Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage

This focused update about antiplatelet agents to reduce the high risk of major adverse cardiovascular events after stroke due to spontaneous (nontraumatic) intracerebral hemorrhage (ICH) complements earlier updates about blood pressure-lowering, lipid-lowering, and oral anticoagulation or left atrial appendage occlusion for atrial fibrillation after ICH. When used for secondary prevention in people without ICH, antiplatelet agents reduce the risk of major adverse cardiovascular event (rate ratio, 0.81 [95% CI, 0.75-0.87]) and might increase the risk of ICH (rate ratio, 1.67 [95% CI, 0.97-2.90]). Before 2019, guidance for clinical decisions about antiplatelet agent use after ICH has focused on estimating patients' predicted absolute risks and severities of ischemic and hemorrhagic major adverse cardiovascular event and applying the known effects of these drugs in people without ICH to estimate whether individual ICH survivors in clinical practice might be helped or harmed by antiplatelet agents. In 2019, the main results of the RESTART (Restart or Stop Antithrombotics Randomized Trial) randomized controlled trial including 537 survivors of ICH associated with antithrombotic drug use showed, counterintuitively, that antiplatelet agents might not increase the risk of recurrent ICH compared to antiplatelet agent avoidance over 2 years of follow-up (12/268 [4%] versus 23/268 [9%]; adjusted hazard ratio, 0.51 [95% CI, 0.25-1.03]; P=0.060). Guidelines in the United States, Canada, China, and the United Kingdom and Ireland have classified the level of evidence as B and indicated that antiplatelet agents may be considered/reasonable after ICH associated with antithrombotic agent use. Three subsequent clinical trials have recruited another 174 participants with ICH, but they will not be sufficient to determine the effects of antiplatelet therapy on all major adverse cardiovascular events reliably when pooled with RESTART. Therefore, ASPIRING (Antiplatelet Secondary Prevention International Randomized Study After Intracerebral Hemorrhage) aims to recruit 4148 ICH survivors to determine the effects of antiplatelet agents after ICH definitively overall and in subgroups. </p

Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy:Systematic review and meta-analysis

BACKGROUND:We sought to summarize Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) features of intracerebral hemorrhage (ICH) associated with cerebral amyloid angiopathy (CAA) in published observational radio-pathological studies. METHODS:In November 2016, two authors searched OVID Medline (1946-), Embase (1974-) and relevant bibliographies for studies of imaging features of lobar or cerebellar ICH with pathologically proven CAA ("CAA-associated ICH"). Two authors assessed studies' diagnostic test accuracy methodology and independently extracted data. RESULTS:We identified 22 studies (21 cases series and one cross-sectional study with controls) of CT features in 297 adults, two cross-sectional studies of MRI features in 81 adults and one study which reported both CT and MRI features in 22 adults. Methods of CAA assessment varied, and rating of imaging features was not masked to pathology. The most frequently reported CT features of CAA-associated ICH in 21 case series were: subarachnoid extension (pooled proportion 82%, 95% CI 69-93%, I2 = 51%, 12 studies) and an irregular ICH border (64%, 95% CI 32-91%, I2 = 85%, five studies). CAA-associated ICH was more likely to be multiple on CT than non-CAA ICH in one cross-sectional study (CAA-associated ICH 7/41 vs. non-CAA ICH 0/42; χ2 = 7.8, p = 0.005). Superficial siderosis on MRI was present in 52% of CAA-associated ICH (95% CI 39-65%, I2 = 35%, 3 studies). CONCLUSIONS:Subarachnoid extension and an irregular ICH border are common imaging features of CAA-associated ICH, but methodologically rigorous diagnostic test accuracy studies are required to determine the sensitivity and specificity of these features

