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    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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The Impact of Sedation on Cardio-Cerebrovascular Adverse Events after Surveillance Esophagogastroduodenoscopy in Patients with Gastric Cancer: A Nationwide Population-Based Cohort Study

Sang Yoon Kim1 , Jun Kyu Lee2 , Kwang Hyuck Lee3 , Jae-Young Jang4 , Byung-Wook Kim5 , Endoscopic Sedation Committee of Korean Society of Gastrointestinal Endoscopy (KSGE)

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1Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, Korea; 2Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea; 3Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea; 5Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea

Correspondence to: Jun Kyu Lee
ORCID https://orcid.org/0000-0002-2694-3598
E-mail jeromee1971@daum.net

Received: February 8, 2023; Revised: April 12, 2023; Accepted: April 19, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(2):245-256. https://doi.org/10.5009/gnl230043

Published online June 15, 2023, Published date March 15, 2024

Copyright © Gut and Liver.

Abstract

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Background/Aims: The impact of sedation on cardio-cerebrovascular (CCV) adverse events after esophagogastroduodenoscopy (EGD) in patients with gastric cancer (GC) is unclear. We investigated the incidence rate and impact of sedation on CCV adverse events after surveillance EGD in patients with GC.
Methods: We performed a nationwide population-based cohort study using the Health Insurance Review and Assessment Service databases from January 1, 2018, to December 31, 2020. Using a propensity score-matched analysis, patients with GC were divided into two groups: sedative agent users and nonusers for surveillance EGD. We compared the occurrence of CCV adverse events within 14 days between the two groups.
Results: Of the 103,463 patients with GC, newly diagnosed CCV adverse events occurred in 2.57% of patients within 14 days after surveillance EGD. Sedative agents were used in 41.3% of the patients during EGD. The incidence rates of CCV adverse events with and without sedation were 173.6/10,000 and 315.4/10,000, respectively. Between sedative agent users and nonusers based on propensity score matching (28,008 pairs), there were no significant differences in the occurrence of 14-day CCV, cardiac, cerebral, and other vascular adverse events (2.28% vs 2.22%, p=0.69; 1.44% vs 1.31%, p=0.23; 0.74% vs 0.84%, p=0.20; 0.10% vs 0.07%, p=0.25, respectively).
Conclusions: Sedation during surveillance EGD was not associated with CCV adverse events in patients with GC. Therefore, the use of sedative agents may be considered in patients with GC during surveillance EGD without excessive concerns about CCV adverse events.

Keywords: Adverse events, Stomach neoplasms, Esophagogastroduodenoscopy, Sedatives

INTRODUCTION

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Survival rates of patients with gastric cancer (GC) have improved with early detection and advances in treatment, but prognosis remains poor.1 Recurrence is an important concern even in GC patients undergoing curative therapy.2 Several guidelines from the National Comprehensive Cancer Network, European Society for Medical Oncology, Japanese Gastric Cancer Association, and Korean Gastric Cancer Association recommend regular follow-up examinations such as blood tests, abdominal computed tomography, and esophagogastroduodenoscopy (EGD) for GC. However, there is no consensus on the strategy of surveillance.3-6 Among the follow-up examinations, EGD is considered to enable early detection of recurrent GC, which often appears as subtle mucosal changes.7 Therefore, surveillance EGD at regular intervals is recommended by clinicians for patients with GC. Although surveillance EGD is generally regarded as safe, EGD itself or the use of sedative agents during EGD has some potential to cause adverse events.8-10 Particularly, cardio-cerebrovascular (CCV) adverse events following EGD may be responsible for a majority of the mortality. In a nationwide survey study in the United States, the risk of cardiac adverse events was one of the main considerations for clinicians in deciding whether to use sedative agents during EGD.11 Several studies have reported CCV adverse events following diagnostic EGD in the average-risk population.8,9,12,13 However, data on CCV adverse events following surveillance EGD in patients with GC have not been reported. Therefore, we aimed to investigate the incidence of CCV adverse events, including cardiac and cerebral adverse events, arterial thromboembolism (ATE), and pulmonary embolism (PE), after surveillance EGD with or without sedation in patients with GC. Additionally, we evaluated the impact of sedation during EGD on CCV adverse events in GC patients using the Health Insurance Review and Assessment Service (HIRA) database.

MATERIALS AND METHODS

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1. Data source and study population

Almost all Koreans (98%) are mandatorily enrolled in the National Health Insurance Service, which is the only insurer in South Korea.14 The HIRA database in South Korea was created for the process of reimbursing claims for healthcare services under the National Health Insurance Service.15 This database contains the claim records of examinations, procedures, and prescriptions as well as the socio-demographic information of all insured Koreans. From 2013, the government of South Korea has implemented an expansion policy of health insurance, called the copayment decreasing policy, to reduce the high medical expenditure of the four major serious diseases (cancer, cardiac disease, cerebrovascular disease, and rare incurable disease). From February 2017, patients with these diseases can receive expanded insurance coverage for the use of any sedative agent, including propofol, during endoscopy and monitoring fees for sedated endoscopy, which are not covered by insurance for the general population. Therefore, a study using the HIRA data for patients with GC, one of the four major serious diseases, can reflect accurate information on the sedative agents used during endoscopy and allow us to perform a nationwide population-based study.

The study population comprised 126,507 individuals aged 20 to 99 years who had been diagnosed with GC and had been granted a copayment decreasing policy for cancer (V193 code) from January 1, 2018, to December 31, 2018 (Supplementary Table 1). In this study, the HIRA database was used to identify whether sedation was used during EGD and the detailed types of sedative agents used in patients with GC. Sedated endoscopy was defined as the prescription of a patient’s monitoring fee for sedated endoscopy (EA002 code) and the intravenous administration of sedative agents, such as midazolam, propofol, lorazepam, or diazepam, according to the Korea Pharmaceutical Information Service on the same day as the EGD (Supplementary Table 2).

We set the 12 months before surveillance EGD as a washout period to minimize the confounding effects of previously diagnosed CCV adverse events. Diagnoses were coded according to the International Classification of Diseases, 10th Revision.15,16 The codes and descriptions of CCV adverse events are presented in Supplementary Table 3. The exclusion criteria were (1) patients with GC who did not undergo surveillance EGD after the diagnosis of GC (n=4,204) and underwent only therapeutic endoscopy (n=899) (Fig. 1). The codes and descriptions of gastrointestinal endoscopy are presented in Supplementary Table 4, and (2) previous diagnosis of or treatment for CCV diseases within 12 months before surveillance EGD in patients with GC (n=17,941) (Fig. 1). Patients with GC for whom anticoagulant agents and thrombolytics were prescribed (including oral administration for more than 30 days, subcutaneous injection for more than 5 days, and intravenous administration more than once) were also considered as previously diagnosed CCV patients. Drug codes of anticoagulant agents and thrombolytics were retrieved from the Korea Pharmaceutical Information Service (Supplementary Table 5).17

Figure 1.Flow diagram of the study population.
HIRA, Health Insurance Review and Assessment Service; EGD, esophagogastroduodenoscopy; CCV, cardio-cerebrovascular; MI, myocardial infarction; IHD, ischemic heart disease; TIA, transient ischemic attack; ATE, arterial thromboembolism.

A total of 103,463 eligible patients with GC were included in this study. Using propensity score-matched analysis, patients with GC were divided into two groups: those who received sedative agents for surveillance EGD (sedation group) and those who did not (non-sedation group). We defined chronic underlying diseases based on the International Classification of Diseases, 10th Revision codes for hypertension, diabetes mellitus, valvular heart disease, hyperlipidemia, chronic pulmonary disease, renal disease, connective tissue disorder, liver disease, and cancer/metastatic cancer (Supplementary Table 6). We classified the use of antiplatelet agents as present or absent for >30 days before EGD (Supplementary Table 7). This study was approved by the Institutional Review Board of Dongguk University Ilsan Hospital (IRB number: DUIH 2022-02-001). Written informed consent was waived.

2. Clinical outcomes

The primary outcome of this study was newly diagnosed CCV adverse events after surveillance EGD in patients with GC. Newly diagnosed CCV adverse events was defined as hospitalization with a CCV at least once or as an outpatient clinic or emergency room visit with a CCV adverse events at least twice from the same day (Day 0) to 14 days after surveillance EGD.9 These CCV adverse events were categorized as cardiac adverse events (angina, cardiac dysrhythmia, hypertensive heart disease, acute myocardial infarction, hypotension, acute ischemic heart disease, or cardiac arrest), stroke/transient ischemic attack (TIA) (ischemic stroke, hemorrhagic stroke, or TIA), and ATE/PE (ATE or PE) (Supplementary Table 3). According to a previous systematic review and meta-analysis, we stratified CCV adverse events into major and minor CCV adverse events based on their severity.18 Major CCV adverse events were defined as acute myocardial infarction, cardiac arrest, ischemic stroke, hemorrhagic stroke, ATE, and PE. Minor CCV adverse events were defined as angina, cardiac dysrhythmia, hypertensive heart disease, hypotension, acute ischemic heart disease, and TIA. We investigated the overall incidence and percentage of CCV adverse events and of those occurring within 0–3, 4–7, and 8–14 days after endoscopic surveillance. If CCV adverse events occurred multiple times within 14 days of surveillance EGD, only the first CCV adverse event was included in the analysis. The control group comprised patients without CCV adverse events within 14 days of surveillance EGD. In case of multiple EGDs per patient in the control group, one of the EGDs was randomly selected and included in the analysis. The secondary outcome of this study was whether the use of sedative agents for surveillance EGD was associated with the occurrence of CCV adverse events in patients with GC.

3. Statistical analysis

Categorical data were described using numbers with percentages and compared using the chi-square test or Fisher exact test, as appropriate. Descriptive statistics for continuous variables are summarized as means with standard deviation. The incidence rate of CCV adverse events was calculated as the number of incident cases divided by 10,000. For propensity score matching, a 1:1 matching process without replacements was performed using a greedy algorithm with 0.05 caliper (0.25 multiplied by the standard deviation of the logit of the propensity score), yielding 28,008 subjects in the non-sedation group and 28,008 matched subjects in the sedation group. Propensity scores were created to control for known clinically relevant factors and were calculated using age group, sex, type of healthcare institution, type of insurance, route of EGD, types of chronic disease, stage of GC, and use of antiplatelet agents. Absolute standardized mean differences were estimated for all baseline covariates before and after matching to assess imbalance before matching and balance after matching. An absolute standardized mean difference of less than 0.1 for a given covariate indicated a relatively small imbalance. This category was used to create propensity scores. Outcomes were compared between groups based on propensity score matching. In the univariate analyses, continuous variables were analyzed using the Student t-test, and categorical variables were analyzed using the chi-square test. Variables with a p<0.05 in univariate analysis were selected for multivariate logistic regression analyses to evaluate independent risk factors for CCV adverse events. A p-value of <0.05 was considered significant. Analyses were performed using the SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).

