NIH Public Access Author Manuscript Europace. Author manuscript; available in PMC 2008 December 10.

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1 NIH Public Access Author Manuscript Published in final edited form as: Europace September ; 9(Suppl 4): iv1 iv3. doi: /europace/eum165. On the relationship among QT interval, atrial fibrillation, and torsades de pointes Dan M. Roden, M.D., Prince Kannankeril, M.D., M.S.C.I., and Dawood Darbar, M.D., Ph.D. Departments of Medicine. Pediatrics, and Pharmacology, Vanderbilt University School of Medicine, Nashville The uncommon congenital syndromes of QT prolongation associated with a high risk of sudden death were first described in the 1950s and 1960s, 1 3 and the term torsades de pointes was coined in the mid-1960s to describe the peculiar polymorphic ventricular tachycardia that can arise at slow heart rates when the QT is very long. 4 The notion that drugs could produce a very similar clinical syndrome, with striking QT prolongation and polymorphic tachycardia, was first noted in the same era, 5,6 and became increasingly well recognized with antiarrhythmic therapies during the 1970s and 1980s. The idea that non-cardiovascular drugs could prolong the QT interval, and trigger torsades de pointes (or even sudden death), remained an arrhythmia curiosity until the initial report of terfenadine-associated torsades de pointes in the late 1980s. 7 Review of the extant safety data, and a series of clinical and in vitro mechanistic studies, identified inhibition of CYP3A4-mediated terfenadine biotransformation to an antihistamine metabolite (fexofenadine) as the major mechanism Terfenadine itself turned out to be a very potent QT prolonging agent, and that is now well recognized as a reflection of its ability to block the rapid component of the cardiac delayed rectifier I Kr. Indeed, block of I Kr, or in occasional instances reduction of the current by other mechanisms, 11,12 is the major mechanism underlying virtually all forms of drug-induced torsades de pointes. 13 The reason the terfenadine incident proved so important for drug development was not only the elucidation of underlying mechanisms, but also the recognition that a even a small risk of a very serious side effect, such as drug-induced torsades de pointes, could upset the balance between risk and benefit that goes into the prescription of any drug. In the case of terfenadine, regulatory agencies viewed the benefit as reduction of relatively mild symptoms, and thus even a small risk of torsades de pointes was viewed as quite ominous. A series of regulatory opinions over the last decade and half has now culminated in a consensus view that all new drug entities should be evaluated for QT prolonging potential usually through a thorough QT trial, and that drug-induced QT prolongation of as little as seconds (6 milliseconds) may indicate that the new drug in question will receive greater regulatory scrutiny. 14,15 The notion that a 6 ms change in QT interval in an individual, or even in a population, could possibly have any physiologic or regulatory significance seems farfetched until one recognizes that this is exactly the degree of QT prolongation seen with usual doses of terfenadine. 16 Thus, the 6 ms signal is an indication for regulators and drug developers to examine further the likelihood that subgroups at special risk, such as those with underlying cardiovascular disease or those receiving interacting drugs, may be exposed. This concept has led to a series of debates during FDA hearings and other settings around new antipsychotic, antibiotic, and neurological drugs (to name a few) in which the relative risks are weighed against the potential benefits of new drug entities. These debates are inevitably characterized by discussion of the risk imposed by Correspondence: Dan M. Roden, M.D., Professor of Medicine and Pharmacology, Director, Oates Institute for Experimental Therapeutics, Assistant Vice-Chancellor for Personalized Medicine, Vanderbilt University School of Medicine, 1285 Medical Research Building IV, Nashville, TN 37232, Telephone: , Fax: , dan.roden@vanderbilt.edu.

