European Stroke Journal

In patients with spontaneous intracerebral haemorrhage, it is uncertain if diagnostic and therapeutic measures are time-sensitive on their impact on the outcome. We sought to determine the influence of the time to admission to a comprehensive stroke centre on the outcome of patients with acute intracerebral haemorrhage.

We studied a prospective database of consecutive patients with intracerebral haemorrhage attended at two comprehensive stroke centres (2005–2017). We excluded patients with an unwitnessed time of onset of the intracerebral haemorrhage, or previous modified Rankin Scale >3 or in those in whom withdrawal of life-sustaining interventions were decided <24 h from admission. We recorded the time from the intracerebral haemorrhage onset to admission, demographic, clinical, radiological data, the functional outcome (favourable when modified Rankin Scale ≤3) and mortality at 90 days. We conducted a propensity score-matching analysis to evaluate functional outcome and mortality.

We included 487 patients (mean age 72.3 ± 13.9 years), and 53.2% were men. Compared to patients with an admission >110 min, patients who were admitted ≤110 min were significantly younger, and had higher National Institutes of Health Stroke Scale scores. Moreover, patients admitted ≤110 min were more likely to have basal ganglia intracerebral haemorrhage, and to show neurological deterioration. The propensity score groups were well matched. We did not find an association between time to admission and the favourable outcome (OR: 1.42 (95% CI: 0.93–2.16)) or mortality (OR: 0.64 (0.41–0.99)) at 90 days.

Our results suggest that in patients with intracerebral haemorrhage and known symptom onset who are admitted to a comprehensive stroke centre, an early admission (≤110 min) does not influence the outcome at 90 days.

Seizures are common after intracerebral haemorrhage. Tranexamic acid increases the risk of seizures in non-intracerebral haemorrhage population but its effect on post-intracerebral haemorrhage seizures is unknown. We explored the risk factors and outcomes of seizures after intracerebral haemorrhage and if tranexamic acid increased the risk of seizures in the Tranexamic acid for IntraCerebral Haemorrhage-2 trial.

Seizures were reported prospectively up to day 90. Cox regression analyses were used to determine the predictors of seizures within 90 days and early seizures (≤7 days). We explored the effect of early seizures on day 90 outcomes.

Of 2325 patients recruited, 193 (8.3%) had seizures including 163 (84.5%) early seizures and 30 (15.5%) late seizures (>7 days). Younger age (adjusted hazard ratio (aHR) 0.98 per year increase, 95% confidence interval (CI) 0.97–0.99; p = 0.008), lobar haematoma (aHR 5.84, 95%CI 3.58–9.52; p < 0.001), higher National Institute of Health Stroke Scale (aHR 1.03, 95%CI 1.01–1.06; p = 0.014) and previous stroke (aHR 1.66, 95%CI 1.11–2.47; p = 0.013) were associated with early seizures. Tranexamic acid did not increase the risk of seizure within 90 days. Early seizures were associated with worse modified Rankin Scale (adjusted odds ratio (aOR) 1.79, 95%CI 1.12–2.86, p = 0.015) and increased risk of death (aOR 3.26, 95%CI 1.98–5.39; p < 0.001) at day 90.

Discussion and conclusion: Lobar haematoma was the strongest independent predictor of early seizures after intracerebral haemorrhage. Tranexamic acid did not increase the risk of post-intracerebral haemorrhage seizures in the first 90 days. Early seizures resulted in worse functional outcome and increased risk of death.

Bleeding is the main safety concern of treatment with antiplatelet drugs. We aimed to refine prediction of major bleeding on antiplatelet treatment after a transient ischaemic attack (TIA) or stroke by assessing the added value of new predictors to the existing S₂TOP-BLEED score.

We used Cox regression analysis to study the association between candidate predictors and major bleeding among 2072 patients with a transient ischaemic attack or ischaemic stroke included in a population-based study (Oxford Vascular Study – OXVASC). An updated model was proposed and validated in 1094 patients with a myocardial infarction included in OXVASC. Models were compared with c-statistics, calibration plots, and net reclassification improvement.

