Factors influencing the use of different methods of consent in a randomized acute stroke trial: The Third International Stroke Trial (IST-3).

BACKGROUND: Obtaining informed consent in people with acute stroke is complex since many, as a direct result of their stroke, lose capacity to make important decisions. Furthermore, reperfusion interventions are time dependent necessitating rapid consent. We developed four different consent approaches to facilitate recruitment of a broad range of patients in the Third International Stroke Trial (IST-3). AIMS: To describe the clinical characteristics of patients recruited by different consent methods and the association between these methods and time from stroke onset to randomization. METHODS: IST-3 was a randomized controlled trial of thrombolysis for acute ischemic stroke. Clinicians could use one of four consent procedures: written consent, witnessed consent, assent, or a waiver of consent. We analyzed the relationship between consent procedure and baseline variables. The effect of consent procedure on delay time from onset to randomization was determined using analysis of variance to adjust for confounding effects. RESULTS: Of the 3035 patients recruited, the method of consent was known for 3034 (99.9%), and it was written in 985 subjects (32.5%), witnessed verbal consent in 280 (9.2%), assent by relative in 1727 (56.9%), and waiver of consent in 42 subjects (1.4%). Assent was required in 63.4% for those presenting 0-3 h from stroke onset (written consent in 25.3%). Patients with more severe neurological deficits (or with a non-lacunar hemispheric stroke syndrome) were less likely to give written consent. Mean delay between onset and randomization varied significantly between consent types (one-way analysis of variance: F = 15.7 on 3 df, p < 0.0001) (longest at 4.06 h for signed consent and 3.46 h for waiver of consent). CONCLUSIONS: Acute stroke trials requiring written informed consent would result in substantial selection bias. Flexible consent methods will ensure a broad range of patients are recruited, enabling trial results to be widely generalizable.Registration: This study's registered number is ISRCTN25765518.

Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient-data meta-analysis of randomized trials.

Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke.

BACKGROUND: Low-molecular-weight heparins (LMWHs) and heparinoids are anticoagulants that may have more powerful antithrombotic effects than standard unfractionated heparin (UFH) but a lower risk of bleeding complications. This is an update of the original Cochrane Review of these agents, first published in 2001 and last updated in 2008. OBJECTIVES: To determine whether antithrombotic therapy with LMWHs or heparinoids is associated with a reduction in the proportion of people who are dead or dependent for activities in daily living compared with UFH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library Issue 1, 2017), MEDLINE (1966 to February 2017), and Embase (1980 to February 2017). We also searched trials registers to February 2017: ClinicalTrials.gov, EU Clinical Trials Register, Stroke Trials Registry, ISRCTN Registry and the World Health Organization (WHO) International Clinical Trials Registry Platform. SELECTION CRITERIA: Unconfounded randomised trials comparing LMWH or heparinoids with standard UFH in people with acute ischaemic stroke, in which participants were recruited within 14 days of stroke onset. DATA COLLECTION AND ANALYSIS: Two review authors independently chose studies for inclusion, assessed risk of bias and trial quality, extracted and analysed the data. Differences were resolved by discussion. MAIN RESULTS: We included nine trials involving 3137 participants. We did not identify any new trials for inclusion in this updated review. None of the studies reported data on the primary outcome in sufficient detail to enable analysis for the review. Overall, there was a moderate risk of bias in the included studies. Compared with UFH, there was no evidence of an effect of LMWH or heparinoids on death from all causes during the treatment period (96/1616 allocated LMWH/heparinoid versus 78/1486 allocated UFH; odds ratio (OR) 1.06, 95% CI 0.78 to 1.47; 8 trials, 3102 participants, low quality evidence). LMWH or heparinoid were associated with a significant reduction in deep vein thrombosis (DVT) compared with UFH (OR 0.55, 95% CI 0.44 to 0.70, 7 trials, 2585 participants, low quality evidence). However, the number of the major clinical events such as pulmonary embolism (PE) and intracranial haemorrhage was too small to provide a reliable estimate of the effects. AUTHORS' CONCLUSIONS: Treatment with a LMWH or heparinoid after acute ischaemic stroke appears to decrease the occurrence of DVT compared with standard UFH, but there are too few data to provide reliable information on their effects on other important outcomes, including functional outcome, death and intracranial haemorrhage.

The forecast for future clinical trials and clinical trialists-Storms or sunshine?

