Outcome assessment by central adjudicators in randomised stroke trials: Simulation of differential and non-differential misclassification

INTRODUCTION: Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results. Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000–10,000), overall event rate (10%–50%) and treatment effect (0.67–0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level. RESULTS: For the five trials, the range of unweighted kappa values were reduced from 0.89–0.97 to 0.65–0.85 before the treatment effect was altered. This corresponded to 2.1%–6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant. DISCUSSION: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment. CONCLUSION: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary

Representation of Women in Stroke Clinical Trials: A Review of 281 Trials Involving More Than 500,000 Participants

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81-0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71-0.74), trials with a mean age of participants <70 years (PPR 0.81; 95% CI 0.78-0.84), nonacute interventions (PPR 0.80; 95% CI 0.76-0.84), and rehabilitation trials (PPR 0.77; 95% CI 0.71-0.83). These findings did not significantly change over the period from 1990 to 2020 (p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials

Protocol for a prospective collaborative systematic review and meta-analysis of individual patient data from randomised controlled trials of vasoactive drugs in acute stroke: the Blood pressure in Acute Stroke Collaboration, stage-3 (BASC-3)

Rationale Despite several large clinical trials assessing blood pressure lowering in acute stroke, equipoise remains, particularly for ischaemic stroke. The ‘Blood pressure in Acute Stroke Collaboration’ (BASC) commenced in the mid 1990s focusing on systematic reviews and meta-analysis of blood pressure lowering in acute stroke. From the start, BASC planned to assess safety and efficacy of blood pressure lowering in acute stroke using individual patient data. Aims To determine the optimal management of blood pressure in patients with acute stroke, encompassing both intracerebral haemorrhage and ischaemic stroke. Secondary aims are to assess which clinical and therapeutic factors may alter the optimal management of high blood pressure in patients with acute stroke and to assess the effect of vasoactive treatments on haemodynamic variables. Methods and design Individual patient data from randomised controlled trials of blood pressure management in participants with ischaemic stroke and/or intracerebral haemorrhage enrolled during the ultra-acute (pre-hospital), hyper-acute (<6 hours), acute (<48 hours) and sub-acute (<168 hours) phases of stroke. Study outcomes The primary effect variable will be functional outcome defined by the ordinal distribution of the modified Rankin Scale; analyses will also be carried out in prespecified subgroups to assess the modifying effects of stroke-related and pre-stroke patient characteristics. Key secondary variables will include clinical, haemodynamic and neuroradiological variables; safety variables will comprise death and serious adverse events. Discussion Study questions will be addressed in stages, according to the protocol, before integrating these into a final overreaching analysis. We invite eligible trials to join the collaboration

Influence of including patients with pre-morbid disability in acute stroke trials : The HeadPoST experience

Background: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. Methods: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 (“early ΔmRS”), and poor outcome (mRS score 3–6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0–1 versus 2–5. Results: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2–5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14–1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. Conclusions: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect. Clinical Trial Registration: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017)

Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

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 prestrike 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

Posterior circulation stroke diagnosis using HINTS in patients presenting with acute vestibular syndrome: A systematic review

PurposeAcute vestibular syndrome – vertigo, nausea/vomiting, nystagmus and gait unsteadiness – is common, and differentiating posterior circulation stroke from a peripheral cause can be challenging. The National Institute of Health Stroke Scale (NIHSS) does not include acute vestibular syndrome, and early computed tomography scanning cannot rule out acute ischaemia. A positive Head Impulse–Nystagmus–Test of Skew (HINTS) test suggests posterior circulation stroke in acute vestibular syndrome when any of three signs are present: normal horizontal head impulse, gaze-direction nystagmus or eye skew deviation. This systematic review examined the accuracy of positive HINTS in identifying posterior circulation stroke in acute vestibular syndrome patients.MethodsWe searched MEDLINE (1966 to 21 December 2017), EMBASE (1980 to December 2017), Web of Science and scanned bibliographies. Two authors independently screened relevant articles and extracted data. We included studies where HINTS was used to identify posterior circulation stroke with diagnosis confirmed using magnetic resonance imaging.FindingsSix studies (n = 644 patients) were identified. Acute stroke was confirmed in 200 (31.1%) patients. There was a 15-fold increased risk of posterior circulation stroke in patients with positive HINTS test compared to those with no abnormality (RR: 15.84, 95% CI: 5.25–47.79). For any stroke, the pooled sensitivity was 95.5% (95% CI: 92.6–98.4%) and specificity was 71.2% (95% CI: 67.0–75.4%).Discussion and ConclusionThe data suggest that the HINTS test as one element of clinical evaluation is useful to differentiate posterior circulation stroke from peripheral causes in acute vestibular syndrome. Further studies are needed to validate HINTS as a clinical prediction tool in emergency department settings and selection of patients for reperfusion treatment

