European Stroke Organisation (ESO) standard operating procedure for the preparation and publishing of guidelines.

The first European Stroke Organization (ESO) standard operating procedure (SOP) published in 2015 aimed at the implementation the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to provide evidence-based guidelines for stroke management. This second ESO-SOP is aiming at further increase of the practicability of ESO guidelines and its technical implications. Authors comprised of the members of the ESO guideline Board and ESO Executive Committee. The final document was agreed on by several internal reviews. The second SOP comprises of the following aspects: rational for the SOP, the introduction of expert consensus statements, types of guideline documents, structures involved and detailed description of the guideline preparation process, handling of financial and intellectual conflicts of interest (CoI), involvement of ESO members in the guideline process, review process, authorship and publication policy, updating of guidelines, cooperation with other societies, and dealing with falsified data. This second SOP supersedes the first SOP published in 2015.

Uncertainties in short term prediction of atmospheric dispersion of radionuclides. A case study of a hypothetical accident in a nuclear floating power plant off the West coast of Norway.

Short-term predictions for dispersion of radionuclides in the atmosphere following releases from nuclear incidents are associated with uncertainties originating from meteorology, source term and parameterization. Characterization of these uncertainties is of key importance for preparedness, decision making during an accident and for the further uncertainty propagation in the subsequent modelling of human and ecosystem exposures. Increased traffic of nuclear-propulsion vessels in Norwegian territorial waters gives rise to growing concern of a potential nuclear accident along the coast of Norway. In the present study, we have quantified and inter-compared the uncertainties associated with the model outputs for a hypothetical loss of coolant accident with an ensuing fire in a nuclear vessel situated along the Norwegian coastline, applying two different atmospheric dispersion models: the SNAP Lagrangian particle model (SNAP-Severe Nuclear Accident Program) and the DIPCOT Lagrangian puff model (DIPCOT - Dispersion over Complex Terrain). The case highlights a situation with atmospheric transport from the offshore area to the coast of Western Norway, combined with large wet deposition in inland mountainous terrain, i.e. a common weather situation in this region. The meteorological data include an Ensemble Prediction System with nine ensemble members in addition to a deterministic base run. Five different 7 h emission scenarios with the same total released activity were considered. Hourly wind data at 10 m above ground for a 24 h period, showed that 36% of the wind direction and 41% of the wind speed data were outside the spread of the meteorological ensemble. About 55% and 13% of the measured values fell outside the ensemble for hourly 2 m above ground temperatures and 3 hourly accumulated precipitation, respectively, indicating that the ensemble did not cover all uncertainties in the meteorological fields. The maps of accumulated concentrations and depositions were qualitatively similar for the two models, but SNAP predicted higher accumulated concentration levels compared to DIPCOT for quite large areas, while DIPCOT yielded larger total depositions in the same areas. Furthermore, the direction, speed of movement and spatial extension of the radioactive plume from the accident varied considerably from one model to the other. The spread in the dispersion of the radionuclides ranged from a factor of about 1-3 in the source area to a factor of about 2-5 further away. The spreads due to meteorology and emission scenarios were of similar magnitude. Considering the ratio of the 50th percentiles of the two models, the spread varied by a factor of about 1-9, indicating that uncertainties arising from the formulation of the dispersion model could be as important or even larger than those associated with meteorology and emissions. Thus, it is recommended to include the uncertainty originating from the choice of the dispersion model into the overall uncertainty of short-term prediction of the dispersion of radionuclides and to exploit this further by generating an ensemble of several dispersion models.

Value of treatment by comprehensive stroke services for the reduction of critical gaps in acute stroke care in Europe.