Independent predictors for major bleeding on top of S₂TOP-BLEED variables were peptic ulcer (hazard ratio (HR): 1.72; 1.04–2.86), cancer (HR: 2.40; 1.57–3.68), anaemia (HR: 1.55; 0.99–2.44) and renal failure (HR: 2.20; 1.57–4.28). Addition of those variables improved discrimination from 0.69 (0.64–0.73) to 0.73 (0.69–0.78) in the TIA/stroke cohort (p = 0.01). Performance improved particularly for upper gastro-intestinal bleeds (0.70; 0.64–0.75 to 0.77; 0.72–0.82). Net reclassification improved over the entire range of the score (net reclassification improvement: 0.56; 0.36–0.76). In the validation cohort, discriminatory performance improved from 0.68 (0.62–0.74) to 0.70 (0.64–0.76).

Peptic ulcer, cancer, anaemia and renal failure improve predictive performance of the S₂TOP-BLEED score for major bleeding after stroke. Future external validation studies will be required to confirm the value of the STOP-BLEED+ score in transient ischaemic attack/stroke patients.

Alterations in haemoglobin levels are frequent in stroke patients. The prognostic meaning of anaemia and polyglobulia on outcomes in patients treated with intravenous thrombolysis is ambiguous.

In this prospective multicentre, intravenous thrombolysis register-based study, we compared haemoglobin levels on hospital admission with three-month poor outcome (modified Rankin Scale 3–6), mortality and symptomatic intracranial haemorrhage (European Cooperative Acute Stroke Study II-criteria (ECASS-II-criteria)). Haemoglobin level was used as continuous and categorical variable distinguishing anaemia (female: <12 g/dl; male: <13 g/dl) and polyglobulia (female: >15.5 g/dl; male: >17 g/dl). Anaemia was subdivided into mild and moderate/severe (female/male: <11 g/dl). Normal haemoglobin level (female: 12.0–15.5 g/dl, male: 13.0–17.0 g/dl) served as reference group. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated with logistic regression models.

Among 6866 intravenous thrombolysis-treated stroke patients, 5448 (79.3%) had normal haemoglobin level, 1232 (17.9%) anaemia – of those 903 (13.2%) had mild and 329 (4.8%) moderate/severe anaemia – and 186 (2.7%) polyglobulia. Anaemia was associated with poor outcome (OR_adjusted 1.25 (1.05–1.48)) and mortality (OR_adjusted 1.58 (1.27–1.95)). In anaemia subgroups, both mild and moderate/severe anaemia independently predicted poor outcome (OR_adjusted 1.29 (1.07–1.55) and 1.48 (1.09–2.02)) and mortality (OR_adjusted 1.45 (1.15–1.84) and OR_adjusted 2.00 (1.46–2.75)). Each haemoglobin level decrease by 1 g/dl independently increased the risk of poor outcome (OR_adjusted 1.07 (1.02–1.11)) and mortality (OR_adjusted 1.08 (1.02–1.15)). Anaemia was not associated with occurrence of symptomatic intracranial haemorrhage. Polyglobulia did not change any outcome.

The more severe the anaemia, the higher the probability of poor outcome and death. Severe anaemia might be a target for interventions in hyperacute stroke.

Anaemia on admission, but not polyglobulia, is a strong and independent predictor of poor outcome and mortality in intravenous thrombolysis-treated stroke patients.

Missing outcome data may undermine interpretation of randomised clinical trials by weakening power and limiting apparent effect size. We assessed bias and inefficiency of two imputation methods commonly used in stroke trials evaluating the efficacy of iv thrombolysis.

We searched the virtual international stroke trials archive (VISTA)-acute for ischaemic stroke patients with 90-day modified Rankin scale as an outcome, and known thrombolysis status. We excluded any with missing 30-day modified Rankin scale. We planned two analyses; first, we calculated odds ratios for outcome in thrombolysed versus not thrombolysed from imputed-only data, (a) among patients with missing modified Rankin scale 90 and (b) among matched patients with intact data (using propensity score methods and relevant covariates). Imputation approaches were last observation carried forward (LOCF) or multiple imputation. Outcome comparisons used dichotomisation and shift analysis. Thereafter, we calculated whole-population odds ratios using LOCF and multiple imputation (also through dichotomisation and shift analysis); first with the original 1.5% missing outcome data, and then artificially increasing the burden (5%; 10%; 20%; 30%).

