Table of Contents  

Brainin: Update on acute stroke therapy

Acute stroke therapy update

A few decades ago, stroke was considered largely untreatable. In the 1980s, large studies showed that aspirin, given in the acute setting for 10 days, reduces the risk of recurrent stroke. There followed the development of an armamentarium of other antithrombotics for long-term use. All were shown to be effective for stroke prevention showing an efficiency of 1–2% per year. The incidence of recurrent stroke is estimated at 4–5% per year, which shows that these effect sites are important.

Since then, acute stroke therapy has developed enormously and treatment is now provided on acute stroke units, and comprises intravenous thrombolysis and, more recently, endovascular thrombectomy. Fluid, electrolyte and blood pressure management, as well as swallowing assessment, protective intubation and artificial ventilation, and, in selected cases, hibernation, improve outcomes in both ischaemic and haemorrhagic stroke.

The principles of all therapeutic measures are based on rapid recognition of symptoms, treatment as a medical emergency, avoidance of intrahospital delays and early prevention and treatment of complications such as aspiration and pneumonia.

‘Time is brain’ has become the universal credo of acute therapy and, indeed, all outcomes are strongly time dependent (in ischaemia, 2 million neurons are lost per minute).

This time criticality results from the pathophysiology of the penumbra, the area of potential salvageable brain tissue surrounding an ischaemic area. This tissue becomes unsalvageable within a short period, with necrosis and apoptosis manifesting within a few hours; rarely this time may be extended to a day or two.

Measures to reduce intrahospital delays have been studied and can result in a powerful reduction in time to treatment. Most importantly, as shown in cohort studies, shortening the length of time it takes to transport the patient to and from the initial computerized tomography (CT) unit is quite effective in improving patient outcomes. In addition, the ready availability of thrombolytic agents and commencing therapy while the patient is still on the CT table lead to better outcomes. While thrombolysis with a recombinant tissue plasminogen activator has been shown effective when applied 4.5 hours of stroke onset, commencing treatment within the ‘golden’ hour (within 90 minutes of onset) doubles the improvement rates of patients without increasing haemorrhagic side-effects.

All major scientific societies have published guidelines that include recommendations for the effective set-up of stroke units for the treatment of acute stroke.13

In Austria, for example, stroke units were established in the early 1990s and conform to evidence-based guidelines (see Figure 1). Transport times to a stroke unit are now under 45 minutes, which is unique at a national level. Today, there are 38 stroke units serving 8 million inhabitants. Even the mountain regions are now covered, partly with the assistance of helicopters. The short median onset to treatment time allows for a total intravenous thrombolysis rate of 20%. If the contraindications for thrombolysis are considered, the actual rate is greater than 60%. Detailed studies of stroke severity, prehospital transport mode, among others, have been reported in detail.4

FIGURE 1

Meta-analysis of all thrombectomy trials versus i.v. thrombolysis shows a clear benefit for thrombectomy in ischaemic strokes with proximal occlusions (M1 middle cerebral artery segment or carotid T occlusions).

8-4-7-fig1.jpg

For many years it was thought that development of drugs with a neuroprotective capacity was feasible, and that these would prolong the survival of the tissue at risk of becoming necrotic. Unfortunately, until today, it was not possible to find sufficient proof of this. A larger number of medications have been tested for their neuroprotective capacity and none of them was clearly shown to be effective.5 This was disappointing for researchers, clinicians and the industry alike, and today it is largely thought that the main reason for this lack of conclusive information was because of how the preclinical research phase was designed. It is now held that the preceding animal research was not sufficient to justify phase III clinical trials, mostly because the animals that were selected were young and healthy rather than aged and hypertensive, the wrong ischaemia model was selected in such animals and the delay in reperfusion was disregarded, despite, inevitably, playing a role in human real-life situations.6

