Studies & registries


The management of stroke can be divided into several major areas:

  1. Stroke prevention, including management of risk factors
  2. Optimisation of general physiological conditions in the setting of an acute stroke
  3. Treatment of an acute stroke – thrombolysis and revascularisation
  4. Management of complications following an acute stroke
  5. Rehabilitation – restoring as much function as possible to a patient after a stroke
  6. Secondary prevention – avoidance of a recurrent stroke

In the acute stroke setting, Time is brain and the studies and registries in this section concentrate on how a patient should be managed on arrival at the hospital, including the advantage of treatment in a stroke unit, the evidence for thrombolysis, the benefits of rt-PA, and the importance of time.


Recently, Goyal et al. prospectively meta-analysed data from the control arm of the HERMES collaboration* of 7 recent clinical trials, which randomised patients with ischaemic stroke due to large vessel occlusion (LVO), to receive either endovascular thrombectomy (EVT) added to intravenous alteplase, or intravenous alteplase only. By pooling individual data from the patients who received intravenous alteplase only, it was shown that faster intravenous thrombolysis delivery directly correlates with less disability defined by the modified ranking scale (mRS) at 3 months. The disability outcomes were less favourable with slower onset-to-treatment time (OTT), and better outcomes were strongly associated with faster treatment (door-to-needle time (DTN) <30 minutes). A decline in the benefit from OTT for every 15-minute delay in alteplase start was found to be associated with 8 fewer patients per 1000 achieving excellent outcome at 3 months (mRS, 0-1). Moreover, this decline was more drastic with DTN time, where for every 15-minute delay in alteplase start, 20 fewer patients per 1000 achieved an excellent outcome (mRS, 0-1) at 3 months.


Onset-to-treatment time (OTT) per 1h (OR, 95% CI)

Door-to-needle time (DTN) per 1 h (OR, 95% CI)

Modified Rankin Scale


0.80 (0.68-0.95)

0.55 (0.37-0.81)


0.82 (0.66-1.03)

0.47 (0.28-0.80)


0.76 (0.58-0.99)

0.51 (0.29-0.92)

Table: Effect of OTT and DTN on functional outcomes in patients with acute stroke

*HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) consists of collaboration by the investigators of ESCAPE, EXTEND-IA, MR CLEAN, PISTE, REVASCAT, SWIFT PRIME and THRACE trials.1



  1. Goyal M., et al. Rapid Alteplase Administration Improves Functional Outcomes in Patients With Stroke due to Large Vessel Occlusions. Stroke 2019;50:645–651.


Each minute of delay diminishes reperfusion therapy efficacy and worsens patient outcomes in acute stroke; therefore, speed is essential in early patient management. Accurate identification of acute stroke by Emergency Medical Dispatchers (EMD) is essential for timely and purposeful deployment of Emergency Medical Services (EMS), and a prerequisite for operating mobile stroke units. However, precision of EMD stroke recognition is currently modest. Factors associated with incorrect dispatch codes can be identified by cross-linking dispatch codes and EMS patient records, allowing the development of targets for improvement.



To identify targets for improving dispatcher stroke identification, in order to improve the speed of early stroke and transient ischemic attack (TIA) treatment management.



  • 28% of patients did not receive a high-priority stroke dispatch code
  • 20% of patients received an incorrect dispatch code
  • Independent predictors of dispatcher missed acute stroke included a bystander caller, confusion, fall at onset, and older age.
  • 71.7% of analysed call recordings revealed targets for improvement, including failure to recognize a Face Arm Speech Time (FAST) test symptom and failure to thoroughly evaluate symptoms.
  • Of all dispatcher missed acute stroke/ TIA patients, confusion and/or a fall at onset were present in 49.1% of cases
  • Further systematic questioning would have resulted in a correct high-priority stroke dispatch in calls with symptom evaluation failure



Targets for refining dispatcher stroke identification, and thus reducing pre hospital delays include:

  • Developing stroke screening in calls reporting a fall or confusion
  • Improved FAST symptom recognition and symptom evaluation training
  • Developing training algorithms and question phrasing in both systems using automated dispatching algorithms and more autonomous systems
  • Trained dispatcher or applied algorithm vigilance when stroke screening is reasonable and necessary
  • Interventional studies targeting elements of dispatching procedures, to create evidence-based guidelines and to fine-tune existing standard operating procedures



  1. Matilla, O, et al. Targets for improving dispatcher identification of acute stroke. Int J Stroke 2019; 0(0): 1–8


Endovascular treatment (EVT) is the current standard of care for patients with acute ischaemic stroke caused by an intracranial large vessel occlusion of the anterior circulation. All major guidelines recommend intravenous thrombolysis (IVT) before EVT in eligible patients.