Activation of Nrf2 to optimise immune responses to intracerebral haemorrhage

Haemorrhage into the brain parenchyma can be devastating. This manifests as spontaneous intracerebral haemorrhage (ICH) after head trauma, and in the context of vascular dementia. Randomised controlled trials have not reliably shown that haemostatic treatments aimed at limiting ICH haematoma expansion and surgical approaches to reducing haematoma volume are effective. Consequently, treatments to modulate the pathophysiological responses to ICH, which may cause secondary brain injury, are appealing. Following ICH, microglia and monocyte derived cells are recruited to the peri-haematomal environment where they phagocytose haematoma breakdown products and secrete inflammatory cytokines, which may trigger both protective and harmful responses. The transcription factor Nrf2, is activated by oxidative stress, is highly expressed by central nervous system microglia and macroglia. When active, Nrf2 induces a transcriptional programme characterised by increased expression of antioxidant, haem and heavy metal detoxification and proteostasis genes, as well as suppression of proinflammatory factors. Therefore, Nrf2 activation may facilitate adaptive-protective immune cell responses to ICH by boosting resistance to oxidative stress and heavy metal toxicity, whilst limiting harmful inflammatory signalling, which can contribute to further blood brain barrier dysfunction and cerebral oedema. In this review, we consider the responses of immune cells to ICH and how these might be modulated by Nrf2 activation. Finally, we propose potential therapeutic strategies to harness Nrf2 to improve the outcomes of patients with ICH

Patent Foramen Ovale, Ischemic Stroke and Migraine: Systematic Review and Stratified Meta-Analysis of Association Studies

BACKGROUND: Observational data have reported associations between patent foramen ovale (PFO), cryptogenic stroke and migraine. However, randomized trials of PFO closure do not demonstrate a clear benefit either because the underlying association is weaker than previously suggested or because the trials were underpowered. In order to resolve the apparent discrepancy between observational data and randomized trials, we investigated associations between (1) migraine and ischemic stroke, (2) PFO and ischemic stroke, and (3) PFO and migraine. METHODS: Eligibility criteria were consistent; including all studies with specifically defined exposures and outcomes unrestricted by language. We focused on studies at lowest risk of bias by stratifying analyses based on methodological design and quantified associations using fixed-effects meta-analysis models. RESULTS: We included 37 studies of 7,686 identified. Compared to reports in the literature as a whole, studies with population-based comparators showed weaker associations between migraine with aura and cryptogenic ischemic stroke in younger women (OR 1.4; 95% CI 0.9–2.0; 1 study), PFO and ischemic stroke (HR 1.6; 95 CI 1.0–2.5; 2 studies; OR 1.3; 95% CI 0.9–1.9; 3 studies), or PFO and migraine (OR 1.0; 95% CI 0.6–1.6; 1 study). It was not possible to look for interactions or effect modifiers. These results are limited by sources of bias within individual studies. CONCLUSIONS: The overall pairwise associations between PFO, cryptogenic ischemic stroke and migraine do not strongly suggest a causal role for PFO. Ongoing randomized trials of PFO closure may need larger numbers of participants to detect an overall beneficial effect

Selective outcome reporting in randomised controlled trials including participants with stroke or transient ischaemic attack:A systematic review

IntroductionThe prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown.Materials and methodsWe searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group.ResultsOf 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB.DiscussionThe prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample.ConclusionWork is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes

Can an ethics officer role reduce delays in research ethics approval? A mixed-method evaluation of an improvement project.

OBJECTIVE: Frustration continues to be directed at delays in gaining approvals for undertaking health research in the UK. We aimed to evaluate the impact of an ethics officer intervention on rates of favourable opinions (approval) and provisional opinions (requiring revision and resubmission) and on the time taken to reach a final opinion by research ethics committees (RECs), to characterise how the role operated in practice, and to investigate applicants' views. DESIGN: Mixed-method study involving (i) a 2-group, non-randomised before-and-after intervention study of RECs assigned an ethics officer and a matched comparator group; (ii) a process evaluation involving a survey of applicants and documentary analysis. PARTICIPANTS: 6 RECs and 3 associated ethics officers; 18 comparator RECs; REC applicants. RESULTS: Rates of provisional and favourable opinions between ethics officer and comparator RECs did not show a statistically significant effect of the intervention (logistic regression, p=0.26 for favourable opinions and p=0.31 for provisional opinions). Mean time to reach a decision showed a non-significant reduction (ANOVA, p=0.22) from 33.3 to 32.0 days in the ethics officer RECs compared with the comparator RECs (32.6 to 32.9 days). The survey (30% response rate) indicated applicant satisfaction and also suggested that ethics officer support might be more useful before submission. Ethics officers were successful in identifying many issues with applications, but the intervention did not function exactly as designed: in 31% of applicants, no contact between the applicants and the ethics officer took place before REC review. LIMITATIONS: This study was a non-randomised comparison cohort study. Some data were missing. CONCLUSIONS: An ethics officer intervention, as designed and implemented in this study, did not increase the proportion of applications to RECs that were approved on first review and did not reduce the time to a committee decision.The ethics officer pilot and the controlled evaluation was funded by the HRA. The process evaluation was conducted and funded separately by MD-W’s Wellcome Trust Investigator Award WT097899 with no HRA oversight or involvement beyond facilitating access to the database. MD-W’s contribution to this paper was also supported by University of Leicester study leave at the Dartmouth Institute for Health Policy and Clinical Practice. RA-SS was funded by a Medical Research Council senior clinical fellowship.This is the final version of the article. It first appeared from BMJ Group via http://dx.doi.org/10.1136/bmjopen-2016-01197

