How Often Do QT-prolonging Drugs Really Prolong QT? A Systematic Review

Objectives: To systematically evaluate the incidence and prevalence of drug-induced QT interval prolongation and torsades de pointes (TdP) among adults exposed to QT-prolonging medications. Design: Systematic review of observational and interventional studies identified through MEDLINE (via PubMed). Setting: Primary and secondary care settings, including inpatient and outpatient populations, across multiple geographical regions. Participants: Adult patients (18 years and older) receiving QT-prolonging drugs and undergoing electrocardiographic monitoring. Studies reporting QTc prolongation using predefined thresholds were eligible. A total of 14,756 participants were included across 42 studies. Intervention: Exposure to QT-prolonging medications. Primary and Secondary Outcomes: The primary outcome was the incidence or prevalence of significant QTc prolongation, defined as QTc >500 ms or an increase in QTc (ΔQTc) ≥60 ms. The secondary outcome was the occurrence of TdP. Results: Of 501 records, 42 studies met the inclusion criteria: 5 were interventional and 37 observational, involving a total of 14,756 patients. Methadone was the most frequently studied drug (17 studies), with reported QTc >500 ms incidence ranging from 0% to 16.2%, and TdP prevalence up to 3.6% and incidence of up to 3.2%. Other frequently studied drugs included hydroxychloroquine (5 studies), azithromycin (4 studies), and antipsychotics such as haloperidol and quetiapine. Incidence of QTc >500 ms varied considerably across settings and drug classes, influenced by heterogeneous QTc correction formulas. Conclusions: Drug-induced QTc prolongation is not uncommon across a range of widely used medications, especially in psychiatric care, yet its monitoring and risk remain inconsistently assessed, particularly in outpatient settings. While TdP was rarely reported, QTc >500 ms occurred with notable frequency. Significant heterogeneity in QTc definitions, study populations, and ECG methodologies limits cross-study comparability, underscoring the need for greater standardization.