In a recent meta-analysis of randomized trials, the effect of EVT was not influenced by IVT, raising the question of whether IVT is beneficial to patients with a large vessel occlusion.

Theoretical advantages of IVT before EVT include early reperfusion, faster procedural times, lysis of distal emboli, and improved microvascular reperfusion. Potential disadvantages include delayed initiation of EVT, thrombus fragmentation, major bleeding, potential neurotoxicity, and disruption of the blood–brain barrier



To compare clinical and procedural outcomes, safety, and workflow between acute ischaemic stroke patients with a large vessel occlusion treated with both IVT and EVT to those treated with EVT alone using data of the MR CLEAN (Multicenter Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands) Registry.



  • Modified Rankin Scale (mRS) scores at 90 days were more favourable in patients in the IVT+EVT group than in the EVT-alone group.
  • Functional independence at 90 days was achieved in 41% of patients with IVT+EVT, compared with 29% of patients with EVT alone.
  • Change in National Institutes of Health Stroke Scale (NIHSS) from baseline to 24 to 48 hours (Delta NIHSS) was larger and mortality was lower in the IVT+EVT group.
  • Among non-transferred patients, median door-to-groin puncture time was 11 minutes longer in the IVT+EVT group, while among transferred patients door-to-groin puncture time was the same in both groups.
  • The risk of severe extracranial hemorrhage and symptomatic intracranial hemorrhage (sICH) did not differ between groups



  • Patients treated with IVT+EVT had better clinical outcomes than patients who received EVT alone.
  • Until results of ongoing randomized trials are published, current guidelines should remain unchanged.



  1. Chalos et al, 2019. Endovascular Treatment with or Without Prior Intravenous Alteplase for Acute Ischemic Stroke. J Am Heart Assoc. 2019;8:e011592


Several randomized controlled trials demonstrated the efficacy of mechanical thrombectomy (MT) in patients with acute ischaemic stroke caused by a proximal intracranial occlusion in the anterior circulation.

A meta-analysis confirmed that, compared with intra venous thrombolysis (IVT) alone, endovascular thrombectomy as add-on to IVT increased the prob ability of good outcome, without increasing the risk of symptomatic haemorrhage, after large vessel ischaemic stroke in the anterior circulation.

Current guidelines therefore recommend to treat eligible patients with IVT before MT. However, whether MT alone may achieve better or at least equal clinical outcome than MT combined with IVT is a matter of debate.



To compare the outcome of patients with acute ischaemic stroke due to proximal intracranial artery occlusion in the anterior cerebral circulation, eligible for IVT according to current guidelines, treated with combined therapy with those who underwent primary MT, included in the Italian Registry of Endovascular Stroke Treatments.



  • A shift in the 90-day modified Rankin Scale (mRS) distributions toward a better outcome was found in favour of the combined treatment.
  • Time from symptom onset to first hospital arrival, median time from onset to ECC arrival and time from onset to CT scan were similar in the two groups.
  • Patients who underwent combined treatment had a significantly longer time from onset to groin puncture. Median onset to end of treatment time was slightly higher in IVT-MT patients than in MT patients, without statistically significant differences.
  • Median time from groin puncture to end of procedure was shorter for patients who underwent combined treatment than for MT patients.
  • The proportion of people surviving with mRS 0–3 was significantly higher in the combined treatment group, while risk of death or very unfavourable outcome (mRS 5–6) was significantly lower in the same arm
  • The 90-day case fatality rate was lower in patients treated with combined therapy than in those who underwent primary MT.



  • IVT treatment before MT procedure can lead to a better outcome, without affecting safety in patients with anterior circulation stroke due to large artery occlusion, and eligible to IVT.
  • There was a significant shift in the distribution of the primary-outcome scores in favour of the combined intervention.
  • Combined IVT and MT could be associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion.
  • This supports the current guidelines of treating eligible patients with IVT before MT. Our results, although an increased risk of symptomatic haemorrhage should be taken into account.