Association Between Beta-Blocker or Statin Drug Use and the Risk of Hemorrhage From Cerebral Cavernous Malformations

BACKGROUND: We aimed to determine the association between beta-blocker or statin drug use and the future risk of symptomatic intracranial hemorrhage or persistent/progressive focal neurological deficit from cerebral cavernous malformations (CCM). METHODS: The population-based Scottish Audit of Intracranial Vascular Malformations prospectively identified adults resident in Scotland first diagnosed with CCM during 1999 to 2003 or 2006 to 2010. We compared the association between beta-blocker or statin drug use after first presentation and the occurrence of new intracranial hemorrhage or persistent/progressive focal neurological deficit due to CCM for up to 15 years of prospective follow-up. We confirmed proportional hazards and used survival analysis with multivariable adjustment for age, intracranial hemorrhage at CCM presentation, and brain stem CCM location. RESULTS: Sixty-three (21%) of 300 adults used beta-blockers (27/63 [43%] used propranolol), and 73 (24%) used statin drugs over 3634 person-years of follow-up. At baseline, the only statistically significant imbalances in prespecified potential confounders were age by statin use and intracranial hemorrhage at presentation by beta-blocker use. Beta-blocker use was associated with a lower risk of new intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.09 [95% CI, 0.01–0.66]; P=0.018). Statin use was associated with a nonsignificant lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit (adjusted hazard ratio, 0.37 [95% CI, 0.01–1.07]; P=0.067). CONCLUSIONS: Beta-blocker, but not statin, use was associated with a lower risk of intracranial hemorrhage or persistent/progressive focal neurological deficit in patients with CCM

Completeness of reporting of randomised controlled trials including people with transient ischaemic attack or stroke: A systematic review

Objective: To assess the adherence of stroke randomised controlled trials (RCTs) to CONSORT reporting guidelines, and investigate the factors that are associated with completeness of reporting. Design: Two reviewers assessed the published report of the final primary results of stroke RCTs with a 10-point truncated CONSORT reporting checklist, to investigate adherence over time, univariable associations, and independent associations with total CONSORT reporting score in a multiple linear regression model. Data sources: Random sample of stroke RCTs from the Cochrane Stroke Group’s Trial Register. Eligibility criteria: Primary published report of the final results of transient ischaemic attack (TIA) or stroke RCTs, published in English in 1997-2016 inclusive. Results: In this random sample of 177 stroke RCTs, the mean score on the truncated CONSORT checklist was 5.8 (SD 2.2); reporting improved from 1997-2000 (4.9 SD 2.0) to 2001-2009 (5.8 SD 2.1) and to 2010-2016 (6.8 SD 2.1). A higher CONSORT score was independently associated with publication during epochs following a revision of CONSORT reporting guidelines (pandlt;0.001), journal endorsement of the CONSORT reporting guideline at the time of RCT publication (pandlt;0.001), and modified journal impact factor using median citation distribution (p=0.012). Conclusions: Stroke RCT reporting to CONSORT standards has improved over time, but could be better. Journal endorsement and enforcement of CONSORT reporting guidelines could further improve the reporting of stroke RCTs.</p