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

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

Medication Persistence Rates and Factors Associated with Persistence in Patients Following Stroke: A Cohort Study

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Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial

SummaryBackgroundFew 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.MethodsIn 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.FindingsAt 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.InterpretationIST-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.FundingUK 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

Canadian Stroke Best Practice Recommendations: Hyperacute Stroke Care Guidelines, Update 2015

The 2015 update of the Canadian Stroke Best Practice Recommendations Hyperacute Stroke Care guideline highlights key elements involved in the initial assessment, stabilization, and treatment of patients with transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and acute venous sinus thrombosis. The most notable change in this 5th edition is the addition of new recommendations for the use of endovascular therapy for patients with acute ischemic stroke and proximal intracranial arterial occlusion. This includes an overview of the infrastructure and resources required for stroke centers that will provide endovascular therapy as well as regional structures needed to ensure that all patients with acute ischemic stroke that are eligible for endovascular therapy will be able to access this newly approved therapy; recommendations for hyperacute brain and enhanced vascular imaging using computed tomography angiography and computed tomography perfusion; patient selection criteria based on the five trials of endovascular therapy published in early 2015, and performance metric targets for important time-points involved in endovascular therapy, including computed tomography-to-groin puncture and computed tomography-to-reperfusion times. Other updates in this guideline include recommendations for improved time efficiencies for all aspects of hyperacute stroke care with a movement toward a new median target door-toneedle time of 30 min, with the 90th percentile being 60 min. A stronger emphasis is placed on increasing public awareness of stroke with the recent launch of the Heart and Stroke Foundation of Canada FAST signs of stroke campaign; reinforcing the public need to seek immediate medical attention by calling 911; further engagement of paramedics in the prehospital phase with prehospital notification to the receiving emergency department, as well as the stroke team, including neuroradiology; updates to the triage and same-day assessment Conflict of interest: Leanne K. Casaubon: Medtronic (as an independent study patient assessor for a cardiac TAVI study); NoNO Inc. as site PI for the Frontier study of NA-1 neuroprotective in stroke; Covidien as an advisory board member. Jean-Martin Boulanger: conference speaker for BI Novartis, Sanofi Aventis, Merck, Merz, Allergan, Pfizer, Bayer, Boehringer Ingelheim. Gord Gubitz: speaker for Bayer, Boehringer Ingleheim, and BMS Pfizer. Dr. Michael D. Hill: Heart and Stroke Foundation of Alberta Board Chair, salary award holder; Vernalis Group Ltd and Merck Ltd Consultant; Hoffmann-LaRoche Canada, provided drug for clinical trial, consultancy and CME lecturer; Coviden, research grant holder; Servier Canada, CME lecturer (funds donated to charity); BMS Canada, consultancy (funds donated to charity); Alberta Innovates Health Solutions, program grant award; principal investigator, ESCAPE trial. Brian Moses: speaker for AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi Aventis, and Servier; speaker and advisory board member for BMS, Eli Lilly, Merck, NovoNordisk, Pfizer; advisory board member for Medtronic. Funding: The development of the Canadian Stroke Best Practice Recommendations is funded in their entirety by the Heart and Stroke Foundation, Canada. No funds for the development of these guidelines come from commercial interests, including pharmaceutical and medical device companies. All members of the recommendation writing groups and external reviewers are volunteers and do not receive any remuneration for participation in guideline development, updates, and reviews. All participants complete a conflict of interest declaration prior to participation. of patients with transient ischemic attack; updates to blood pressure recommendations for the hyperacute phase of care for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The goal of these recommendations and supporting materials is to improve efficiencies and minimize the absolute time lapse between stroke symptom onset and reperfusion therapy, which in turn leads to better outcomes and potentially shorter recovery times

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