More recently, endovascular therapy studies in acute ischaemic stroke have been performed and have unequivocally reported favourable results. Using a stent-retrieving device for M1 and carotid T occlusions, the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) study was the first to report a good outcome. In this study, ischaemic stroke patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 17 were randomly allocated to endovascular therapy (within 6 hours) or intravenous (i.v.) thrombolysis (within 4.5 hours): the proportion of patients achieving a good outcome at day 90, defined as a modified Rankin Scale (mRS) score of 0–2 (which denotes a state between complete cure and minimal disability), was 33% and 19%, respectively, which was clearly significant.7

Details of other studies that followed are listed in Table 1,810 and the results of a meta-analysis of all studies comparing thrombectomy with thrombolysis are shown in Figure 1; thrombectomy was clearly superior to i.v. thrombolysis in large-vessel occlusion cases.11

TABLE 1

Randomized endovascular acute stroke studies performed to date. The essential features of the trial design and results are shown

MR CLEAN SWIFT PRIME EXTEND-IA ESCAPE
No. of centres (no. of participants in intervention group) 16 centres (n = 233) 39 centres (n = 98) 14 centres (n = 35) 22 centres (n = 165)
Mean age of participants (years) 65.8 65.0 68.6 71.0
NIHSS score 17 (14–21) 17 (13–20) 17 (13–20) 16 (13–20)
Klinisches syndrome 100% anterior circulation 100% anterior circulation 100% anterior circulation 100% anterior circulation
Time from stroke onset To groin puncture: 260 minutes To groin puncture: 224 minutes To groin puncture: 210 minutes To first reperfusion: 241 minutes
mRS 0–2 at 90 days 32.6% vs. 19.1% for control 60% vs. 36% for control (NNT 4) 71% vs. 40% for control 53% vs. 29.3% for control
Mortality at 90 days 21% (control 22%) 9% (control 12%) 9% (control 20%) 10.4% (control 19%)
sICH 7.7% (control 6.4%) 0% (control 3%) 0% (control 6%) 3.6% (control 2.7%)
TICI 2b/3 No occlusion on follow up CTA: 75.4% 88% 86% 72.4%

CTA, computerized tomography angiography; ESCAPE, Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times; EXTEND-IA, Extending the Time for Thrombolysis in Emergency Neurological Deficits – Intra-Arterial; NNT, number needed to treat; sICH, symptomatic intracerebral haemorrhage (severe adverse effect); SWIFT PRIME, *Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke; TICI, thrombolysis in cerebral infarction; TICI 2b/3, denotes complete or near complete recanalization of occluded vessel.

*Solitare™ FR revascularization device (Medtronic, Minneapolis, MN, USA).

Early recurrent strokes aggravate the neurological deficits of the index stroke and are associated with a longer duration of hospitalization and reduced functional outcome. For most patients, current guidelines recommend a medium dose of aspirin in the acute phase after ischaemic stroke. In contrast, however, the use of dual- or triple-antiplatelet therapy is standard practice for acute coronary syndrome. Early trials of dual antiplatelet therapy for secondary stroke prevention found no benefit but an increased risk of haemorrhages compared with monotherapy. Recently the randomized Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial showed that Chinese patients with transient ischaemic attack (TIA) or minor ischaemic strokes (defined as NIHSS ≤ 3), at moderate to high risk of recurrent stroke [defined as ABCD² (age, blood pressure, clinical features, duration of TIA and presence of diabetes mellitus) score ≥ 4], benefited when treated within 24 hours for 21 days with dual therapy (clopidogrel and aspirin) compared with aspirin alone.12 Stroke recurrence within 90 days was 8.2% in the clopidogrel–aspirin group compared with 11.7% in the aspirin group, without increased risk of haemorrhages in the dual therapy group.12 The advantage of the dual-agent treatment was apparent during the first few days and was retained over the next year.13 A meta-analysis of 14 studies, mainly driven by the CHANCE trial, which contributed more than half of the patients, supports the conclusion that dual therapy is more effective than monotherapy in reducing the risk of early recurrent stroke.14 The results of two ongoing studies, Platelet-Oriented Inhibition in New TIA (POINT) and Triple Antiplatelets for Reducing Dependency After Ischemic Stroke (TARDIS), will give more information on the generalizability of the results of the CHANCE trial.

