Recanalisation therapies for wake-up stroke
This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the efficacy and safety of intravenous thrombolytic drug therapies and other recanalisation therapies for acute ischaemic stroke presenting upon awakening.
Acute ischaemic stroke is a major cause of mortality and morbidity worldwide (Lozano 2012). Intravenous thrombolysis and other recanalisation therapies may restore perfusion and improve clinical outcomes if given within a few hours after stroke onset (Wardlaw 2012).
About one in five strokes occur during sleep (Bassetti 1999). Individuals with stroke symptoms presenting on awakening have traditionally been considered ineligible for thrombolytic treatment because the time of stroke onset is unknown. However, these people may benefit from thrombolytic treatment if the onset of stroke was shortly before awakening. Several studies suggest that the onset of stroke during sleep is close to awakening, and that people with wake-up stroke and people with stroke onset within 4.5 hours of waking share many clinical findings and findings on brain imaging (Roveri 2011; Silva 2010). Registry studies suggest that intravenous thrombolysis is safe in people with wake-up stroke (Barreto 2009; Manawadu 2013; Meretoja 2010), but the efficacy and safety of intravenous thrombolysis and other recanalisation therapies in people with acute ischaemic stroke on awakening have not been established.
The benefits of intravenous thrombolytic therapy and intra-arterial stroke therapy have been assessed in other reviews (O'Rourke 2010; Wardlaw 2012). However, the benefit of recanalisation therapies in people with wake-up stroke may differ from that in people with stroke whilst awake because the onset of stroke in wake-up stroke is unknown and because changes in cerebral blood flow and metabolism occur throughout the sleep-wake cycle (Madsen 1991).
We aim to perform a systematic review of all randomised controlled trials (RCTs) of intravenous thrombolysis and other recanalisation therapies versus control in people with acute ischaemic stroke presenting on awakening.
Description of the condition
Stroke is globally the second leading cause of death (Lozano 2012) and the third leading cause of loss of disability-adjusted life-years (Murray 2012). Most strokes are caused by blockage of an intracranial artery by a clot (ischaemic stroke).
Description of the intervention
Recanalisation therapies for acute ischaemic stroke include intravenous administration of thrombolytic drugs and intra-arterial therapies.
Thrombolytic drugs given intravenously are used most commonly and work by dissolving blood clots. These drugs include urokinase, recombinant pro-urokinase (rpro-UK), streptokinase (SK) and recombinant tissue plasminogen activator (rt-PA) including alteplase, duteplase, lumbrokinase, tenecteplase, reteplase and desmoteplase. Alteplase is the only thrombolytic drug with a licence for treating acute ischaemic stroke up to 4.5 hours after symptom onset. The recommended dose of alteplase is 0.9 mg per kg of body weight (maximum 90 mg), with 10% as a bolus and the rest infused intravenously over 60 minutes.
Intra-arterial therapies include administration of thrombolytic drugs through an intra-arterial catheter, mechanical thrombus disruption using a microcatheter or guidewire, angioplasty and the use of endovascular devices. The benefit of mechanical thrombus disruption and endovascular devices is covered in another Cochrane review (O'Rourke 2010). Our review differs from O'Rourke 2010 in that we include only people with wake-up strokes.
How the intervention might work
Interventions may restore perfusion to the ischaemic brain parenchyma, which may reduce damage to the brain parenchyma and improve clinical outcome.
Why it is important to do this review
Intravenous thrombolysis with alteplase is the only approved reperfusion therapy for acute ischaemic stroke. Currently, only a minority of stroke patients are treated because of strict inclusion criteria. About one in five strokes occur during sleep; these people are ineligible for thrombolytic drug therapy because the time of stroke onset is unknown. However, they may benefit from reperfusion therapies if stroke onset was shortly before awakening.
The efficacy and safety of intravenous thrombolytic drugs and intra-arterial treatments in people with acute ischaemic stroke upon awakening have not been established. If recanalisation therapies provide any benefit for these individuals, the proportion of stroke patients who might benefit from such treatments could be increased.
To assess the efficacy and safety of intravenous thrombolytic drug therapies and other recanalisation therapies for acute ischaemic stroke presenting upon awakening.
Criteria for considering studies for this review
Types of studies
We will include RCTs.
Types of participants
People with acute ischaemic stroke presenting upon awakening (with neuroimaging excluding intracranial haemorrhage before randomisation). If a trial has recruited both people with wake-up strokes and those with strokes that occur whilst the individual is awake, we will contact the trial authors to request data on only those with wake-up strokes. If these data are unavailable, we will not include the trial.
Types of interventions
We will include all types of thrombolytic drugs, given in any dose by intravenous route: urokinase, rpro-UK, SK and rt-PA including alteplase, duteplase, lumbrokinase, tenecteplase and desmoteplase.
