This study involved a total of 33,421 for the FQs group and 133,684 for the FQs free controls. Of the enrolled patients (n=167,105), collagen-associate adverse effects developed in 85 (0.051%) in 6-month tracking, including 0.051% in the FQs study cohort (17 in 33,421) and 0.051% (68 in 133,684) in the FQs-free comparison cohort.
Baseline characteristics of patients
Baseline characteristics of case patients and comparators are listed in the Table 1. There were no significant differences between the FQs group and FQ-free group in the distributions of age and sex, but the proportion of catastrophic illness was slightly higher in the FQs group than the FQs-free groups (0.6 vs. 0.38).
Table 1. Characteristics of Study
Collagen-associated adverse events
In the cohort, we did not observe any case of tendons rupture, retinal detachments, aortic aneurysms, and aortic dissection. Patients with collagen-associated adverse events (GI perforation) in FQs group included 1 individual in 7-day tracking, 3 individuals in 14-days tracking, 4 individuals in 28-days tracking, 12 individuals in 3-month tracking, and 17 individuals in 6-month tracking. However, patients with collagen-associated adverse events (GI perforation) in FQs free group were 2 individuals in 3-days tracking, 6 individuals in 7-days tracking, 10 individuals in 14-days tracking, 45 individuals in 3-month tracking, 68 individuals in 6-month tracking. (Figure.1) The crude HR for collagen-associated adverse events in FQs group was 0.997 (95% CIs; 0.586-1.696; p=0.990). (Table 2.)
Table 2. Factors of Gastrointestinal Perforation in 6-month Tracking by Using Cox Regression.
Risk of collagen-associated adverse events
After adjusting for age, sex, catastrophic illness, low-income household, seasons, levels of urbanization and healthcare, the adjusted HR for collagen-associated adverse events in FQs group was 1.330 (95% CI; 0.778-2.276; p=0.255). After multivariate analysis, we noticed that patient’s age was associated with the risk of GI perforation. As shown in Table 2, the risk of collagen-associate adverse effect was lower in patients aged 5~9 years old (aHR=0.433; 95% CIs=0.179-0.952; p=0.040), patients aged 10~14 years old (aHR=0.386; 95% CI=0.163-0.909; p=0.028).
Subgroup analyses
The association of FQs with subsequent GI perforation was stratified by baseline demographic, catastrophic illness, low-income household, seasons, levels of urbanization and healthcare. Analyses of factors of GI perforation in 6-month tracking stratified by the aforementioned variables were performed by Cox regression as shown in Table 3. We did not observe any statistically significant difference between FQs group and FQs-free group after subgroup analyses of gender, age, catastrophic illness, low-income household, seasons, levels of urbanization and healthcare.
Table 3. Factors of Gastrointestinal Perforation in 6-month Tracking by Variables Listed in the Table by Using Cox Regression.
Stratified by fluoroquinolones
Also, we did the subgroup analysis to confirm the association of FQs subgroup with subsequent GI perforation in different tracking periods by using Cox regression. In 3-day tracking period, we observed 2 events from FQs-free group. In 7-day tracking period, we observed 1 event from ofloxacin in the FQs group, and 6 events from FQs-free group. In 14-day tracking period, we observed 1 event from ciprofloxacin, 1 event from norfloxacin, and 1 event from ofloxacin in the FQs group, and 10 events from FQs-free group. In 28-day tracking period, we observed 1 event from ciprofloxacin, 1 event from norfloxacin, 2 events from ofloxacin in the FQs group, and 14 events from FQs-free group. In 3-month tracking period, we observed 1 event from ciprofloxacin, 3 events from norfloxacin, and 8 events from ofloxacin in the FQs group, and 45 events from FQs-free group. In 6-month tracking period, we observed 1 event from ciprofloxacin, 3 events from norfloxacin, and 13 events from ofloxacin in the FQs group, and 68 events from FQs-free group. The incidence rate and adjusted HR are listed in Table 4. None of them were statistically significant difference between FQs group and FQs-free group.
Table 4. Factors of Gastrointestinal Perforation Stratified by Fluoroquinolones Subgroup in Different Tracking Period by Using Cox Regression.