Risk factors for QTc-prolongation: systematic review of the evidence

Int J Clin Pharm. 2017 Feb;39(1):16-25. doi: 10.1007/s11096-016-0414-2. Epub 2016 Dec 23.


Background QTc-interval prolongation has been associated with serious adverse events, such as Torsade de Pointes and sudden cardiac death. In the prevention of QTc-prolongation, special attention should go to high-risk patients. Aim of the review The aim of this review is to summarize and assess the evidence for different risk factors for QTc-prolongation (demographic factors, comorbidities, electrolytes, QTc-prolonging medication). Methods Potential studies were retrieved based on a systematic search of articles published until June 2015 in the databases Medline and Embase. Both terms about QTc-prolongation/Torsade de Pointes and risk factors were added in the search strategy. The following inclusion criteria were applied: randomized controlled trials and observational studies; inclusion of ≥500 patients from a general population (not limited to specific disease states); assessment of association between QTc-interval and risk factors. For the articles that met the inclusion criteria, the following data were extracted: study design, setting and study population, number of patients and cases of QTc-prolongation, method of electrocardiogram-monitoring, QTc-correction formula, definition of QTc-prolongation, statistical methods and results. Quality assessment was performed using the GRADE approach (for randomized controlled trials) and the STROBE-recommendations (for observational studies). Based on the number of significant results and the level of significance, a quotation of the evidence was allocated. Results Ten observational studies could be included, with a total of 89,532 patients [prospective cohort design: N = 6; multiple regression analyses: N = 5; median STROBE score = 17/22 (range 15-18)]. Very strong evidence was found for hypokalemia, use of diuretics, antiarrhythmic drugs and QTc-prolonging drugs of list 1 of CredibleMeds. Little or no evidence was found for hyperlipidemia, the use of digoxin or statins, neurological disorders, diabetes, renal failure, depression, alcohol abuse, heart rate, pulmonary disorders, hormone replacement therapy, hypomagnesemia, history of a prolonged QTc-interval/Torsade de Pointes, familial history of cardiovascular disease, and the use of only QTc-prolonging drugs of list 2 or 3 of CredibleMeds. Conclusion This systematic review gives a clear overview of the available evidence for a broad range of risk factors for QTc-prolongation.

Keywords: QTc-prolongation; Risk factors; Sudden cardiac death; Systematic review; Torsade de Pointes.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Age Factors
  • Anti-Arrhythmia Agents / adverse effects
  • Brugada Syndrome / diagnosis
  • Brugada Syndrome / etiology
  • Brugada Syndrome / physiopathology
  • Cardiac Conduction System Disease
  • Diuretics / adverse effects
  • Electrocardiography / trends
  • Humans
  • Long QT Syndrome / diagnosis*
  • Long QT Syndrome / etiology*
  • Long QT Syndrome / physiopathology
  • Prospective Studies
  • Randomized Controlled Trials as Topic / methods
  • Risk Factors
  • Smoking / adverse effects
  • Smoking / physiopathology


  • Anti-Arrhythmia Agents
  • Diuretics