Electronic informed consent: effects on enrolment, practical and economic benefits, challenges, and drawbacks-a systematic review of studies within randomized controlled trials.

BACKGROUND: Enrolment is one of the most challenging aspects of conducting clinical trials, preceded by the process of informed consent (IC). Different strategies to improve recruitment in clinical trials have been used, including electronic IC. During COVID-19 pandemic, barriers to enrolment have been evident. Although digital technologies were acknowledged as the future of clinical research and potential advantages were shown for recruitment, electronic informed consent (e-IC) has not yet been globally adopted. The purpose of this review is to investigate the effect of using e-IC on enrolment, practical and economic benefits, challenges, and drawbacks when compared to traditional informed consent, through a systematic review. METHODS: Embase, Global Health Library, Medline, and The Cochrane Library databases were searched. No limit was set for publication date, age, sex, or study design. We included all studies within a randomized controlled trial (RCT), published in English, Chinese or Spanish, evaluating the electronic consent process used in the parent RCT. Studies were included if any of the three components ((i) information provision, (ii) participant's comprehension, (iii) signature) of the IC process was designed as electronic, whether administered remotely or face-to-face. The primary outcome was the rate of enrolment to the parent trial. Secondary outcomes were summarized according to the various findings reported on the use of electronic consent. RESULTS: From a total of 9069 titles, 12 studies were included in the final analysis with a total of 8864 participants. Five studies of high heterogeneity and risk of bias showed mixed results on the efficacy of e-IC on enrolment. Data of included studies suggested e-IC could improve comprehension and recall of study-related information. Meta-analysis could not be conducted due to different study designs and outcome measures and the predominantly qualitative findings. CONCLUSION: Few published studies have investigated the impact of e-IC on enrolment and findings were mixed. e-IC may improve participant's comprehension and recall of information. High-quality studies are needed to evaluate the potential benefit of e-IC to increase clinical trial enrolment. TRIAL REGISTRATION: PROSPERO CRD42021231035 . Registration date: 19-Feb-2021.

Reporting "specific abilities" after major stroke to better describe prognosis.

INTRODUCTION: If health professionals are to involve major stroke patients and their families in making decisions about treatments, they need to describe prognosis in terms that are easily understood. We suggest that referring to "specific abilities", such as ability to be independent, walk, talk, eat normally, be continent, live without severe pain, live without major anxiety or depression and to live at home may be more easily understood than terms such as disabled based on the modified Rankin scale (mRs). OBJECTIVE: We aimed to describe the "specific abilities" and quality of life of patients in each mRs level at six months after major stroke. PATIENTS AND METHODS: A longitudinal cohort study of patients admitted to hospital with major stroke with follow up at six months. RESULTS: We recruited 403 patients, mean age 77.5yrs. The number (%) in each mRs level at six months was 0 (no problems): 8(2%), 1: 45(11.2%), 2: 7(1.7%), 3: 149(37.1%), 4: 46(11.4%), 5: 36(9.0%) and 6(dead) 111(27.6%). Patients within each mRs level varied with respect to their "specific abilities" and quality of life. For example, of the 36(9%) patients with mRs 5, 30(83%) could talk, 14(39%) were continent, 33(92%) were not in severe pain, 22(61%) did not have major anxiety/depression and 5(14%) could live at home. Their median utility (derived from HRQoL) was -0.08 (range -0.35 to 0.43). DISCUSSION AND CONCLUSIONS: Describing prognosis with the mRs does not convey the variation in specific abilities and HRQoL amongst patients with major stroke. Therefore, describing prognosis in terms of "specific abilities" may be more appropriate.

Fluoxetine to improve functional outcomes in patients after acute stroke: the FOCUS RCT.

