Abstract
Background and objective
Due to conflicting results in multiple studies, uncertainty remains regarding sex differences in severity and mortality after intracerebral hemorrhage (ICH). We investigated the impact of sex on ICH severity, expansion, and mortality.
Methods
We analyzed prospectively collected ICH patients and assessed clinical variables and mortality rate. Mediation analyses were used to examine associations between sex and mortality and sex and hematoma expansion.
Results
2212 patients were investigated, 53.5 % male. Men with ICH were younger (72 vs. 77 years), had greater smoking and alcohol use, and were more likely to have hypertension, diabetes, hypercholesterolemia and coronary artery disease (all p< 0.05). Lobar hemorrhages were more frequent in women (47.6% vs 38.4%, p<0.001). Male sex was a risk factor for hematoma expansion (Odd Ratio (OR) 1.7, 95% confidence interval (CI) 1.15 – 2.50, p=0.007). Multivariable analysis found that male sex was independently associated with 90-day mortality (OR 2.15 (95% CI 1.46–3.19), p<0.001), and one-year mortality (Hazard Ratio 1.28 (95% CI: 1.09–1.50), p=0.003). Early hematoma expansion mediated a portion of the association between sex and mortality (mediation p=0.02).
Conclusions
Men with ICH experience a higher risk of both expansion and early and late mortality, even after controlling for known risk factors. Further research is needed to explore the biological mechanisms underlying these observed differences.
Keywords: Keywords : Sex, ICH, Hematoma Expansion, Mortality
Graphical Abstract
Introduction
Intracerebral hemorrhage (ICH) comprises up to 15% of all strokes(1) with 30-day mortality ranging from 34.6 % to 59.0%(2). Prior studies have demonstrated sex differences in incidence and outcome of cardiovascular diseases(3), and while sex differences in ischemic stroke have been extensively studied(4), uncertainty exists regarding the role of sex in risk and outcome of ICH. A recent review on this topic(5) highlighted the challenges of heterogeneity in outcome measures, potential confounders, and baseline differences in populations studied(6). As a result, findings have varied from observations of higher odds of early mortality in women(7–9) to the opposite, with a relative risk of 0.8 for ICH death (age-standardized)(10). Moreover, hypotheses pertaining to the pathophysiological mechanisms explaining possible sex-related differences in either risk or outcome have been predominantly derived from the preclinical setting, making it difficult to define an informed hypothesis regarding expectations for sex-related differences in ICH risk or severity.
The objective of the present study was to investigate whether ICH patients show sex-specific differences in severity, evolution and outcome of the disease in a large population of consecutive cases presenting to Massachusetts General Hospital (MGH) over more than two decades.
Methods
Participants
All aspects of the study were approved by the Institutional Review Board (IRB). Informed written or verbal consent was obtained by patients or family members or was explicitly waived by the IRB. We retrospectively analyzed an ongoing prospective cohort of patients with primary ICH, as previously described(11). Briefly, study subjects were consecutive patients with ICH and age ≥18 years admitted to the MGH from January 1994 to April 2015 and were excluded if there was evidence of 1) traumatic intracranial bleeding, 2) intracranial tumor, aneurysm or other vascular malformation presumed to be the cause of the hemorrhage, 3) hemorrhagic conversion of acute brain infarction, 5) missing data on clinical or demographic variables.
Clinical Variables
Demographic and clinical data were systematically collected through patient and family member interviews and retrospective review of hospital charts. Survival data were obtained via follow up by phone, or updated from hospital records supplemented by the Social Security Death Index. We collected data including sex, age, history of hypertension, diabetes mellitus, hypercholesterolemia and coronary artery disease (CAD), alcohol consumption, smoking, and antiplatelet therapy and oral anticoagulant treatment. Prior functional dependence was defined as requiring assistance at least in one instrumental activity of daily living (IADL)(12). For the index hospital stay, we collected the following data: international normalized ratio (INR) on admission, systolic (SBP) and diastolic blood pressure (DPB) on admission, Glasgow Coma Scale (GCS) at presentation, and any limitation of care (defined as presence of “do-not-resuscitate/do-not- intubate” code status or a “comfort measure only” order). We also recorded recurrence of primary ICH in the studied period and divided the year of the index ICH into quartiles. Finally, participants self-identified race and ethnicity at enrollment, choosing from the options recommended by the Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity(13).