RESULTS

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1. Baseline characteristics of the study population

Of the 103,463 patients with GC, sedative agent users and nonusers consisted of 42,686 (41.3%) and 60,777 patients (58.7%), respectively. For sedation during EGD, midazolam, propofol, midazolam+propofol, midazolam+lorazepam/diazepam, propofol+lorazepam/diazepam, or midazolam+propofol+lorazepam/diazepam were used. The proportion of sedative agents used is shown in Fig. 2. Men comprised 64.0% of sedative agent users and 69.4% of nonusers (p<0.001). The mean ages of the sedative agent users and nonusers were 57.2±8.4 and 68.7±10.8 years old, respectively (p<0.001). Proportions of old age (≥65 years), chronic disease, advanced stage of GC, and use of antiplatelet agents were significantly higher in the non-sedation group. Meanwhile, the proportion of EGD performed in tertiary hospitals was significantly higher in the sedation group. Using propensity score matching, 28,008 pairs of sedative agent users and nonusers were analyzed. The baseline characteristics of the study participants before and after propensity score matching are shown in Table 1.

Figure 2.Use of sedative agents during surveillance esophagogastroduodenoscopy in patients with gastric cancer.

Table 1. Baseline Characteristics of the Study Population

CharacteristicUnmatchedPropensity score-matched (1:1)
Total
(n=103,463)		Sedative agentsp-value*ASMDTotal
(n=56,016)		Sedative agentsASMD
Users (n=42,686)Nonusers (n=60,777)Users (n=28,008)Nonusers (n=28,008)
Sex, No. (%)<0.0010.120.10
Male69,513 (67.2)27,308 (64.0)42,205 (69.4)17,433 (31.1)9,045 (32.3)8,388 (29.95)
Female33,950 (32.8)15,378 (36.0)18,572 (30.6)38,583 (68.8)18,963 (67.7)19,620 (70.05)
Age, mean±SD, yr63.6±11.257.2±8.468.1±10.8<0.0011.1360.4±9.759.3±8.061.6±11.11.13
Age group, No. (%)<0.0011.031.03
20–64 yr53,827 (52.0)33,631 (78.8)20,196 (33.2)37,984 (67.8)18,953 (67.7)19,031 (68.0)
≥65 yr49,636 (48.0)9,055 (21.2)40,581 (66.8)18,032 (32.2)9,055 (32.3)8,977 (32.1)
Types of healthcare institution, No. (%)†<0.0010.290.29
Tertiary hospital74,919 (72.4)32,996 (77.3)41,923 (69.0)42,100 (75.2)21,270 (75.9)20,830 (74.4)
General hospital23,830 (23.0)9,062 (21.2)14,768 (24.3)12,567 (22.4)6,111 (21.8)6,456 (23.1)
Standard hospital1,371 (1.3)304 (0.7)1,067 (1.8)621 (1.1)303 (1.1)318 (1.1)
Private clinic3,343 (3.2)324 (0.8)3,019 (5.0)728 (1.3)324 (1.2)404 (1.4)
Types of insurance, No. (%)<0.0010.090.08
National health insurance98,785 (95.5)41,202 (96.5)57,583 (94.7)53,691 (95.8)26,874 (96.0)26,817 (95.8)
Medical benefit system4,678 (4.6)1,484 (3.5)3,194 (5.3)2,325 (4.2)1,134 (4.1)1,191 (4.2)
Routes of undergoing EGD, No. (%)0.95<0.0010.01
Outpatient94,844 (91.7)39,133 (91.7)55,711 (91.7)50,778 (90.7)24,888 (88.9)25,890 (92.4)
Inpatient8,619 (8.3)3,553 (8.3)5,066 (8.3)5,238 (9.3)3,120 (11.1)2,118 (7.6)
Types of chronic disease, No. (%)
Hypertension33,211 (32.1)10,670 (25.0)22,541 (37.1)<0.0010.2617,668 (31.5)9,875 (35.3)7,793 (27.9)0.26
Diabetes mellitus20,683 (20.0)7,060 (16.5)13,623 (22.4)<0.0010.1511,235 (20.1)6,271 (22.4)4,964 (17.7)0.16
Valvular disease492 (0.5)102 (0.2)390 (0.6)<0.0010.06181 (0.3)96 (0.3)85 (0.3)0.06
Hyperlipidemia29,858 (28.9)11,833 (27.7)18,025 (29.7)<0.0010.0417,491 (31.2)9,983 (35.6)7,508 (26.8)0.05
Chronic pulmonary disease24,678 (23.9)8,897 (20.8)15,781 (26.0)<0.0010.1214,462 (25.8)8,482 (30.3)5,980 (21.4)0.12
Renal disease2,101 (2.0)535 (1.3)1,566 (2.6)<0.0010.10898 (1.6)486 (1.7)412 (1.5)0.09
Connective tissue disorder1,608 (1.6)613 (1.4)995 (1.6)0.010.02922 (1.7)538 (1.9)384 (1.4)0.01
Liver disease2,899 (2.8)1,157 (2.7)1,742 (2.9)0.140.011,788 (3.2)1,039 (3.7)749 (2.7)0.007
Cancer/metastatic cancer13,587 (13.1)5,211 (12.2)8,376 (13.8)<0.0010.057,830 (14.0)4,571 (16.3)3,259 (11.6)0.05
Stage of gastric cancer, No. (%)0.010.020.02
Early48,517 (46.9)20,172 (47.3)28,345 (46.6)25,446 (45.4)12,706 (45.4)12,740 (45.5)
Advanced14,780 (14.3)5,928 (13.9)8,852 (14.6)8,560 (15.3)4,430 (15.8)4,130 (14.8)
Unspecified40,166 (38.8)16,586 (38.9)23,580 (38.8)22,010 (39.3)10,872 (38.8)11,138 (39.8)
Use of antiplatelet agents, No. (%)<0.0010.120.11
No100,094 (96.7)41,805 (97.9)58,289 (95.9)54,540 (97.4)27,235 (97.2)27,305 (97.5)
Yes3,369 (3.3)881 (2.1)2,488 (4.1)1,476 (2.6)773 (2.8)703 (2.5)

ASMD, absolute standardized mean differences; EGD, esophagogastroduodenoscopy.

*p-values for differences were determined using the chi-square or Wilcoxon rank sum test for unmatched data; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals are more specialized in treating severe diseases than general hospitals, mostly university hospitals.

2. Incidence rates of CCV adverse events

Among the study subjects, 2,658 patients (2.57%) experienced CCV adverse events within 14 days of surveillance EGD (Table 2). Major CCV adverse events occurred in 1,055 patients (1.02%), cardiac adverse events in 1,597 (1.54%), stroke/TIA in 963 (0.93%), and ATE/PE in 98 (0.09%). The incidence rate of CCV adverse events (per 10,000 persons) within 14 days was 315.4 for surveillance EGD without sedation and 173.6 for surveillance EGD with sedation (Table 2). According to the period after surveillance EGD, CCV adverse events within 14 days were subcategorized as occurring within 0–3, 4–7, and 8–14 days. The incidence rates of all types of CCV adverse events (overall CCV, major CCV, minor CCV, cardiac, stroke/TIA, and ATE/PE) in both EGD with sedation and EGD without sedation groups were the highest within 0 to 3 days of surveillance EGD in patients with GC (Supplementary Tables 8 and 9).

Table 2. CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer

Overall CCVMajor CCV*Cardiac adverse eventStroke/TIAATE/PE
Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons
Total adverse events within 14 days2,658 (2.57)256.91,055 (1.02)102.01,597 (1.54)154.3963 (0.93)93.198 (0.09)9.5
Without sedation1,917 (3.15)315.4778 (1.28)128.01,130 (1.86)186.0721 (1.19)118.666 (0.11)10.8
With sedation741 (1.74)173.6277 (0.65)64.9467 (1.09)109.4242 (0.57)56.732 (0.07)7.5
Midazolam387 (1.53)152.9138 (0.55)54.5249 (0.98)98.4123 (0.49)48.615 (0.06)5.9
Propofol143 (2.01)201.457 (0.80)80.285 (1.20)119.749 (0.69)69.09 (0.13)12.7
Midazolam+ propofol206 (2.04)204.478 (0.77)77.4132 (1.31)131.066 (0.65)65.58 (0.08)7.9
Midazolam+lorazepam or diazepam2 (2.15)215.11 (1.08)107.51 (1.08)107.51 (1.08)107.500.0
Propofol+lorazepam or diazepam00.000.000.000.000.0
Midazolam+propofol+lorazepam or diazepam3 (4.76)476.23 (4.76)476.200.03 (4.76)476.200.0

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism.

*Major CCV adverse events were defined as acute myocardial infarction, cardiac arrest, ischemic stroke, hemorrhagic stroke, ATE, or PE.

3. Propensity score-matched analysis: 14-day CCV adverse events according to presence or absence of sedation

In the propensity score-matched cohorts, CCV adverse events occurred in 1,261 patients with GC (2.25%). There were 770 (1.37%) cardiac adverse events, 442 (0.79%) stroke/TIA, and 49 (0.09%) ATE/PE (Table 3). There were no significant differences in the occurrence of overall CCV adverse events between the sedation and non-sedation groups (2.28% vs 2.22%, p=0.69). In addition, cardiac adverse events (1.44% vs 1.31%, p=0.23), stroke/TIA (0.74% vs 0.84%, p=0.20), and ATE/PE (0.10% vs 0.07%, p=0.25) were not significantly different between the sedation and non-sedation groups.

Table 3. Outcomes of CCV Adverse Events in the Unmatched and Propensity Score-Matched Groups

Unmatched patientsPropensity score-matched (1:1) patients
Total
(n=103,463)		Received sedative
agents (n=42,686)		Did not receive sedative agents (n=60,777)p-value*Total
(n=56,016)		Received sedative
agents (n=28,008)		Did not receive sedative agents (n=28,008)p-value*
CCV adverse events2,658 (2.57)741 (1.74)1,917 (3.15)<0.0011,261 (2.25)638 (2.28)623 (2.22)0.69
Cardiac adverse events1,597 (1.54)467 (1.09)1,130 (1.86)<0.001770 (1.37)402 (1.44)368 (1.31)0.23
Stroke/TIA963 (0.93)242 (0.57)721 (1.19)<0.001442 (0.79)207 (0.74)235 (0.84)0.20
ATE/PE98 (0.09)32 (0.07)66 (0.11)0.1049 (0.09)29 (0.10)20 (0.07)0.25

Data are presented as number (%).

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism.

*p-values were determined using the chi-square test or Fisher exact test.