Stroke is the second leading cause of death and dependency in Europe and costs the European Union more than €30bn, yet significant gaps in the patient pathway remain and the cost-effectiveness of comprehensive stroke care to meet these needs is unknown. The European Brain Council Value of Treatment Initiative combined patient representatives, stroke experts, neurological societies and literature review to identify unmet needs in the patient pathway according to Rotterdam methodology. The cost-effectiveness of comprehensive stroke services was determined by a Markov model, using UK cost data as an exemplar and efficacy data for prevention of death and dependency from published systematic reviews and trials, expressing effectiveness as quality-adjusted life-years (QALYs). Model outcomes included total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). Key unmet needs in the stroke patient pathway included inadequate treatment of atrial fibrillation (AF), access to neurorehabilitation and implementation of comprehensive stroke services. In the Markov model, full implementation of comprehensive stroke services was associated with a 9.8% absolute reduction in risk of death of dependency, at an intervention cost of £9566 versus £6640 for standard care, and long-term care costs of £35 169 per 5.1251 QALYS vs. £32 347.40 per 4.5853 QALYs, resulting in an ICER of £5227.89. Results were robust in one-way and probabilistic sensitivity analyses. Implementation of comprehensive stroke services is a cost-effective approach to meet unmet needs in the stroke patient pathway, to improve acute stroke care and support better treatment of AF and access to neurorehabilitation.

Predictors of Poor Prognosis in Recurrent Hepatitis C After Liver Transplantation.

BACKGROUND: Hepatitis C is a common indication for liver transplantation (LT). Hepatitis C virus (HCV) recurrence is universal in viremic patients. This recurrence is frequently very aggressive, with graft loss in less than 5 years. Our aim is to detect which factors are related to worse fibrosis at 1 year post-LT. PATIENTS AND METHODS: Records of all HCV-positive transplanted patients in Hospital Universitario Nuestra Señora de la Candelaria from 1996 to 2014 were collected. The variables analyzed were donor and recipient age and gender, hypertension, diabetes, viral genotype, viral load at LT, hepatocellular carcinoma in the explant, anticoagulation or antiplatelet treatment, year of transplantation, and mean levels of tacrolimus in the first month. Severe recurrence was defined as fibrosis F3 by biopsy, liver stiffness > 9.5 kPa by transient elastography, or hepatic venous pressure gradient > 5 mm Hg at 1 year post-LT. Univariate and multivariate analyses were performed. RESULTS: From a sample of 112 patients, 88 patients met inclusion criteria. Mean recipient age was 52.8 ± 8.0 years and 70.5% were men. Mean donor age was 46.4 ± 16.1 years and 59.1% were men. Severe recurrence occurred in 23.9%. Univariate analyses showed 3 variables were statistically significant: donor age (P = .03), recipient age (P = .008), and presence of hepatocellular carcinoma (P = .01). Only the 2 first variables remained significant in the multivariate model (P = .009 and P = .044 respectively). Hepatocellular carcinoma was probably related to older recipients becoming a confounding factor. CONCLUSIONS: In our study, donor and recipient age both conferred a worse prognosis in terms of fibrosis progression in patients with liver transplant due to HCV.

ACPA-positive primary Sjögren's syndrome: true primary or rheumatoid arthritis-associated Sjögren's syndrome?

OBJECTIVES: Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5-10% of primary Sjögren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. PATIENTS AND METHODS: ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria. RESULTS: At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5-10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA. CONCLUSIONS: Median term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.

Blood pressure and hypertension in athletes: a systematic review.

OBJECTIVE: Hypertension is reported to be the most prevalent risk factor for cardiovascular disease in elite athletes. We aimed to review blood pressure (BP) and prevalence of hypertension in different elite athletes, and study whether there was an association between high BP and left ventricular hypertrophy (LVH). METHODS: A systematic review of studies reporting BP in athletes using search strategies developed for PubMed and EMBASE, including only studies with ≥100 participants. We collected data on BP, prevalence of hypertension, LVH and methods of BP measurement. RESULTS: Of 3723 records identified, 51 met the inclusion criteria. These included men and women (n=138,390), aged mostly between 18 and 40 years, from varied sports disciplines. Mean systolic BP varied from 109±11 to 138±7 mm Hg and mean diastolic BP from 57±12 to 92±10 mm Hg. Strength-trained athletes had higher BP than endurance-trained athletes (131.3±5.3/77.3±1.4 vs 118.6±2.8/71.8±1.2 mm Hg, p<0.05), and there was a trend towards a higher BP in athletes training ≥10 h compared with others (121.8±3.8/73.8±2.5 vs 117.6±3.3/66.8±6.9, p=0.058), but overall there was no significant difference in BP between athletes and controls. The prevalence of hypertension varied from 0% to 83%. Some studies showed an association between high BP and LVH. Measurement methods were poorly standardised. CONCLUSIONS: BP and prevalence of hypertension in athletes varied considerably partly because of variations in methodology, but type and intensity of training may contribute towards higher BP. High BP may be associated with LVH.

