QT Prolongation, Ventricular Arrhythmia, and Cardiac Arrest Signals During Ceftriaxone Co-therapy with Individual Proton Pump Inhibitors: A Multidatabase Study

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The concomitant use of ceftriaxone and proton pump inhibitors (PPIs) is common in hospital practice. However, it is unclear whether individual PPIs differ in their effects on QT interval prolongation, ventricular arrhythmia, or cardiac arrest, collectively termed as QVC events. We conducted a two-stage, real-world study. First, we screened the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction (CVAR) database with standard disproportionality measures (reporting odds ratio and proportional reporting ratio) and six drug-drug interaction (DDI) algorithms to identify combination signals that exceeded component signals. Second, we validated signal-positive combinations in the Medical Information Mart for Intensive Care IV (MIMIC-IV) intensive care unit (ICU) electronic health record (EHR) cohort by assembling adult inpatients with overlapping ceftriaxone-PPI exposures. The primary outcome was 28-day QVC events. Multivariable Cox proportional hazards models were the main analysis and complemented by propensity score matching, inverse probability of treatment weighting, and Fine-Gray competing-risk models. To address external generalisability, an additional validation was performed using ECG-ViEW II, an Asian electrocardiogram-linked real-world database. The combination of ceftriaxone and lansoprazole was significantly associated with QVC events, revealing notable DDIs (e.g., in FAERS, Ω025 = 0.54). To validate these findings, a cohort of 5,594 patients receiving ceftriaxone combined with PPIs from the MIMIC-IV database was analyzed using Cox proportional hazards models. The analyses corroborated the initial findings (lansoprazole vs. other PPIs, multivariate HR = 1.30; 95% CI: 1.10-1.54), with the risk associated with the three PPI combinations ranked as lansoprazole > pantoprazole > omeprazole. ECG-ViEW II provided supportive Asian external validation, showing a higher QVC risk for ceftriaxone plus lansoprazole than for ceftriaxone plus other PPIs. Evidence from two national pharmacovigilance systems and an ICU EHR cohort indicated that PPI choice modified cardiac safety during ceftriaxone therapy. Lansoprazole co-use confers a higher risk of QVC, whereas omeprazole appears relatively safer. Therefore, prospective confirmation is warranted.

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