Prehospital Transdermal Glyceryl Trinitrate for Ultra-Acute Intracerebral Hemorrhage: Data From the RIGHT-2 Trial.

Background and Purpose- Pilot trials suggest that glyceryl trinitrate (GTN; nitroglycerin) may improve outcome when administered early after stroke onset. Methods- We undertook a multicentre, paramedic-delivered, ambulance-based, prospective randomized, sham-controlled, blinded-end point trial in adults with presumed stroke within 4 hours of ictus. Participants received transdermal GTN (5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days in hospital. The primary outcome was the 7-level modified Rankin Scale at 90 days assessed by central telephone treatment-blinded follow-up. This prespecified subgroup analysis focuses on participants with an intracerebral hemorrhage as their index event. Analyses are intention-to-treat. Results- Of 1149 participants with presumed stroke, 145 (13%; GTN, 74; sham, 71) had an intracerebral hemorrhage: time from onset to randomization median, 74 minutes (interquartile range, 45-110). By admission to hospital, blood pressure tended to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified Rankin Scale score at 90 days was nonsignificantly higher in the GTN group: adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98-3.57). A prespecified global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) was worse with GTN; Mann-Whitney difference, 0.18 (95% CI, 0.01-0.35; Wei-Lachin test). GTN was associated with larger hematoma and growth, and more mass effect and midline shift on neuroimaging, and altered use of hospital resources. Death in hospital but not at day 90 was increased with GTN. There were no significant between-group differences in serious adverse events. Conclusions- Prehospital treatment with GTN worsened outcomes in patients with intracerebral hemorrhage. Since these results could relate to the play of chance, confounding, or a true effect of GTN, further randomized evidence on the use of vasodilators in ultra-acute intracerebral hemorrhage is needed. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN26986053.

Triple versus guideline antiplatelet therapy to prevent recurrence after acute ischaemic stroke or transient ischaemic attack: the TARDIS RCT.

BACKGROUND: Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding. OBJECTIVE: To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA. DESIGN: International prospective randomised open-label blinded end-point parallel-group superiority clinical trial. SETTING: Acute hospitals at 106 sites in four countries. PARTICIPANTS: Patients > 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke). INTERVENTIONS: Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days. MAIN OUTCOME MEASURES: The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life. RESULTS: The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, n = 1556; guideline, n = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; p = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; p = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; p = 0.88). LIMITATIONS: Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power. CONCLUSIONS: The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA. FUTURE WORK: The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47823388. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 48. See the NIHR Journal Library website for further project information. The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) vanguard phase was funded by the British Heart Foundation (grant PG/08/083/25779, from 1 April 2009 to 30 September 2012) and indirect funding was provided by the Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. There was no commercial support for the trial and antiplatelet drugs were sourced locally at each site. The trial was sponsored by the University of Nottingham.

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.

BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05-3·16, p<0·0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Baseline characteristics of the 3096 patients recruited into the 'Triple Antiplatelets for Reducing Dependency after Ischemic Stroke' trial.

Background The risk of recurrence following ischemic stroke or transient ischemic attack is highest immediately after the event. Antiplatelet agents are effective in reducing the risk of recurrence and two agents are superior to one in the early phase after ictus. Design The triple antiplatelets for reducing dependency after ischemic stroke trial was an international multicenter prospective randomized open-label blinded-endpoint trial that assessed the safety and efficacy of short-term intensive antiplatelet therapy with three agents (combined aspirin, clopidogrel and dipyridamole) as compared with guideline treatment in acute ischemic stroke or transient ischemic attack. The primary outcome was stroke recurrence and its severity, measured using the modified Rankin Scale at 90 days. Secondary outcomes included recurrent vascular events, functional measures (cognition, disability, mood, quality of life), and safety (bleeding, death, serious adverse events). Data are number (%) or mean (standard deviation, SD). Results Recruitment ran from April 2009 to March 2016; 3096 patients were recruited from 106 sites in four countries (Denmark 1.6%, Georgia 2.7%, New Zealand 0.2%, UK 95.4%). Randomization characteristics included: age 69.0 (10.1) years; male 1945 (62.8%); time onset to randomization 29.4 (11.9) h; stroke severity (National Institutes for Health Stroke Scale) 2.8 (3.6); blood pressure 143.5 (18.2)/79.5 (11.4) mmHg; IS 2143 (69.2%), transient ischemic attack 953 (30.8%). Conclusion Triple antiplatelets for reducing dependency after ischemic stroke was a large trial of intensive/triple antiplatelet therapy in acute ischemic stroke and transient ischemic attack, and included participants from four predominantly Caucasian countries who were representative of patients in many western stroke services.

Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial (ISRCTN47823388).

RATIONALE: The risk of recurrence following a stroke or transient ischemic attack is high, especially immediately after the event. HYPOTHESIS: Because two antiplatelet agents are superior to one in patients with non-cardioembolic events, more intensive treatment might be even more effective. SAMPLE SIZE ESTIMATES: The sample size of 4100 patients will allow a shift to less recurrence, and less severe recurrence, to be detected (odds ratio 0·68) with 90% power at 5% significance. METHODS AND DESIGN: Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (ISRCTN47823388) is comparing the safety and efficacy of intensive (combined aspirin, clopidogrel, and dipyridamole) vs. guideline antiplatelet therapy, both given for one-month. This international collaborative parallel-group prospective randomized open-label blinded-end-point phase III trial plans to recruit 4100 patients with acute ischemic stroke or transient ischemic attack. Randomization and data collection are performed over a secure Internet site with real-time data validation and concealment of allocation. Outcomes, serious adverse events, and neuroimaging are adjudicated centrally with blinding to treatment allocation. STUDY OUTCOME: The primary outcome is stroke recurrence and its severity ('ordinal recurrence' based on modified Rankin Scale) at 90 days, with masked assessment centrally by telephone. Secondary outcomes include vascular events, functional measures (disability, mood, cognition, quality of life), and safety (bleeding, death, serious adverse events). DISCUSSION: The trial has recruited more than 50% of its target sample size (latest number: 2399) and is running in 104 sites in 4 countries. One-third of patients presented with a transient ischemic attack.

Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial.

BACKGROUND: Extracranial carotid and vertebral artery dissection is an important cause of stroke, especially in young people. In some observational studies it has been associated with a high risk of recurrent stroke. Both antiplatelet drugs and anticoagulant drugs are used to reduce risk of stroke but whether one treatment strategy is more effective than the other is unknown. We compared their efficacy in the Cervical Artery Dissection in Stroke Study (CADISS), with the additional aim of establishing the true risk of recurrent stroke. METHODS: We did this randomised trial at hospitals with specialised stroke or neurology services (39 in the UK and seven in Australia). We included patients with extracranial carotid and vertebral dissection with onset of symptoms within the past 7 days. Patients were randomly assigned (1:1) by an automated telephone randomisation service to receive antiplatelet drugs or anticoagulant drugs (specific treatment decided by the local clinician) for 3 months. Patients and clinicians were not masked to allocation, but investigators assessing endpoints were. The primary endpoint was ipsilateral stroke or death in the intention-to-treat population. The trial was registered with EUDract (2006-002827-18) and ISRN (CTN44555237). FINDINGS: We enrolled 250 participants (118 carotid, 132 vertebral). Mean time to randomisation was 3·65 days (SD 1·91). The major presenting symptoms were stroke or transient ischaemic attack (n=224) and local symptoms (headache, neck pain, or Horner's syndrome; n=26). 126 participants were assigned to antiplatelet treatment versus 124 to anticoagulant treatment. Overall, four (2%) of 250 patients had stroke recurrence (all ipsilateral). Stroke or death occurred in three (2%) of 126 patients versus one (1%) of 124 (odds ratio [OR] 0·335, 95% CI 0·006-4·233; p=0·63). There were no deaths, but one major bleeding (subarachnoid haemorrhage) in the anticoagulant group. Central review of imaging failed to confirm dissection in 52 patients. Preplanned per-protocol analysis excluding these patients showed stroke or death in three (3%) of 101 patients in the antiplatelet group versus one (1%) of 96 patients in the anticoagulant group (OR 0·346, 95% CI 0·006-4·390; p=0·66). INTERPRETATION: We found no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. Diagnosis of dissection was not confirmed after review in many cases, suggesting that radiographic criteria are not always correctly applied in routine clinical practice. FUNDING: Stroke Association.