Cochrane Stroke Group: twenty years of evidence-based stroke medicine.

The Cochrane Stroke Group was one of the first specialist review groups set up within The Cochrane Collaboration and has been in existence for 20 years. Its key outputs include a number of high profile reviews in the area of the management of stroke, which have become one of the most important sources of information for clinical practice guidelines. The work of the group is only possible through a collaborative network of staff, editors, and authors.

Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.

We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.

Tivozanib: practical implications for renal cell carcinoma and other solid tumors.

Tivozanib is a recently developed, small-molecule tyrosine kinase inhibitor with specific affinity for the vascular endothelial growth factor receptor (VEGFR) family of kinases. Given known relevance of VHL (Von Hippel-Lindau disease tumor suppressor) deregulation in the clear cell variant of renal cell carcinoma, renal cell carcinoma remains an area of interest and subject of recent registration trials with this approach. TIVO-1, a phase III study evaluating tivozanib versus sorafenib in the first-line setting, met its primary endpoint of progression-free survival (11.9 months for tivozanib vs. 9.1 months for sorafenib), with a manageable toxicity profile, leading to formal consideration of regulatory approval in this setting. This review focuses on the preclinical development, pharmacokinetics and early clinical activity of tivozanib in renal cell carcinoma and other solid tumors.

Thrombolytic treatment for stroke in the Scandinavian countries.

OBJECTIVE: We wanted to describe the use of thrombolytic treatment for stroke in Scandinavia, to assess stroke doctors' opinions on this treatment, to identify barriers against treatment, and to suggest improvements to overcome these barriers. METHODS: We sent questionnaires to 493 Scandinavian doctors, who were involved in acute stroke care. RESULTS: We received 453 (92%) completed questionnaires. Overall, 1.9% (range per hospital 0-13.9%) of patients received thrombolytic treatment. A majority (94%) of the respondents was convinced of the beneficial effects of thrombolytic treatment and many (85%) felt that its risks were acceptable. Main barriers were: unawareness of stroke symptoms among patients (82%) and their failure to respond adequately (54%); ambulance services not triaging acute stroke as urgent (23%); and insufficient in-hospital routines (15%). The respondents suggested that the following measures should be prioritized to increase the treatment's use: educational programmes to improve public awareness on stroke and how to respond (96%); education of in-hospital (88%) and prehospital (76%) medical staff. CONCLUSIONS: A large majority of Scandinavian doctors regard thrombolytic treatment for stroke as beneficial, yet its implementation in clinical practice has so far been poor. Our survey identified important barriers and potential measures that could increase its future use.

Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Recently, a new MeCP2 isoform was described, MeCP2_e1, which skips exon 2 and has an alternative N-terminus, translated from exon 1, whereas MeCP2_e2 is translated from a start codon in exon 2. Since the incorporation of exon 1 into standard sequencing protocols for RTT, few exon 1 mutations have been described and are thus assumed to be only rare causes of RTT. Also, studies have suggested that the frameshift mutations identified in exon 1 affect both isoforms. Our aim in this study was to assess the frequency of mutations in exon 1, their relationship to phenotype, and the implications on the etiological role for the isoform MeCP2_e1 in RTT, versus the previously described isoform, MeCP2_e2. We sequenced MECP2 in 51 females with various clinical presentations, including developmental delay, autism, atypical and classical RTT, referred to our laboratories for testing. In patients with identified mutations, X-chromosome inactivation was analyzed. We identified four patients with exon 1 mutations; three were novel (c.1A > T; c.1A > G; c.5C > T), two of which affected the start codon, one a missense change, and one patient had a previously reported splice site mutation, c.62 + 1delGT. The four patients fit criteria for classical RTT, and thus these findings add support to previous reports that exon 1 mutations may be associated with a severe phenotype. Also, these findings add significant weight to the mounting evidence suggesting that the MeCP2_e1 isoform is the etiologically relevant form of the protein.

"Two per cent isn't a lot, but when it comes to death it seems quite a lot anyway": patients' perception of risk and willingness to accept risks associated with thrombolytic drug treatment for acute stroke.