BACKGROUND: Our Cochrane review of selective serotonin inhibitors for stroke recovery indicated that fluoxetine may improve functional recovery, but the trials were small and most were at high risk of bias. OBJECTIVES: The Fluoxetine Or Control Under Supervision (FOCUS) trial tested the hypothesis that fluoxetine improves recovery after stroke. DESIGN: The FOCUS trial was a pragmatic, multicentre, parallel-group, individually randomised, placebo-controlled trial. SETTING: This trial took place in 103 UK hospitals. PARTICIPANTS: Patients were eligible if they were aged ≥ 18 years, had a clinical stroke diagnosis, with focal neurological deficits, between 2 and 15 days after onset. INTERVENTIONS: Patients were randomly allocated 20 mg of fluoxetine once per day or the matching placebo for 6 months via a web-based system using a minimisation algorithm. MAIN OUTCOME MEASURES: The primary outcome was the modified Rankin Scale at 6 months. Patients, carers, health-care staff and the trial team were masked to treatment allocation. Outcome was assessed at 6 and 12 months after randomisation. Patients were analysed by their treatment allocation as specified in a published statistical analysis plan. RESULTS: Between 10 September 2012 and 31 March 2017, we recruited 3127 patients, 1564 of whom were allocated fluoxetine and 1563 of whom were allocated placebo. The modified Rankin Scale score at 6 months was available for 1553 out of 1564 (99.3%) of those allocated fluoxetine and 1553 out of 1563 (99.4%) of those allocated placebo. The distribution across modified Rankin Scale categories at 6 months was similar in the two groups (common odds ratio adjusted for minimisation variables 0.951, 95% confidence interval 0.839 to 1.079; p = 0.439). Compared with placebo, patients who were allocated fluoxetine were less likely to develop a new episode of depression by 6 months [210 (13.0%) vs. 269 (16.9%), difference -3.78%, 95% confidence interval -1.26% to -6.30%; p = 0.003], but had more bone fractures [45 (2.9%) vs. 23 (1.5%), difference 1.41%, 95% confidence interval 0.38% to 2.43%; p = 0.007]. There were no statistically significant differences in any other recorded events at 6 or 12 months. Health economic analyses showed no differences between groups in health-related quality of life, hospital bed usage or health-care costs. LIMITATIONS: Some non-adherence to trial medication, lack of face-to-face assessment of neurological status at follow-up and lack of formal psychiatric diagnosis during follow-up. CONCLUSIONS: 20 mg of fluoxetine daily for 6 months after acute stroke did not improve patients' functional outcome but decreased the occurrence of depression and increased the risk of fractures. These data inform decisions about using fluoxetine after stroke to improve functional outcome or to prevent or treat mood disorders. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) (Australasia/Vietnam) and Efficacy oF Fluoxetine - a randomisEd Controlled Trial in Stroke (EFFECTS) (Sweden) trials recruited an additional 2780 patients and will report their results in 2020. These three trials have an almost identical protocol, which was collaboratively developed. Our planned individual patient data meta-analysis will provide more precise estimates of the effects of fluoxetine after stroke and indicate whether or not effects vary depending on patients' characteristics and health-care setting. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83290762. 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. 24, No. 22. See the NIHR Journals Library website for further project information. The Stroke Association (reference TSA 2011101) funded the start-up phase.

Fluoxetine, sometimes referred to by the drug company name Prozac, has been used for many years to treat people who are depressed, including after a stroke. However, studies have suggested that treatment with fluoxetine started soon after a stroke might improve patients' physical recovery. The Fluoxetine Or Control Under Supervision (FOCUS) trial recruited 3127 volunteers who had had a stroke within the previous 2 weeks from 103 UK hospitals between 2012 and 2017. Participants were randomly allocated to take a 6-month course of fluoxetine or an identical placebo capsule containing no fluoxetine. They were followed up at 6 months and 12 months after recruitment. Patients completed questionnaires that indicated how much they had recovered, and also measured their mood, fatigue and quality of life. The results of the trial showed that the physical recovery of patients was very similar in both groups. This indicates that fluoxetine does not improve physical outcomes of stroke patients. However, participants receiving fluoxetine were less likely to develop depression after the stroke but once the fluoxetine was stopped these effects on mood disappeared. Unfortunately, patients on fluoxetine were slightly more likely to fall and fracture a bone than those on placebo. The FOCUS trial is the first of three large randomised controlled trials testing fluoxetine in stroke patients to be completed. The FOCUS trial results suggest that patients with stroke should not routinely be treated with fluoxetine. The other two trials will give us further information about the effects of fluoxetine after stroke and whether or not its effects differ between countries or ethnic groups.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis.

BACKGROUND: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. METHODS/DESIGN: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. DISCUSSION: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020. TRIAL REGISTRATION: FOCUS: ISRCTN , ISRCTN83290762 . Registered on 23 May 2012. EudraCT, 2011-005616-29. Registered on 3 February 2012. AFFINITY: Australian New Zealand Clinical Trials Registry, ACTRN12611000774921 . Registered on 22 July 2011. EFFECTS: ISRCTN , ISRCTN13020412 . Registered on 19 December 2014. Clinicaltrials.gov, NCT02683213 . Registered on 2 February 2016. EudraCT, 2011-006130-16 . Registered on 8 August 2014.

