NIHR Signal Surgical clot removal within seven hours of stroke improves function

Published on 13 December 2016

For ischaemic stroke caused by a blood clot, early surgical clot removal alongside medical treatment improves functional outcomes at three months compared with medical treatment alone.

Urgent stroke treatment is known to improve outcomes. Endovascular thrombectomy is a relatively new technique to mechanically remove the clot, where this is possible. Uncertainty over the optimal timing of the procedure led to this review.

This analysis of 1,287 patients in five trials found that endovascular thrombectomy improves outcomes only if performed within seven hours of initial stroke symptoms. The earlier that the clot was removed the better; the minimum “time to treatment” in the trials was 3 hours. Functional benefits lasting longer than three months are not yet known.

Current UK guidelines support endovascular thrombectomy if performed within five hours of stroke onset, so this review adds strong evidence to support the approach.

Hospitals need to have the resources, training and expertise in place to deliver this intervention. The findings reinforce the need for rapid hospital transfer and diagnosis so that patients eligible for the procedure can be treated as soon as possible.

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Why was this study needed?

Around 152,000 people in England have a stroke every year, and most of these (85%) are caused by a blood clot (ischaemic). Endovascular thrombectomy aims to remove the clot, restore blood flow to the blocked area (reperfusion) and limit the brain damage caused.

Five individual randomised controlled trials demonstrated that endovascular thrombectomy improves functional outcomes at three months. Until now, the trial results had not been pooled and the optimal timing of the procedure was unclear. Normally clot removal is recommended within six hours of initial stroke symptoms, but some international guidelines suggest it can still be undertaken up to eight or 12 hours.

The researchers of those five individual trials decided to pool their patient level data to determine the time-window in which endovascular thrombectomy gives most benefit, and see to what extent treatment delay is associated with poorer outcomes.

What did this study do?

This review pooled individual patient data from 1,287 adults with ischaemic stroke included in five existing randomised controlled trials with timed outcomes.

The trials compared endovascular thrombectomy plus standard medical therapy with medical therapy alone. Standard therapy included intravenous clot-busting drugs (thrombolysis) if indicated, though slightly fewer in the intervention arm received this (83% vs. 87% of controls).

The main outcome of interest was degree of disability at three months assessed using the modified Rankin Scale (mRS). Scores range from 0 to 6 with lower scores indicating less disability. Other outcomes included functional independence (mRS score 0 to 2), death and bleeding in the brain.

All trials were assessed as low risk of bias, although patients were aware of treatment given, and four trials finished early due to positive results.

What did it find?

  • Endovascular thrombectomy improved disability scores at three months compared with medical therapy alone.  Groups were similar at baseline. The average mRS score at 90 days was 2.9 (95% confidence interval [CI] 2.7 to 3.1) compared to 3.6 (95% CI 3.5 to 3.8) with standard medical therapy.
  • Average time from symptom onset to start of endovascular thrombectomy was four hours. The chance of improved disability scores compared with medical therapy declined with increasing time to treatment initiation. For example, treatment at three hours gave 2.79 improved odds (95% CI 1.96 to 3.98) while treatment at six hours gave 1.98 improved odds (95% CI 1.30 to 3.0). Thrombectomy no longer gave any statistically significant benefit if delayed to eight hours (odds ratio 1.57, 95% CI 0.86 to 2.88).
  • Researchers calculated that endovascular thrombectomy conclusively improved outcomes compared with medical therapy only if started up to 7 hours and 18 minutes after symptom onset.
  • The chance of functional independence (mRS score 2 or less) at three months similarly declined with increasing time from symptom onset to reperfusion. Rates of functional independence were 64.1% with thrombectomy at three hours compared to 46.1% with thrombectomy at 8 hours.
  • Time from symptom onset to reperfusion did not affect rates of death or bleeding into the brain.

What does current guidance say on this issue?

NICE 2008 guidelines on management of stroke states that urgent treatment improves outcomes. NICE 2016 procedural guidance on mechanical removal of clots confirms that the procedure can be a safe and effective treatment option. For appropriate patients, it should be delivered by trained staff within a well organised stroke service.

The Royal College of Physician’s 2016 guidelines on management of stroke state how endovascular therapy has been a major area of development since 2012. If indicated by brain imaging, combined thrombolysis and endovascular thrombectomy is recommended if the procedure can begin within five hours of symptom onset. In very specific circumstances, depending on clot location and if imaging shows salvageable brain tissue, this may be performed up to 12 or 24 hours after onset.

What are the implications?

This pooled data highlights the need for urgent assessment, diagnosis and treatment within stroke care. Endovascular thrombectomy can improve functional outcomes, but only if initiated within seven hours of onset of stroke symptoms. The sooner the procedure can be started, the greater the benefit within this windows. Longer term benefits in function beyond three months are not yet known.