BACKGROUND: Thrombolytic drugs to treat an acute ischaemic stroke reduce the risk of death or major disability. The treatment is, however, also associated with an increased risk of potentially fatal intracranial bleeding. This confronts the patient with the dilemma of whether or not to take a risk of a serious side effect in order to increase the likelihood of a favourable outcome. OBJECTIVE: To explore acute stroke patients' perception of risk and willingness to accept risks associated with thrombolytic drug treatment. DESIGN: Eleven patients who had been informed about thrombolytic drug treatment and had been through the process of deciding whether or not to participate in a thrombolytic drug trial went through repeated qualitative, semistructured interviews. RESULTS: Many patients showed a limited perception of the risks connected with thrombolytic drug treatment. Some perceived the risk as not relevant to them and were reluctant to accept that treatment could cause harm. Others seemed to be aware that treatment would mean exposure to risk. The patients' willingness to take a risk also varied substantially. Several statements revealed ambiguity and confusion about being involved in a decision about treatment. The patients' reasoning about risk was put into the context of their health-related experiences and life histories. Several patients wanted the doctor to be responsible for the decisions. CONCLUSION: Acute stroke patients' difficulties in perceiving and processing information about risk may reduce their ability to be involved in clinical decisions where risks are involved.

A step-wise approach to find a valid and feasible method to detect non-adherence to tuberculosis drugs.

A step-wise approach to identify valid and feasible methods to detect non-adherence to tuberculosis drugs was evaluated in a prospective study among pulmonary tuberculosis patients in an outpatient clinic in Indonesia. First, adherence was measured by self-reporting with the standardized Morisky questionnaire, physician assessment, pill-count, visit attendance, diary and an electronic medication event monitoring system (MEMS). Next, validity of single methods was assessed against MEMS as gold standard. Feasibility of methods was then judged by physicians in the field. Finally, when valid and feasible methods were combined, it appeared that self-reporting by a questionnaire plus physician assessment could identify all non-adherent patients. It is recommended to use a systematic approach to develop a valid and locally feasible combination of methods to detect non-adherence to TB drugs.

I don't like that, it's tricking people too much...: acute informed consent to participation in a trial of thrombolysis for stroke.

BACKGROUND: Informed consent is regarded as a contract between autonomous and equal parties and requires the elements of information disclosure, understanding, voluntariness and consent. The validity of informed consent for critically ill patients has been questioned. Little is known about how these patients experience the process of consent. OBJECTIVE: The aim of this study was to explore critically ill patients' experience with the principle of informed consent in a clinical trial and their ability to give valid informed consent. DESIGN: 11 stroke patients who had been informed about thrombolytic treatment and had been through the process of deciding whether or not to participate in a thrombolysis trial went through repeated qualitative semistructured interviews. RESULTS: None of the patients had any clear understanding of the purpose of the trial. Neither did they understand the principles of randomisation and voluntariness. Reasons for giving or not giving consent were trust, conceptions of benefits and risks and altruism. Several patients found it immoral to involve patients in the consent procedure and argued that this was the doctors' responsibility. Others argued that it is a duty to question patients and perceived it as a sign of being treated with respect and dignity. A majority of the patients found the consent process vague and ambiguous. CONCLUSIONS: The results indicate that the principle of informed consent from critically ill patients cannot be seen as a contract between equal and autonomous parties. Further studies are needed to explore critically ill patients' experiences with the process of informed consent.

Thrombolysis for acute ischaemic stroke.