The Clots in Legs Or sTockings after Stroke (CLOTS) 3 trial: a randomised controlled trial to determine whether or not intermittent pneumatic compression reduces the risk of post-stroke deep vein thrombosis and to estimate its cost-effectiveness.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of death and morbidity in stroke patients. There are few data concerning the effectiveness of intermittent pneumatic compression (IPC) in treating patients with stroke. OBJECTIVES: To establish whether or not the application of IPC to the legs of immobile stroke patients reduced their risk of deep vein thrombosis (DVT). DESIGN: Clots in Legs Or sTockings after Stroke (CLOTS) 3 was a multicentre, parallel-group, randomised controlled trial which allocated patients via a central randomisation system to IPC or no IPC. A technician blinded to treatment allocation performed compression duplex ultrasound (CDU) of both legs at 7-10 days and 25-30 days after enrolment. We followed up patients for 6 months to determine survival and later symptomatic VTE. Patients were analysed according to their treatment allocation. SETTING: We enrolled 2876 patients in 94 UK hospitals between 8 December 2008 and 6 September 2012. INCLUSION CRITERIA: patients admitted to hospital within 3 days of acute stroke and who were immobile on the day of admission (day 0) to day 3. EXCLUSION CRITERIA: age < 16 years; subarachnoid haemorrhage; and contra-indications to IPC including dermatitis, leg ulcers, severe oedema, severe peripheral vascular disease and congestive cardiac failure. INTERVENTIONS: Participants were allocated to routine care or routine care plus IPC for 30 days, or until earlier discharge or walking independently. MAIN OUTCOME MEASURES: The primary outcome was DVT in popliteal or femoral veins, detected on a screening CDU, or any symptomatic DVT in the proximal veins, confirmed by imaging, within 30 days of randomisation. The secondary outcomes included death, any DVTs, symptomatic DVTs, pulmonary emboli, skin breaks on the legs, falls with injury or fractures and duration of IPC use occurring within 30 days of randomisation and survival, symptomatic VTE, disability (as measured by the Oxford Handicap Scale), quality of life (as measured by the European Quality of Life-5 Dimensions 3 Level questionnaire) and length of initial hospital stay measured 6 months after randomisation. RESULTS: We allocated 1438 patients to IPC and 1438 to no IPC. The primary outcome occurred in 122 (8.5%) of 1438 patients allocated to IPC and 174 (12.1%) of 1438 patients allocated to no IPC, giving an absolute reduction in risk of 3.6% [95% confidence interval (CI) 1.4% to 5.8%] and a relative risk reduction of 0.69 (95% CI 0.55 to 0.86). After excluding 323 patients who died prior to any primary outcome and 41 who had no screening CDU, the primary outcome occurred in 122 of 1267 IPC participants compared with 174 of 1245 no-IPC participants, giving an adjusted odds ratio of 0.65 (95% CI 0.51 to 0.84; p = 0.001). Secondary outcomes in IPC compared with no-IPC participants were death in the treatment period in 156 (10.8%) versus 189 (13.1%) (p = 0.058); skin breaks in 44 (3.1%) versus 20 (1.4%) (p = 0.002); and falls with injury in 33 (2.3%) versus 24 (1.7%) (p = 0.221). Among patients treated with IPC, there was a statistically significant improvement in survival to 6 months (hazard ratio 0.86, 95% CI 0.73 to 0.99; p = 0.042), but no improvement in disability. The direct cost of preventing a DVT was £1282 per event (95% CI £785 to £3077). CONCLUSIONS: IPC is an effective and inexpensive method of reducing the risk of DVT and improving survival in immobile stroke patients. FUTURE RESEARCH: Further research should test whether or not IPC improves survival in other groups of high-risk hospitalised medical patients. In addition, research into methods to improve adherence to IPC might increase the benefits of IPC in stroke patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93529999. FUNDING: The start-up phase of the trial (December 2008-March 2010) was funded by the Chief Scientist Office of the Scottish Government (reference number CZH/4/417). The main phase of the trial was funded by the National Institute for Health Research Health Technology Assessment programme (reference number 08/14/03). Covidien Ltd (Mansfield, MA, USA) lent its Kendall SCD™ Express sequential compression system controllers to the 105 centres involved in the trial and donated supplies of its sleeves. It also provided logistical help in keeping our centres supplied with sleeves and training materials relevant to the use of their devices. Recruitment and follow-up were supported by the National Institute for Health Research-funded UK Stroke Research Network and by the Scottish Stroke Research Network, which was supported by NHS Research Scotland.