4. Factors associated with 14-day CCV adverse events following surveillance EGD

Multivariate analysis of unmatched data revealed that men (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.23 to 1.47; p<0.001), old age (≥65 years) (OR, 1.87; 95% CI, 1.69 to 2.07; p<0.001), advanced stage of GC (OR, 0.83; 95% CI, 0.73 to 0.95; p=0.02), insurance covered by medical benefit system (OR, 1.20; 95% CI, 1.03 to 1.40; p=0.02), inpatient based EGD (OR, 1.73; 95% CI, 1.54 to 1.94; p<0.001), chronic comorbid diseases (hypertension [OR, 1.88; 95% CI, 1.72 to 2.04; p<0.001], diabetes mellitus [OR, 1.10; 95% CI, 1.00 to 1.20; p=0.04], valvular heart disease [OR, 2.15; 95% CI, 1.55 to 3.00; p<0.001], hyperlipidemia [OR, 1.30; 95% CI, 1.20 to 1.42; p<0.001]), and use of antiplatelet agents (OR, 7.20; 95% CI, 6.48 to 7.99; p<0.001) were independent factors for 14-day CCV adverse events following surveillance EGD in patients with GC (Table 4). Compared with non-use, the use of sedative agents was not associated with 14-day CCV adverse events after surveillance EGD in patients with GC (OR, 0.92; 95% CI, 0.84 to 1.02; p=0.11).

Table 4. Clinical Factors Associated with CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer

VariableCCV adverse eventsMultivariate analysis*
Control (n=100,805)Case (n=2,658)p-valueOR (95% CI)p-value
Sex<0.001
Female33,268 (33.0)682 (25.7)Reference
Male67,537 (67.0)1,976 (74.3)1.34 (1.23–1.47)<0.001
Age group<0.001
20–64 yr53,091 (52.7)736 (27.7)Reference
≥65 yr47,714 (47.3)1,922 (72.3)1.87 (1.69–2.07)<0.001
Stage of gastric cancer0.01
Early47,202 (46.8)1,315 (49.5)Reference
Advanced14,456 (14.3)324 (12.2)0.83 (0.73–0.95)0.02
Unspecified39,147 (38.8)1,019 (38.3)0.93 (0.86–1.02)0.65
Types of healthcare institution†<0.001
Tertiary hospital73,207 (72.6)1,712 (64.4)Reference
General hospital23,030 (22.9)800 (30.1)1.17 (1.07–1.28)0.26
Standard hospital1,316 (1.3)55 (2.1)1.15 (0.86–1.54)0.70
Private clinic3,252 (3.2)91 (3.4)1.09 (0.87–1.35)0.89
Types of insurance<0.001
National health insurance96,351 (95.6)2,434 (91.6)Reference
Medical benefit system4,454 (4.4)224 (8.4)1.20 (1.03–1.40)0.02
Routes of undergoing EGD<0.001
Outpatient92,597 (91.9)2,247 (84.5)Reference
Inpatient8,208 (8.1)411 (15.5)1.73 (1.54-1.94)<0.001
Types of chronic disease
Hypertension31,679 (31.4)1,532 (57.6)<0.0011.88 (1.72–2.04)<0.001
Diabetes mellitus19,831 (19.7)852 (32.1)<0.0011.10 (1.00–1.20)0.04
Valvular heart disease446 (0.4)46 (1.7)<0.0012.15 (1.55–3.00)<0.001
Hyperlipidemia28,721 (28.5)1,137 (42.8)<0.0011.30 (1.20–1.42)<0.001
Chronic pulmonary disease23,812 (23.6)866 (32.6)<0.0011.08 (0.99–1.18)0.09
Renal disease1,957 (1.9)144 (5.4)<0.0011.07 (0.88–1.29)0.49
Connective tissue disorder1,549 (1.5)59 (2.2)0.011.04 (0.79–1.37)0.79
Liver disease2,796 (2.8)103 (3.9)<0.0011.05 (0.85–1.30)0.63
Cancer/metastatic cancer13,138 (13.0)449 (16.9)<0.0011.01 (0.91–1.13)0.84
Sedation during EGD<0.001
Non-sedation58,860 (58.4)1,917 (72.1)Reference
Sedation41,945 (41.6)741 (27.9)0.92 (0.84–1.02)0.11
Use of antiplatelet agents<0.001
No98,090 (97.3)2,004 (75.4)Reference
Yes2,715 (2.7)654 (24.6)7.20 (6.48–7.99)<0.001

Data are presented as number (%).

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval.

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, status of sedation, and use of antiplatelet agents; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals, mostly university hospitals, are more specialized in treating severe diseases than general hospitals.

5. Impact of types of sedative agents on CCV adverse events following surveillance EGD

We stratified the variables of sedation during surveillance EGD according to the sedative agent used. This multivariate analysis of unmatched data revealed that there was no association between the risk of CCV adverse events and type of sedative agent (midazolam [OR, 0.84; 95% CI, 0.75 to 0.95; p=0.94], propofol [OR, 1.03; 95% CI, 0.86 to 1.24; p=0.93], midazolam+propofol [OR, 1.04; 95% CI, 0.89 to 1.21; p=0.93], midazolam+lorazepam or diazepam [OR, 0.42; 95% CI, 0.06 to 3.06; p=0.97], propofol+lorazepam or diazepam [OR, <0.01; 95% CI, 0.00 to 999.99; p=0.93], midazolam+propofol+lorazepam or diazepam [OR, 1.47; 95% CI, 0.44 to 5.00; p=0.91]) (Supplementary Table 10). Subsequently, we assessed the impact of each sedative agent on adverse cardiac events, stroke/TIA, and ATE/PE after surveillance EGD in patients with GC (Table 5). On multivariate analyses of unmatched data, compared to non-use of sedative agents, the type of sedative agent during surveillance EGD was not significantly associated with cardiac adverse events, stroke/TIA, and ATE/PE.

Table 5. Clinical factors Associated with CCV Adverse Events, Cardiac Adverse Events, Stroke/TIA, and ATE/PE within 14 Days of Surveillance EGD in Patients with Gastric Cancer According to the Type of Sedative Agent

VariableMultivariate analysis*
(cardiac adverse events)		Multivariate analysis*
(stroke/TIA)		Multivariate analysis*
(ATE/PE)
OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-value
Age group
20–64 yrReference-Reference-Reference-
≥65 yr1.58 (1.40–1.80)<0.0012.32 (1.96–2.76)<0.0012.74 (1.62–4.65)<0.001
Sedation during EGD
Non-sedationReference-Reference-Reference-
Midazolam alone0.88 (0.76–1.03)0.930.77 (0.62–0.94)0.950.97 (0.53–1.77)0.93
Propofol alone0.99 (0.79–1.26)0.940.99 (0.74–1.35)0.941.89 (0.91–3.94)0.92
Midazolam+propofol1.08 (0.89–1.31)0.930.96 (0.73–1.25)0.951.08 (0.50–2.36)0.93
Midazolam+lorazepam or diazepam0.74 (0.10–5.40)0.940.00 (0.00–999.99)0.950.00 (0.00–999.99)0.97
Propofol+lorazepam or diazepam0.00 (0.00–999.99)0.970.00 (0.00–999.99)0.970.00 (0.00–999.99)0.98
Midazolam+propofol+lorazepam or diazepam0.00 (0.00–999.99)0.955.32 (1.56–18.20)0.910.00 (0.00–999.99)0.97

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval.

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, type of sedative agent, and use of antiplatelet agents.

DISCUSSION

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This population-based matched cohort study using the HIRA database showed that the incidence rate of 14-day CCV adverse events after surveillance EGD was 256.9/10,000 patients with GC. EGD under sedation had lower incidence rates of CCV adverse events, major CCV, cardiac adverse events, stroke/TIA, and ATE/PE than EGD without sedation in patients with GC. Regardless of the type of sedative agent used, sedation during EGD was not associated with an increase in 14-day CCV adverse events following EGD in patients with GC.

In a previous study on a claim-based cohort in South Korea, the proportion of EGD under sedation was 24.8% of the average-risk population aged 40 to 99 years, and the incidence rate of 14-day CCV adverse events after diagnostic EGD was 282.5/10,000.9 The previous study showed that sedation during diagnostic endoscopy including colonoscopy was an independent risk factor for CCV adverse events (OR, 1.12; 95% CI, 1.09 to 1.14; p<0.001), but the OR was relatively low. Sedation during only diagnostic EGD had little effect on CCV adverse events in both younger (20 to 64 years) and older (70 to 99 years) patients. As a major limitation of claim-based studies for the general population, the previous study was not able to identify the data for the use of propofol alone. However, in the current study, the use of propofol was covered by a special insurance system called the copayment-decreasing policy. Thus, we could identify that sedative agents were used in 41.3% of GC patients during surveillance EGD using the HIRA database. By obtaining an accurate history of sedative use, we demonstrated that sedation during EGD did not affect the development of CCV adverse events in patients with GC, regardless of the sedative agent used.

For patients diagnosed with GC, there are few international recommendations for the regimen, interval, or duration of follow-up. Patients with GC have a risk of metachronous GC of about 3% to 4% per year in the remnant stomach.19,20 Therefore, surveillance EGD is necessary to monitor the recurrence of GC. However, it is extremely difficult to establish any recommendation on how often EGD should be performed uniformly for patients with GC because the risk of recurrence, stages of cancer, and treatment regimens are different. Surveillance EGD after endoscopic therapy for early GC was recommended at least annually in the Korean guidelines and annually or biannually in the Japanese guidelines.5,6 National Comprehensive Cancer Network guidelines recommend the interval of surveillance EGD after R0 resection for GC as every 3 to 6 months for the first 3 years and every 6 months for 3 to 5 years.21 European Society for Medical Oncology suggested symptom-based follow-up for most cases because randomized studies evaluating follow-up strategies are lacking.4 In this study, surveillance EGD was performed at least once a year in most GC patients.

Regarding quality assurance of EGD, sedation during EGD might improve patient tolerance and enhance the detection rate of GC.22,23 Therefore, sedation is used for EGD in more than 90% of patients in the United States and more than half the patients in European and Asian countries.11,24,25 Meanwhile, there is some concern that sedation during EGD may contribute to the development of CCV adverse events.26 Several studies reported that sedation may lead to development of cardiovascular adverse events ranging from transient hypoxia to severe cardiorespiratory adverse events and death.27,28 However, other studies have shown that sedation during EGD may relieve patients’ anxiety or discomfort and have a positive effect on the stabilization of blood pressure and heart rate.29,30 Our study on patients with GC showed that EGD under sedation had lower incidence rates of overall CCV adverse events than that with EGD without sedation. This can be explained as follows. Regardless of sedation, insertion of the EGD scope itself could cause stressful conditions and hypoxia by narrowing the upper airway,31,32 and result in cardiopulmonary changes such as tachycardia, hypertension, and arrhythmias.10,12,33 Therefore, the use of sedative agents may be effective in reducing the stress response rather than causing additional harm to the cardiovascular system.

Regarding benefits and risks for undergoing EGD, the upper age limit remains debatable.18,34-38 Some previous studies proved the efficacy and safety of endoscopy; thus, advanced age is not a reason to refrain from performing endoscopy.36,38,39 However, other studies have shown that adverse events are inevitable during EGD with increasing age.18,40 The effect of EGD on the heart and circulatory system was studied by Ross and Newton41 using continuous noninvasive monitoring. They showed that blood pressure is increased in the later part of endoscopy and sustained for a long time in the elderly, thus increasing risk to the circulatory system. Consistent with the previous study, our results showed that older age (≥65 years) is a significant risk factor for CCV adverse events after surveillance EGD, compared with patients aged 40 to 69 years. Therefore, comorbidities or performance status must be considered, particularly in elderly patients with GC.

