Dofetilide for Atrial Arrhythmias in Congenital Heart Disease: A Multicenter Study

Background: Very little is known about use of the class III antiarrhythmic dofetilide in patients with congenital heart disease (CHD).
Methods: A multicenter retrospective review of experience with dofetilide in CHD patients was undertaken.
Results: Twenty adults with CHD and refractory atrial arrhythmias were treated with dofetilide at four institutions over a 7-year period. Three (15%) experienced adverse effects during in-hospital initiation of dofetilide (two with torsade de pointes, one with excessive QTc prolongation) and were not continued on this therapy. The remaining 17 were discharged taking dofetilide, with either resolved or improved arrhythmia. One was lost to follow-up. Five subsequently discontinued dofetilide due to waning effectiveness, manifest by recurrence of their arrhythmias. Eleven (55%) remained on dofetilide at most recent visit, with a median follow-up of nearly 1 year. Seven of these 11, or 35% of the CHD patients originally started on dofetilide, experienced a complete resolution of their arrhythmia. The remaining four had breakthrough episodes of atrial arrhythmia, but remained on dofetilide. No patient experienced torsade de pointes after the in-hospital initiation period.
Conclusions: Used appropriately, dofetilide appears to be a viable adjunct to catheter-based ablation and alternative pharmacological approaches for the treatment of atrial arrhythmias in adult patients with congenital heart disease.     

Long QTc interval and torsade de pointes caused by fluconazole

OBJECTIVE: To describe a patient who developed torsade de pointes while being treated with fluconazole. CASE SUMMARY: A 33-year-old woman with a 5 year history of systemic lupus erythematosus was admitted to the intensive care unit because of respiratory insufficiency due to Candida albicans pneumonia. Therapy with intravenous fluconazole 200 mg/day, with dose later adjusted according to her renal function, was started. Prolongation of the QTc interval and torsade de pointes occurred. Initially, domperidone, which had been initiated the day before fluconazole, was suspected as the possible cause and was discontinued; ultimately, both drugs were discontinued. However, torsade de pointes recurred several weeks later when the patient was treated with fluconazole for a second time and disappeared again on withdrawal of the drug. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The risk of torsade de pointes does not correlate in a linear fashion with prolongation of the QTc interval, but an interval beyond 500 msec is considered a significant risk factor. Given that both fluconazole and domperidone are metabolized by the cytochrome P450 system, they may intensify each other's proarrhythmic effects, particularly in patients with concurrent renal dysfunction. These risks are of particular concern in patients whose baseline QTc interval is prolonged for any reason. CONCLUSIONS: From the case history, as well as use of the Naranjo scale, we concluded that fluconazole was the highly probable cause of the development of torsade de pointes in our patient.     

QT Prolongation and Torsade de Pointes Ventricular Tachycardia Produced by Ketanserin

A 65-year-old man with arterial hypertension received oral treatment with Ketanserin, a new drug, during a period of five months. He developed marked QT interval prolongation and have several Stokes-Adams attacks. A Holter recording obtained during one of these episodes showed torsade de pointes ventricular tachycardia. The arrhythmias occurred during maximum QT interval prolongation, The correlation between Ketanserin and QT interval prolongation was evaluated by using several Holter studies during administration and withdrawal of the drug. The effect of Ketanserin on the QTc interval was analyzed retrospectively in six patients who had been taking the drug orally. Following a period of four to eight months, the QTc interval was prolonged by the drug (5 to 31%, mean 17%) in five patients. We conclude that torsade de pointes is a potential hazard of long-term treatment with Ketanserin.     

Measurement of QTc in patients receiving chronic methadone therapy

Recent reports suggest that methadone may prolong the QTc interval and cause torsades de pointes. This study was conducted to evaluate the prevalence of QTc prolongation during oral methadone therapy and identify factors associated with prolongation. Patients receiving oral methadone as treatment for chronic pain or addiction were eligible for the study. One hundred four patients who were receiving > or = 20 mg methadone per day for > or = 2 weeks underwent electrocardiograms to measure QTc interval duration. Sixty-three (61%) patients were male and 63 (61%) were receiving methadone maintenance for opioid addiction. The mean (+/- SD) age was 45.3 +/- 9.4 years. The median (range) methadone dose was 110 mg/day (20-1200 mg/day); median (range) number of months on methadone was 12.5 months (1-444 months). The median (range) QTc interval was 428 msec (396-494 msec). Thirty-three percent had QTc prolongation (males 40%, females 20%; P=0.03). No patient had a QTc longer than 500 msec. Significant dose response was observed in males on methadone <12 months (rho=0.60, P=0.02). Our study suggests that methadone may prolong the QTc interval in specific subpopulations but poses little risk of serious prolongation.     

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.     

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.     

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.     

Marked QT prolongation and ventricular tachycardia of a transient nature in young children with cardiomyopathy

Significant prolongation of the QT interval in pediatric patients with cardiomyopathy is rare. We report two cases of dilated myopathy with transient and dramatic QT prolongation. Both had associated ventricular arrhythmias, with one having torsade de pointes, and the other nonsustained ventricular tachycardia. Normalization of their QTc occurred as their ventricular function improved.     

Torsade de pointes

A case is described of torsade de pointes in a 41 year old woman with pre-existing QTc prolongation, potentially exacerbated by treatment with sotalol. Previous cardiac investigations had been normal and after a second episode of ventricular fibrillation the patient was referred for electrophysiological studies. The authors review the physiology, causes, and treatment of QTc prolongation and torsade de pointes.     

Poster Session 2-1: Pharmacological and Cellular Therapy Monday, April 3, 2006, 4:00–5:30pm

Prof. Yuji Nakazato ¹ , Masayuki Yasuda ¹ , Hiroto Tsuchiya ¹ , Akitoshi Sasaki ¹ , Takashi Tokano ¹ , Hiroyuki Daida ^{1   1} Cardiology, Juntendo University, Tokyo, Japan
The purpose of this study is to clarify the efficacy and safety of bepridil for persistent atrial fibrillation (AF). Method: Bepridil (100-200mg/day) was administered to 159 patients (141 males, mean age 58 years) with persistent AF. The effects of conversion and maintenance of sinus rhythm were evaluated. If sinus restoration was not obtained until 3 months observation, DC cardioversion was performed. Results: In 87 of 159 patients (55%), sinus rhythm was restored within an average 2.1 months following administration of bepridil. 74 of those 87 patients (85%) have been maintained in sinus rhythm for the average follow-up of 16 months. The 31 out of remaining 72 patients failed pharmacological conversion and performed DC cardioversion. All of the patients restored sinus rhythm, and 18 of them (58%) maintained sinus rhythm for an average of 20 months. Although ECG revealed significant prolongation of QT interval from 0.38/0.03 to 0.42/0.06 sec, QTc was unchanged and no serious adverse complications including torsade de pointes were recognized. Conclusion: Bepridil is clinically safe and useful with favorable efficacy for conversion and maintenance of sinus rhythm in patients with persistent AF.     

The Influence of Specific and Nonspecific Potassium Current Blockade on the Defibrillation Energy Requirement of Biphasic Shock

Block of delayed rectifier potassium current (I_K) is known to decrease defibrillation energy requirements (DERs). We tested the hypothesis that there would be no difference in DER reduction with a nonspecific I_K (I_Kr+ I_KS) blocker, ambasilide, and a specific I_Kr blocker, dofetilide. Methods: An anesthetized canine model (n = 30) of internal transvenous defibrillation with biphasic shocks was used. Ambasilide (n = 9; dose: 4.8 mg/kg, then 9.6 mg/kg/hour), dofetilide (n = 10; dose: 10 (μg/kg, then 3.6 (μg/kg/hour), or matched placebo (n = 11) were administered. DERs (J) were determined in triplicate using an increment-decrement protocol at baseline and during each treatment. ECG intervals were measured at baseline and during each treatment. ANOVA with post-hoc Bonferroni test was used for statistical analysis. Results: Ambasilide resulted in a +23.5 ± 4.06% prolongation of the QTc interval, while dofetilide resulted in a +20.5%± 3.76% prolongation of the QTc interval. Thus, the two drugs resulted in comparable prolongation of the QTc interval (P < 0.05 compared to placebo). Both drugs significantly reduced the DER (-17.7%± 5.33% reduction by ambasilide, and -21.9%± 5.21% reduction by dofetilide, P < 0.05 compared to placebo). There was no difference in the magnitude of DER reduction between the two treatments. Conclusions: Administration of equipotent doses (as indicated by QTc changes) of ambasilide or dofetilide had comparable effects on DERs. Selectivity of I_K blockade has no significant effect on the magnitude of reduction in DERs.     

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.     

The successful use of parenteral methadone in a patient with a prolonged QTc interval

Recent case reports have raised concerns about the potential for methadone to prolong the QTc interval (QT corrected for heart rate) and predispose patients to torsade de pointes (TdP), a life-threatening arrhythmia. We present a case report that describes the successful use of parenteral and oral methadone in a patient with uncontrolled cancer pain and a history of QTc prolongation. We describe an approach to the use of methadone in this patient and review both case reports and recent prospective studies that have evaluated the risk of TdP and the long-term outcome with respect to the development of TdP in patients receiving methadone for chronic pain or addiction.     

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.     

Medical toxicologists’ practice patterns regarding drug-induced QT prolongation in overdose patients: A survey in the United States of America,Europe, and Asia Pacific region

Abstract

Objective. To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. Methods. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. Results. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty-five percent and 36% believed magnesium could shorten QTc and prevent torsades de pointes, respectively. In addition, almost 90% believed administering 1–2 boluses of intravenous magnesium is safe, even when serum magnesium is not available. In regards to cardiac pacing of patients with QT prolongation and torsades de pointes, only 38% of the participating toxicologists’ responses agreed with AHA/ACC/ESC recommendations. Furthermore, 21% would not pace a patient who developed torsades de pointes regardless of the scenario. Discussion and conclusions. The results indicate that medical toxicologists have considerable heterogeneity in terms of management practices for overdose patients with QT prolongation and torsades de pointes. Medical toxicologists may benefit from developing evidence-based consensus guidelines for the management of this relatively common finding in overdose of QT-prolonging drugs.     

Methadone: to ECG or not to ECG...That is still the question

There is significant controversy about the potential deleterious effect of methadone on cardiac conduction. Although several reports suggest that patients receiving methadone are at increased risk for QTc prolongation and torsade de pointes, a potentially fatal arrhythmia, others have not replicated these findings. Hence, it is not surprising that there is no consensus on when to perform an electrocardiogram, a simple test to assess the QTc interval, during methadone therapy. Most of the uncertainty is generated by the lack of large controlled studies. This review presents the current data on this issue in an effort to help in the decision-making process until more conclusive data become available.     

Effect of ciprofloxacin and levofloxacin on the QT interval: is this a significant "clinical" event?

BACKGROUND: The widespread use of the fluoroquinolones has raised the question of the cardiac safety of these medications. This widespread use of this class of antibiotics has displayed their safety profile, which is actually more favorable than many other drug classes. The cardiac toxicity issue at the center of this discussion is the prolongation of the QT interval leading to torsade de pointes. Ciprofloxacin and levofloxacin, two of the more commonly used fluoroquinolones, are considered less likely than other fluoroquinolones to prolong the QT interval. The authors set out to evaluate the effect on the QT interval of patients after administration of ciprofloxacin and levofloxacin. METHODS: A prospective evaluation of 38 consecutive patients evaluated by the infectious disease service and receiving either ciprofloxacin or levofloxacin was undertaken. Twelve-lead electrocardiograms were obtained at baseline and at least 48 hours after the first dose of the antibiotic was administered. Both the longest QT interval and the mean QT interval were evaluated. To account for variations in heart rate, the corrected QT interval was calculated by using Bazett's formula (QTc = QT(square root of) R-R). Statistical analysis was undertaken to assess for the presence of a change after the administration of the antibiotic. RESULTS: Thirty-eight patients (mean age, 65 +/- 19 years), 23 women and 15 men, were studied. There was a small but significant increase in the longest QTc intervals over baseline in patients receiving levofloxacin; there was no significant change in the mean QTc interval. However, one patient who received levofloxacin was, statistically, an outlier and, on retrospective analysis, had demonstrated severe electrolyte disturbances at the time of the study. When this patient was excluded, the increase in the longest QTc interval was not significant. Patients receiving ciprofloxacin did not demonstrate any significant change in the longest QTc interval or mean QTc interval. CONCLUSIONS: Neither levofloxacin nor ciprofloxacin significantly prolonged the mean QTc interval over baseline. When electrolyte deficiencies in one of the patients evaluated were taken into account, this also held true for the longest QTc interval. There is, therefore, evidence that taking ciprofloxacin or levofloxacin, assuming that there are not any concurrent risk factors, will not cause a significant prolongation in the QT interval.     

Serum quinidine concentrations and effect on QT dispersion and interval

OBJECTIVE: To establish a relationship between serum quinidine concentrations (SQCs) and QT interval dispersion, compared with corresponding QT intervals, in order to identify a reason why many reports describe torsade de pointes as occurring at subtherapeutic concentrations. DESIGN: Retrospective study. SETTING: University teaching hospital. PARTICIPANTS: Eleven patients with atrial arrhythmias managed with quinidine therapy. MAIN OUTCOME MEASURES: Patients with subtherapeutic (<2 microg/mL) and therapeutic (2-5 microg/mL) SQCs with corresponding 12-lead electrocardiograms (ECGs) (25 mm/sec) and baseline ECG were evaluated for QT interval dispersion, calculated as the maximum minus the minimum QT interval on the 12-lead ECG. RESULTS: Mean +/- SD subtherapeutic and therapeutic SQCs were 1.48 +/- 0.39 microg/mL and 3.78 +/- 0.88 microg/mL (p < 0.001). Baseline values for QT/QTc intervals were 376.4 +/- 59.2/429.5 +/- 57.3 msec. At subtherapeutic and therapeutic SQCs, mean QT/QTc intervals were 403.6 +/- 59.9/450.5 +/- 38.5 msec and 439.1 +/- 48.9/472.4 +/- 44.6 msec, respectively. Mean QT dispersion was 47 +/- 16.2 msec at baseline, 98.2 +/- 27.5 msec at subtherapeutic SQC, and 70.9 +/- 33.9 msec at therapeutic SQCs (p = 0.001 for overall analysis; p < 0.001 for baseline vs. subtherapeutic concentrations; p = NS for therapeutic vs. subtherapeutic in post hoc comparison). CONCLUSIONS: Despite QT interval lengthening with increasing SQCs, QT dispersion was numerically greatest at subtherapeutic SQCs. Further study is required to determine the value of QT dispersion as a tool for identifying proarrhythmic risk with drugs that prolong the QT interval.     

Azithromycin-induced torsade de pointes

Although erythromycin frequently induces long QT interval and torsade de pointes, the newer drug, azithromycin, has rarely been reported to be associated with torsade de pointes. We report here the occurrence of a significant typical QT prolongation within a few hours after taking azithromycin which lead to torsade de pointes.