  1. Casetta et al, 2019. Combined intravenous and endovascular treatment versus primary mechanical thrombectomy. The Italian Registry of Endovascular Treatment in Acute Stroke. International Journal of Stroke. doi:10.1177/1747493019851279. Published online ahead of print.


Thrombolytic therapy for acute ischaemic stroke has been approached cautiously because there were high rates of intracerebral haemorrhage in early clinical trials. The NINDS Investigators performed a randomised, double-blind trial of intravenous recombinant tissue plasminogen activator (rt-PA) for ischaemic stroke after recent pilot studies suggested that rt-PA was beneficial when treatment was begun within three hours of the onset of stroke.


NINDS showed that:

  • For all stroke subtypes, treatment with intravenous rt-PA within 3 hours of the onset of ischaemic stroke improved clinical outcome at 3 months.
  • The greater proportion of patients were left with minimal or no deficit at 3 months after treatment with rt-PA
  • Treatment with rt-PA compared with placebo was not accompanied by an increase in severe disability or mortality.



In comparison to placebo, patients treated with rt-PA within 3 hours of an acute ischaemic stroke had approximately 30% less disability.



  1. NINDS Investigators. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995,333(24):1581-1587.


  • The efficacy of rt-PA is highest if initiated within 90 min of stroke symptom onset. However, many stroke victims do not reach a centre equipped to administer rt-PA in time, so that worldwide, <5% of acute ischaemic stroke patients are treated with rt-PA within 3 hours of stroke symptom onset.
  • rt-PA was approved by the EU regulatory authority EMEA in 2002 for use within 3 h of ischaemic stroke with two post-approval requirements:
    • All patients should be registered in the SITS internet database and entered into an observational safety study, SITS-MOST.
    • A randomised trial of rt-PA versus placebo should be performed, with an extended therapeutic window greater than 3 hours.
  • A pooled analysis of individual patient data (N=2,775) from 6 trials of i.v. rt-PA vs. placebo in 2004 showed that the effective treatment window may extend to 4.5 hours.



The objective of this double-blind, parallel-group, placebo controlled study was to evaluate the efficacy and safety of intravenous thrombolysis using rt-PA administered 3 to 4.5 hours after onset of stroke symptoms in patients with acute ischaemic stroke.


Summary of ECASS 3

  • Patients were eligible for inclusion if they were 18 to 80 years of age, had received a clinical diagnosis of acute ischaemic stroke, and were able to receive the study drug within 3 to 4.5 hours. A cerebral computer tomographic (CT) scan was required before randomisation to exclude patients who had an intracranial haemorrhage or major ischaemic infarction.
  • 821 patients in 19 European countries were enrolled.
  • Out of the randomised groups, 375 patients were treated with 0.9 mg intravenous rt-PA per kg body weight (with an upper, limit of 90 mg) and 355 patients received placebo.
  • Primary endpoint was disability at 90 days, dichotomised as a favourable outcome (a score of 0 or 1 on the modified Rankin scale).
  • In this study, a 52.4% favourable outcome for patients in the rt-PA group compared to 45.2% in the placebo group was reported (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).


Figure 1: The primary endpoint of ECASS 3 (intention-to-treat population)

The primary endpoint of ECASS 3 (intention-to-treat population)


  • The overall rate of symptomatic intracranial haemorrhage (sICH) was low with rt-PA (2.4%) and comparable to the 3-hour time window.
  • Even though the rate of intracranial haemorrhage was higher than with placebo (27% vs. 17.6%; p=0.001; for sICH, 2.4% vs. 0.2%; p=0.008), there was no significant difference in the rate of mortality or other severe adverse events (7.7% and 8.4%, respectively; p=0.68).

These findings are consistent with the results from other randomised, controlled trials of thrombolysis in patients with acute ischaemic stroke.



While the trial outcome showed that rt-PA is safe and effective up to 4.5 hours after the onset of acute ischaemic stroke symptoms, patients should be treated as early as possible to maximise the benefit.

Having more time does not mean we should be allowed to take more time.


  1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.


ECASS 3: Further analysis

  • 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 mRS 0-1 at day 90, sICH, and death.


ECASS 3 further analysis results

  • rt-PA was effective across a wide range of subgroups for patients with an acute ischaemic stroke, treated in the 3-4.5 hour time window. In particular this benefit was independent of stroke severity.