Chronic underlying diseases, such as hypertension, hyperlipidemia, and valvular heart disease are well-known risk factors for the development of CCV adverse events. Hypertensives might develop cardiovascular diseases 5 years earlier than those without hypertension.42 In a study using Framingham Offspring Cohort data, prolonged hyperlipidemia in early adulthood increases the risk of coronary heart disease in a dose-responsive fashion.43 Valvular heart disease could contribute to arrhythmia and major cardiac adverse events.44,45 In accordance with previous studies, the present study demonstrated that valvular heart disease is associated with a markedly high risk of CCV adverse events after surveillance EGD in patients with GC. In addition, we investigated whether the use of antiplatelet agents, including aspirin, could predispose patients to CCV adverse events. Although we could not accurately identify whether antiplatelet agents were discontinued before EGD through the HIRA database, guidelines from South Korea do not recommend discontinuation of antiplatelet agents before low-risk endoscopy such as surveillance EGD.46 Our findings showed that the use of antiplatelet agents is associated with a higher occurrence of CCV adverse events. This finding indicates that GC patients on antiplatelet therapy are more susceptible to CCV adverse events following surveillance EGD. These results may help inform patients and clinicians in examining different regimens and modalities for follow-up of GC.

This study had several limitations. First, it focused on patients with GC, not the general population. Second, sedative agents used for surveillance EGD are mostly administered by endoscopists in South Korea. Anesthesiologists administer sedative agents for surveillance EGD in special situations requiring deep sedation or close monitoring. However, such cases are rare and were not identified in the present study. Third, the HIRA database was generated for healthcare service reimbursement and was not designed for research purposes. Therefore, the data may not be consistent with actual diagnoses and do not include laboratory tests or imaging examinations. In the HIRA database, patients with GC were classified as having early GC, advanced GC, and unspecified GC. This classification may not accurately reflect the actual stage of GC. The proportion of patients with unspecified stages of GC was approximately 40%. Fourth, GC patients with severe comorbidities could have selectively undergone EGD without sedation according to the patients’ or clinicians’ own choice, resulting in selection bias. Moreover, CCV adverse events after surveillance EGD are rare. Therefore, we used propensity score matching to reduce bias. Fifth, the reasons for using antiplatelet agents in patients without a history of CCV diseases were not identified in this study. Sixth, we could not analyze the follow-up outcomes, such as mortality, of the patients who underwent 14-day CCD adverse events after surveillance EGD. Lastly, the HIRA database contains no information about the depth of sedation or sedation policy for each healthcare institution.

In conclusion, sedation during surveillance EGDs did not appear to increase CCV adverse events following EGD in patients with GC. These findings suggest that sedative agents can be safely used during surveillance EGDs in patients with GC without undue concern for CCV adverse events.

ACKNOWLEDGEMENTS

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This study was supported by a grant from the Korean Gastrointestinal Endoscopy Research Foundation 2020 Investigation Grant.

This study used the Health Insurance Review and Assessment Service (HIRA) databases (Study Number: M20220221837). The authors thank the Korean HIRA for providing the insurance claims data. The authors deeply thank Hui Seung Lee for the analysis of the data.

CONFLICTS OF INTEREST

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B.W.K. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS

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Study concept and design: S.Y.K., J.K.L. Data acquisition: S.Y.K., J.K.L. Data analysis and interpretation: S.Y.K., J.K.L., K.H.L., J.Y.J., B.W.K. Drafting of the manuscript: S.Y.K. Critical revision of the manuscript for important intellectual content: J.K.L., K.H.L., J.Y.J., B.W.K. Statistical analysis: S.Y.K., J.K.L. Obtained funding: J.K.L. Administrative, technical, or material support; study supervision: J.K.L., K.H.L., J.Y.J., B.W.K. Approval of final manuscript: all authors.

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Article

Original Article

Gut and Liver 2024; 18(2): 245-256

Published online March 15, 2024 https://doi.org/10.5009/gnl230043

Copyright © Gut and Liver.

The Impact of Sedation on Cardio-Cerebrovascular Adverse Events after Surveillance Esophagogastroduodenoscopy in Patients with Gastric Cancer: A Nationwide Population-Based Cohort Study

Sang Yoon Kim1 , Jun Kyu Lee2 , Kwang Hyuck Lee3 , Jae-Young Jang4 , Byung-Wook Kim5 , Endoscopic Sedation Committee of Korean Society of Gastrointestinal Endoscopy (KSGE)

1Department of Internal Medicine, Myongji Hospital, Hanyang University College of Medicine, Goyang, Korea; 2Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea; 3Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Korea; 5Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea

Correspondence to:Jun Kyu Lee
ORCID https://orcid.org/0000-0002-2694-3598
E-mail jeromee1971@daum.net

Received: February 8, 2023; Revised: April 12, 2023; Accepted: April 19, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: The impact of sedation on cardio-cerebrovascular (CCV) adverse events after esophagogastroduodenoscopy (EGD) in patients with gastric cancer (GC) is unclear. We investigated the incidence rate and impact of sedation on CCV adverse events after surveillance EGD in patients with GC.
Methods: We performed a nationwide population-based cohort study using the Health Insurance Review and Assessment Service databases from January 1, 2018, to December 31, 2020. Using a propensity score-matched analysis, patients with GC were divided into two groups: sedative agent users and nonusers for surveillance EGD. We compared the occurrence of CCV adverse events within 14 days between the two groups.
Results: Of the 103,463 patients with GC, newly diagnosed CCV adverse events occurred in 2.57% of patients within 14 days after surveillance EGD. Sedative agents were used in 41.3% of the patients during EGD. The incidence rates of CCV adverse events with and without sedation were 173.6/10,000 and 315.4/10,000, respectively. Between sedative agent users and nonusers based on propensity score matching (28,008 pairs), there were no significant differences in the occurrence of 14-day CCV, cardiac, cerebral, and other vascular adverse events (2.28% vs 2.22%, p=0.69; 1.44% vs 1.31%, p=0.23; 0.74% vs 0.84%, p=0.20; 0.10% vs 0.07%, p=0.25, respectively).
Conclusions: Sedation during surveillance EGD was not associated with CCV adverse events in patients with GC. Therefore, the use of sedative agents may be considered in patients with GC during surveillance EGD without excessive concerns about CCV adverse events.

Keywords: Adverse events, Stomach neoplasms, Esophagogastroduodenoscopy, Sedatives

INTRODUCTION

Survival rates of patients with gastric cancer (GC) have improved with early detection and advances in treatment, but prognosis remains poor.1 Recurrence is an important concern even in GC patients undergoing curative therapy.2 Several guidelines from the National Comprehensive Cancer Network, European Society for Medical Oncology, Japanese Gastric Cancer Association, and Korean Gastric Cancer Association recommend regular follow-up examinations such as blood tests, abdominal computed tomography, and esophagogastroduodenoscopy (EGD) for GC. However, there is no consensus on the strategy of surveillance.3-6 Among the follow-up examinations, EGD is considered to enable early detection of recurrent GC, which often appears as subtle mucosal changes.7 Therefore, surveillance EGD at regular intervals is recommended by clinicians for patients with GC. Although surveillance EGD is generally regarded as safe, EGD itself or the use of sedative agents during EGD has some potential to cause adverse events.8-10 Particularly, cardio-cerebrovascular (CCV) adverse events following EGD may be responsible for a majority of the mortality. In a nationwide survey study in the United States, the risk of cardiac adverse events was one of the main considerations for clinicians in deciding whether to use sedative agents during EGD.11 Several studies have reported CCV adverse events following diagnostic EGD in the average-risk population.8,9,12,13 However, data on CCV adverse events following surveillance EGD in patients with GC have not been reported. Therefore, we aimed to investigate the incidence of CCV adverse events, including cardiac and cerebral adverse events, arterial thromboembolism (ATE), and pulmonary embolism (PE), after surveillance EGD with or without sedation in patients with GC. Additionally, we evaluated the impact of sedation during EGD on CCV adverse events in GC patients using the Health Insurance Review and Assessment Service (HIRA) database.

MATERIALS AND METHODS

1. Data source and study population

Almost all Koreans (98%) are mandatorily enrolled in the National Health Insurance Service, which is the only insurer in South Korea.14 The HIRA database in South Korea was created for the process of reimbursing claims for healthcare services under the National Health Insurance Service.15 This database contains the claim records of examinations, procedures, and prescriptions as well as the socio-demographic information of all insured Koreans. From 2013, the government of South Korea has implemented an expansion policy of health insurance, called the copayment decreasing policy, to reduce the high medical expenditure of the four major serious diseases (cancer, cardiac disease, cerebrovascular disease, and rare incurable disease). From February 2017, patients with these diseases can receive expanded insurance coverage for the use of any sedative agent, including propofol, during endoscopy and monitoring fees for sedated endoscopy, which are not covered by insurance for the general population. Therefore, a study using the HIRA data for patients with GC, one of the four major serious diseases, can reflect accurate information on the sedative agents used during endoscopy and allow us to perform a nationwide population-based study.

The study population comprised 126,507 individuals aged 20 to 99 years who had been diagnosed with GC and had been granted a copayment decreasing policy for cancer (V193 code) from January 1, 2018, to December 31, 2018 (Supplementary Table 1). In this study, the HIRA database was used to identify whether sedation was used during EGD and the detailed types of sedative agents used in patients with GC. Sedated endoscopy was defined as the prescription of a patient’s monitoring fee for sedated endoscopy (EA002 code) and the intravenous administration of sedative agents, such as midazolam, propofol, lorazepam, or diazepam, according to the Korea Pharmaceutical Information Service on the same day as the EGD (Supplementary Table 2).

We set the 12 months before surveillance EGD as a washout period to minimize the confounding effects of previously diagnosed CCV adverse events. Diagnoses were coded according to the International Classification of Diseases, 10th Revision.15,16 The codes and descriptions of CCV adverse events are presented in Supplementary Table 3. The exclusion criteria were (1) patients with GC who did not undergo surveillance EGD after the diagnosis of GC (n=4,204) and underwent only therapeutic endoscopy (n=899) (Fig. 1). The codes and descriptions of gastrointestinal endoscopy are presented in Supplementary Table 4, and (2) previous diagnosis of or treatment for CCV diseases within 12 months before surveillance EGD in patients with GC (n=17,941) (Fig. 1). Patients with GC for whom anticoagulant agents and thrombolytics were prescribed (including oral administration for more than 30 days, subcutaneous injection for more than 5 days, and intravenous administration more than once) were also considered as previously diagnosed CCV patients. Drug codes of anticoagulant agents and thrombolytics were retrieved from the Korea Pharmaceutical Information Service (Supplementary Table 5).17

Figure 1. Flow diagram of the study population.
HIRA, Health Insurance Review and Assessment Service; EGD, esophagogastroduodenoscopy; CCV, cardio-cerebrovascular; MI, myocardial infarction; IHD, ischemic heart disease; TIA, transient ischemic attack; ATE, arterial thromboembolism.

