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Research Article| Volume 425, 117446, June 15, 2021

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Case fatality of hospital-treated intracerebral hemorrhage in Finland – A nationwide population-based registry study

  • Jussi O.T. Sipilä
    Correspondence
    Corresponding author at: Department of Neurology, North Karelia Central Hospital, Tikkamäentie 16, FI-80521 Joensuu, Finland.
    Affiliations
    Department of Neurology, North Karelia Central Hospital, Siun Sote, Joensuu, Finland

    Neurocenter, Department of Neurology, Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland
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  • Jori O. Ruuskanen
    Affiliations
    Neurocenter, Department of Neurology, Clinical Neurosciences, Turku University Hospital and University of Turku, Turku, Finland
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  • Päivi Rautava
    Affiliations
    Department of Public Health, University of Turku and Turku Clinical Research Centre, Turku University Hospital, Turku, Finland
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  • Ville Kytö
    Affiliations
    Heart Center, Turku University Hospital, Turku, Finland

    Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

    Center for Population Health Research, Turku University Hospital and University of Turku, Turku, Finland

    Administrative Center, Hospital District of Southwest Finland, Turku, Finland
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Open AccessPublished:April 12, 2021DOI:https://doi.org/10.1016/j.jns.2021.117446

      Highlights

      • 30-day mortality after ICH has continued to decline in Finland.
      • Both short- and long-term survival is heavily dependent on patient age.
      • Male sex was independently associated with a higher risk of death in the long term.
      • Comorbidities were also independently associated with survival.
      • Excess mortality incurred by ICH was high.

      Abstract

      Background

      Case-fatality of Intracerebral hemorrhage (ICH) has been reported to have improved in some areas recently. Previous reports have shown that in Finland ICH survival has improved already from the 1980s. We aimed to investigate if this trend has continued and to assess possible predictors for death.

      Methods

      All patients hospitalized for ICH in Finland in 2004–2018 over 16 years of age were identified from a national registry. Survival was analyzed using the national causes of death registry with median follow-up of 5.1 years (max 15.0 years).

      Results

      20,391 persons with ICH (53.5% men) were identified. Patient age increased during the study period with men being younger than women. One-month case-fatality was 28.4% and decreased during the study period. One-month and long-term case-fatality increased with patient age. Five-year survival was over 64% in patients <65 years of age and < 33% in those >75 years of age. In a multivariate analysis patient age, sex, comorbidity burden and diagnoses of atrial fibrillation, hypertension and coagulopathy were all independently associated with both 30-day and long-term survival. Survival was better in men than women at all time points but in the multivariate analysis male sex was associated with a slightly higher risk (hazard ratio 1.10, 95% CI 1.06–1.14) of death in the long-term follow-up. Compared to general population, excess case-fatality was high and highly age-dependent in both sexes.

      Conclusions

      Case-fatality of hospital-treated ICH has continued to decrease in Finland. Prognosis is strongly associated with patient age and more modestly with patient sex and comorbidities.