Transient ischaemic attack: a qualitative study of the long term consequences for patients.

BACKGROUND: Transient ischaemic attack (TIA) is characterised by its transient nature with symptoms of neurological dysfunction resolving within 24 hours. The occurrence of TIA is a major risk factor for stroke with 10-15% of TIA patients going on to have ischaemic stroke. Internationally, recommendations for the management of TIA focus on the need for early diagnosis and medical management of the acute increased risk of ischaemic stroke. However there is a limited amount of evidence that some patients suffer enduring consequences as a result of this 'transient' event. This paper focusses on patients' long term lived experience following a TIA. METHODS: Semi structured interviews were carried out with patients who had a TIA between two and 24 months previously. Participants were asked about their TIA, the advice and management received and any changes made as a result of the TIA. Interviews were recorded and transcribed verbatim. Thematic content analysis involved scrutinising transcripts to look for links and associations within and between accounts in a process similar to the grounded theory approach of open coding. The category of transience emerged and was explored in more detail to examine the enduring consequences of TIA. RESULTS: Thirty nine patients aged between 31 and 89 years were interviewed. Accounts detailed the long term impact of the TIA and the subsequent 'at risk' status, on the physical and psychosocial wellbeing of participants. Some participants sought to proactively manage the consequences of their TIA but found it difficult to obtain the information and support they needed, whereas others felt that no further action was needed to prevent future stroke. CONCLUSION: Current definitions conceptualise TIA as a transient event however our study suggests that some patients experienced long term consequences as a result of their TIA. These included anxiety and uncertainty in the light of their increased stroke risk. TIA patients need access to detailed, evidence based stroke prevention information from a credible source, and support to help them understand and apply the information over time, if they are to effectively self-manage the long term consequences of TIA and reduce their risk of future stroke.

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.

BACKGROUND: The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. METHODS: In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ≥50% during follow-up. RESULTS: Carotid stenosis longer than 0.65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2.79 (1.17-6.65), P = 0.02] and carotid endarterectomy [2.43 (1.03-5.73), P = 0.04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1.68 (1.12-2.53), P = 0.01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0.003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. CONCLUSIONS: Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials.

Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial.

BACKGROUND: Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy. METHODS: Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470. FINDINGS: 1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17-6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10-8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40-3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38-5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29-6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45-27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7. INTERPRETATION: The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.

The effect of graduated compression stockings on long-term outcomes after stroke: the CLOTS trials 1 and 2.

BACKGROUND AND PURPOSE: Most randomized controlled trials of venous thromboembolism prophylaxis have focused on reduction of deep vein thrombosis, predominantly asymptomatic deep vein thrombosis, detected on imaging. We aimed to estimate the effects of graduated compression stockings on venous thromboembolism events, survival, and functional status at 6 months after stroke. METHODS: The CLOTS Trials adopted an international multicentre, parallel group design, with central randomization and a 1:1 treatment allocation. In CLOTS Trial 1, 2518 immobile stroke patients were allocated thigh-length graduated compression stockings or not, and in CLOTS trial 2, 3014 to thigh-length or below-knee graduated compression stockings. We measured vital status, Oxford Handicap Scale, and quality of life (EQ5D-3 L) at 6 months. RESULTS: We compared survival in patients enrolled in Trials 1 and 2 with a Cox proportional hazards model, including variables included in our minimization algorithm. In both trials, allocation to thigh-length graduated compression stockings was associated with a very slight, but nonsignificant, increased hazard of death in the first 6 months (Trial 1: hazard ratio, 1.087; 95% confidence interval, 0.913-1.295; and Trial 2: hazard ratio, 1.037; 95% confidence interval, 0.892-1.205). There were no statistically significant differences in venous thromboembolism events, Oxford Handicap Scale, or EQ5D-3 L between the treatment groups in CLOTS Trials 1 or 2. CONCLUSIONS: Although underpowered to detect clinically important effects on long-term outcomes, our results effectively exclude a >10% relative reduction in the hazard of death within 6 months associated with the use of thigh-length stockings. No other long-term benefits were apparent.

