Neurocrit Care DOI 10.1007/s12028-014-9990-y
REVIEW ARTICLE
The Subarachnoid Hemorrhage International Trialists (SAHIT) Repository: Advancing Clinical Research in Subarachnoid Hemorrhage Blessing N. R. Jaja • Daniel Attalla • R. Loch Macdonald • Tom A. Schweizer • Michael D. Cusimano • Nima Etminan • Daniel Hanggi • David Hasan • S. Claiborne Johnston • Peter Le Roux • Benjamin Lo • Ada Louffat-Olivares • Stephan Mayer • Andrew Molyneux • Adam Noble • Audrey Quinn • Thomas Schenk • Julian Spears • Jeffrey Singh • Michael Todd • James Torner • Ming Tseng • William van den Bergh • Mervyn D. I. Vergouwen George K. C. Wong
•
Ó Springer Science+Business Media New York 2014
Abstract Researchers and other stakeholders continue to express concern about the failure of randomized clinical trials (RCT) in subarachnoid hemorrhage (SAH) to show efficacy of new treatments. Pooled data may be particularly useful to generate hypotheses about causes of poor outcomes and reasons for failure of RCT in SAH, and strategies to improve them. Investigators conducting SAH research collaborated to share data with the intent to develop a large repository of pooled individual patient data for exploratory analysis and testing of new hypotheses relevant to improved trial design and analysis in SAH. This repository currently contains information on 11,443 SAH patients from 14 clinical databases, of which 9 are datasets of recent RCTs and 5 are datasets of prospective B. N. R. Jaja D. Attalla R. L. Macdonald (&) T. A. Schweizer M. D. Cusimano B. Lo A. Louffat-Olivares J. Spears Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada e-mail: [email protected] N. Etminan D. Hanggi Department of Neurosurgery, Medical Faculty Heinrich Heine University, Du¨sseldorf, Germany D. Hasan M. Todd J. Torner University of Iowa, Iowa City, IA, USA S. C. Johnston University of California San Francisco, San Francisco, CA, USA P. Le Roux Jefferson University, Philadelphia, PA, USA
observational studies and hospital registries. Most patients were managed in the last 15 years. Data validation and quality checks have been conducted and are satisfactory. Data is available on demographic, clinical, neuroimaging, and laboratory results and various outcome measures. We have compiled the largest known dataset of patients with SAH. The SAHIT repository may be an important resource for advancing clinical research in SAH and will benefit from contributions of additional datasets. Keywords Subarachnoid hemorrhage Clinical trials Database Cerebrovascular disease Intracranial aneurysm Stroke
S. Mayer Columbia University, New York, NY, USA A. Molyneux Oxford University, Oxford, UK A. Noble Kings College London, London, UK A. Quinn The General Infirmary, Leeds, UK T. Schenk Friedrich-Alexander University, Erlangen, Germany J. Singh University of Toronto, University Health Network, Toronto, ON, Canada M. Tseng Medicines and Healthcare Products Regulatory Agency, London, UK
123
Neurocrit Care
Introduction Subarachnoid hemorrhage from ruptured intracranial aneurysm is an important cause of premature death and disability [1, 2]; and though the case fatality rate has decreased recently [3], overall mortality rate remains high (about 45 % in some series) [4], and the functional outcomes of survivors have been less than satisfactory [2]. Considerable resources have been devoted to developing novel therapies and to translate these into potentially successful clinical interventions in randomized clinical trials (RCT). Little success has been achieved so far [5]. Among the 50 or more RCT conducted to date, only two have demonstrated robust beneficial effects: the British Aneurysm Nimodipine Trial (BRANT) to determine the efficacy of oral nimodipine to reduce cerebral infarction and poor outcome [6], and the International Subarachnoid Aneurysm Trial (ISAT) to compare the safety and efficacy of endovascular coiling with microsurgical clipping in patients at equipoise to receive either treatment [7]. The failure of RCTs in SAH could be attributable to a number of factors including suboptimal study design and analysis [8]. In order to begin to address some of the issues, a group of investigators interested in SAH research collaborated to establish a large multinational network with the primary purpose to contribute and pool anonymized individual patient data (IPD) from clinical trials and institutionally-collected prospective databases under ethically approved protocols. The goal is to use the resource for exploratory analysis and testing of hypothesis aimed at optimizing the design and analysis of future clinical trials in SAH. This data repository is called the Subarachnoid Hemorrhage International Trialists (SAHIT) Repository [9]. Pooling data from multiple studies has been done in head injury trials and ischemic stroke and has led to recommendations for trial design in both conditions but to the best of our knowledge this approach has not been taken in SAH [10, 11]. In the present paper, our aim is to provide a description of the content and the process of data archiving in the SAHIT repository. Methods Investigators shared anonymized IPD of previous RCTs [7, 12–17], and prospective institutional datasets under W. van den Bergh University Medical Center Groningen, Groningen, The Netherlands