      Keywords

      1. Introduction

      Stroke causes the greatest loss of most age-standardised disability-adjusted life years (DALY) of all neurological disorders [
      GBD 2016 Neurology Collaborators
      Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ]. Intracerebral hemorrhage (ICH) is the deadliest form of stroke and its case-fatality remained unchanged for decades [
      • van Asch C.J.
      • Luitse M.J.
      • Rinkel G.J.
      • van der Tweel I.
      • Algra A.
      • Klijn C.J.
      Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.
      ]. Some recent studies have shown decreasing short- and long-term case-fatality rates, but this trend is not uniform [
      • Pinho J.
      • Costa A.S.
      • Araújo J.M.
      • Amorim J.M.
      • Ferreira C.
      Intracerebral hemorrhage outcome: a comprehensive update.
      ,
      • Jolink W.M.
      • Klijn C.J.
      • Brouwers P.J.
      • Kappelle L.J.
      • Vaartjes I.
      Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage.
      ,
      • Béjot Y.
      • Grelat M.
      • Delpont B.
      • Durier J.
      • Rouaud O.
      • Osseby G.V.
      • Hervieu-Bègue M.
      • Giroud M.
      • Cordonnier C.
      Temporal trends in early case-fatality rates in patients with intracerebral hemorrhage.
      ,
      • Carlsson M.
      • Wilsgaard T.
      • Johnsen S.H.
      • Vangen-Lønne A.M.
      • Løchen M.L.
      • Njølstad I.
      • Mathiesen E.B.
      Temporal trends in incidence and case fatality of intracerebral hemorrhage: the Tromsø study 1995-2012.
      ]. In Finland, short-term case fatality after ICH has consistently declined between 1983 and 2014 while incidence rates remained stable [
      • Sivenius J.
      • Tuomilehto J.
      • Immonen-Räihä P.
      • et al.
      Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study.
      ,
      • Sipilä J.O.T.
      • Ruuskanen J.O.
      • Kauko T.
      • Rautava P.
      • Kytö V.
      Seasonality of stroke in Finland.
      ]. Furthermore, ten-year survival improved between 1999 and 2007, increasing median survival by one year [
      • Meretoja A.
      • Kaste M.
      • Roine R.O.
      • et al.
      Trends in treatment and outcome of stroke patients in Finland from 1999 to 2007. PERFECT Stroke, a nationwide register study.
      ]. More recent, long-term data with as complete coverage as possible are needed to verify these trends and to assess possible predictors for death short and long-term. Therefore, we conducted a nationwide registry study spanning 15 years until 2018.

      2. Materials and methods

      2.1 Data collection

      All admissions to neurological, neurosurgical and intensive care wards with ICH (International Classification of Diseases, 10th revision, or ICD-10, codes I61.X) as the primary diagnosis between January 1, 2004-December 31, 2018 were identified from the Care Register for Health Care, a mandatory database for all public health care hospital discharges in Finland. All university and central hospitals (N = 20) that provide acute stroke care on mainland Finland were included in the search. In Finland, diagnostics of ICH is always verified by neuroimaging and treatment follows international guidelines. Only one admission per patient was included. Patients under 16 years of age, patients with concurrent diagnostic codes of rehabilitation (Z50, N = 34), cranial trauma (S06.X, N = 322) or previous ICH (I69.1, N = 97), and patients with missing survival data (N = 98) were excluded. Follow-up was defined as short-term (first 30 days) or long-term; all patients were followed-up until death or the end of the study period (Dec 31, 2018) whichever happened first, with a maximum follow-up being 15 years.
      Fatality data were obtained from Statistics Finland, the national census entity. Relevant co-morbidities were identified using ICD-10 coding, and Charlson Comorbidity Index (CCI) score including AIDS/HIV, dementia, diabetes, chronic pulmonary disease, cerebrovascular disease, heart failure, hemi- or paraplegia, liver disease, malignancies, myocardial infarction, peptic ulcer disease, peripheral vascular disease, rheumatic disease, and renal disease was calculated as previously described [
      • Quan H.
      • Sundararajan V.
      • Halfon P.
      • et al.
      Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
      ]. Excess case-fatality after ICH was calculated by subtracting the baseline fatality in the corresponding age, sex, and calendar year specific group in the total Finnish population from case-fatality after ICH. This study was approved by the National Institute for Health and Welfare of Finland (THL, permission no: THL/2245/5.05.00/2019) and Statistics Finland (TK-53-484-20). This was a retrospective register study, and thus no ethical board review or informed consent was required, and the participants were not contacted. The legal basis for processing personal data is public interest and scientific research (EU General Data Protection Regulation 2016/679, Article 6(1)(e) and Article 9(2)(j); Data Protection Act, Section 4 and 6).

      2.2 Statistical methods

      Shapiro-Wilk and Kolmogorov-Smirnov tests were used to assess the distribution of continuous variables. Independent samples t-test was used to analyze age between sexes. Patient age trends were analyzed with linear correlation analysis. Survival was analyzed with the Kaplan-Meier method. Predictors of survival were analyzed with Cox regression. Multivariate Cox model included age, sex, CCI, atrial fibrillation, hypertension, coagulopathy (ICD-10 codes D65-D68, D69.1, D69.3-D69.6), and study era which all were deemed clinically relevant for modelling. Follow-up included 71,332 person-years with median duration of 5.1 years in survivors (interquartile range 2.2–9.1, max. 15.0 years). Statistical significance was inferred at P-value <0.05. Analyses were conducted using SPSS Statistics, version 26 and SAS, version 9.4.

