Effect of Pre-Antibiotic Use Before First Stroke Incidence on Recurrence and Mortality: A Longitudinal Study Using the Korean National Health Insurance Service Database

Figures & data

Figure 1 Flowchart of patient inclusion in this study.

Abbreviations: AIS, acute ischemic stroke; AHS, acute hemorrhagic stroke.

Table 1 Baseline Characteristics of Patients with Primary AIS and AHS

Variables	AIS Group (n = 159,181)	AHS Group (n = 49,077)	p-value^b
Age, years	68.5 ± 11.5	67.6 ± 11.2	<0.001
Women, n (%)	78,134 (49.1)	26,013 (53.0)	<0.001
Socioeconomic status, n (%)			<0.001
Level 1	53,184 (33.4)	15,442 (31.5)
Level 2	47,244 (29.7)	15,665 (31.9)
Level 3	58,753 (36.9)	17,970 (36.6)
Hypertension, n (%)	149,622 (94.0)	41,557 (84.7)	<0.001
Diabetes, n (%)	46,152 (29.0)	7547 (15.4)	<0.001
Dyslipidemia, n (%)	76,647 (48.2)	13,177 (26.8)	<0.001
Prior antibiotics use, n (%)	75,605 (47.5)	21,125 (43.0)	<0.001
Antibiotics classes, n (%)
Class 1	41,705 (26.2)	11,788 (24.0)	<0.001
Class 2	20,569 (12.9)	5633 (11.5)	<0.001
Class 3	5819 (3.7)	1670 (3.4)	0.008
Class 4	43,044 (27.0)	11,522 (23.5)	<0.001
Class 5^a	None	None
Class 6	650 (0.4)	182 (0.4)	0.27
Class 7	2829 (1.8)	724 (1.5)	<0.001

Notes: ^ano one in this study’s cohort took Class 5 antibiotics. ^bindependent t-test for continuous variables and Chi-square (trend) test for categorical variables.

Abbreviations: AHS, acute hemorrhagic stroke; AIS, acute ischemic stroke.

Table 2 Secondary Outcomes in Each Group

Secondary Events	AIS Group (n = 159,181)	AHS Group (n = 49,077)	p-value^a
Secondary AIS, n (%)	33,491 (21.0)	3676 (7.5)	<0.001
Secondary MI, n (%)	2746 (1.7)	411 (0.9)
Secondary AHS, n (%)	3886 (2.4)	8547 (17.4)
Death, n (%)	73,300 (46.1)	24,990 (50.9)
No event, n (%)	45,758 (28.8)	11,453 (23.3)

Note: ^aChi-square trend test.

Abbreviations: AHS, acute hemorrhagic stroke; AIS, acute ischemic stroke; MI, myocardial infarction.

Table 3 Cox-Proportional Hazards Models for Secondary AIS, AHS, and Death According to Pre-Antibiotics Use

Variable	aHR^a	95% CI	p-value	Secondary Events
AIS group with pre-antibiotics use	1.03	1.01–1.05	0.009	AIS
AHS group with pre-antibiotics use	0.98	0.92–1.04	0.49
AIS group with pre-antibiotics use	0.95	0.89–1.01	0.09	AHS
AHS group with pre-antibiotics use	1.08	1.03–1.12	<0.001
AIS group with pre-antibiotics use	0.95	0.94–0.96	<0.001	Death
AHS group with pre-antibiotics use	0.96	0.96–1.01	0.18

Note: ^aadjusted for age, sex, hypertension, diabetes, dyslipidemia, and socioeconomic status.

Abbreviations: AHS, acute hemorrhagic stroke; AIS, acute ischemic stroke; aHR, adjusted hazard ratio; ^|CI, confidence interval.

Figure 2 Kaplan–Meier curves for the cumulative probability according to pre-antibiotic use. P-values derived from the Log rank test are reported. (A) Pre-antibiotic use significantly increases the cumulative probability of secondary AIS in the AIS group and (B) secondary AHS in the AHS group. In contrast, (C) pre-antibiotic use in the AIS group significantly decreases the cumulative probability of death.

Abbreviations: AIS, acute ischemic stroke; AHS, acute hemorrhagic stroke.

Table 4 Cox-Proportional Hazards Models According to Pre-Antibiotics Class

Antibiotics Classes	Secondary AIS in the AIS Group^a		Secondary AHS in the AHS Group^a		Death in the AIS Group^a
	aHR^b (95% CI)	p-value	aHR^b (95% CI)	p-value	aHR^b (95% CI)	p-value
Class 1	1.00 (0.98–1.03)	0.91	1.06 (1.01–1.11)	0.01	0.96 (0.95–0.98)	<0.001
Class 2	1.07 (1.03–1.10)	<0.001	1.03 (0.97–1.10)	0.33	0.99 (0.97–1.01)	0.21
Class 3	0.96 (0.91–1.02)	0.17	1.03 (0.93–1.15)	0.55	1.05 (1.01–1.09)	0.02
Class 4	1.05 (1.03–1.08)	<0.001	1.06 (1.01–1.11)	0.02	0.98 (0.96–0.99)	0.004
Class 6	1.05 (0.89–1.24)	0.55	0.86 (0.58–1.27)	0.44	1.27 (1.15–1.40)	<0.001
Class 7	0.96 (0.88–1.04)	0.31	1.19 (1.02–1.39)	0.03	1.00 (0.95–1.05)	0.96

Notes: ^aevents showed significance in previous cox-regression analyses (in Table 3). ^badjusted for age, sex, hypertension, diabetes, dyslipidemia, and socioeconomic status.

Abbreviations: AHS, acute hemorrhagic stroke; AIS, acute ischemic stroke; ^|aHR, adjusted hazard ratio; CI, confidence interval.

Figure 3 The feature importance of each antibiotic class is derived from the multivariable Cox regression analyses. Each antibiotics class’s importance is calculated using the proportion of the χ² values. (A) Pre-antibiotic use of class 2 and class 4 was relatively important among all classes for the secondary AIS in the AIS group. (B) In the AHS group, pre-antibiotic use of class 1, class 4, and class 7 were relatively important for the risk of secondary AHS. Finally, (C) pre-antibiotic use of class 1, class 6, and class 4 were relatively important for decreased mortality in the AIS group.

Abbreviations: AIS, acute ischemic stroke; AHS, acute hemorrhagic stroke.