Endovascular thrombectomy needs to be delivered within a well-organised stroke service. For hospitals that have the ability to deliver this intervention there are resource implications. Hyper-acute stroke services will need round the clock intervention teams, and these plus the support staff will need training in the procedure. Hospitals may need to refine their policies around speed of care and develop performance indicators.

Citation and Funding

Saver JL, Goyal M, van der Lugt A, et al; HERMES Collaborators. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA. 2016;316(12):1279-88.

This project was funded by a grant from Medtronic to the University of Calgary.

Bibliography

Intercollegiate Stroke Working Party. National clinical guideline for stroke. Fifth edition. Royal College of Physicians; 2016.

NHS Choices. Stroke. London: Department of Health; 2014.

NICE. Mechanical clot retrieval for treating acute ischaemic stroke. IPG 548. London: National Institute for Health and Care Excellence; 2016.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2008.

White PM, Bhalla A, Dinsmore J, et al, on behalf of British Association of Stroke Physicians, British Society of Neuroradiologists, Intercollegiate Stroke Working Party, Neuroanaesthesia and Neurocritical Care Society of GB & Ireland, UK Neurointerventional Group. Standards for providing safe acute ischaemic stroke thrombectomy. BASP. 2015.

Why was this study needed?

Around 152,000 people in England have a stroke every year, and most of these (85%) are caused by a blood clot (ischaemic). Endovascular thrombectomy aims to remove the clot, restore blood flow to the blocked area (reperfusion) and limit the brain damage caused.

Five individual randomised controlled trials demonstrated that endovascular thrombectomy improves functional outcomes at three months. Until now, the trial results had not been pooled and the optimal timing of the procedure was unclear. Normally clot removal is recommended within six hours of initial stroke symptoms, but some international guidelines suggest it can still be undertaken up to eight or 12 hours.

The researchers of those five individual trials decided to pool their patient level data to determine the time-window in which endovascular thrombectomy gives most benefit, and see to what extent treatment delay is associated with poorer outcomes.

What did this study do?

This review pooled individual patient data from 1,287 adults with ischaemic stroke included in five existing randomised controlled trials with timed outcomes.

The trials compared endovascular thrombectomy plus standard medical therapy with medical therapy alone. Standard therapy included intravenous clot-busting drugs (thrombolysis) if indicated, though slightly fewer in the intervention arm received this (83% vs. 87% of controls).

The main outcome of interest was degree of disability at three months assessed using the modified Rankin Scale (mRS). Scores range from 0 to 6 with lower scores indicating less disability. Other outcomes included functional independence (mRS score 0 to 2), death and bleeding in the brain.

All trials were assessed as low risk of bias, although patients were aware of treatment given, and four trials finished early due to positive results.

What did it find?

  • Endovascular thrombectomy improved disability scores at three months compared with medical therapy alone.  Groups were similar at baseline. The average mRS score at 90 days was 2.9 (95% confidence interval [CI] 2.7 to 3.1) compared to 3.6 (95% CI 3.5 to 3.8) with standard medical therapy.
  • Average time from symptom onset to start of endovascular thrombectomy was four hours. The chance of improved disability scores compared with medical therapy declined with increasing time to treatment initiation. For example, treatment at three hours gave 2.79 improved odds (95% CI 1.96 to 3.98) while treatment at six hours gave 1.98 improved odds (95% CI 1.30 to 3.0). Thrombectomy no longer gave any statistically significant benefit if delayed to eight hours (odds ratio 1.57, 95% CI 0.86 to 2.88).
  • Researchers calculated that endovascular thrombectomy conclusively improved outcomes compared with medical therapy only if started up to 7 hours and 18 minutes after symptom onset.
  • The chance of functional independence (mRS score 2 or less) at three months similarly declined with increasing time from symptom onset to reperfusion. Rates of functional independence were 64.1% with thrombectomy at three hours compared to 46.1% with thrombectomy at 8 hours.
  • Time from symptom onset to reperfusion did not affect rates of death or bleeding into the brain.

What does current guidance say on this issue?

NICE 2008 guidelines on management of stroke states that urgent treatment improves outcomes. NICE 2016 procedural guidance on mechanical removal of clots confirms that the procedure can be a safe and effective treatment option. For appropriate patients, it should be delivered by trained staff within a well organised stroke service.

The Royal College of Physician’s 2016 guidelines on management of stroke state how endovascular therapy has been a major area of development since 2012. If indicated by brain imaging, combined thrombolysis and endovascular thrombectomy is recommended if the procedure can begin within five hours of symptom onset. In very specific circumstances, depending on clot location and if imaging shows salvageable brain tissue, this may be performed up to 12 or 24 hours after onset.

