Atrial fibrillation signals associated with overactive bladder drugs across JADER and FAERS: disproportionality and time-to-onset analyses

Figures

• 

  FIGURE 1. Study workflow. Data preprocessing (deduplication and integration), construction of a patient-level dataset, case selection, and analyses—including disproportionality screening, subgroup stratification, and time-to-onset (TTO)—were performed in JADER and FAERS. Abbreviations: AF, atrial fibrillation; BCPNN, Bayesian confidence propagation neural network; DEMO, demographic table; DRUG, drug table; FAERS, FDA Adverse Event Reporting System; HIST, medical history table; ICSR, individual case safety report; JADER, Japanese Adverse Drug Event Report database; OAB, overactive bladder; OUTC, outcome table; PRR, proportional reporting ratio; REAC, adverse event table; ROR, reporting odds ratio; THER, therapy table; TTO, time-to-onset.

• 

  FIGURE 2. Primary disproportionality screening of AF reports associated with OAB drugs in JADER and FAERS. Top: JADER; bottom: FAERS. From left to right, the table shows drug, N, ROR (95% CI) with p-value, PRR025 and χ2, IC025, a forest plot of ROR (dashed line at ROR = 1), and check marks indicating whether the predefined thresholds were met for ROR, PRR, and IC (Methods 2.3). IC strength is color-coded: light blue for 0 < IC025 < 1.5, blue for 1.5 ≤ IC025 < 3.0, and dark blue for IC025 ≥ 3.0. Source data for Figure 2 are available in Supplementary Data S2. Abbreviations: AF, atrial fibrillation; OAB, overactive bladder; JADER, Japanese Adverse Drug Event Report database; FAERS, FDA Adverse Event Reporting System; N, number of reports; CI, confidence interval; ROR, reporting odds ratio; PRR, proportional reporting ratio; IC, information component; PRR025/IC025, lower 95% CI bounds for PRR/IC.

• 

  FIGURE 3. Stratified disproportionality screening of AF reports for solifenacin and mirabegron in JADER and FAERS. Top to bottom panels: solifenacin in JADER; solifenacin in FAERS; mirabegron in JADER; mirabegron in FAERS. Results are stratified by sex, age group, and concomitant medication count. From left to right, the table shows the stratum, N, ROR (95% CI) with p-value, PRR025 and χ2, IC025, a forest plot of ROR (dashed line at ROR = 1), and check marks indicating whether predefined thresholds were met for ROR, PRR, and IC (Methods 2.3). IC strength is color-coded: light blue for 0 < IC025 < 1.5, blue for 1.5 ≤ IC025 < 3.0, and dark blue for IC025 ≥ 3.0. Source data for Figure 3 are available in Supplementary Data S3. Abbreviations: AF, atrial fibrillation; JADER, Japanese Adverse Drug Event Report database; FAERS, FDA Adverse Event Reporting System; N, number of reports; CI, confidence interval; ROR, reporting odds ratio; PRR, proportional reporting ratio; IC, information component; PRR025/IC025, lower 95% confidence bounds for PRR/IC; Drugs <5/≥5, concomitant medication count strata.

• 

  FIGURE 4. Panels: Left, solifenacin; right mirabegron. Colors: JADER (orange), FAERS (blue). Points: each dot represents one stratum (sex, age, concomitant medication count); where present, an “Overall (N)” point summarizes the pre-stratified result for that database and drug. Axes: x = ln(ROR); y = –log10(p). Point size reflects the number of reports. Reference lines: vertical at ln(ROR) = 0 (no disproportionality) and horizontal at –log10(p) = 1.30 (p = 0.05). These plots illustrate reporting patterns from the analysis pipeline outputs and are not used for hypothesis testing. Abbreviations: ROR, reporting odds ratio; ln, natural logarithm; p, p-value; JADER, Japanese Adverse Drug Event Report database; FAERS, FDA Adverse Event Reporting System. (Age bands on the plots are abbreviated but correspond to 20–69 years and 70–99 years, as defined in Methods.)

• 

  FIGURE 5. Panels: Upper left, solifenacin in JADER; upper right, solifenacin in FAERS; lower left, mirabegron in JADER; lower right, mirabegron in FAERS. Elements: a Weibull probability density curve, a histogram of report counts (5‐day bins), and a boxplot summarizing TTO within 2 years (0–730 days) after drug initiation. Axes: x = probability density; y β days. Panel titles indicate the database; colors follow a consistent plotting palette. These visuals are descriptive and support the interpretation of failure types derived from the Weibull shape parameter β. Abbreviations: AF, atrial fibrillation; TTO, time-to‐onset; JADER, Japanese Adverse Drug Event Report database; FAERS, FDA Adverse Event Reporting System; β, Weibull shape parameter.

• 

  FIGURE 6. Cumulative proportion of atrial fibrillation (AF) reports associated with solifenacin and mirabegron in JADER and FAERS. KM curves were generated using TTO within 2 years (0–730 days) after drug initiation. Axes: x = TTO (days); y = cumulative proportion of reports (%). Line styles: solid (solifenacin), dash–dot (mirabegron). Colors: JADER (orange), FAERS (blue). This descriptive visualization highlights early clustering of AF onset and is not intended for hypothesis testing. An untruncated version covering the full observation window is provided as Supplementary Figure S4. Abbreviations: AF, atrial fibrillation; KM, Kaplan–Meier; TTO, time-to-onset; JADER, Japanese Adverse Drug Event Report database; FAERS, FDA Adverse Event Reporting System.