Functional outcome and survival following spontaneous intracerebral hemorrhage: A retrospective population‐based study

Abstract Background Accurate and reliable clinical and radiological predictors of intracerebral hemorrhage (ICH) outcomes are needed to optimize treatment of ICH. The aim of this study was to investigate functional outcome and identify predictors of severe disability or death following ICH. Materials and methods Retrospective population‐based study of spontaneous ICH. Clinical and radiological data were obtained from electronic medical records, and functional outcome estimated using the modified Rankin Scale (mRS) before ICH and at 3 and 12 months after ICH. Results Four hundred and fifty‐two patients were included (mean age 74.8 years, 45.6% females). Proportion of fatal outcome at 1 week was 22.1%, at 3 months 39.2%, and at 12 months 44.9%. Median mRS score before the ICH was 1 (interquartile range [IQR] 2); for survivors at 3 months, it was 5 (IQR 3); and at 12 months, it was 3 (IQR 2). Independent predictors of severe disability (mRS of 5) or death (mRS of 6) were use of oral antithrombotic drugs (OR 2.2, 95% CI 1.3–3.8, p = 0.04), mRS score before the ICH (OR 1.8, 95% CI 1.4–2.2, p < 0.001), Glasgow Coma Scale (GCS) on admission (OR 8.3, 95% CI 3.5–19.7, p < 0.001), hematoma volume >60 ml (OR 4.5, 05% CI 2.0–10.2, p < 0.001), and intraventricular hematoma extension (OR 1.8, 95% CI 0.8–4.2, p < 0.001). Conclusion Intracerebral hemorrhage is associated with high mortality, and more than one third of survivors end up with severe disability or death 3 months later. Predictors of severe disability or death were use of oral antithrombotic drugs, functional disability prior to ICH, low GCS on admission, larger hematoma volume, and intraventricular hematoma extension.


| Norwegian patient registry
Norwegian patient registry (NRF) is a national administrative health registry containing person identifiable information on all inpatient and outpatient treatment by the public Norwegian specialist health care services. The database contains demographic, administrative, and health related data, such as dates of admission and discharge, and primary and unlimited number of secondary diagnoses according to the 10th revision of the International Classification of Diseases (ICD-10), including codes for diagnostic and therapeutic procedures.
All discharge diagnoses are exclusively assigned by the physicians treating the patient, and cannot later be altered. The registry receives data monthly and is used for reimbursement purposes, hospital activity statistics, and research (Varmdal et al., 2016). Coding of ICH discharge diagnoses in the NPR is of high quality, with positive predictive values for ICH hospital admissions exceeding 95% (Oie et al., 2018).

| Study population
The study was carried out within the population of Sør-Trøndelag Patients with a primary diagnosis of spontaneous ICH (ICD-10 codes I61.0-I61.9) and a residential address within Sør-Trøndelag County were included in the study. After review of hospital records and diagnostic images, we excluded traumatic ICH, ICH related to intracranial tumors, extra-axial intracranial hemorrhages, and ICH related to parenteral thrombolytic treatment (inpatient ICH). Patients with isolated intraventricular hemorrhage were included. Patients whose records were not found, or episodes of ICH occurring outside the study period were excluded from the analyses. Patients from the study area who were hospitalized elsewhere for ICH and subsequently transferred to St. Olavs University hospital were included.
All included patients were aged 18 years or older.