ECASS 3: Conclusions

  • Intravenous rt-PA initiated for the treatment of acute ischaemic stroke (AIS), 3-4.5 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 … 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.



  1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.
  2. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363(9411):768-774.
  3. Schellinger PD, Kaste M, Hacke W. An update on thrombolytic therapy for acute stroke. Curr Opin Neurol 2004; 17(1);69-77.
  4. Bluhmki E, et al. Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol 2009;8:1095-1102.


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 3-4.5 hour time window after stroke onset vs. non-thrombolytic therapy.
  • Initial concerns following the publication of ECASS 3, about increasing delays in administration of rt-PA to patients with an acute ischaemic stroke, were not confirmed and in fact the proportion of patients with a door-to-needle time <60 min increased.


Figure 2: Impact of ECASS 3 on time to thrombolysis

Impact of ECASS 3 on time to thrombolysis



  1. Tung CE et al. Cost-effectiveness of tissue-type plasminogen activator in the 3- to 4.5-hour time window for acute ischemicstroke. Stroke 2011;42:2257-2262.
  2. Ingall TJ. Intravenous thrombolysis for acute ischemic stroke: time is prime.Stroke 2009;40:2264-2265.
  3. Minnerup J, 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;42:2838-2843.


The ENchanted Control of Hypertension And Thrombolysis stroke stuDy (ENCHANTED) is an investigator-initiated, randomised, controlled non-inferiority trial, with a 2x2, multi-centre, open label, PROBE design (intention-to-treat, ITT, analysis).1 The study enrolled patients with an acute ischaemic stroke who are eligible for thrombolysis:

  • The first part of the study (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;1
  • Part B compares early intensive systolic blood pressure (SBP) lowering (target 130-140 mmHg) with guideline-recommended BP lowering (<180 mmHg) with respect to the risk of any ICH.1

Figure 1: ENCHANTED 2x2 study design

ENCHANTED 2x2 study design

Inclusion & exclusion criteria

  • Patients were included if aged 18 or over, with a clinical diagnosis of acute ischaemic stroke confirmed by brain imaging, who were eligible to receive rt-PA treatment within 4.5 hours of symptom onset.2
  • Patients with a systolic blood pressure between 150 – 220 mmHg were also randomised to receive early intensive BP lowering (target SBP 140 mmHg) or standard guideline-recommended BP lowering (target SBP <180 mmHg).2
  • Patients that were unlikely to benefit from the intervention due to pre-existing disability (e.g. advanced dementia), with a high risk of mortality within 24 h, or other pre-existing medical illness that may affect outcomes were the main exclusion criteria from the study.2

Primary outcome(for both study arms)1,2

  • Combined outcome of death or disability (mRS 2-6) at 90 days to determine non-inferiority of low-dose rt-PA vs. standard-dose rt-PA

Key secondary outcomes1,2

  • Intracerebral haemorrhage (ICH) - SITS-MOST definition, with neurological deterioration from baseline
  • Any other ICH, determined on brain imaging within 7 days after treatment
  • Neurological deterioration from baseline
  • mRS at 90 days
  • Other clinical measures, health-related quality of life (HRQoL)
  • Death

Part A: rt-PA dose



  • rt-PA is currently licensed for use at a dose of 0.9 mg/kg body weight in most countries. In Japan, the licensed dose is 0.6 mg/kg.
  • Asians appear to have an increased risk of sICH that can be contributed to genetic differences in coagulation and fibrinolysis pathways compared to Caucasians.5
  • The standard dose of rt-PA has been associated with an increased risk of sICH in Asian patients.6-10
  • It has been shown that most clots typically dissolve shortly after the injection of rt-PA3, although the infusion lasts for one hour.


