Three-Year Survival and Stroke Recurrence Rates in Patients With Primary Intracerebral Hemorrhage
Background and Purpose— There are few studies on the prognosis after primary intracerebral hemorrhages, and they reported big differences in mortality rates. Our aim was to evaluate mortality and stroke recurrence rates in relation to hemorrhage characteristics, demographic and clinical factors, in a large unselected patient cohort.
Methods— We analyzed consecutive cases of first-ever primary intracerebral hemorrhages from 1993 to 2000 in a prospective stroke register covering the Malmö region, Sweden (population approximately 250 000). Mortality rates during 28 days and 3 years of follow-up and recurrence rates were analyzed.
Results— A total of 474 cases were identified (46% women). In patients <75 years of age, 20% of the women and 23% of the men died within 28 days (P=0.38). The corresponding figures in patients ≥75 years were 26% and 41%, respectively (P=0.02). Male sex was an independent risk factor both for 28-day (OR, 1.5; 95% CI, 1.008 to 2.2) and 3-year mortality (OR, 1.7; 95% CI, 1.3 to 2.3). Other independent predictors of death were high age, central and brain stem hemorrhage location, intraventricular hemorrhage, increased volume, and decreased consciousness level. The recurrence rate was 5.1 per 100 person-years, 2.3 per 100 person-years for intracerebral hemorrhage and 2.8 per 100 person-years for cerebral infarction. Only age >65 years was significantly related to recurrent stroke.
Conclusion— Women had better survival than men after primary intracerebral hemorrhages. The difference is largely explained by a higher 28-day mortality in male patients >75 years. However, the underlying reasons are yet to be explored.
- acute stroke
- cerebrovascular disease
- diabetes mellitus
- intracerebral hemorrhage
- intracranial hemorrhage
- stroke management
In Western communities, approximately 10% of all strokes are due to primary intracerebral hemorrhage (PICH).1–3⇓⇓ Recent studies have reported considerable variation in outcome with 1-month case-fatality rates between 13% and 51%.4–10⇓⇓⇓⇓⇓⇓ Few large studies have reported long-term prognostic factors4,5,9,11⇓⇓⇓ and stroke recurrence rates12 in this patient group. Old age and factors related to hemorrhage severity (volume, intraventricular hemorrhage, and decreased level of consciousness) have a negative influence on outcome after PICH, whereas the impact of sex, hemorrhage location, and anticoagulation treatment is inconsistent between studies.4,5,8⇓⇓
The aim of this study was to explore the 28-day case-fatality rate (CFR) and 3-year mortality rate after first-ever PICH in relation to sex, age, hemorrhage characteristics, level of consciousness, vascular risk factors, and anticoagulation therapy in an unselected patient cohort. We also determined the recurrence rate of stroke, both intracerebral hemorrhage and cerebral infarction, over a 3-year period.
Methods and Materials
Stroke Cases: Ascertainment and Classification
This study includes all cases with first-ever intracerebral hemorrhage registered in the Malmö stroke register, STROMA,1,13⇓ between January 1993 and December 2000. The STROMA register searches for and validates cases of stroke, both first and recurrent stroke events according to the same case ascertainment procedure. Malmö University Hospital is the only hospital serving the population (n = approximately 250 000) of Malmö. Primary care and nursing homes work in collaboration with the University Hospital, and patients with symptoms of stroke at those healthcare facilities are routinely referred to the hospital for further examination and thus captured through systemic search of medical records. Only stroke cases in Malmö citizens as verified by the Swedish population register are included in STROMA. The case-finding, made by a specialized research nurse, includes a continuous broad search among patients admitted to the emergency and admission department, the neurological wards, and ambulatory department as well as other relevant hospital wards for neurological symptoms and diagnosis that could indicate stroke. Patients initially hospitalized for other reasons are also included in the case-finding procedure. Supported by a senior neurologist (H.P.-R.), all possible stroke cases are validated by review of the patients’ records. Stroke is defined as rapidly developed clinical signs of local or global loss of cerebral function that lasted for >24 hours or led to death within 24 hours following the World Health Organization’s definition.14 The stroke subtypes (cerebral infarction, intracerebral hemorrhage, subarachnoidal hemorrhage, and unspecified stroke) are coded according to International Classification of Diseases, 9th and 10th Revision.15 Intracerebral hemorrhage (International Classification of Diseases codes 431 and I61, respectively) is considered when CT, MRI, or autopsy shows intraparenchymal blood in the brain. Angiography is carried out in selected cases with hemorrhagic stroke, that is, in whom hemorrhage location, age, or clinical situation was suggestive of a vascular malformation.
In all verified cases with intracerebral hemorrhage, one of the authors (E.Z.) reviewed the CT images with assistance from a neuroradiologist (Dr Toivo Matilainen) with respect to hemorrhage volume, presence of intraventricular hemorrhage, and location of the hemorrhage. In this review, cases were excluded if the hemorrhage was considered to be secondary (eg, caused by arteriovenous malformation/aneurysm [n=21], thrombolysis of acute myocardial infarction [n=5], hemorrhagic infarction [n=10], tumor [n=5]). In 11 cases, the diagnosis of intracerebral hemorrhage could not be verified. In total, 52 cases were excluded in this study.
Hemorrhage location was classified into 4 categories: lobar (predominantly cortical or subcortical white matter), central (predominantly basal ganglia, internal capsule, periventricular white matter), cerebellum, and brainstem. Due to the small number of recurrent events, only 2 categories were used when exploring the recurrence rates (lobar versus nonlobar [central, brain stem, cerebellar]). Volume was categorized into 3 groups: <30 mL, 30 to 60 mL, and >60 mL. Hemorrhage volume was calculated by using the formula A×B×C/2.16
In 9 cases, only medical or autopsy records were available, and the presence or absence of intraventricular hemorrhage could not be verified. In one of these cases, data on hematoma volume were missing as well.
Data on vascular risk factors at the time of stroke, and level of consciousness on admission, were retrieved from the patient records. After risk factors were collected, data on treatment for hypertension, current or former smoking, ischemic heart disease (ie, history of angina pectoris and/or cardiac infarction), and diabetes mellitus were collected. Data on risk factors were missing as follows: treatment for hypertension (n=79), smoking (n=191), ischemic heart disease (n=77), and diabetes (n=83). Level of consciousness was assessed according to the Reaction Level Scale (RLS 85 scale).17 The RLS scores were categorized into 3 groups: RLS score=1 (alert), RLS score=2 to 3 (drowsy), and RLS score=4 to 8 (unconscious). Information was not available in 5 cases. In patients with RLS score ≥4, we collected information about surgical therapy and discharge destination (own home, rehabilitation ward, or nursing home) from the medical records.
Information about oral anticoagulation treatment (OAT) at the time of the stroke event was collected from the patient records and from the patient register at the Anticoagulation Clinic of Malmö University Hospital.
Date and cause of death were obtained from the National Cause of Death Register18 and mortality rates during 28 days (28-day CFR) or 3 years after the PICH event were calculated. Stroke recurrence rates within 3 years from PICH were calculated in 28-day survivors using data from the STROMA register.
This project was approved by the local ethics committee (LU 78-02 and LU 238-02).
Logistic regression, with sex as the dependent variable, was used to compare baseline characteristics in men and women. Due to the short follow-up time, a logistic regression model, with fatal outcome as the dependent variable, was used to explore risk factors for 28-day CFR. Cox proportional hazards model was used to study risk factors for 3-year mortality and stroke recurrence rates. First, the various risk factors were entered individually. Age, sex, and risk factors with P<0.2 were considered potential confounding factors and were entered into the multivariate models. Cases with missing data on vascular risk factors (see previously) were coded in separate categories to keep them in the multivariate analysis. The proportional hazards assumption was confirmed by plotting the hazard rates for the various risk factors over time. The statistical analyses were conducted by the computer software SPSS (Version 14.0).
