Acta Neurol Scand 2015: 132: 410–416 DOI: 10.1111/ane.12410
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Long-term subarachnoid haemorrhage survivors still die due to cerebrovascular causes Lindgren C, S€ oderberg S, Koskinen L-OD, Hultin M, Edvardsson L, Naredi S. Long-term subarachnoid haemorrhage survivors still die due to cerebrovascular causes. Acta Neurol Scand 2015: 132: 410–416. © 2015 John Wiley & Sons A/SPublished by John Wiley & Sons Ltd. Objective – Subarachnoid haemorrhage (SAH) is associated with sympathetic nervous activation and inflammation. SAH could therefore theoretically be a risk factor for development of cardiovascular disease. The aim of this study was to investigate whether long-term (≥1 year) SAH survivors had an increased risk of death due to cardiovascular causes. Material & methods – SAH patients ≥18 years treated at Ume a University Hospital between 1986 and 2006 were eligible for inclusion. Deceased patients were identified in the Swedish population register. Death certificates from long-term SAH survivors and causes of death in the general population were obtained from the National Board of Health and Welfare, Sweden. The prevalence of comorbidities at the time of SAH was compared with the distribution of cardiovascular risk factors in the northern Sweden MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) health survey. Analyses were stratified for age and sex. Results – In the SAH patients, the median year of SAH was 1992 and the median year of death was 2001. The MONICA survey in 1994 and the distribution of deaths in the general population in 2001 were used for comparison.Long-term SAH survivors had, compared to the general population, a significantly increased risk for death due to cerebrovascular disease (P < 0.0001), but not for death due to cardiovascular disease. Hypertension was more common in SAH patients compared to survey participants (P < 0.01). Conclusion – Cerebrovascular causes of death were significantly more common in long-term survivors after SAH compared to the general population.
Subarachnoid haemorrhage (SAH) is a devastating disease with an overall mortality of about 35% (1). The global incidence of SAH is nine cases per 100,000 person years (PY), but the incidence of SAH varies in different parts of the world (2). Northern Sweden has one of the highest incidences worldwide with 13 and 24 cases per 100,000 PY in men and women, respectively (3). SAH is associated with systemic cardiovascular complications potentially due to increased levels 410
C. Lindgren1, S. S€oderberg2, L.-O. D. Koskinen3, M. Hultin1, L. Edvardsson2, S. Naredi4 1 Department of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Ume a University, Ume a, Sweden; 2Department of Public Health and Clinical Medicine, Medicine, Ume a University, Ume a, Sweden; 3Department of Pharmacology and Clinical Neuroscience, Neurosurgery, Ume a University, Ume a, Sweden; 4Department of Anaesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Key words: cardiovascular disease; cerebrovascular disease; epidemiology; subarachnoid haemorrhage C. Lindgren, MD, PhD, Department of Surgical and Perioperative Sciences, Anaesthesiology and Intensive Care, Ume a University, S-901 85 Ume a, Sweden Tel.: +46 (0) 70 3987158 Fax: +46 (0) 90 131388 e-mail: [email protected]
Accepted for publication March 20, 2015
of circulating catecholamines (4, 5). SAH is also associated with a massive systemic inflammatory response, indicated by elevated levels of inflammatory markers (6–11). Cardiovascular disease has been linked to activation of the sympathetic nervous system and to inflammation (12, 13). Theoretically, SAH could thus induce cardiovascular disease. The aim of this study was to investigate whether long-term (≥1 year) SAH survivors have an increased risk of death due to cardiovascular causes compared to the general population in the same geographical area.
