Atypical proarrhythmia with dofetilide: monomorphic VT and exercise-induced torsade de pointes

Proarrhythmia with dofetilide has most typically taken the form of torsade de pointes (TdP) and generally occurs early with therapy, such that in-hospital initiation of dofetilide with 3 days of continuous electrocardiogram monitoring is recommended. This article reports two unusual variants of ventricular proarrhythmia with dofetilide: (1) nonsustained runs of monomorphic ventricular tachycardia shortly after taking the first dose of dofetilide, confirmed by rechallenge; and (2) TdP that followed the development of isolated ventricular premature beats during an exercise test in a patient with neither excessive QT prolongation on dofetilide nor any ectopy whatsoever during in-hospital telemetric monitoring but with significant QT interval prolongation after the postectopic pause. These cases demonstrate that clinicians must be alert to the appearance of proarrhythmia with dofetilide at times other than early during drug initiation if the electrophysiological milieu is altered during nonhospital activity and/or of a pattern other than TdP.     

The safety and efficacy of ibutilide in children and in patients with congenital heart disease

BACKGROUND: The safety and efficacy of ibutilide in the cardioversion of atrial flutter and atrial fibrillation in children and in patients with congenital heart disease (CHD) is unknown. METHODS: Data from 19 patients (age 6 months to 34 years, median 16 years) who received ibutilide for atrial flutter or atrial fibrillation between 1996 and 2005 was retrospectively reviewed. There were 15 patients with CHD (14 had prior heart surgery); four children had normal heart structure. RESULTS: There were 74 episodes of atrial flutter and four episodes of atrial fibrillation (median episodes per patient was one, range 1-31). Ibutilide converted 55 of all the episodes (71%). Ibutilide was successful during its first-ever administration in 12 of 19 patients (63%). Fourteen episodes in six patients required electrical cardioversion after ibutilide failed. There were no episodes of symptomatic bradycardia. One patient went into torsade de pointes and one patient had nonsustained ventricular tachycardia. CONCLUSION: With careful monitoring, ibutilide can be an effective tool in selected patients for cardioversion of atrial flutter.     

Haloperidol-induced torsade de pointes.

OBJECTIVE: To report a case of torsade de pointes related to the administration of high-dose intravenous haloperidol for the treatment of severe agitation. CASE SUMMARY: Reports in the literature of intravenous haloperidol-induced torsade de pointes are rare. We describe the case of a 41-year-old white woman with no predisposing factors who developed torsade de pointes 55 minutes after a dose of intravenous haloperidol 80 mg (total dosage 915 mg over 7 d). The results of the electrocardiogram were consistent with torsade de pointes and showed a prolonged QTc interval of 610 milliseconds. Intravenous magnesium sulfate 2 g/100 mL NaCl 0.9% was administered, which controlled the arrhythmia. The patient received one additional 80-mg haloperidol dose six hours after the arrhythmia-triggering dose, without reoccurrence of torsade de pointes. Haloperidol was then discontinued, and the patient had no further arrhythmias. CONCLUSIONS: Our case report and others from the literature suggest that intravenous haloperidol administration may prolong QT intervals in some patients, precipitating the potentially life-threatening arrhythmia torsade de pointes. Clinicians should be aware of haloperidol's potential to induce torsade de pointes, since it is used regularly for agitation and delirium in the critical care arena.     

Initial Experience with Catheter Ablation Using Remote Magnetic Navigation in Adults with Complex Congenital Heart Disease and in Small Children

Background: The improved outcomes and increased availability of surgery for congenital heart disease (CHD) over the last three decades have created a small but steadily increasing subset of patients with unique needs: children and adults with complex arrhythmias in the setting of structural cardiac abnormalities. Radiofrequency catheter ablation (RFCA) in these patients, and in small children with normal cardiac anatomy, is effective but challenging. An understanding of specific anatomical and electrophysiological characteristics of these patients and the technical challenges in addressing them are critical to the success of this therapy. Tools specifically designed for intracardiac diagnosis and therapy in anatomically complex and/or small hearts remain scarce.
Aims: We report single-center results from an ongoing registry of all patients with congenital heart disease and all children with complex arrhythmias in which the Magnetic Navigation System (MNS) was used.
Results: Included in this report are 12 patients with CHD in whom 17 tachyarrhythmias were treated, and 11 pediatric patients with normal cardiac anatomy who each had a single arrhythmia. The procedures' duration and the duration of fluoroscopy time as well as arrhythmia recurrence rates were comparable to those found in previous reports of procedures performed in adults with structurally normal hearts, and the incidence of complications was quite low.
Discussion: In patients with complex congenital malformations, retrograde mapping of the pulmonary venous atrium was feasible, eliminating the need for puncture of the atrial septum, or surgically placed baffle in many cases. Moreover, the design of the catheter eliminated the need for multiple mapping and ablation catheters.
Conclusion: Our findings suggest that RFCA using the MNS for arrhythmias after surgery for congenital heart disease and in pediatric patients is safe and effective.     

Phase IV trial evaluating the effectiveness and safety of dofetilide

BACKGROUND: Dofetilide gained Food and Drug Administration approval for persistent atrial fibrillation/flutter (AFF) based on 2 randomized, placebo-controlled, dose-ranging studies. Concerns of proarrhythmia have prompted the manufacturer to develop specific treatment guidelines. OBJECTIVE: To determine the effectiveness and safety of dofetilide in clinical practice as well as to ascertain whether clinicians are following established dosing guidelines. METHODS: This retrospective analysis evaluated guideline adherence and safety in patients who received dofetilide at a tertiary care medical center. Safety assessment included monitoring for the occurrence of excessive QTc interval prolongation and torsade de pointes. Excessive QTc interval prolongation was defined as >15% above baseline after the first dose or >500 msec following any dose (>550 msec in patients with ventricular conduction abnormalities). Patients were included in the effectiveness assessment if they received at least 36 hours of dofetilide for persistent AFF, received an appropriate dose per guidelines, and did not receive direct current cardioversion during the evaluation period. We compared the 36-hour conversion rate with dofetilide in this study with that observed in the EMERALD and SAFIRE-D trials using the Z test, and we evaluated the incidence of excessive QTc interval prolongation in high-risk subgroups by chi(2) analysis. RESULTS: Investigators identified 107 patients. The primary indication for dofetilide was AFF, with 58.9% receiving the drug for paroxysmal disease. Prescribing followed established guidelines, except that it was used intermittently by nonconfirmed prescribers (5.6%) and/or at inconsistent doses (14%). Excessive prolongation of the QTc interval occurred in 17.8% of patients after the first dose and 26.2% during subsequent doses; prolongation was more common in those with structural heart disease (p < 0.01). No patients developed torsade de pointes. In the effectiveness assessment (n = 25), the conversion of persistent AFF at 36 hours was higher than in previous studies (48% vs 27.2%; p = 0.05). CONCLUSIONS: In clinical practice, the conversion of persistent AFF with dofetilide is at least comparable to premarketing studies, with a similar safety profile. Institutions should continue to emphasize adherence with established treatment guidelines.     

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.     

Propafenone-Induced Torsade de Pointes: Cross-Reactivity with Quinidine

A 77-year-oid/emale with new onset atrial fibrillation occurring in the absence of structural heart disease developed torsade de pointes during therapy with quinidine bisulfate 500 mg orally every 8 hours. Ten days after quinidine therapy had been discontinued she developed torsade de pointes while receiving propafenone 300 mg orally every 8 hours. This case demonstrates that propafenone may be associated with torsade de pointes and suggests a cross-reactivity between this effect and prior occurrence of torsade de pointes on Class IA antiarrhythmic drug therapy.     

Incidence and type of cardiac arrhythmias in critically ill patients: a single center experience in a medical-cardiological ICU

OBJECTIVE: To determine the frequency and types of significant, sustained arrhythmias in a mixed ICU. DESIGN AND SETTING: Prospective, observational study in a medical-cardiological-postoperative ICU at a university hospital. Patients: 133 consecutive patients with arrhythmias. MEASUREMENTS AND RESULTS: All patients had continuous ECG monitoring and automatic arrhythmia detection. We assessed: (a) sustained (>30 s) tachyarrhythmias; (b) all tachyarrhythmias requiring therapy; (c) bradycardias of fewer than 40 beats/min or requiring intervention. There were 310 arrhythmia episodes: 278 tachyarrhythmias (108 narrow-QRS complex, 168 wide-QRS complex; 179 regular, 97 irregular) and 32 bradycardias. Of the 278 tachycardias in 54 patients, 135 (48.6%) were ventricular. There were 13 episodes of torsade de pointes (4.67%) in five patients. Of the 278 tachycardiac episodes 83 were atrial fibrillation (29.8%, 63 patients), 10 atrial flutter (3.6%, 8 patients), 21 supraventricular tachycardias (7.55%, 7 patients), and 2 ectopic junctional tachycardia (0.72%, 1 patient). The number of patients showing significant arrhythmias was comparable over the years (11-12/1996: 4/28 [14.3], 1997: 52/302 [17.2%], 1998: 55/286 [19.2%], 22/140 [15.7%] 1-7/1999). The ICU stay was significantly longer in arrhythmia patients than in 623 patients without arrhythmias (median 4 vs. 14 days), and there was a trend towards higher mortality (40/133, 30.8%, vs. 132/623, 21.2%, P=0.061, log-rank). CONCLUSION: Only one-fifth of patients in this mixed ICU had significant arrhythmias, taking a contemporary definition of arrhythmias. Ventricular tachycardia and atrial fibrillation were the most frequent arrhythmias.     

Torsade de pointes ventricular tachycardia during low dose intermittent dobutamine treatment in a patient with dilated cardiomyopathy and congestive heart failure

The authors describe the case of a 56-year-old woman with chronic, severe heart failure secondary to dilated cardiomyopathy and absence of significant ventricular arrhythmias who developed QT prolongation and torsade de pointes ventricular tachycardia during one cycle of intermittent low dose (2.5 mcg/kg per min) dobutamine. This report of torsade de pointes ventricular tachycardia during intermittent dobutamine supports the hypothesis that unpredictable fatal arrhythmias may occur even with low doses and in patients with no history of significant rhythm disturbances. The mechanisms of proarrhythmic effects of Dubutamine are discussed.     

Dofetilide: a class III-specific antiarrhythmic agent

OBJECTIVE: To review published reports on the pharmacology and clinical use of dofetilide in the management of cardiac dysrhythmias. DATA SOURCES: A MEDLINE search (January 1966-June 1999) was performed using dofetilide and UK-68,798 as key words. English-language articles were identified, and the references of these articles were used to further identify pertinent articles. STUDY SELECTION: All acquired studies and reviews discussing the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of dofetilide were reviewed. DATA EXTRACTION: Articles were selected based on quality of review of the pharmacology and clinical use of dofetilide. Given the paucity of data on the clinical pharmacology and use of dofetilide, most articles obtained were used, including abstracts when full reports were not available. DATA SYNTHESIS: Dofetilide is a relatively specific class III antiarrhythmic agent. It increases action potential duration and effective refractory period without impacting conduction velocity. These actions of dofetilide are explained by its ability to inhibit the rapid component of the delayed, outward-rectifying potassium current, thus blocking the efflux of potassium during repolarization. Introductory investigations suggest that dofetilide may be of use in treating and preventing atrial dysrhythmias such as atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. Dofetilide may also have a role in preventing ventricular tachycardia from occurring. Some data also suggest that dofetilide may improve the morbidity of heart failure patients. Currently, the most troublesome adverse effect of dofetilide is its propensity to induce ventricular proarrhythmias, especially torsade de pointes. CONCLUSIONS: Based on the data currently available, dofetilide should have a role in the pharmacotherapy of cardiac dysrhythmias, especially those of atrial origin. More data on its efficacy and tolerability are needed, however, to fully delineate dofetilide's role amid currently available antiarrhythmic agents.     

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.     

Coronary artery disease potentiates response to dofetilide for rhythm control of atrial fibrillation

Background: Dofetilide, a class III antiarrhythmic, is one of the few alternatives to amiodarone in patients with atrial fibrillation (AF) and heart failure or coronary artery disease (CAD). While amiodarone has been extensively studied, little is known about predictors of response to dofetilide. We sought to identify clinical parameters associated with dofetilide success in a large cohort of patients with AF. Methods/Results: A total of 287 patients with AF started on dofetilide between 2001 and 2008 were included. Dofetilide was deemed “completely effective” if the patient remained on dofetilide at follow‐up and had no recurrences of AF clinically or by electrocardiogram. Dofetilide efficacy was analyzed in relation to clinical variables relevant to AF and AF recurrence. After a follow‐up of 10.2 ± 7.7 months, 54.7% of the patients remained on dofetilide and it was completely effective in 26.8%. The discontinuation rate during initial hospitalization was 13.3% from excessive QT prolongation and one patient with torsades de pointes (successfully treated). A history of CAD was the only univariate predictor of efficacy (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.29–4.01, P < 0.05). CAD remained the only significant factor associated with efficacy of dofetilide in a multivariate regression model (OR 2.01, 95% CI 1.11–3.70, P < 0.05, n = 270). The overall efficacy of dofetilide in patients with CAD was 41.1%, compared to 23.5% in those without CAD (P < 0.05). Conclusions: In this large cohort of patients with AF, underlying coronary disease was significantly associated with dofetilide success. This finding may have utility for clinical decisions regarding initiation of dofetilide. (PACE 2012; 35:170–173)     

Efficacy and cost analysis of ibutilide

OBJECTIVE: To determine the efficacy and safety of ibutilide in atrial fibrillation (AF) and atrial flutter (AFl) in a clinical setting and to compare the cost of first-line ibutilide with that of projected first-line electrical cardioversion (EC) from a hospital and third-party payer perspective. METHODS: Medical records of all patients (n = 60) who received ibutilide from August 1996 to March 1998 were reviewed. Efficacy was defined as successful conversion to sinus rhythm within 60 minutes of the end of the infusion, and the maintenance of sinus rhythm until hospital discharge. Safety was evaluated by determining the incidence of torsade de pointes. Charges for EC and drug administration were obtained from the hospital database and converted to costs using cost/charge ratios. Hospital costs included drug, drug administration, cardiac intensive care laboratory fee, and the cost of managing torsade de pointes. The third-party payer calculation included all of the above plus the cardiologist and anesthesiologist fees. RESULTS: Fifty percent of patients with AF or AFl were successfully converted with ibutilide; 67% of these remained in sinus rhythm at hospital discharge. Three patients experienced nonsustained torsade de pointes; all resolved with pharmacologic management. From a hospital perspective, the cost of first-line ibutilide was greater than the cost of first-line EC ($280 vs. $138 per patient). However, from a third-party payer perspective, the use of ibutilide saved approximately $324 per patient ($718 vs. $1042). CONCLUSIONS: The efficacy and safety of ibutilide in the clinical setting are consistent with data reported in clinical trials. In contrast to a previous decision analysis, ibutilide was not associated with cost savings from a hospital perspective, but was from a payer perspective.     

Doxepin Induced Torsade De Pointes

A case of torsade de pointes with normal QT interval secondary to the administration of small amounts of doxepin is presented. Electrophysiological studies during rechallenge with doxepin demonstrated replication of the patient's spontaneous arrhythmia. Evaluation of syncope in patients taking doxepin should include careful evaluation for torsade de pointes.     

Comparison of microvolt T-wave alternans measurements using atrial pacing compared to atropine administration

Background: Microvolt T-wave alternans (MTWA) has been associated with malignant ventricular arrhythmias in patients (pts) with structural heart disease. MTWA has been shown to be a strong heart rate-dependent arrhythmia marker. However, in clinical practice some pts in which MTWA should be assessed are unable to perform physical exercise to increase heart rate due to various reasons.
Methods: In this study, we investigated the feasibility of noninvasive MTWA measurement by using intravenous atropine to increase heart rate and compared the results to MTWA measurement by right atrial (RA) pacing during electrophysiologic (EP) study in 27 consecutive pts (53 ± 14 years; nine women). Determining the arrhythmia event-rate, a follow-up of 18 months was performed in all pts.
Results: Using atropine, five pts (18%) did not reach the target heart rate (105 bpm). In the remaining group of pts, concordant results for MTWA assessment could be found in 21 pts (96%). Comparing MTWA positive tests there were slightly higher amplitudes using right atrial (RA) pacing than atropine (7.0 ± 2.3μV vs 6.3 ± 2.2μV, P = 0.03; r = 0.97). During follow-up all pts with a positive MTWA test had documented ventricular arrhythmias. There were no arrhythmic events in the MTWA negative group.
Conclusion: Whenever target heart rate for MTWA evaluation is obtained by intravenous atropine, the results are comparable to RA pacing. In using atropine there has been observed no pharmacologically influenced increase of MTWA voltage leading to false positive MTWA results. Therefore the use of atropine can be recommended as a safe, non-invasive, and reliable method for MTWA assessment.     

Marked QT prolongation and torsades de pointes secondary to acute ischemia in an elderly man taking dofetilide for atrial fibrillation: a cautionary tale

Dofetilide has been shown to be effective and safe in maintaining sinus rhythm in patients with persistent atrial fibrillation and congestive heart failure. Because of serious side effects of an increase in the QT interval causing torsades de pointes, dofetilide must be initiated with close monitoring of the QT interval in an inpatient setting. However, little has been reported about conditions surrounding the change in QT interval after the steady state is achieved that may have implications in the safety and efficacy of the drug. We report marked QT prolongation and torsades de pointes in a setting of flash pulmonary edema resulting from acute myocardial ischemia in a patient who was being treated with dofetilide for atrial fibrillation. Our case reminds the clinicians that the adverse and proarrhythmic effects of dofetilide can occur due to changes in the arrhythmic substrate during acute severe ischemia.     

Ibutilide for pharmacological cardioversion of atrial fibrillation and flutter: impact of race on efficacy and safety

OBJECTIVE: To evaluate the racial differences in the efficacy and safety of ibutilide in patients with recent-onset (<2 weeks) atrial fibrillation and atrial flutter. METHODS: This study included 58 consecutive patients with recent-onset atrial fibrillation (n = 34) and atrial flutter (n = 24). The mean age was 65.7 +/- 14.6 years (range, 37-86 years), 47% were women (n = 27) and 34% (n = 20) were African Americans. The duration of arrhythmia ranged from 3 hours to 2 weeks. All patients had echocardiography, were on therapeutic anticoagulation, had a fairly well controlled ventricular rate, normal QTc interval on 12-lead electrocardiography, and normal serum electrolytes. Ibutilide was administered as an intravenous infusion with a maximal dose of 2 mg. RESULTS: The overall conversion rate to sinus rhythm was 66% (n = 38), with 62% (n = 21) with atrial fibrillation and 71% (n = 17) of atrial flutter. Most conversions (84%) occurred within 45 minutes of ibutilide infusion. The mean time to arrhythmia conversion was 37.4 +/- 59.8 minutes. Race had a significant impact on efficacy, with increased conversions seen in African Americans (P = 0.004) and increased nonconversion seen in whites (P = 0.02). Successful conversion was not affected by the left atrial size or the presence of valvular heart disease, hypertension, heart failure, coronary heart disease, and diabetes mellitus. QTc intervals were prolonged after drug administration, with a mean change of 24.6 milliseconds for all patients. The QTc prolongation after drug administration was greater in African Americans than in whites (27.4 vs. 23.3 milliseconds). Torsade de pointes occurred in 4 patients (3 African Americans) and was treated with intravenous magnesium sulfate and electrical cardioversion. CONCLUSION: Ibutilide used for pharmacological cardioversion of atrial fibrillation and atrial flutter is more effective in African Americans but carries a higher risk of torsade de pointes.     

Magnesium Therapy in Ventricular Arrhythmias

Magnesium (Mg) is the known activator of 300 enzymes which govern energy utilization, cell permeability, and ionic membrane currents in the cardiac conducting cells. This may explain the antiarrhythmic efficacy of Mg in specific clinical settings, despite its only modest electrophysiological effects. This review summarizes the effect of Mg administration in four clinical conditions: in digitalis toxicity; in drug-induced torsade de pointes; in patients with chronic diuretic therapy; and in acute myocardial infarction. Mg effectively abolished ventricular tachyarrhythmias associated with digitalis intoxication. This effect of Mg is related to the activation of sodium-potassium ATP-ase, which is inhibited by digitalis. Drug-induced torsade de pointes was promptly abolished by Mg sulfate in the clinical setting. Experimental studies showed that Mg suppresses the early afterdepolarizations and the triggered activity responsible for occurrence of the arrhythmia. In diuretic-treated hypertensives, potassium depletion has been associated with increased ventricular ectopy and sudden death. Mg has been found to be an important adjuvant for intracellular repletion of potassium in these patients. Several randomized, double-blind studies in patients with acute infarction showed that Mg administered on admission improved survival or reduced the incidence of complex ventricular arrhythmias. Thus, Mg should be employed as first-line therapy in digitalis intoxication and drug-related torsade de pointes, and should be considered an important adjuvant therapy in hypertensives treated with diuretics and patients with acute myocardial infarction.     

Flecainide‐Associated Bradycardia‐Dependent Torsade de Pointes: Another Potential Mechanism of Proarrhythmia

Although flecainide has a risk of proarrhythmia in patients with structural heart disease, its mechanism has been mainly ascribed to use‐dependency and a rapid ventricular response to organized atrial tachyarrhythmias or to ventricular tachycardia. We present a patient who experienced recurrent syncope due to bradycardia‐dependent torsade de pointes (TdP) associated with flecainide‐related bradycardia and QT prolongation. Bradycardia‐dependent TdP with QT prolongation can be considered as one of mechanisms of flecainide‐induced proarrhythmia.     

Proarrhythmia

Proarrhythmia is defined as the aggravation of an existing arrhythmia or the development of a new arrhythmia secondary to antiarrhythmic drug. Proarrhythmic events include drug-induced bradyarrhythmias, atrial and ventricular proarrhythmias. New onset sustained or incessant ventricular tachycardia and torsade de pointes can be life threatening. This article reviews the incidence, aggravating factors, and treatment of proarrhythmia.