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BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Background and Purpose— We updated our previous review from 1996 on the risk of rupture of unruptured intracranial aneurysms, aiming to include the newly published articles. Methods— We reviewed all studies from our former meta-analysis and performed a Medline search for new studies published after 1996. We calculated overall risks of rupture for studies with a mean follow-up time of 10 years. Relative risks (RR) were calculated by comparing the risk of rupture in patients with and without potential risk factors. We aimed to perform multivariable analyses of the different risk factors with meta-regression analysis. Results— We included 19 studies (10 new) with 4705 patients and 6556 unruptured aneurysms (follow-up 26 122 patient-years). The overall rupture risks were 1.2% (follow-up 10 years). In the univariable analysis, statistically significant risk factors for rupture were age >60 years (RR 2.0; 95% confidence interval [CI], 1.1 to 3.7), female gender (RR 1.6; 95% CI, 1.1 to 2.4), Japanese or Finnish descent (RR 3.4; 95% CI, 2.6 to 4.4), size >5 mm (RR 2.3; 95% CI, 1.0 to 5.2), posterior circulation aneurysm (RR 2.5; 95% CI, 1.6 to 4.1), and symptomatic aneurysm (RR 4.4; 95% CI, 2.8 to 6.8). Meta-regression analysis yielded implausible results. Conclusions— Age, gender, population, size, site, and type of aneurysm should be considered in the decision whether to treat an unruptured aneurysm. Pooled multivariable analyses of individual data are needed to identify independent risk factors and to provide more reliable risk estimates for individual patients.

Intracranial aneurysm is probably a complex disease with both genetic and non-genetic or environmental risk factors contributing to the etiology of the disease. A disruption of the extracellular matrix (ECM) of the arterial wall is a likely factor in the pathogenesis of intracranial aneurysms. We analyzed 44 potential candidate genes involved in the maintenance of the integrity of the ECM in 382 Dutch Caucasian patients with intracranial aneurysms and 609 Dutch Caucasian controls for 384 tag single nucleotide polymorphisms (SNPs) using the GoldenGate assay on an Illumina BeadStation 500 GX. We identified SNPs that were associated with intracranial aneurysms (P< 0.01) in six of these 44 genes: serpinel (SERPINE1, P = 0.0008), transforming growth factor beta induced (TGFBI, P = 0.0026), perlecan (HSPG2, P = 0.0044), fibronectin (FN1, P = 0.0069), fibrillin 2 (FBN2, P = 0.0077) and alpha 1 type IV collagen (COL4A1, P = 0.0087). In a second independent cohort of 310 Dutch Caucasian intracranial aneurysm patients and 336 Dutch Caucasian controls, the association for the HSPG2 gene [combined odds ratio (OR) 1.33, 95% confidence interval (Cl) 1.13-1.57, P = 6 x 10 -4 ] was replicated. The population attributable risk (PAR) for this SNP is 19%. Combining the two cohorts still showed association for the SERPINE1 (combined OR 1.27, 95% Cl 1.07-1.50, P = 0.004, PAR 6%), FBN2 (combined OR 1.37, 95% Cl 1.07-1.75, P=0.01, PAR 3%) and COL4A1 (combined OR 1.22, 95% Cl 1.05-1.42, P = 0.007, PAR 7%) genes. These PARs are likely to be overestimates as they are calculated from the joint analyses combining stages 1 and 2 of our association study. Our findings indicate that variation in genes involved in the maintenance of the integrity of the ECM of the arterial wall plays a role in susceptibility to intracranial aneurysms. These findings further support our hypothesis that diminished maintenance of the ECM of the arterial wall is important in the development of intracranial aneurysms.

Background and Purpose— Because intracranial aneurysms develop during life, patients with subarachnoid hemorrhage (SAH) and successfully occluded aneurysms are at risk for a recurrence. We studied the incidence of and risk factors for recurrent SAH in patients who regained independence after SAH and in whom all aneurysms were occluded by means of clipping. Methods— From a cohort of patients with SAH admitted between 1985 and 2001, we included those patients who were discharged home or to a rehabilitation facility. We interviewed these patients about new episodes of SAH. We retrieved all medical records and radiographs in case of reported recurrences. If patients had died, we retrieved the cause of death. We analyzed the incidence of and risk factors for recurrent SAH by Kaplan-Meier curves and Cox regression analysis. Results— Of 752 patients with 6016 follow-up years (mean follow up 8.0 years), 18 had a recurrence. In the first 10 years after the initial SAH, the cumulative incidence of recurrent SAH was 3.2% (95% confidence interval [CI], 1.5% to 4.9%) and the incidence rate 286 of 100 000 patient-years (95% CI, 160 to 472 per 100 000). Risk factors were smoking (hazard ratio [HR], 6.5; 95% CI, 1.7 to 24.0), age (HR, 0.5 per 10 years; 95% CI, 0.3 to 0.8) and multiple aneurysms at the time of the initial SAH (HR, 5.5; 95% CI, 2.2 to 14.1). Conclusions— After SAH, the incidence of a recurrence within the first 10 years is 22 (12 to 38) times higher than expected in populations with comparable age and sex. Whether this increased risk justifies screening for recurrent aneurysms in patients with a history of SAH requires further study.

