There exist individual, institutional and national barriers to change, none more so than when introducing new therapies into medical practice especially those that involve organizational change. This ...paper, presented as an address to the joint meeting of the Association of British Neurologists and the Indian Academy of Neurology in October 2007, explores these barriers in the context of the instruction of thrombolytic therapy for patients with acute ischaemic stroke and suggests how they might be overcome using evidence from relevant clinical trials and observational studies.
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.
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.
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.
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.
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.
ISRCTN25765518.
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.
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).
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.
Currently our standard of practice is that patients undergoing carotid artery stenting (CAS) may be safely discharged on the first day post-procedure. However, many patients are completely ...independent on the evening of procedure. Therefore we sought to establish the safety and feasibility of same-day discharge by assessing frequency and time of complications in the first 30 days after CAS.
Case records for 208 consecutive patients who had undergone CAS from October 1999 to October 2002 were retrospectively reviewed. Excluded were four cases in which combined CAS and carotid endarterectomy was performed to treat synchronous stenosis. Of the remaining 204 cases, involving 201 patients (three patients underwent staged bilateral CAS), 173 (84.8%) were symptomatic and 31 (15.2%) were asymptomatic.
Thirty-eight major events or death (inclusive of all neurologic events and any complications that required treatment) were recorded in the first 30 days after CAS, for an event rate of 18.6% per case. These were 7 (3.4%) major access site complications; 18 (8.8%) neurologic events, of which 10 (4.9%) were transient ischemic events and 8 (3.9%) were strokes (including minor, major, and fatal stroke); 8 (3.9%) cardiovascular complications; and five (2.5%) other events. Twenty (52.6%) events occurred in the first 6 hours after CAS, 2 (5.3%) between 6 and 12 hours, 3 (7.9%) between 12 and 24 hours, and 13 (34.2%) 24 hours to 30 days post procedure. Four (2.0%) deaths were recorded in this period, 1 secondary to stroke, 1 from a perforated myocardium from a temporary pacing wire, and 2 from unrelated causes. The 30-days stroke and death rate was 5.4% (11 of 204 patients).
Time of complications suggests that outpatient performance of CAS is feasible and safe in selected patients.
Summary 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.
Objective: Neuroprotection during carotid stenting has the potential to reduce procedural atheroembolic sequelae. We report the United Kingdom experience of NeuroShield (MedNova Ltd, Horsham, West ...Sussex, United Kingdom). Methods: We performed a prospective cohort analysis of 50 consecutive patients (50 lesions) in a regional vascular tertiary referral center (catchment area one million) that provides an institutional service for the short term. The subjects were all the patients referred for carotid stenting after preassessment by a multidisciplinary team. All the patients underwent pretreatment with antiplatelet agents. Forty-two patients had atherosclerotic stenosis of the carotid bifurcation between 70% and 95% (with North American Symptomatic Carotid Endarterectomy Trial criteria). Six patients had restenosis after endarterectomy. Two had previous local radiotherapy. Forty-two patients were symptomatic (amaurosis fugax/central retinal artery occlusion in 11 cases, and hemispheric transient ischemic attack/cerebrovascular accident in 31 cases). Eight patients were asymptomatic with bilateral high-grade stenoses, with six cases before coronary artery bypass grafting. The intervention performed was protected primary carotid stenting. Outcome measures were procedural atheroembolic events, including all-stroke and death rates up to 30 days, and analysis of retrieved debris in a subset of 11 cases. Results: The technical success rate was 50/50 (100%) for stenting and 49/50 (98%) for filter placement/retrieval. Technical complications comprised nonsymptomatic spasm at the filter site (flow limiting in two cases and non-flow limiting in five cases). Procedural events were one minor stroke (patient fully recovered within 48 hours) in a complex clinical setting and one ventricular fibrillation arrest in a patient before coronary artery bypass grafting who was resuscitated without neurologic event. At 30 days, the death or major disability from stroke rate was 2/50 (4%). No cases were atheroembolic. The all-stroke/death rate was 3/50 (6%). The two deaths were the result of a fatal hemorrhagic stroke that occurred at 4 days and was thought to be caused by reperfusion and a perforated ventricle caused by a temporary pacing wire. One femoral pseudoaneurysm followed failed closure device deployment and required percutaneous thrombin injection. The mean particle number per patient was 12 (range, 0 to 41). The mean particle diameter was 284.9 μm (range, 31 to 1430 μm). The mean ellipsoid volume load was 0.1602 mm3 (range, 0.0005 to 0.1968 mm3). Conclusion: Carotid stenting protected with NeuroShield is safe. The filter traps embolic debris liberated during the procedure. (J Vas Surg 2002;35:966-72.)