| Baseline recordings
ICH was defined as clinical symptoms of stroke combined with the presence of parenchymal hemorrhage on a cerebral CT (cCT) scan.
Time of ictus was defined as the time when neurological symptoms appeared. Demographic data, comorbidities, clinical and radiological data, and information about surgical interventions were retrieved from the electronic medical records. The Charlson comorbidity index was used to estimate comorbidity, a scoring system predicting 10year survival in patients with multiple comorbidities. In addition to vascular comorbidities, it includes dementia and malignancy which are often not included in other scoring systems (Charlson, Pompei, Ales, & MacKenzie, 1987;Sundararajan et al., 2004).
Use of oral antithrombotic medications (OAM) at the time of hospital admission was also registered, including both antiplatelet agents (aspirin, dipyridamole, acetylsalicylic acid-dypiridamole, and clopidogrel) and anticoagulant agents (warfarin, dabigatran, apixaban, and rivaroxaban).
A baseline cCT scan was available for all included patients, except for patients transferred from hospitals outside Norway. Four of the authors, blinded to patient characteristics, assessed all cCTs.
Hematoma location was classified as lobar (cortical or subcortical white matter), deep (thalamus and basal ganglia), brainstem, or cerebellum. Hematoma volume was calculated manually with the formula A × B × C /2 cm 3 (Kothari et al., 1996). The presence of intraventricular hemorrhage was registered, and a modified Graeb score (mGS) was calculated for intraventricular hemorrhages (Hinson, Hanley, & Ziai, 2010). Hematoma expansion was determined if sequential brain imaging was available, and defined as a relative parenchymal volume increase of more than 33% from initial to follow-up imaging within 3 to 72 hr (Kuramatsu et al., 2015).
If more than one follow-up imaging session was performed, the one closest to the 24-hr time was chosen. Patients with hematoma evacuation before any follow-up imaging were excluded from the hematoma expansion analysis.

| Outcome assessment
All included patients were followed up for a minimum of 12 months.
Level of consciousness, determined by Glasgow Coma Scale (GCS), is routinely scored for all patients admitted to the hospital, and was found in the electronic medical records. Functional outcome was determined using the modified Rankin Scale (mRS) score before the ICH, and at 3 and 12 months after ICH. The mRS score prior to and immediately after the ICH is routinely scored on admission to the stroke unit by stroke physicians, nurses, and physiotherapists. Three months after discharge, stroke patients receive either an outpatient or home visit where mRS is usually scored (Indredavik, Fjaertoft, Ekeberg, Loge, & Morch, 2000). This information is available in the electronic medical records. The mRS scores at 12 months were scored by two of the authors (LRØ, MAM) based on information from the electronic medical records. Patients with mRS of 5 were classified as having severe disability and mRS 6 as dead. As an additional indicator for clinical outcome, cohabitation before and after the ICH was assessed. The date of death was provided by either the electronic medical record or Norwegian Institute of Public Health.

| S TATI S TI C S
Statistical analyses were performed with SPSS 24.0. Descriptive statistics were computed for baseline characteristics. To compare users and nonusers of OAM, we used independent samples t tests for continuous variables, and chi-square test for categorical variables.
Predictors of severe disability or death (mRS 5 and 6) at 3 months were analyzed using Cox regression analyses. Variables from the univariable analyses with a p-value <0.10 were included in the multivariable model. Effect sizes were presented as odds ratio with 95% confidence intervals. p-Values <0.05 were considered statistically significant. Survival analyses of patients younger or older than 75 years and users and nonusers of OAM were analyzed with logrank tests and visualized using Kaplan-Meier curves. Aggregated exposure for inhabitants of Sør-Trøndelag County between 1 January 2008 and 31 December 2014 was used to calculate the crude incidence rate.

| RE SULTS
In total, 561 patients with spontaneous ICH requiring hospitalization were identified in the NPR within the study period, and based on our inclusion and exclusion criteria, 452 patients were included for further analyses.

| Patient characteristics
Crude annual incidence rate between 2008 and 2014 in Sør-Trøndelag County was 21.5 per 100,000 per year. Patient and hematoma characteristics are presented in Table 1. The mean age was 74.8 years and 45.6% were females. Past history of arterial hypertension was present in 52.7% (n = 238) and a history of diabetes in 11.7% (n = 53). The mean Charlson comorbidity index score was 1.4 (SD 1.6). At the time of the ICH, a total of 56.6% (n = 256) used OAM, with antiplatelet drugs (37.2%) being more frequently used than anticoagulants (22.8%). 14 patients (5.5%) used both antiplatelets and anticoagulants at the time of ICH. Novel oral anticoagulants (NOAC) were introduced in the last part of the inclusion period, and only 1 patient used NOAC (rivaroxaban), whereas the others used warfarin with a mean INR value of 2.8 on admission. As presented in Table 4, users of OAM were older than nonusers (78.6 vs. 69.4 years, mean difference 9.2 years, 95% CI 7.0-11.3, p < 0.001). In total, 9.5% (n = 43) underwent early surgical treatment for the bleeding. Of these, 6.2% (n = 28) underwent hematoma evacuation, and 0.7% (n = 3) received an additional craniectomy (Table 1).
Overall, the mean baseline hematoma volume was 33.1 ml (SD 45.7).

