Version May 2024
INTRODUCTION — Dofetilide is a class III antiarrhythmic agent (table 1) available for the acute termination of atrial fibrillation or flutter, as well as prevention of atrial fibrillation or flutter recurrence. Dofetilide has also been used in an off-label manner to treat paroxysmal supraventricular tachycardias. Some investigators have studied the efficacy of dofetilide in the treatment of life-threatening ventricular arrhythmias, although the drug is not approved for this indication. In contrast to some other antiarrhythmic medications, dofetilide appears to be hemodynamically safe for use in patients with heart failure or a prior myocardial infarction [1]. Because of a relatively high risk of torsades de pointes as an adverse effect of dofetilide, it has extensive contraindications for its use and rigorous dosing guidelines.
The basic pharmacologic properties of dofetilide, its clinical uses, and its safety profile are discussed in detail here. Alternative treatment approaches for supraventricular and ventricular arrhythmias are discussed separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrioventricular nodal reentrant tachycardia", section on 'Initial management' and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".)
ELECTROPHYSIOLOGY — Dofetilide is a class III antiarrhythmic agent that blocks the delayed rectifier cardiac potassium channel and prolongs repolarization (table 1). Dofetilide has relative selectivity for blocking the rapidly-activating component of the delayed rectifier potassium current (IKr) at concentrations of 10 to 30 nanomol/L [2,3]. At these concentrations, it does not block the slow component of the delayed rectifier potassium current (IKs) or the inward rectifier (IKi) and does not affect calcium currents. Evidence from one study shows that dofetilide and several other drugs known to cause torsades de pointes (d-sotalol, thioridazine, and erythromycin) increase the late sodium current (INaL) in cardiac cells, an action (IC50 = 0.1 micromol/L) that could contribute to their arrhythmogenic potential [4].
As a result of its electrophysiologic actions on IKr and possibly INaL, dofetilide has a selective effect on the QT interval of the surface ECG. In clinical electrophysiologic studies, it prolongs the QT interval with little, if any, effect on QT dispersion [5]. Purkinje fibers from female dogs are more sensitive to dofetilide than fibers from male dogs, which is consistent with the threefold greater incidence of torsades de pointes in women and the observation that women are more likely to require dose reduction or discontinuation than men [6,7].
Like other class III agents, dofetilide exhibits reverse use dependency (greater prolongation of repolarization and the refractory period during slower heart rates). The drug prolongs the effective refractory period of atrial and ventricular myocardium and accessory pathways, but it has no effect on conduction parameters, sinus cycle length, or sinus node recovery [8,9]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)
PHARMACOLOGIC DATA/PHARMACOKINETICS — The oral doses of dofetilide that have been used in clinical trials range from 125 to 500 mcg twice daily. Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is completely absorbed after oral administration, and bioavailability ranges from 75 to 100 percent [10]. Elimination is predominantly renal (80 percent), with only 20 percent hepatic conversion to inactive metabolites [11]. The elimination half-life is approximately ten hours after intravenous or oral administration. Clearance has been estimated to be 0.35 L/hour/kg [12].
There is a very linear relationship between the dose administered, plasma concentration of dofetilide, and its effect on the QT interval after both oral and intravenous administration [12]. This observation indicates that it is unlikely that there are important effects of the metabolites on potassium channels and supports earlier work examining the activities of the metabolites in vitro.
Although some safety and efficacy trials with intravenous dofetilide have been performed, dofetilide is not available for intravenous administration in the United States [13-17].
METABOLISM AND DRUG INTERACTIONS — Dofetilide, like most other potassium channel blockers, is metabolized predominantly by the CYP3A4 family of enzymes in the liver and gastrointestinal tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycin, clarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide [18]. The QT-prolonging effects and the risk of torsades de pointes can be increased by coadministration of dofetilide with other drugs that also prolong the QT interval or drugs that interfere with renal elimination of dofetilide (eg, cimetidine, verapamil, trimethoprim, alone or in combination with sulfamethoxazole, prochlorperazine, hydrochlorothiazide, alone or in combination with triamterene, megestrol, dolutegravir, or ketoconazole). Additional information can also be found using the drug interactions program. Dofetilide has been studied in experiments that examine concomitant administration of QT-prolonging drugs. Some examples have shown nearly additive effects on QT interval and action potential duration, while others have shown inhibitory effects dependent on the order in which the drugs were administered [19-21]. As a result, while caution is appropriate to avoid additive or synergistic effects, resulting in QT prolongation and increased risk of torsades de pointes, the presence of inhibitory effects of certain drug-drug combinations indicates the need for additional research to gain a better understanding of drug-drug interaction on the QT interval and action potential duration. There is frequent use of diuretics among those requiring dofetilide. The concomitant use of hydrochlorothiazide almost doubles the degree of heart-rate–corrected QT interval prolongation related to decreased dofetilide clearance and diuretic-induced hypokalemia [22].
