Flecainide acetate is used orally to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia). Based on information from the National Heart, Lung, and Blood Institute (NHLBI) describing interim results of the Cardiac Arrhythmia Suppression Trial (CAST) (see the opening discussion in Cautions), FDA and the manufacturer have notified health-care professionals that flecainide therapy should be reserved for the suppression and prevention of documented ventricular arrhythmias that, in the clinician's judgment, are considered life-threatening.
Because of the drug's arrhythmogenic potential and associated risk of death identified in CAST, use of flecainide for less severe arrhythmias (e.g., nonsustained ventricular tachycardia, frequent ventricular premature complexes [VPCs]), even when they are symptomatic, no longer is recommended. The findings of CAST involved a select patient population with recent myocardial infarction, mild-to-moderate left ventricular dysfunction (e.g., mean baseline ejection fraction of 0.4), and asymptomatic or mildly symptomatic ventricular arrhythmias (mean baseline VPCs of 127/hour as evidenced via ambulatory ECG [Holter] monitoring during at least 18 hours of analyzable time, with about 20% of patients exhibiting at least one run of nonsustained ventricular tachycardia during such monitoring); such patients also had demonstrated drug-induced suppressibility of VPCs during the initial phase of the open trial. It currently is not known whether the findings of CAST can be extrapolated to other patient populations with nonlife-threatening ventricular arrhythmias (e.g., patients with arrhythmias in the absence of ventricular dysfunction, myocardial ischemia, or recent myocardial infarction). CAST principally involved suppression and prevention of VPCs, with only about 10% of patients exhibiting more than a single run of tachycardia at baseline. Some clinicians also question whether the results of CAST even can be extrapolated to patients with recurrent nonsustained ventricular tachycardia and ventricular dysfunction, since these patients are known to be at high risk of sudden death if untreated, and since CAST did not include sufficient numbers of such patients to clearly determine the benefit-to-risk ratio. However, despite the limitations of the CAST findings, the manufacturer, FDA, and other experts consider the potential risks of flecainide therapy substantial and currently do not recommend use of the drug in any patient with nonlife-threatening ventricular arrhythmias in the absence of substantial evidence of safety and efficacy. They state that it is prudent to consider the risks of class IC antiarrhythmic agents and current lack of evidence of improved survival unacceptable in patients without life-threatening ventricular arrhythmias, even in patients experiencing unpleasant but nonlife-threatening signs and symptoms. However, some clinicians, while recognizing the strong evidence of risk in the patient population studied in CAST and the substantial limitations of current evidence on safety and efficacy in other patient populations, question such an extreme limitation of usage.
Life-threatening Ventricular Arrhythmias
The optimum role of flecainide in the suppression and prevention of ventricular arrhythmias remains to be clearly determined.
In addition, it remains to be determined whether antiarrhythmic agents, including flecainide, have a beneficial effect on mortality or sudden death. Although flecainide has been used as a first-line agent for chronic suppression and prevention of ventricular arrhythmias in carefully selected patients, further studies are needed to evaluate the long-term efficacy and safety and the relative role of the drug. Therefore, it is recommended that flecainide generally be reserved for patients who have an insufficient therapeutic response to, or who do not tolerate, conventional orally administered antiarrhythmic agents (e.g., class IA agents). In addition, because of flecainide's arrhythmogenic potential, some clinicians would avoid use of the drug as a first-line agent in patients with life-threatening ventricular arrhythmias who also have congestive heart failure or substantial ventricular dysfunction. While it currently is not known whether the findings of the CAST study apply to class IC antiarrhythmic agents other than flecainide and encainide, some experts state that, in the absence of specific evidence of safety and efficacy, other class IC drugs should be considered to share the risks of flecainide and encainide.
There is relatively limited experience with the use of flecainide for suppression and prevention of recurrent life-threatening ventricular arrhythmias. In the management of severe refractory arrhythmias, the efficacy of flecainide appears to be comparable to that of other first-line antiarrhythmic agents, with the drug being effective in up to about 40% of patients. Younger patients and patients without coronary heart disease and/or substantial ventricular dysfunction appear to have a greater likelihood of responding to flecainide. Further studies, including comparative studies with other antiarrhythmic agents, are needed to evaluate the use of flecainide in the management of life-threatening ventricular arrhythmias.
Limited information is available on the use of flecainide in conjunction with other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias.(See Drug Interactions: Antiarrhythmic Agents.)In a limited number of patients, flecainide has been combined with amiodarone, with good results in selected patients; however, use of these two agents in combination requires extreme caution and is generally reserved for patients with life-threatening ventricular arrhythmias inadequately controlled by single-agent therapy with amiodarone or another antiarrhythmic agent. Combination antiarrhythmic therapy for severe refractory ventricular arrhythmias is generally empiric and must be individualized.