      3. Results

      We identified 20,391 persons hospitalized because of ICH (53.5% men) (Table 1). Men were younger than women and mean patient age increased from 68.9 (standard deviation 13.1) years to 72.3 (standard deviation 13.1) years during the study period (r = 0.080, p < 0.001). Altogether 12,190 patients (79.3%) died during the follow-up. Case-fatality was 28.4% during the first 30 days but survival improved during the study period (Table 2). Half of these patients died during the first three days with no difference between sexes (Table 2). After the first month, survival decreased more slowly but steadily and was consistently poorer in women compared to men (Table 2). Both 30-day and long-term case fatality were higher the older the patient was (Table 2; Fig. 1). A multivariate Cox model showed that patient age, sex, CCI and diagnoses of atrial fibrillation, hypertension and coagulopathy were all independently associated with both 30-day and long-term survival (Table 2). Compared to general population, excess case-fatality incurred by ICH was high and increased with age in both sexes (Table 3).
      Table 1Baseline characteristics of the study cohort.
      VariableTotalMenWomenP-value
      N = 20,391N = 10,891N = 9500
      Age, years (SD)70.5 (13.1)67.8 (12.8)73.5 (12.8)<0.0001
       16–542390 (11.7%)1551 (14.2%)839 (8.8%)
       55–643550 (17.4%)2385 (21.9%)1165 (12.3%)
       65–755562 (27.3%)3359 (30.8%)2203 (23.2%)
       75–846341 (31.1%)2819 (25.9%)3522 (37.1%)
       ≥ 852548 (12.5%)777 (7.1%)1771 (18.6%)
      CCI<0.0001
       08228 (40.4%)4358 (40.0%)3870 (40.7%)
       15418 (26.6%)2740 (25.2%)2678 (28.2%)
       23324 (16.3%)1769 (16.2%)1555 (16.4%)
       31681 (8.2%)973 (8.9%)708 (7.5%)
       ≥ 41740 (8.5%)1051 (9.7%)689 (7.3%)
      Hypertension9563 (46.9%)4990 (45.8%)4573 (48.1%)0.001
      Atrial fibrillation4077 (20.0%)2178 (20.0%)1899 (20.0%)0.988
      Coagulopathy185 (0.9%)105 (1.0%)80 (0.8%)0.359
      Study era0.261
       2004–20086603 (32.4%)3581 (32.9%)3022 (31.8%)
       2009–20136714 (32.9%)3565 (32.7%)3149 (33.2%)
       2014–20187074 (34.7%)3745 (34.4%)3329 (35.0%)
      CCI = Charlson comorbidity index score.
      Table 2Predictors of 30-day and long-term case-fatality.
      Variable30-day case-fatalityLong-term case-fatality
      Maximum follow-up 15.0 years (except 14.1 years for CCI and 12.3 years for coagulopathy).
      Case-fatalityUnivariateMultivariateCase-fatalityUnivariateMultivariate
      HR (95%CI)HR (95%CI)HR (95%CI)HR (95%CI)
      Sex
       Female29.5%Ref.Ref.81.0%Ref.Ref.