Baseline data on hemorrhage characteristics and clinical factors are shown in Table 1 and Table 2. A total of 474 cases of PICH were identified. Mean age was 73 years, 29% of the patients were ≥80 years, and 46% were female. Women were significantly older than men (77±11 versus 69±12 years; P<0.001). Mean volume was 26.6 mL (median volume, 11 mL; Table 1). In patients with OAT, the mean age was 75 years versus 72 years in patients without OAT (P=0.2) and the mean hemorrhage volume was 30.2 mL versus 26.2 mL in patients without OAT (P=0.5).
28-Day Case Fatality
The survival rates after PICH in relation to age and sex are presented in Figure 1. The 28-day CFR for all patients was 26% (n=125). Of the deaths, 42% occurred during the first 2 days. Men had higher 28-day CFR than women (Table 3). The difference in survival between the sexes was most marked in patients ≥75 years (Figure 1). In this age group, the 28-day CFR was 41% in male patients versus 26% in women (P=0.02). The 28-day CFR in patients <75 years was 23% in men versus 20% in women (P=0.38). After adjustment for other risk factors, the sex difference in 28-day CFR reached statistical significance (Table 3).
The 28-day CFR in relation to hemorrhage volume and location is shown in Figure 2. Patients on OAT had a 34% 28-day CFR as compared with 25% in patients without OAT (P=0.2). For those who died within 28 days, cause of death was PICH for 90.4% of the cases, cardiac event in 4.8%, and other causes in 4.8%.
The overall 3-year mortality rate was 49% (n=232). The proportion of deaths, in relation to baseline characteristics, is shown in Table 4. Men had higher 3-year mortality than women, again driven by the higher 28-day CFR in men ≥75 years (Figure 1). Besides male sex and old age, intraventricular hemorrhage, volume >30 mL, brainstem hemorrhage, and RLS grade ≥2 were associated with higher 3-year mortality after adjustment in the multivariate analysis (Table 4). For those who survived 28 days, but died within 3 years, cause of death was PICH in 47% of the cases, cardiac event in 15%, malignancy in 6%, infection in 7%, and other causes in 25%.
RLS scores ≥4 were associated with substantially increased mortality rates (Tables 3 and 4⇑). However, even in this group, 23 patients (25%) survived the first 28 days, and 12 of them were alive after 3 years. Thirteen patients had lobar, 9 central, and one cerebellar hemorrhage location. Patient records were reviewed for 19 of the 23 survivors. Craniotomy was performed in 5 of them: one with cerebellar, one with putaminal, and 3 patients with lobar hemorrhage. Six (4 operated) of the 19 patients were discharged to their own homes or rehabilitation ward and 13 to a nursing home. All 19 patients were highly dependent in daily activities on discharge. Age >65 years (OR, 5.6; 95% CI, 1.5 to 20.6), nonlobar hemorrhage (OR, 3.3; 95% CI, 1.1 to 9.9), and intraventricular hemorrhage (OR, 6.1; 95% CI, 1.8 to 20.9) were independent predictors for 28-day mortality in patient with RLS ≥4.
The crude recurrence rates in patients who survived 28 days (n=353), in relation to sex, age, and hemorrhage locus, are presented in Table 5. In total, 12% (5.1 per 100 person-years) of the patients had a recurrent stroke event, either a new PICH (2.3 per 100 person-years) or a cerebral infarction (2.8 per 100 person-years). Two of these patients had 2 recurrent stroke events during the follow-up period. After adjustment for sex, age, and hemorrhage location of the first PICH, only age (hazard ratio, 2.9; 95% CI, 1.2 to 6.6 for age 65 to 74 years and hazard ratio, 2.9; 95% CI, 1.2 to 7.2 for age ≥75 versus age <65) was an independent risk factor for recurrence, either PICH or cerebral infarction.