We will include all types of intra-arterial treatments: administration of thrombolytic drugs through intra-arterial catheters, mechanical thrombus disruption using a microcatheter or guidewires or both, angioplasty and the use of endovascular devices.
The comparison therapy will be standard medical care or placebo.
Types of outcome measures
Functional outcome at the end of the follow-up period. We will define favourable functional outcome as a modified Rankin scale (mRS) score of 0 to 2. If the mRS score is not reported, we will use the trial's definition of functional outcome.
Death from all causes within seven to 14 days and at the end of follow-up.
Symptomatic intracranial haemorrhage within seven to 14 days.
Quality of life at the end of follow-up.
Neurological status at seven to 14 days and at the end of follow-up.
Search methods for identification of studies
See the 'Specialized register' section in the Cochrane Stroke Group module. We will search for trials in all languages and will arrange for the translation of relevant articles when necessary.
We will search the Cochrane Stroke Group trials register and the following electronic databases.
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue).
MEDLINE (from 1948) (Appendix 1).
EMBASE (from 1980).
We developed the MEDLINE search strategy with the help of the Cochrane Stroke Group Trials Search Co-ordinator and will adapt it for the other databases.
We will search the following ongoing trials registers.
Searching other resources
In an effort to identify further published, unpublished and ongoing trials, we will:
screen reference lists of relevant trials;
contact principal investigators of identified trials;
use the Science Citation Index Cited Reference search for forward tracking of relevant references;
identify and handsearch the proceedings of relevant conferences; and
contact manufacturers of relevant devices and equipment.
Data collection and analysis
Selection of studies
One review author (HL) will independently screen titles and abstracts of references obtained as a result of our searching activities and will exclude obviously irrelevant reports. We will retrieve the full-text articles for the remaining references, and two review authors (HL and EBM) will independently screen the full-text articles and identify studies for inclusion; they will also identify and record reasons for exclusion of ineligible studies. We will resolve disagreements through discussion, or, if required, we will consult a third person (EB). We will collate multiple reports of the same study so that each study, not each reference, is the unit of interest in the review. We will record the selection process and will complete a PRISMA flow diagram.
Data extraction and management
Two review authors (HL and EBM) will independently extract data from the report of each eligible trial onto a specially designed data extraction form. These review authors will not be blinded to journal or institution.
We will extract the following data from each report.
We will extract the numbers of participants in the intervention and control groups who:
died within the first seven to 14 days;
died at the end of follow-up;
developed symptomatic intracranial haemorrhage within the first seven to 14 days after stroke; and
were independent (mRS score 0 to 2) at three months or end of follow-up. If possible, we will also extract the number of participants in each mRS category.
One review author (HL) will enter the data into the Cochrane Review Manager software, RevMan (RevMan 2012). Another review author (EB) will check these data against the hard copy data extraction forms to correct any clerical data entry errors. If any relevant data are missing from the available publications, we will make direct contact with the relevant principal investigators.
Assessment of risk of bias in included studies
Two review authors (HL and EBM) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements by discussion or by involving another review author (EB). We will assess the risk of bias according to the following domains.
Random sequence generation.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
We will grade the risk of bias for each domain as high, low or unclear and will provide information from the study report together with a justification for our judgement in the 'Risk of bias' tables.
Measures of treatment effect
For dichotomous outcomes, we will calculate a weighted estimate of treatment effects across trials and will report odds ratios (ORs) with 95% confidence intervals (CIs). When continuous scales of measurement are used to assess the effects of treatment, we will use the mean difference (MD). For studies that use different scales for assessment of similar outcomes, we will report standardised mean differences (SMDs).
Dealing with missing data
If the published information does not allow intention-to-treat analysis, we will contact the study authors to ask for follow-up data as complete as possible on all randomly assigned participants for the originally proposed period of follow-up. If the data on these participants remain unavailable, we will provide a worst-case scenario analysis for the composite outcome of 'death and severe disability'. In this sensitivity analysis, it is assumed that participants who were lost to follow-up in the treatment group had the worst outcomes and participants who were lost to follow-up in the control group had the best outcomes.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. We will assess heterogeneity according to Chapter 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of reporting biases
We will use funnel plots to assess reporting bias.
We will calculate a weighted estimate of the typical treatment effect across trials by means of a random-effects model.
Subgroup analysis and investigation of heterogeneity
When possible, we will perform separate analyses in the following subgroups.
Participants characterised by specific imaging criteria (e.g. findings of ischaemic penumbra).
Participants treated at different time intervals (e.g. within three hours after awakening or longer than three hours after awakening).
We will perform a sensitivity analysis to test whether results differ when we exclude trials with high risk of bias.