Table 1 Criteria for data inclusion in SAHIT repository Express intention or be approached to contribute data Finalize regulatory agreement for data sharing Have minimum of 50 patients in dataset Data prospectively collected with ethics approval Data has information on at least age, sex, some measure of neurologic status and outcome Documented patient selection criteria and data dictionary
predefined criteria [18–21] (Table 1). Data, on receipt at the coordinating center at St. Michael’s Hospital, Toronto, Canada, were immediately documented and backed up in a secure hospital drive. The first task was to examine and resolve inconsistencies in variables definitions, coding and extent of missing data guided by the data dictionary provided with the data and review of related publications on the source data. In many instances we had course to communicate directly with data providers by emails, telephone, and in a few instances hold one-on-one meetings. We identified a number of variables that were completely available and that could be standardized uniformly across datasets. The datasets were imported into SPSS software (version19, IBM Corporation, New York, USA) and reformatted into a uniform format for data management. Key variables were standardized across datasets by recoding, and then extracted along with the identity number provided in the source dataset, and pooled into a single dataset for further quality checks. We did data validation by comparing results of frequency distributions and cross tabulations between source data, published results on source data and the pooled data. All data manipulations were done independently by two trained persons, one using Excel 2010 (Microsoft, Redmond, WA, USA and the other Stata (version 12.1, College Station, TX, USA); the results were compared and any inconsistencies resolved by discussions and further consultations. All datasets were archived in a secured hospital network and ongoing quality checks and backups performed on a regular basis. We also developed an Excel matrix and codebook documenting detailed information on variables provided in the datasets available in the repository, including information on their coding, any manipulations done to ensure variable standardization and other information that may be useful to guide prospective investigators who desire to use the repository. The Excel matrix is made available to all members of the collaboration to inform study design as well as to those interested in participating.
M. D. I. Vergouwen University Medical Center Utrecht, Utrecht, The Netherlands
Results
G. K. C. Wong Chinese University of Hong Kong, Hong Kong, China
As of January 16th, 2014, the SAHIT repository contains data on 11,443 SAH patients from 14 datasets, of which 9
123
P-II and P-III
P-II and P-III
P-III
P-III
P-II
P-III
P-III
P-IV
P-II
Hospital registry
Hospital registry
Hospital registry
Prospective Cohort
MASH-I
MASH-II
IMASH
Tirilazad
CONS-I
ISAT
IHAST
MAPS
HHU
SHOP
D-SAT
Chicago
Leeds
Type
Prospective hospital dataset Prospective hospital dataset
Prospective hospital dataset
Effect of headmotion and fibrinolysis
Establish TAR rates for Matrix 2 and GDC coils
Intraop. cooling to improve outcome
Coiling versus clipping
Safety of clazosentan
Tirilazad to reduce poor outcome
Mg. to improve clinical outcome
ASA to reduce DIND
Mg. to reduce DCI
Purpose
U Leeds, UK
U Chicago, USA
U Washington, USA
Columbia U, USA
Single center: Germany
Multicenter: NA, Europe and Asia
Multicenter: NA, Europe and Asia
Multicenter: mostly Europe
Multicenter: NA, Europe
Multicenter: NA, Asia, Europe
Multicenter: Mostly Asia
Multicenter: Netherland, Scotland and Chile
Multicenter: Netherland, Scotland and Chile
Study population
Table 2 Characteristics of studies in the SAHIT repository
1995–2002
1983–1993
1996–2012
2008–2011
2007–2011
2000–2003
1997–2002
2005–2006
1991–1997
2002–2008
2000–2011
2000–2011
Enrolment
RS, Neurcognitive battery
RS
B48 h
B48 h
GOS, RS, Barthel, NIHSS
GOS, RS, Barthel, NIHSS
GOS, clot clearance rate, DCI
TAR and RS
GOSE
RS
GOSE
GOS
GOSE
DCI and RS
DCI and RS
Outcome measure
B72 h