The 28-day CFR in the present study was in the lower range compared with other large studies of Western populations, which have reported CFR between 24% and 51%.4–6,8–10⇓⇓⇓⇓⇓ This could in part be explained by differences between study samples and designs, for example with respect to inclusion of patients with previous stroke,4,8⇓ admission rates of the centers,4,8,9⇓⇓ and ethnicity,4 all of which are factors that could influence on PICH and stroke mortality.19–21⇓⇓
In our study, male sex was an independent risk factor for short- and long-term mortality. Although women had lower short-term mortality after stroke overall in some studies,6,22–24⇓⇓⇓ the results are not consistent.25,26⇓ In a Finnish study, long-term mortality after PICH was higher in men.5 Other studies did not report any sex differences in PICH mortality.4,5,9,27⇓⇓⇓ A majority (90%) of the cases who died within 28 days died as a direct consequence of the PICH. Even if short-term survival highly depends on stroke severity,28 there were no sex differences in hemorrhage characteristics in this study.
The better survival in women could largely be explained by better survival in female patients >75 years. This is in accordance with previous studies on patients with stroke,22,29⇓ but to our knowledge, this has not been shown specifically for PICH. In the general population, men are at higher risk of cardiovascular diseases,30 and a similar relationship has been reported from patients with stroke.22,31⇓ The cardiovascular comorbidities showed no significant differences between sexes in the present study, except for smoking, which was more frequent in men. However, we had a high percentage of missing data. Cases with ischemic heart disease had higher short- and long-term mortality, but the difference was not significant after adjustment for other confounding factors. Antihypertensive treatment was associated with reduced short- and long-term mortality, although this was not significant after risk factor adjustment. It has been shown that very few PICH cases occur among individuals with normal blood pressure,32 and it is likely that most cases in the untreated group had high blood pressure. Elevated blood pressure on admission is predictive for early death after PICH, independently of a history of hypertension.33 However, we did not collect information on blood pressure levels on admission.
Patients with OAT have approximately 10 times higher risk of intracerebral hemorrhage as compared with the general population34 and a 50% CFR has been reported in this group.35 In our population, 28-day CFR was 34%. Most of the former studies included cases with previous stroke, which hypothetically could result in increased hemorrhage expansion and higher CFRs. In one fourth of the ICH events, the hemorrhage volume increases during the first hours after onset,36 independently of the baseline volume,37 and the expansion seems to be more pronounced in OAT-related hemorrhages.38,39⇓ Whether OAT is associated with larger baseline volume is still controversial.38,39⇓ In our study, there was no statistically significant difference in mean volume between OAT- and non-OAT-related hemorrhages. However, our analysis was based on early CT scan findings and we could not study possible differences in later volume growth.
Cases with cerebellar hemorrhage had the highest survival rates, in line with previous studies.4,8⇓ However, as a consequence of the anatomic conditions, the differences between fatal versus nonfatal volumes are small (Figure 2), which illustrates the importance of a multifactorial view in the management of patients with PICH, as pointed out by others.7 In contrast to previous studies,4,8⇓ besides brainstem location, central location was also associated with increased mortality in our patients.
Level of consciousness often has a considerable influence on the decision of early do-not-resuscitate orders.40 This topic includes a complexity of factors that are beyond the goal of our study.41 However, there are few data on survival rates in unconscious patients from unselected PICH samples.7,8⇓ In our study, 25% (23 patients) of the unconscious patients survived 4 weeks and 6 patients could return to their own homes or to a rehabilitation ward, although with major neurological deficits.
Only age >65 years was an independent predictor for recurrent stroke. Recurrent ischemic stroke and hemorrhagic stroke occurred at approximately the same rate, in line with former results,42–44⇓⇓ but we could not identify any differences in risk factors for subtypes of recurrent stroke.
The main strength of this study is that our sample derives from a stroke register that covers a well-defined geographical area. The admission rate of patients with stroke to our hospital is high, approximately 800 patients per year, and this study is, up to now, the largest Western single-center prospective study on PICH prognosis.
Surgical therapy is so far recommended only in selected cerebellar and lobar hemorrhages,47 and we do not believe that adjustment for surgery in our analysis would have changed our results.