Intracerebral haemorrhage is associated with high early case fatality and poor functional outcome.

Blood pressure lowering in acute intracerebral haemorrhage (ICH) might be a promising approach. The randomized Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT-2) investigated the effect of intensive blood pressure reduction (defined as a target systolic level of < 140 mmHg within 1 hour) compared with guideline-based standard treatment (target systolic level of < 180 mmHg). The group differences were non-significant for the dichotomous analysis of the primary outcome death or major disability (defined as mRS score 3–6) at 90 days: 52.0% receiving intensive treatment, compared with 55.6% receiving standard treatment [odds ratio (OR) 0.87; 95% confidence interval (CI) 0.75–1.01; P = 0.06]. However, the prespecified ordinal analysis showed significantly lower mRS scores with intensive blood pressure lowering (OR 0.87; 95% CI 0.77–1.00; P = 0.04).15

The haemostatic drug recombinant activated factor VII (rFVIIa) was found to reduces haematoma growth, as shown in a meta-analysis, but does not improve patient survival or functional outcome.16

Early surgical haematoma evacuation within 12  hours of randomization plus medical treatment, compared with medical treatment alone, did not result in more favourable outcome in patients with lobar ICH in the second Surgical Trial in Lobar Intracerebral Hemorrhage (STICH-II trial).17 However, a meta-analysis of 15 trials, including STICH-II, suggests that surgery for ICH in any location was superior to conservative treatment, but there was significant heterogeneity between the trials.17

In summary, therapy of acute stroke has made significant advances. The set-up of acute stroke units allows the establishment of thrombolysis as an effective therapy across regions or whole countries. The addition of endovascular therapy for acute stroke demands the setup of specialized stroke centres that are able to perform catheter interventions 24 hours a day and 7 days a week.

References

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Reiner-Deitemyer V, Teuschl Y, Matz K, et al. Helicopter transport of stroke patients and its influence on thrombolysis rates. Stroke 2011; 42:1295–1300. http://dx.doi.org/10.1161/STROKEAHA.110.604710

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O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol 2006; 59:467–77.

6. 

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7. 

Berkhemer OA, Fransen PS, Beumer D, et al.; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372:11–20. http://dx.doi.org/10.1056/NEJMoa1411587

8. 

Saver JL, Goyal M, Bonafe A, et al.; SWIFT PRIME Investigators. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med 2015; 372:2285–95. http://dx.doi.org/10.1056/NEJMoa1415061

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Campbell BC, Mitchell PJ, Kleinig TJ, et al.; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372:1009–18. http://dx.doi.org/10.1056/NEJMoa1414792

10. 

Goyal M, Demchuk AM, Menon BK, et al.; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372:1019–30. http://dx.doi.org/10.1056/NEJMoa1414905

11. 

Wahlgren N, Moreira T, Michel P, et al. ESO–KSU, ESO, ESMINT, ESNT and EAN: Mechanical thrombectomy in acute ischemic stroke: Consensus statement. Int J Stroke; in press.

12. 

Wang Y, Wang Y, Zhao X, et al.; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369:11–19. http://dx.doi.org/10.1056/NEJMoa1215340

13. 

Wang Y, Pan Y, Zhao X, et al.; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack (CHANCE) trial: one-year outcomes. Circulation 2015; 132:40–6. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014791

14. 

Wong KS, Wang Y, Leng X, et al. Early dual versus mono antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis. Circulation 2013; 128:1656–66. http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003187

15. 

Anderson CS, Heeley E, Huang Y, et al.; INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355–65. http://dx.doi.org/10.1056/NEJMoa1214609

16. 

Yuan ZH, Jiang JK, Huang WD, Pan J, Zhu JY, Wang JZ. A meta-analysis of the efficacy and safety of recombinant activated factor VII for patients with acute intracerebral hemorrhage without hemophilia. J Clin Neurosci 2010; 17:685–93. http://dx.doi.org/10.1016/j.jocn.2009.11.020

17. 

Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM; STICH II Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382:397–408. http://dx.doi.org/10.1016/S0140-6736(13)60986-1


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