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  • Author or Editor: Ewout W. Steyerberg x
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Chantal W. P. M. Hukkelhoven, Ewout W. Steyerberg, Elana Farace, J. Dik F. Habbema, Lawrence F. Marshall and Andrew I. R. Maas

Object. Regional differences have been shown in patient characteristics and case management within multiple unselected series of patients suffering from traumatic brain injury (TBI). One might expect that such regional heterogeneity would be small in a more selected population of a randomized clinical trial. The goal of this study was to examine what regional differences in patient characteristics, case management, and outcomes exist between continents and among countries within a patient population included in a randomized clinical trial.

Methods. Data were extracted from two concurrently conducted randomized clinical trials of the drug tirilazad; the designs of these studies were similar. The studies included 1701 patients with severe and 476 patients with moderate TBI. Differences were primarily investigated between studies performed in Europe and North America, but also among European regions and between Canada and the United States. Associations among regions and outcomes (6-month mortality rate and Glasgow Outcome Scale scores) were studied using multivariable logistic regression analysis.

Comparisons between continents and among regions within Europe showed differences in the distribution of patient ages, causes of injury, and several clinical characteristics (motor score, pupillary reactivity, hypoxia, hypotension, intracranial pressure [ICP]), and findings on computerized tomography scans. Secondary referrals occurred 2.5 times more frequently in Europe. Within Europe secondary referral was mainly associated with an increased proportion of patients with mass lesions (46% in the European Study compared with 40% in the North American Study). Therapy for lowering ICP was more frequently applied in North America. After adjustments for case mix and management, mortality and unfavorable outcomes were significantly higher in Europe (odds ratios = 1.58 and 1.46, respectively). Significant differences in outcome between regions within Europe or within North America were not observed.

Conclusions. Despite the use of a strict study protocol, considerable differences in patient characteristics and case management exist between continents and among countries, reflecting variations in social, cultural, and organizational aspects. Outcomes of TBI may be worse in Europe compared with North America, but this finding requires further study.

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Blessing N. R. Jaja, Hester Lingsma, Ewout W. Steyerberg, Tom A. Schweizer, Kevin E. Thorpe and R. Loch Macdonald

OBJECT

Neuroimaging characteristics of ruptured aneurysms are important to guide treatment selection, and they have been studied for their value as outcome predictors following aneurysmal subarachnoid hemorrhage (SAH). Despite multiple studies, the prognostic value of aneurysm diameter, location, and extravasated SAH clot on computed tomography scan remains debatable. The authors aimed to more precisely ascertain the relation of these factors to outcome.

METHODS

The data sets of studies included in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository were analyzed including data on ruptured aneurysm location and diameter (7 studies, n = 9125) and on subarachnoid clot graded on the Fisher scale (8 studies; n = 9452) for the relation to outcome on the Glasgow Outcome Scale (GOS) at 3 months. Prognostic strength was quantified by fitting proportional odds logistic regression models. Univariable odds ratios (ORs) were pooled across studies using random effects models. Multivariable analyses were adjusted for fixed effect of study, age, neurological status on admission, other neuroimaging factors, and treatment modality. The neuroimaging predictors were assessed for their added incremental predictive value measured as partial R2.

RESULTS

Spline plots indicated outcomes were worse at extremes of aneurysm size, i.e., less than 4 or greater than 9 mm. In between, aneurysm size had no effect on outcome (OR 1.03, 95% CI 0.98–1.09 for 9 mm vs 4 mm, i.e., 75th vs 25th percentile), except in those who were treated conservatively (OR 1.17, 95% CI 1.02–1.35). Compared with anterior cerebral artery aneurysms, posterior circulation aneurysms tended to result in slightly poorer outcome in patients who underwent endovascular coil embolization (OR 1.13, 95% CI 0.82–1.57) or surgical clipping (OR 1.32, 95% CI 1.10–1.57); the relation was statistically significant only in the latter. Fisher CT subarachnoid clot burden was related to outcome in a gradient manner. Each of the studied predictors accounted for less than 1% of the explained variance in outcome.

CONCLUSIONS

This study, which is based on the largest cohort of patients so far analyzed, has more precisely determined the prognostic value of the studied neuroimaging factors. Treatment choice has strong influence on the prognostic effect of aneurysm size and location. These findings should guide the development of reliable prognostic models and inform the design and analysis of future prospective studies, including clinical trials.

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Blessing N. R. Jaja, Hester Lingsma, Tom A. Schweizer, Kevin E. Thorpe, Ewout W. Steyerberg and R. Loch Macdonald

OBJECT

The literature has conflicting reports about the prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to investigate the prognostic value of premorbid hypertension and neurological status in the SAH International Trialists repository.