What are the implications?

This pooled data highlights the need for urgent assessment, diagnosis and treatment within stroke care. Endovascular thrombectomy can improve functional outcomes, but only if initiated within seven hours of onset of stroke symptoms. The sooner the procedure can be started, the greater the benefit within this windows. Longer term benefits in function beyond three months are not yet known.

Endovascular thrombectomy needs to be delivered within a well-organised stroke service. For hospitals that have the ability to deliver this intervention there are resource implications. Hyper-acute stroke services will need round the clock intervention teams, and these plus the support staff will need training in the procedure. Hospitals may need to refine their policies around speed of care and develop performance indicators.

Citation and Funding

Saver JL, Goyal M, van der Lugt A, et al; HERMES Collaborators. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA. 2016;316(12):1279-88.

This project was funded by a grant from Medtronic to the University of Calgary.

Bibliography

Intercollegiate Stroke Working Party. National clinical guideline for stroke. Fifth edition. Royal College of Physicians; 2016.

NHS Choices. Stroke. London: Department of Health; 2014.

NICE. Mechanical clot retrieval for treating acute ischaemic stroke. IPG 548. London: National Institute for Health and Care Excellence; 2016.

NICE. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. CG68. London: National Institute for Health and Care Excellence; 2008.

White PM, Bhalla A, Dinsmore J, et al, on behalf of British Association of Stroke Physicians, British Society of Neuroradiologists, Intercollegiate Stroke Working Party, Neuroanaesthesia and Neurocritical Care Society of GB & Ireland, UK Neurointerventional Group. Standards for providing safe acute ischaemic stroke thrombectomy. BASP. 2015.

Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis

Published on 28 September 2016

Saver, J. L.,Goyal, M.,van der Lugt, A.,Menon, B. K.,Majoie, C. B.,Dippel, D. W.,Campbell, B. C.,Nogueira, R. G.,Demchuk, A. M.,Tomasello, A.,Cardona, P.,Devlin, T. G.,Frei, D. F.,du Mesnil de Rochemont, R.,Berkhemer, O. A.,Jovin, T. G.,Siddiqui, A. H.,van Zwam, W. H.,Davis, S. M.,Castano, C.,Sapkota, B. L.,Fransen, P. S.,Molina, C.,van Oostenbrugge, R. J.,Chamorro, A.,Lingsma, H.,Silver, F. L.,Donnan, G. A.,Shuaib, A.,Brown, S.,Stouch, B.,Mitchell, P. J.,Davalos, A.,Roos, Y. B.,Hill, M. D.

Jama Volume 316 , 2016

IMPORTANCE: Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of treatment time with outcomes would help to guide implementation. OBJECTIVE: To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS: Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES: Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS: Among all 1287 patients (endovascular thrombectomy + medical therapy [n = 634]; medical therapy alone [n = 653]) enrolled in the 5 trials (mean age, 66.5 years [SD, 13.1]; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 [95% CI, 0.76 to 0.93]; ARD, -6.7%) and less functional independence (OR, 0.81 [95% CI, 0.71 to 0.92], ARD, -5.2% [95% CI, -8.3% to -2.1%]), but no change in mortality (OR, 1.12 [95% CI, 0.93 to 1.34]; ARD, 1.5% [95% CI, -0.9% to 4.2%]). CONCLUSIONS AND RELEVANCE: In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.

The modified Rankin Scale (mRS) runs from 0 to 6, Zero being perfect health without symptoms and six equivalent to death.

  1. No symptoms.
  2. No significant disability. Able to carry out all usual activities, despite some symptoms.
  3. Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
  4. Moderate disability. Requires some help, but able to walk unassisted.
  5. Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
  6. Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
  7. Dead.

Expert commentary

Thrombectomy is a disruptive innovation which is highly effective in an ischaemic stroke caused by a large vessel occlusion. Time is critically important. For every 15 minutes earlier treatment is delivered to 100 patients, four avoid long term disability. It took 15 years for the NHS to develop hyper-acute stroke services that rapidly deliver intravenous thrombolysis after trial evidence of efficacy. Delivering thrombectomy is a greater challenge because of the need to develop new 24/7 stroke interventional teams. The JAMA paper tells us the NHS needs to confront inter-professional turf wars over who should deliver thrombectomy, and invest in developing integrated hyper-acute care pathways and teams that can rapidly deliver thrombectomy - we cannot afford the alternative of long term disability.

Professor Gary A Ford, Chief Executive Officer, Oxford Academic Health Science Network; Consultant Physician, Oxford University Hospitals NHS Foundation Trust; Visiting Professor of Clinical Pharmacology, University of Oxford