We cannot rule out that some patients with PICH could have died suddenly without reaching a hospital and therefore could have been missed. However, a review of all autopsy records (by Dr H. Pessah-Rasmussen) of out-of-hospital deaths in Malmö, in 1989 and 1990, revealed only 7 missed cases (0.6% of all stroke events) that died of stroke outside of the hospital.
In conclusion, in this large Swedish cohort, we found that one fourth of the patients died within 28 days and half within 3 years after the PICH event. Hemorrhage severity, central and brainstem hemorrhage location as well as old age had a negative influence on survival. Women had better survival than men, largely explained by a higher short-term mortality in male patients >75 years. However, the underlying reasons for the sex differences in survival are yet to be explored.
We thank Ingela Jerntorp, research nurse, for work with the STROMA register and assistance in case finding. We also thank Toivo Matilainen, in postum, neuroradiologist at Malmö University Hospital, for helpful assistance with review of images.
Sources of Funding
This study was supported by the Swedish Stroke Foundation, the Swedish Research Council, the Swedish Heart Lung Foundation, and the funds of Lunds University and Malmö University Hospital.
- Received April 24, 2009.
- Accepted May 20, 2009.
- ↵Pessah-Rasmussen H, Engström G, Jerntorp I, Janzon L. Increasing stroke incidence and decreasing case fatality, 1989–1998: a study from the Stroke register in Malmo, Sweden. Stroke. 2003; 34: 913–918.
- ↵Islam MS, Anderson CS, Hankey GJ, Hardie K, Carter K, Broadhurst R, Jamrozik K. Trends in incidence and outcome of stroke in Perth, Western Australia during 1989 to 2001: the Perth Community Stroke Study. Stroke. 2008; 39: 776–782.
- ↵Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D, Moomaw CJ, Sauerbeck L, Schneider A, Broderick JP, Woo D. Long-term mortality after intracerebral hemorrhage. Neurology. 2006; 66: 1182–1186.
- ↵Fogelholm R, Murros K, Rissanen A, Avikainen S. Long term survival after primary intracerebral haemorrhage: a retrospective population based study. J Neurol Neurosurg Psychiatry. 2005; 76: 1534–1538.
- ↵Hallström B, Norrving B, Lindgren A. Stroke in Lund-Orup, Sweden: improved long-term survival among elderly stroke patients. Stroke. 2002; 33: 1624–1629.
- ↵Inagawa T, Ohbayashi N, Takechi A, Shibukawa M, Yahara K. Primary intracerebral hemorrhage in Izumo City, Japan: incidence rates and outcome in relation to the site of hemorrhage. Neurosurgery. 2003; 53: 1283–1297;discussion 1297–1298.
- ↵Sacco S, Marini C, Toni D, Olivieri L, Carolei A. Incidence and 10-year survival of intracerebral hemorrhage in a population-based registry. Stroke. 2009; 40: 394–399.
- ↵Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology. 2001; 56: 773–777.
- ↵Jerntorp P, Berglund G. Stroke registry in Malmo, Sweden. Stroke. 1992; 23: 357–361.
- ↵World Health Organization. International Classification of Diseases, 10th Revision. Available at: apps.who.int/classifications/apps/icd/icd10online/. Accessed August 21, 2009.
- ↵Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996; 27: 1304–1305.
- ↵The National Register of Cause of Death. Stockholm, Sweden: Centre for Epidemiology, the National Board of Health and Welfare; 2002.
- ↵Ayala C, Greenlund KJ, Croft JB, Keenan NL, Donehoo RS, Giles WH, Kittner SJ, Marks JS. Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995–1998. Am J Epidemiol. 2001; 154: 1057–1063.
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- ↵Zia E, Hedblad B, Pessah-Rasmussen H, Berglund G, Janzon L, Engström G. Blood pressure in relation to the incidence of cerebral infarction and intracerebral hemorrhage. Hypertensive hemorrhage: debated nomenclature is still relevant. Stroke. 2007; 38: 2681–2685.
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