REVIEW ARTICLE
The Subarachnoid Hemorrhage International Trialists (SAHIT) Repository: Advancing Clinical Research in Subarachnoid Hemorrhage Blessing N. R. Jaja • Daniel Attalla • R. Loch Macdonald • Tom A. Schweizer • Michael D. Cusimano • Nima Etminan • Daniel Hanggi • David Hasan • S. Claiborne Johnston • Peter Le Roux • Benjamin Lo • Ada Louffat-Olivares • Stephan Mayer • Andrew Molyneux • Adam Noble • Audrey Quinn • Thomas Schenk • Julian Spears • Jeffrey Singh • Michael Todd • James Torner • Ming Tseng • William van den Bergh • Mervyn D. I. Vergouwen George K. C. Wong
•
Ó Springer Science+Business Media New York 2014
Abstract Researchers and other stakeholders continue to express concern about the failure of randomized clinical trials (RCT) in subarachnoid hemorrhage (SAH) to show efficacy of new treatments. Pooled data may be particularly useful to generate hypotheses about causes of poor outcomes and reasons for failure of RCT in SAH, and strategies to improve them. Investigators conducting SAH research collaborated to share data with the intent to develop a large repository of pooled individual patient data for exploratory analysis and testing of new hypotheses relevant to improved trial design and analysis in SAH. This repository currently contains information on 11,443 SAH patients from 14 clinical databases, of which 9 are datasets of recent RCTs and 5 are datasets of prospective B. N. R. Jaja D. Attalla R. L. Macdonald (&) T. A. Schweizer M. D. Cusimano B. Lo A. Louffat-Olivares J. Spears Division of Neurosurgery, Department of Surgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada e-mail: [email protected] N. Etminan D. Hanggi Department of Neurosurgery, Medical Faculty Heinrich Heine University, Du¨sseldorf, Germany D. Hasan M. Todd J. Torner University of Iowa, Iowa City, IA, USA S. C. Johnston University of California San Francisco, San Francisco, CA, USA P. Le Roux Jefferson University, Philadelphia, PA, USA
observational studies and hospital registries. Most patients were managed in the last 15 years. Data validation and quality checks have been conducted and are satisfactory. Data is available on demographic, clinical, neuroimaging, and laboratory results and various outcome measures. We have compiled the largest known dataset of patients with SAH. The SAHIT repository may be an important resource for advancing clinical research in SAH and will benefit from contributions of additional datasets. Keywords Subarachnoid hemorrhage Clinical trials Database Cerebrovascular disease Intracranial aneurysm Stroke
S. Mayer Columbia University, New York, NY, USA A. Molyneux Oxford University, Oxford, UK A. Noble Kings College London, London, UK A. Quinn The General Infirmary, Leeds, UK T. Schenk Friedrich-Alexander University, Erlangen, Germany J. Singh University of Toronto, University Health Network, Toronto, ON, Canada M. Tseng Medicines and Healthcare Products Regulatory Agency, London, UK
123
Neurocrit Care
Introduction Subarachnoid hemorrhage from ruptured intracranial aneurysm is an important cause of premature death and disability [1, 2]; and though the case fatality rate has decreased recently [3], overall mortality rate remains high (about 45 % in some series) [4], and the functional outcomes of survivors have been less than satisfactory [2]. Considerable resources have been devoted to developing novel therapies and to translate these into potentially successful clinical interventions in randomized clinical trials (RCT). Little success has been achieved so far [5]. Among the 50 or more RCT conducted to date, only two have demonstrated robust beneficial effects: the British Aneurysm Nimodipine Trial (BRANT) to determine the efficacy of oral nimodipine to reduce cerebral infarction and poor outcome [6], and the International Subarachnoid Aneurysm Trial (ISAT) to compare the safety and efficacy of endovascular coiling with microsurgical clipping in patients at equipoise to receive either treatment [7]. The failure of RCTs in SAH could be attributable to a number of factors including suboptimal study design and analysis [8]. In order to begin to address some of the issues, a group of investigators interested in SAH research collaborated to establish a large multinational network with the primary purpose to contribute and pool anonymized individual patient data (IPD) from clinical trials and institutionally-collected prospective databases under ethically approved protocols. The goal is to use the resource for exploratory analysis and testing of hypothesis aimed at optimizing the design and analysis of future clinical trials in SAH. This data repository is called the Subarachnoid Hemorrhage International Trialists (SAHIT) Repository [9]. Pooling data from multiple studies has been done in head injury trials and ischemic stroke and has led to recommendations for trial design in both conditions but to the best of our knowledge this approach has not been taken in SAH [10, 11]. In the present paper, our aim is to provide a description of the content and the process of data archiving in the SAHIT repository. Methods Investigators shared anonymized IPD of previous RCTs [7, 12–17], and prospective institutional datasets under W. van den Bergh University Medical Center Groningen, Groningen, The Netherlands