A total of 103,463 eligible patients with GC were included in this study. Using propensity score-matched analysis, patients with GC were divided into two groups: those who received sedative agents for surveillance EGD (sedation group) and those who did not (non-sedation group). We defined chronic underlying diseases based on the International Classification of Diseases, 10th Revision codes for hypertension, diabetes mellitus, valvular heart disease, hyperlipidemia, chronic pulmonary disease, renal disease, connective tissue disorder, liver disease, and cancer/metastatic cancer (Supplementary Table 6). We classified the use of antiplatelet agents as present or absent for >30 days before EGD (Supplementary Table 7). This study was approved by the Institutional Review Board of Dongguk University Ilsan Hospital (IRB number: DUIH 2022-02-001). Written informed consent was waived.

2. Clinical outcomes

The primary outcome of this study was newly diagnosed CCV adverse events after surveillance EGD in patients with GC. Newly diagnosed CCV adverse events was defined as hospitalization with a CCV at least once or as an outpatient clinic or emergency room visit with a CCV adverse events at least twice from the same day (Day 0) to 14 days after surveillance EGD.9 These CCV adverse events were categorized as cardiac adverse events (angina, cardiac dysrhythmia, hypertensive heart disease, acute myocardial infarction, hypotension, acute ischemic heart disease, or cardiac arrest), stroke/transient ischemic attack (TIA) (ischemic stroke, hemorrhagic stroke, or TIA), and ATE/PE (ATE or PE) (Supplementary Table 3). According to a previous systematic review and meta-analysis, we stratified CCV adverse events into major and minor CCV adverse events based on their severity.18 Major CCV adverse events were defined as acute myocardial infarction, cardiac arrest, ischemic stroke, hemorrhagic stroke, ATE, and PE. Minor CCV adverse events were defined as angina, cardiac dysrhythmia, hypertensive heart disease, hypotension, acute ischemic heart disease, and TIA. We investigated the overall incidence and percentage of CCV adverse events and of those occurring within 0–3, 4–7, and 8–14 days after endoscopic surveillance. If CCV adverse events occurred multiple times within 14 days of surveillance EGD, only the first CCV adverse event was included in the analysis. The control group comprised patients without CCV adverse events within 14 days of surveillance EGD. In case of multiple EGDs per patient in the control group, one of the EGDs was randomly selected and included in the analysis. The secondary outcome of this study was whether the use of sedative agents for surveillance EGD was associated with the occurrence of CCV adverse events in patients with GC.

3. Statistical analysis

Categorical data were described using numbers with percentages and compared using the chi-square test or Fisher exact test, as appropriate. Descriptive statistics for continuous variables are summarized as means with standard deviation. The incidence rate of CCV adverse events was calculated as the number of incident cases divided by 10,000. For propensity score matching, a 1:1 matching process without replacements was performed using a greedy algorithm with 0.05 caliper (0.25 multiplied by the standard deviation of the logit of the propensity score), yielding 28,008 subjects in the non-sedation group and 28,008 matched subjects in the sedation group. Propensity scores were created to control for known clinically relevant factors and were calculated using age group, sex, type of healthcare institution, type of insurance, route of EGD, types of chronic disease, stage of GC, and use of antiplatelet agents. Absolute standardized mean differences were estimated for all baseline covariates before and after matching to assess imbalance before matching and balance after matching. An absolute standardized mean difference of less than 0.1 for a given covariate indicated a relatively small imbalance. This category was used to create propensity scores. Outcomes were compared between groups based on propensity score matching. In the univariate analyses, continuous variables were analyzed using the Student t-test, and categorical variables were analyzed using the chi-square test. Variables with a p<0.05 in univariate analysis were selected for multivariate logistic regression analyses to evaluate independent risk factors for CCV adverse events. A p-value of <0.05 was considered significant. Analyses were performed using the SAS software (version 9.4; SAS Institute Inc., Cary, NC, USA).

RESULTS

1. Baseline characteristics of the study population

Of the 103,463 patients with GC, sedative agent users and nonusers consisted of 42,686 (41.3%) and 60,777 patients (58.7%), respectively. For sedation during EGD, midazolam, propofol, midazolam+propofol, midazolam+lorazepam/diazepam, propofol+lorazepam/diazepam, or midazolam+propofol+lorazepam/diazepam were used. The proportion of sedative agents used is shown in Fig. 2. Men comprised 64.0% of sedative agent users and 69.4% of nonusers (p<0.001). The mean ages of the sedative agent users and nonusers were 57.2±8.4 and 68.7±10.8 years old, respectively (p<0.001). Proportions of old age (≥65 years), chronic disease, advanced stage of GC, and use of antiplatelet agents were significantly higher in the non-sedation group. Meanwhile, the proportion of EGD performed in tertiary hospitals was significantly higher in the sedation group. Using propensity score matching, 28,008 pairs of sedative agent users and nonusers were analyzed. The baseline characteristics of the study participants before and after propensity score matching are shown in Table 1.

Figure 2. Use of sedative agents during surveillance esophagogastroduodenoscopy in patients with gastric cancer.

Table 1 . Baseline Characteristics of the Study Population.

CharacteristicUnmatchedPropensity score-matched (1:1)
Total
(n=103,463)		Sedative agentsp-value*ASMDTotal
(n=56,016)		Sedative agentsASMD
Users (n=42,686)Nonusers (n=60,777)Users (n=28,008)Nonusers (n=28,008)
Sex, No. (%)<0.0010.120.10
Male69,513 (67.2)27,308 (64.0)42,205 (69.4)17,433 (31.1)9,045 (32.3)8,388 (29.95)
Female33,950 (32.8)15,378 (36.0)18,572 (30.6)38,583 (68.8)18,963 (67.7)19,620 (70.05)
Age, mean±SD, yr63.6±11.257.2±8.468.1±10.8<0.0011.1360.4±9.759.3±8.061.6±11.11.13
Age group, No. (%)<0.0011.031.03
20–64 yr53,827 (52.0)33,631 (78.8)20,196 (33.2)37,984 (67.8)18,953 (67.7)19,031 (68.0)
≥65 yr49,636 (48.0)9,055 (21.2)40,581 (66.8)18,032 (32.2)9,055 (32.3)8,977 (32.1)
Types of healthcare institution, No. (%)†<0.0010.290.29
Tertiary hospital74,919 (72.4)32,996 (77.3)41,923 (69.0)42,100 (75.2)21,270 (75.9)20,830 (74.4)
General hospital23,830 (23.0)9,062 (21.2)14,768 (24.3)12,567 (22.4)6,111 (21.8)6,456 (23.1)
Standard hospital1,371 (1.3)304 (0.7)1,067 (1.8)621 (1.1)303 (1.1)318 (1.1)
Private clinic3,343 (3.2)324 (0.8)3,019 (5.0)728 (1.3)324 (1.2)404 (1.4)
Types of insurance, No. (%)<0.0010.090.08
National health insurance98,785 (95.5)41,202 (96.5)57,583 (94.7)53,691 (95.8)26,874 (96.0)26,817 (95.8)
Medical benefit system4,678 (4.6)1,484 (3.5)3,194 (5.3)2,325 (4.2)1,134 (4.1)1,191 (4.2)
Routes of undergoing EGD, No. (%)0.95<0.0010.01
Outpatient94,844 (91.7)39,133 (91.7)55,711 (91.7)50,778 (90.7)24,888 (88.9)25,890 (92.4)
Inpatient8,619 (8.3)3,553 (8.3)5,066 (8.3)5,238 (9.3)3,120 (11.1)2,118 (7.6)
Types of chronic disease, No. (%)
Hypertension33,211 (32.1)10,670 (25.0)22,541 (37.1)<0.0010.2617,668 (31.5)9,875 (35.3)7,793 (27.9)0.26
Diabetes mellitus20,683 (20.0)7,060 (16.5)13,623 (22.4)<0.0010.1511,235 (20.1)6,271 (22.4)4,964 (17.7)0.16
Valvular disease492 (0.5)102 (0.2)390 (0.6)<0.0010.06181 (0.3)96 (0.3)85 (0.3)0.06
Hyperlipidemia29,858 (28.9)11,833 (27.7)18,025 (29.7)<0.0010.0417,491 (31.2)9,983 (35.6)7,508 (26.8)0.05
Chronic pulmonary disease24,678 (23.9)8,897 (20.8)15,781 (26.0)<0.0010.1214,462 (25.8)8,482 (30.3)5,980 (21.4)0.12
Renal disease2,101 (2.0)535 (1.3)1,566 (2.6)<0.0010.10898 (1.6)486 (1.7)412 (1.5)0.09
Connective tissue disorder1,608 (1.6)613 (1.4)995 (1.6)0.010.02922 (1.7)538 (1.9)384 (1.4)0.01
Liver disease2,899 (2.8)1,157 (2.7)1,742 (2.9)0.140.011,788 (3.2)1,039 (3.7)749 (2.7)0.007
Cancer/metastatic cancer13,587 (13.1)5,211 (12.2)8,376 (13.8)<0.0010.057,830 (14.0)4,571 (16.3)3,259 (11.6)0.05
Stage of gastric cancer, No. (%)0.010.020.02
Early48,517 (46.9)20,172 (47.3)28,345 (46.6)25,446 (45.4)12,706 (45.4)12,740 (45.5)
Advanced14,780 (14.3)5,928 (13.9)8,852 (14.6)8,560 (15.3)4,430 (15.8)4,130 (14.8)
Unspecified40,166 (38.8)16,586 (38.9)23,580 (38.8)22,010 (39.3)10,872 (38.8)11,138 (39.8)
Use of antiplatelet agents, No. (%)<0.0010.120.11
No100,094 (96.7)41,805 (97.9)58,289 (95.9)54,540 (97.4)27,235 (97.2)27,305 (97.5)
Yes3,369 (3.3)881 (2.1)2,488 (4.1)1,476 (2.6)773 (2.8)703 (2.5)

ASMD, absolute standardized mean differences; EGD, esophagogastroduodenoscopy..

*p-values for differences were determined using the chi-square or Wilcoxon rank sum test for unmatched data; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals are more specialized in treating severe diseases than general hospitals, mostly university hospitals..

2. Incidence rates of CCV adverse events

Among the study subjects, 2,658 patients (2.57%) experienced CCV adverse events within 14 days of surveillance EGD (Table 2). Major CCV adverse events occurred in 1,055 patients (1.02%), cardiac adverse events in 1,597 (1.54%), stroke/TIA in 963 (0.93%), and ATE/PE in 98 (0.09%). The incidence rate of CCV adverse events (per 10,000 persons) within 14 days was 315.4 for surveillance EGD without sedation and 173.6 for surveillance EGD with sedation (Table 2). According to the period after surveillance EGD, CCV adverse events within 14 days were subcategorized as occurring within 0–3, 4–7, and 8–14 days. The incidence rates of all types of CCV adverse events (overall CCV, major CCV, minor CCV, cardiac, stroke/TIA, and ATE/PE) in both EGD with sedation and EGD without sedation groups were the highest within 0 to 3 days of surveillance EGD in patients with GC (Supplementary Tables 8 and 9).