Other Ventricular Arrhythmias
Controlled and uncontrolled clinical studies in patients with chronic stable ventricular arrhythmias have shown that flecainide is highly effective in suppressing and preventing nonsustained ventricular tachycardia and frequent VPCs, including complex VPCs. In short-term clinical studies, flecainide therapy produced at least 80-90% suppression of VPCs in about 80-90% of patients; in many patients, essentially complete suppression of uniform and multiform VPCs, complex VPCs, and/or nonsustained ventricular tachycardia may occur. However, despite such documented evidence of efficacy in suppressing and preventing these arrhythmias, there currently is no evidence of beneficial effect on mortality, and in at least one patient population (those with mild-to-moderate ventricular dysfunction and recent myocardial infarction) with such arrhythmias, there was evidence of substantial risk (including mortality and nonfatal cardiac arrest) associated with flecainide or encainide therapy.(See the opening discussion of Cautions.)Therefore, use of flecainide in nonlife-threatening ventricular arrhythmias currently is not recommended by the manufacturer, FDA, and other experts.
Flecainide is used for the prevention of paroxysmal supraventricular tachyarrhythmias (PSVT), including atrioventricular (AV) nodal reentrant tachycardia and AV reentrant tachycardia (Wolff-Parkinson-White syndrome); other symptomatic, disabling supraventricular tachycardias of unspecified mechanisms; and symptomatic, disabling supraventricular arrhythmias (paroxysmal atrial fibrillation/flutter [PAF]) in patients without structural heart disease. Controlled and uncontrolled clinical studies have shown that flecainide may prevent or delay recurrence of PSVT and PAF episodes or may increase the interval between episodes of PSVT and PAF in 31-81% of patients, depending on the type of arrhythmia; suppression of arrhythmias refractory to other antiarrhythmic agents also has occurred. In some patients with atrial fibrillation or flutter associated with ventricular preexcitation and Wolff-Parkinson-White syndrome, flecainide may slow the ventricular rate or possibly restore and maintain normal sinus rhythm. Because of the risk of proarrhythmia, flecainide should not be used in patients with structural heart disease or ischemic heart disease.
Based on findings from the CAST study of substantial flecainide/encainide-associated risk in certain patients with ventricular arrhythmias, some experts currently caution that use of flecainide in supraventricular arrhythmias be limited to the management of symptomatic, disabling supraventricular arrhythmias (paroxysmal atrial fibrillation, AV junctional tachycardias) in patients without structural heart disease. However, some clinicians state that even these patients may be at risk of developing drug-induced arrhythmogenic effects (e.g., during exercise testing). The risks versus benefits of flecainide for the management of such arrhythmias in patients with structural heart defects remains to be elucidated, and assessment of the possible risks and potential benefits in such patients must be individualized.
Paroxysmal Supraventricular Tachycardia
For acute conversion of PSVT, vagal maneuvers, IV adenosine, AV nodal blocking agents (e.g., calcium-channel blocking agents, β-adrenergic blocking agents), and/or synchronized cardioversion are the treatments of choice. Oral flecainide is one of several drugs that may be used for the ongoing management of patients with PSVT who do not have structural or ischemic heart disease; use of flecainide generally is reserved for patients in whom other therapies are ineffective or contraindicated. In a randomized, placebo-controlled, crossover study in 34 patients with symptomatic PSVT, episodes of PSVT occurred in 85% of patients receiving placebo but in only about 21% of patients receiving flecainide acetate in a median dosage of 300 mg daily (range: 100-400 mg daily in 2 divided doses) during the 16-week study period. The median time before initial recurrence of PSVT exceeded 55 days in patients receiving flecainide compared with 11 days in those receiving placebo, while median intervals between episodes of PSVT exceeded 55 days in patients receiving flecainide compared with 12 days in those receiving placebo.
Paroxysmal Atrial Fibrillation and Flutter
In another randomized, crossover placebo-controlled study in 48 patients with PAF, episodes of PAF occurred in 92% of patients receiving placebo versus 69% of patients who received flecainide acetate daily in a median dosage of 300 mg daily (range: 100-600 mg daily in 2 divided doses) during the 8-week study period. The median time before initial recurrence of PAF was approximately 15 days in patients receiving flecainide versus 3 days in those receiving placebo, while the median interval between episodes of PAF was 27 days in patients receiving flecainide and approximately 6 days in patients receiving placebo.