Which stroke patients gain most from intermittent pneumatic compression: further analyses of the CLOTS 3 trial.

BACKGROUND: The CLOTS 3 trial showed that intermittent pneumatic compression (IPC) reduced the risk of DVT and improved survival after stroke. AIMS: To provide additional information which may help clinicians target IPC on the most appropriate patients by exploring the variation in its effects on subgroups defined by predicted prognosis. METHODS: A multicentre, parallel group, randomized trial enrolled immobile acute stroke patients and allocated them to IPC or no IPC. The primary outcome was proximal DVT at 30 days. Secondary outcomes at six-months included survival, disability, quality of life, and hospital costs. We stratified patients into quintiles according to their predicted prognosis at randomization, based on the Six Simple Variable model. RESULTS: Between December 2008 and September 2012, we enrolled 2876 patients in 94 UK hospitals. Patients with the best predicted outcome had the lowest absolute risk of proximal DVT (6·7%) and death by six-months (9·3%). Allocation to IPC had little effect on DVT, survival, disability, quality of life, hospital length of stay, or costs. In patients with the worst predicted outcomes, the overall risk of DVT and death was 16·0% and 51·3%, respectively. IPC reduced DVT (odds reduction 34%) and improved survival 17% and significantly increased length of stay and hospital costs. In the three intermediate quintiles, IPC reduced the odds of DVT (35-43%) and improved survival (11-13%). Disability and quality of life at six-months depended on baseline severity but was not influenced significantly by IPC. CONCLUSIONS: IPC appears to reduce the risk of DVT and probably improves survival in all immobile stroke patients, other than the fifth with the best prognosis. It therefore seems reasonable to recommend that IPC should be considered in all immobile stroke patients, but that the final decision should be based on a judgment about the individual's prognosis. In some, their prognosis for survival with an acceptable quality of life will be so poor that use of IPC might be considered futile, while at the other end of the spectrum, patients' risk of DVT, and of dying from VTE, may not be high enough to justify the modest cost and inconvenience of IPC use.

The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: a study protocol for three multicentre randomised controlled trials.

BACKGROUND: Several small trials have suggested that fluoxetine improves neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials that aim to determine whether routine administration of fluoxetine (20 mg daily) for 6 months after acute stroke improves patients' functional outcome. METHODS/DESIGN: The three trial investigator teams have collaboratively developed a core protocol. Minor variations have been tailored to the national setting in the UK (FOCUS), Australia and New Zealand (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will subsequently provide the most precise estimate of the overall effect of fluoxetine after stroke and establish whether any effects differ between trials and subgroups of patients. The trials include patients ≥18 years old with a clinical diagnosis of stroke, persisting focal neurological deficits at randomisation between 2 and 15 days after stroke onset. Patients are randomised centrally via web-based randomisation systems using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Our primary outcome measure is the modified Rankin scale (mRS) at 6 months. Secondary outcomes include the Stroke Impact Scale, EuroQol (EQ5D-5 L), the vitality subscale of the Short-Form 36, diagnosis of depression, adherence to medication, adverse events and resource use. Outcomes are collected at 6 and 12 months. The methods of collecting these data are tailored to the national setting. If FOCUS, AFFINITY and EFFECTS combined enrol 6000 participants as planned, they would have 90 % power (alpha 5 %) to detect a common odds ratio of 1.16, equivalent to a 3.7 % absolute difference in percentage with mRS 0-2 (44.0 % to 47.7 %). This is based on an ordinal analysis of mRS adjusted for baseline variables included in the minimisation algorithm. DISCUSSION: If fluoxetine is safe and effective in promoting functional recovery, it could be rapidly, widely and affordably implemented in routine clinical practice and reduce the burden of disability due to stroke. FOCUS: ISRCTN83290762 (23/05/2012), AFFINITY: ACTRN12611000774921 (22/07/2011). EFFECTS: ISRCTN13020412 (19/12/2014).

The impact of stroke unit care on outcome in a Scottish stroke population, taking into account case mix and selection bias.

