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Survival rate and death risk for associated pulmonary arterial hypertension: A retrospective population-based study

Article information

Precis Future Med. 2024;8(1):2-9
Publication date (electronic) : 2024 March 29
doi : https://doi.org/10.23838/pfm.2023.00142
1Department of Nursing, Yong-In Arts & Science University, Yongin, Korea
2Imaging Center, Heart Vascular Stroke Institute, Samsung Medical Center, Seoul, Korea
3The National Health Insurance Service, Wonju, Korea
4Central Regional Center for Disease Control and Prevention, Korea Disease Control and Prevention Agency, Seoul, Korea
5Department of Nursing, Gangseo University, Seoul, Korea
6Division of Cardiology, Department of Internal Medicine, Heart Brain Hospital, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Korea
7Graduate School of Clinical Nursing Science, Sungkyunkwan University, Seoul, Korea
Corresponding author: Kyeongsug Kim Graduate School of Clinical Nursing Science, Sungkyunkwan University, 115 Irwon-ro, Gangnam-gu, Seoul 06355, Korea Tel: +82-2-2148-9758 E-mail: kyeongsug.kim@samsung.com
*Sujin Kim and Shin Yi Jang contributed equally to this study as first authors.
Received 2023 October 31; Revised 2024 March 8; Accepted 2024 March 21.

Abstract

Purpose

This study aimed to assess the survival rate (SR) and death risk for associated pulmonary arterial hypertension (aPAH; 10th revision of the International Statistical Classification of Diseases [ICD-10], I27.2) in Koreans.

Methods

The data were collected from the Korean National Health Insurance Service from 2006 through 2017 (n= 15,448). We analyzed the SR using the Kaplan-Meier method and carried out Cox proportional hazards analyses.

Results

Patients’ mean age upon aPAH diagnosis was 60.1±24.0 years, and 60.7% of the patients were female. The 10-year SR of aPAH was 46.3% (95% confidence interval, 45.0 to 47.6). The factors associated with an increase in the adjusted death risk included age of 0 to 9 years, advancing age, male sex, lower income level, and comorbidities including diabetes mellitus, myocardial infarction, heart failure, hemorrhagic stroke, chronic kidney disease, malignant neoplasm, hereditary hemorrhagic telangiectasia, and systemic lupus erythematosus.

Conclusion

The 10-year SR of aPAH was over 46%. The risk of death from aPAH was significantly higher with advancing age, sex, lower income level, and comorbidities.

INTRODUCTION

Pulmonary arterial hypertension (PAH) is caused by a small lesion within the pulmonary artery, leading to a reduction in the space within the blood vessels. PAH is more commonly associated with normal or low cardiac output in the setting of right heart failure. Additionally, pre-capillary pulmonary hypertension is generally associated with a low pulmonary arterial wedge pressure of less than 15 mm Hg. The clinical classification for pulmonary hypertension has used the Updated Classification of pulmonary hypertension [1] since the 5th World Symposium on Pulmonary Hypertension in 2013. During the 1970s and 1980s, the median survival with idiopathic PAH was 2.8 years in the United States based on the idiopathic PAH prospective registry [2,3] and 3.4 years in the United Kingdom [4]. However, the median surviving year for Spanish PAH patients grew from 1984 to 2014, reaching 9 years [5], attributable to the development and improvement of numerous PAH treatments.

While the survival rate (SR) for associated pulmonary arterial hypertension (aPAH) has improved with advancements in treatment, conditions such as connective tissue disease, human immunodeficiency virus (HIV) infection, portal hypertension, and others can lead to the occurrence of PAH. Furthermore, the prognosis of aPAH remains poor and is even worse for individuals with aPAH and hereditary hemorrhagic telangiectasia (HHT; Rendu-Osler-Weber disease) [6]. However, only a few studies have examined the SR or death risk for aPAH. Therefore, we aimed to assess the SR and death risk for aPAH patients in Korea from 2006 to 2017 using Korean National Health Insurance Service (KNHIS) data.

METHODS

Study population

Data were collected from KNHIS records from 2006 until 2017 and included diagnoses related to aPAH according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10, I27.2; n= 15,448).

KNHIS database

The KNHIS data, excluding foreigners, for health insurance subscribers and medical aid recipients, comprises the following four databases: (1) qualification database containing age, sex, type of subscription (e.g., insured employees, insured self-employed individuals, or medical aid beneficiaries), income rank, and death; (2) medical check-up database containing general health examination data for the insured employees every 1 or 2 years, and data for insured self-employed and insured employees who receive lifetime transition period medical check-ups at age 40 years and 66 years; (3) medical institution database containing the clinic type, number of beds, number of medical doctors, and location of each medical care institution; and (4) treatment database containing the diseases, ICD-10 disease codes, and prescriptions of all subscribers. The treatment database has four categories: medicine, dentistry, oriental medicine, and pharmacy. Among these four categories, we used only the medicine data. Overall, we used variables from both the qualification and treatment databases [7-9].

Definition of variables

Age was categorized as 0–9, 10–19, 20–29, 30–39, 40–49, 50– 59, 60–69, 70–79, and 80 years or older. The socioeconomic factors, including the percentile income level groups used to calculate the national health insurance premium, were divided into 20 groups and further categorized as upper, medium, and lower.

Comorbidities

We described initial comorbidities that were present at main and additional diagnoses of aPAH as follows: hypertension (ICD-10: I10, I11, I12, I13, I15); diabetes mellitus (ICD-10: E10, E11, E12, E13, E14); dyslipidemia (ICD-10: E78); myocardial infarction (ICD-10: I21, I22, I25.2); heart failure (ICD-10: I11.1, I50, I97.1); atrial fibrillation (ICD-10: I48); ischemic stroke (ICD-10: I63, I64); hemorrhagic stroke (ICD-10: I60, I61, I62); transient ischemic attack (ICD-10: G45); chronic kidney disease (ICD-10: N18, N19); malignant neoplasm (ICD-10: C00-C97); epistaxis (ICD-10: R04.0); hemoptysis (ICD-10: R04.2); arteriovenous malformation (ICD-10: I28.0, I77.0, Q27.3, Q28.0, Q28.2); anemia (ICD-10: D50, D51, D52, D53, D55, D56, D57, D58, D59); HHT (ICD-10: I78.0); acquired immune deficiency syndrome (AIDS) (ICD-10: B20, B21, B22, B23, B24, Z21); and systemic lupus erythematosus (ICD-10: M32.0).

Cause of death

In this study, we used mortality data of the Korean population from 2006 through 2018. We evaluated the primary causes of death as follows: certain infections and parasitic diseases (ICD-10: A00–B99); malignant neoplasm (ICD-10: C00–C97); benign neoplasm (ICD-10: D00–D48) and diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (ICD-10: D50–D89); endocrine, nutritional, and metabolic diseases (ICD-10: E00–E90); mental and behavioral disorders (ICD-10: F01–F99); diseases of the nervous system (ICD-10: G00–G98); diseases of the circulatory system (ICD-10: I00–I99); diseases of the respiratory system (ICD-10: J00–J98); diseases of the digestive system (ICD-10: K00–K92); diseases of the skin and subcutaneous tissue (ICD-10: L00–L99); diseases of the musculoskeletal system and connective tissue (ICD-10: M00–M99); diseases of the genitourinary system (ICD-10: N00–N99); pregnancy, childbirth and the puerperium (ICD-10: O00–O99); certain conditions originating in the perinatal period (ICD-10: P00–P96); congenital malformations, deformations and chromosomal abnormalities (ICD-10: Q00–Q99); symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified (ICD-10: R00–R99); injury, poisoning, and certain other consequences of external causes (ICD-10: S00–T98); and not provided. When the cause of death was diseases of the circulatory system (ICD-10: I00–I99), it was categorized as cardiovascular death.

Statistical methods

Differences in age, comorbidities, and cause of death were analyzed by sex using the student’s t-test for continuous variables and the chi-square test for categorical variables. The Kaplan-Meier method was used to compare survival among aPAH patients by age group, sex, HHT, systemic lupus erythematosus, and AIDS using log-rank tests. Simple and multiple Cox proportional hazards analyses for aPAH were performed using the variables of age, sex, income level, and comorbidities (hypertension, diabetes mellitus, dyslipidemia, myocardial infarction, heart failure, atrial fibrillation, ischemic stroke, hemorrhagic stroke, transient ischemic attack, chronic kidney disease, malignancy neoplasm, HHT, AIDS, and systemic lupus erythematosus).

Ethics

This study protocol was reviewed and approved by the Institutional Review Board of Samsung Medical Center (IRB number 2017-02-032). We were unable to obtain informed consent from all study participants because we employed secondary, pre-processed large data collected nationally.

RESULTS

Table 1 shows the distribution of patients in Korea newly diagnosed with aPAH between 2006 and 2017. Upon an aPAH diagnosis, the mean age was 60.1± 24.0 years (58.1± 25.0 years for males and 61.5± 23.3 years for females, P< 0.001). The proportion of females was 60.7%. The proportion of patients by socioeconomic position was 43.3% in the upper group, 25.5% in the medium group, and 31.2% in the lower group. The proportions of comorbidities with aPAH were 20.7% for hypertension, 9.43% for diabetes mellitus, 7.79 % for dyslipidemia, 1.32% for myocardial infarction, 17.5% for heart failure, 10.0% for atrial fibrillation, 2.14% for ischemic stroke, 0.38% for hemorrhagic stroke, 3.29% for chronic kidney disease, 4.87% for malignant neoplasm, 2.10% for anemia, 0.03% for HHT, 0.07% for AIDS, and 4.17% for systemic lupus erythematosus. During the study period, 38.7% of the patients in our study population died. The major causes of death were circulatory system diseases. The factors associated with an increase in the adjusted death risk included age of 0 to 9 years, advancing age, male sex, lower socioeconomic group, and the comorbidities of diabetes mellitus, myocardial infarction, heart failure, hemorrhagic stroke, chronic kidney disease, malignant neoplasm, HHT, and systemic lupus erythematosus. The adjusted death risk for aPAH decreased with the comorbidities of hypertension, dyslipidemia, and atrial fibrillation.

Distribution of general and clinical characteristics, causes of death, and death risk from associated pulmonary arterial hypertension (ICD-10, I27.2; n=15,448)

The 10-year SR of aPAH was 46.3%: 40.1% in males and 50.3% in females (P< 0.001). The 10-year SR for aPAH in the 0–9, 10–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and older than 80 years groups was 84.4%, 79.3%, 82.3%, 81.0%, 73.1%, 59.8%, 44.9%, 27.9%, and 11.3%, respectively (P < 0.001). Furthermore, the 9-year SR for aPAH with cardiovascular death was 0.06%, and the 4-year SR for aPAH with HHT was 37.5%. The 10-year SR for systemic lupus erythematosus and AIDS was 64.5% and 78.7%, respectively (Fig. 1, Supplementary Table 1).

Fig. 1.

Survival curve of associated pulmonary arterial hypertension (aPAH, 10th revision of the International Statistical Classification of Diseases [ICD-10], I27.2) in Korea. (A) Survival rates in aPAH overall, by sex (P<0.001), and by cause of death (P<0.05), (B) aPAH survival rates by age group (P<0.001), (C) by hereditary hemorrhagic telangiectasia (HHT) (P<0.001), (D) by systemic lupus erythematosus (SLE) (P<0.001), and (E) by acquired immune deficiency syndrome (AIDS) (P=0.129).

DISCUSSION

In this study, the distribution of males to females with aPAH was about 4:6. The death risk for aPAH was significantly higher in males than in females, and the SR was lower in males. In this study, the death risk from aPAH was significantly higher with age, in the lower socioeconomic group, and among patients with diabetes mellitus, myocardial infarction, hemorrhagic stroke, or malignant neoplasm. This result is consistent with those calculated with Korean idiopathic PAH death risk and SR using KNHIS data [10]. The death risk for aPAH was also significantly higher with chronic kidney disease, heart failure, or systemic lupus erythematosus. The adjusted death risk for aPAH was significantly higher in cases with HHT (Rendu-Osler-Weber disease) than in cases without. We are unable to compare our data with the results of other studies because few studies have calculated the SR and hazard ratio (HR) for aPAH with HHT using population-based data. Consequently, we conducted an additional analysis of HHT data. The resulting distribution of SR and HR for HHT during the decade of our study period is provided in Supplementary Tables 1, 2.

HHT is a rare, autosomal dominant inherited disorder caused by fibrovascular dysplasia. The three most commonly involved gene mutations are endoglin (ENG), activin receptor-like kinase 1 (ACVRL1), and SMAD4. All the proteins produced by these genes are found in the endothelial cells of blood vessels, where they interact with growth factors to regulate blood vessel development. The bone morphogenetic protein receptor type II [11], ACVRL1, ENG, SMAD9, SMAD1, T-box 4, eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4), potassium voltage-gated channel subfamily A member 3 [12], potassium voltage-gated channel subfamily A member 5 [13], and caveolin-1 [14] genes are all expressed in PAH. The EIF2AK4 gene is also expressed in pulmonary veno-occlusive disease [15]. The ring finger protein 213 gene is expressed in both moyamoya disease and PAH [16], and ACVRL1 [6] and ENG genes [12] are expressed in both PAH and HHT. However, we could not confirm the genetic components of PAH or HHT in our study population due to limitations in the KNHIS data. The Mayo Clinic recommends that patients diagnosed with definite HHT receive both transthoracic echocardiography and right-sided heart catheterization to evaluate suspected PH [17]. Therefore, we recommend that patients diagnosed with HHT and PAH receive genetic testing using next generation sequencing that includes the aforementioned PAH- and HHT-related genes and periodic echocardiography tests. PAH must be detected early in patients with HHT to improve their prognosis by providing faster treatment. In this study, the death risk associated with systemic lupus erythematosus in PAH was high. The SR for patients with systemic lupus erythematosus in PAH vary between across different studies [18,19], and it is evident that the presence of PAH adversely impacts the survival of systemic lupus erythematosus. In the case of patients with AIDS and PAH, unfortunately, there are no research results to accurately compare with the findings of this study. However, the treatment survival outcomes from the Spanish Registry of Pulmonary Arterial Hypertension (REHAP) were favorable when these included HIV infection, these findings were similar to that of our study [20].

On the contrary, the risk of death from aPAH was lower in patients with hypertension, dyslipidemia, or atrial fibrillation. Patients with hypertension and PAH likely received the same anti-hypertensive medications as those used to treat patients with aPAH. In this study, more than three-quarters of the patients with aPAH were 50 years or older. More than 80% of female Koreans in their 50s or older have dyslipidemia and are likely undergoing treatment [21], which might have affected their chances of surviving with aPAH. Nonetheless, a limitation of this study is the unavailability of the drug histories of patients with aPAH. Currently, no straightforward explanation for the lower risk of death from aPAH with atrial fibrillation is available. Further research is required to investigate the connection between aPAH and atrial fibrillation.

Half of the deaths in our study population were caused by circulatory system and respiratory system diseases. On the other hand, the major causes of death among Koreans overall, are (in order): malignant neoplasm, heart disease, cerebrovascular attack, pneumonia, and suicide [22]. Other research based on KNHIS data on diseases such as Takayasu’s arteritis [8], thromboangiitis obliterans [23], and adults with congenital heart disease [9] also found a lower SR or higher HR with age, similar to our results. However, we also found a higher HR among the 0–9-year-old individuals in this study. The reason for the higher HR in the 0–9-year-old age group seems to be related to congenital heart disease. In this study, there was no additional analysis regarding the association with suspected congenital heart disease, so it cannot be determined. Furthermore, we did not conclude that the cause of death in aPAH is solely due to natural aging.

The 10-year SR for aPAH was 46.3% in this study. The 4.55-year survival for aPAH with HHT was 0% in this study. The 10-year SR for systemic lupus erythematosus and AIDS with aPAH was higher than that in cases without these conditions. Unfortunately, there are almost no previous studies to compare the 10-year SR with the above results.

This study has a few limitations. First, the data include aPAH and the initial comorbidities using ICD-10 codes. Therefore, SR and HR for aPAH in this study might be over- or under-estimated. Second, the national health insurance benefit records might have missed patients with aPAH who did not use medical services, paid for their own medical expenses, or had medical aid [8]. Third, the KNHIS data do not contain the results of medical examinations such as genetic tests, echocardiography, or right heart catheterization. Therefore, we cannot easily explain the causal relationships between aPAH and comorbidities.

In conclusion, the 10-year SRs for aPAH were 46%. The risk of death from aPAH was significantly higher with advancing age, sex, lower income level, and comorbidities including diabetes mellitus, myocardial infarction, heart failure, hemorrhagic stroke, chronic kidney disease, malignant neoplasm, HHT, and systemic lupus erythematosus. Our reported patterns of SR and death risk for aPAH should be considered in future research designs and policies for cardiovascular healthcare services.

Supplementary materials

Supplementary Table 1.

Survival rate (%) and 95% confidence interval overall, by sex, by age group, by cause of death, by HHT, by SLE, and by AIDS for associated pulmonary artery hypertension (ICD-10: I27.2)

pfm-2023-00142-Supplementary-Table-1.pdf
Supplementary Table 2.

Distribution of general, clinical characteristics, and causes of death and death risk for HHT (n=2,874)

pfm-2023-00142-Supplementary-Table-2.pdf

Notes

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: SK, SYJ, SRS, EJC, KK.

Acquisition, analysis, or interpretation of data: SK, SYJ, SYL, SRS, SY, CKL, EJC, KK.

Drafting the work or revising: SK, SYJ, KK.

Final approval of the manuscript: SK, SYJ, SYL, SRS, SY, CKL, EJC, KK.

Acknowledgements

We used data from the National Health Insurance Service (Research management number NHIS-2019-1-147), but the study results are not related to the National Health Insurance Service.

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Article information Continued

Fig. 1.

Survival curve of associated pulmonary arterial hypertension (aPAH, 10th revision of the International Statistical Classification of Diseases [ICD-10], I27.2) in Korea. (A) Survival rates in aPAH overall, by sex (P<0.001), and by cause of death (P<0.05), (B) aPAH survival rates by age group (P<0.001), (C) by hereditary hemorrhagic telangiectasia (HHT) (P<0.001), (D) by systemic lupus erythematosus (SLE) (P<0.001), and (E) by acquired immune deficiency syndrome (AIDS) (P=0.129).

Table 1.

Distribution of general and clinical characteristics, causes of death, and death risk from associated pulmonary arterial hypertension (ICD-10, I27.2; n=15,448)

Variable Total (n=15,448) Male (n=6,086) Female (n=9,362) P-valuea) Crude HR (95% CI) Adjusted HR (95% CI)b)
Age (yr) 60.1±24.0 58.1±25.0 61.5±23.3 <0.001
 0–9 1,207 (7.81) 621 (10.2) 586 (6.26) <0.001 1.44 (1.04–1.99)d) 1.60 (1.14–2.24)d)
 10–19 174 (1.13) 90 (1.48) 84 (0.90) 1.30 (0.79–2.12) 1.37 (0.83–2.28)
 20–29 426 (2.76) 144 (2.37) 282 (3.01) 1.0 1.0
 30–39 801 (5.19) 253 (4.16) 548 (5.85) 1.31 (0.93–1.84) 1.46 (1.03–2.08)d)
 40–49 1,288 (8.34) 477 (7.83) 811 (8.66) 1.95 (1.43–2.66)c) 2.16 (1.56–2.98)c)
 50–59 1,995 (12.9) 834 (13.7) 1,161 (12.4) 2.89 (2.14–3.90)c) 3.14 (2.30–4.30)c)
 60–69 2,588 (16.8) 1,137 (18.7) 1,451 (15.5) 4.54 (3.39–6.09)c) 5.06 (3.71–6.89)c)
 70–79 3,830 (24.8) 1,555 (25.6) 2,275 (24.3) 6.29 (4.71–8.41)c) 7.36 (5.42–10.0)c)
 ≥80 3,139 (20.3) 975 (16.0) 2,164 (23.1) 10.5 (7.88–14.0)c) 10.6 (7.97–14.2)c)
Male sex 6,086 (39.3) 6,086 (100) 0 - 1.35 (1.29–1.42)c) 1.48 (1.40–1.56)c)
Income level 0.001
 Upper 6,633 (43.3) 2,645 (43.5) 4,030 (43.1) 1.0 1.0
 Medium 3,913 (25.5) 1,626 (26.7) 2,316 (24.7) 0.83 (0.78–0.89)c) 1.02 (0.95–1.09)
 Lower 4,787 (31.2) 1,815 (29.8) 3,016 (32.2) 1.04 (0.98–1.11) 1.14 (1.07–1.21)c)
Comorbidities
 Hypertension 3,190 (20.7) 1,076 (17.6) 2,114 (22.5) <0.001 0.91 (0.85–0.97)d) 0.78 (0.73–0.83)c)
 Diabetes mellitus 1,456 (9.43) 610 (10.0) 846 (9.04) 0.040 1.38 (1.27–1.49)c) 1.18 (1.09–1.28)c)
 Dyslipidemia 1,204 (7.79) 452 (7.43) 752 (8.03) 0.170 0.56 (0.50–0.63)c) 0.55 (0.49–0.62)c)
 Myocardial infarction 204 (1.32) 112 (1.84) 92 (0.98) <0.001 1.76 (1.47–2.10)c) 1.34 (1.12–1.63)c)
 Heart failure 2,697 (17.5) 1,033 (16.9) 1,664 (17.7) 0.200 1.48 (1.39–1.57)c) 1.26 (1.19–1.35)c)
 Atrial fibrillation 1,548 (10.0) 643 (10.5) 905 (9.67) 0.069 1.27 (1.17–1.38)c) 0.91 (0.84–0.99)d)
 Ischemic stroke 331 (2.14) 127 (2.09) 204 (2.18) 0.698 1.34 (1.15–1.57)c) 1.06 (0.90–1.24)
 Hemorrhagic stroke 59 (0.38) 24 (0.39) 35 (0.37) 0.840 1.63 (1.14–2.23)d) 1.52 (1.07–2.17)d)
 Transient ischemic attack 41 (0.27) 16 (0.26) 25 (0.27) 0.961 0.90 (0.55–1.47) 0.75 (0.46–1.23)
 Chronic kidney disease 508 (3.29) 232 (3.81) 276 (2.95) 0.003 1.93 (1.72–2.16)c) 1.78 (1.59–2.00)c)
 Malignant neoplasm 752 (4.87) 381 (6.26) 371 (3.96) <0.001 2.66 (2.43–2.92)c) 2.29 (2.09–2.51)c)
 Epistaxis 6 (0.04) 5 (0.08) 1 (0.01) 0.027 - -
 Hemoptysis 96 (0.62) 50 (0.82) 46 (0.49) 0.010 - -
 Arteriovenous malformation 6 (0.04) 2 (0.03) 4 (0.04) 0.761 - -
 Anemia 325 (2.10) 88 (1.45) 237 (2.53) <0.001 - -
 Hereditary hemorrhagic telangiectasia 4 (0.03) 1 (0.02) 3 (0.03) 0.556 2.39 (0.77–7.39) 3.19 (1.03–9.93)d)
 Acquired immune deficiency syndrome 10 (0.07) 5 (0.08) 5 (0.05) 0.491 0.35 (0.09–1.43) 0.69 (0.17–2.79)
 Systemic lupus erythematosus 644 (4.17) 56 (0.92) 588 (6.28) <0.001 0.53 (0.45–0.62)c) 1.61 (1.36–1.90)c)
Death 5,975 (38.7) 2,665 (43.7) 3,310 (35.3) <0.001 - -
Cause of death <0.001
 Certain infections and parasitic diseases (A00-B99) 204 (3.41) 98 (3.68) 106 (3.20) - -
 Malignant neoplasm (C00-C97) 744 (12.5) 401 (15.0) 343 (10.4) - -
 Benign neoplasm (D00-D48) and diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (D50-D89) 50 (0.84) 22 (0.83) 28 (0.85) - -
 Endocrine, nutritional, and metabolic diseases (E00-E90) 176 (2.95) 73 (2.74) 103 (3.11) - -
 Mental and behavioral disorders (F01-F99) 36 (0.60) 12 (0.45) 24 (0.73) - -
 Diseases of the nervous system (G00-G98) 78 (1.31) 30 (1.13) 48 (1.45) - -
 Diseases of the circulatory system (I00-I99) 1,523 (25.5) 584 (21.9) 939 (28.4) - -
 Diseases of the respiratory system (J00-J98) 1,282 (21.5) 709 (26.6) 573 (17.3) - -
 Diseases of the digestive system (K00-K92) 143 (2.39) 64 (2.40) 79 (2.39) - -
 Diseases of the skin and subcutaneous tissue (L00-L99) 5 (0.08) 2 (0.08) 3 (0.09) - -
 Diseases of the musculoskeletal system and connective tissue (M00-M99) 210 (3.51) 35 (1.31) 175 (5.29) - -
 Diseases of the genitourinary system (N00-N99) 186 (3.11) 80 (3.00) 106 (3.20) - -
 Pregnancy, childbirth, and the puerperium (O00-O99) 1 (0.02) 0 (0.00) 1 (0.03) - -
 Certain conditions originating in the perinatal period (P00-P96) 56 (0.94) 25 (0.94) 31 (0.94) - -
 Congenital malformation, deformations, and chromosomal abnormalities (Q00-Q99) 125 (2.09) 67 (2.51) 58 (1.75) - -
 Symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified (R00-R99) 211 (3.53) 73 (2.74) 138 (4.17) - -
 Injury, poisoning, and certain other consequences of external causes (S00-T98) 150 (2.51) 71 (2.66) 79 (2.39) - -
 Not provided 795 (13.3) 319 (12.0) 476 (14.4) - -

Values are presented as mean±standard deviation or number (%).

ICD-10, 10th revision of the International Statistical Classification of Diseases; HR, hazard ratio; CI, confidence interval.

a)

Student’s t-test or χ2-test;

b)

Estimated by a Cox proportional hazard model analysis using the variables indicated in the table;

c)

P<0.001;

d)

P<0.05.