Prognostic Factors in Aneurysmal Subarachnoid Hemorrhage

208 Pages·2014·1.87 MB·English

Prognostic Factors in Aneurysmal Subarachnoid Hemorrhage: Pooled
Analyses of Individual Patient Data and Development of Novel Risk
Scores in Large Cohorts of International Patients

by

Blessing Nathan Romey Jaja

A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy,
Graduate Department of the Institute of Medical Science
University of Toronto

© Copyright by Blessing Nathan Romey Jaja 2014
Prognostic Factors in Aneurysmal Subarachnoid Hemorrhage: Pooled Analyses of
Individual Patient Data and Development of Novel Risk Scores in Large Cohorts of
International Patients

Blessing Nathan Romey Jaja
Doctor of Philosophy
Institute of Medical Science
University of Toronto
2014

Abstract
Primary studies reporting prognostic associations in aneurysmal subarachnoid hemorrhage
(SAH) are often insufficiently powered, use data of limited representativeness and scarcely
examine the added value of prognostic factors above those of other known factors. Hence,
considerable knowledge gaps and conflicting results exist in the literature on the nature and
extent of prognostic associations in SAH. Prognostic factors have been combined to develop
prediction models and risk scores for early outcome prediction after SAH. None is routinely
applied in clinical or research settings; some major constraints relate to lack of evidence on the
predictive accuracy, reliability and generalizability of reported risk scores. The global aim of this
research was to address these challenges and contribute to improved understanding of prognostic
associations in SAH by analysing large cohorts of SAH patients reflecting a broad spectrum of
settings. Pooled analyses of patient-level data from multiple randomized clinical trials and
prospective hospital registries involving 10963 patients demonstrated a strong prognostic effect
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of admission neurologic status on 3-month outcome according to Glasgow outcome score. Age
had a moderate effect on outcome; premorbid hypertension and subarachnoid clot burden on the
Fisher scale were weak predictors of outcome. Patient’s sex had no independent predictive
value. Prognostic effect of aneurysm size and location depended on treatment modality. Novel
prognostic scores were developed combining these predictors for early prediction of mortality
and unfavorable outcomes at 3 months, and demonstrated adequate performance at bootstrap
(AUC: 0.77 – 0.83) and at cross validation. Using 2 nationally representative administrative
datasets, socioeconomic status and race/ethnicity were explored as latent prognostic factors in
SAH. Multinomial logistic regression analysis demonstrated socioeconomic status, measured as
neighborhood income status, was associated with inpatient mortality risk after admission for
SAH. The extent of the association could be related to health care system under which treatment
was provided. Race/ethnicity was independently associated with inpatient mortality. Patients of
Hispanic ethnicity had the best outcomes and Asia/Pacific Islanders experienced the worst
outcomes during the inpatient course. This research has provided higher level evidence than prior
studies on studied prognostic factors and reliable tools for early prediction of outcome after
hospitalization for SAH.

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Acknowledgements

Certain persons and institutions were instrumental to the successful completion of this
project. They deserve mention and my vote of thanks, for without them this project would have
been only a pipe dream. Of special mention is my supervisor, Dr. R. Loch Macdonald, who I
would like to thank immensely for giving me the opportunity to undertake this research, and for
his patience, understanding, continued guidance and support through the course of the research
program. I would like to express gratitude to my Program Advisory Committee members, Drs.
Mohammed Mamdani, Gustavo Saposnik, Kevin Thorpe and Peter Austin for providing
expertise and insightful comments which gave direction to and helped shape the final outcome of
the research. May I also acknowledge the consultations and invaluable statistical guidance that I
received from Prof. Ewout W. Steyerberg and Dr. Hester Lingsma, Department of Public Health,
Erasmus MC - University Medical Center Rotterdam, Netherland.
I am grateful to members of the Subarachnoid Hemorrhage International Trialists
(SAHIT) collaboration for contributing institutional clinical data on subarachnoid hemorrhage
patients which served as the primary source of patient data for the research. Also deserving of
mention are the Canadian Institute for Health Information for providing free access to their
Discharge Abstract Database, and the Agency for Healthcare Quality and Research (Rockville,
MD), USA, for access to the Healthcare Cost and Utilization Project Nationwide Inpatient
sample.
May I also acknowledge funding support from the Canadian Institute for Health
Research, University of Toronto Open fellowship and conference grant, Division of
Neurosurgery, St. Michael’s Hospital, and the Rivers State Government of Nigeria.
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To my friends, Dr. Ken Simiyu and Khwaka Kukubo, thank you for your encouragement,
support, and the many opportunities for relaxation and comic relief from the long hours of data
management and computation. To my parents, thank you for your persistent prayers,
unconditional love and for inculcating in me the values of academics. To my family, particularly
Benita, thank you for your personal sacrifices, and for enduring the long periods of my absence.
Finally, I thank the good Lord for the blessing of life, health and faith to start and
complete the onerous task of doctoral-level training.