BACKGROUND AND AIM: Randomised trials indicate that stroke unit care reduces morbidity and mortality after stroke. Similar results have been seen in observational studies but many have not corrected for selection bias or independent predictors of outcome. We evaluated the effect of stroke unit compared with general ward care on outcomes after stroke in Scotland, adjusting for case mix by incorporating the six simple variables (SSV) model, also taking into account selection bias and stroke subtype. METHODS: We used routine data from National Scottish datasets for acute stroke patients admitted between 2005 and 2011. Patients who died within 3 days of admission were excluded from analysis. The main outcome measures were survival and discharge home. Multivariable logistic regression was used to estimate the OR for survival, and adjustment was made for the effect of the SSV model and for early mortality. Cox proportional hazards model was used to estimate the hazard of death within 365 days. RESULTS: There were 41 692 index stroke events; 79% were admitted to a stroke unit at some point during their hospital stay and 21% were cared for in a general ward. Using the SSV model, we obtained a receiver operated curve of 0.82 (SE 0.002) for mortality at 6 months. The adjusted OR for survival at 7 days was 3.11 (95% CI 2.71 to 3.56) and at 1 year 1.43 (95% CI 1.34 to 1.54) while the adjusted OR for being discharged home was 1.19 (95% CI 1.11 to 1.28) for stroke unit care. CONCLUSIONS: In routine practice, stroke unit admission is associated with a greater likelihood of discharge home and with lower mortality up to 1 year, after correcting for known independent predictors of outcome, and excluding early non-modifiable mortality.

An assessment of the cost-effectiveness of magnetic resonance, including diffusion-weighted imaging, in patients with transient ischaemic attack and minor stroke: a systematic review, meta-analysis and economic evaluation.

BACKGROUND: Patients with transient ischaemic attack (TIA) or minor stroke need rapid treatment of risk factors to prevent recurrent stroke. ABCD2 score or magnetic resonance diffusion-weighted brain imaging (MR DWI) may help assessment and treatment. OBJECTIVES: Is MR with DWI cost-effective in stroke prevention compared with computed tomography (CT) brain scanning in all patients, in specific subgroups or as 'one-stop' brain-carotid imaging? What is the current UK availability of services for stroke prevention? DATA SOURCES: Published literature; stroke registries, audit and randomised clinical trials; national databases; survey of UK clinical and imaging services for stroke; expert opinion. REVIEW METHODS: Systematic reviews and meta-analyses of published/unpublished data. Decision-analytic model of stroke prevention including on a 20-year time horizon including nine representative imaging scenarios. RESULTS: The pooled recurrent stroke rate after TIA (53 studies, 30,558 patients) is 5.2% [95% confidence interval (CI) 3.9% to 5.9%] by 7 days, and 6.7% (5.2% to 8.7%) at 90 days. ABCD2 score does not identify patients with key stroke causes or identify mimics: 66% of specialist-diagnosed true TIAs and 35-41% of mimics had an ABCD2 score of ≥ 4; 20% of true TIAs with ABCD2 score of < 4 had key risk factors. MR DWI (45 studies, 9078 patients) showed an acute ischaemic lesion in 34.3% (95% CI 30.5% to 38.4%) of TIA, 69% of minor stroke patients, i.e. two-thirds of TIA patients are DWI negative. TIA mimics (16 studies, 14,542 patients) make up 40-45% of patients attending clinics. UK survey (45% response) showed most secondary prevention started prior to clinic, 85% of primary brain imaging was same-day CT; 51-54% of patients had MR, mostly additional to CT, on average 1 week later; 55% omitted blood-sensitive MR sequences. Compared with 'CT scan all patients' MR was more expensive and no more cost-effective, except for patients presenting at > 1 week after symptoms to diagnose haemorrhage; strategies that triaged patients with low ABCD2 scores for slow investigation or treated DWI-negative patients as non-TIA/minor stroke prevented fewer strokes and increased costs. 'One-stop' CT/MR angiographic-plus-brain imaging was not cost-effective. LIMITATIONS: Data on sensitivity/specificity of MR in TIA/minor stroke, stroke costs, prognosis of TIA mimics and accuracy of ABCD2 score by non-specialists are sparse or absent; all analysis had substantial heterogeneity. CONCLUSIONS: Magnetic resonance with DWI is not cost-effective for secondary stroke prevention. MR was most helpful in patients presenting at > 1 week after symptoms if blood-sensitive sequences were used. ABCD2 score is unlikely to facilitate patient triage by non-stroke specialists. Rapid specialist assessment, CT brain scanning and identification of serious underlying stroke causes is the most cost-effective stroke prevention strategy. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Does intermittent pneumatic compression reduce the risk of post stroke deep vein thrombosis? The CLOTS 3 trial: statistical analysis plan.