       Male27.5%0.92 (0.87–0.97)1.05 (0.99–1.11)77.9%0.90 (0.87–0.93)1.10 (1.06–1.14)
      Age, years
       16–5416.4%Ref.Ref.42.5%Ref.Ref.
       55–6420.2%1.26 (1.11–1.43)1.24 (1.10–1.41)58.5%1.44 (1.32–1.58)1.41 (1.30–1.54)
       65–7524.8%1.59 (1.42–1.77)1.52 (1.36–1.70)83.3%2.33 (2.15–2.52)2.21 (2.04–2.39)
       75–8433.8%2.26 (2.03–2.52)2.09 (1.88–2.34)97.0%3.90 (3.61–4.21)3.59 (3.31–3.88)
       ≥ 8542.5%3.23 (2.88–3.62)2.98 (2.64–3.36)100%6.02 (5.53–6.55)5.50 (5.04–6.00)
      CCI
       022.9%Ref.Ref.67.1%Ref.Ref.
       128.7%1.29 (1.21–1.38)1.22 (1.14–1.31)76.6%1.36 (1.30–1.42)1.26 (1.20–1.32)
       231.2%1.42 (1.32–1.53)1.31 (1.21–1.42)85.3%1.77 (1.68–1.86)1.53 (1.45–1.62)
       335.6%1.68 (1.53–1.84)1.50 (1.37–1.65)91.1%2.10 (1.97–2.24)1.73 (1.62–1.85)
       ≥ 440.9%1.98 (1.82–2.16)1.84 (1.68–2.02)97.3%2.79 (2.62–2.97)2.34 (2.19–2.50)
      Hypertension
       No30.0%Ref.Ref.79.2%Ref.Ref.
       Yes26.6%0.86 (0.82–0.91)0.75 (0.71–0.79)79.7%0.95 (0.92–0.97)0.77 (0.74–0.79)
      Atrial fibrillation
       No26.0%Ref.Ref.76.8%Ref.Ref.
       Yes37.9%1.57 (1.48–1.66)1.26 (1.19–1.34)90.9%1.76 (1.68–1.83)1.21 (1.15–1.26)
      Coagulopathyy
       No28.3%Ref.Ref.74.2%Ref.Ref.
       Yes43.4%1.73 (1.38–2.15)1.74 (1.40–2.17)76.3%1.56 (1.30–1.87)1.54 (1.29–1.85)
      Study Era
       2004–200830.0%Ref.Ref.
       2009–201328.3%0.97 (0.91–1.03)0.90 (0.85–0.96)
       2014–201827.9%0.95 (0.89–1.01)0.82 (0.77–0.88)
      CCI = Charlson co-morbidity index score.
      a Maximum follow-up 15.0 years (except 14.1 years for CCI and 12.3 years for coagulopathy).
      Fig. 1
      Fig. 1Survival by age. Numbers of patients at risk are presented in Supplement Table.
      Table 3Fatality rates by age and sex in the general population (baseline) and the ICH patients.
      PatientsBaseline-fatality (%)ICH case-fatality (%)Excess fatality (%)
      MenN1-year30-day1-year30-day1-year30-day
      16–5415510.380.0320.8616.1220.4816.09
      55–6423851.080.0926.8720.7725.7920.68
      65–7433592.270.1935.3025.7033.0325.51
      75–8428195.850.4848.4135.6442.5635.16
      85-77714.511.1965.9748.4251.4647.23
      Overall10,8911.980.1636.9527.4534.9727.29
      PatientsBaseline-fatality (%)ICH case-fatality (%)Excess fatality (%)
      WomenN1-year30-day1-year30-day1-year30-day
      16–548390.170.0121.0816.8120.9116.80
      55–6411650.480.0424.3519.1623.8719.12
      65–7422031.140.0930.8323.4829.6923.39
      75–8435223.730.3145.0632.3841.3332.07
      85-177111.180.9261.3443.8550.1642.93
      Overall95002.450.2040.1029.4537.6529.25
      ICH, intracranial hemorrhage.