The cerebral hemodynamic sequelae of interventions in patients with severe internal carotid artery (ICA) stenoses are not fully understood. In this study, we sought to determine the immediate changes ...in cerebral perfusion characteristics, determined by MR imaging in patients who have undergone unilateral transluminal angioplasty and stent placement.
Eleven patients with symptomatic high-grade ICA stenosis underwent MR imaging within 4 hours before and within 3 hours after carotid stent placement. First-pass gadolinium-enhanced imaging of perfusion was performed by using a gradient-recalled echo-planar technique. Localized relative cerebral blood volume (rCBV) and bolus first-moment transit time (TT(FM)) were calculated for different vascular territories (middle, anterior, and posterior cerebral arteries) in each hemisphere.
Significantly longer TT(FM) (P <.005) was observed in the symptomatic territory of the middle cerebral artery before intervention. After intervention, TT(FM) remained significantly longer in this territory (P <.05). However, the magnitude of the interhemispheric asymmetry had declined significantly (50-60% reduction; P <.05). No significant differences or changes in rCBV were identified between hemispheres, between images, or in areas of unilateral leptomeningeal enhancement after intervention.
MR can demonstrate short-term partial resolution of timing asymmetry in interhemispheric perfusion after angioplasty and stent insertion for severe stenosis of the ICA.
Summary Background Few data are available from randomised trials about the effect of thrombolysis with alteplase on long-term functional outcome in patients who have had acute ischaemic stroke and no ...trial has reported effects on health-related quality of life. A secondary objective of the third International Stroke Trial (IST-3) was to assess the effect of thrombolysis on such outcomes at 18 months. Methods In this open-label, international, multicentre, randomised, controlled trial, 3035 patients with ischaemic stroke from 12 countries were randomly allocated within 6 h of onset via a secure central system to either intravenous alteplase (0·9 mg/kg; n=1515) plus standard care or standard care alone (control; n=1520). 2348 patients were scheduled for 18-month follow-up. For our main analysis, survivors were assessed at 18 months with the Oxford handicap scale (OHS; the primary outcome was the adjusted odds of OHS score 0–2). We also used the EuroQoL (EQ) instrument and asked questions about overall functioning and living circumstances. We analysed the OHS and the five EQ domains by ordinal logistic regression and calculated the mean difference between treatment groups in EQ utility index and visual analogue scale score. Analyses were adjusted for key baseline prognostic factors. This study is registered with controlled-trials.com , number ISRCTN25765518. Findings At 18 months, 408 (34·9%) of 1169 patients in the alteplase group versus 414 (35·1%) of 1179 in the control group had died (p=0·85). 391 (35·0%) of 1117 patients versus 352 (31·4%) of 1122 had an OHS score of 0–2 (adjusted odds ratio OR 1·28, 95% CI 1·03–1·57; p=0·024). Treatment was associated with a favourable shift in the distribution of OHS grades (adjusted common OR 1·30, 95% CI 1·10–1·55; p=0·002). Alteplase treatment was associated with significantly higher overall self-reported health (adjusted mean difference in EQ utility index 0·060; p=0·019). The differences between the groups in visual analogue scale score and the proportion living at home were not significant. Interpretation IST-3 provides evidence that thrombolysis with intravenous alteplase for acute ischaemic stroke does not affect survival, but does lead to statistically significant, clinically relevant improvements in functional outcome and health-related quality of life that are sustained for at least 18 months. Funding UK Medical Research Council, Health Foundation UK, Stroke Association UK, Research Council of Norway, 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, Swiss National Research Foundation, Swiss Heart Foundation, Assessorato alla Sanita (Regione dell'Umbria, Italy), and Danube University.
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