Randomized controlled trials are the most unbiased way to evaluate many types of healthcare interventions. Pharmaceutical and medical technology industries play an important role in developing and testing new interventions that have commercial potential. However, many interventions for the prevention, treatment and rehabilitation of stroke are either not drugs or devices or have no commercial potential. Like many other clinicians who are uncertain about the value of existing or new treatments, we are involved in investigator-led clinical trials to resolve treatment uncertainties. There is common agreement that investigator-led clinical trials are facing increasing difficulties and that as a result clinicians may be deterred from pursuing clinical trials as a research career. In this article, we express our concerns for the future of such trials, balanced with the hope that systems to foster and sustain this important type of research in the future can be developed.

Corticosteroids for acute ischaemic stroke.

BACKGROUND: The majority of strokes are due to cerebral infarction. Ischaemic cerebral tissue tends to develop cytotoxic oedema which, if the blood-brain barrier is disrupted, may be followed by vasogenic oedema. Large infarcts can develop life-threatening massive oedema. Early treatment with corticosteroids could theoretically help reduce both cytotoxic and vasogenic oedema and so improve the clinical outcome after a stroke. OBJECTIVES: To assess the effect of corticosteroids in acute presumed ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched: 17 February 2011). SELECTION CRITERIA: Published randomised trials comparing corticosteroids with placebo or a control group in people with acute (presumed or definite) ischaemic stroke. Trials were included if treatment began within 48 hours of stroke onset and if clinical outcomes were assessed. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, assessed trial quality and extracted the data. MAIN RESULTS: Eight trials involving 466 people were included. Details of trial quality that may relate to bias were not available for most trials. No difference was shown in the odds of death within one year (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.57 to 1.34). Treatment did not appear to improve functional outcome in survivors. Seven trials reported neurological impairment but pooling the data was impossible because no common scale or time interval was used. The results were inconsistent between individual trials. The only adverse effects reported were small numbers of gastrointestinal bleeds, infections and deterioration of hyperglycaemia across both groups. The results are unchanged since the previous update. AUTHORS' CONCLUSIONS: There is not enough evidence to evaluate corticosteroid treatment for people with acute presumed ischaemic stroke. The conclusions are unchanged since the previous update.

Physical methods for preventing deep vein thrombosis in stroke.

BACKGROUND: Deep vein thrombosis (DVT) and resulting pulmonary embolism (PE) are important complications of stroke. Physical methods to reduce the risk of DVT and PE, such as graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) applied to the legs, do not appear to be associated with any bleeding risk and reduce the risk of DVT in some categories of surgical patients. We sought to assess their effects in stroke patients. OBJECTIVES: To assess the effectiveness and safety of physical methods of reducing the risk of DVT, fatal or non-fatal PE and death in patients with recent stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE (1966 to November 2009), EMBASE (1980 to November 2009), CINAHL (1982 to November 2009) and The British Nursing Index (1985 to November 2009). We screened reference lists of all relevant papers, searched ongoing trials registers (November 2009) and contacted experts in the field. SELECTION CRITERIA: Unconfounded randomised controlled trials comparing physical methods for reducing the risk of DVT with control and in which prophylaxis was started within seven days of the onset of stroke. DATA COLLECTION AND ANALYSIS: Two review authors searched for trials and extracted data. MAIN RESULTS: We identified two trials of GCS that included 2615 patients and two small studies of IPC that included 177 patients. Overall, physical methods were not associated with a significant reduction in DVTs during the treatment period (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.70 to 1.04) or deaths (OR 1.12, 95% CI 0.87 to 1.45). Use of GCS was not associated with any significant reduction in risk of DVT (OR 0.88, 95% CI 0.72 to 1.08) or death (OR 1.13, 95% CI 0.87 to 1.47) at the end of follow up. IPC was associated with a non-significant trend towards a lower risk of DVTs (OR 0.45, 95% CI 0.19 to 1.10) with no evidence of an effect on deaths (OR 1.04, 95% CI 0.37 to 2.89). AUTHORS' CONCLUSIONS: Evidence from randomised trials does not support the routine use of GCS to reduce the risk of DVT after acute stroke. There is insufficient evidence to support the routine use of IPC to reduce the risk of DVT in acute stroke and further larger randomised studies of IPC are needed to reliably assess the balance of risks and benefits of this intervention.

Surgery for cervical radiculopathy or myelopathy.