Pressor therapy in acute ischaemic stroke: an updated systematic review

Background Low blood pressure (BP) in acute ischaemic stroke (AIS) is associated with poor functional outcome, death, or severe disability. Increasing BP might benefit patients with post-stroke hypotension including those with potentially salvageable ischaemic penumbra. This updated systematic review considers the present evidence regarding the use of vasopressors in AIS. Methods We searched the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and trial databases using a structured search strategy. We examined reference lists of relevant publications for additional studies examining BP elevation in AIS. Results We included 27 studies involving 1886 patients. Nine studies assessed increasing BP during acute reperfusion therapy (intravenous thrombolysis, mechanical thrombectomy, intra-arterial thrombolysis or combined). Eighteen studies tested BP elevation alone. Phenylephrine was the most commonly used agent to increase BP (n = 16 studies), followed by norepinephrine (n = 6), epinephrine (n = 3) and dopamine (n = 2). Because of small patient numbers and study heterogeneity, a meta-analysis was not possible. Overall, BP elevation was feasible in patients with fluctuating or worsening neurological symptoms, large vessel occlusion with labile BP, sustained post-stroke hypotension and ineligible for intravenous thrombolysis or after acute reperfusion therapy. The effects on functional outcomes were largely unknown and close monitoring is advised if such intervention is undertaken. Conclusion Although theoretical arguments support increasing BP to improve cerebral blood flow and sustain the ischaemic penumbra in selected AIS patients, the data are limited and results largely inconclusive. Large, randomised controlled trials are needed to identify the optimal BP target, agent, duration of treatment and effects on clinical outcomes.acceptedVersio

INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4) : study protocol for a randomized controlled trial

Background: Early pre-hospital initiation of blood pressure (BP) lowering could improve outcomes for patients with acute stroke, by reducing hematoma expansion in intracerebral hemorrhage (ICH), and time to reperfusion treatment and risk of intracranial hemorrhage in ischemic stroke (IS). We present the design of the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4). Methods: A multi-center, ambulance-delivered, prospective, randomized, open-label, blinded endpoint (PROBE) assessed trial of pre-hospital BP lowering in 3116 hypertensive patients with suspected acute stroke at 50+ sites in China. Patients are randomized through a mobile phone digital system to intensive BP lowering to a target systolic BP of < 140 mmHg within 30 min, or guideline-recommended BP management according to local protocols. After the collection of in-hospital clinical and management data and 7-day outcomes, trained blinded assessors conduct telephone or face-to-face assessments of physical function and health-related quality of life in participants at 90 days. The primary outcome is the physical function on the modified Rankin scale at 90 days, analyzed as an ordinal outcome with 7 categories. The sample size was estimated to provide 90% power (α = 0.05) to detect a 22% reduction in the odds of a worse functional outcome using ordinal logistic regression. Discussion: INTERACT4 is a pragmatic clinical trial to provide reliable evidence on the effectiveness and safety of ambulance-delivered hyperacute BP lowering in patients with suspected acute stroke. Trial registration: ClinicalTrials.gov NCT03790800. Registered on 2 January 2019; Chinese Trial Registry ChiCTR1900020534. Registered on 7 January 2019. All items can be found in this protocol paper

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials

Background - The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. Methods - In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. Findings - We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42–1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13–0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77–4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78–2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70–1·79]; I2=0%). Interpretation - For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. Funding - British Heart Foundation