Table 1 Criteria for data inclusion in SAHIT repository Express intention or be approached to contribute data Finalize regulatory agreement for data sharing Have minimum of 50 patients in dataset Data prospectively collected with ethics approval Data has information on at least age, sex, some measure of neurologic status and outcome Documented patient selection criteria and data dictionary
predefined criteria [18–21] (Table 1). Data, on receipt at the coordinating center at St. Michael’s Hospital, Toronto, Canada, were immediately documented and backed up in a secure hospital drive. The first task was to examine and resolve inconsistencies in variables definitions, coding and extent of missing data guided by the data dictionary provided with the data and review of related publications on the source data. In many instances we had course to communicate directly with data providers by emails, telephone, and in a few instances hold one-on-one meetings. We identified a number of variables that were completely available and that could be standardized uniformly across datasets. The datasets were imported into SPSS software (version19, IBM Corporation, New York, USA) and reformatted into a uniform format for data management. Key variables were standardized across datasets by recoding, and then extracted along with the identity number provided in the source dataset, and pooled into a single dataset for further quality checks. We did data validation by comparing results of frequency distributions and cross tabulations between source data, published results on source data and the pooled data. All data manipulations were done independently by two trained persons, one using Excel 2010 (Microsoft, Redmond, WA, USA and the other Stata (version 12.1, College Station, TX, USA); the results were compared and any inconsistencies resolved by discussions and further consultations. All datasets were archived in a secured hospital network and ongoing quality checks and backups performed on a regular basis. We also developed an Excel matrix and codebook documenting detailed information on variables provided in the datasets available in the repository, including information on their coding, any manipulations done to ensure variable standardization and other information that may be useful to guide prospective investigators who desire to use the repository. The Excel matrix is made available to all members of the collaboration to inform study design as well as to those interested in participating.
M. D. I. Vergouwen University Medical Center Utrecht, Utrecht, The Netherlands
Results
G. K. C. Wong Chinese University of Hong Kong, Hong Kong, China
As of January 16th, 2014, the SAHIT repository contains data on 11,443 SAH patients from 14 datasets, of which 9
123
P-II and P-III
P-II and P-III
P-III
P-III
P-II
P-III
P-III
P-IV
P-II
Hospital registry
Hospital registry
Hospital registry
Prospective Cohort
MASH-I
MASH-II
IMASH
Tirilazad
CONS-I
ISAT
IHAST
MAPS
HHU
SHOP
D-SAT
Chicago
Leeds
Type
Prospective hospital dataset Prospective hospital dataset
Prospective hospital dataset
Effect of headmotion and fibrinolysis
Establish TAR rates for Matrix 2 and GDC coils
Intraop. cooling to improve outcome
Coiling versus clipping
Safety of clazosentan
Tirilazad to reduce poor outcome
Mg. to improve clinical outcome
ASA to reduce DIND
Mg. to reduce DCI
Purpose
U Leeds, UK
U Chicago, USA
U Washington, USA
Columbia U, USA
Single center: Germany
Multicenter: NA, Europe and Asia
Multicenter: NA, Europe and Asia
Multicenter: mostly Europe
Multicenter: NA, Europe
Multicenter: NA, Asia, Europe
Multicenter: Mostly Asia
Multicenter: Netherland, Scotland and Chile
Multicenter: Netherland, Scotland and Chile
Study population
Table 2 Characteristics of studies in the SAHIT repository
1995–2002
1983–1993
1996–2012
2008–2011
2007–2011
2000–2003
1997–2002
2005–2006
1991–1997
2002–2008
2000–2011
2000–2011
Enrolment
RS, Neurcognitive battery
RS
B48 h
B48 h
GOS, RS, Barthel, NIHSS
GOS, RS, Barthel, NIHSS
GOS, clot clearance rate, DCI
TAR and RS
GOSE
RS
GOSE
GOS
GOSE
DCI and RS
DCI and RS
Outcome measure
B72 h
