| 2. |
- Malik, Rainer, et al.
(författare)
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Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration
- 2016
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Ingår i: Neurology. - 1526-632X. ; 86:13, s. 26-1217
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
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| 3. |
- Shoamanesh, Ashkan, et al.
(författare)
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Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke) : an international, randomised, double-blind, placebo-controlled, phase 2b trial
- 2022
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Ingår i: The Lancet. - 0140-6736. ; 400:10357, s. 997-1007
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown. Methods: In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26–52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose–response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete. Findings: Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0–4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79–1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93–1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85–1·32]; t statistic –0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91–2·71]). Interpretation: In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke. Funding: Bayer AG.
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| 4. |
- Gameiro, Joana, et al.
(författare)
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Prognosis of cerebral vein thrombosis presenting as isolated headache: Early vs. late diagnosis
- 2012
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Ingår i: Cephalalgia. - : SAGE Publications. - 0333-1024 .- 1468-2982. ; 32:5, s. 407-412
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To analyse the outcome of cerebral venous thrombosis (CVT) patients presenting with isolated headache, specifically to compare isolated headache patients with early vs. late CVT diagnosis. Method: In the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) database we compared the outcome of patients with isolated headache and a CVT diagnosed early (<= 7 days from onset) vs. late (> 7 days). We retrieved 100 patients with isolated headache, 52 patients with early CVT diagnosis (early isolated headache) and 48 with late CVT diagnosis (late isolated headache). Results: Neurological worsening was more frequent within early isolated headache patients (23% vs. 8%) (p = 0.045). At the last follow-up (median 411 days), 93% patients had a complete recovery, and 4% were dead or dependent, with no significant difference between early isolated headache and late isolated headache. Conclusion: The outcome of CVT patients with isolated headache diagnosed early or late was similarly favourable, but there was a higher proportion of neurological worsening in the acute phase among early isolated headache patients, who need close neurological monitoring.
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