We thank Brenda Thomas from the Cochrane Stroke Group for developing the MEDLINE search strategies used in the review.
Appendix 1. MEDLINE search strategy
This search strategy will be adapted for the other databases.
1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or brain ischemia/ or exp brain infarction/ or hypoxia-ischemia, brain/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid artery, internal, dissection/ or intracranial arterial diseases/ or cerebral arterial diseases/ or infarction, anterior cerebral artery/ or infarction, middle cerebral artery/ or infarction, posterior cerebral artery/ or exp "intracranial embolism and thrombosis"/ or exp stroke/ or vertebral artery dissection/
2. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw.
3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw.
4. 1 or 2 or 3
5. wakefulness/ or sleep/
6. (wake up or wake-up or wakes up or wakes-up).tw.
7. (waking$ or awake$ or awoke).tw.
8. (during adj5 sleep$).tw.
9. (whil$ adj5 (sleep$ or asleep)).tw.
10. ((unknown or unclear or uncertain or indefinite or "not known") adj10 onset).tw.
11. 5 or 6 or 7 or 8 or 9 or 10
12. thrombolytic therapy/
13. fibrinolytic agents/ or fibrinolysin/ or plasminogen/ or tissue plasminogen activator/ or exp plasminogen activators/ or urokinase-type plasminogen activator/ or exp streptokinase/
15. (thromboly$ or fibrinoly$ or recanalis$ or recanaliz$).tw.
16. ((clot$ or thrombus) adj5 (lyse or lysis or dissolve$ or dissolution or bust$)).tw.
17. (tPA or t-PA or rtPA or rt-PA or plasminogen or plasmin or alteplase or actilyse).tw.
18. (tPA or t-PA or rtPA or rt-PA or plasminogen or plasmin or alteplase or actilyse).nm.
19. (anistreplase or streptodornase or streptokinase or urokinase or pro?urokinase or rpro?uk or lumbrokinase or duteplase or lanoteplase or pamiteplase or reteplase or saruplase or staphylokinase or streptase or tenecteplase or desmoteplase or amediplase or monteplase or nasaruplase or silteplase).tw.
20. (anistreplase or streptodornase or streptokinase or urokinase or pro?urokinase or rpro?uk or lumbrokinase or duteplase or lanoteplase or pamiteplase or reteplase or saruplase or staphylokinase or streptase or tenecteplase or desmoteplase or amediplase or monteplase or nasaruplase or silteplase).nm.
21. radiography, interventional/ or radiology, interventional/
22. catheterization/ or angioplasty/ or angioplasty, balloon/ or angioplasty, balloon, laser-assisted/ or angioplasty, laser/ or atherectomy/ or balloon dilatation/ or catheter ablation/
24. mechanical thrombolysis/ or thrombectomy/ or embolectomy/
25. blood vessel prosthesis/ or blood vessel prosthesis implantation/
26. Cerebral Revascularization/ or reperfusion/ or dilatation/
27. (interventional adj3 (radiolog$ or radiograph$ or neuroradiolog$)).tw.
28. (angioplast$ or stent$).tw.
29. (thrombectomy or embolectomy or atherect$).tw.
30. (thromboaspiration or arterial recanali?ation).tw.
31. ((mechanical or radiolog$ or pharmacomechanical or laser or endovascular or neurovascular) adj5 (thrombolys$ or reperfusion or fragmentation or aspiration or recanali?ation or clot lys$)).tw.
32. ((clot or thrombus or thrombi or embol$) adj5 (aspirat$ or remov$ or retriev$ or fragment$ or retract$ or extract$ or obliterat$ or dispers$ or disrupt$ or disintegrate$)).tw.
33. ((retrieval or extraction) adj5 device$).tw.
34. endoluminal repair$.tw.
35. (blood vessel adj5 (prosthesis or implantat$)).tw.
36. ((merci or concentric) adj retriever).tw.
37. (endovascular snare$ or neuronet or microsnare or X-ciser or angiojet).tw.
38. ultrasonics/ or ultrasonic therapy/ or ultrasonography/ or exp ultrasonography, doppler/ or ultrasonography, interventional/
39. (ultrasound$ or ultrasonic$ or ultrasonogra$ or sonograph$ or insonation).tw.
40. ((transcranial adj5 doppler) or TCD or TCCD).tw.
42. (sonothrombolysis or sonothromboly$ or sonolys$ or sonothrombotripsy or thrombotripsy).tw.
44. 4 and 11 and 43
45. exp animals/ not humans.sh.
46. 44 not 45
Contributions of authors
HL: conception and design of the review, drafting of the protocol.
EB and EBM: conception and design of the review, commenting on protocol drafts.
Declarations of interest