Computed Tomography (CT) image acquisition and analysis
Non-contrast CT (NCCT) was performed and reviewed in a blinded fashion, as described(14), to determine ICH location (deep, lobar or infratentorial), presence of intraventricular extension of the hematoma, and hematoma volume (calculated with semi-automated computer assisted technique [Analyze Direct 11.0 software]). For the identification of Spot Sign presence, computed tomography angiography (CTA) images were obtained and reviewed as previously described(15). ICH expansion was defined as hematoma growth > 33% or > 6 mL from baseline ICH volume on the follow up CT taken at 24 h.(16,17)
Statistical Analyses
Categorical variables were expressed as count (%) while continuous variables as median (interquartile range, IQR) or mean (standard deviation, SD) as appropriate, and were compared using the χ2 test or the Mann-Whitney test. The association between sex and 90-days mortality was investigated using multivariate logistic regression. First, we tested a model with all the known predictors of ICH mortality, followed by a more comprehensive model with all the variables differing in the univariate comparison between male and female (p value <0.05) and the period of enrollment (See Table 2 legend, for all the covariates included). We further tested our results against the one-year mortality rate, using a Cox proportional hazards model for time-to-event mortality, adjusted by the same variables described above. The relationship between sex and hematoma expansion was investigated using multivariable logistic regression, accounting for known predictors of ICH growth(16) (imaging model 1), and for warfarin and antiplatelet medication, time from onset to baseline CT, baseline hematoma volume, DBP, SBP, spot sign, and ICH location (imaging model 2). To identify whether variables differing between men and women interacted with sex in the determination of mortality, we performed formal mediation analyses using the mediation package in R (The R Foundation for Statistical Computing) software version 3.2.3 (http://cran.r-project.org/web/packages/mediation/index.html); all other analyses were performed using the statistical package SPSS v. 21, 2012 (www.spss.com). P values < 0.05 were considered statistically significant.
Table 2.
Multivariate logistic regression models between mortality and male sex and between ICH expansion and male sex
| mortality 90 days | ||||
|---|---|---|---|---|
| OR | CI (95%) | p | R 2 | |
| Model 1 | 2.15 | 1.46–3.19 | <0.001 | 0.55 |
| Model 2 | 2.07 | 1.19–3.59 | 0.010 | 0.53 |
| ICH expansion | ||||
| Imaging model 1 | 1.70 | 1.15–2.50 | 0.007 | 0.17 |
| Imaging model 2 | 2.03 | 1.09–3.79 | 0.027 | 0.23 |
Model 1 : age, ICH Location, ICH volume, GCS, IVH, prior dependence, limitation of care.
Model 2 : age, Hispanics ethnicity, ICH Location, ICH volume, GCS, IVH, prior dependence, limitation of care, diabetes, CAD, hypercholesterolemia, hypertension, smoking, alcohol, warfarin, statin and antiplatelet use, systolic and diastolic blood pressure and time of ICH.
Imaging model 1: Adjusted for warfarin use, time from onset to baseline CT, baseline hematoma volume
Imaging model 2: Adjusted for warfarin use, time from onset to baseline CT, baseline hematoma volume, diastolic blood pressure, systolic blood pressure, spot sign, intracerebral hemorrhage location, antiplatelet use
CI = confidence interval, ICH = intracerebral hemorrhage, OR = odds ratio, GCS = Glasgow coma scale, IVH = intraventricular hematoma, CAD= coronary artery disease
Results
A total of 2403 patients with ICH were screened and 2212 met the eligibility criteria (median age 75 y/o, 53.5 % males). Compared to the study population, patients excluded from the analysis showed lower GCS and higher rate of prior dependence; however, they did not differ for age, race, sex, hematoma expansion or mortality (all p values > 0.10). Men with ICH had greater smoking and alcohol use, and were more likely to suffer from hypertension, diabetes, hypercholesterolemia and coronary artery disease [Table 1]. Consistently, men were more likely to be on antiplatelet, warfarin and statin therapy and showed higher initial DBP (94±23 vs 89±21 mmHg). Women were older (average 77 vs. 72 years), more likely to be dependent (p<0.001) and to suffer from lobar hemorrhages (p<0.001).
Table 1.