BACKGROUND: The majority of strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred. Successful treatment could mean that the patient is more likely to make a good recovery from their stroke. Thrombolytic drugs however, can also cause serious bleeding in the brain which can be fatal. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke. OBJECTIVES: The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched January 2003), MEDLINE (1966- January 2003) and EMBASE (1980-January 2003). In addition we contacted researchers and pharmaceutical companies, attended relevant conferences and handsearched four Japanese journals. SELECTION CRITERIA: Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed. The extracted data were verified by the principal investigators of all major trials. Thus published and unpublished data were obtained where available. MAIN RESULTS: Eighteen trials including 5727 patients were included, but not all trials contributed data to each outcome examined in this review. Sixteen trials were double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the rest used the intravenous route. About 50% of the data (patients and trials) come from trials testing intravenous tissue plasminogen activator. There are few data from patients aged over 80 years. Much of the data comes from trials conducted in the first half of the 1990s when, in an effort to reduce delays to trial drug administration, on site randomisation methods were used that, in consequence, limited the ability to stratify randomisation on key prognostic variables. Several trials, because of the biological effects of thrombolysis combined with the follow-up methods used, did not have complete blinding of outcome assessment. Thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up at three to six months (OR 0.84, 95% CI 0.75 to 0.95). This was in spite of a significant increase in : the odds of death within the first ten days (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.46 to 2.24), the main cause of which was fatal intracranial haemorrhage (OR 4.34, 95% CI 3.14 to 5.99). Symptomatic intracranial haemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22). Thrombolytic therapy also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials that could have been due to many trial features including : thrombolytic drug used, variation in the use of aspirin and heparin, severity of the stroke (both between trials and between treatment groups within trials), and time to treatment. Trials testing intravenous recombinant tissue plasminogen activator suggested that it may be associated with slightly less hazard and more benefit than other drugs when given up to six hours after stroke but these are non-random comparisons - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.17, 95% CI 0.95 to 1.45, dead or dependent at the end of follow-up OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly comparedup OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly compared rt-PA with any other thrombolytic agent. There is some evidence that antithrombotic drugs given soon after thrombolysis may increase the risk of death. REVIEWER'S CONCLUSIONS: Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial haemorrhage, and deaths at follow-up at three to six months. The data from trials using intravenous recombinant tissue plasminogen activator, from which there are the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials for some outcomes and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the latest time window, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a licence exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given. To avoid the problem of data missing from some trials for some key outcomes encountered in this review to date, and to assist future metaanalyses, future trialists should try to collect data in such a way as to be compatible with the basic outcome assessments reviewed here (eg early death, fatal intracranial haemorrhage, poor functional outcome).

Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis.

BACKGROUND AND PURPOSE: Recombinant tissue plasminogen activator (rtPA; Actilyse) is not as widely used in clinical practice as it could be. Have new data since 1995 strengthened the evidence sufficiently to justify more widespread use of rtPA? METHODS: We performed a sequential year-to-year cumulative meta-analysis of randomized controlled trials of rtPA in acute ischemic stroke. RESULTS: Although the amount of data has doubled since 1995, effect estimates for key outcomes remain imprecise, and significant between-trial heterogeneity persists. In the most recent analysis, rtPA up to 6 hours after stroke yielded 55 fewer dead or dependent people per 1000 treated (95% CI, 18 to 92) despite some risk (nonsignificant excess of 19 deaths per 1000 patients treated; 95% CI, 6 fewer to 48 more). Severity of stroke, patient age, and aspirin use were possible sources of heterogeneity. CONCLUSIONS: Despite doubling of the data since 1995, the magnitude of risks and benefits with rtPA remains imprecise. This gap in knowledge may be hindering clinical use of rtPA and can be filled only by new trials designed to address these specific issues.

Surgical decompression for cerebral oedema in acute ischaemic stroke.

BACKGROUND: The high mortality that follows a large cerebral infarction is in part due to brain oedema. Oedema causes mass-effect with raised intracranial pressure and herniation. Medical therapies are used to reduce intracranial pressure but outcome is poor in spite of treatment. Decompressive surgical techniques that attempt to relieve high intracranial pressure due to oedema have been described, but their efficacy in reducing case fatality and disability is uncertain. OBJECTIVES: To compare medical therapy plus decompressive surgery with medical therapy alone on the outcomes death and 'death or dependency' in patients with an acute ischaemic stroke complicated by clinical and radiologically confirmed cerebral oedema. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (4 October 2001). In addition, we searched the following electronic databases: the Cochrane Controlled Trials Register (Cochrane Library, issue 3, 2001), MEDLINE (1966 - April 2002), EMBASE (1980 - April 2002), and SCISEARCH (to April 2002). We also searched the reference lists of all relevant articles retrieved and contacted individual investigators and experts in the field. SELECTION CRITERIA: Randomised controlled studies comparing the outcome of treatment with decompressive surgical intervention with treatment not involving surgery. We aimed to include only those studies with low or moderate risk of bias. DATA COLLECTION AND ANALYSIS: Titles retrieved by searching were assessed for relevance by one author. Data were extracted independently by two authors with discussion to resolve differences. Relevant sub-group analyses were planned and we planned to calculate Peto odds ratios with 95% confidence intervals. MAIN RESULTS: Over 9000 citations were retrieved and inspected for relevance. We identified no randomised-controlled trials to include in a meta-analysis. Five observational studies reporting comparative data were found along with a number of small series and single case reports. Two ongoing randomised-controlled trials were identified. REVIEWER'S CONCLUSIONS: There is no evidence from randomised-controlled trials to support the use of decompressive surgery for the treatment of cerebral oedema in acute ischaemic stroke. Evidence from randomised-controlled trials is needed to accurately assess the effect of decompressive surgery.