BACKGROUND: Venous thromboembolism (VTE) is a common and important complication of stroke. The CLOTS 3 trial aims to determine whether, compared with best medical care, best medical care plus intermittent pneumatic compression (IPC) in immobile stroke patients reduces the risk of proximal deep vein thrombosis (DVT). METHODS/DESIGN: The CLOTS 3 trial is a multicenter, parallel group trial with centralized randomization (minimization) to ensure allocation concealment. The protocol has been published (Trials 2012, 13:26) and is available in full at: http://www.clotstrial.com. Between December 2008 and September 2012, 105 centers in the UK recruited 2,876 immobile stroke patients within the first 3 days of their hospital admission. Patients were allocated to best medical care or best medical care plus IPC. Ultrasonographers performed a compression Doppler ultrasound scan to detect DVT in each treatment group at 7 to 10 days and 25 to 30 days. The primary outcome cluster includes symptomatic or asymptomatic DVT in the popliteal or femoral veins detected on either scan. Patients will be followed up by postal or telephone questionnaire at 6 months from randomization to detect later symptomatic DVT and pulmonary embolism (PE), and to measure functional outcome (Oxford Handicap Scale) and quality of life (EQ-5D-3L). The ultrasonographers performing the scans are blinded to treatment allocation, whereas the patients and caregivers are not. The trial has more than 90% power to detect a 4% absolute difference (12% versus 8%) in risk of the primary outcome and includes a health economic analysis.Follow-up will be completed in April 2013 and the results reported in May 2013. In this update, we describe the statistical analysis plan. TRIAL REGISTRATION: ISRCTN: ISRCTN93529999.

Does intermittent pneumatic compression reduce the risk of post stroke deep vein thrombosis? The CLOTS 3 trial: study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80,000 patients each year are admitted to U.K. hospitals with an acute stroke and are immobile. At least 10% will develop a proximal deep vein thrombosis in the first month and 1.5% a pulmonary embolus. Although hydration, antiplatelet treatment and early mobilisation may reduce the risk of deep vein thrombosis, there are currently no preventive strategies which have been clearly shown to be both effective and safe. Anticoagulation increases the risks of bleeding and compression stockings are ineffective. Systematic reviews of small randomized trials of intermittent pneumatic compression have shown that this reduces the risk of deep vein thrombosis in patients undergoing surgery, but that there are few data concerning its use after stroke. The CLOTS trial 3 aims to determine whether, compared with best medical care, best medical care plus intermittent pneumatic compression in immobile stroke patients reduces the risk of proximal deep vein thrombosis. METHODS/DESIGN: CLOTS Trial 3 is a parallel group multicentre trial; with centralized randomisation (minimisation) to ensure allocation concealment. Over 80 centres in the U.K. will recruit 2800 immobile stroke patients within the first 3 days of their hospital admission. Patients will be allocated to best medical care or best medical care plus intermittent pneumatic compression. Ultrasonographers will perform a Compression Duplex Ultrasound Scan to detect deep vein thrombosis in each treatment group at about 7-10 days and 25-30 days. The primary outcome cluster includes symptomatic or asymptomatic deep vein thrombosis in the popliteal or femoral veins detected on either scan. Patients are then followed up by postal or telephone questionnaire at 6 months from randomisation to detect later symptomatic deep vein thrombosis and pulmonary emboli and to establish their functional outcome (Oxford handicap scale) and quality of life (EQ5D-3 L). The ultrasonographers performing the scans are blinded to treatment allocation, whereas the patients and caregivers are not. The trial has 90% power to detect a 4% absolute difference in risk of the primary outcome and includes a health economic analysis. DISCUSSION: The trial started recruitment in Dec 2008 and will complete recruitment during 2012. It will report results in 2013. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN93529999.

Research governance impediments to clinical trials: a retrospective survey.