The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.

BACKGROUND: Thrombolysis is of net benefit in patients with acute ischaemic stroke, who are younger than 80 years of age and are treated within 4·5 h of onset. The third International Stroke Trial (IST-3) sought to determine whether a wider range of patients might benefit up to 6 h from stroke onset. METHODS: In this international, multicentre, randomised, open-treatment trial, patients were allocated to 0·9 mg/kg intravenous recombinant tissue plasminogen activator (rt-PA) or to control. The primary analysis was of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. The study is registered, ISRCTN25765518. FINDINGS: 3035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1515 in the rt-PA group vs 1520 in the control group), of whom 1617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0-2; adjusted odds ratio [OR] 1·13, 95% CI 0·95-1·35, p=0·181; a non-significant absolute increase of 14/1000, 95% CI -20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1·27 (95% CI 1·10-1·47, p=0·001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6·94, 95% CI 4·07-11·8; absolute excess 58/1000, 95% CI 44-72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1·60, 95% CI 1·22-2·08, p=0·001; absolute increase 37/1000, 95% CI 17-57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group). INTERPRETATION: For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. Benefit did not seem to be diminished in elderly patients. FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, Arbetsmarknadens Partners Forsakringsbolag (AFA) Insurances Sweden, Swedish Heart Lung Fund, The Foundation of Marianne and Marcus Wallenberg, Polish Ministry of Science and Education, the Australian Heart Foundation, Australian National Health and Medical Research Council (NHMRC), Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita, Regione dell'Umbria, Italy, and Danube University.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited.

BACKGROUND: Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit. DESIGN: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics. RESULTS: The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials. CONCLUSION: The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials. TRIAL REGISTRATION: ISRCTN25765518.

Can clinical features distinguish between immobile patients with stroke at high and low risk of deep vein thrombosis? Statistical modelling based on the CLOTS trials cohorts.

BACKGROUND: Deep vein thrombosis (DVT) is an important complication of stroke. Guidelines recommend that DVT prophylaxis should be guided by an assessment of the individual patient's risk. The authors aimed to develop and test models to predict DVT risk. METHODS: The Clots in Legs Or sTockings after Stroke (CLOTS) Trial 1 randomised 2518 immobile patients with acute stroke to thigh-length graduated compression stockings (GCS) or no GCS and CLOTS Trial 2 randomised 3114 to thigh-length or below-knee GCS. The authors collected potential predictive variables at baseline and detected DVTs with compression duplex ultrasound scans at about 7-10 days and 25-30 days. The authors developed models with logistic regression to predict DVT in 1242 Trial 2 patients who had two scans and tested the models in the 1422 Trial 1 patients with two scans by estimating the area under the receiver operating characteristic curve (AUC). RESULTS: 168 (11.8%) patients in Trial 1 and 122 (9.8%) in Trial 2 had proximal DVTs. A model based on the Trial 2 cohort contained four of the 12 baseline variables: dependent before stroke (OR=3.62, 95% CI 2.15 to 6.08), unable to lift arms off bed (OR 1.89, 95% CI 1.23 to 2.90), history of DVT/pulmonary embolism (OR 3.69, 95% CI 1.98 to 6.88) and diabetes (OR 0.55, 95% CI 0.30 to 0.99). The AUC in the development cohort was 0.65 but only 0.57, 95% CI (0.53 to 0.61) in the Trial 1 cohort, indicating poor discrimination. CONCLUSIONS: Unfortunately, models based on clinical factors alone discriminate poorly between immobile patients with stroke at high and low risk, and would not facilitate individual tailoring of DVT prophylaxis strategies.

Long-term results of carotid artery stents to manage symptomatic carotid artery stenosis and factors that affect outcome.

