Summary Background Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a ...minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort. Methods In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0–18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681. Findings At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio OR 1·35, 95% CI 1·06–1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0–2; OR 1·25; 95% CI 0·92–1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07–1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm). Interpretation Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years. Funding UK Medical Research Council.
Summary Background Our aim was to assess the long-term risks of death, disability, and rebleeding in patients randomly assigned to clipping or endovascular coiling after rupture of an intracranial ...aneurysm in the follow-up of the International Subarachnoid Aneurysm Trial (ISAT). Methods 2143 patients with ruptured intracranial aneurysms were enrolled between 1994 and 2002 at 43 neurosurgical centres and randomly assigned to clipping or coiling. Clinical outcomes at 1 year have been previously reported. All UK and some non-UK centres continued long-term follow-up of 2004 patients enrolled in the original cohort. Annual follow-up has been done for a minimum of 6 years and a maximum of 14 years (mean follow-up 9 years). All deaths and rebleeding events were recorded. Analysis of rebleeding was by allocation and by treatment received. ISAT is registered, number ISRCTN49866681. Findings 24 rebleeds had occurred more than 1 year after treatment. Of these, 13 were from the treated aneurysm (ten in the coiling group and three in the clipping group; log rank p=0·06 by intention-to-treat analysis). There were 8447 person-years of follow-up in the coiling group and 8177 person-years of follow-up in the clipping group. Four rebleeds occurred from a pre-existing aneurysm and six from new aneurysms. At 5 years, 11% (112 of 1046) of the patients in the endovascular group and 14% (144 of 1041) of the patients in the neurosurgical group had died (log-rank p=0·03). The risk of death at 5 years was significantly lower in the coiling group than in the clipping group (relative risk 0·77, 95% CI 0·61–0·98; p=0·03), but the proportion of survivors at 5 years who were independent did not differ between the two groups: endovascular 83% (626 of 755) and neurosurgical 82% (584 of 713). The standardised mortality rate, conditional on survival at 1 year, was increased for patients treated for ruptured aneurysms compared with the general population (1·57, 95% CI 1·32–1·82; p<0·0001). Interpretation There was an increased risk of recurrent bleeding from a coiled aneurysm compared with a clipped aneurysm, but the risks were small. The risk of death at 5 years was significantly lower in the coiled group than it was in the clipped group. The standardised mortality rate for patients treated for ruptured aneurysms was increased compared with the general population. Funding UK Medical Research Council.
BACKGROUND AND PURPOSE—The natural history of unruptured intracranial aneurysms remains unclear, and management strategy is not well defined.
METHODS—From January 2003 to December 2012, we enrolled ...patients with aneurysm in our institution. In total, 2252 patients with 2897 aneurysms were eligible for analysis, and 1960 eligible aneurysms were conservatively managed. Precise 3-dimensional evaluation was conducted using computed tomography angiography, digital subtraction angiography, or magnetic resonance angiography. We then assessed the risk of aneurysm rupture, mortality, and morbidity associated with aneurysm characteristics, demographics, and known health/lifestyle risk factors.
RESULTS—The mean follow-up duration was 7388 aneurysm-years. During observation, 56 aneurysms ruptured, resulting in an overall rupture rate per year of 0.76% (95% confidence interval, 0.58–0.98). The mean initial visit to rupture interval was 547 days. Aneurysm size, location, daughter sac, and history of subarachnoid hemorrhage were significant independent predictors for aneurysm rupture. Aneurysms that were ≥5 mm were associated with a significantly increased risk of rupture when compared with 2- to 4-mm aneurysms (unadjusted hazard ratio, 12.24; 95% confidence interval, 7.15–20.93). Of 56 patients who experienced hemorrhage, 29 (52 %) died or were rendered severely disabled. Of the patients who had large or giant aneurysms, none recovered without deficits, and the mortality rate after rupture was 69%. For aneurysms sized <5 mm, the mortality rate was 18%.
CONCLUSIONS—Larger aneurysms are at greater risk for rupture and poor outcome. Ethnic factors may play a role in the risk of rupture.
BACKGROUND AND PURPOSE—Early prediction of clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH) is still lacking accuracy. In this observational cohort study, we aimed to develop and ...validate an accurate bedside prediction model for clinical outcome after aSAH, to aid decision-making at an early stage.
METHODS—For the development of the prediction model, a prospectively kept single-center cohort of 1215 aSAH patients, admitted between 1998 and 2014, was used. For temporal validation, a prospective cohort of 224 consecutive aSAH patients from the same center, admitted between 2015 and 2017, was used. External validation was performed using the ISAT (International Subarachnoid Aneurysm Trial) database (2143 patients). Primary outcome measure was poor functional outcome 2 months after aSAH, defined as modified Rankin Scale score 4–6. The model was constructed using multivariate regression analyses. Performance of the model was examined in terms of discrimination and calibration.
RESULTS—The final model included 4 predictors independently associated with poor outcome after 2 monthsage, World Federation of Neurosurgical Societies grade after resuscitation, aneurysm size, and Fisher grade. Temporal validation showed high discrimination (area under the receiver operating characteristic curve, 0.90; 95% CI, 0.85–0.94), external validation showed fair to good discrimination (area under the receiver operating characteristic curve, 0.73; 95% CI, 0.70–0.76). The model showed satisfactory calibration in both validation cohorts. The SAFIRE grading scale was derived from the final modelsize of the aneurysm, age, Fisher grade, world federation of neurosurgical societies after resuscitation.
CONCLUSIONS—The SAFIRE grading scale is an accurate, generalizable, and easily applicable model for early prediction of clinical outcome after aSAH.