OBJECTIVE: We sought to evaluate the delays, between-centre variations in practice, and opportunity costs attributable to delays in research governance approval of clinical trials in the United Kingdom. DESIGN: Retrospective survey. SETTING: Research and Development (R&D) departments at 50 UK National Health Service hospital trusts governing 57 hospital sites. PARTICIPANTS: R&D departments participating in four randomized multicentre clinical trials coordinated by our Neurosciences Trials Unit. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Median delay between application and research governance approval. RESULTS: Only half of the R&D departments used the UK online R&D form. Only a single copy of the application was required by 96% of R&D departments. The median delay between application and research governance approval was 44 working days (inter-quartile range 23-80). A delay of >20 working days was incurred by 43 applications (75%), of which 24 (56%) were not explicable and 11 (20%) were attributable to local funding negotiations. Based on the trial randomization rates at each centre, 108 patients (17% of all patients randomized) could have been randomized during the delay, at a crude cost to funding agencies of 53,743 pounds; if a four week delay was deemed acceptable, 75 patients (12% of all patients randomized) could have been randomized during unacceptable delays, at a crude cost to funding agencies of 37,700 pounds. CONCLUSIONS: The UK research governance system incurs unacceptably long and costly delays for clinical trials. Urgent reform is needed, including rapid design and uniform implementation of the 'bureaucracy busting' measures in Best Research for Best Health.

Interobserver agreement for the bedside clinical assessment of suspected stroke.

BACKGROUND AND PURPOSE: Stroke remains primarily a clinical diagnosis, with information obtained from history and examination determining further management. We aimed to measure inter-rater reliability for the clinical assessment of stroke, with emphasis on items of history, timing of symptom onset, and diagnosis of stroke or mimic. We explored reasons for poor reliability. METHODS: The study was based in an urban hospital with an acute stroke unit. Pairs of observers independently assessed suspected stroke patients. Findings from history, neurological examination, and the diagnosis of stroke or mimic, were recorded on a standard form. Reliability was measured by the kappa statistic. We assessed the impact of observer experience and confidence, time of assessment, and patient-related factors of age, confusion, and aphasia on inter-rater reliability. RESULTS: Ninety-eight patients were recruited. Most items of the history and the diagnosis of stroke were found to have moderate to good inter-rater reliability. There was agreement for the hour and minute of symptom onset in only 45% of cases. Observer experience and confidence improved reliability; patient-related factors of confusion and aphasia made the assessment more difficult. There was a trend for worse inter-rater reliability among patients assessed very early and very late after symptom onset. CONCLUSIONS: Clinicians should be aware that inter-rater reliability of the clinical assessment is affected by a variety of factors and is improved by experience and confidence. Our findings have implications for training of doctors who assess patients with suspected stroke and identifies the more reliable components of the clinical assessment.

Cost-effectiveness of thrombolysis with recombinant tissue plasminogen activator for acute ischemic stroke assessed by a model based on UK NHS costs.

BACKGROUND AND PURPOSE: Thrombolytic therapy is licensed for use in highly selected patients with acute ischemic stroke. We aimed to model the health economic impact of limited use of thrombolytic therapy and to assess whether it was likely to be cost-effective when used more widely in the UK National Health Service (NHS). METHODS: The authors formed a discussion panel to develop the decision-analysis model of acute stroke care. It consisted of Markov state-transition processes, with probabilities of different health states determined by certain key variables. The range of estimates of efficacy of recombinant tissue plasminogen activator (rt-PA) was taken from an update to a Cochrane systematic review of randomized trials of thrombolysis. Data on outcome after stroke were taken from our hospital-based stroke register, supplemented by data derived from relevant literature sources. RESULTS: The model suggested that compared with standard care, if eligible patients were treated with rt-PA up to 6 hours, there was a 78% probability of a gain in quality-adjusted survival during the first year, at a cost of pound 13 581 per quality-adjusted life-year (QALY) gained. Over a lifetime, rt-PA was associated with cost-savings of pound 96 565 per QALY. However, the estimates were imprecise and highly susceptible to the assumptions used in the economic model; under several plausible assumptions, rt-PA was much less cost-effective than standard care, and under others, a great deal more cost-effective. CONCLUSIONS: The estimates of effectiveness and cost-effectiveness were imprecise. Although the benefits appeared promising, the data did not support the widespread use of thrombolytic therapy outside the terms of the current restricted license in routine clinical practice in the NHS. There is a case for new large-scale randomized trials comparing thrombolytic therapy with control up to 6 hours to determine more precisely the effects of rt-PA on short-term and long-term survival and its cost-effectiveness when used in a wider range of patients.