Bushfire-smoke trigger hospital admissions with cerebrovascular diseases: Evidence from 2019-20 bushfire in Australia.

INTRODUCTION: Exposure to ambient air pollution is strongly associated with increased cerebrovascular diseases. The 2019-20 bushfire season in Australia burnt 5.4 million hectares of land in New South Wales alone, with smoke so severe it affected cities in Argentina, 11,000 km away. The smoke emitted by bushfires consists of both gaseous and particle components. It is important to note that exposure to particulate matter has been shown to be linked to a heightened risk of stroke, which is the primary kind of cerebrovascular illness, as well as an increased likelihood of hospitalisations and mortality. However, the available data is inadequate in terms of documenting the response of patients diagnosed with a proven cerebrovascular illness to bushfire smoke. Additionally, there is a lack of information about the health effects associated with particulate matter throughout the bushfire season and on days when smoke was present in 2019 and 2020.Therefore, we aimed to determine the effects of (i) short-term air pollution triggered by bushfires and (ii) high smoke days in increasing the daily number of hospital admissions with cerebrovascular diseases. MATERIALS AND METHODS: Hospitalisation data were accessed from the admitted patient dataset from seven local Government areas of Hunter New England Local Health District. The bushfire period was defined from 1 October 2019 to 10 February 2020, and a same period from 2018-19 as the control. High bushfire smoke days were days when the average daily concentration of particulate matter was higher than the 95th percentile of the control period. Poisson regression models and fixed effect meta-analysis were used to analyse the data. RESULTS: In total, 275 patients with cerebrovascular admissions were identified, with 147 (53.5%) during the bushfire (2019-20) and 128 (46.5%) in the control period (2018-19). There was no significant increase in daily admissions for cerebrovascular disease (Incidence Rate Ratio, IRR: 1.04; 95% CI: 0.81-1.34; p-value: 0.73), acute stroke (IRR: 1.15; 95% CI: 0.88-1.50; p-value: 0.29) or acute ischaemic stroke (IRR: 1.18; 95% CI: 0.87-1.59; p-value: 0.28), over the entire bushfire period. However, the high bushfire smoke days were associated with increased acute ischaemic stroke-related hospital admissions across lead 0-3 and the highest cumulative effect was observed with lead 0 (IRR:1.52; 95% CI: 1.01-2.29; p-value: 0.04). In addition, during the bushfire period, particulate matter, both PM10 and PM2.5 (defined as particulates that have an effective aerodynamic diameter of 10, and 2.5 microns, respectively), were also associated with increased acute ischaemic stroke admissions with a lag of 0-3 days. DISCUSSION AND CONCLUSION: The results suggested a possible association between particulate matter and high smoke days with increased hospital admissions due to acute ischaemic stroke during the recent Australian bushfire season.

Exploring ischemic core growth rate and endovascular therapy benefit in large core patients.

After stroke onset, ischemic brain tissue will progress to infarction unless blood flow is restored. Core growth rate measures the infarction speed from stroke onset. This multicenter cohort study aimed to explore whether core growth rate influences benefit from the reperfusion treatment of endovascular thrombectomy in large ischemic core stroke patients. It identified 134 patients with large core volume >70 mL assessed on brain perfusion image within 9 hours of stroke onset. Of 134 patients, 71 received endovascular thrombectomy and 63 did not receive the treatment. Overall, poor outcomes were frequent, with 3-month severed disability or death rate at 56% in treatment group and 68% in no treatment group (p = 0.156). Patients were then stratified by core growth rate. For patients with 'ultrafast core growth' of >70 mL/hour, rates of poor outcome were especially high in patients without endovascular thrombectomy (n = 13/14, 93%) and relatively lower in patients received the treatment (n = 12/20, 60%, p = 0.033). In contrast, for patients with core growth rate <70 mL/hour, there was not a large difference in poor outcomes between patients with and without the treatment (55% vs. 61%, p = 0.522). Therefore, patients with 'ultrafast core growth' might stand to benefit the most from endovascular treatment.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.