      4. Discussion

      This nationwide study showed that case fatality after hospital-treated intracerebral hemorrhage has continued to decline in Finland. The prognosis depended primarily on the patients' age but was also affected by sex and comorbidity.
      In our study, less than 29% of the ICH patients died within the first 30 days, while three decades ago, half of ICH patients in Central Finland died within the first four weeks [
      • Fogelholm R.
      • Murros K.
      • Rissanen A.
      • Avikainen S.
      Long term survival after primary intracerebral haemorrhage: a retrospective population based study.
      ]. Of note, the study in Central Finland also included patients who died before reaching the hospital but since they only consisted 7.3% of their cohort, the relative decrease in short-term case-fatality is still over 30% between the current study and the old Central Finland cohort. Other previous reports have shown that the trend of declining ICH case-fatality has continued for over three decades in Finland [
      • Sivenius J.
      • Tuomilehto J.
      • Immonen-Räihä P.
      • et al.
      Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study.
      ,
      • Sipilä J.O.T.
      • Ruuskanen J.O.
      • Kauko T.
      • Rautava P.
      • Kytö V.
      Seasonality of stroke in Finland.
      ]. Moreover, long-term survival after ICH increased between 1999 and 2007 [
      • Béjot Y.
      • Grelat M.
      • Delpont B.
      • Durier J.
      • Rouaud O.
      • Osseby G.V.
      • Hervieu-Bègue M.
      • Giroud M.
      • Cordonnier C.
      Temporal trends in early case-fatality rates in patients with intracerebral hemorrhage.
      ] and our data showed that this trend has also continued.
      Decreasing ICH case-fatality in Finland has been attributed to improvements in systems of stroke care [
      • Meretoja A.
      • Kaste M.
      • Roine R.O.
      • et al.
      Trends in treatment and outcome of stroke patients in Finland from 1999 to 2007. PERFECT Stroke, a nationwide register study.
      ]. Indeed, Finland has attained a high level of acute stroke care capability [
      • Aguiar de Sousa D.
      • von Martial R.
      • Abilleira S.
      • Gattringer T.
      • Kobayashi A.
      • Gallofré M.
      • Fazekas F.
      • Szikora I.
      • Feigin V.
      • Caso V.
      • Fischer U.
      Access to and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44 European countries.
      ]. Previous data have shown that preceding functional disability predicts severe disability or death after ICH [
      • Øie L.R.
      • Madsbu M.A.
      • Solheim O.
      • et al.
      Functional outcome and survival following spontaneous intracerebral hemorrhage: a retrospective population-based study.
      ]. The improved physical and cognitive performance levels of the Finnish elderly and the generally improved life expectance therefore also contribute [
      • Koivunen K.
      • Sillanpää E.
      • Munukka M.
      • Portegijs E.
      • Rantanen T.
      Cohort differences in maximal physical performance: a comparison of 75- and 80-year-old men and women born 28 years apart. [published online September 4, 2020].
      ,
      • Munukka M.
      • Koivunen K.
      • von Bonsdorff M.
      • et al.
      Birth cohort differences in cognitive performance in 75- and 80-Year-Olds – A comparison of two cohorts over 28 years. [published online September 12, 2020].
      ,
      • Women'’s and Men'’s Life Expectancy
      ]. Considering that the number and population proportion of elderly people have increased in Finland but ICH admission rates have remained stable [
      • Sipilä J.O.T.
      • Ruuskanen J.O.
      • Kauko T.
      • Rautava P.
      • Kytö V.
      Seasonality of stroke in Finland.
      ], it also seems that the Finnish elderly have become less prone to ICH in general. However, since these trends are surely not exclusively Finnish, it is unclear why short-term case-fatality has not decreased more uniformly internationally [
      • van Asch C.J.
      • Luitse M.J.
      • Rinkel G.J.
      • van der Tweel I.
      • Algra A.
      • Klijn C.J.
      Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.
      ,
      • Pinho J.
      • Costa A.S.
      • Araújo J.M.
      • Amorim J.M.
      • Ferreira C.
      Intracerebral hemorrhage outcome: a comprehensive update.
      ]. Regional factors concerning population characteristics, public health and care delivery systems may be implicated. Indeed, there was no apparent change over time in the 12-month case-fatality proportions in the four studies from the United Kingdom included in the recent meta-analysis whereas the three studies included from Italy suggested a slight decreasing trend [
      • Pinho J.
      • Costa A.S.
      • Araújo J.M.
      • Amorim J.M.
      • Ferreira C.
      Intracerebral hemorrhage outcome: a comprehensive update.
      ]. Recent studies from the Netherlands and Dijon, France reported declining case fatality while data from Tromsø, Norway show no change [
      • Jolink W.M.
      • Klijn C.J.
      • Brouwers P.J.
      • Kappelle L.J.
      • Vaartjes I.
      Time trends in incidence, case fatality, and mortality of intracerebral hemorrhage.
      ,
      • Béjot Y.
      • Grelat M.
      • Delpont B.
      • Durier J.
      • Rouaud O.
      • Osseby G.V.
      • Hervieu-Bègue M.
      • Giroud M.
      • Cordonnier C.
      Temporal trends in early case-fatality rates in patients with intracerebral hemorrhage.
      ,
      • Carlsson M.
      • Wilsgaard T.
      • Johnsen S.H.
      • Vangen-Lønne A.M.
      • Løchen M.L.
      • Njølstad I.
      • Mathiesen E.B.
      Temporal trends in incidence and case fatality of intracerebral hemorrhage: the Tromsø study 1995-2012.
      ]. Longitudinal data from different countries and in-depth analyses are apparently needed.
      Our findings concerning predictors of death after ICH provided few surprises. Association between age and case-fatality is intuitive. In crude rates, women had worse survival. However, they were also older and in the multivariate analysis there was no difference between sexes in short-term case fatality and men were in a slightly higher risk of death in the long term like they are in the general population [
      • Women'’s and Men'’s Life Expectancy
      ]. Compared to general population, excess case-fatality rates of ICH patients were also slightly higher in men compared to women, but the relative difference was very small. Earlier studies have provided conflicting results on sex differences in case fatality after ICH [
      • van Asch C.J.
      • Luitse M.J.
      • Rinkel G.J.
      • van der Tweel I.
      • Algra A.
      • Klijn C.J.
      Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis.
      ,
      • Marini S.
      • Morotti A.
      • Ayres A.M.
      • et al.
      Sex differences in intracerebral hemorrhage expansion and mortality.
      ,
      • Fukuda-Doi M.
      • Yamamoto H.
      • Koga M.
      • et al.
      Sex differences in blood pressure-lowering therapy and outcomes following intracerebral hemorrhage: results from ATACH-2.
      ]. These discrepancies may result from differences in ethnic backgrounds and baseline characteristics of the investigated populations, study inclusion criteria and sample sizes.
      Our data showed that comorbidities were associated with a higher risk of death and a higher number of comorbidities was associated with a higher risk of death. Increasing CCI score has also previously been reported to be a predictor of severe disability or death within 3 months [
      • Øie L.R.
      • Madsbu M.A.
      • Solheim O.
      • et al.
      Functional outcome and survival following spontaneous intracerebral hemorrhage: a retrospective population-based study.
      ]. The only exception in our data was hypertension, a recorded diagnosis of which was associated with a smaller risk of death. This could be a chance finding, but patients without a hypertension diagnosis might also have more often had causes such as amyloid angiopathy or anticoagulation behind their ICH. Both of these become more common with increasing age so the increase in mean patient age we observed suggests that a shift in the case mix is possible towards more of these conditions as underlying causes of ICH. Moreover, decreases in blood pressure levels and in the proportion of smokers over recent decades in Finland have probably decreased the prevalence of hypertensive vasculopathy [
      • Borodulin K.
      • Vartiainen E.
      • Peltonen M.
      • et al.
      Forty-year trends in cardiovascular risk factors in Finland.
      ].
      Main strength of the study is the use of mandatory data with complete coverage in a nationwide setup as only public hospitals treat acute stroke in Finland. However, retrospective studies and administrative data have their inherent problems. Thus, we have no patient-level data on neuroimaging, medications, or functional outcome after ICH. Main discharge diagnosis codes in the Care Register for Health Care have been proven valid, but coding of co-diagnoses is not as complete [
      • Sund R.
      Quality of the Finnish hospital discharge register: a systematic review.
      ].
      In conclusion, short-term ICH case-fatality has continued to decline in Finland. Survival was strongly associated with patient age, and more modestly with sex and comorbidities.

      Funding

      Government's Special Financial Transfer tied to academic research in Health Sciences (Finland) and grant funding of the Finnish Cultural Foundation and the Paulo Foundation. The funding sources had no role in in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

      Disclosures

      Jussi Sipilä has received honoraria (Merck, Pfizer, Sanofi), consultancy fees (Medaffcon), travel grants and congress sponsorship (Abbvie, Orion Pharma, Merck Serono, Novartis) and holds shares (Orion Corporation).
      Jori Ruuskanen has received scientific consultancy fees (Merck, Sandoz), speaker fees (Merck, Biogen Idec, UCB Pharma, Bayer) and travel grants and congress sponsorship (BMS, Sanofi-Genzyme, TEVA, Bayer).
      Päivi Rautava has nothing to declare.
      Ville Kytö has received scientific consultancy fees (AstraZeneca), speaker fees (Bayer, Boehringer-Ingelheim, Roche) and travel grants and congress sponsorship (AstraZeneca, Boehringer-Ingelheim, Bayer, Pfizer).

      Data availability

      We are not permitted to disclose data to third parties. Requests to access the data set may be sent to Findata.

      Appendix A. Supplementary data

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