We considered 9657 patients from eight of the studies included in VISTA, 3034 (31%) thrombolysed. Missing data replacement by LOCF with analysis by dichotomisation gave the highest estimate of thrombolysis influence. Imputing while increasing the burden of missing data progressively raised the odds ratios estimates, though thresholds for overestimation were 10% for LOCF; 20% for multiple imputation.

Discussion: Replacing missing outcome data tended to overestimate differences of thrombolysed versus non-thrombolysed patients, but had minimal impact below a 10% burden of missing data.

Conclusion: In the specific context of acute stroke trials testing iv thrombolytics, replacing missing data by carrying forward the last observation tended to overestimate treatment odds ratios more than multiple imputation.

There is conflicting evidence on the impact of atrial fibrillation (AF) type, i.e. non-paroxysmal AF or paroxysmal AF, on thromboembolic recurrence. The consensus of risk equivalence is greatly based on historical evidence, focussing on initial stroke risks. We conducted a systematic review and meta-analysis to describe the impact of AF type on the risk of thromboembolic recurrence, mortality and major haemorrhage in patients with previous stroke.

We systematically searched four multidisciplinary databases from inception to December 2018. We selected observational studies investigating clinical outcomes in patients with ischaemic stroke and AF, stratified by AF type. We assessed all included studies for risk of bias using the ‘Risk of Bias In Non-randomised Studies – of Exposures’ tool. The Comprehensive Meta-Analysis Software was used to calculate odds ratios from crude event rates.

After reviewing 14,127 citations, we selected 108 studies for full-text screening. We extracted data from a total of 26 studies, reporting outcomes on 23,054 patients. Overall, risk of bias was moderate. The annual incidence rates of thromboembolism in patients with non-paroxysmal AF and paroxysmal AF were 7.1% (95% confidence interval: 4.2–11.7) and 5.2% (95% confidence interval: 3.2–8.2), respectively. The odds ratio for thromboembolism in patients with non-paroxysmal AF versus paroxysmal AF was 1.47 (95% confidence interval: 1.08–1.99, p = 0.013). The annual mortality rates in patients with non-paroxysmal AF and paroxysmal AF were 20.0% (95% confidence interval: 13.2–28.0) and 10.1% (95% confidence interval: 5.4–17.3), respectively, and odds ratio was 1.90 (95% confidence interval: 1.43–2.52, p < 0.001). There was no difference in rates of major haemorrhage, odds ratio  = 1.01 (95% confidence interval: 0.61–1.69, p = 0.966).

In patients with prior stroke, non-paroxysmal AF is associated with significantly higher risk of thromboembolic recurrence and mortality than paroxysmal AF. Although current guidelines make no distinction between non-paroxysmal AF and paroxysmal AF for secondary stroke prevention, future guidance and risk stratification tools may need to consider this differential risk (PROSPERO ID: CRD42019118531).

About one-fourth of ischaemic strokes are classified as embolic strokes of undetermined source. Lambl’s excrescences are commonly seen on cardiac valves, and data are limited on whether they may be a source of embolization. We examined the relationship between Lambl’s excrescences and embolic stroke of undetermined source.

We performed a case-control study of patients in the Cornell AcutE Stroke Academic Registry. Stroke aetiologies were adjudicated using the Trial of Org 10172 in Acute Stroke Treatment and embolic stroke of undetermined source criteria. We included patients with acute ischaemic stroke between 2011 and 2016 who underwent transthoracic or transoesophageal echocardiography within six months of hospitalisation. Cases were embolic stroke of undetermined source patients and controls were patients with an identified, non-cardioembolic stroke aetiology (i.e. small- or large-vessel strokes). Multiple logistic regression was used to evaluate the association between Lambl’s excrescences and embolic stroke of undetermined source after adjustment for demographics, comorbidities and mode of echocardiography.

A total of 923 patients met the criteria for this analysis, including 530 with embolic stroke of undetermined source and 393 with small- or large-vessel strokes. Lambl’s excrescences were identified in 47 (8.9%) patients with embolic stroke of undetermined source and 11 (2.8%) patients with small- or large-artery strokes, but the majority (54/58) of Lambl’s excrescences were visualised on transoesophageal echocardiogram and embolic stroke of undetermined source patients were more likely to undergo transoesophageal echocardiogram. After adjustment for demographics, comorbidities and mode of echocardiography, we found no association between the presence of Lambl’s excrescences and embolic stroke of undetermined source (odds ratio 0.9; 95% confidence interval 0.4–2.3).

