 1 Adverse reactions in myocardial infarction, pulmonary embolism and ischaemic stroke System Organ Class Adverse Reaction Haemorrhage very common intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to 15 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. mRS of 5 and 6). bleeding from damaged blood vessels (such as haematoma) common intracerebral haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial infarction and acute pulmonary embolism pharyngeal haemorrhage gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, rectal haemorrhage, haematemesis, melaena, mouth haemorrhage, gingival bleeding) ecchymosis urogenital haemorrhage (such as haematuria, haemorrhage urinary tract) injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage) uncommon pulmonary haemorrhage (such as haemoptysis, hemothorax, respiratory tract haemorrhage) epistaxis ear haemorrhage rare eye haemorrhage pericardial haemorrhage retroperitoneal bleeding (such as retroperitoneal haematoma) not known*** bleeding in parenchymatous organs (such as hepatic haemorrhage) ***Frequency calculation: This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than “rare”, but might be lower. Precise frequency estimation is not possible as the adverse drug reaction did not occur in a clinical trial database of 8299 patients.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Table 1 Adverse reactions in myocardial infarction, pulmonary embolism and ischaemic stroke (continued) System Organ Class Adverse Reaction Immune system disorders* rare hypersensitivity / anaphylactoid reactions (e.g. allergic reactions including rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated with allergic reactions) very rare serious anaphylaxis Nervous system disorders events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis) often in association with concurrent ischaemic or haemorrhagic cerebrovascular events Cardiac disorders** very common recurrent ischaemia / angina pectoris, hypotension and heart failure / pulmonary oedema common cardiogenic shock, cardiac arrest and reinfarction uncommon reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block first degree to atrioventricular block complete, atrial fibrillation / flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation, electromechanical dissociation [EMD]) mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral embolism, ventricular septal defect *Immune system disorders: Transient antibody formation to Actilyse has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established. **Cardiac disorders: As with other thrombolytic agents, the events described above under the respective section have been reported as sequelae of myocardial infarction and / or thrombolytic administration. These cardiac events can be life-threatening and may lead to death.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Table 1 Adverse reactions in myocardial infarction, pulmonary embolism and ischaemic stroke (continued) System Organ Class Adverse Reaction Vascular disorders rare embolism which may lead to corresponding consequences in the organs concerned Gastrointestinal disorders nausea not known*** vomiting Investigations uncommon blood pressure decreased body temperature increased Injury and poisoning and procedural complications fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned Surgical and medicinal procedures blood transfusions (necessary) ***Frequency calculation: This adverse reaction has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than “rare”, but might be lower. Precise frequency estimation is not possible as the adverse drug reaction did not occur in a clinical trial database of 8299 patients. Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 4.9 Overdose The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma is recommended and if necessary, synthetic antifibrinolytics may be administered. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antithrombotic agents, ATC code: B01AD02 The active ingredient of Actilyse is alteplase a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot. Due to its relative fibrin-specificity alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60 % at 4 hours, which is generally reverted to more than 80 % after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively after 4 hours and increase again to more than 80 % at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients. In a study including more than 40,000 patients with an acute myocardial infarction (GUSTO) the administration of 100 mg alteplase over 90 minutes, with concomitant intravenous heparin infusion, led to a lower mortality after 30 days (6.3 %) as compared to the administration of streptokinase, 1.5 million U over 60 minutes, with subcutaneous or intravenous heparin (7.3 %). Actilyse-treated patients showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the streptokinase-treated patients. No differences in patency rates were noted at 180 minutes or longer. 30-day-mortality is reduced as compared to patients not undergoing thrombolytic therapy. The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is reduced. Global ventricular function as well as regional wall motion is less impaired as compared to patients receiving no thrombolytic therapy.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. Myocardial infarction A placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30 day mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after symptom onset may still be beneficial. Pulmonary embolism In patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary artery pressure. Mortality data are not available. Acute ischaemic stroke patients In two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable outcome with alteplase, compared to placebo (no or minimal disability). These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime two European studies and an additional USA study had failed to provide the respective evidence in settings essentially not compliant with the current EU product information. The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours in Europe. Treatment administration in the ECASS III study was in line with the European SmPC for Actilyse in its stroke indication, except the upper end of the time of treatment window i.e. 4.5 hours. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI ; P=0.038). The incidence of any ICH/SICH was higher with alteplase vs. placebo (any ICH 27.0% vs 17.6%, p=0.0012; SICH by ECASS III definition 2.4% versus 0.2 %, p = 0.008). Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681). Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-clinical benefit for Actilyse in the 3 to 4.5 hour time window, while pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours. The safety and efficacy of Actilyse for acute ischaemic stroke treatment up to 4.5 hours time stroke onset time to start of treatment (OTT) has been assessed by an ongoing registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome data of treated patients in the 0 to 3 hour time window were compared with data from patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3 months were similar comparing the 3 to 4.5 hour time window (12.0%) with the 0 to 3.0 hours time window (12.3%) with an unadjusted OR 0.97 (95% CI: , p=0.70) and an adjusted OR 1.26 (95% CI: , p= The SITS observational data support clinical trial evidence of stroke onset time to start of treatment (OTT) as an important predictor of outcome following acute stroke treatment with alteplase.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 5.2 Pharmacokinetic properties Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance ml/min.). The relevant plasma half-life t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10 % of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured. 5.3 Preclinical safety data In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were found. No indications of a mutagenic potential were found in mutagenic tests. In pregnant animals no teratogenic effects were observed after intravenous infusion of pharmacologically effective doses. In rabbits embryotoxicity (embryolethality, growth retardation) was induced by more than 3 mg/kg/day. No effects on peri-postnatal development or on fertility parameters were observed in rats with doses up to 10 mg/kg/day.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Powder: Arginine Phosphoric acid, dilute Polysorbate 80 Solvent: Water for injections 6.2 Incompatibilities The reconstituted solution may be diluted with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg alteplase per ml. Further dilution, the use of water for injections for dilution or in general the use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due to increasing formation of turbidity of the reconstituted solution. Actilyse should not be mixed with other medicinal products neither in the same infusion vial nor the same catheter (not even with heparin). 6.3 Shelf life Unopened vials 3 years Reconstituted solution The reconstituted solution has been demonstrated to be stable for 24 hours at 2°C – 8°C and for 8 hours at 25°C. From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.4 Special precautions for storage Store in the original package in order to protect from light. Do not store above 25 °C. For storage conditions after reconsititution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Powder: 10 ml, 20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with aluminium/plastic flip-off caps. Solvent: For the 10 mg, 20 mg and 50 mg presentations, the water for injections is filled into either 10 ml, 20 ml or 50 ml vials, depending on the size of the powder vials. The water for injections vials are sealed with rubber stoppers and aluminium/plastic flip-off caps. Transfer cannulas (included with presentations of 20 mg and 50 mg only) Presentations: 10 mg: 1 vial with 467 mg powder for solution for injection and infusion 1 vial with 10 ml of water for injections 20 mg: 1 vial with 933 mg powder for solution for injection and infusion 1 vial with 20 ml of water for injections 1 transfer cannula 50 mg: 1 vial with 2333 mg powder for solution for injection and infusion 1 vial with 50 ml of water for injections Not all presentations may be marketed.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.6 Special precautions for disposal and other handling For reconstitution to a final concentration of 1 mg alteplase per ml the full volume of solvent provided should be transferred to the vial containing the Actilyse powder. To this purpose a transfer cannula is included with the 20 mg and 50 mg presentations, which is to be used. For the 10 mg presentation a syringe should be used. For reconstitution to a final concentration of 2 mg alteplase per ml only half of the solvent provided should be used (as per table below). In these cases always a syringe should be used to transfer the required amount of solvent to the vial containing the Actilyse powder. Under aseptic conditions the content of an injection vial of Actilyse (10 mg or 20 mg or 50 mg) is dissolved with water for injections according to the following table to obtain either a final concentration of 1 mg alteplase/ml or 2 mg alteplase/ml: Actilyse dry substance 10 mg 20 mg 50 mg (a) Volume of sterilised water for injections to be added to dry substance 10 mL 20 mL 50 mL Final concentration: 1 mg alteplase/mL (b) Volume of sterilised water for injections to be added to dry substance 5 mL 25 mL 2 mg alteplase/mL The reconstituted solution should then be administered intravenously. The 1 mg/mL reconstituted solution may be diluted further with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg/ml. A further dilution of the 1 mg/mL reconstituted solution with sterilised water for injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended. Actilyse should not be mixed with other medicinal products in the same infusion-vial (not even with heparin). For incompatibilities see section 6.2. The reconstituted solution is for single use only. Any unused solution or waste material should be disposed in accordance with the local requirements.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.6 Special precautions for disposal and other handling (continued) Instructions for reconstituting Actilyse

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.6 Special precautions for disposal and other handling (continued) Instructions for reconstituting Actilyse (continued) (*if a transfer cannula is included in the kit. The reconstitution can also be performed with a syringe and a needle.)

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 6.6 Special precautions for disposal and other handling (continued) Instructions for reconstituting Actilyse (continued)

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. 7. MARKETING AUTHORISATION HOLDER Boehringer Ingelheim International GmbH, Binger Str. 173, D Ingelheim am Rhein, Germany [To be completed nationally] PLEASE ALWAYS CHECK YOUR LOCAL PRESCRIBING INFORMATION.

Actilyse® reconstitution video

Actilyse® reconstitution video
Watch the Actilyse® reconstitution video

Acute Stroke Slide Kit August 2017

Acute Stroke Slide Kit August 2017.

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Acute Stroke Slide Kit August 2017.

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