BACKGROUND: Cervical spondylosis causes pain and disability by compressing the spinal cord or roots. Surgery to relieve the compression may reduce the pain and disability, but is associated with a small but definite risk. . OBJECTIVES: To determine whether: 1) surgical treatment of cervical radiculopathy or myelopathy is associated with improved outcome, compared with conservative management and 2) timing of surgery (immediate or delayed pending persistence/progression of relevant symptoms and signs) has an impact on outcome. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, and EMBASE to 1998 for the original review. A revised search was run in CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, and CINAHL (January 1998 to June 2008) to update the review.Authors of the identified randomised controlled trials were contacted for additional published or unpublished data. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials allocating patients with cervical radiculopathy or myelopathy to 1) "medical management" or "decompressive surgery (with or without fusion) plus medical management" 2) "early decompressive surgery" or "delayed decompressive surgery". DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and extracted data. MAIN RESULTS: Two trials (N = 149) were included. In both trials, allocation concealment was inadequate and arrangements for blinding of outcome assessment were unclear.One trial (81 patients with cervical radiculopathy) found that surgical decompression was superior to physiotherapy or cervical collar immobilization in the short-term for pain, weakness or sensory loss; at one year, there were no significant differences between groups.One trial (68 patients with mild functional deficit associated with cervical myelopathy) found no significant differences between surgery and conservative treatment in three years following treatment. A substantial proportion of cases were lost to follow-up. AUTHORS' CONCLUSIONS: Both small trials had significant risks of bias and do not provide reliable evidence on the effects of surgery for cervical spondylotic radiculopathy or myelopathy. It is unclear whether the short-term risks of surgery are offset by long-term benefits. Further research is very likely to have an impact on the estimate of effect and our confidence in it.There is low quality evidence that surgery may provide pain relief faster than physiotherapy or hard collar immobilization in patients with cervical radiculopathy; but there is little or no difference in the long-term.There is very low quality evidence that patients with mild myelopathy feel subjectively better shortly after surgery, but there is little or no difference in the long-term.

Magnetic resonance imaging versus computed tomography for detection of acute vascular lesions in patients presenting with stroke symptoms.

BACKGROUND: Magnetic resonance imaging (MRI) is increasingly used for the diagnosis of acute ischaemic stroke but its sensitivity for the early detection of intracerebral haemorrhage has been debated. Computed tomography (CT) is extensively used in the clinical management of acute stroke, especially for the rapid exclusion of intracerebral haemorrhage. OBJECTIVES: To compare the diagnostic accuracy of diffusion-weighted MRI (DWI) and CT for acute ischaemic stroke, and to estimate the diagnostic accuracy of MRI for acute haemorrhagic stroke. SEARCH STRATEGY: We searched MEDLINE and EMBASE (January 1995 to March 2009) and perused bibliographies of relevant studies for additional references. SELECTION CRITERIA: We selected studies that either compared DWI and CT in the same patients for detection of ischaemic stroke or examined the utility of MRI for detection of haemorrhagic stroke, had imaging performed within 12 hours of stroke onset, and presented sufficient data to allow construction of contingency tables. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data on study characteristics and measures of accuracy. We assessed data on ischaemic stroke using random-effects and fixed-effect meta-analyses. MAIN RESULTS: Eight studies with a total of 308 participants met our inclusion criteria. Seven studies contributed to the assessment of ischaemic stroke and two studies to the assessment of haemorrhagic stroke. The spectrum of patients was relatively narrow in all studies, sample sizes were small, there was substantial incorporation bias, and blinding procedures were often incomplete. Amongst the patients subsequently confirmed to have acute ischaemic stroke (161/226), the summary estimates for DWI were: sensitivity 0.99 (95% CI 0.23 to 1.00), specificity 0.92 (95% CI 0.83 to 0.97). The summary estimates for CT were: sensitivity 0.39 (95% CI 0.16 to 0.69), specificity 1.00 (95% CI 0.94 to 1.00). The two studies on haemorrhagic stroke reported high estimates for diffusion-weighted and gradient-echo sequences but had inconsistent reference standards. We did not calculate overall estimates for these two studies. We were not able to assess practicality or cost-effectiveness issues. AUTHORS' CONCLUSIONS: DWI appears to be more sensitive than CT for the early detection of ischaemic stroke in highly selected patients. However, the variability in the quality of included studies and the presence of spectrum and incorporation biases render the reliability and generalisability of observed results questionable. Further well-designed studies without methodological biases, in more representative patient samples, with practicality and cost estimates are now needed to determine which patients should undergo MRI and which CT in suspected acute stroke.