DRUG APPROVAL AND RESTRICTIONS — The US Food and Drug Administration (FDA) approved the use of dofetilide for the cardioversion of atrial fibrillation (AF) and atrial flutter (AFl) to normal sinus rhythm and for maintenance of normal sinus rhythm in symptomatic patients with AF/AFl. Several other countries worldwide have also approved its use; however, widespread approval and usage have been somewhat limited due to safety concerns. Because of the risk of torsades de pointes, the FDA recommends that patients initiating or reinitiating dofetilide must be placed in a facility for a minimum of three days that can provide dosing based on estimated creatinine clearance, cardiac monitoring, and cardiac resuscitation. The majority (ie, 75 percent) of episodes of torsades de pointes have occurred within the three-day period of initial dosing and at the time of peak increase in the QT interval [23]. However, late occurrence is possible and has been reported.
PROTOCOL FOR ADMINISTRATION — In an effort to optimize efficacy and safety, the initiation or reinitiation of dofetilide should occur in a controlled fashion according to the FDA-recommended dose protocol (figure 1).
Deviation from the FDA-recommended protocol is required in up to 45 percent of cases, often due to adverse events [24]. When patients require reinitiation of therapy or dose increase, experience suggests that the recommended protocol and hospital admission should be implemented [25].
SPECIFIC INDICATIONS — Because dofetilide can cause life-threatening ventricular arrhythmias, it is recommended that it should be reserved for patients in whom atrial fibrillation/atrial flutter (AF/AFl) is highly symptomatic or has resulted in heart failure. Although not approved for use, it has been evaluated in small studies in patients with other supraventricular arrhythmias and ventricular tachycardia.
Oral dofetilide for atrial fibrillation/atrial flutter termination and prevention — Dofetilide is indicated for the conversion of atrial fibrillation/atrial flutter (AF/AFl) and maintenance of normal sinus rhythm (delay in time to recurrence of AF/AFl) in patients whose arrhythmia is of greater than one-week duration and who have been converted to normal sinus rhythm.
Oral dofetilide has been evaluated for the cardioversion of atrial fibrillation (AF) or atrial flutter (AFl) to normal sinus rhythm and for the prevention of recurrent AF or atrial flutter.
●To evaluate the efficacy of dofetilide in termination of atrial arrhythmias, the SAFIRE-D study randomly assigned 325 patients with AF (n = 277) or AFl (n = 48) to 125, 250, and 500 mcg of dofetilide twice daily or placebo [26]. Overall conversion rates were 6, 10, and 30 percent, respectively, versus 1.2 percent for placebo. At a dose of 500 mcg twice daily, the conversion rates for AF and atrial flutter were 22 and 67 percent, respectively. For those patients who responded to dofetilide, conversion to sinus rhythm occurred within 24 hours in 70 percent and within 36 hours in 91 percent. (See "Atrial fibrillation: Cardioversion".)
●The SAFIRE-D trial also evaluated the long-term efficacy of dofetilide for maintenance of sinus rhythm in 204 patients with AF who were successfully cardioverted electrically or pharmacologically with dofetilide and maintained on a dofetilide dose of 125, 250, or 500 mcg twice daily or placebo [26]. The probability of remaining in sinus rhythm at one year was 40, 37, and 58 percent versus 25 percent for placebo. The all-cause mortality was the same in the four groups. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".)
