Studies & registries

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.

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

Rationale

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.
 

Objectives

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

Results

• 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
   

Conclusion

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
   

Rationale

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.
 

Objectives

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.
 

Results

• 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.
   

Conclusion

• 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.
   

Rationale

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 probability 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.
 

Objectives

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.
 

Results

• 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.
   

Conclusion

• 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.
   

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.
   

Conclusion

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

Rationale

• 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.
   

Objective

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 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.
 

Conclusion

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.
 

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 3h
  ●  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.
   

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

ENCHANTED study

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

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 outcomes^1,2

• 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

Rationale

• 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.

Objective

• 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

Results

• 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

*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

• 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

Conclusions

• 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

Rationale

• 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

Objective

• 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

Overview

• 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.