2 Roden et al. Page 2 a given degree of QT prolongation within the population, since new drug studies are only conducted in several thousand patients at most, and even the riskiest of non-cardiovascular drugs producing QT prolongation will not generate even a single episode of torsades de pointes in such a small data set. That is, the acceptable incidence of torsades de pointes with noncardiovascular therapies is not well defined, but is certainly less that 1 in 10,000 or more patients exposed. By contrast, it is well recognized that antiarrhythmic drugs such as sotalol, dofetilide, ibutilide, and quinidine carry a torsades risk of 1% or more The mechanisms whereby these drugs produce torsades de pointes seems no different from others, and so one must assume that the increased incidence reflects enhanced risk among patients with certain forms of cardiovascular disease likely to be treated with these agents. Thus, while many risk factors have been described for drug-associated torsades de pointes (female gender, hypokalemia, slow heart rates and complete heart block, and DNA variants in ion channel or other genes), the presence of concomitant heart disease that is itself an indication for antiarrhythmic therapy seems a very powerful risk factor as well. Some clinical trials suggest that congestive heart failure 18,22 also contribute to this risk, and this would further help explain the higher incidence of torsades de pointes during antiarrhythmic therapy, compared to non-cardiovascular therapy that also blocks I Kr. The mechanisms whereby some patients seem to be at much higher risk than others remain incompletely understood. We have proposed the idea of repolarization reserve which suggests that multiple mechanisms contribute to normal repolarization, 23,24 so that removal of any one of these (by disease, subclinical mutation in an ion channel or other gene, etc.) may be without consequence until a drug is added at which point the reduced repolarization reserve becomes evident by marked QT prolongation and torsades de pointes. Atrial fibrillation is the current primary indication for antiarrhythmic drug therapy. 25 To date, drugs used to maintain sinus rhythm in patients with atrial fibrillation fall into one of three broad categories. The first are those whose electrophysiologic toxicity is characterized by QT prolongation and torsades de pointes. The second, exemplified by flecainide and perhaps propafenone, have sodium channel block as their major mechanisms of action and electrophysiologic toxicity due to excess sodium channel block is a risk with these agents; such toxicity can include atrial flutter with 1:1 AV conduction (also seen with other antiarrhythmics), as well as sustained ventricular tachycardia and an increase in sudden death in patients with coronary disease and recent myocardial infarction. 26,27 The third category of drugs used in the treatment of atrial fibrillation is mixed pharmacologic actions exemplified by amiodarone, which despite producing both sodium channel block and marked QT prolongation, does not produce much in the way of serious drug-related proarrhythmia. The mechanisms whereby by amiodarone can produce such striking QT prolongation and yet produce a small risk of torsades de pointes are incompletely understood; likely explanations include block of some inward arrhythmogenic current such as that through calcium channels or sodium calcium exchange, or decreased heterogeneity of action potential durations across the ventricular wall. The important point is that this experience demonstrates there is not a consistent link between the extent of QT prolongation and the risk of serious QT-related proarrhythmia. 28 One common clinical observation is that the vast majority of cases of torsades de pointes in patients with atrial fibrillation occur after conversion to sinus rhythm. 29 This may reflect the decrease in heart rate that often accompanies such conversion, but studies that we conducted in the late 1990s indicated that the mechanisms must be more complicated. In a small study, we examined the extent of QT prolongation by intravenous dofetilide during atrial fibrillation and shortly after conversion to sinus rhythm. Despite the fact that dofetilide did not change heart rate, the extent of QT prolongation was much greater in the sinus rhythm setting than in the atrial fibrillation setting. 30 Indeed, more recently, we have shown that QT-RR slopes are extraordinarily flat during atrial fibrillation (i.e. even with long pauses, the QT interval does

3 Roden et al. Page 3 References not prolong), and steepen very sharply, to greater than normal values, shortly after conversion to sinus rhythm. 31 We infer that atrial fibrillation itself may exert a heretofore poorly understood influence on the QT interval both during arrhythmia and shortly after its conversion to normal rhythm. Understanding the mechanisms underlying such an effect would be an important step towards understanding the increased risk of torsades de pointes when an I Kr blocker is used in a patient with atrial fibrillation. Detailed examination of the relationships among I Kr block, action potential prolongation, heterogeneity of repolarization times, perturbed intracellular calcium control, torsades de pointes, and its potential degeneration to ventricular fibrillation have provided a superb model for translational science. Advances have been made by scientists at all levels of this chain of evidence that links I Kr block to sudden death, from basic and clinical geneticists and electrophysiologists, to experts in regulatory science. Proarrhythmia and other forms of serious drug-related toxicity are the Achilles heel of drug therapy in atrial fibrillation. The development of new compounds with different targets of action and perhaps mixed drug effects (like amiodarone) may therefore represent an advance in the field, assuming efficacy can be demonstrated and no serious toxicity arises in clinical trials or in post-marketing surveillance; AZD7009 is one example of a series of drugs under development with this rationale. In this supplement, the science around this chain of evidence is examined in a series of manuscripts. Charles Antzelevitch reviews the ionic, molecular, and cellular of QTY prolongation and torsades. Shantsila, Watson, and Lip examine in further detail the relationship between QT prolongation and torsades, especially in the setting of treatment for AF. Darpo describes the problems in identifying cases of drug-induced arrhythmias, and finally Ahmad and Dorian probe the question of whether there is an inevitable relationship between QT prolongation and proarrhythmia. It is clear that new drugs lacking proarrhythmic or other serious toxicity potential would provide important new tools to practitioners who are seeing large numbers of patients with symptomatic atrial fibrillation for whom currently available therapies are unsuitable. 1. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J 1957;54: [PubMed: ] 2. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare in eta pediatrica. Clin Pediatr 1963;45: Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc 1964;54: Dessertenne F. La tachycardie ventriculaire à deux foyers opposés variables. Arch Mal Coeur 1966;59: [PubMed: ] 5. Selzer A, Wray HW. Quinidine syncope, paroxysmal ventricular fibrillations occurring during treatment of chronic atrial arrhythmias. Circulation 1964;30:17. [PubMed: ] 6. Redleaf PD, Lerner IJ. Thiazide-induced hypokalemia with associated major ventricular arrhythmias: Report of a case and comment on therapeutic use of bretylium. JAMA 1968;608: [PubMed: ] 7. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr. Torsades de pointes occurring in association with terfenadine use. JAMA 1990;264: [PubMed: ] 8. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992;52: [PubMed: ] 9. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993;269: [PubMed: ]

4 Roden et al. Page Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993;269: [PubMed: ] 11. Ficker E, Kuryshev YA, Dennis AT, Obejero-Paz C, Wang L, Hawryluk P, Wible BA, Brown AM. Mechanisms of arsenic-induced prolongation of cardiac repolarization. Mol Pharmacol 2004;66: [PubMed: ] 12. Kuryshev YA, Ficker E, Wang L, Hawryluk P, Dennis AT, Wible BA, Brown AM, Kang J, Chen XL, Sawamura K, Reynolds W, Rampe D. Pentamidine-induced long QT syndrome and block of herg trafficking. J Pharmacol Exp Ther 2005;312: [PubMed: ] 13. Roden DM, Viswanathan PC. Genetics of acquired long QT syndrome. J Clin Invest 2005;115: [PubMed: ] 14. Darpo B, Nebout T, Sager PT. Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline. J Clin Pharmacol 2006;46: [PubMed: ] 15. Shah RR. Drugs, QTc interval prolongation and final ICH E14 guideline : an important milestone with challenges ahead. Drug Saf 2005;28: [PubMed: ] 16. Pratt CM, Ruberg S, Morganroth J, McNutt B, Woodward J, Harris S, Ruskin J, Moye L. Doseresponse relation between terfenadine (Seldane) and the QTc interval on the scalar electrocardiogram: distinguishing a drug effect from spontaneous variability. Am Heart J 1996;131: [PubMed: ] 17. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990;65:74A 81A. 18. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999;341: [PubMed: ] 19. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. Circulation 1990;82: [PubMed: ] 20. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986;111: [PubMed: ] 21. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK, VanderLugt JT. The Ibutilide Repeat Dose Study Investigators. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Circulation 1996;94: [PubMed: ] 22. Kober L, Bloch Thomsen PE, Moller M, Torp-Pedersen C, Carlsen J, Sandoe E, Egstrup K, Agner E, Videbaek J, Marchant B, Camm AJ. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study Group. Lancet 2000;356: [PubMed: ] 23. Roden DM. Taking the idio out of idiosyncratic - predicting torsades de pointes. PACE 1998;21: [PubMed: ] 24. Roden DM. Long QT syndrome: reduced repolarization reserve and the genetic link. J Intern Med 2006;259: [PubMed: ] 25. Darbar D, Roden DM. Future of antiarrhythmic drugs. Curr Opin Cardiol 2006;21: [PubMed: ] 26. Roden, DM.; Anderson, ME. Proarrhythmia. In: Kass, RS.; Clancy, CE., editors. Antiarrhythmic Therapy. Springer-Verlag; Naccarelli GV, Wolbrette DL, Luck JC. Proarrhythmia. Med Clin North Am 2001;85: [PubMed: ]xii 28. Hondeghem LM. Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T- wave, incriminates safe drugs, and misses profibrillatory drugs. J Cardiovasc Electrophysiol 2006;17: [PubMed: ] 29. Koster RW, Wellens HJJ. Quinidine-induced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;38: [PubMed: ]

5 Roden et al. Page Choy AMJ, Darbar D, Dell Orto S, Roden DM. Increased sensitivity to QT prolonging drug therapy immediately after cardioversion to sinus rhythm. J Am Coll Cardiol 1999;34: [PubMed: ] 31. Darbar D, Harris PA, Hardy A, Frye-Anderson A, White B, Norris KJ, Roden DM. Marked steepening of QT restitution following cardioversion of atrial fibrillation. Heart Rhythm 2004;1:S192.