●Acute conversion versus long-term arrhythmia free survival – In retrospective studies of patients who initiated dofetilide during persistent AF/AFl, between 45 and 56 percent have converted to sinus rhythm during dofetilide loading [27,28]. Female gender, history of AFl, greater number of prior catheter ablations, shorter duration of current AF/AFl, and presentation in AFl were all associated with acute pharmacologic conversion (p = 0.001, 0.05, 0.001, 0.003, and 0.003, respectively) [27]. Pharmacologic conversion was not significantly associated with time to AF/AFl recurrence (HR = 0.79, 95% CI 0.57-1.10, p = 0.2). Acute pharmacologic conversion of persistent AF/AFl to sinus rhythm frequently occurs during dofetilide loading but does not predict long-term arrhythmia control, which was moderate at best.
●Comparative efficacy – In an observational study of 5952 consecutive patients with AF who were prescribed amiodarone (n = 2266), dronedarone (n = 488), dofetilide (n = 539), sotalol (n = 1718), or class 1C agents (n = 941) and followed for a median of 18 months, amiodarone, class 1C agents, and sotalol were associated with less AF recurrence than dofetilide or dronedarone [29].
●Another observational study suggests that when properly initiated and monitored, dofetilide's efficacy and safety are comparable to that of amiodarone. The study assessed rhythm control with dofetilide in 657 patients with AF and/or atrial flutter and AF. Dofetilide was successfully initiated in 87 percent of patients, including 89 percent with persistent AF and 11 percent with paroxysmal AF. During a mean follow-up of 19±7 months, sinus rhythm was maintained in 63 percent of 573 dofetilide-treated patients. At 12 months, dofetilide patients had a similar likelihood of experiencing recurrent atrial arrhythmias compared with 2476 patients on amiodarone for rhythm control (37 versus 39 percent). The efficacy of dofetilide and amiodarone was similar in subgroups, including patients >75 years of age, low ventricular ejection fraction, obesity, renal insufficiency, and prior catheter ablation for AF [30].
●Rapid conversion of patients who were refractory or intolerant of amiodarone to dofetilide therapy was successful in 66 percent of 179 patients who had an ICD in place and for whom amiodarone had been discontinued for seven days [31].
Dofetilide for preventing recurrence of paroxysmal supraventricular tachycardia — Dofetilide (500 mcg twice daily) was compared with propafenone (150 mg three times daily) and placebo for the prevention of recurrent paroxysmal supraventricular tachycardia (PSVT) in a trial of 122 patients [32]. After six months of therapy, freedom from episodes of PSVT was the same with dofetilide and propafenone (50 and 54 versus 6 percent for placebo); the median number of episodes of PSVT in those with recurrences was also the same with these two agents (1 and 0.5 versus 5 for placebo).
Ventricular tachyarrhythmias — Animal studies have suggested that dofetilide reduces the incidence of sustained ventricular tachyarrhythmias during acute myocardial ischemia [33]. However, comprehensive studies of dofetilide in patients with life-threatening ventricular tachyarrhythmias are limited.
Oral dofetilide (500 mcg twice daily) was compared with oral sotalol (160 mg twice daily) in a randomized, crossover comparative trial of 135 patients with ischemic heart disease and ventricular tachycardia (VT) induced during electrophysiologic testing [34]. Patients underwent repeat electrophysiologic testing after three to five days of therapy and then crossed over to the alternate drug. The response rate was the same with dofetilide and sotalol (36 versus 34 percent), but only 18 percent responded to both drugs. Drug-related adverse effects were significantly less frequent with dofetilide.
Oral dofetilide has also been evaluated patients with an ICD, yielding mixed results. Among one cohort of 174 patients with an implantable cardioverter-defibrillator (ICD), dofetilide did not reduce the incidence of ICD interventions for ventricular tachycardia or ventricular fibrillation (VF) compared with placebo; however, the incidence of pause-dependent torsades de pointes was significantly higher with dofetilide (17 versus 6 percent for placebo) [35]. However, in a smaller cohort of 30 patients with ICDs for secondary prevention who were treated with dofetilide and followed for an average of 32 months, dofetilide led to significant reductions in VT and VF as well as ICD therapies delivered [36].
Pending the completion of additional prospective studies of dofetilide, we do not suggest its routine use as a first-line antiarrhythmic drug for the treatment of ventricular tachyarrhythmias.