  • To assess the non-inferior efficacy and safety of low-dose (0.6 mg/kg) intravenous 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.1,2


  • 3,310 patients (median age of 67, 63% were Asian) were randomised to low-dose rt-PA (n=1607) or standard-dose rt-PA (n=1599).2
  • 53.2% of patients who received low dose rt-PA met the primary outcome of death or disability (primary outcome measure), compared to 51.1% on standard dose (OR 1.09; 95% CI 0.95 – 1.25).2
  • The upper limit set for non-inferiority was 1.14, which was exceeded, and thus the trial failed to demonstrate non-inferiority (p=0.51 for non-inferiority).2

Figure 2: Forest plot for the primary outcome, death or disability (mRS 2-6) at 90 days

Forest plot for the primary outcome, death or disability (mRS 2-6) at 90 days


*adjustment for time from stroke onset to randomisation, score as a continuous measure on the National Institutes of Health stroke scale (NIHSS), age, sex, ethnicity, pre-morbid score of 0 or 1 on the mRS, pre-morbid use of aspirin, other antiplatelet agent or warfarin, and any history of stroke, coronary artery disease, diabetes mellitus and atrial fibrillation.
Adapted from Anderson C, et al. N Engl J Med 2016;374(24):2313-2323. Suppl. DOI: 10.1056/NEJMoa1515510. Presented by Craig Anderson at ESOC 2016, Barcelona, Spain.

  • 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. 10.3%, p=0.07); however, more patients in the standard-dose group had mRS scores of 0-1 compared to the low-dose group (48.9% vs. 46.8% respectively); p=0.04 for non-inferiority of low-dose rt-PA (Figure 3).2

Figure 3: Secondary outcome: unadjusted ordinal shift mRS scores

Secondary outcome: unadjusted ordinal shift mRS scores


  • Major sICH occurred in 1.0% of patients who received the lower dose of rt-PA, and 2.1% of those with the standard rt-PA dose (p=0.01).2
  • No significant difference was seen in the treatment groups for the occurrence of serious adverse events (p=0.16), but fatal cerebral haemorrhage was increased in the standard dose group vs. the lower dose (2.5% vs. 1.3%, p=0.02).2


  • 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 symptomatic intracerebral haemorrhages; however, mortality was not significantly different in the two groups at 90 days.

Part B: blood pressure control


  • Blood pressure (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.1
  • The Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT-2) reported that although the primary endpoint of death and disability was not reduced in patients with spontaneous ICH (within the previous 6h) and elevated SBP with intensive BP-lowering treatment compared to standard treatment, and ordinal analysis shift of the modified Rankin scores did show improved functional outcomes in this group (OR for greater disability, 0.87; 95% CI, 0.77 to 1.00; p=0.04).11,12
  • Intensive lowering of BP trended towards reduced risk of death or disability, but this did not reach significance (p=0.06). Thus, the benefit of intensive lowering of BP in the hyperacute phase of acute ischaemic stroke remains to be definitively determined.11,12


  • To test whether early, intensive lowering of BP (systolic target 130-140 mmHg) displays superior efficacy and reduces risk of any ICH compared to the current guideline recommendation of a systolic target of <180 mmHg.1


  • Recruitment of 4800 patients is ongoing (as of November 2016).
  • Part B has the specific inclusion criteria that subjects have a sustained, elevated BP level of 150 to 220 mmHg, and are able to receive immediate, intensive BP lowering or conservative management of BP levels.
  • These patients are randomly assigned to either an early, intensive blood pressure regime (systolic blood pressure of <140 mmHg within 1 hour), or a systolic blood pressure of <180 mmHg as per the current guidelines.
  • Results are expected in 2018.

MRI-based patient selection

  • With the development of improved imaging techniques, much emphasis is being placed on the use of imaging to identify suitable patients for thrombolytic therapy, based on the mismatch concept.
  • 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.


What is mismatch?

  • Historically defined on MRI as the difference in volume of a lesion on diffusion-weighted imaging (DWI) lesion and perfusion-weighted imaging (PWI).
  • Classically, mismatch is confirmed when PWI > DWI by at least 20%.
  • However, the DWI lesion is only an approximation of the infarct, and may show some degree of reversibility in a minority of patients.
  • PWI without any thresholding identifies all brain tissue with hypoperfusion.
  • Other mismatch definitions include:
    • Clinical DWI mismatch – a higher NIHSS score than the DWI lesion size would suggest
    • MRA DWI mismatch – MRA vessel occlusion is more proximal and involves more brain tissue than the infarcted tissue shown on DWI
    • FLAIR DWI mismatch – a positive lesion is seen on DWI but not on FLAIR images


Figure 3: Imaging on presentation of acute ischaemic stroke

Imaging on presentation of acute ischaemic stroke


Figure 4: Imaging after treatment of AIS with intravenous rt-PA

Imaging after treatment of AIS with intravenous rt-PA


  • 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

  • The target mismatch pattern was associated with substantial benefit from early reperfusion in 67% of patients compared to 19% without early reperfusion (p=0.011).
  • A malignant MRI pattern (a large DWI and/or PWI lesion volume >100 ml, with a prolonged ≥Tmax 8 sec) was associated with a high risk of fatal sICH following reperfusion.
  • Small DWI and PWI lesions were associated with favourable outcomes.