Table 2 . CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer.

Overall CCVMajor CCV*Cardiac adverse eventStroke/TIAATE/PE
Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons
Total adverse events within 14 days2,658 (2.57)256.91,055 (1.02)102.01,597 (1.54)154.3963 (0.93)93.198 (0.09)9.5
Without sedation1,917 (3.15)315.4778 (1.28)128.01,130 (1.86)186.0721 (1.19)118.666 (0.11)10.8
With sedation741 (1.74)173.6277 (0.65)64.9467 (1.09)109.4242 (0.57)56.732 (0.07)7.5
Midazolam387 (1.53)152.9138 (0.55)54.5249 (0.98)98.4123 (0.49)48.615 (0.06)5.9
Propofol143 (2.01)201.457 (0.80)80.285 (1.20)119.749 (0.69)69.09 (0.13)12.7
Midazolam+ propofol206 (2.04)204.478 (0.77)77.4132 (1.31)131.066 (0.65)65.58 (0.08)7.9
Midazolam+lorazepam or diazepam2 (2.15)215.11 (1.08)107.51 (1.08)107.51 (1.08)107.500.0
Propofol+lorazepam or diazepam00.000.000.000.000.0
Midazolam+propofol+lorazepam or diazepam3 (4.76)476.23 (4.76)476.200.03 (4.76)476.200.0

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism..

*Major CCV adverse events were defined as acute myocardial infarction, cardiac arrest, ischemic stroke, hemorrhagic stroke, ATE, or PE..

3. Propensity score-matched analysis: 14-day CCV adverse events according to presence or absence of sedation

In the propensity score-matched cohorts, CCV adverse events occurred in 1,261 patients with GC (2.25%). There were 770 (1.37%) cardiac adverse events, 442 (0.79%) stroke/TIA, and 49 (0.09%) ATE/PE (Table 3). There were no significant differences in the occurrence of overall CCV adverse events between the sedation and non-sedation groups (2.28% vs 2.22%, p=0.69). In addition, cardiac adverse events (1.44% vs 1.31%, p=0.23), stroke/TIA (0.74% vs 0.84%, p=0.20), and ATE/PE (0.10% vs 0.07%, p=0.25) were not significantly different between the sedation and non-sedation groups.

Table 3 . Outcomes of CCV Adverse Events in the Unmatched and Propensity Score-Matched Groups.

Unmatched patientsPropensity score-matched (1:1) patients
Total
(n=103,463)		Received sedative
agents (n=42,686)		Did not receive sedative agents (n=60,777)p-value*Total
(n=56,016)		Received sedative
agents (n=28,008)		Did not receive sedative agents (n=28,008)p-value*
CCV adverse events2,658 (2.57)741 (1.74)1,917 (3.15)<0.0011,261 (2.25)638 (2.28)623 (2.22)0.69
Cardiac adverse events1,597 (1.54)467 (1.09)1,130 (1.86)<0.001770 (1.37)402 (1.44)368 (1.31)0.23
Stroke/TIA963 (0.93)242 (0.57)721 (1.19)<0.001442 (0.79)207 (0.74)235 (0.84)0.20
ATE/PE98 (0.09)32 (0.07)66 (0.11)0.1049 (0.09)29 (0.10)20 (0.07)0.25

Data are presented as number (%)..

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism..

*p-values were determined using the chi-square test or Fisher exact test..

4. Factors associated with 14-day CCV adverse events following surveillance EGD

Multivariate analysis of unmatched data revealed that men (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.23 to 1.47; p<0.001), old age (≥65 years) (OR, 1.87; 95% CI, 1.69 to 2.07; p<0.001), advanced stage of GC (OR, 0.83; 95% CI, 0.73 to 0.95; p=0.02), insurance covered by medical benefit system (OR, 1.20; 95% CI, 1.03 to 1.40; p=0.02), inpatient based EGD (OR, 1.73; 95% CI, 1.54 to 1.94; p<0.001), chronic comorbid diseases (hypertension [OR, 1.88; 95% CI, 1.72 to 2.04; p<0.001], diabetes mellitus [OR, 1.10; 95% CI, 1.00 to 1.20; p=0.04], valvular heart disease [OR, 2.15; 95% CI, 1.55 to 3.00; p<0.001], hyperlipidemia [OR, 1.30; 95% CI, 1.20 to 1.42; p<0.001]), and use of antiplatelet agents (OR, 7.20; 95% CI, 6.48 to 7.99; p<0.001) were independent factors for 14-day CCV adverse events following surveillance EGD in patients with GC (Table 4). Compared with non-use, the use of sedative agents was not associated with 14-day CCV adverse events after surveillance EGD in patients with GC (OR, 0.92; 95% CI, 0.84 to 1.02; p=0.11).

Table 4 . Clinical Factors Associated with CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer.

VariableCCV adverse eventsMultivariate analysis*
Control (n=100,805)Case (n=2,658)p-valueOR (95% CI)p-value
Sex<0.001
Female33,268 (33.0)682 (25.7)Reference
Male67,537 (67.0)1,976 (74.3)1.34 (1.23–1.47)<0.001
Age group<0.001
20–64 yr53,091 (52.7)736 (27.7)Reference
≥65 yr47,714 (47.3)1,922 (72.3)1.87 (1.69–2.07)<0.001
Stage of gastric cancer0.01
Early47,202 (46.8)1,315 (49.5)Reference
Advanced14,456 (14.3)324 (12.2)0.83 (0.73–0.95)0.02
Unspecified39,147 (38.8)1,019 (38.3)0.93 (0.86–1.02)0.65
Types of healthcare institution†<0.001
Tertiary hospital73,207 (72.6)1,712 (64.4)Reference
General hospital23,030 (22.9)800 (30.1)1.17 (1.07–1.28)0.26
Standard hospital1,316 (1.3)55 (2.1)1.15 (0.86–1.54)0.70
Private clinic3,252 (3.2)91 (3.4)1.09 (0.87–1.35)0.89
Types of insurance<0.001
National health insurance96,351 (95.6)2,434 (91.6)Reference
Medical benefit system4,454 (4.4)224 (8.4)1.20 (1.03–1.40)0.02
Routes of undergoing EGD<0.001
Outpatient92,597 (91.9)2,247 (84.5)Reference
Inpatient8,208 (8.1)411 (15.5)1.73 (1.54-1.94)<0.001
Types of chronic disease
Hypertension31,679 (31.4)1,532 (57.6)<0.0011.88 (1.72–2.04)<0.001
Diabetes mellitus19,831 (19.7)852 (32.1)<0.0011.10 (1.00–1.20)0.04
Valvular heart disease446 (0.4)46 (1.7)<0.0012.15 (1.55–3.00)<0.001
Hyperlipidemia28,721 (28.5)1,137 (42.8)<0.0011.30 (1.20–1.42)<0.001
Chronic pulmonary disease23,812 (23.6)866 (32.6)<0.0011.08 (0.99–1.18)0.09
Renal disease1,957 (1.9)144 (5.4)<0.0011.07 (0.88–1.29)0.49
Connective tissue disorder1,549 (1.5)59 (2.2)0.011.04 (0.79–1.37)0.79
Liver disease2,796 (2.8)103 (3.9)<0.0011.05 (0.85–1.30)0.63
Cancer/metastatic cancer13,138 (13.0)449 (16.9)<0.0011.01 (0.91–1.13)0.84
Sedation during EGD<0.001
Non-sedation58,860 (58.4)1,917 (72.1)Reference
Sedation41,945 (41.6)741 (27.9)0.92 (0.84–1.02)0.11
Use of antiplatelet agents<0.001
No98,090 (97.3)2,004 (75.4)Reference
Yes2,715 (2.7)654 (24.6)7.20 (6.48–7.99)<0.001

Data are presented as number (%)..

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval..

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, status of sedation, and use of antiplatelet agents; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals, mostly university hospitals, are more specialized in treating severe diseases than general hospitals..

5. Impact of types of sedative agents on CCV adverse events following surveillance EGD

We stratified the variables of sedation during surveillance EGD according to the sedative agent used. This multivariate analysis of unmatched data revealed that there was no association between the risk of CCV adverse events and type of sedative agent (midazolam [OR, 0.84; 95% CI, 0.75 to 0.95; p=0.94], propofol [OR, 1.03; 95% CI, 0.86 to 1.24; p=0.93], midazolam+propofol [OR, 1.04; 95% CI, 0.89 to 1.21; p=0.93], midazolam+lorazepam or diazepam [OR, 0.42; 95% CI, 0.06 to 3.06; p=0.97], propofol+lorazepam or diazepam [OR, <0.01; 95% CI, 0.00 to 999.99; p=0.93], midazolam+propofol+lorazepam or diazepam [OR, 1.47; 95% CI, 0.44 to 5.00; p=0.91]) (Supplementary Table 10). Subsequently, we assessed the impact of each sedative agent on adverse cardiac events, stroke/TIA, and ATE/PE after surveillance EGD in patients with GC (Table 5). On multivariate analyses of unmatched data, compared to non-use of sedative agents, the type of sedative agent during surveillance EGD was not significantly associated with cardiac adverse events, stroke/TIA, and ATE/PE.

Table 5 . Clinical factors Associated with CCV Adverse Events, Cardiac Adverse Events, Stroke/TIA, and ATE/PE within 14 Days of Surveillance EGD in Patients with Gastric Cancer According to the Type of Sedative Agent.

VariableMultivariate analysis*
(cardiac adverse events)		Multivariate analysis*
(stroke/TIA)		Multivariate analysis*
(ATE/PE)
OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-value
Age group
20–64 yrReference-Reference-Reference-
≥65 yr1.58 (1.40–1.80)<0.0012.32 (1.96–2.76)<0.0012.74 (1.62–4.65)<0.001
Sedation during EGD
Non-sedationReference-Reference-Reference-
Midazolam alone0.88 (0.76–1.03)0.930.77 (0.62–0.94)0.950.97 (0.53–1.77)0.93
Propofol alone0.99 (0.79–1.26)0.940.99 (0.74–1.35)0.941.89 (0.91–3.94)0.92
Midazolam+propofol1.08 (0.89–1.31)0.930.96 (0.73–1.25)0.951.08 (0.50–2.36)0.93
Midazolam+lorazepam or diazepam0.74 (0.10–5.40)0.940.00 (0.00–999.99)0.950.00 (0.00–999.99)0.97
Propofol+lorazepam or diazepam0.00 (0.00–999.99)0.970.00 (0.00–999.99)0.970.00 (0.00–999.99)0.98
Midazolam+propofol+lorazepam or diazepam0.00 (0.00–999.99)0.955.32 (1.56–18.20)0.910.00 (0.00–999.99)0.97

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval..

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, type of sedative agent, and use of antiplatelet agents..