Descriptive characteristics of studied population and differences according to gender
| Male (n =1184) | Female (n = 1028) | p-value | |
|---|---|---|---|
| Age (y), median (IQR) | 72 (62–80) | 77 (68–84) | <0.001 |
| Hispanics, n (%) | 69/905(7.6) | 41/791(5.2) | 0.048 |
| Race, n (%) | 0.166 | ||
| White | 1001(84.5) | 894 (87.0) | |
| Blacks | 65 (5.5) | 54 (5.3) | |
| Asians | 64 (5.4) | 51 (5.0) | |
| Other/Unknown | 54 (4.6) | 29 (2.8) | |
| History of hypertension, n (%) | 947 (80.0) | 780 (75.9) | 0.020 |
| History of diabetes, n (%) | 291 (24.6) | 175 (17.0) | <0.001 |
| History of hypercholesterolemia, n (%) | 469 (39.6) | 345 (33.6) | 0.004 |
| History of CAD, n (%) | 319/1180 (27.0) | 174/1023 (17.0) | <0.001 |
| Smoking, n (%) | 589/955 (61.7) | 343/807 (42.5) | <0.001 |
| Alcohol, n (%) | 246/903 (27.2) | 77/783 (9.8) | <0.001 |
| Antiplatelet treatment, n (%) | 611 (51.6) | 471 (45.8) | 0.007 |
| Warfarin treatment, n (%) | 284 (24.0) | 205 (19.9) | 0.024 |
| Statin treatment, n (%) | 408 (34.5) | 276 (26.8) | <0.001 |
| Prior dependence, n (%) | 129/1086 (11.9) | 152/944 (16.1) | 0.005 |
| SBP, mean ± SD, mmHg | 176±36 | 175±36 | 0.284 |
| DBP, mean ± SD, mmHg | 94±23 | 89±21 | <0.001 |
| Baseline ICH volume, median (IQR), mL | 17 (6–48) | 17 (5–46) | 0.189 |
| Admission GCS, median (IQR) | 14 (7–15) | 14 (8–15) | 0.895 |
| ICH location, n (%) | <0.001 | ||
| lobar, n (%) | 455(38.4) | 489 (47.6) | |
| deep, n (%) | 599 (50.6) | 429 (41.7) | |
| infratentorial, n (%) | 130 (11.0) | 110 (10.7) | |
| IVH presence, n (%) | 607 (51.3) | 499 (48.5) | 0.216 |
| Symptoms onset to CT, min (IQR) | 255 (119–476) | 275 (118–489) | 0.527 |
| Surgery | 74(6.3) | 62 (6.1) | 0.859 |
| Hematoma expansion, n (%) | 146/781 (18.7) | 77/625 (12.4) | 0.001 |
| Spot sign, n (%) | 121/487 (24.8) | 78/407 (19.2) | 0.044 |
| Limitation of care, n (%) | 369/1052(35.1) | 341/889 (38.4) | 0.143 |
| Recurrence, n (%) | 72 (6.1) | 69 (6.7) | 0.601 |
| 90 days mortality, n (%) | 445(6) | 375 (36.5) | 0.597 |
| 1 year mortality, n (%) | 509 (43.0) | 430 (41.8) | 0.605 |
| Recurrence, n (%) | 72 (6.1) | 69 (6.7) | 0.601 |
CAD = coronary artery disease, DBP = diastolic blood pressure, IQR = interquartile range, ICH = intracerebral hemorrhage, IVH = intraventricular hemorrhage, SBP = systolic blood pressure.
Impact of sex on ICH mortality
Univariate analysis between sexes did not show significant differences in 90 days and one-year mortality. However, in multivariable logistic regression, male sex was an independent predictor of mortality at 90 days. This was consistent across both models that correct for known outcome predictors and for differences between sexes (surgery and limitation of care were not included as they did not significantly differ between sexes) [Table 2]. This observed association between male sex and mortality remained significant when mortality was analyzed in our time-to-event analysis at one year [Supplemental Figure 1].
Impact of sex on ICH expansion
A total of 1406 subjects (63.5 %) had a follow up NCCT available for hematoma expansion analysis. Differences between male and female followed the same profile of the cohort for the mortality analyses, [Supplemental Table 1], notably there were no sex-based differences in availability of follow-up NCCT (p>0.1). ICH expansion was significantly more frequent in men (19% vs. 12.4%, p=0.001), and this difference persisted after adjustment for known predictors of hematoma growth [Table 2, imaging model 1] and other potential confounders [Table 2, imaging model 2].
Mediation analysis of sex-related differences in ICH mortality by hematoma expansion
Because hematoma expansion is a known predictor of ICH mortality(18,19), we investigated observed sex-based differences in hematoma expansion and mortality using a formal mediation analysis [Figure 1]. Having demonstrated separate associations in multivariate analyses for sex and mortality, and for sex and expansion, the same models were used to fit the mediation analyses. The analysis showed that 20% (95% CI = 4%–92%) of the observed effect of sex on risk mortality at 90 days could be accounted for by risk of expansion (mediation p = 0.02). The incorporation of additional variables differing between sexes demonstrated no other statistically significant mediators. Consistent with our mediation analysis demonstrating only a partial effect of expansion on the sex–outcome relationship, inclusion of hematoma expansion as a covariate in both models of mortality did not eliminate the effect of sex on outcome (Model 1: OR 2.08 (95% CI 1.31–3.29), p= 0.02. Model 2: OR 1.88 (95% CI 1.01–3.49) p=0.047).