BACKGROUND: Limited data are available about the long-term outcomes of the use of carotid artery stents in symptomatic patients and the impact of patient variables on the durability of endovascular carotid procedures. Outcome data previously reported from registry series mix symptomatic and asymptomatic patients. We present analysis of long-term follow-up, with independent neurological assessment, for patients with symptomatic high-grade carotid lesions undergoing stenting to identify patients at risk of recurrence. METHODS AND RESULTS: Prospectively collected data on 563 carotid stenting procedures in a single center were analyzed. Univariate and multivariate techniques were used to identify risk groups and beneficial technical adaptations. Ipsilateral stroke rates for all patients were 4.8%, 7.0%, and 9.5% at 30 days, 1 year, and 4 years, respectively. The rates improved to 2.7%, 4.1%, and 4.5% when patients were treated with optimal therapy. Retinal events had a lower risk of long-term recurrent ipsilateral stroke (hazard ratio=0.228, CI=0.082 to 0.632, P=0.004) than cerebral events. A recurrent or residual stenosis of >50% had a statistically significant effect on long-term stroke recurrence in multivariate analysis (hazard ratio=2.187, CI=1.173 to 4.078, P=0.014). CONCLUSIONS: Patients with retinal presentations are a lower risk group to treat. Residual stenosis or restenosis >50% has a statistically significant trend to an increased risk of recurrence for ipsilateral stroke in the long term in this population. In our patients, a combination of procedural modifications and pharmacological changes seems to improve outcomes.

Filter-protected versus unprotected carotid artery stenting: a randomised trial.

BACKGROUND: Our aim was to determine whether filter protection reduces embolisation to the brain during carotid artery stenting (CAS). METHODS: Thirty patients with symptomatic carotid artery stenosis > or =70% (North American Symptomatic Carotid Endarterectomy Trial) were randomly assigned to filter-protected or unprotected CAS. Diffusion-weighted magnetic resonance imaging (DWI) of the brain was performed before and at 3 time points after CAS. In a subset of patients, high-intensity transient signals on transcranial Doppler (TCD) were recorded with categorisation of emboli. Data were independently reviewed off-site. RESULTS: There were no significant differences in mean age, proportion of octogenarians or presenting symptoms between the groups. On procedural DWI (1-3 and 24 h after stenting), there were 7/24 (29%) and 4/22 (18%) new lesions in protected and unprotected patients respectively (p = 0.38). At 30 days there were 9/33 (26%) and 4/33 (12%) lesions in protected and unprotected patients, respectively (p = 0.1). On TCD there were significantly more signals in total as well as particulate emboli during filter-protected CAS (426.5 and 251.3) than during unprotected CAS (165.2 and 92) - p = 0.01 and 0.03, respectively. CONCLUSIONS: Filter-protected CAS is associated with an increase in new lesions on DWI and significantly higher rates of total and particulate microembolisation on TCD than unprotected CAS. The clinical significance of these findings requires further study.

Endovascular treatment with angioplasty or stenting versus endarterectomy in patients with carotid artery stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.

BACKGROUND: Endovascular treatment (angioplasty with or without stenting) is an alternative to carotid endarterectomy for carotid artery stenosis but there are scarce long-term efficacy data showing that it prevents stroke. We therefore report the long-term results of the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). METHODS: Between March, 1992, and July, 1997, patients who presented at a participating centre with a confirmed stenosis of the internal carotid artery that was deemed equally suitable for either carotid endarterectomy or endovascular treatment were randomly assigned to either treatment in equal proportions by telephone or fax from the randomisation service at the Oxford Clinical Trials Unit, UK. Patients were seen by an independent neurologist at 1 and 6 months after treatment and then every year after randomisation for as long as possible, up to a maximum of 11 years. Major outcome events were transient ischaemic attack, non-disabling, disabling, and fatal stroke, myocardial infarction, and death from any other cause. Outcomes were adjudicated on by investigators who were masked to treatment. Analysis was by intention to treat. This study is registered, number ISRCTN 01425573. FINDINGS: 504 patients with stenosis of the carotid artery (90% symptomatic) were randomly assigned to endovascular treatment (n=251) or surgery (n=253). Within 30 days of treatment, there were more minor strokes that lasted less than 7 days in the endovascular group (8 vs 1) but the number of other strokes in any territory or death was the same (25 vs 25). There were more cranial nerve palsies (22 vs 0) in the endarterectomy group than in the endovascular group. Median length of follow up in both groups was 5 years (IQR 2-6). By comparing endovascular treatment with endarterectomy after the 30-day post-treatment period, the 8-year incidence and hazard ratio (HR) at the end of follow-up for ipsilateral non-perioperative stroke was 11.3% versus 8.6% (HR 1.22, 95% CI 0.59-2.54); for ipsilateral non-perioperative stroke or TIA was 19.3% versus 17.2% (1.29, 0.78-2.14); and for any non-perioperative stroke was 21.1% versus 15.4% (1.66, 0.99-2.80). INTERPRETATION: More patients had stroke during follow-up in the endovascular group than in the surgical group, but the rate of ipsilateral non-perioperative stroke was low in both groups and none of the differences in the stroke outcome measures was significant. However, the study was underpowered and the confidence intervals were wide. More long-term data are needed from the on going stenting versus endarterectomy trials. FUNDING: British Heart Foundation; UK National Health Service Management Executive; UK Stroke Association.