Anticoagulants versus antiplatelet agents for acute ischaemic stroke.

BACKGROUND: Antiplatelet agents produce a small, but worthwhile benefit in long-term functional outcome and survival, and have become standard treatment for acute ischaemic stroke. Anticoagulants are often used as an alternative treatment, despite evidence that they are ineffective in producing long-term benefits. We wanted to review trials which have directly compared anticoagulants and antiplatelet agents, to assess whether any anticoagulant regimen offers net advantages over antiplatelet agents, overall or in some particular category of patients (e.g. patients with atrial fibrillation). OBJECTIVES: a) To assess the effectiveness of anticoagulants compared with antiplatelet agents in acute ischaemic stroke b) To assess whether the addition of anticoagulants to antiplatelet agents offers any net advantage over antiplatelet agents alone. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register, the Cochrane Controlled Trials Register (Central/CCTR), the trials register held by the Antithrombotic Therapy Trialists' Collaboration, MEDLINE (1966-2000), and EMBASE (1980-2000). All searches were performed during April and May 2001. SELECTION CRITERIA: Truly unconfounded, randomised-controlled trials comparing anticoagulants with antiplatelet agents, or anticoagulants and antiplatelet agents with antiplatelet agents alone, given within 14 days of onset of presumed or confirmed ischaemic stroke. DATA COLLECTION AND ANALYSIS: Both reviewers independently selected trials for inclusion in the review, assessed trial quality and extracted data. MAIN RESULTS: A total of 16,558 patients from four trials contributed to the analyses. The methodological quality was high in all four trials. The anticoagulants tested were unfractionated heparin (UFH) and low molecular-weight heparin. Aspirin was used as control in all trials. Overall, there was no evidence that anticoagulants were superior to aspirin in reducing 'death or dependency' at long-term follow-up (odds ratio [OR] 1.07, 95% confidence interval [95% CI] 0.98-1.15). Compared with aspirin, anticoagulants were associated with a small but significant increase in the number of deaths at the end of follow-up (OR 1.10, 95% CI 1.01-1.29), equivalent to 20 more deaths (95% CI 0-30) per 1000 patients treated; a significant increased risk of symptomatic intracranial haemorrhage (OR 2.35, 95% CI 1.49-3.46); and a non-significant increased risk of 'any recurrent stroke' during treatment (OR 1.20, 95% CI 0.99-1.46). These neutral or adverse effects outweighed a small, but significant effect on symptomatic deep vein thrombosis (OR 1.20, 95% CI 0.07-0.58), equivalent to 10 fewer (95% CI 0-30) DVTs by 14 days per 1000 patients treated with anticoagulants instead of aspirin. Subgroup analysis could not identify any type, dose, or route of administration of anticoagulants associated with net benefit, or any benefit in patients with atrial fibrillation. Overall, the combination of UFH and aspirin did not appear to be associated with a net advantage over aspirin alone. A subgroup analysis showed that, compared with aspirin, the combination of low-dose UFH and aspirin was associated with a marginally significant reduced risk of 'any recurrent stroke' (OR 0.75, 95% CI 0.56-1.03) and a marginally significant reduced risk of death at 14 days (OR 0.84, 95% CI 0.69-1.01), and with no clear adverse effect on death at end of follow-up (OR 0.98, 95% CI 0.85-1.12). REVIEWER'S CONCLUSIONS: Anticoagulants offered no net advantages over antiplatelet agents in acute ischaemic stroke. The combination of low-dose UFH and aspirin appeared in a subgroup analysis to be associated with net benefits compared with aspirin alone, and this merits further research.