Self-administration for Conversion of Paroxysmal Atrial Fibrillation
Limited evidence suggests that out-of-hospital self-administration of a single oral loading dose of flecainide or propafenone (''pill-in-the-pocket'' approach) is safe and effective for terminating recent-onset paroxysmal atrial fibrillation and can reduce hospitalizations and emergency room visits in carefully selected patients who have mild or no heart disease. In-hospital administration of flecainide or propafenone (as immediate-release tablets) as a single oral dose for terminating acute atrial fibrillation has been shown to be effective with a low incidence of adverse effects in several randomized, controlled studies; however, the safety of such treatment without initial evaluation in a hospital setting or in patients with substantial structural heart disease has not been established. In addition, additional study and experience are required to assess the possible need for concomitant antithrombotic (e.g., warfarin) therapy and potential for adverse drug interactions (e.g., with warfarin or digoxin) in patients self-administering antiarrhythmic agents for recent-onset paroxysmal atrial fibrillation on an out-of-hospital basis.
In a prospective, uncontrolled study, 268 patients (18-75 years of age) with mild or no heart disease who had hemodynamically well-tolerated atrial fibrillation of recent (less than 48 hours) onset were treated in-hospital (i.e., in the emergency room or cardiology ward) with a single oral dose of flecainide or immediate-release propafenone (according to clinician preference) to restore normal sinus rhythm. Patients weighing 70 kg or more received 300 mg of flecainide acetate or 600 mg of propafenone hydrochloride and those weighing less than 70 kg received 200 mg of flecainide acetate or 450 mg of propafenone hydrochloride. In-hospital treatment was considered effective if conversion of atrial fibrillation to sinus rhythm occurred within 6 hours of administration of the antiarrhythmic agent without clinically important adverse effects (i.e., symptomatic hypotension, symptomatic bradycardia after restoration of sinus rhythm, dyspnea, presyncope, syncope, conversion to atrial flutter or atrial tachycardia, or episodes of sustained or unsustained ventricular tachycardia). The time to conversion to sinus rhythm following in-hospital treatment with flecainide or propafenone in these patients averaged 135 minutes (median: 120 minutes). Patients in whom inpatient administration of these antiarrhythmics was effective and who were not excluded during subsequent examination were discharged and given flecainide or propafenone for treatment of subsequent episodes of palpitations (presumed recurrent atrial fibrillation) on an outpatient basis. These patients were instructed to take a single oral dose of the assigned antiarrhythmic drug 5 minutes after noting the onset of palpitations (self-assessed) and then to assume a resting state (e.g., a supine or sitting position) until resolution of the palpitations or for at least four hours.
Analysis of data from 2 of the study sites indicated that 12% of patients presenting to the emergency room for recent-onset atrial fibrillation were candidates for out-of-hospital treatment with propafenone or flecainide. During a mean follow-up period of 15 months (range: 7-19 months), 79% of patients included in the out-of-hospital phase of the study experienced episodes of palpitations (presumed atrial fibrillation); patients self-administered propafenone hydrochloride (mean dose: 555 mg) or flecainide acetate (mean dose: 263 mg) within a mean of 36 minutes (median: 10 minutes) after the onset of symptoms in 92% of such episodes. Each antiarrhythmic agent was effective in interrupting 94% of episodes of palpitations (a primary end point); time to resolution of symptoms after drug administration averaged 113 minutes (median: 98 minutes). In patients who had multiple recurrences of palpitations during the follow-up period, self-administration of flecainide or propafenone terminated all such episodes in 84% of patients. Self-administration of oral flecainide or propafenone also was associated with reductions in emergency room visits and hospital admissions (secondary end points); calls for emergency room intervention during the study averaged 4.9 per month compared with 45.6 per month during the year prior to the study, while the number of hospitalizations averaged 1.6 per month during the study compared with 15 per month during the prior year.
Atrial Fibrillation and Flutter
Flecainide is considered a drug of choice for pharmacologic cardioversion of atrial fibrillation or atrial flutter. Conversion of atrial fibrillation or flutter to normal sinus rhythm may be associated with embolism, particularly when the arrhythmia has been present for more than 48 hours, unless the patient is adequately anticoagulated.
Limited data suggest that oral flecainide may also improve control of ventricular rate at rest and during exercise in digitalized patients with atrial fibrillation in whom cardiac glycosides alone may not provide adequate control.
Some clinicians do not recommend the use of antiarrhythmic agents in patients with atrial fibrillation or flutter, because increased mortality has been reported in patients receiving antiarrhythmic therapy after conversion of atrial fibrillation to normal sinus rhythm.
Flecainide is one of several drugs that may be used for the ongoing management of focal atrial tachycardia or junctional tachycardia in patients without structural or ischemic heart disease. Limited data suggest that oral flecainide may be effective in suppressing and preventing recurrent atrial tachycardia.