Long-term risk of carotid restenosis in patients randomly assigned to endovascular treatment or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.

BACKGROUND: In the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), early recurrent carotid stenosis was more common in patients assigned to endovascular treatment than it was in patients assigned to endarterectomy (CEA), raising concerns about the long-term effectiveness of endovascular treatment. We aimed to investigate the long-term risks of restenosis in patients included in CAVATAS. METHODS: 413 patients who were randomly assigned in CAVATAS and completed treatment for carotid stenosis (200 patients had endovascular treatment and 213 patients had endarterectomy) had prospective clinical follow-up at a median of 5 years and carotid duplex ultrasound at a median of 4 years. We investigated the cumulative long-term incidence of carotid restenosis after endovascular treatment and endarterectomy, the effect of the use of stents on restenosis after endovascular treatment, risk factors for the development of restenosis, and the effect of carotid restenosis on the risk of recurrent cerebrovascular events. Analysis was by intention to treat. This study is registered, number ISRCTN01425573. FINDINGS: Severe carotid restenosis (>or=70%) or occlusion occurred significantly more often in patients in the endovascular arm than in patients in the endarterectomy arm (adjusted hazard ratio [HR] 3.17, 95% CI 1.89-5.32; p<0.0001). The estimated 5-year incidence of restenosis was 30.7% in the endovascular arm and 10.5% in the endarterectomy arm. Patients in the endovascular arm who were treated with a stent (n=50) had a significantly lower risk of developing restenosis of 70% or greater compared with those treated with balloon angioplasty alone (n=145; HR 0.43, 0.19-0.97; p=0.04). Current smoking or a history of smoking was a predictor of restenosis of 70% or more (2.32, 1.19-4.54; p=0.01) and the early finding of moderate stenosis (50-69%) up to 60 days after treatment was associated with the risk of progression to restenosis of 70% or more (3.76, 1.88-7.52; p=0.0002). The composite endpoint of ipsilateral non-perioperative stroke or transient ischaemic attack occurred more often in patients in whom restenosis of 70% or more was diagnosed in the first year after treatment compared with patients without restenosis of 70% or more (5-year incidence 23%vs 11%; HR 2.18, 1.04-4.54; p=0.04), but the increase in ipsilateral stroke alone was not significant (10%vs 5%; 1.67, 0.54-5.11). INTERPRETATION: Restenosis is about three times more common after endovascular treatment than after endarterectomy and is associated with recurrent ipsilateral cerebrovascular symptoms; however, the risk of recurrent ipsilateral stroke is low. Further data are required from on-going trials of stenting versus endarterectomy to ascertain whether long-term ultrasound follow-up is necessary after carotid revascularisation. FUNDING: British Heart Foundation; UK National Health Service Management Executive; UK Stroke Association.

Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke.

BACKGROUND: Intravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit. DESIGN: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With 3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit. TRIAL PROCEDURES: Patients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24-48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0-2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol). TRIAL REGISTRATION: ISRCTN25765518.