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Table of Contents
Abstract ............................................................................................................................................ii
Acknowledgements ......................................................................................................................... iv
List of Tables ................................................................................................................................... x
List of Figures ................................................................................................................................. xi
List of appendices .......................................................................................................................... xii
Symbols and Abbreviations .......................................................................................................... xiii
Chapter 1 ......................................................................................................................................... 1
Introduction and literature review ................................................................................................... 1
1.1 Introduction .......................................................................................................................... 2
1.2 Pathobiology of aneurysmal subarachnoid hemorrhage ...................................................... 2
1.2.1 Risk factors for aneurysmal subarachnoid hemorrhage ................................................... 3
1.2.1.1 Modifiable risk factors ..................................................................................................... 4
1.2.1.2 Non modifiable risk factors ...................................................................................... 4
1.2.2 Pathophysiology of aneurysmal subarachnoid hemorrhage ............................................. 7
1.3 Diagnosis and clinical presentation ..................................................................................... 9
1.4 Treatment of aneurysmal subarachnoid hemorrhage ......................................................... 12
1.5 Prognosis of aneurysmal subarachnoid hemorrhage .......................................................... 13
1.6 Prognostic Factors in aneurysmal subarachnoid hemorrhage ............................................ 15
1.6.1 Demographic factors ...................................................................................................... 17
1.6.2 Clinical factors ............................................................................................................... 22
1.6.3 Neuroimaging factors ..................................................................................................... 28
1.6.4 Physiologic factors and biomarkers ............................................................................... 29
1.7 Limitations of prognostic studies ....................................................................................... 30
1.8 Prognostic models in SAH: How reliable are available models to predict outcome of
patients with SAH? ....................................................................................................................... 32
1.8.1 Results of systematic review of prognostic models in SAH .......................................... 34
1.8.2 Implications of findings of the systematic review ......................................................... 38
1.9 Conclusion ......................................................................................................................... 41
Chapter 2 ....................................................................................................................................... 50
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Study Methodology ....................................................................................................................... 50
2.1 Introduction ........................................................................................................................ 51
2.2 Study rationale: Towards providing higher level evidence of prognostic associations and
better prognostic models in SAH .................................................................................................. 51
2.3 Hypothesis and research contributions .............................................................................. 54
2.4 Research Ethics Board Approvals ..................................................................................... 57
2.5 Study population ................................................................................................................ 57
2.6 Independent (Predictors) variables .................................................................................... 60
2.7 Dependent (Outcome) Variables........................................................................................ 60
2.8 Approach to statistical analyses ......................................................................................... 61
2.8.1 Descriptive analysis........................................................................................................ 61
2.8.2 Univariable prognostic association ................................................................................ 61
2.8.3 Multivariable prognostic association ............................................................................. 62
2.8.4 Quantification of the magnitude of prognostic associations .......................................... 62
2.8.5 Secondary analyses: interaction effects and subgroup analysis ..................................... 63
2.9 Handling of missing data ................................................................................................... 64
2.10 Statistical software ............................................................................................................. 64
Chapter 3 ....................................................................................................................................... 67
Prognostic value of hospital admission characteristics in aneurysmal subarachnoid hemorrhage:
Meta-analyses of individual participant data in the subarachnoid hemorrhage international
trialists (SAHIT) repository .......................................................................................................... 67
3.1 Introduction ........................................................................................................................ 68
3.2 PART A: Demographic factors - age and sex .................................................................... 68
3.2.1 Methods .......................................................................................................................... 69
3.2.2 Results ............................................................................................................................ 70
3.2.3 Discussion ...................................................................................................................... 71
3.3 PART B: Clinical factors - premorbid hypertension and admission neurologic status ..... 77
3.3.1 Methods .......................................................................................................................... 77
3.3.2 Results ............................................................................................................................ 78
3.3.3 Discussion ...................................................................................................................... 78
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3.4 PART C: Neuroimaging factors: Fisher CT clot burden, aneurysm location and size ...... 89
3.4.1 Methods .......................................................................................................................... 90
3.4.2 Results ............................................................................................................................ 91
3.4.3 Discussion ...................................................................................................................... 93
Chapter 4 ....................................................................................................................................... 99
SAHIT score: Novel prognostic scores for early prediction of outcome after aneurysmal
subarachnoid hemorrhage ............................................................................................................. 99
4.1 Introduction ...................................................................................................................... 100
4.2 Methods............................................................................................................................ 101
4.2.1 Study population .......................................................................................................... 101
4.2.2 Variable selection ......................................................................................................... 102
4.2.3 Outcome measure ........................................................................................................ 102
4.2.4 Model development ...................................................................................................... 102
4.2.5 Model performance ...................................................................................................... 103
4.2.6 Model Validation.......................................................................................................... 104
4.3 Results .............................................................................................................................. 105
4.3.1 Model performance ...................................................................................................... 105
4.3.2 Model presentation ....................................................................................................... 106
4.4 Discussion ........................................................................................................................ 107
Chapter 5 ..................................................................................................................................... 123
Investigating socioeconomic status and race/ethnicity as latent prognostic factors in aneurysmal
subarachnoid hemorrhage ........................................................................................................... 123
5.1 Introduction ...................................................................................................................... 124
5.2 Part A: Socioeconomic status and inpatient mortality risk after SAH ............................. 124
5.2.1 Methods ........................................................................................................................ 125
5.2.2 Results .......................................................................................................................... 128
5.2.3 Discussion .................................................................................................................... 129
5.3 Part B: Race/ethnicity and inpatient mortality risk after SAH ........................................ 136
5.3.1 Methods ........................................................................................................................ 136
5.3.2 Results .......................................................................................................................... 138
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5.3.3 Discussion .................................................................................................................... 139
Chapter 6 ..................................................................................................................................... 146
General discussion and conclusion ............................................................................................. 146
6.1 Introduction ...................................................................................................................... 147
6.2 Strength of the research ................................................................................................... 147
6.3 Summary of research findings and contributions to knowledge ...................................... 149
6.4 Limitations of the research ............................................................................................... 154
6.5 Directions for future research .......................................................................................... 157
6.5.1 Confirmatory study of the prognostic value of other factors ....................................... 157
6.5.2 Validation of Risk Scores in Subarachnoid Aneurysm (VISA) ................................... 158
6.5.3 Center variability in outcomes of SAH ........................................................................ 159
6.5.4 Type and timing of outcome assessment ..................................................................... 161
6.6 Conclusion ....................................................................................................................... 163
Appendices .................................................................................................................................. 189

