Abstract
Long QT syndrome (LQTS) is a disorder of the heart’s electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6–204.6), 17.3 (14.7–20.4), 52.0 (43.4–62.4), 13.9 (11.5–16.7), 69.3 (55.3–86.8), 54.2 (43.2–68.0), 4.7 (3.8–5.8), 19.9 (15.9–25.0), 8.1 (6.5–10.1), 3.2 (2.5–4.1), 7.1 (5.5–9.2), and 254.8 (168.5–385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0–35.8) and 18.0 (6.0–43.0) days, respectively. The lower 95% confidence interval of the shape parameter β of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.
Highlights
Long QT syndrome (LQTS) is a disorder of the heart’s electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal
Standardized MedDRA Queries (SMQs) are groupings of preferred terms (PTs) according to the level that relates to a defined medical condition, and the included terms may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc [12]
The number of case reports extracted by searching using the SMQ for torsade de pointes/QT prolongation (SMQ code: 20000001) with PTs matching a “narrow” scope, a “broad” scope, and the PTs selected by Iribarren et al were 9,823 (2.4%), 2,732 (0.7%), and 2,002 (0.5%), respectively
Summary
Long QT syndrome (LQTS) is a disorder of the heart’s electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. Drug-induced LQTS can be caused by a variety of drugs; anti-arrhythmic drugs and other non-cardiac drugs such as antipsychotics, antibiotics and anti-allergic drugs [1]. Drug-induced LQTS are estimated to occur at rates of approximately 2.0–8.8% among patients prescribed anti-arrhythmic drugs and thousandth or millionth part of those prescribed non-cardiac drugs [1,4,5,6]. Spontaneous reporting systems (SRSs), wherein clinicians report their concerns about potential drug-induced adverse events during their normal diagnostic assessments of patients, are useful for the detection of rare and severe adverse events. The reporting odds ratio (ROR) has been developed for use with SRS data as a measure of the relative risk for drug-associated adverse events [7,8]
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