| Functional outcome
Clinical presentation and functional outcome are presented in Table 2. Median GCS score on admission was 14 (IQR 6). Median mRS score before the ICH was 1 (IQR 2); for survivors at 3 months, the median mRS was 5 (IQR 3); and at 12 months, median mRS was 3 (IQR 2). The proportion of fatal outcome during the first week  survivors at 3 months, 52 (18.9%) were severe disabled (mRS 5), and at 12 months, 12 (4.8%) had mRS 5. Functional status before, and at 3 and 12 months is presented in Figure 1.
The univariate analyses (

| D ISCUSS I ON
This retrospective population-based study in a high resource setting shows that ICH is associated with high mortality, and the majority of survivors become dependent of care.
Independent predictors of severe disability or death at three months were use of OAM, functional disability prior to the ICH, low GCS score on admission, larger hematoma volume, and presence of intraventricular extension. Only age <75 years was an independent predictor of favorable outcome at three months.
However, it is difficult to compare results across studies due to variation in inclusion criteria, outcome measures, and statistical analyses.
In line with previous studies, we found that the patients' initial level of consciousness, baseline hematoma volume, hematoma growth, hydrocephalus, and intraventricular extension were the most important prognostic factors of ICH (Bhatia et al., 2013;Davis et al., 2006;Flemming et al., 2001;Nilsson et al., 2002;Safatli et al., 2016;Sarker et al., 2008). Given the association of poor outcome with hematoma expansion, accurate and reliable predictors of expansion are needed. In contrast to volume and location, secondary hematoma growth is potentially modifiable, and prevention of such expansion should still be a major therapeutic target in the management of ICH. The spot sign observed on CT angiography (CTA) has been found to independently predict poor outcome (Demchuk et al., 2012). We did not evaluate the spot sign in our study as CT angiography was only available for some of the included patients. Predictors of hematoma growth on noncontrast computed tomography, such as the blend sign and hypodensities, have been found to predict outcome in patients with ICH (Sporns, Kemmling, Minnerup, Hanning, & Heindel, 2018 TA B L E 3 Factors associated with severe disability or death (mRS score 5-6) at 3-month follow-up | 7 of 9 ØIE Et al.
perihemorrhagic edema has been found to be an independent predictor of functional outcome after ICH (Volbers et al., 2018).
Incidence of ICH is increasing with age for both genders; however, consistent with previously published studies, neither gender nor age were significant predictors of severe outcome in our study (Broderick et al., 2007;Safatli et al., 2016). Conflicting results have been reported for hematoma location, and some studies have found infratentorial location to be associated with increased mortality (Safatli et al., 2016), while others failed to show an association (Bhatia et al., 2013). In the present study, hematoma location was not an independent prognostic factor of severe disability or death.  (Gulati et al., 2015).
Patients who survive ICH may have risk factors for future thromboembolic events, but the role of OAM remains a therapeutic dilemma with conflicting evidence and contradictory recommendations (Biffi et al., 2017;Pennlert et al., 2015). There is currently a lack of solid evidence to guide decisions on whether and when to start or restart treatment in ICH survivors, and both well designed randomized controlled trials and observational studies should be encouraged (Perry et al., 2017).
In the present cohort, patients who underwent neurosurgical interventions did not exhibit better outcome. At 3 months, more than one third of the patients receiving surgical management were dead (mRS 6), and another one third had severe disability (mRS 5). Our