Long-term survivors and subarachnoid haemorrhage Material and methods
Ume a University Hospital (UUH) is the only hospital in northern Sweden with a neurosurgical department. It has responsibility for the four northernmost counties in Sweden (V€asternorrland, J€ amtland, V€asterbotten, Norrbotten), together covering more than half of the area of Sweden. The population was 900,875 inhabitants in 1986 and 880,465 inhabitants in 2006. Eligible for inclusion in this study were 1846 patients, aged 18 years or older, treated at the neurosurgical department at UUH between 1 January 1986 and 31 December 2006 with a diagnosis of SAH. The International Classification of Diseases (ICD), ninth revision (ICD-9-SE), codes 430, were used for the period 1986 to 1994, and ICD-10-SE codes I60.0 through I60.9 were used for the period 1995 to 2006. In case of multiple admissions, only the first event was registered. Medical records for all patients with a registered SAH diagnosis were retrieved. The intention was to only include patients with a cerebral aneurysm as the cause of SAH. Patients with documented other cause for the SAH diagnosis such as perimecencephalic SAH, haemorrhage from arteriovenous malformations, intracerebral haematomas and traumatic SAH were excluded. Patients with intracerebral haematomas not caused by SAH but incorrectly diagnosed as SAH were also excluded. Date and characteristics for the SAH event, sex, age, and comorbidities such as myocardial infarction, hypertension, diabetes mellitus and stroke were documented. Medical treatment and previous or current tobacco use was noted. The dataset with identified patients with SAH was cross-linked with the Swedish population register hosted by the Swedish Tax Agency (Skatteverket, Stockholm, Sweden), and deceased patients that had survived their SAH ≥1 year, until 31 December 2006 were identified (Fig. 1). These 162 patients formed the core cohort. Death certificates for these patients were obtained from the National Board of Health and Welfare (Socialstyrelsen, Stockholm, Sweden). From the death certificates, dates of death and causes of death (immediate cause of death plus up to three underlying causes) according to ICD-10-SE or ICD-9-SE were registered. Causes of death were divided in four larger categories: 1. Cerebrovascular causes (ICD-10-SE: I60.0I60.9, ICD-9-SE: 430) 2. Cardiovascular causes (ICD-10-SE: I10-I15, I20-I25, I70-I99, ICD-9-SE: 4010-4059, 4114149, 4400-4489)
Figure 1. Formation of core cohort. UUH = Ume a University Hospital. aAccording to the medical records of the neurosurgical department at Ume a University Hospital, 1846 patients were treated at the neurosurgical department with a diagnosis of SAH. For SAH diagnosis, the Swedish International Classification of Diseases (ICD-SE) was used. The International Classification of Diseases (ICD), ninth revision (ICD-9-SE), codes 430, was used for the period 1986 to 1994, and ICD-10-SE codes I60.0 through I60.9 were used for the period 1995 to 2006. bAccording to the Swedish national population registry available at the Swedish tax agency, 1250 patients with a SAH diagnosis between 1986 and 2006 were still alive in 2006. cIn 81 patients with a registered SAH diagnosis, no medical records could be found. dSixty-five patients with a SAH diagnosis was excluded. Forty-four patients had a verified cause of the SAH other than aneurysmal (19 intracerebral haematomas, 11 arteriovenous malformations, nine traumatic SAH, two perimecencephalic SAH, two brain tumours with haemorrhage, one haemorrhagic infarction), eight patients had a SAH before 1986, three patients had aneurysm surgery at another neurosurgical clinic, 10 patients had no SAH at all (diagnosis error).
3. Neoplasms (ICD-10-SE: C00-D48, ICD-9-SE: 1400-2299) 4. All other causes 411
Lindgren et al. cally treated hypertension or diabetes mellitus, documented myocardial infarction or stroke and tobacco use were noted. For comparison with the core cohort, the year of the closest health survey to the median year of onset of SAH in the core cohort was chosen. The core cohort and the comparative MONICA cohort were stratified according to sex and age and the median year of SAH in the core cohort (60 years).