Two types of treatment are being used for patients with ruptured intracranial aneurysms: endovascular detachable-coil treatment or craniotomy and clipping. We undertook a randomised, multicentre ...trial to compare these treatments in patients who were suitable for either treatment because the relative safety and efficacy of these approaches had not been established. Here we present clinical outcomes 1 year after treatment.
2143 patients with ruptured intracranial aneurysms, who were admitted to 42 neurosurgical centres, mainly in the UK and Europe, took part in the trial. They were randomly assigned to neurosurgical clipping (n=1070) or endovascular coiling (n=1073). The primary outcome was death or dependence at 1 year (defined by a modified Rankin scale of 3–6). Secondary outcomes included rebleeding from the treated aneurysm and risk of seizures. Long-term follow up continues. Analysis was in accordance with the randomised treatment.
We report the 1-year outcomes for 1063 of 1073 patients allocated to endovascular treatment, and 1055 of 1070 patients allocated to neurosurgical treatment. 250 (23·5%) of 1063 patients allocated to endovascular treatment were dead or dependent at 1 year, compared with 326 (30·9%) of 1055 patients allocated to neurosurgery, an absolute risk reduction of 7·4% (95% CI 3·6–11·2, p=0·0001). The early survival advantage was maintained for up to 7 years and was significant (log rank p=0·03). The risk of epilepsy was substantially lower in patients allocated to endovascular treatment, but the risk of late rebleeding was higher.
In patients with ruptured intracranial aneurysms suitable for both treatments, endovascular coiling is more likely to result in independent survival at 1 year than neurosurgical clipping; the survival benefit continues for at least 7 years. The risk of late rebleeding is low, but is more common after endovascular coiling than after neurosurgical clipping.
Because the long-term security of endovascular treatments remains uncertain, a follow-up study of the patients treated in the International Subarachnoid Aneurysm Trial was performed to compare the ...frequency, timing, and consequences of aneurysm recurrence.
Patient data were reclassified by actual treatment performed. Aneurysm and patient characteristics, including occlusion grades, time and type of retreatment, and clinical outcomes, were compared. The relationship between these variables and late retreatment as a surrogate for recurrence was analyzed by means of the Cox proportional hazards model.
Retreatment was performed in 191 of 1096 (17.4%) patients after primary endovascular coiling (EVT) and in 39 of 1012 patients (3.8%) after neurosurgical clipping. After EVT, 97 (8.8%) patients were retreated early and 94 (9.0%) late, 7 (0.6%) after rebleeding and 87 (8.3%) without. The mean time to late retreatment was 20.7 months. After neurosurgical clipping, 30 (2.9%) patients were retreated early and 9 (0.85%) late, 3 (0.3%) after rebleeding and 6 (0.6%) without. The mean time to late retreatment was 5.7 months. The hazard ratio (HR) for retreatment after EVT was 6.9 (95% CI=3.4 to 14.1) after adjustment for age (P=0.001, HR=0.97, 95% CI=0.95 to 0.98), lumen size (P=0.006, HR=1.1, 95% CI=1.03 to 1.18), and incomplete occlusion (P<0.001, HR=7.6, 95% CI=3.3 to 17.5).
Late retreatment was 6.9 times more likely after EVT. Younger age, larger lumen size, and incomplete occlusion were risk factors for late retreatment after EVT. After neurosurgical clipping, retreatments were earlier; whereas EVT retreatments continued to be performed throughout the follow-up period. Short-term follow-up imaging is therefore insufficient to detect recurrences after EVT.
Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the ...impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
PURPOSE—The aim of this updated statement is to provide comprehensive and evidence-based recommendations for management of patients with unruptured intracranial aneurysms.
METHODS—Writing group ...members used systematic literature reviews from January 1977 up to June 2014. They also reviewed contemporary published evidence-based guidelines, personal files, and published expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulated recommendations using standard American Heart Association criteria. The guideline underwent extensive peer review, including review by the Stroke Council Leadership and Stroke Scientific Statement Oversight Committees, before consideration and approval by the American Heart Association Science Advisory and Coordinating Committee.
RESULTS—Evidence-based guidelines are presented for the care of patients presenting with unruptured intracranial aneurysms. The guidelines address presentation, natural history, epidemiology, risk factors, screening, diagnosis, imaging and outcomes from surgical and endovascular treatment.
The trial on endovascular management of unruptured intracranial aneurysms (TEAM), a prospective randomized trial comparing coiling and conservative management, initiated in September 2006, was ...stopped in June 2009 because of poor recruitment (80 patients). Aspects of the trial design that may have contributed to this failure are reviewed in the hope of identifying better ways to successfully complete this special type of pragmatic trial which seeks to test two strategies that are in routine clinical use. Cultural, conceptual and bureaucratic hurdles and difficulties obstruct all trials. These obstacles are however particularly misplaced when the trial aims to identify what a good medical practice should be. A clean separation between research and practice, with diverging ethical and scientific requirements, has been enforced for decades, but it cannot work when care needs to be provided in the presence of pervasive uncertainty. Hence valid and robust scientific methods need to be legitimately re-integrated into clinical practice when reliable knowledge is in want. A special status should be reserved for what we would call 'clinical care trials', if we are to practice in a transparent and prospective fashion a medicine that leads to demonstrably better patient outcomes.
We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of ...patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups.
Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat.
Four hundred ninety-four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram (P=0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum (P=0.064; range, 4-34 months). The clinical outcomes did not differ between the groups.
There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory. Clinical Trial Registration Information- URL: www.controlled-trials.com. Unique Identifier: ISRCTN82461286.
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