DISCUSSION

This population-based matched cohort study using the HIRA database showed that the incidence rate of 14-day CCV adverse events after surveillance EGD was 256.9/10,000 patients with GC. EGD under sedation had lower incidence rates of CCV adverse events, major CCV, cardiac adverse events, stroke/TIA, and ATE/PE than EGD without sedation in patients with GC. Regardless of the type of sedative agent used, sedation during EGD was not associated with an increase in 14-day CCV adverse events following EGD in patients with GC.

In a previous study on a claim-based cohort in South Korea, the proportion of EGD under sedation was 24.8% of the average-risk population aged 40 to 99 years, and the incidence rate of 14-day CCV adverse events after diagnostic EGD was 282.5/10,000.9 The previous study showed that sedation during diagnostic endoscopy including colonoscopy was an independent risk factor for CCV adverse events (OR, 1.12; 95% CI, 1.09 to 1.14; p<0.001), but the OR was relatively low. Sedation during only diagnostic EGD had little effect on CCV adverse events in both younger (20 to 64 years) and older (70 to 99 years) patients. As a major limitation of claim-based studies for the general population, the previous study was not able to identify the data for the use of propofol alone. However, in the current study, the use of propofol was covered by a special insurance system called the copayment-decreasing policy. Thus, we could identify that sedative agents were used in 41.3% of GC patients during surveillance EGD using the HIRA database. By obtaining an accurate history of sedative use, we demonstrated that sedation during EGD did not affect the development of CCV adverse events in patients with GC, regardless of the sedative agent used.

For patients diagnosed with GC, there are few international recommendations for the regimen, interval, or duration of follow-up. Patients with GC have a risk of metachronous GC of about 3% to 4% per year in the remnant stomach.19,20 Therefore, surveillance EGD is necessary to monitor the recurrence of GC. However, it is extremely difficult to establish any recommendation on how often EGD should be performed uniformly for patients with GC because the risk of recurrence, stages of cancer, and treatment regimens are different. Surveillance EGD after endoscopic therapy for early GC was recommended at least annually in the Korean guidelines and annually or biannually in the Japanese guidelines.5,6 National Comprehensive Cancer Network guidelines recommend the interval of surveillance EGD after R0 resection for GC as every 3 to 6 months for the first 3 years and every 6 months for 3 to 5 years.21 European Society for Medical Oncology suggested symptom-based follow-up for most cases because randomized studies evaluating follow-up strategies are lacking.4 In this study, surveillance EGD was performed at least once a year in most GC patients.

Regarding quality assurance of EGD, sedation during EGD might improve patient tolerance and enhance the detection rate of GC.22,23 Therefore, sedation is used for EGD in more than 90% of patients in the United States and more than half the patients in European and Asian countries.11,24,25 Meanwhile, there is some concern that sedation during EGD may contribute to the development of CCV adverse events.26 Several studies reported that sedation may lead to development of cardiovascular adverse events ranging from transient hypoxia to severe cardiorespiratory adverse events and death.27,28 However, other studies have shown that sedation during EGD may relieve patients’ anxiety or discomfort and have a positive effect on the stabilization of blood pressure and heart rate.29,30 Our study on patients with GC showed that EGD under sedation had lower incidence rates of overall CCV adverse events than that with EGD without sedation. This can be explained as follows. Regardless of sedation, insertion of the EGD scope itself could cause stressful conditions and hypoxia by narrowing the upper airway,31,32 and result in cardiopulmonary changes such as tachycardia, hypertension, and arrhythmias.10,12,33 Therefore, the use of sedative agents may be effective in reducing the stress response rather than causing additional harm to the cardiovascular system.

Regarding benefits and risks for undergoing EGD, the upper age limit remains debatable.18,34-38 Some previous studies proved the efficacy and safety of endoscopy; thus, advanced age is not a reason to refrain from performing endoscopy.36,38,39 However, other studies have shown that adverse events are inevitable during EGD with increasing age.18,40 The effect of EGD on the heart and circulatory system was studied by Ross and Newton41 using continuous noninvasive monitoring. They showed that blood pressure is increased in the later part of endoscopy and sustained for a long time in the elderly, thus increasing risk to the circulatory system. Consistent with the previous study, our results showed that older age (≥65 years) is a significant risk factor for CCV adverse events after surveillance EGD, compared with patients aged 40 to 69 years. Therefore, comorbidities or performance status must be considered, particularly in elderly patients with GC.

Chronic underlying diseases, such as hypertension, hyperlipidemia, and valvular heart disease are well-known risk factors for the development of CCV adverse events. Hypertensives might develop cardiovascular diseases 5 years earlier than those without hypertension.42 In a study using Framingham Offspring Cohort data, prolonged hyperlipidemia in early adulthood increases the risk of coronary heart disease in a dose-responsive fashion.43 Valvular heart disease could contribute to arrhythmia and major cardiac adverse events.44,45 In accordance with previous studies, the present study demonstrated that valvular heart disease is associated with a markedly high risk of CCV adverse events after surveillance EGD in patients with GC. In addition, we investigated whether the use of antiplatelet agents, including aspirin, could predispose patients to CCV adverse events. Although we could not accurately identify whether antiplatelet agents were discontinued before EGD through the HIRA database, guidelines from South Korea do not recommend discontinuation of antiplatelet agents before low-risk endoscopy such as surveillance EGD.46 Our findings showed that the use of antiplatelet agents is associated with a higher occurrence of CCV adverse events. This finding indicates that GC patients on antiplatelet therapy are more susceptible to CCV adverse events following surveillance EGD. These results may help inform patients and clinicians in examining different regimens and modalities for follow-up of GC.

This study had several limitations. First, it focused on patients with GC, not the general population. Second, sedative agents used for surveillance EGD are mostly administered by endoscopists in South Korea. Anesthesiologists administer sedative agents for surveillance EGD in special situations requiring deep sedation or close monitoring. However, such cases are rare and were not identified in the present study. Third, the HIRA database was generated for healthcare service reimbursement and was not designed for research purposes. Therefore, the data may not be consistent with actual diagnoses and do not include laboratory tests or imaging examinations. In the HIRA database, patients with GC were classified as having early GC, advanced GC, and unspecified GC. This classification may not accurately reflect the actual stage of GC. The proportion of patients with unspecified stages of GC was approximately 40%. Fourth, GC patients with severe comorbidities could have selectively undergone EGD without sedation according to the patients’ or clinicians’ own choice, resulting in selection bias. Moreover, CCV adverse events after surveillance EGD are rare. Therefore, we used propensity score matching to reduce bias. Fifth, the reasons for using antiplatelet agents in patients without a history of CCV diseases were not identified in this study. Sixth, we could not analyze the follow-up outcomes, such as mortality, of the patients who underwent 14-day CCD adverse events after surveillance EGD. Lastly, the HIRA database contains no information about the depth of sedation or sedation policy for each healthcare institution.

In conclusion, sedation during surveillance EGDs did not appear to increase CCV adverse events following EGD in patients with GC. These findings suggest that sedative agents can be safely used during surveillance EGDs in patients with GC without undue concern for CCV adverse events.

ACKNOWLEDGEMENTS

This study was supported by a grant from the Korean Gastrointestinal Endoscopy Research Foundation 2020 Investigation Grant.

This study used the Health Insurance Review and Assessment Service (HIRA) databases (Study Number: M20220221837). The authors thank the Korean HIRA for providing the insurance claims data. The authors deeply thank Hui Seung Lee for the analysis of the data.

CONFLICTS OF INTEREST

B.W.K. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

AUTHOR CONTRIBUTIONS

Study concept and design: S.Y.K., J.K.L. Data acquisition: S.Y.K., J.K.L. Data analysis and interpretation: S.Y.K., J.K.L., K.H.L., J.Y.J., B.W.K. Drafting of the manuscript: S.Y.K. Critical revision of the manuscript for important intellectual content: J.K.L., K.H.L., J.Y.J., B.W.K. Statistical analysis: S.Y.K., J.K.L. Obtained funding: J.K.L. Administrative, technical, or material support; study supervision: J.K.L., K.H.L., J.Y.J., B.W.K. Approval of final manuscript: all authors.

Fig 1.

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Figure 1.Flow diagram of the study population.
HIRA, Health Insurance Review and Assessment Service; EGD, esophagogastroduodenoscopy; CCV, cardio-cerebrovascular; MI, myocardial infarction; IHD, ischemic heart disease; TIA, transient ischemic attack; ATE, arterial thromboembolism.
Gut and Liver 2024; 18: 245-256https://doi.org/10.5009/gnl230043

Fig 2.

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Figure 2.Use of sedative agents during surveillance esophagogastroduodenoscopy in patients with gastric cancer.
Gut and Liver 2024; 18: 245-256https://doi.org/10.5009/gnl230043

