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1.  Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial 
International Journal of Stroke  2014;9(3):372-374.
High blood pressure is common during the acute phase of stroke and is associated with a poor outcome. However, the management of high blood pressure remains unclear. The ‘Efficacy of Nitric Oxide in Stroke’ trial tested whether transdermal glyceryl trinitrate, a nitric oxide donor that lowers blood pressure, is safe and effective in improving outcome after acute stroke. Efficacy of Nitric Oxide in Stroke is an international multicenter, prospective, randomized, single-blind, blinded endpoint trial, with funding from the UK Medical Research Council. Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140–220 mmHg were randomized to glyceryl trinitrate or no glyceryl trinitrate and, where relevant, to continue or stop prestroke antihypertensive therapy. The primary outcome is shift in modified Rankin Scale at three-months. Patients or relatives gave written informed (proxy) consent, and all sites had research ethics approval. Analyses will be done by intention to treat. This paper and attachment describe the trial's statistical analysis plan, developed prior to unblinding of date. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the two primary publications and some secondary publications. The database will be locked in late February 2014 in preparation for presentation of the results in May 2014. The data from the trial will improve the precision of the estimates of the overall treatment effects (efficacy and safety) of results from completed trials of blood pressure management in acute stroke, and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate, and of continuing (vs. stopping) prestroke antihypertensive medications, in acute stroke.
doi:10.1111/ijs.12235
PMCID: PMC4235425  PMID: 24588789
acute stroke trial; blood pressure; glyceryl trinitrate; intracerebral hemorrhage; ischemic stroke; statistical analysis plan
2.  Prevention of Decline in Cognition after Stroke Trial (PODCAST): a study protocol for a factorial randomised controlled trial of intensive versus guideline lowering of blood pressure and lipids 
Trials  2013;14:401.
Background
Stroke is a common cause of cognitive impairment and dementia. However, effective strategies for reducing the risk of post-stroke dementia remain undefined. Potential strategies include intensive lowering of blood pressure and/or lipids.
Methods/Design
Design: multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial phase IV trial in secondary and primary care.
Participants: 100 participants from 30 UK Stroke Research Network sites who are post- ischemic stroke or intracerebral haemorrhage by three to seven months.
Interventions - all patients (1:1): intensive versus guideline blood pressure lowering (target systolic < 125 mmHg versus < 140 mmHg).
Interventions - ischemic stroke (1:1): intensive versus guideline lipid lowering (target low density lipoprotein-cholesterol (LDL-c) < 1.4 mmol/l versus < 3 mmol/l).
Hypotheses: does ‘intensive’ blood pressure lowering therapy and/or ‘intensive’ lipid control reduce cognitive decline and dementia in people with ischemic stroke; and does ‘intensive’ blood pressure lowering therapy reduce cognitive decline and dementia in patients with hemorrhagic stroke.
Primary outcome: Addenbrooke’s Cognitive Examination-Revised.
Secondary outcomes: feasibility of recruitment and retention of participants, tolerability and safety of the interventions, achieving and maintaining the blood pressure and lipid targets, maintaining differences in systolic blood pressure (> 10 mmHg) and low density lipoprotein-cholesterol (> 1 mmol/l) between the treatment groups, and performing clinic and telephone follow-up of cognition measures.
Randomisation: using stratification, minimization and simple randomization.
Blinding: participants receive open-label management. Cognition is assessed both unblinded (in clinic) and blinded (by telephone) to treatment. Adjudication of events (dementia, vascular, serious adverse events) is blinded to management.
Discussion
The PODCAST trial is ongoing with 78 patients recruited to date from 22 sites. Outcomes of cognitive impairment and dementia are accruing.
Trial registration
ISRCTN85562386
doi:10.1186/1745-6215-14-401
PMCID: PMC4222827  PMID: 24266960
Stroke; Post-stroke cognitive impairment; Post-stroke dementia; Blood pressure lowering; Lipid lowering
3.  The Cog-4 Subset of the National Institutes of Health Stroke Scale as a Measure of Cognition: Relationship with Baseline Factors and Functional Outcome after Stroke Using Data from the Virtual International Stroke Trials Archive 
Stroke Research and Treatment  2013;2013:562506.
Background. Assessing poststroke cognitive impairment is complex. A subscale of the NIHSS, the Cog-4, has been proposed as a quick test of “cognitive impairment.” but a study of its properties in a larger dataset is lacking. Methods. Data from 9,147 patients with acute stroke from the VISTA archive was used to generate Cog-4 scores. The statistical properties of Cog-4, its relationship with baseline clinical characteristics, and other functional outcome measures at day 90 were assessed. Results. Mean age of patients was 69.2 years and 45.8%, were females. Day-90 Cog-4 was highly positively skewed (skewness 0.926). Patients with left hemispheric stroke had higher day-90 Cog-4 score (P < 0.001). Age, stroke severity, and previous stroke were significant predictors of Cog-4. Cog-4 was significantly correlated with dependency (modified Rankin Scale, rs = 0.512), and disability (Barthel Index, rs = −0.493). Conclusions. The Cog-4 scale at day 90 cannot be considered a useful test of cognition since it only superficially measures cognition. It is heavily dependent on the side of stroke, is inevitably associated with functional outcome (being a subset of the NIHSS), and suffers from a profound “floor” effect. Specific and validated measures are more appropriate for the assessment of poststroke cognition than Cog-4.
doi:10.1155/2013/562506
PMCID: PMC3622404  PMID: 23589782
4.  Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the “Rapid Intervention with GTN in Hypertensive Stroke Trial” (RIGHT, ISRCTN66434824) 
Stroke Research and Treatment  2012;2012:385753.
Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.
doi:10.1155/2012/385753
PMCID: PMC3480012  PMID: 23125943
5.  A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility 
PLoS ONE  2008;3(8):e2852.
Background
Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke.
Methodology/Principal Findings
A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01).
Conclusions/Significance
Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy.
Trial Registration
Controlled-Trials.com ISRCTN83673558
doi:10.1371/journal.pone.0002852
PMCID: PMC2481397  PMID: 18682741

Results 1-5 (5)