The median year of death in the core cohort was 2001. For comparison of causes of death in the core cohort with the general population, data on causes of death 2001 in the four northern counties were obtained from the open database of the National Board of Health and Welfare Sweden (http://www.socialsyrelsen.se/statistik/ statistikdatabas). The age and sex distribution and the prevalence of comorbidities present in the core cohort were compared with data from the northern Sweden MONICA (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) project (14). Five population-based surveys of randomly chosen subjects aged 25–74 years were performed in the two northernmost counties (V€ asterbotten and Norrbotten) during the period studied (1986, 1990, 1994, 1999 and in 2004). Comorbidities regarding hypertension, diabetes mellitus, tobacco use and previous cerebro-/cardiovascular disease were in the MONICA cohort based on the following questions in a questionnaire:
The Mann–Whitney test was used for comparison of male and female patients in the core cohort regarding year/age of the SAH and year/age of death. Fisher0 s exact test or the chi-square test was used for comparison between groups regarding place of resident, comorbidity and cause of death.
1. During the past 2 weeks, have you taken medicine for high blood pressure? 2. Do you have diabetes? How do you treat your diabetes? 3. Do you currently smoke cigarettes? Have you previously smoked cigarettes regularly? Have you ever smoked a pipe? Have you ever used snuff? 4. Have you ever been hospitalised for heart infarction? Have you ever had a stroke?
The Regional Ethical Review Board in Ume a, Sweden, approved this study (Dnr.07-186M). Results
In total, 1846 patients were treated at the neurosurgical department at UUH with a diagnosis of SAH during the period 1986 to 2006. Altogether 596 patients (32%) deceased before 31 December 2006. The core cohort of 162 patients was created according to criteria given in Fig. 1 (deceased
In the core cohort, data on comorbidities were taken from the medical records. PharmacologiTable 1 Basic characteristics of the core cohort All Core cohort number (%) Age at SAH, years median (range) Age at death, years median (range) Year of SAH median (range) Year of death median (range) Years from SAH to death median (range) County of residence number (%) Norrbottena V€asterbottena J€amtland V€asternorrland
P = 0.03
44/162 53/162 19/162 46/162
ns, non-significant. County included in the MONICA health project.
(27) (33) (12) (28)
19/73 26/73 12/73 16/73
(26) (36) (16) (22)
25/89 27/89 7/89 30/89
(28) (30) (8) (34)
Long-term survivors and subarachnoid haemorrhage during the study period but surviving the index SAH with more than 1 year). Basal characteristics of the 162 patients in the core cohort are presented in Table 1. The median year for the SAH in the core cohort was 1992, and the MONICA survey in 1994 was chosen as the control group. Sixty per cent of the SAH patients came from the area covered by the MONICA survey (the two northernmost counties). Hypertension was more common in SAH patients compared to controls from the 1994 MONICA survey. After stratification for sex and age (60 years), hypertension was more common Table 2 Comorbidities at admittance in the core cohort of patients with subarachnoid haemorrhage (SAH) compared to individuals in a Swedish health project (MONICA 1994), divided in ≤60 years vs >60 year Core cohort n (%) ≤60 years all AMI 3/77 Stroke 1/83 DM 0/75 HT 24/74 Tobacco 34/43 >60 year all AMI 6/76 Stroke 5/79 DM 4/75 HT 41/87 Tobacco 27/44 Male ≤60 year AMI 1/43 Stroke 1/43 DM 0/39 HT 13/40 Tobacco 17/20 Male >60 year AMI 4/30 Stroke 2/30 DM 1/30 HT 12/29 Tobacco 12/15 Female ≤60 year AMI 2/34 Stroke 0/40 DM 0/36 HT 11/34 Tobacco 17/23 Female >60 year AMI 2/46 Stroke 3/49 DM 3/49 HT 29/58 Tobacco 15/29
MONICA 1994 n (%) (4) (1)
Chi-square test P
AMI Stroke DM HT Tobacco
33/2648 22/2945 31/2646 157/2631 692/2395
(1) (1) (1) (6) (29)
ns ns na