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List of Tables

Table 1.1 – Approaches adopted by previous studies to analyze age effect on outcome ............. 43
Table 1.2 – Studies identifying independent predictors of poor outcome in multivariable analysis
....................................................................................................................................................... 45
Table 1.3 – Characteristics of studies reporting prognostic models in SAH ................................ 48
Table 1.4 – Approach to model development in previous studies reporting prognostic models in
SAH............................................................................................................................................... 49
Table 1.5 – Approach to model validation in previous studies..................................................... 49
Table 2.1 – Characteristics of studies in the SAHIT repository ................................................... 65
Table 3.1 – Results of adjusted analysis of the prognostic effect of age and sex ......................... 76
Table 3.2 – Distribution of premorbid hypertension and neurologic status by 3-month GOS ..... 84
Table 3.3 – Adjusted effects of premorbid hypertension and neurologic status ........................... 84
Table 3.4 – Relation of premorbid hypertension to comorbid conditions and complications ...... 85
Table 3.5 – Distribution of ruptured aneurysm location, diameter and Fisher clot burden by study
....................................................................................................................................................... 95
Table 3.6 – Distribution of aneurysm location by treatment modality ......................................... 95
Table 3.7 – Distribution of aneurysm location, diameter and Fisher clot burden by GOS .......... 95
Table 3.8 – Adjusted effects of studied neuroimaging factors ..................................................... 96
Table 4.1 – Baseline distribution of variables by study cohort................................................... 112
Table 4.2 – Association between predictors and 3-month outcome ........................................... 113
Table 4.3 – Performance indices of the six models at bootstrap validation ............................... 114
Table 4.4 – Performance indices at leave-one-study-out cross validation.................................. 115
Table 4.5 – Model coefficients to obtain linear predictors for computing outcome probabilities
..................................................................................................................................................... 122
Table 5.1 – Baseline characteristics of US patients by quartile of median household income .. 133
Table 5.2 – Baseline characteristics of Canadian patients by quintile of median household
income ......................................................................................................................................... 134
Table 5.3 – Relation of neighborhood income to in-hospital mortality and discharge to iPAC for
US patients .................................................................................................................................. 134
Table 5.4 – Relation of neighborhood income status to in-hospital mortality and discharge to
iPAC for Canadian patients ........................................................................................................ 135
Table 5.5 – Baseline distribution of variables according to race/ethnicity status ....................... 143
Table 5.6 – Results of multivariable analysis of the relation of race/ethnicity to in-hospital
mortality ...................................................................................................................................... 144

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