Objective: Patients who have been successfully treated for subarachnoid hemorrhage (SAH) are at risk for new episodes. The authors studied the effect of screening with CT angiography (CTA) for new aneurysms. Methods: In a decision model, the authors compared the strategies “screening” and “no screening” after SAH. A literature review yielded the risks of aneurysm recurrence, complications of CTA, and re-treatment. The authors estimated the expected number of quality-adjusted life-years (QALYs), the number of SAH, and the mortality and disability rates for both strategies. They evaluated screening at intervals of 2, 5, and 10 years after SAH, using 10 years and remaining life expectancy as time horizon. Results: The expected number of QALYs 10 years after clipping was virtually the same for no screening (8.33), screening once after 5 years (8.28), and screening every 2 years (8.27). With screening every 2 years, the expected rate of new SAH decreased from 1.9 to 0.5%, and mortality decreased from 0.9 to 0.6%; however, the disability rate increased from 0.5 to 1.9%. Results were comparable with remaining life expectancy as time horizon and for screening after initial treatment with coils. The key estimates of the analyses were the incidence and rupture rate of new aneurysms, the risk of dying from recurrent SAH, the utility of disability, and the risk of complications from DSA and re-treatment. Conclusions: Presently, screening for new aneurysms after subarachnoid hemorrhage cannot be recommended. Screening may prevent new episodes of subarachnoid hemorrhage but with too high a cost in terms of complications from preventive treatment.

Background and Purpose— In families with ≥2 first-degree relatives with subarachnoid hemorrhage (SAH), screening for aneurysms is often recommended. The benefit of repeated screening and the interval at which screening should be performed are unknown. We studied patient compliance and the yield of repeated screening for familial intracranial aneurysms. Methods— Relatives with familial SAH screened between 1990 and 1997 were advised to return every 5 years for follow-up screening with MR angiography. If neurosurgical clipping had been performed in the past, screening was done with CT angiography. We analyzed the results for the group as a whole and for the subgroups of relatives with and without previous aneurysms. Results— Of 129 relatives who were advised to undergo further screening, 27 did not return, 74 had 1 repeated screening, and 28 had a second repeated screening. We detected 10 new aneurysms in 9 of the 102 screened relatives (9%), 3 of the 19 relatives with previous aneurysms (16%), and 6 of the 83 relatives without previous aneurysms (7%). One of the 9 subjects with a new aneurysm and 1 other relative had an SAH 3 years after a negative screening procedure. Conclusions— In persons with familial occurrence of aneurysms, the motivation for repeated screening every 5 years is high and the yield is considerable, particularly in relatives who have been treated for aneurysms in the past. The occurrence of SAH

Objective: We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. Methods: In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size–weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. Results: GRS were higher in IA at the MCA in the Dutch ( p = 2.5 × 10 −4 ), Finnish ( p = 0.039), and combined cohort ( p = 4.9 × 10 −5 ). GRS were not associated with familial IA in the Dutch ( p = 0.34), Finnish ( p = 0.45), and combined cohort ( p = 0.98), or with age at time of IA rupture in the Dutch ( p = 0.28), Finnish ( p = 0.86), and combined cohort ( p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67–1.20) for familial IA, 1.03 (0.79–1.34) for lower age, and 1.54 (1.20–1.98) for MCA aneurysms. Conclusions: Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.

Background and Purpose— Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods— Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. Results— Genome-wide evidence of association was detected in the discovery sample on chromosome 9 ( CDKN2BAS ; rs10733376: P −11 ), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9 , was associated with IA (rs10230207; P =4.14×10 −8 ). This association replicated in the Dutch sample ( P =0.01) but failed to show association in the Finnish sample ( P =0.25). Meta-analysis results of the 3 cohorts reached statistical significant ( P =9.91×10 −10 ). Conclusions— We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9 ), suggesting a possible genetic link between this stroke subtype and IA.

Background and Purpose— In families with ≥2 relatives with intracranial aneurysms (IAs), screening for IAs in asymptomatic first-degree relatives is often recommended. We assessed the long-term psychosocial impact of such screening. Methods— We identified all persons with IA (screen-positives) and matched them for age and sex with 2 controls without IA (screen-negatives) from hospital-based registers of familial IA. Persons underwent telephone interviews using questionnaires that covered the areas of psychosocial impact of screening, health-related quality of life (HRQoL), and mood. Data were compared between screen-positives and screen-negatives, and with reference populations. Results— Overall, 105 persons from 33 families with IA were included, of whom 35 were screen-positive and 70 were screen-negative. Of the screen-positives, 12 (44%) had reduced their work and 23 (66%) had experienced changes in ≥1 area of independence, self-esteem, future outlook, or personal relationships. In contrast, only 1 (2%) screen-negative person had stopped working and 12 (17%) others had experienced changes in their self-esteem, future outlook, or relationships. Screen-positives had lower HRQoL compared with screen-negatives and the reference population, whereas both screen groups had higher mean depression scores than the reference population. Despite these effects, only 3 persons regretted participating in screening. Conclusion— Although screening for IA is an important preventative strategy in high-risk individuals, it is associated with considerable psychosocial effects, both positive and negative. Greater awareness of such outcomes, and appropriate intervention where necessary, would appear to be a necessary component of IA screening programs.