International Journal of Clinical Pharmacy

, Volume 40, Issue 5, pp 1372–1379 | Cite as

Development of a risk model for predicting QTc interval prolongation in patients using QTc-prolonging drugs

  • Anita N. Bindraban
  • José Rolvink
  • Florine A. Berger
  • Patricia M. L. A. van den Bemt
  • Aaf F. M. Kuijper
  • Ruud T. M. van der Hoeven
  • Aukje K. Mantel-Teeuwisse
  • Matthijs L. BeckerEmail author
Research Article


Background Numerous drugs prolong the QTc interval on the ECG and potentially increase the risk of cardiac arrhythmia. This risk is clinically relevant in patients with additional risk factors. Objective The objective was to develop and validate a risk model to predict QTc interval prolongation of eligible ECGs. Setting Spaarne Gasthuis (Haarlem/Hoofddorp, The Netherlands). Method A dataset was created from ECGs recorded in patients using one or more QTc prolonging drugs, in the period January 2013 and October 2016. In the development set, independent risk factors for QTc interval prolongation were determined using binary logistic regression. Risk scores were assigned based on the beta coefficient. In the risk-score validation set, the area under the ROC-curve, sensitivity and specificity were calculated. Main outcome measure QTc interval prolongation, defined as a QTc interval > 500 ms. Results In the development set 12,949 ECGs were included and in the risk-score validation set 6391 ECGs. The proportion of ECGs with a prolonged QTc interval in patients with no risk factors in the risk-score validation set was 2.7%, while in patients with a high risk score the proportion was 26.1%. The area under the ROC curve was 0.71 (95% CI 0.68–0.73). The sensitivity and specificity were 0.81 and 0.48, respectively. Conclusion A risk model was developed and validated for the prediction of QTc interval prolongation. This risk model can be implemented in a clinical decision support system, supporting the management of the risks involved with QTc interval prolonging drugs.


Model development QTc interval prolongation QTc prolonging drugs Risk model 



We would like to thank Karlijn van Stralen for her help in methodological and statistical issues.


No special funding was received for performing this study.

Conflicts of interest

All authors declare that they have no conflict of interest.


  1. 1.
    Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–22.CrossRefGoogle Scholar
  2. 2.
    Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–72.CrossRefGoogle Scholar
  3. 3.
    Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362–7.CrossRefGoogle Scholar
  4. 4.
    The European Agency for the Evaluation of Medicinal Products. Committee for proprietary medicinal products. [internet] London: 1997. [cited 27 feb 2018] The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products; 1997.
  5. 5.
    Beitland S, Platou ES, Sunde K. Drug-induced long QT syndrome and fatal arrhythmias in the intensive care unit. Acta Anaesthesiol Scand. 2014;58:266–72.CrossRefGoogle Scholar
  6. 6. Oro Valley, AZ: Arizona Center for Education and Research on Therapeutics. [cited 27 feb 2018]; 2015.
  7. 7.
    Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil. 2005;12:363–8.CrossRefGoogle Scholar
  8. 8.
    Sohaib SM, Papacosta O, Morris RW, Macfarlane PW, Whincup PH. Length of the QT interval: determinants and prognostic implications in a population-based prospective study of older men. J Electrocardiol. 2008;41:704–10.CrossRefGoogle Scholar
  9. 9.
    Schwartz PJ, Woosley RL. Predicting the unpredictable: drug-Induced QT prolongation and Torsades de Pointes. J Am Coll Cardiol. 2016;67:1639–50.CrossRefGoogle Scholar
  10. 10.
    Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3:241–53.CrossRefGoogle Scholar
  11. 11.
    Tisdale JE, Jaynes HA, Kingery JR, Mourad NA, Trujillo TN, Overholser BR, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6:479–87.CrossRefGoogle Scholar
  12. 12.
    Tisdale JE, Jaynes HA, Kingery JR, Overholser BR, Mourad NA, Trujillo TN, et al. Effectiveness of a clinical decision support system for reducing the risk of QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2014;7:381–90.CrossRefGoogle Scholar
  13. 13.
    Sharma S, Martijn Bos J, Tarrell RF, Simon GJ, Morlan BW, Ackerman MJ, et al. Providers’ response to clinical decision support for QT prolonging drugs. J Med Syst. 2017;41(10):161.CrossRefGoogle Scholar
  14. 14.
    Bazett HC. An analysis of the time-relations of the electrocardiograms. Heart. 1920;7:353–70.Google Scholar
  15. 15.
    Pickham D, Helfenbein E, Shinn JA, Chan G, Funk M, Weinacker A, et al. High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality: results of the QT in practice (QTIP) study. Crit Care Med. 2012;40:394–9.CrossRefGoogle Scholar
  16. 16.
    Trojak B, Astruc K, Pinoit JM, Chauvet-Gelinier JC, Ponavoy E, Bonin B, et al. Hypokalemia is associated with lengthening of QT interval in psychiatric patients on admission. Psychiatry Res. 2009;169:257–60.CrossRefGoogle Scholar
  17. 17.
    Mangoni AA, Kinirons MT, Swift CG, Jackson SH. Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. Age Ageing. 2003;32:326–31.CrossRefGoogle Scholar
  18. 18.
    Jardin CG, Putney D, Michaud S. Assessment of drug-induced torsade de pointes risk for hospitalized high-risk patients receiving QT-prolonging agents. Ann Pharmacother. 2014;48:196–202.CrossRefGoogle Scholar
  19. 19.
    van der Sijs H, Mulder A, van Gelder T, Aarts J, Berg M, Vulto A. Drug safety alert generation and overriding in a large Dutch university medical centre. Pharmacoepidemiol Drug Saf. 2009;18:941–7.CrossRefGoogle Scholar
  20. 20.
    Nanji KC, Slight SP, Seger DL, Cho I, Fiskio JM, Redden LM, et al. Overrides of medication-related clinical decision support alerts in outpatients. J Am Med Inform Assoc. 2014;21:487–91.CrossRefGoogle Scholar
  21. 21.
    Haugaa KH, Bos JM, Tarrell RF, Morlan BW, Caraballo PJ, Ackerman MJ. Institution-wide QT alert system identifies patients with a high risk of mortality. Mayo Clin Proc. 2013;88:315–25.CrossRefGoogle Scholar
  22. 22.
    Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm. 2008;5:1015–8.CrossRefGoogle Scholar
  23. 23.
    Vandenberk B, Vandael E, Robyns T, Vandenberghe J, Garweg C, Foulon V, et al. Which QT Correction Formulae to Use for QT Monitoring? J Am Heart Assoc. 2016;5(6):e003264.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Anita N. Bindraban
    • 1
    • 2
  • José Rolvink
    • 1
  • Florine A. Berger
    • 3
  • Patricia M. L. A. van den Bemt
    • 3
  • Aaf F. M. Kuijper
    • 4
  • Ruud T. M. van der Hoeven
    • 1
  • Aukje K. Mantel-Teeuwisse
    • 2
  • Matthijs L. Becker
    • 1
    Email author
  1. 1.Pharmacy Foundation of Haarlem HospitalsHaarlemThe Netherlands
  2. 2.Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht Institute for Pharmaceutical Sciences (UIPS)UtrechtThe Netherlands
  3. 3.Department of Hospital PharmacyErasmus University Medical CentreRotterdamThe Netherlands
  4. 4.Department of CardiologySpaarne GasthuisHoofddorpThe Netherlands

Personalised recommendations