Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review Article
  • Published:
International Journal of Clinical Pharmacy Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Drew BJ, Ackerman MJ, Funk M, Gibler WB, Kligfield P, Menon V, et al. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2010;55:934–47.

    Article  PubMed  PubMed Central  Google Scholar 

  2. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70:16–23.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Bazett HC. An analysis of the time-relations of the electrocardiograms. Heart. 1920;7:353–70.

    Google Scholar 

  4. Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol. 2001;12:411–20.

    Article  CAS  PubMed  Google Scholar 

  5. Rautaharju PM, Surawicz B, Gettes LS, Bailey JJ, Childers R, Deal BJ, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part IV: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology. J Am Coll Cardiol. 2009;53:982–91.

    Article  PubMed  Google Scholar 

  6. Vandenberk B, Vandael E, Spriet I, Garweg C, Vandenberghe J, Van Den Bosch B, et al. Which QT correction formulae to use for QT monitoring? J Am Heart Assoc. 2016;. doi:10.1161/JAHA.116.003264.

    PubMed  PubMed Central  Google Scholar 

  7. CPMP/986/96. The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. London: Committee for Proprietary Medicinal Products; 1997.

    Google Scholar 

  8. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3:241–53.

    Article  PubMed  PubMed Central  Google Scholar 

  9. U.S. Department of Health and Human Services. Guidance for Industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005.

  10. Woosley RL, Romero KA. QTdrugs List, December 2015, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755. www.crediblemeds.org. Accessed 12 April 2016.

  11. European Medicines Agency (EMA): Restrictions on the use of domperidone-containing medicines, EMA/465179/2014. http://www.ema.europa.eu. Accessed 4 April 2016.

  12. Beach SR, Celano CM, Noseworthy PA, Januzzi JL, Huffman JC. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics. 2013;54:1–13.

    Article  PubMed  Google Scholar 

  13. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–22.

    Article  CAS  PubMed  Google Scholar 

  14. Schachtele S, Tumena T, Gassmann KG, Fromm MF, Maas R. Implementation of warnings from Dear Doctor Letters (Rote-Hand-Briefe): an analysis of medication data from a large cohort of elderly patients. Dtsch Arztebl Int. 2014;111:255–63.

    PubMed  PubMed Central  Google Scholar 

  15. Ames D, Camm J, Cook P, Falkai P, Gury C, Hurley R, et al. Minimizing the risks associated with QTc prolongation in people with schizophrenia. A consensus statement by the Cardiac Safety in Schizophrenia Group. Encephale. 2002;28:552–62.

    CAS  PubMed  Google Scholar 

  16. Royal College of Psychiatrists L. Consensus statement on high-dose antipsychotic medication. 2005.

  17. 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.

    Article  PubMed  Google Scholar 

  18. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.

    Article  PubMed  PubMed Central  Google Scholar 

  20. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–7.

    Article  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. Grandinetti A, Seifried S, Mor J, Chang HK, Theriault AG. Prevalence and risk factors for prolonged QTc in a multiethnic cohort in rural Hawaii. Clin Biochem. 2005;38:116–22.

    Article  CAS  PubMed  Google Scholar 

  23. Sohaib SMA, 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.

    Article  PubMed  Google Scholar 

  24. Akylbekova EL, Crow RS, Johnson WD, Buxbaum SG, Njemanze S, Fox E, et al. Clinical correlates and heritability of QT interval duration in blacks the Jackson Heart Study. Circ Arrhythm Electrophysiol. 2009;2:427–32.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Pasquier M, Pantet O, Hugli O, Pruvot E, Buclin T, Waeber G, et al. Prevalence and determinants of QT interval prolongation in medical inpatients. Intern Med J. 2012;42:933–40.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. Soliman EZ, Howard G, Cushman M, Kissela B, Kleindorfer D, Le Anh MS, et al. Prolongation of QTc and risk of stroke: the REGARDS (REasons for Geographic and Racial Differences in Stroke) Study. J Am Coll Cardiol. 2012;59:1460–7.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ. 2013;346:f288.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jardin CGM, 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.

    Article  PubMed  Google Scholar 

  31. Ponte ML, Keller GA, Di Girolamo G. Mechanisms of drug induced QT interval prolongation. Curr Drug Saf. 2010;5:44–53.

    Article  CAS  PubMed  Google Scholar 

  32. Digby GC, Perez Riera AR, Barbosa BR, Simpson CS, Redfearn DP, Methot M, et al. Acquired long QT interval: a case series of multifactorial QT prolongation. Clin Cardiol. 2011;34:577–82.

    Article  PubMed  Google Scholar 

  33. Girardin FR, Gex-Fabry M, Berney P, Shah D, Gaspoz JM, Dayer P. Drug-induced long QT in adult psychiatric inpatients: the 5-year cross-sectional ECG screening outcome in psychiatry study. Am J Psychiat. 2013;170:1468–76.

    Article  PubMed  Google Scholar 

  34. Woosley RL, Romero K. Assessing cardiovascular drug safety for clinical decision-making. Nat Rev Cardiol. 2013;10:330–7.

    Article  PubMed  Google Scholar 

Download references

Funding

Ph.D. student E.V. is supported by funding of the Belgian government agency for Innovation by Science and Technology (IWT). R.W. is supported as a clinical researcher by the Fund for Scientific Research Flanders.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, O&N2, Box 521, 3000, Leuven, Belgium

    Eline Vandael & Veerle Foulon

  2. Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium

    Bert Vandenberk & Rik Willems

  3. Department of Cardiology, University Hospitals Leuven, 3000, Leuven, Belgium

    Bert Vandenberk & Rik Willems

  4. Department of Neurosciences, KU Leuven, 3000, Leuven, Belgium

    Joris Vandenberghe

  5. Department of Psychiatry, University Hospitals Leuven, 3000, Leuven, Belgium

    Joris Vandenberghe

Authors
  1. Eline Vandael
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bert Vandenberk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joris Vandenberghe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rik Willems
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Veerle Foulon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eline Vandael.

Ethics declarations

Conflicts of interest

None.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 299 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vandael, E., Vandenberk, B., Vandenberghe, J. et al. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm 39, 16–25 (2017). https://doi.org/10.1007/s11096-016-0414-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11096-016-0414-2

Keywords

Search

Navigation