Heart failure — Both animal and human studies have shown that dofetilide does not have a negative inotropic effect on left ventricular contractility [37,38]. In a clinical study of patients with class II or III heart failure, intravenous dofetilide (8 mcg/kg), which is not available in all countries, did not alter left ventricular contractility or ventricular volumes [38]. In addition, because of the limited number of antiarrhythmic medications available for use in patients with heart failure or reduced left ventricular systolic function, there is interest in developing additional antiarrhythmic medications for use in this population. Despite this potential interest, there remain limited data with mixed outcomes regarding the safety and efficacy of dofetilide use in such patients, particularly in those with advanced heart failure.
There are limited post-approval data and safety outcomes with dofetilide use in patients with reduced left ventricular ejection fraction. In a retrospective review from a single center, dofetilide as an initial antiarrhythmic strategy for atrial fibrillation in left ventricular ejection fraction ≤35 percent was associated with improvement in left ventricular ejection fraction >35 percent in 73 percent of patients, precluding the need for primary prevention implantable cardioverter defibrillator in most patients [39].
The DIAMOND-CHF trial evaluated the safety of dofetilide compared with placebo in 1518 patients with symptomatic heart failure and left ventricular dysfunction (left ventricular ejection fraction ≤35 percent), including 391 with AF at baseline [23]. After one month of therapy, 12 percent of patients with AF at baseline had sinus rhythm restored compared with only 1 percent receiving placebo. After a mean follow-up of 18 months, there was no overall difference in mortality between the two groups (41 versus 42 percent). In a subsequent analysis, a difference in mortality was noted according to baseline corrected QT (QTc) interval [40]. In those with a QTc interval <429 milliseconds, dofetilide was associated with a significant reduction in mortality (risk ratio 0.4, 95% CI 0.3 to 0.8), while it tended to increase mortality in those with a QTc interval >479 milliseconds (risk ratio 1.3, 95% CI 0.8 to 1.9). In these same patients, the incidence of torsades de pointes was 3.3 percent; three-quarters of these episodes occurred within the first three days while the patient was in the hospital. (See "The management of atrial fibrillation in patients with heart failure".)
Postmyocardial infarction — Dofetilide has been evaluated and appears safe for use in patients with a history of myocardial infarction (MI). The DIAMOND-MI trial enrolled 1510 patients with an acute MI and a left ventricular ejection fraction ≤35 percent. Patients were randomly assigned to dofetilide (500 mcg twice per day) or placebo within seven days of the MI [41]. The one year mortality was 31 percent, and the incidence of arrhythmic deaths was 17 percent. Total mortality, cardiac mortality, arrhythmic mortality, and the combined end point of cardiac death and resuscitation were the same in both groups. In addition, there was evidence of antiarrhythmic efficacy of dofetilide. Among patients receiving dofetilide, there was a lower incidence of new atrial fibrillation and a higher rate of conversion of atrial fibrillation to sinus rhythm (42.4 versus 12.5 percent for placebo).
Torsades de pointes developed in 0.9 percent of patients treated with dofetilide, most of which occurred within the first four days of treatment. However, the patients in this trial were scrutinized carefully to exclude those with known risk factors for torsade, which may explain why the incidence of torsade was lower than in some other studies noted above.
Use of dofetilide in patients with left ventricular hypertrophy
●United States guidelines recommend avoiding pure class III antiarrhythmics such as dofetilide in patients with significant left ventricular hypertrophy (LVH) due to concerns for increased risk of death.
●However, in a propensity-matched cohort of 718 patients with AF and LVH, dofetilide was not associated with increased mortality at three years (the primary outcome). Patients (≥18 years of age with AF and LVH ≥1.4) were treated with dofetilide, and a control group of patients without a history of antiarrhythmic drug use were propensity matched. Total all-cause hospitalizations were higher in the control group, but hospitalizations for AF were no different. Given the current options available, these preliminary findings suggest that further studies of dofetilide in patients with LVH are reasonable for managing symptomatic AF [42].
SAFETY — There is concern about the safety of dofetilide, which like other class III antiarrhythmic agents (figure 1) is associated with a risk of torsades de pointes [43,44]. Torsades de pointes has been reported in up to 3 percent of patients receiving dofetilide [15,45]. In a pooled analysis from the dofetilide treated patients in the DIAMOND-HF and DIAMOND-MI trials (where the incidence of torsades de pointes was 2.1 percent), the risk of torsades de pointes was greater in women than in men (OR 2.2), and in patients with NYHA class III or IV heart failure (OR 3.2) [46]. Despite the increased risk of torsade de pointes, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials did not show an increase in mortality with dofetilide use (adjusted hazard ratio 1.1) [47].
To evaluate the incidence and risk factors for in-hospital adverse events as well as the long-term safety of continued use of dofetilide, one study conducted a retrospective chart review of a cohort of 1404 patients initially receiving loading doses for AF suppression between 2008 and 2012 [48]. Of the 17 patients (1.2 percent) who developed torsades de pointes during loading, 10 had a cardiac arrest requiring resuscitation (with one death), five had syncope/presyncope, and two were asymptomatic. Dofetilide loading doses were stopped for 105 patients (7.5 percent) due to excessive QTc prolongation or torsades de pointes. Variables that correlated with torsades de pointes were female gender, 500 mcg dose, reduced ejection fraction, and increase in QTc from baseline. One-year all-cause mortality was higher in patients who continued dofetilide compared with those who discontinued use (HR 2.48, 95% CI 1.08 to 5.71, p = 0.03). Those patients who experienced a torsades de pointes event had higher one-year all-cause mortality than those who did not (17.6 versus 3 percent at one year, p<0.001).
Because excessive QT prolongation is assumed to be a critical component of torsades de pointes, orally administered magnesium citrate has been used to shorten dofetilide-induced QT prolongation [49]. Intravenous magnesium may also increase the chemical cardioversion rate and lower the incidence of torsades de pointes [50]. (See 'Oral dofetilide for atrial fibrillation/atrial flutter termination and prevention' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".)
SUMMARY AND RECOMMENDATIONS
●Electrophysiology – Dofetilide is a class III antiarrhythmic agent (table 1) that blocks the delayed rectifier cardiac potassium channel and increases the late sodium current, both actions that prolong repolarization. (See 'Electrophysiology' above.)
●Ventricular tachyarrhythmias – For patients who are candidates for other antiarrhythmic drugs (ie, amiodarone, sotalol, etc), we do not suggest the routine use of dofetilide as a first-line antiarrhythmic drug for the treatment of ventricular tachyarrhythmias. This is based on the lack of prospective efficacy data showing improvement in outcomes over other medications when dofetilide is used for the treatment of ventricular tachyarrhythmias. (See 'Ventricular tachyarrhythmias' above.)
●Protocol for administration – In an effort to optimize efficacy and safety, the initiation or reinitiation of dofetilide should occur in a controlled fashion according to the US Food and Drug Administration (FDA)-recommended dose protocol (figure 1).
●Drug approval and restrictions – The use of dofetilide is approved by FDA and several countries worldwide. Its use in the US is contingent upon the following restrictions (see 'Drug approval and restrictions' above):
•Patients must be hospitalized for a minimum of three days for dofetilide initiation to monitor creatinine clearance, QT interval, and cardiac rhythm (figure 1). Most episodes of torsades de pointes occur within this three day period, the time of peak increase in the QT interval, but rarely torsades de pointes can occur later.
•Hospitalization with monitoring is recommended when therapy has been interrupted and is to be reinitiated or when dose increase is considered necessary.
•Dofetilide is contraindicated in patients with congenital long QT syndrome, a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities), severe renal insufficiency (CCr <20 mL/min), known hypersensitivity, and in patients taking drugs known to slow its renal elimination (eg, cimetidine, verapamil, trimethoprim, alone or in combination with sulfamethoxazole, prochlorperazine, hydrochlorothiazide, alone or in combination with triamterene, megestrol, dolutegravir, and ketoconazole).
●Specific indications – Dofetilide appears to be safe for use in patients with a history of heart failure or prior myocardial infarction. In patients with heart failure, however, there is a suggestion of increased mortality in patients with a baseline corrected QT (QTc) interval >479 milliseconds. (See 'Heart failure' above and 'Postmyocardial infarction' above.)
●Safety – Like other class III antiarrhythmic agents, dofetilide is associated with dose-dependent prolongation of the QT interval and a risk of torsades de pointes, which has been reported in up to 3 percent of patients receiving dofetilide. This risk may be attenuated with concomitant magnesium therapy, careful attention to modifiable risk factors, and participation of clinical pharmacists to help manage the treatment initiation protocol required by the FDA. (See 'Safety' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Raymond Woosley, MD, PhD, who contributed to an earlier version of this topic review.
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