We found no association between Lambl’s excrescences and embolic stroke of undetermined source. These results do not support the hypothesis that Lambl’s excrescences are an occult cause of embolic stroke of undetermined source.

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.

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.

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.

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.

Approaches to economic evaluations of stroke therapies are varied and inconsistently described. An objective of the European Stroke Organisation (ESO) Health Economics Working Group is to standardise and improve the economic evaluations of interventions for stroke.

The ESO Health Economics Working Group and additional experts were contacted to develop a protocol and a guidance document for data collection for economic evaluations of stroke therapies. A modified Delphi approach, including a survey and consensus processes, was used to agree on content. We also asked the participants about resources that could be shared to improve economic evaluations of interventions for stroke.

Of 28 experts invited, 16 (57%) completed the initial survey, with representation from universities, government, and industry. More than half of the survey respondents endorsed 13 specific items to include in a standard resource use questionnaire. Preferred functional/quality of life outcome measures to use for economic evaluations were the modified Rankin Scale (14 respondents, 88%) and the EQ-5D instrument (11 respondents, 69%). Of the 12 respondents who had access to data used in economic evaluations, 10 (83%) indicated a willingness to share data. A protocol template and a guidance document for data collection were developed and are presented in this article.

The protocol template and guidance document for data collection will support a more standardised and transparent approach for economic evaluations of stroke care.

Cerebrovascular diseases associated with pregnancy and postpartum period are uncommon; however, they can have an important impact on health of both women and foetus or newborn.

To evaluate the frequency, characteristics and management of cerebrovascular events in pregnant/postpartum women, to clarify pathophysiological mechanisms underlying the occurrence of these events including biomolecular aspects, and to assess the short- and long-term cerebrovascular and global cardiovascular outcome of these patients, their predictors and infant outcome.

This is an observational, prospective, multicentre, international case–control study. The study will include patients with cerebrovascular events during pregnancy and/or within six months after delivery. For each included case, two controls will be prospectively recruited: one pregnant or puerperal subject without any history of cerebrovascular event and one non-pregnant or non-puerperal subject with a recent cerebrovascular event. All controls will be matched by age, ethnicity and type of cerebrovascular event with their assigned cases. The pregnant controls will be matched also by pregnancy weeks/trimester. Follow-up will last 24 months for the mother and 12 months for the infant.

To better understand causes and outcomes of uncommon conditions like pregnancy/postpartum-related cerebrovascular events, the development of multisite, multidisciplinary registry-based studies, such as the Stroke in Pregnancy and Postpartum study, is needed in order to collect an adequate number of patients, draw reliable conclusions and give definite recommendations on their management.

Despite the availability of prevention and therapies of stroke, their implementation in clinical practice, even of low-cost ones, remains poor. In 2015, the European Stroke Organisation (ESO) initiated the ESO Enhancing and Accelerating Stroke Treatment (EAST) program, which aims to improve stroke care quality, primarily in Eastern Europe. Here, we describe its methods and milestones.

The ESO EAST program is using an implementation strategy based on a ‘detecting-understanding-reducing disparities’ conceptual framework: stroke care quality is first measured (after developing a platform for data collection), gaps are identified in the current service delivery, and ultimately feedback is provided to participating hospitals, followed by the application of interventions to reduce disparities. The ESO EAST program is carried out by establishing a stroke quality registry, stroke management infrastructure, and creating education and training opportunities for healthcare professionals.

Program management and leadership infrastructure has been established in 19 countries (Country Representatives in 22 countries, National Steering Committee in 19 countries). A software platform for data collection and analysis: Registry of Stroke Care Quality was developed, and launched in 2016, and has been used to collect data from over 90,000 patients from >750 hospitals and 56 countries between September 2016 and May 2019. Training in thrombolysis, nursing and research skills has been initiated.

ESO EAST is the first pan-Eastern European (and beyond) multifaceted quality improvement intervention putting evidence-informed policies into practice. Continuous monitoring of stroke care quality allows hospital-to-hospital and country-to-country benchmarking and identification of the gaps and needs in health care.