Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Randomised, controlled trial of CT perfusion and angiography compared to CT alone in thrombolysis-eligible acute ischaemic stroke patients: the Penumbra and Recanalisation Acute Computed Tomography in Ischaemic Stroke Evaluation (PRACTISE) trial

Introduction: The role of CT angiography (CTA) and CT perfusion (CTP) in patient selection for thrombolysis <4.5 h after onset is unclear. Additional imaging may improve specificity of diagnosis by excluding stroke mimics or those without salvageable tissue, but may delay treatment. Patients and methods: In a multicentre prospective randomised trial, thrombolysis-eligible patients <4.5 h from symptom onset were randomised 1:1 to non-contrast CT (NCCT) or multimodal CT (NCCT + CTA + CTP). The primary endpoint was the proportion receiving thrombolysis. Secondary end-points were times to decision-making and treatment delivery, early neurological recovery, functional recovery at 3 months and incidence of symptomatic intracerebral haemorrhage (SICH). Results: Between March 2015 and May 2018, 271 patients were randomised, 134 to multimodal CT and 137 to NCCT. After initial NCCT, 114 had no contraindication to thrombolysis in the multimodal CT group and 108 in the NCCT group. Mean age was 67.5 years and median NIHSS score was 6 (interquartile range 3–12). Fewer patients assigned multimodal CT received thrombolysis (56/114, 49.1%) compared to NCCT (73/108, 67.6%, adjusted odds ratio (aOR) 0.46 (95% CI: 0.25–0.83), p = 0.0102). Times to treatment decision or thrombolytic administration, early neurological recovery and day 90 functional outcome did not differ significantly. SICH occurred in two patients, both assigned NCCT. Mortality was 6/114 (5.3%) in the multimodal CT group compared to 11/108 (10.2%; aOR 0.46 (95% CI: 0.16, 1.31), p = 0.147) in the NCCT group. Discussion: Despite fewer patients receiving thrombolysis after multimodal imaging, treatment decision times and clinical outcomes did not differ significantly. Multimodal CT may identify patients who do not require thrombolysis such as stroke mimics and non-disabling strokes. Conclusion: Among acute stroke patients imaged <4.5 h from symptom onset, multimodal CT reduced use of thrombolysis. Treatment decision times and clinical outcomes did not differ between groups

Prevention of Stroke in Intracerebral Haemorrhage Survivors with Atrial Fibrillation: Rationale and Design for PRESTIGE-AF Trial.

Adequate secondary prevention in survivors of intracerebral hemorrhage (ICH) who also have atrial fibrillation (AF) is a long-standing clinical dilemma because these patients are at increased risk of recurrent ICH as well as of ischemic stroke. The efficacy and safety of oral anticoagulation, the standard preventive medication for ischemic stroke patients with AF, in ICH patients with AF are uncertain. PRESTIGE-AF is an international, phase 3b, multi-center, randomized, open, blinded end-point assessment (PROBE) clinical trial that compared the efficacy and safety of direct oral anticoagulants (DOACs) with no DOAC (either no antithrombotic treatment or any antiplatelet drug). Randomization occurred in a 1:1 ratio and stratification was based on ICH location and sex. The two co-primary binary endpoints included ischemic stroke and recurrent ICH which will be analyzed hierarchically according to the intention-to-treat principle. Secondary efficacy endpoints encompassed all-stroke and systemic embolism, all-cause and cardiovascular mortality, major adverse cardiac events, and net clinical benefit. Secondary safety endpoints included any major hemorrhage and intracranial hemorrhage. All outcome events were adjudicated by an independent committee. Results of PRESTIGE-AF are expected to support risk-adjusted secondary prevention in ICH survivors with AF and to inform clinical guideline recommendations

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. Methods: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30–30·30 million) new cases of TBI and 0·93 million (0·78–1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331–412) per 100 000 population for TBI and 13 (11–16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40–57·62 million) and of SCI was 27·04 million (24·98–30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (−0·2% [–2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (−3·6% [–7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0–10·4 million) YLDs and SCI caused 9·5 million (6·7–12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82–141) per 100 000 for TBI and 130 (90–170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. Interpretation: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Funding: Bill & Melinda Gates Foundation

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial.

Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage. PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete. Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73-83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7-2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01-0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14-2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43-12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95-60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68-8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14-2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died. No patients died in the placebo group. DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients. European Commission

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial

Background: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. Methods: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0–5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. Findings: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88–1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4–10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (&lt;1%) in the control group (RR 4·2; 95% CI 0·9–19·7, p=0·059). Interpretation: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation