The major causes of death in patients with abdominal aortic aneurysm (AAA) are cardiovascular disease and cancer. The purpose of this study was to evaluate the effect of AAA on long-term survival in lung cancer patients. All patient data with degenerative type AAA and lung cancer over 50 years of age during the period 2009 to 2018 was collected retrospectively from a National Health Insurance Service (NHIS) administrative database and matched to lung cancer patients without AAA by age, sex, metastasis, and other comorbidities. Mortality rate was compared between the groups. A total of 956 AAA patients who could be matched with patients without AAA were included, and 3824 patients in the matched group were used for comparison. Patients with AAA showed higher risk of death compared with the matched cohort (adjusted hazard ratio (HR) 1.14, 95% confidence interval (CI) 1.06–1.23, p < 0.001). When compared to a matched group of untreated AAA patients, patients with of history of AAA exhibited a significantly increased risk of overall mortality [HR (95%CI) 1.219 (1.113–1.335), p <.001, adjusted HR (95% CI) 1.177 (1.073–1.291), p =.001]. By contrast, mortality risk of AAA patients treated either by endovascular abdominal aortic repair or open surgical repair was not significantly different from that of the matched group (p = 0.079 and p = 0.625, respectively). The mortality risk was significantly higher when AAA was present in lung cancer patients, especially in patients with unrepaired AAA, suggesting the need for continuous cardiovascular risk management.
Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta, where the diameter exceeds 3 cm or is more than 50% larger than normal[
All data of AAA patients over 50 years of age in a National Health Insurance Service (NHIS) administrative database covering approximately 98% of the South Korean population was collected retrospectively for the period 2009 to 2018. The study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by Asan medical center Institutional Review Board (approval number: 2020-1242) and informed written consent was waived by Asan medical center Institutional Review Board due to the retrospective nature of the study. The manuscript follows the guidelines of the RECORD statement, extended from the STROBE statement.
The inclusion and exclusion criteria for AAA are as follows: Patients over 50 years with a degenerative type of AAA are included, while ruptured AAA and non-degenerative types of AAA are excluded. A flow diagram illustrating the selection of study participants is depicted in Fig. 1. To exclude non-degenerative cases of AAA, such as those related to trauma, only the data of patients over 50 years of age was accessed. Patients with AAA were identified by ICD-10 codes including I71.3–4 and I71.8–9. Initial screening included ruptured AAA cases because the diagnosis of some cases was miscoded. Patients with a rupture code who survived more than 90 days without treatment were classified as unruptured AAA. Ruptured AAA patients were then excluded. Patients with a relevant ICD-10 code of AAA who visited the outpatient clinic only once were excluded due to uncertainty of the diagnosis. In order to limit the analysis to degenerative AAA, patients with the following conditions were excluded: (
Graph: Figure 1Flow diagram.
The demographic variables included age, sex, and comorbidities. The comorbidities were selected using the Charlson Comorbidity Index (CCI), a method of categorising comorbidities based on ICD-10 codes, and grouped based on CCI scores 0-1, 2, and ≥ 3[
The statistical differences in the patient characteristics based on the history of AAA were computed using the standardised mean difference (SMD), with a SMD of less than 0.1 considered to indicate a balance between the groups. The prevalence of all-cause mortality in cancer patients with and without a history of AAA was compared. All-cause mortality was calculated at 30 days and at the end of the study period after AAA repair. The overall mortality rate is presented along with the age-standardised rate. Kaplan–Meier curves was used to depict the cumulative incidence of all-cause mortality. A statistical comparison between the survival of the AAA group and that of the matched group was performed to estimate the effect of AAA on death in cancer patients treated by EVAR or OSR. Univariate (crude) and multivariate (adjusted) Cox-proportional hazards regression analyses were performed to assess associations between AAA and the occurrence of all-cause deaths. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes were calculated in AAA patients with and without a cancer history. The Cox-proportional regression models were adjusted for CCI. All analyses were performed using SAS 7.1 software (SAS Institute, Cary, NC, USA), and the statistical significance level was set to α = 0.05.
Among patients with degenerative unruptured AAA, 4984 patients had cancer, and the most common types were lung (20.0%), stomach (11.9%), prostate (8.3%), and colon (7.1%). Among 995 lung cancer patients, 956 patients who could be matched with those without AAA were used for the analysis, and 3824 patients in the matched group were used for comparison.
Patients' characteristics are summarised in Table 1. There were no significant differences in the matched variables (sex, age and metastasis) between the two groups (SMD < 0.001). With the exception of diabetes mellitus, patients with cancer had more comorbidities (SMD = 0.013) and a higher CCI score (SMD = 0.274).
Table 1 Patients' characteristics.
AAA with cancer Matched cohort SMD (n = 956) ( Age (years), mean (SD) 75.0 (7.0) 75.0 (7.0) <.001 Men, n (%) 832 (87.0) 3328 (87.0) <.001 Comorbidities, n (%) Diabetes mellitus 329 (34.4) 1340 (35.0) 0.013 Hypertension 739 (77.3) 2356 (61.6) 0.346 Dyslipidemia 708 (74.1) 2068 (54.1) 0.426 Chronic kidney disease 100 (10.5) 144 (3.8) 0.263 ESRD 19 (2.0) 19 (0.5) 0.135 Cerebrovascular accident 8 (0.8) 24 (0.6) 0.177 Ischaemic heart disease 35 (3.7) 39 (1.0) 0.17 Heart failure 186 (19.5) 379 (9.9) 0.272 Charlson Comorbidity Index, mean (SD) 5.81 (3.64) 4.95 (3.53) 0.24 0–2 166 (17.4) 1021 (26.7) 0.274 3–4 241 (25.2) 1083 (28.3) 5 549 (57.4) 1720 (45.0) Alcohol, n (%) 0.149 None 455 (47.6) 1697 (44.4) < 3 d/week 152 (15.9) 737 (19.3) ≥ 3 d/week 46 (4.8) 282 (7.4) No response/Missing 303 (31.7) 1108 (28.9) Smoking, n (%) 0.151 Non-smoker 194 (20.3) 950 (24.8) Ex-smoker 215 (22.5) 958 (25.1) Current smoker 244 (25.5) 810 (21.2) No response/Missing 303 (31.7) 1106 (28.9) Cancer surgery, n (%) 772 (80.8) 3008 (78.7) 0.052 Chemotherapy, n (%) 81 (8.5) 285 (7.5) 0.038
SMD, standardised mean difference.
Figure 2 shows Kaplan–Meier curves for the cumulative incidence of overall mortality for patients with a history of AAA. The median follow-up period was 6.13 years (interquartile range: 3.05–6.54). AAA patients with lung cancer had a higher overall mortality risk than those in the matched non-AAA group. During the entire study period, the risk of death among patients with AAA was high, and both curves converged to approximately 75% after 8 years. Table 2 shows that the all-cause mortality rate in lung cancer patients with AAA and the matched controls. Patients with AAA had a higher risk of death than the matched cohort (adjusted HR 1.14, 95% CI 1.06–1.23, p < 0.001). The risk of death was compared between the patients with AAA and matched cohorts based on the variables used for matching, including age, sex, and metastasis. In men, patients in the AAA group had a higher risk of death than those in the matched group, even after adjustment for CCI (adjusted HR 1.16, 95% CI 1.07–1.26, p < 0.001). By contrast, in women, there were no significant differences between the two groups (p > 0.05). AAA patients who were diagnosed with lung cancer at ages 65–79 or > 80 years had a higher risk of death than the controls (p = 0.005 and p = 0.021, respectively). Patients with AAA had a higher risk of death irrespective of whether they had metastasis or not (p = 0.039 and p = 0.001, respectively).
Graph: Figure 2Risk of death of lung cancer patients with abdominal aortic aneurysm (AAA) and of the matched control.
Table 2 Comparison of mortality rate between lung cancer patients with abdominal aortic aneurysm (AAA) and matched control (no AAA).
AAA (n = 956) no AAA (n = 3824) HR (95% CI) P HRa (95% CI) P Total Death PY Mortality rate (/100PYs) Total Death PY Mortality rate (/100PYs) Total 956 747 1303.8 57.3 3824 2815 6288.1 44.8 1.19 (1.10–1.28) <.001 1.14 (1.06–1.23) 0.001 Sex Men 832 661 1090.8 60.6 3328 2488 5360.9 46.4 1.20 (1.11–1.30) 0.000 1.16 (1.07–1.26) < 0.001 Women 124 86 213.0 40.4 496 327 927.1 35.3 1.11 (0.90–1.38) 0.341 1.05 (0.84–1.30) 0.690 Age at Dx* 50–64 81 47 200.3 23.5 324 166 853.2 19.5 1.18 (0.91–1.54) 0.216 1.08 (0.82–1.43) 0.573 65–79 625 479 906.0 52.9 2500 1815 4394.3 41.3 1.19 (1.08–1.32) 0.000 1.16 (1.04–1.28) 0.005 80 + 250 221 197.6 111.9 1000 834 1040.6 80.1 1.22 (1.06–1.40) 0.006 1.18 (1.03–1.37) 0.021 Metastasis No 829 630 1211.2 52.0 3316 2365 5813.1 40.7 1.19 (1.09–1.29) <.001 1.16 (1.06–1.26) 0.001 Yes 127 117 92.6 126.3 508 450 475.0 94.7 1.24 (1.02–1.51) 0.0324 1.24 (1.01–1.51) 0.039
*Age at lung cancer diagnosis. HR calculated to consider matched nature. HR
In the AAA group, 416 patients underwent treatment for AAA; 232 with endovascular abdominal aortic aneurysm repair (EVAR) and 84 with open surgical repair (OSR). Demographic data of subgroups are summarised in Supplementary Table 1. Figure 3 depicts the HRs for the mortality rate of AAA and matched group patients grouped by treatment type. When the matched group was compared with the untreated AAA patients, patients with a history of AAA exhibited a significantly higher risk of overall mortality [HR (95%CI) 1.219 (1.113–1.335), p < 0.001, adjusted HR (95% CI) 1.177 (1.073–1.291), p = 0.001] than those without. Conversely, the mortality risk of AAA patients treated either by EVAR or OSR was not significantly different from the matched group (p = 0.079 and p = 0.625, respectively).
Graph: Figure 3Forest plot comparing the mortality rate in patients with abdominal aortic aneurysm (AAA) and their matched cohort using treatment-related variables, including no treatment, endovascular aneurysm repair (EVAR), and open surgical repair (OSR). Adjusted HR; adjusted for Charlson Comorbidity Index.
The long-term prognosis in patients with AAA has been reported in many studies[
By contrast, patients who underwent either EVAR or OSR exhibited a mortality risk similar to that of the control group. It seems rather strange that there was no difference in mortality risk between the matched groups of patients with large AAAs that were indicated for treatment. After successful surgical repair of an abdominal aortic aneurysm, patients have an increased risk of death from cardiovascular causes for many years, and a significant association between aortic diameter and cardiovascular mortality has been reported[
The principal limitations of the present study are its retrospective design and the uncertainty in the assignment of cancer stage due to the nature of the administrative database. Furthermore, potential confounding variables, including smoking status, comorbidities, and socioeconomic factors, may have influenced the mortality outcomes, which were not comprehensively controlled for in our analysis. The smoking habit appeared to have the most significant influence on mortality outcomes among them, and an effort was made to incorporate this information into the analysis by integrating national health check-up data with our database. However, approximately 30% of the data was encountered being missing. However, we tried to overcome this limitation by matching metastatic status when defining the control group. The strength of the present study includes its size and long-term follow-up without censoring. The present study also benefited from the inclusion of patients who were diagnosed with cancer after the diagnosis of AAA, which reduced bias from the morbidity period of cancer. Another strength of this study is that it evaluated survival in untreated patients.
The effect of AAA on survival of lung cancer patients reported here may have implications for management strategies of AAA patients regardless of treatment in the future. The ultimate goal is to reduce cardiovascular risk and improve long-term survival in this population. Future studies conducted in international settings or incorporating a comprehensive assessment of cancer staging and different treatment modalities are necessary to enhance the universal applicability of our findings. Furthermore, given the significance of gender differences in AAA and lung cancer, it is crucial to prioritize gender diversity in their participant selection.
The significant increase in mortality of lung cancer patients with AAA, especially untreated patients, suggests that cardiovascular risk should be managed to improve long-term survival of cancer patients.
Conceptualization: K.H. Data curation: K.H., K.T.W., K.Y.J., K.S. Formal analysis: Kim YJ, Kim S. Funding acquisition: K.T.W. Investigation: K.H., G.J.G., H.Y. Methodology: K.H., K.Y.J. Software: K.Y.J., K.S. Validation: C.Y.P., G.J.G., H.Y., L.S.A. Visualization: K.H., K.Y.J. Writing - original draft: K.H. Writing - review & editing: K.T.W., C.Y.P., G.J.G., H.Y., L.S.A.
This study was supported by a grant from Asan Institute for Life Sciences and Corporate Relations of Asan Medical Center, Seoul, Korea.
The data that support the findings of this study are available from National Health Insurance Service of Korea but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the corresponding author upon reasonable request and with permission of National Health Insurance Service of Korea.
The authors declare no competing interests.
Graph: Supplementary Table 1.
The online version contains supplementary material available at https://doi.org/10.1038/s41598-023-46196-8.
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By Hyangkyoung Kim; Tae-Won Kwon; Yong-Pil Cho; Jun Gyo Gwon; Youngjin Han; Sang Ah Lee; Ye-Jee Kim and Seonok Kim
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