Figure 1.
Mediation analysis and percentages of effect size for sex association with mortality at 90 days. For any variable, we report the average proportion mediated and its p value. ICH = intracerebral hemorrhage; PM=proportion mediated; CAD= coronary artery disease.
Discussion
In this hospital-based ICH cohort, we observed sex-related differences in ICH risk factor profile, severity and mortality. Our results suggest that male sex is independently associated with the risk of death at 90 days. Analyses of mortality at one year were consistent with these findings. Exploratory analysis on the possible mechanism for this difference suggested that this association is at least partially mediated by a male predilection towards early hematoma expansion.
Mortality differences at 90 days and one year were not significant in univariate analysis, and this may be explained by important differences in baseline characteristics between men and women. In absolute terms, the mortality rates were indeed similar, despite men being overall younger, and having a better pre-stroke functional status. It was only after adjusting for these relevant baseline differences and multiple potential confounders in multivariable analysis that the association between male sex and mortality after ICH became apparent.
An increased burden of vascular risk factors and cardiovascular diseases(1,20–24) have been repeatedly observed in aging men compared with women, and it is therefore unsurprising that similar baseline disparities are seen in our cohort of ICH patients. Discrepancies in the literature for sex-related differences in ICH outcome could be accounted for by heterogeneity in outcome quantification(7,25–28) or modeling of outcome based solely on univariate analysis(9). Similarly, sample size limitations could explain the lack of observed mortality differences in other reports(5), and in the recently published study of Roquer and colleagues(29). The present study benefits from a larger sample size and the inclusion of CT-based hematoma expansion data, which provides additional insight into potential mechanisms of the observed differences in ICH mortality.
The putative pathways involved in sex-related differences in response to brain injury are complex and multiple biological pathways may play a role(30–32). Tissue-specific responses to sex hormones have been implicated in differences between traumatic brain injury outcomes between sexes(33). Given the age distribution of our female participants, most or all are likely postmenopausal. We lack information on exposure to hormone replacement therapy (HRT) in our study population, but given prior observations demonstrating association between initiation of hormone replacement therapy and ICH risk(34), underreporting of HRT use in our study would seem more likely to bias results towards a null result.
In addition to a lack of information on HRT use, this study has several limitations. First, our observations are derived from a retrospective, single-center analysis of patients presenting to a large tertiary-care referral center. Our results may therefore be susceptible to selection bias due to severity of disease at presentation. Second, the ICH patients enrolled in this study were predominantly white and non-Hispanic. Socioethnic disparities in minority populations could provoke sex-specific differences in ICH severity and/or outcome that could not be inferred by the present study. Third, our data are derived from a long recruitment period over 21 years. Although ICH admission rates and in-hospital mortality have not significantly changed over the last two decades(9), and our analyses took into account the period of the index ICH, bias remains possible. Finally, although we have included several multivariable models composed of known risk factors and observed covariates to attempt to control for such a possibility, the potential for residual unmeasured confounding remains.
Our study demonstrates a higher risk of early and late mortality in men compared to women, that appears to be partially mediated by a greater risk for hematoma expansion. While confirmation in other large cohorts comprised of more heterogeneous racial and ethnic composition are needed, these findings highlight the pressing need to explore sex-related biological pathways in brain injury and support investigation of sex-specific treatment modalities.
Supplementary Material
Highlights.
The role of sex in intracerebral hemorrhage severity and outcome remains poorly characterized.
Male sex is an independent predictor of poor outcome
Multiple regression and proportional hazards models ensure consistency of observations
This association appears to be mediated by an increased risk of intracerebral hemorrhage expansion
Acknowledgments
Sources of funding
This study was supported by the following awards from the NINDS: K23NS086873, R01NS059727, R01AG26484, P50NS061343
None of the funding entities had any involvement in study design; data collection, analysis, and interpretation; writing of the manuscript; or decision to submit the study for publication.
Abbreviations
- ICH
Intracerebral hemorrhage
- MGH
Massachusetts General Hospital
- IRB
Institutional Review Board
- CAD
Coronary Artery Disease
- IADL
Instrumental Activity Of Daily Living
- INR
International Normalized Ratio
- SBP
Systolic Blood Pressure
- DPB
Diastolic Blood Pressure
- GCS
Glasgow Coma Scale
- CT
Computed Tomography
- NCCT
Non-contrast CT
- CTA
Computed Tomography Angiography
- IQR
Interquartile Range
- SD
Standard deviation
- HRT
Hormone Replacement Therapy
Footnotes
Disclosures
Joshua N. Goldstein reports research funding from NIH, Boehringer Ingelheim, Pfizer, and Portola.
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