Table 1 Baseline Characteristics of the Study Population

CharacteristicUnmatchedPropensity score-matched (1:1)
Total
(n=103,463)		Sedative agentsp-value*ASMDTotal
(n=56,016)		Sedative agentsASMD
Users (n=42,686)Nonusers (n=60,777)Users (n=28,008)Nonusers (n=28,008)
Sex, No. (%)<0.0010.120.10
Male69,513 (67.2)27,308 (64.0)42,205 (69.4)17,433 (31.1)9,045 (32.3)8,388 (29.95)
Female33,950 (32.8)15,378 (36.0)18,572 (30.6)38,583 (68.8)18,963 (67.7)19,620 (70.05)
Age, mean±SD, yr63.6±11.257.2±8.468.1±10.8<0.0011.1360.4±9.759.3±8.061.6±11.11.13
Age group, No. (%)<0.0011.031.03
20–64 yr53,827 (52.0)33,631 (78.8)20,196 (33.2)37,984 (67.8)18,953 (67.7)19,031 (68.0)
≥65 yr49,636 (48.0)9,055 (21.2)40,581 (66.8)18,032 (32.2)9,055 (32.3)8,977 (32.1)
Types of healthcare institution, No. (%)†<0.0010.290.29
Tertiary hospital74,919 (72.4)32,996 (77.3)41,923 (69.0)42,100 (75.2)21,270 (75.9)20,830 (74.4)
General hospital23,830 (23.0)9,062 (21.2)14,768 (24.3)12,567 (22.4)6,111 (21.8)6,456 (23.1)
Standard hospital1,371 (1.3)304 (0.7)1,067 (1.8)621 (1.1)303 (1.1)318 (1.1)
Private clinic3,343 (3.2)324 (0.8)3,019 (5.0)728 (1.3)324 (1.2)404 (1.4)
Types of insurance, No. (%)<0.0010.090.08
National health insurance98,785 (95.5)41,202 (96.5)57,583 (94.7)53,691 (95.8)26,874 (96.0)26,817 (95.8)
Medical benefit system4,678 (4.6)1,484 (3.5)3,194 (5.3)2,325 (4.2)1,134 (4.1)1,191 (4.2)
Routes of undergoing EGD, No. (%)0.95<0.0010.01
Outpatient94,844 (91.7)39,133 (91.7)55,711 (91.7)50,778 (90.7)24,888 (88.9)25,890 (92.4)
Inpatient8,619 (8.3)3,553 (8.3)5,066 (8.3)5,238 (9.3)3,120 (11.1)2,118 (7.6)
Types of chronic disease, No. (%)
Hypertension33,211 (32.1)10,670 (25.0)22,541 (37.1)<0.0010.2617,668 (31.5)9,875 (35.3)7,793 (27.9)0.26
Diabetes mellitus20,683 (20.0)7,060 (16.5)13,623 (22.4)<0.0010.1511,235 (20.1)6,271 (22.4)4,964 (17.7)0.16
Valvular disease492 (0.5)102 (0.2)390 (0.6)<0.0010.06181 (0.3)96 (0.3)85 (0.3)0.06
Hyperlipidemia29,858 (28.9)11,833 (27.7)18,025 (29.7)<0.0010.0417,491 (31.2)9,983 (35.6)7,508 (26.8)0.05
Chronic pulmonary disease24,678 (23.9)8,897 (20.8)15,781 (26.0)<0.0010.1214,462 (25.8)8,482 (30.3)5,980 (21.4)0.12
Renal disease2,101 (2.0)535 (1.3)1,566 (2.6)<0.0010.10898 (1.6)486 (1.7)412 (1.5)0.09
Connective tissue disorder1,608 (1.6)613 (1.4)995 (1.6)0.010.02922 (1.7)538 (1.9)384 (1.4)0.01
Liver disease2,899 (2.8)1,157 (2.7)1,742 (2.9)0.140.011,788 (3.2)1,039 (3.7)749 (2.7)0.007
Cancer/metastatic cancer13,587 (13.1)5,211 (12.2)8,376 (13.8)<0.0010.057,830 (14.0)4,571 (16.3)3,259 (11.6)0.05
Stage of gastric cancer, No. (%)0.010.020.02
Early48,517 (46.9)20,172 (47.3)28,345 (46.6)25,446 (45.4)12,706 (45.4)12,740 (45.5)
Advanced14,780 (14.3)5,928 (13.9)8,852 (14.6)8,560 (15.3)4,430 (15.8)4,130 (14.8)
Unspecified40,166 (38.8)16,586 (38.9)23,580 (38.8)22,010 (39.3)10,872 (38.8)11,138 (39.8)
Use of antiplatelet agents, No. (%)<0.0010.120.11
No100,094 (96.7)41,805 (97.9)58,289 (95.9)54,540 (97.4)27,235 (97.2)27,305 (97.5)
Yes3,369 (3.3)881 (2.1)2,488 (4.1)1,476 (2.6)773 (2.8)703 (2.5)

ASMD, absolute standardized mean differences; EGD, esophagogastroduodenoscopy.

*p-values for differences were determined using the chi-square or Wilcoxon rank sum test for unmatched data; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals are more specialized in treating severe diseases than general hospitals, mostly university hospitals.

Table 2 CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer

Overall CCVMajor CCV*Cardiac adverse eventStroke/TIAATE/PE
Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons		Events,
No. (%)		Incidence rate
per 10,000
persons
Total adverse events within 14 days2,658 (2.57)256.91,055 (1.02)102.01,597 (1.54)154.3963 (0.93)93.198 (0.09)9.5
Without sedation1,917 (3.15)315.4778 (1.28)128.01,130 (1.86)186.0721 (1.19)118.666 (0.11)10.8
With sedation741 (1.74)173.6277 (0.65)64.9467 (1.09)109.4242 (0.57)56.732 (0.07)7.5
Midazolam387 (1.53)152.9138 (0.55)54.5249 (0.98)98.4123 (0.49)48.615 (0.06)5.9
Propofol143 (2.01)201.457 (0.80)80.285 (1.20)119.749 (0.69)69.09 (0.13)12.7
Midazolam+ propofol206 (2.04)204.478 (0.77)77.4132 (1.31)131.066 (0.65)65.58 (0.08)7.9
Midazolam+lorazepam or diazepam2 (2.15)215.11 (1.08)107.51 (1.08)107.51 (1.08)107.500.0
Propofol+lorazepam or diazepam00.000.000.000.000.0
Midazolam+propofol+lorazepam or diazepam3 (4.76)476.23 (4.76)476.200.03 (4.76)476.200.0

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism.

*Major CCV adverse events were defined as acute myocardial infarction, cardiac arrest, ischemic stroke, hemorrhagic stroke, ATE, or PE.

Table 3 Outcomes of CCV Adverse Events in the Unmatched and Propensity Score-Matched Groups

Unmatched patientsPropensity score-matched (1:1) patients
Total
(n=103,463)		Received sedative
agents (n=42,686)		Did not receive sedative agents (n=60,777)p-value*Total
(n=56,016)		Received sedative
agents (n=28,008)		Did not receive sedative agents (n=28,008)p-value*
CCV adverse events2,658 (2.57)741 (1.74)1,917 (3.15)<0.0011,261 (2.25)638 (2.28)623 (2.22)0.69
Cardiac adverse events1,597 (1.54)467 (1.09)1,130 (1.86)<0.001770 (1.37)402 (1.44)368 (1.31)0.23
Stroke/TIA963 (0.93)242 (0.57)721 (1.19)<0.001442 (0.79)207 (0.74)235 (0.84)0.20
ATE/PE98 (0.09)32 (0.07)66 (0.11)0.1049 (0.09)29 (0.10)20 (0.07)0.25

Data are presented as number (%).

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism.

*p-values were determined using the chi-square test or Fisher exact test.

Table 4 Clinical Factors Associated with CCV Adverse Events within 14 Days of Surveillance EGD in Patients with Gastric Cancer

VariableCCV adverse eventsMultivariate analysis*
Control (n=100,805)Case (n=2,658)p-valueOR (95% CI)p-value
Sex<0.001
Female33,268 (33.0)682 (25.7)Reference
Male67,537 (67.0)1,976 (74.3)1.34 (1.23–1.47)<0.001
Age group<0.001
20–64 yr53,091 (52.7)736 (27.7)Reference
≥65 yr47,714 (47.3)1,922 (72.3)1.87 (1.69–2.07)<0.001
Stage of gastric cancer0.01
Early47,202 (46.8)1,315 (49.5)Reference
Advanced14,456 (14.3)324 (12.2)0.83 (0.73–0.95)0.02
Unspecified39,147 (38.8)1,019 (38.3)0.93 (0.86–1.02)0.65
Types of healthcare institution†<0.001
Tertiary hospital73,207 (72.6)1,712 (64.4)Reference
General hospital23,030 (22.9)800 (30.1)1.17 (1.07–1.28)0.26
Standard hospital1,316 (1.3)55 (2.1)1.15 (0.86–1.54)0.70
Private clinic3,252 (3.2)91 (3.4)1.09 (0.87–1.35)0.89
Types of insurance<0.001
National health insurance96,351 (95.6)2,434 (91.6)Reference
Medical benefit system4,454 (4.4)224 (8.4)1.20 (1.03–1.40)0.02
Routes of undergoing EGD<0.001
Outpatient92,597 (91.9)2,247 (84.5)Reference
Inpatient8,208 (8.1)411 (15.5)1.73 (1.54-1.94)<0.001
Types of chronic disease
Hypertension31,679 (31.4)1,532 (57.6)<0.0011.88 (1.72–2.04)<0.001
Diabetes mellitus19,831 (19.7)852 (32.1)<0.0011.10 (1.00–1.20)0.04
Valvular heart disease446 (0.4)46 (1.7)<0.0012.15 (1.55–3.00)<0.001
Hyperlipidemia28,721 (28.5)1,137 (42.8)<0.0011.30 (1.20–1.42)<0.001
Chronic pulmonary disease23,812 (23.6)866 (32.6)<0.0011.08 (0.99–1.18)0.09
Renal disease1,957 (1.9)144 (5.4)<0.0011.07 (0.88–1.29)0.49
Connective tissue disorder1,549 (1.5)59 (2.2)0.011.04 (0.79–1.37)0.79
Liver disease2,796 (2.8)103 (3.9)<0.0011.05 (0.85–1.30)0.63
Cancer/metastatic cancer13,138 (13.0)449 (16.9)<0.0011.01 (0.91–1.13)0.84
Sedation during EGD<0.001
Non-sedation58,860 (58.4)1,917 (72.1)Reference
Sedation41,945 (41.6)741 (27.9)0.92 (0.84–1.02)0.11
Use of antiplatelet agents<0.001
No98,090 (97.3)2,004 (75.4)Reference
Yes2,715 (2.7)654 (24.6)7.20 (6.48–7.99)<0.001

Data are presented as number (%).

CCV, cardio-cerebrovascular; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval.

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, status of sedation, and use of antiplatelet agents; †Standard hospitals have more than 30 beds, whereas general hospitals have more than 100 beds and at least seven medical departments. Tertiary hospitals, mostly university hospitals, are more specialized in treating severe diseases than general hospitals.

Table 5 Clinical factors Associated with CCV Adverse Events, Cardiac Adverse Events, Stroke/TIA, and ATE/PE within 14 Days of Surveillance EGD in Patients with Gastric Cancer According to the Type of Sedative Agent

VariableMultivariate analysis*
(cardiac adverse events)		Multivariate analysis*
(stroke/TIA)		Multivariate analysis*
(ATE/PE)
OR (95% CI)p-valueOR (95% CI)p-valueOR (95% CI)p-value
Age group
20–64 yrReference-Reference-Reference-
≥65 yr1.58 (1.40–1.80)<0.0012.32 (1.96–2.76)<0.0012.74 (1.62–4.65)<0.001
Sedation during EGD
Non-sedationReference-Reference-Reference-
Midazolam alone0.88 (0.76–1.03)0.930.77 (0.62–0.94)0.950.97 (0.53–1.77)0.93
Propofol alone0.99 (0.79–1.26)0.940.99 (0.74–1.35)0.941.89 (0.91–3.94)0.92
Midazolam+propofol1.08 (0.89–1.31)0.930.96 (0.73–1.25)0.951.08 (0.50–2.36)0.93
Midazolam+lorazepam or diazepam0.74 (0.10–5.40)0.940.00 (0.00–999.99)0.950.00 (0.00–999.99)0.97
Propofol+lorazepam or diazepam0.00 (0.00–999.99)0.970.00 (0.00–999.99)0.970.00 (0.00–999.99)0.98
Midazolam+propofol+lorazepam or diazepam0.00 (0.00–999.99)0.955.32 (1.56–18.20)0.910.00 (0.00–999.99)0.97

CCV, cardio-cerebrovascular; TIA, transient ischemic attack; ATE, arterial thromboembolism; PE, pulmonary embolism; EGD, esophagogastroduodenoscopy; OR, odds ratio; CI, confidence interval.

*Multivariate analysis adjusted for sex, age, stage of gastric cancer, type of healthcare institution, type of insurance, route of endoscopy, type of chronic disease, type of sedative agent, and use of antiplatelet agents.

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Gut and Liver

Vol.18 No.5
September, 2024

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pISSN 1976-2283
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