Conclusions from DEFUSE

  • 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.



  1. Albers G, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.
  • In this study, 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 (N=1,210 patients).
  • 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) and onset to treatment time (OTT) as variables.


Results of Take 5

  • sICH rates were 5.3%, 3.1%, and 4.0%, mortality was 13.7%, 12.4%, and 12.1% (both non-significant).
  • 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%: odds ratio, OR=1.349 (1.041-1.747, p=0.023). For MRI 3h it was 1.558.


Figure 5: Take 5: Safety and efficacy multivariate analysis




  • MRI-based thrombolysis within and beyond the 3-h time window is at least as safe and possibly more effective than CT-based thrombolysis.



  1. Schellinger P, et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke 2007;38:2640-2645.


  • EPITHET was a randomised, double-blind, placebo-controlled trial to determine whether rt-PA administered 3-6 hours after stroke onset decreases infarct growth in patients with a known PWI/DWI mismatch.



  • 52 patients were randomly assigned to rt-PA and 49 patients to placebo.
  • Mean age was 71·6 years, and median NIHSS score was 13.
  • 85 of 99 (86%) patients had mismatch of PWI and DWI.
  • The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with rt-PA and 1.78 with placebo; the median relative infarct growth was 1.18 with rt-PA and 1.79 with placebo.
  • Reperfusion was more common with rt-PA than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than no reperfusion.



  • The EPITHET study confirms the results of DEFUSE.
  • Reperfusion is associated with a better outcome and a reduced infarct growth.



  1. Davis S, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008;7:299-309.
  • CT is sufficient for exclusion of intracranial haemorrhage and therefore decision making for or against thrombolysis.
  • Infarct detection <3 h is achieved in only a third of ischaemic strokes.
  • MRI is more sensitive than CT.
  • Perfusion/diffusion MRI can provide 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.



  1. Albers G, et al; the DEFUSE Investigators. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508-517.
  2. Davis S, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008;7:299-309.
  3. Schellinger P, et al. Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010;75:177-185.


  • The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min.
  • Common data elements from randomised controlled trials of intravenous rt-PA treatment for acute ischaemic stroke were combined and analysed.


Cochrane meta-analysis

  • In the 2009 Cochrane analysis, 9 trials using 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=0.00001), with significant between-trial heterogeneity (I2=66%, p=0.003).



  1. Wardlaw J, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009;4:CD000213. DOI: 10.1002/14651858.CD000213.pub2.


Updated pooled analysis 2010 (including ECASS 3 and EPITHET)

  • Data from ECASS 3 and EPITHET were added to the common data elements from the 6 major trials of rt-PA for acute ischaemic stroke that were analysed in the 2004 pooled analysis.
  • 1,850 patients were treated with rt-PA; 1,820 patients were given placebo
    • Men: 60%
    • Median age: 68 years (IQR 59-74)
    • Median NIHSS: 11 (IQR 7-16)
    • Median time-window: 240 min (IQR 180-284)
  • Separate analyses at four OTT intervals (0-90 min, 91-180 min, 181-270 min, 271-360 min) were undertaken.


Figure 6: Updated pooled analysis: favourable outcome (mRS 0-1) vs. time

Updated pooled analysis: favourable outcome (mRS 0-1) vs. time


Interpretation of the updated pooled analysis

  • Patients with an acute ischaemic stroke selected by clinical symptoms and CT benefit from intravenous rt-PA when treated up to 4.5 h.
  • There is no increase in mortality with rt-PA use compared with placebo 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.



  1. Hacke W, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774.
  2. Lees K, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695-1703.

What is SITS?

  • SITS is an internet-based interactive thrombolysis register.
  • The SITS register is an instrument for clinical centres to follow their own treatment results and compare them with other centres in their own or in collaborating countries.
  • The SITS register is the technical basis for the International Stroke Treatment Register (SITS-ISTR), SITS Stroke Monitoring Study (SITS-MOST) and other studies.
  • 60,249 patients from 1279 centres worldwide were enrolled by December 2011 and recruitment is ongoing.

