Blessing N. R. Jaja

Subarachnoid Hemorrhage International Trialists Data Repository (SAHIT)

The outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved slowly over the past 25 years. This improvement may be due to early aneurysm repair by endovascular or open means, use of nimodipine, and better critical care management. Despite this improvement, mortality remains at about 40%, and many survivors have permanent neurologic, cognitive, and neuropsychologic deficits. Randomized clinical trials have tested pharmacologic therapies, but few have been successful. There are numerous explanations for the failure of these trials, including ineffective interventions, inadequate sample size, treatment side effects, and insensitive or inappropriate outcome measures. Outcome often is evaluated on a good-bad dichotomous scale that was developed for traumatic brain injury 40 years ago. To address these issues, we established the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository. The primary aim of the SAHIT data repository is to provide a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase III trials in aneurysmal SAH. With this aim in mind, we convened a multinational investigator meeting to explore merging individual patient data from multiple clinical trials and observational databases of patients with SAH and to create an agreement under which such a group of investigators could submit data and collaborate. We welcome collaboration with other investigators.

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose— Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale—the VASOGRADE—for prediction of DCI. Methods— We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1–3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. Results— In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77–2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07–4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. Conclusions— The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.

Prognostic value of premorbid hypertension and neurological status in aneurysmal subarachnoid hemorrhage: pooled analyses of individual patient data in the SAHIT repository.

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. Nagelkerkes R(2) 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 (R(2) increase > 10%), while the added predictive value of hypertension was marginal (R(2) 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.

Prognostication of long-term outcomes after subarachnoid hemorrhage: The FRESH score.

To create a multidimensional tool to prognosticate long‐term functional, cognitive, and quality of life outcomes after spontaneous subarachnoid hemorrhage (SAH) using data up to 48 hours after admission.

Effect of Socioeconomic Status on Inpatient Mortality and Use of Postacute Care After Subarachnoid Hemorrhage

Background and Purpose— Studies in the United States and Canada have demonstrated socioeconomic gradients in outcomes of acute life-threatening cardiovascular and cerebrovascular diseases. The extent to which these findings are applicable to subarachnoid hemorrhage is uncertain. This study investigated socioeconomic status-related differences in risk of inpatient mortality and use of institutional postacute care after subarachnoid hemorrhage in the United States and Canada. Methods— Subarachnoid hemorrhage patient records in the US Nationwide Inpatient Sample database (2005–2010) and the Canadian Discharge Abstract Database (2004–2010) were analyzed separately, and summative results were compared. Both databases are nationally representative and contain relevant sociodemographic, diagnostic, procedural, and administrative information. We determined socioeconomic status on the basis of estimated median household income of residents for patient’s ZIP or postal code. Multinomial logistic regression models were fitted with adjustment for relevant confounding covariates. Results— The cohort consisted of 31 631 US patients and 16 531 Canadian patients. Mean age (58 years) and crude inpatient mortality rates (22%) were similar in both countries. A significant income–mortality association was observed among US patients (odds ratio, 0.77; 95% CI, 0.65–0.93), which was absent among Canadian patients (odds ratio, 0.97; 95% CI, 0.85–1.12). Neighborhood income status was not significantly associated with use of postacute care in the 2 countries. Conclusions— Socioeconomic status is associated with subarachnoid hemorrhage inpatient mortality risk in the United States, but not in Canada, although it does not influence the pattern of use of institutional care among survivors in both countries.

Clinical characteristics and outcome of aneurysmal subarachnoid hemorrhage with intracerebral hematoma.

OBJECTIVE Intracerebral hematoma (ICH) with subarachnoid hemorrhage (SAH) indicates a unique feature of intracranial aneurysm rupture since the aneurysm is in the subarachnoid space and separated from the brain by pia mater. Broad consensus is lacking regarding the concept that ultra-early treatment improves outcome. The aim of this study is to determine the associative factors for ICH, ascertain the prognostic value of ICH, and investigate how the timing of treatment relates to the outcome of SAH with concurrent ICH. METHODS The study data were pooled from the SAH International Trialists repository. Logistic regression was applied to study the associations of clinical and aneurysm characteristics with ICH. Proportional odds models and dominance analysis were applied to study the effect of ICH on 3-month outcome (Glasgow Outcome Scale) and investigate the effect of time from ictus to treatment on outcome. RESULTS Of the 5362 SAH patients analyzed, 1120 (21%) had concurrent ICH. In order of importance, neurological status, aneurysm location, aneurysm size, and patient ethnicity were significantly associated with ICH. Patients with ICH experienced poorer outcome than those without ICH (OR 1.58; 95% CI 1.37-1.82). Treatment within 6 hours of SAH was associated with poorer outcome than treatment thereafter (adjusted OR 1.67; 95% CI 1.04-2.69). Subgroup analysis with adjustment for ICH volume, location, and midline shift resulted in no association between time from ictus to treatment and outcome (OR 0.99; 95% CI 0.94-1.07). CONCLUSIONS The most important associative factor for ICH is neurological status on admission. The finding regarding the value of ultra-early treatment suggests the need to more robustly reevaluate the concept that hematoma evacuation of an ICH and repair of a ruptured aneurysm within 6 hours of ictus is the most optimal treatment path.

Racial/ethnic differences in inpatient mortality and use of institutional postacute care following subarachnoid hemorrhage

OBJECT The goal of this study was to determine racial/ethnic differences in inpatient mortality rates and the use of institutional postacute care following subarachnoid hemorrhage (SAH) in the U.S. METHODS A cross-sectional study of hospital discharges for SAH was conducted using the Nationwide Inpatient Sample for the years 2005-2010. Discharges with a principal diagnosis of SAH were identified and abstracted using the appropriate ICD-9-CM diagnostic code. Racial/ethnic groups were defined as white, black, Hispanic, Asian/Pacific Islander (API), and American Indian. Multinomial logistic regression analyses were performed comparing racial/ethnic groups with respect to the primary outcome of risk of in-hospital mortality and the secondary outcome of likelihood of discharge to institutional care. RESULTS During the study period, 31,631 discharges were related to SAH. Race/ethnicity was a significant predictor of death (p = 0.003) and discharge to institutional care (p ≤ 0.001). In the adjusted analysis, compared with white patients, API patients were at higher risk of death (OR 1.34, 95% CI 1.13-1.59) and Hispanic patients were at lower risk of death (OR 0.84, 95% CI 0.72-0.97). The likelihood of discharge to institutional care was statistically similar between white, Hispanic, API, and Native American patients. Black patients were more likely to be discharged to institutional care compared with white patients (OR 1.27, 95% CI 1.14-1.40), but were similar to white patients in the risk of death. CONCLUSIONS Significant racial/ethnic differences are present in the risk of inpatient mortality and discharge to institutional care among patients with SAH in the US. Outcome is likely to be poor among API patients and best among Hispanic patients compared with other groups.

Neuroimaging characteristics of ruptured aneurysm as predictors of outcome after aneurysmal subarachnoid hemorrhage: pooled analyses of the SAHIT cohort.

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 R(2). 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.

Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: The SAHIT multinational cohort study

Abstract Objective To develop and validate a set of practical prediction tools that reliably estimate the outcome of subarachnoid haemorrhage from ruptured intracranial aneurysms (SAH). Design Cohort study with logistic regression analysis to combine predictors and treatment modality. Setting Subarachnoid Haemorrhage International Trialists’ (SAHIT) data repository, including randomised clinical trials, prospective observational studies, and hospital registries. Participants Researchers collaborated to pool datasets of prospective observational studies, hospital registries, and randomised clinical trials of SAH from multiple geographical regions to develop and validate clinical prediction models. Main outcome measure Predicted risk of mortality or functional outcome at three months according to score on the Glasgow outcome scale. Results Clinical prediction models were developed with individual patient data from 10 936 patients and validated with data from 3355 patients after development of the model. In the validation cohort, a core model including patient age, premorbid hypertension, and neurological grade on admission to predict risk of functional outcome had good discrimination, with an area under the receiver operator characteristics curve (AUC) of 0.80 (95% confidence interval 0.78 to 0.82). When the core model was extended to a “neuroimaging model,” with inclusion of clot volume, aneurysm size, and location, the AUC improved to 0.81 (0.79 to 0.84). A full model that extended the neuroimaging model by including treatment modality had AUC of 0.81 (0.79 to 0.83). Discrimination was lower for a similar set of models to predict risk of mortality (AUC for full model 0.76, 0.69 to 0.82). All models showed satisfactory calibration in the validation cohort. Conclusion The prediction models reliably estimate the outcome of patients who were managed in various settings for ruptured intracranial aneurysms that caused subarachnoid haemorrhage. The predictor items are readily derived at hospital admission. The web based SAHIT prognostic calculator (http://sahitscore.com) and the related app could be adjunctive tools to support management of patients.

Effects of decompressive craniectomy on functional outcomes and death in poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis

OBJECTIVE Patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) (World Federation of Neurosurgical Societies Grade IV or V) are often considered for decompressive craniectomy (DC) as a rescue therapy for refractory intracranial hypertension. The authors performed a systematic review and meta-analysis to assess the impact of DC on functional outcome and death in patients after poor-grade aSAH. METHODS A systematic review and meta-analysis were performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles were identified through the Ovid Medline, Embase, Web of Science, and Cochrane Library databases from inception to October 2015. Only studies dedicated to patients with poor-grade aSAH were included. Primary outcomes were death and functional outcome assessed at any time period. Patients were grouped as having a favorable outcome (modified Rankin Scale [mRS] Scores 1-3, Glasgow Outcome Scale [GOS] Scores 4 and 5, extended Glasgow Outcome Scale [GOSE] Scores 5-8) or unfavorable outcome (mRS Scores 4-6, GOS Scores 1-3, GOSE Scores 1-4). Pooled estimates of event rates and odds ratios with 95% confidence intervals were calculated using the random-effects model. RESULTS Fifteen studies encompassing 407 patients were included in the meta-analysis (all observational cohorts). The pooled event rate for poor outcome across all studies was 61.2% (95% CI 52%-69%) and for death was 27.8% (95% CI 21%-35%) at a median of 12 months after aSAH. Primary (or early) DC resulted in a lower overall event rate for unfavorable outcome than secondary (or delayed) DC (47.5% [95% CI 31%-64%] vs 74.4% [95% CI 43%-91%], respectively). Among studies with comparison groups, there was a trend toward a reduced mortality rate 1-3 months after discharge among patients who did not undergo DC (OR 0.58 [95% CI 0.27-1.25]; p = 0.168). However, this trend was not sustained at the 1-year follow-up (OR 1.09 [95% CI 0.55-2.13]; p = 0.79). CONCLUSIONS Results of this study summarize the best evidence available in the literature for DC in patients with poor-grade aSAH. DC is associated with high rates of unfavorable outcome and death. Because of the lack of robust control groups in a majority of the studies, the effect of DC on functional outcomes versus that of other interventions for refractory intracranial hypertension is still unknown. A randomized trial is needed.