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Determinants of Torsades de Pointes in Older Patients with Drug-Associated Long QT Syndrome: A Case-Control Study

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A Commentary to this article was published on 15 July 2014

Abstract

Objective

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS.

Methods

In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP.

Results

The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64–0.88) and a QT cutoff of 550 ms.

Conclusion

The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

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References

  1. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013–22. doi:10.1056/NEJMra032426.

    Article  CAS  PubMed  Google Scholar 

  2. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289(16):2120–7. doi:10.1001/jama.289.16.2120.

    Article  PubMed  Google Scholar 

  3. Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J Suppl. 2001;3(Suppl K):K70–80.

    Article  CAS  Google Scholar 

  4. Poluzzi E, Raschi E, Moretti U, De Ponti F. Drug-induced torsades de pointes: data mining of the public version of the FDA Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf. 2009;18(6):512–8. doi:10.1002/pds.1746.

    Article  CAS  PubMed  Google Scholar 

  5. Molokhia M, Pathak A, Lapeyre-Mestre M, Caturla L, Montastruc JL, McKeigue P. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br J Clin Pharmacol. 2008;66(3):386–95. doi:10.1111/j.1365-2125.2008.03229.x.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Sauer AJ, Newton-Cheh C. Clinical and genetic determinants of torsade de pointes risk. Circulation. 2012;125(13):1684–94. doi:10.1161/CIRCULATIONAHA.111.080887.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov. 2003;2(6):439–47. doi:10.1038/nrd1108.

    Article  CAS  PubMed  Google Scholar 

  8. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21(15):1216–31. doi:10.1053/euhj.2000.2249.

    Article  CAS  PubMed  Google Scholar 

  9. Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wolbrette DL. Risk of proarrhythmia with class III antiarrhythmic agents: sex-based differences and other issues. Am J Cardiol. 2003;91(6A):39D–44D.

    Article  CAS  PubMed  Google Scholar 

  11. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine. 2003;82(4):282–90. doi:10.1097/01.md.0000085057.63483.9b.

    PubMed  Google Scholar 

  12. Timour Q, Frassati D, Descotes J, Chevalier P, Christe G, Chahine M. Sudden death of cardiac origin and psychotropic drugs. Front Pharmacol. 2012;3:76. doi:10.3389/fphar.2012.00076.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Curtis LH, Ostbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al-Khatib SM, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med. 2003;114(2):135–41.

    Article  CAS  PubMed  Google Scholar 

  14. De Ponti F, Poluzzi E, Vaccheri A, Bergman U, Bjerrum L, Ferguson J, et al. Non-antiarrhythmic drugs prolonging the QT interval: considerable use in seven countries. Br J Clin Pharmacol. 2002;54(2):171–7.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Raschi E, Poluzzi E, Zuliani C, Muller A, Goossens H, De Ponti F. Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8-year period. Br J Clin Pharmacol. 2009;67(1):88–98. doi:10.1111/j.1365-2125.2008.03319.x.

    Article  PubMed Central  PubMed  Google Scholar 

  16. 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(4):479–87. doi:10.1161/CIRCOUTCOMES.113.000152.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270(21):2590–7.

    Article  CAS  PubMed  Google Scholar 

  18. Vieweg WV, Wood MA, Fernandez A, Beatty-Brooks M, Hasnain M, Pandurangi AK. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26(12):997–1012. doi:10.2165/11318880-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  19. Darbar D, Kimbrough J, Jawaid A, McCray R, Ritchie MD, Roden DM. Persistent atrial fibrillation is associated with reduced risk of torsades de pointes in patients with drug-induced long QT syndrome. J Am Coll Cardiol. 2008;51(8):836–42. doi:10.1016/j.jacc.2007.09.066.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf. 1999;20(2):109–17.

    Article  CAS  PubMed  Google Scholar 

  21. Strnadova C. The assessment of QT/QTc interval prolongation in clinical trials: a regulatory perspective. Drug Inf J. 2005;39:407–33.

    Google Scholar 

  22. US Food and Drug Administration. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Guidance for industry 2005. Available from: http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm. Accessed 14 Apr 2014.

  23. Houltz B, Darpo B, Edvardsson N, Blomstrom P, Brachmann J, Crijns HJ, et al. Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study. Pacing Clin Electrophysiol. 1998;21(5):1044–57.

    Article  CAS  PubMed  Google Scholar 

  24. Buse A. The likelihood ratio, Wald, and Lagrange multiplier tests: an expository note. Am Stat. 1982;36(3):153–7.

    Article  Google Scholar 

  25. Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavrielatos G, Alexanian IP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol. 2009;98(4):208–12. doi:10.1007/s00392-008-0741-y.

    Article  PubMed  Google Scholar 

  26. Wang L, Wible BA, Wan X, Ficker E. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther. 2007;320(2):525–34. doi:10.1124/jpet.106.113043.

    Article  CAS  PubMed  Google Scholar 

  27. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects: a review with special reference to torsade de pointes tachycardia. Ann Intern Med. 1994;121(7):529–35.

    Article  CAS  PubMed  Google Scholar 

  28. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, et al. The long QT syndrome: prospective longitudinal study of 328 families. Circulation. 1991;84(3):1136–44.

    Article  CAS  PubMed  Google Scholar 

  29. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866–74. doi:10.1056/NEJMoa022147.

    Article  PubMed  Google Scholar 

  30. Ward DE. Prolongation of the QT interval as an indicator of risk of a cardiac event. Eur Heart J. 1988;9(Suppl G):139–44.

    Article  PubMed  Google Scholar 

  31. Hreiche R, Morissette P, Turgeon J. Drug-induced long QT syndrome in women: review of current evidence and remaining gaps. Gender Med. 2008;5(2):124–35. doi:10.1016/j.genm.2008.05.005.

    Article  Google Scholar 

  32. Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8(7):690–5.

    CAS  PubMed  Google Scholar 

  33. Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol. 1993;72(6):17B–22B.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Malik M, Farbom P, Batchvarov V, Hnatkova K, Camm AJ. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart. 2002;87(3):220–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Davey P. How to correct the QT interval for the effects of heart rate in clinical studies. J Pharmacol Toxicol Methods. 2002;48(1):3–9. doi:10.1016/S1056-8719(03)00008-X.

    Article  CAS  PubMed  Google Scholar 

  37. Joy JP, Coulter CV, Duffull SB, Isbister GK. Prediction of torsade de pointes from the QT interval: analysis of a case series of amisulpride overdoses. Clin Pharmacol Ther. 2011;90(2):243–5. doi:10.1038/clpt.2011.107.

    Article  CAS  PubMed  Google Scholar 

  38. Garnett CE, Zhu H, Malik M, Fossa AA, Zhang J, Badilini F, et al. Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am Heart J. 2012;163(6):912–30. doi:10.1016/j.ahj.2012.02.023.

    Article  PubMed  Google Scholar 

  39. Malik M. The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes. Pacing Clin Electrophysiol. 2002;25(2):209–16.

    Article  PubMed  Google Scholar 

  40. Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354(9190):1625–33. doi:10.1016/S0140-6736(99)02107-8.

    Article  CAS  PubMed  Google Scholar 

  41. Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, et al. Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes. Am J Cardiol. 1992;69(6):628–33.

    Article  CAS  PubMed  Google Scholar 

  42. Topilski I, Rogowski O, Rosso R, Justo D, Copperman Y, Glikson M, et al. The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias. J Am Coll Cardiol. 2007;49(3):320–8. doi:10.1016/j.jacc.2006.08.058.

    Article  PubMed  Google Scholar 

  43. de Graaf L, Fabius MA, Diemont WL, van Puijenbroek EP. The Weber-curve pitfall: effects of a forced introduction on reporting rates and reported adverse reaction profiles. Pharm World Sci. 2003;25(6):260–3.

    Article  PubMed  Google Scholar 

  44. Zabel M, Portnoy S, Franz MR. Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study. J Am Coll Cardiol. 1995;25(3):746–52. doi:10.1016/0735-1097(94)00446-W.

    Article  CAS  PubMed  Google Scholar 

  45. Yan GX, Lankipalli RS, Burke JF, Musco S, Kowey PR. Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance. J Am Coll Cardiol. 2003;42(3):401–9.

    Article  PubMed  Google Scholar 

  46. Antzelevitch C. Cardiac repolarization : the long and short of it. Europace. 2005;7(Suppl 2):3–9. doi:10.1016/j.eupc.2005.05.010.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The French Association of Pharmacovigilance Centres (Association Française des Centres Régionaux de Pharmacovigilance) is gratefully acknowledged for allowing access to the data. The authors had full control of primary data from pharmacovigilance reports.

Conflicts of interest

This work was not supported by any academic, company, or sponsor fund. Sylvain Goutelle, Elodie Sidolle, Michel Ducher, Jacques Caron, Quadiri Timour, Patrice Nony and Aurore Gouraud have no conflicts of interest that are relevant to the content of this study. This work has been presented in part as an oral communication at the 6th meeting of the French Societies of Physiology, Pharmacology and Therapeutics (P2T), Grenoble, 22–24 March 2011, and this presentation has been published as an abstract in Fundamental and Clinical Pharmacology 2011;25(Suppl 1):97 [abstract no. 488].

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Authors and Affiliations

  1. Hospices Civils de Lyon, Groupement Hospitalier de Gériatrie, Service Pharmaceutique, Lyon, France

    Sylvain Goutelle, Elodie Sidolle & Michel Ducher

  2. Département de Pharmacologie, Physiologie et Toxicologie, Faculté de Pharmacie de Lyon, ISPB, Université Lyon 1, Lyon, France

    Sylvain Goutelle

  3. Laboratoire de Biométrie et Biologie Evolutive, Université Lyon 1, UMR CNRS 5558, Villeurbanne, France

    Sylvain Goutelle & Patrice Nony

  4. CHRU de Lille, Centre Régional de Pharmacovigilance, Service de Pharmacologie, Lille, France

    Jacques Caron

  5. Hospices Civils de Lyon, Centre Régional de Pharmacovigilance, Lyon, France

    Quadiri Timour & Aurore Gouraud

  6. Laboratoire de Pharmacologie Médicale, EA 4612 Neurocardiologie: Physiopathologie des troubles du Rythme Cardiaque, Université Lyon 1, Lyon, France

    Quadiri Timour

  7. Hospices Civils de Lyon, Service de Pharmacologie Clinique, Lyon, France

    Patrice Nony

  8. Pharmacie, Hôpital Pierre Garraud, 136 rue du Commandant Charcot, 69005, Lyon, France

    Sylvain Goutelle

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  1. Sylvain Goutelle
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  2. Elodie Sidolle
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Correspondence to Sylvain Goutelle.

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Goutelle, S., Sidolle, E., Ducher, M. et al. Determinants of Torsades de Pointes in Older Patients with Drug-Associated Long QT Syndrome: A Case-Control Study. Drugs Aging 31, 601–609 (2014). https://doi.org/10.1007/s40266-014-0188-y

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