For more information on the SITS register and further SITS projects and publications, please visit


  • Randomised controlled trials show thrombolysis to be beneficial when given within 3 hours of ischaemic stroke.
  • rt-PA was approved by the EU regulatory authority EMEA in 2002 for use within 3 hours of ischaemic stroke on two conditions:
    • Patients must be registered in the SITS internet database and entered into an observational safety study, SITS-MOST.
    • A new, randomised trial of rt-PA versus placebo, ECASS 3, be launched, with an extended therapeutic window greater than 3 hours.



  • SITS-MOST was an observational safety monitoring study from patients on the SITS register, within the EU, Norway, Iceland, and Switzerland, to assess whether intravenous 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 randomised controlled clinical trials.



  • 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.
  • The incidence of intracerebral haemorrhage with rt-PA was similar in SITS-MOST and RCTs, when similar definitions of symptomatic intracerebral haemorrhage (sICH) were applied.
  • Mortality was substantially lower in SITS-MOST (11.3%) than in RCTs (17.3%), and may have been due to the lower age and baseline stroke severity in SITS-MOST.



  • Functional independence 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%).
  • The results of SITS-MOST confirm that routine use of rt-PA within 3 hours of ischaemic stroke has a safety profile at least as good as that seen in RCTs.
  • SITS-MOST showed that safety could be maintained across centres, regardless of experience in acute stroke thrombolysis.
  • SITS-MOST 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, & effective treatment.



  • SITS-MOST demonstrated that broad implementation of thrombolysis with rt-PA within 3 hours of onset of stroke symptoms in acute ischaemic stroke is as safe and effective as in randomised controlled clinical trials.



  1. Wahlgren N, et al; the SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-282.
  2. Wahlgren N, et al. Erratum Lancet 2007;369:826.
  • Centres participating in the SITS database are required to enter all patients into SITS-ISTR (International stroke treatment register).
  • Between December 2002 and February 2010, SITS-ISTR looked at a cohort of patients (N=2,376) treated with rt-PA within 3-4.5 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



  • sICH occurred more frequently in patients treated within 3-4.5 hours than in the 0-3 hour group, according to the SITS-MOST definition of sICH (p=0.04), but was not significant for the ECASS II (p=0.35) or NINDS (p=0.66) definitions of sICH.
  • In the adjusted analysis, the rate of sICH was higher when applying the SITS-MOST and ECASS II definitions (p=0.02 for both), but not for the NINDS definition (p=0.06).
  • Mortality at 7 days and at 3 months was not significant in the unadjusted analysis (p=0.46 and 0.70 respectively), but was significant at 3 months for treatment within 3-4.5 hours in the adjusted analysis (p=0.005 compared to p=0.052 for mortality at 7 days).
  • 58% of patients treated within 3 hours and 60% of patients treated within 3-4.5 hours had functional independence (mRS 0-2) at 3 months (p=0.005).



  • 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 3-4.5 hour time window.
  • SITS-ISTR confirms the results of SITS-MOST and reinforces the results of ECASS 3.



  1. Ahmed N, et al; for the SITS Investigators. Implementation and outcome of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 2010;9:866-874.
  2. Wahlgren N, et al; for the SITS Investigators. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008;372:1303-1309.


  • Patients >80 years are underrepresented in approval relevant studies.
  • SITS NEW focused on Asian patients (48 stroke centres from Korea, China, India and Singapore participated).
  • Objective was to evaluate if the results for the use of intravenous rt-PA within 3 hours of symptom onset are consistent compared to rest of the world.

For more information on the SITS register and further SITS projects and publications, please visit


  • The 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.



  • VISTA was established to create a comprehensive resource, comprising patient data from acute stroke, rehabilitation, intracerebral haemorrhage, secondary prevention and observational stroke studies, to promote excellence in stroke care and trial design.



  • VISTA contains data on over 28,000 patients with either ischaemic (91%) or haemorrhagic stroke (9%) (reported December 2011).
  • Patients are aged 18-103 years.
  • Medical history and onset-to-treatment time are readily available, and computed tomography 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.


For more information about the VISTA studies and publications, please visit: