(Circulation. 1996;94:2535-2541.)
© 1996 American Heart Association, Inc.
Articles |
Sex Difference in Risk of Torsade de Pointes With d,l-Sotalol
the Arrhythmia Center, Department of Medicine/Division of Cardiology, Sinai Hospital, Detroit, Mich (M.H.L.), and Bristol-Myers Squibb Co, Princeton, NJ (S.H., D.A., B.Q., D.J.M.).
Correspondence to Michael H. Lehmann, MD, Arrhythmia Center/Sinai Hospital, 14800 W McNichols, Suite 314, Detroit, MI 48235.
Background The present study was undertaken to test the hypothesis that women are more prone than men to develop torsade de pointes (TdP) in a defined cohort of patients exposed to the QT-prolonging antiarrhythmic drug d,l-sotalol.
Methods and Results In a database derived from 22 clinical trials involving 3135 adult patients who received oral d,l-sotalol (median follow-up, 164 days), TdP developed in 44 (1.9%) of 2336 men and in 33 (4.1%) of 799 women (P<.001). Logistic regression analysis identified female sex (P<.0001), presenting arrhythmia of sustained ventricular tachycardia or fibrillation (P<.0001), history of congestive heart failure (P<.001), and d,l-sotalol dose >320 mg/d (P<.001) as factors most predictive of TdP; in addition to these, a serum creatinine >1.4 mg/dL in women and >1.6 mg/dL in men was weakly predictive (P<.05). After adjustment for these risk factors, women had threefold greater odds of developing TdP than men. The sex difference in TdP risk was age independent and could not be explained by differential dose-related bradycardic responses in women versus men.
Conclusions Women are at increased risk of developing TdP during administration of d,l-sotalol. This finding needs to be taken into account, together with other TdP risk factors, when patients are treated with this antiarrhythmic agent. Given the consistency between the present and other recent observations, greater caution in women regarding use of QT-prolonging drugs, in general, is advisable.
Key Words: antiarrhythmia agents • death, sudden • sex • torsade de pointes • women
This article has been cited by other articles:
 |
|
 |
|
  J. P. Piccini, V. Hasselblad, E. D. Peterson, J. B. Washam, R. M. Califf, and D. F. Kong Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J. Am. Coll. Cardiol., September 15, 2009; 54(12): 1089 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maguy, S. Le Bouter, P. Comtois, D. Chartier, L. Villeneuve, R. Wakili, K. Nishida, and S. Nattel Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers: A Potential Role in Conduction Abnormalities Associated With Congestive Heart Failure Circ. Res., May 8, 2009; 104(9): 1113 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Michael, L. Xiao, X.-Y. Qi, D. Dobrev, and S. Nattel Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis Cardiovasc Res, February 15, 2009; 81(3): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D Tobin, M. Kahonen, P. Braund, T. Nieminen, C. Hajat, M. Tomaszewski, J. Viik, R. Lehtinen, G A. Ng, P. W Macfarlane, et al. Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations Int. J. Epidemiol., October 1, 2008; 37(5): 1132 - 1141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Matyal Newly Appreciated Pathophysiology of Ischemic Heart Disease in Women Mandates Changes in Perioperative Management: A Core Review Anesth. Analg., July 1, 2008; 107(1): 37 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kurokawa, M. Tamagawa, N. Harada, S.-i. Honda, C.-X. Bai, H. Nakaya, and T. Furukawa Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization J. Physiol., June 15, 2008; 586(12): 2961 - 2973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-R. Neuberger, C. Mewis, D. J. van Veldhuisen, U. Schotten, I. C. van Gelder, M. A. Allessie, and M. Bohm Management of atrial fibrillation in patients with heart failure Eur. Heart J., November 1, 2007; 28(21): 2568 - 2577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Shantsila, T. Watson, and G. Y. Lip Drug-induced QT-interval prolongation and proarrhythmic risk in the treatment of atrial arrhythmias Europace, September 1, 2007; 9(suppl_4): iv37 - iv44. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Blauwet, S. N. Hayes, D. McManus, R. F. Redberg, and M. N. Walsh Low Rate of Sex-Specific Result Reporting in Cardiovascular Trials Mayo Clin. Proc., February 1, 2007; 82(2): 166 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Imboden, H. Swan, I. Denjoy, I. M. Van Langen, P. J. Latinen-Forsblom, C. Napolitano, V. Fressart, G. Breithardt, M. Berthet, S. Priori, et al. Female Predominance and Transmission Distortion in the Long-QT Syndrome N. Engl. J. Med., December 28, 2006; 355(26): 2744 - 2751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Schulze-Bahr Arrhythmia Predisposition: Between Rare Disease Paradigms and Common Ion Channel Gene Variants J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A67 - A78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
|
|
Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xiao, L. Zhang, W. Han, Z. Wang, and S. Nattel Sex-based transmural differences in cardiac repolarization and ionic-current properties in canine left ventricles Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H570 - H580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tsuji, S. Zicha, X.-Y. Qi, I. Kodama, and S. Nattel Potassium Channel Subunit Remodeling in Rabbits Exposed to Long-Term Bradycardia or Tachycardia: Discrete Arrhythmogenic Consequences Related to Differential Delayed-Rectifier Changes Circulation, January 24, 2006; 113(3): 345 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Kerr and K. Humphries Gender-Related Differences in Atrial Fibrillation J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1307 - 1308. [Full Text] [PDF]
|
|
|
|
|
|
C.-X. Bai, J. Kurokawa, M. Tamagawa, H. Nakaya, and T. Furukawa Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone Circulation, September 20, 2005; 112(12): 1701 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rubinstein, P. J. Zimetbaum, M. E. Josephson, A. Schlegel, K. R. Desai, B. N. Singh, S. N. Singh, and D. Reda Amiodarone versus sotalol for atrial fibrillation. N. Engl. J. Med., August 11, 2005; 353(6): 627 - 630. [Full Text] [PDF]
|
|
|
|
|
|
N. Jochmann, K. Stangl, E. Garbe, G. Baumann, and V. Stangl Female-specific aspects in the pharmacotherapy of chronic cardiovascular diseases Eur. Heart J., August 2, 2005; 26(16): 1585 - 1595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Kaufman, P. A. Zimmermann, T. Wang, G. W. Dennish III, P. D. Barrell, M. L. Chandler, H. L. Greene, and AFFIRM Investigators Risk of proarrhythmic events in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study: A multivariate analysis J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1276 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Amabile and A. P. Spencer Keeping Your Patient With Heart Failure Safe: A Review of Potentially Dangerous Medications Arch Intern Med, April 12, 2004; 164(7): 709 - 720. [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antzelevitch, L. Belardinelli, L. Wu, H. Fraser, A. C. Zygmunt, A. Burashnikov, J. M. Di Diego, J. M. Fish, J. M. Cordeiro, R. J. Goodrow Jr, et al. Electrophysiologic Properties and Antiarrhythmic Actions of a Novel Antianginal Agent Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2004; 9(1_suppl): S65 - S83. [Abstract] [PDF]
|
|
|
|
|
|
J.-S. Hulot, J.-L. Demolis, R. Riviere, S. Strabach, S. Christin-Maitre, and C. Funck-Brentano Influence of endogenous oestrogens on QT interval duration Eur. Heart J., September 2, 2003; 24(18): 1663 - 1667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Bezzina, A. O. Verkerk, A. Busjahn, A. Jeron, J. Erdmann, T. T. Koopmann, Z. A. Bhuiyan, R. Wilders, M. M.A.M. Mannens, H. L. Tan, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization Cardiovasc Res, July 1, 2003; 59(1): 27 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kaab, M. Hinterseer, M. Nabauer, and G. Steinbeck Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome--a case-control pilot study using i.v. sotalol Eur. Heart J., April 1, 2003; 24(7): 649 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. H.T. Wehrens, M. A. Vos, P. A. Doevendans, and H. J.J. Wellens Novel Insights in the Congenital Long QT Syndrome Ann Intern Med, December 17, 2002; 137(12): 981 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Pietila, H. Fodstad, E. Niskasaari, P.a. J. Laitinen, H. Swan, M. Savolainen, Y. A. Kesaniemi, K. Kontula, and H. V. Huikuri association between HERG K897T polymorphism and QT interval in middle-aged finnish women J. Am. Coll. Cardiol., August 7, 2002; 40(3): 511 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Sade, A. Oto, A. Oto, Z. Oner, A. Daver, O. Onalan, B. Bilezikci, and L. Tokgozoglu Adrenal Adenoma Presenting with Torsade de Pointes: A Case Report Angiology, July 1, 2002; 53(4): 471 - 474. [Abstract] [PDF]
|
|
|
|
|
|
T. V. Pham and M. R. Rosen Sex, hormones, and repolarization Cardiovasc Res, February 15, 2002; 53(3): 740 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. V Pham, R. B Robinson, P. Danilo Jr, and M. R Rosen Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current Cardiovasc Res, February 15, 2002; 53(3): 752 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wu and M. E Anderson Reduced repolarization reserve in ventricular myocytes from female mice Cardiovasc Res, February 15, 2002; 53(3): 763 - 769. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Conrath, A. A.M Wilde, R. J.E Jongbloed, M. Alders, I. M van Langen, J Peter van Tintelen, P. A Doevendans, and T. Opthof Gender differences in the long QT syndrome: effects of {beta}-adrenoceptor blockade Cardiovasc Res, February 15, 2002; 53(3): 770 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Eckardt, G. Breithardt, and W. Haverkamp Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 64 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B Huang, D Qin, and N El-Sherif Spatial alterations of Kv channels expression and K+ currents in post-MI remodeled rat heart Cardiovasc Res, November 1, 2001; 52(2): 246 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Han, D. Chartier, D. Li, and S. Nattel Ionic Remodeling of Cardiac Purkinje Cells by Congestive Heart Failure Circulation, October 23, 2001; 104(17): 2095 - 2100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-D. Drici Influence of gender on drug-acquired long QT syndrome Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K41 - K47. [Abstract] [PDF]
|
|
|
|
|
|
E. Schulze-Bahr, W. Haverkamp, L. Eckardt, P. Kirchhof, H. Wedekind, and G. Breithardt Genetic aspects in acquired long QT syndrome -- a piece in the puzzle Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K48 - K52. [Abstract] [PDF]
|
|
|
|
|
|
W. Haverkamp, L. Eckardt, G. Monnig, E. Schulze-Bahr, H. Wedekind, P. Kirchhof, F. Haverkamp, and G. Breithardt Clinical aspects of ventricular arrhythmias associated with QT prolongation Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K81 - K88. [Abstract] [PDF]
|
|
|
|
|
|
T. V. Pham, E. A. Sosunov, R. Z. Gainullin, P. Danilo Jr, and M. R. Rosen Impact of Sex and Gonadal Steroids on Prolongation of Ventricular Repolarization and Arrhythmias Induced by IK-Blocking Drugs Circulation, May 1, 2001; 103(17): 2207 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Rodriguez, M. J. Kilborn, X.-K. Liu, J. C. Pezzullo, and R. L. Woosley Drug-Induced QT Prolongation in Women During the Menstrual Cycle JAMA, March 14, 2001; 285(10): 1322 - 1326. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lande, F. Kyndt, I. Baro, D. Chabannes, P. Boisseau, J.-C. Pony, D. Escande, and H. Le Marec Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype Eur. Heart J., March 1, 2001; 22(5): 410 - 422. [Abstract] [PDF]
|
|
|
|
|
|
S. Nattel Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders Cardiovasc Res, November 1, 2000; 48(2): 188 - 190. [Full Text] [PDF]
|
|
|
|
|
|
W Haverkamp, G Breithardt, A.J Camm, M.J Janse, M.R Rosen, C Antzelevitch, D Escande, M Franz, M Malik, A Moss, 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., August 1, 2000; 21(15): 1216 - 1231. [PDF]
|
|
|
|
|
|
W. Han, Z. Wang, and S. Nattel A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H466 - H474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Haverkamp, G. Breithardt, A.J. Camm, M. J Janse, M. R Rosen, C. Antzelevitch, D. Escande, M. Franz, M. Malik, A. Moss, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications: Report on a Policy Conference of the European Society of Cardiology Cardiovasc Res, August 1, 2000; 47(2): 219 - 233. [Full Text] [PDF]
|
|
|
|
|
|
M. C. Petrie, N. F. Dawson, D. R. Murdoch, A. P. Davie, and J. J. V. McMurray Failure of Women's Hearts Circulation, May 4, 1999; 99(17): 2334 - 2341. [Full Text] [PDF]
|
|
|
|
|
|
C. Rizza, M. Valderrabano, and B. N. Singh Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1999; 4(2): 129 - 134. [Abstract] [PDF]
|
|
|
|
|
|
X.-K. Liu, A. Katchman, S. N. Ebert, and R. L. Woosley The Antiestrogen Tamoxifen Blocks the Delayed Rectifier Potassium Current, IKr, in Rabbit Ventricular Myocytes J. Pharmacol. Exp. Ther., December 1, 1998; 287(3): 877 - 883. [Abstract] [Full Text]
|
|
|
|
|
|
M.-D. Drici, B. C. Knollmann, W.-X. Wang, and R. L. Woosley Cardiac Actions of Erythromycin: Influence of Female Sex JAMA, November 25, 1998; 280(20): 1774 - 1776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Babij, G. R. Askew, B. Nieuwenhuijsen, C.-M. Su, T. R. Bridal, B. Jow, T. M. Argentieri, J. Kulik, L. J. DeGennaro, W. Spinelli, et al. Inhibition of Cardiac Delayed Rectifier K+ Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice Circ. Res., September 21, 1998; 83(6): 668 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Marsh, M. H. Lehmann, R. H. Ritchie, J. K. Gwathmey, G. E. Green, and R. J. Schiebinger Androgen Receptors Mediate Hypertrophy in Cardiac Myocytes Circulation, July 21, 1998; 98(3): 256 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hara, P. Danilo Jr., and M. R. Rosen Effects of Gonadal Steroids on Ventricular Repolarization and on the Response to E4031 J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1068 - 1072. [Abstract] [Full Text]
|
|
|
|
|
|
X.-K. Liu, A. Katchman, M.-D. Drici, S. N. Ebert, I. Ducic, M. Morad, and R. L. Woosley Gender Difference in the Cycle Length-Dependent QT and Potassium Currents in Rabbits J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 672 - 679. [Abstract] [Full Text]
|
|
|
|
|
|
A. A. Grace and A. J. Camm Quinidine N. Engl. J. Med., January 1, 1998; 338(1): 35 - 45. [Full Text] [PDF]
|
|