METHODS

Patient-level meta-analyses were conducted to investigate univariate associations between premorbid hypertension (6 studies; n = 7249), admission neurological status measured on the World Federation of Neurosurgical Societies (WFNS) scale (10 studies; n = 10,869), and 3-month Glasgow Outcome Scale (GOS) score. Multivariable analyses were performed to sequentially adjust for the effects of age, CT clot burden, aneurysm location, aneurysm size, and modality of aneurysm repair. Prognostic associations were estimated across the ordered categories of the GOS using proportional odds models. Nagelkerke's R2 statistic was used to quantify the added prognostic value of hypertension and neurological status beyond those of the adjustment factors.

RESULTS

Premorbid hypertension was independently associated with poor outcome, with an unadjusted pooled odds ratio (OR) of 1.73 (95% confidence interval [CI] 1.50–2.00) and an adjusted OR of 1.38 (95% CI 1.25–1.53). Patients with a premorbid history of hypertension had higher rates of cardiovascular and renal comorbidities, poorer neurological status (p ≤ 0.001), and higher odds of neurological complications including cerebral infarctions, hydrocephalus, rebleeding, and delayed ischemic neurological deficits. Worsening neurological status was strongly independently associated with poor outcome, including WFNS Grades II (OR 1.85, 95% CI 1.68–2.03), III (OR 3.85, 95% CI 3.32–4.47), IV (OR 5.58, 95% CI 4.91–6.35), and V (OR 14.18, 95% CI 12.20–16.49). Neurological status had substantial added predictive value greater than the combined value of other prognostic factors (R2 increase > 10%), while the added predictive value of hypertension was marginal (R2 increase < 0.5%).

CONCLUSIONS

This study confirmed the strong prognostic effect of neurological status as measured on the WFNS scale and the independent but weak prognostic effect of premorbid hypertension. The effect of premorbid hypertension could involve multifactorial mechanisms, including an increase in the severity of initial bleeding, the rate of comorbid events, and neurological complications.

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Chantal W. P. M. Hukkelhoven, Ewout W. Steyerberg, Anneke J. J. Rampen, Elana Farace, J. Dik F. Habbema, Lawrence F. Marshall, Gordon D. Murray and Andrew I. R. Maas

Object. Increasing age is associated with poorer outcome in patients with closed traumatic brain injury (TBI). It is uncertain whether critical age thresholds exist, however, and the strength of the association has yet to be investigated across large series. The authors studied the shape and strength of the relationship between age and outcome, that is, the 6-month mortality rate and unfavorable outcome based on the Glasgow Outcome Scale.

Methods. The shape of the association was examined in four prospective series with individual patient data (2664 cases). All patients had a closed TBI and were of adult age (96% < 65 years of age). The strength of the association was investigated in a metaanalysis of the aforementioned individual patient data (2664 cases) and aggregate data (2948 cases) from TBI studies published between 1980 and 2001 (total 5612 cases). Analyses were performed with univariable and multivariable logistic regression.

Proportions of mortality and unfavorable outcome increased with age: 21 and 39%, respectively, for patients younger than 35 years and 52 and 74%, respectively, for patients older than 55 years. The association between age and both mortality and unfavorable outcome was continuous and could be adequately described by a linear term and expressed even better statistically by a linear and a quadratic term. The use of age thresholds (best fitting threshold 39 years) in the analysis resulted in a considerable loss of information. The strength of the association, expressed as an odds ratio per 10 years of age, was 1.47 (95% confidence interval [CI] 1.34–1.63) for death and 1.49 (95% CI 1.43–1.56) for unfavorable outcome in univariable analyses, and 1.39 (95% CI 1.3–1.5) and 1.46 (95% CI 1.36–1.56), respectively, in multivariable analyses. Thus, the odds for a poor outcome increased by 40 to 50% per 10 years of age.

Conclusions. An older age is continuously associated with a worsening outcome after TBI; hence, it is disadvantageous to define the effect of age on outcome in a discrete manner when we aim to estimate prognosis or adjust for confounding variables.

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Simone A. Dijkland, Blessing N. R. Jaja, Mathieu van der Jagt, Bob Roozenbeek, Mervyn D. I. Vergouwen, Jose I. Suarez, James C. Torner, Michael M. Todd, Walter M. van den Bergh, Gustavo Saposnik, Daniel W. Zumofen, Michael D. Cusimano, Stephan A. Mayer, Benjamin W. Y. Lo, Ewout W. Steyerberg, Diederik W. J. Dippel, Tom A. Schweizer, R. Loch Macdonald and Hester F. Lingsma

OBJECTIVE

Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH).

METHODS

The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1–3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4–6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country.

RESULTS

The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16–1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11–1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00–1.40).

CONCLUSIONS

Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.