Dofetilide (Tikosyn): a new drug to control atrial fibrillation

Dofetilide, a new class III antiarrhythmic agent, selectively blocks a specific cardiac potassium channel, IKr, increasing the effective refractory period of the myocyte and thereby terminating reentrant arrhythmias. Given orally, it appears to effectively convert atrial fibrillation and atrial flutter to sinus rhythm and maintain sinus rhythm after conversion in appropriately selected patients. This paper reviews the pharmacology of dofetilide, the evidence of its effectiveness, and the appropriate precautions in using it. KEY POINTS: Dofetilide is generally well tolerated but like other class III drugs can cause torsades de pointes. The risk is dose-dependent and can be minimized by adjusting the dosage according to creatinine clearance and QT interval, by excluding patients with known risk factors for long QT syndrome and torsades de pointes, and by starting treatment in an inpatient monitored setting for the first 3 days. Unlike other antiarrhythmic agents, oral dofetilide did not increase the mortality rate in clinical studies in postmyocardial infarction patients or those with congestive heart failure at high risk for sudden cardiac death. Concomitant use of drugs that increase the plasma level of dofetilide is contraindicated; these include cimetidine, ketoconazole, trimethoprim-sulfamethoxazole, and verapamil.     

Dofetilide: a new class III antiarrhythmic agent

Dofetilide is a relatively new class III antiarrhythmic agent that selectively blocks the rapid component of the cardiac ion channel delayed rectifier current. This results in an increase in the action potential duration and effective refractory period of the myocyte, thereby terminating reentrant tachyarrhythmias and preventing their re-induction. Oral dofetilide is effective in the conversion of atrial fibrillation and flutter to sinus rhythm and in the maintenance of sinus rhythm after conversion. It is generally well tolerated but like other antiarrhythmic agents in its class, torsades de pointes may be induced as a consequence of therapy. This risk is minimized by dosage adjustment according to creatinine clearance and QT(c) interval, by selecting patients without known risk factors for torsades and by initiating treatment in a monitored hospital setting for the first 3 days. Unlike other antiarrhythmic agents, oral dofetilide did not increase mortality in patients with a recent myocardial infarction or congestive heart failure, hence its importance as an alternative medication for the pharmacological conversion of atrial fibrillation and flutter, and maintenance of sinus rhythm after conversion in patients at high risk of sudden death.     

Antiarrhythmic and proarrhythmic properties of QT-prolonging antianginal drugs

In recent years there has been a major reorientation of drug therapy for cardiac arrhythmias, its changing role, and above all, a radical change in the class of arrhythmia drugs because of their impact on mortality. The decline in the use of sodium-channel blockers has led to an ex panding use of beta-blockers and simple or complex class III agents for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion-channel blocking properties that have less complex adverse reactions. The resulting so-called pure class III agents, such as dofetilide or ibutilide, were found to have antifibrillatory effects in atrial fibrillation and flutter and in ventricular tachyarrhythmias. Such agents are effective and have diversity, but they have come into therapeutics with a price: the sometimes-fatal torsades de pointes. The drug amiodarone, a complex compound that was synthesized as an antianginal agent, has been an exception in this regard. Its therapeutic use is associated with a negligibly low incidence of torsades de pointes, even though the drug produces significant bradycardia and QT lengthening to 500 to 700 msec. Recent electrophysiologic studies suggest that this paradox is likely due to the differential block of ion channels in endocardium, epicardium, midmyocardial (M) cells, and Purkinje fibers in the ventricular myocardium. There is also clinical evidence suggesting that amiodarone reduces the "torsadogenic" effects of pure class III agents. Ranolazine was also synthesized for the development of antianginal properties that stem from a partial inhibition of fatty acid oxidation; it too has been found to have electrophysioloigic properties. These are somewhat similar to those of amiodarone on ion channels in endocardium, epicardium, M cells, and Purkinje fibers in the ventricular myocardium, but the drug does not prolong the QT interval to the same extent as amiodarone does. Thus, the drug produces modest increases in repolarization as judged by its effects on the action potential duration (APD) without the potential for the development of torsades de pointes. By virtue of its suppressant action on early afterdepolarizations and triggered activity in Purkinje fibers and M cells, the drug appears to have a powerful potential for reducing the torsadogenic proclivity of conventional class III antiarrhythmic compounds. The rationale for the therapeutic niche for amiodarone, and especially in the case of ranolazine, in the prevention of drug-induced torsades de pointes is discussed.     

A Canine Model of Torsades de Pointes

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.     

Preventing torsades de pointes by careful cardiac monitoring in hospital settings

In the electrocardiogram, the QT interval represents the time it takes the ventricular myocardium to repolarize. Prolongation of the QT interval indicates congenital or acquired abnormality of cardiac membrane channels. In the critical care setting, acquired long QT interval most commonly results from administration of common pharmacologic agents, including some antiarrhythmics and antibiotics. Patients with prolonged QT interval may be at risk for developing torsades de pointes and cardiac arrest. Furthermore, new-onset bradyarrhythmias and electrolyte disorders may increase this risk. Warning signs of impending sustained torsades de pointes include occurrence of polymorphic ventricular ectopic complexes, T-wave alternans, and nonsustained polymorphic ventricular tachycardia. Measurement and documentation of the QT interval, corrected for heart rate (QTc), is an important component of cardiac monitoring in the critical care setting. When prolonged QTc occurs in patients at risk, specific clinical interventions must be implemented to prevent the occurrence of torsades de pointes.     

QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone

This report documents the occurrence of torsades de pointes (TdP) caused by marked QT interval prolongation in the case of a 71-year-old woman receiving both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The case highlights a previously unknown drug interaction. The role of inhibition of cytochrome P-450 CYP3A4 is discussed.     

Medikamentös induzierte Verlängerung des QT-Intervalls

Prolongation of the ventricular repolarisation manifests itself as a prolongation of the QT intervall on the surface ECG and represents a major risk for a special form of ventricular tachycardia called "torsades de pointes". Torsades de pointes are often self limited and are associated with palpitations, dizziness or syncope. Degeneration into ventricular fibrillation and sudden cardiac death can occur. In addition to the various forms of the congenital long QT syndrome many drugs, such as antiarrhythmic drugs class IA and III, antibiotics, antihistamines, antidepressants, and methadone are known to prolong the QT interval. Most of these drugs block a specific potassium channel substantially involved in the ventricular repolarisation. In addition, drug interaction or disturbances of drug metabolism may play a major role in the acquired form of the long QT syndrome. The individual risk and the potential of a pharmacologic substance to prolong the QT interval are not predictable. Certain risk factors identify patients at higher risk for drug-induced prolongation of the QT interval. Correctable factors include electrolyte disorders (e.g. hypokalemia) and concomitant administration of different QT prolonging drugs. External defibrillation is the therapy of choice in the hemodynamic unstable patient presenting torsades de pointes. In hemodynamic more stable patients application of intravenous magnesium can terminate torsades de pointes (membrane stabilizing properties). Temporary external or transvenous pacing at high heart rate might terminate incessant torsades de pointes by decreasing QT interval. Repeated ECG controls during therapy with QT prolonging drugs are mandatory, especially when drug doses are changed, additional drugs are prescribed, or in case of vomiting and diarrhea. QT prolongation in individual medical therapy is not always predictable. Therefore, updated lists of drugs with the potential of QT prolongation are available on the Internet (e.g. www.qtdrugs.org ).     

Early Afterdepolarizationlike Activity in Patients with Class IA Induced Long QT Syndrome and Torsades de Pointes

Early afterdepolarizations (EADs) have been linked to the mechanism of torsades de pointes in long QT syndrome. The purpose of this study was to investigate the role of EADs in Class IA induced torsades de pointes. We studied nine patients with Class IA induced torsades de pointes at the time this arrhythmia was present (acute period, n = 7) and after Class IA therapy was discontinued (chronic period, n = 6). ECCs and monophasic action potentials were recorded in both periods. In the chronic period, electrophysiological studies were performed before and after disopyramide infusion. In the acute period, QT_c interval was markedly prolonged (655 ± 32 ms^1/2), and EAD-like activity was recorded in all patients. QT_c interval returned to normal (428 ± 45 ms^1/2) and EAD-like activity disappeared after discontinuation of IA drug. Although, in the chronic period, disopyramide infusion prolonged QT_c interval from 428 ± 48 ms^1/2 to 479 ± 31 ms^1/2 and induced EAD in three of six patients, the degree was not as marked as observed in the acute period. EADs may play an important role in the genesis of long QT and torsades de pointes. Disopyramide infusion in the chronic period could not reproduce marked repolarization ahnormalities and torsades de pointes.     

Chronic methadone therapy complicated by torsades de pointes: a case report

Methadone is commonly used by patients presenting to the Emergency Department (ED). The common, acute side effects of central nervous system depression and respiratory depression are easily recognizable by treating physicians as attributable to methadone; however, the cardiac toxicity of chronic methadone use recently has only been recognized. Both chronic use of large doses and a recent increase in the daily dose of methadone have been associated with QT prolongation and subsequent development of torsades de pointes. We describe the case of a 40-year-old woman whose methadone dose recently had been increased to 135 mg per day. She then presented to the ED with symptomatic torsades de pointes. She was stabilized in the ED by cardioversion and infusions of magnesium sulfate and lidocaine. The markedly prolonged corrected QT interval significantly shortened after discontinuing methadone. Inpatient cardiology evaluation found no other cause for the dysrhythmia. She was definitively treated with reduction of the daily methadone dose and an implanted cardioverter-defibrillator.     

Torsades de pointes and QT prolongation due to a combination of loratadine and amiodarone

Torsades de pointes (TdP) has not been previously reported with loratadine. A 73-year old woman on chronic treatment with amiodarone for atrial fibrillation received loratadine and presented with syncope and multiple episodes of TdP. We suggest that QT interval should be monitored whenever loratadine is co-administered with drugs that may potentially prolong QT.     

QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs

A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies.     

New-onset QT prolongation and torsades de pointes accompanied by left ventricular dysfunction secondary to acute pancreatitis

A 70-year-old woman presented with acute pancreatitis and new-onset QT prolongation with subsequent torsades de pointes. Coronary catheterization was performed and was unremarkable. After persistent QT prolongation, despite temporary atrial pacing, a permanent dual chamber cardioverter defibrillator was implanted. In addition to the QT prolongation, significant depression in the left ventricular function was noted. Both resolved once the pancreatitis abated.     

QT Interval Prolongation and Torsades de Pointes Unmasked by Intracoronary Acetylcholine Administration

Intracoronary acetylcholine administration, which was performed to exclude vasospasms, unmasked an abnormal QT interval prolongation and initiated torsades de pointes in a patient with normal QT interval at rest.     

Ibutilide-induced long QT syndrome and torsade de pointes

Ibutilide is a class III antiarrhythmic agent used for the termination of atrial fibrillation and atrial flutter. It mainly affects membrane potassium currents and prolongs the cardiac action potential. This effect is reflected as QT interval prolongation on the surface electrocardiogram. Like other drugs that affect potassium currents, ibutilide is prone to induce a malignant ventricular tachycardia, torsade de pointes. We report four cases of torsade de pointes after administration of ibutilide for pharmacologic cardioversion of atrial fibrillation and atrial flutter; three of these cases required direct current cardioversion for termination of torsade de pointes. All four patients were female. We discuss the risk factors for development of ibutilide-induced torsade de pointes.     

Mechanisms in Adrenergic Dependent Onset of Torsades de Pointes

Pause dependent onset of torsades de pointes is characteristic in acquired long QT syndromes, and the probable mechanism is reentry facilitated by increased disparity of refractoriness following a long cycle. Adrenergic dependent onset is usual in familial long QT syndromes, and the mechanism is uncertain. In this study with a computer simulation of torsades de pointes, possible mechanisms of adrenergic dependent onset have been identified. Decreased refractory periods facilitated the initiation of torsades de pointes by permitting earlier premature excitation and allowing reentry in the presence of the shorter refractory period that had been further shortened by the earlier excitation. In addition, accelerating rate resulted in responses occurring in the presence of refractory periods set by the prior response so each response was premature with respect to the preceding one. The difference between cycle lengths and refractory period decreased with increasing rate leading to the functional block required for initiation of simulated torsades de pointes. Findings define possible mechanisms in which the adrenergic effects of reduced refractory period duration and increased rate may lead to the initiation of torsades de pointes.     

Torsades de pointes following cardioversion: Case history and literature review

Torsades de pointes (TDP) is a relatively uncommon but potentially fatal cardiac arrhythmia which occurs in patients with long QT syndromes (LQTS). This literature review and case history investigate the causes, symptoms, presentation and treatment of torsades, focusing on drug induced torsades developing after successful cardioversion. In torsades, imbalanced positive ion flows result in early after-depolarisations (EADs) and increased variability in repolarisation rates. These combine to create an unstable re-entrant polymorphic ventricular tachycardia (VT) which can cause patients to suffer symptoms progressing from syncope to ventricular fibrillation (VF) arrest. Typically, torsades has a twisting morphological presentation on rhythm strips due to the irregularity of its reentry pattern. The arrhythmia is more common in women. Intravenous magnesium is the initial emergency treatment in torsades.

The case history illustrates the progressive acquisition of risk factors for drug induced torsades in a patient treated with sotalol following cardioversion. Typical progressive rhythm strip, electrocardiograph (ECG), and QT & corrected QT interval (QTc) interval changes occurring with the arrhythmia are presented.     

QT Prolongation Associated with Azithromycin/Amiodarone Combination

Administration of oral azithromycin, in addition to previously well-tolerated long-term amiodarone therapy, was associated with a marked prolongation of QT interval and increased QT dispersion, both substrates for life-threatening ventricular tachyarrhythmia and torsades de pointes. This is a report of QT prolongation and increased QT dispersion associated with the use of azithromycin. The report assumes an added significance, in view of widespread empirical use of this antibiotic for the treatment of lower respiratory infections and belief of its safety in patients with cardiac diseases. Based on the authors' experience, they would like to emphasize that the combination of azithromycin with other drugs known to prolong QT or causing torsades de pointes be used with caution until the question of the proarrhythmic effect of azithromycin is resolved by further studies.     

A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data

BACKGROUND: QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide. METHODS: The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response. RESULTS: A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days. CONCLUSIONS: The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.     

Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease

BACKGROUND: In recent years there has been ain increase in the use of class III antiarrhythmic drugs such as sotalol, amiodarone, and the so-called pure class III compound for the control of cardiac arrhythmias. It appears there has been a corresponding increase in the frequency of torsades de pointes (TdP). METHODS AND RESULTS: The case reported here, a patient on daily renal dialysis for end-stage renal disease, has important implications for class III agents, which are excreted largely by the kidneys. A relatively low dose of sotalol administered for the prevention of recurrences of atrial fabrillation, with a fast ventricular response producing angina, led to modest increases in the QT interval and moderate bradycardia. This culminated in the development of TdP, which deteriorated into ventricular fibrillation, from which the patient could be resuscitated with considerable difficulty. Dialysis after the occurrence of TdP led to further and striking prolongation of the QT interval associated with numerous episodes of TdP for several days before control was achieved. The atrial fibrillation and recurrences of TdP were eventually controlled with oral amiodarone. CONCLUSIONS: This case emphasizes that in the absence of significant renal function, use of sotalol may not be safe because drug accumulation may not be controlled adequately with renal dialysis. In view of this, in patients with end-stage renal disease, the use of sotalol for arrhythmia control appears contraindicated and alternative agents, the excretion of which does not occur by the renal route, should be used.