When given as immediate-release tablets, propafenone hydrochloride is used to prolong the time to recurrence of symptomatic, disabling paroxysmal supraventricular tachycardia (PSVT) (e.g., atrioventricular [AV] nodal reentrant tachycardia or AV reentrant tachycardia [Wolff-Parkinson-White, WPW, syndrome]) and symptomatic, disabling paroxysmal atrial fibrillation/flutter (PAF) in patients without structural heart disease. While comparative studies are limited, propafenone appears to be comparable to other antiarrhythmic agents (e.g., quinidine, disopyramide, flecainide, procainamide, sotalol) in preventing recurrences of PAF and maintaining sinus rhythm following successful cardioversion of atrial fibrillation.
When given as extended-release capsules, propafenone is used to prolong the time to recurrence of symptomatic paroxysmal atrial fibrillation in patients without structural heart disease. The safety and efficacy of propafenone as extended-release capsules have not been established in patients with exclusively PSVT or atrial flutter.
Propafenone also has been used for termination of supraventricular tachycardias; analysis of combined data from controlled and uncontrolled clinical studies in patients receiving oral (immediate-release tablets) or IV (IV dosage form not commercially available in the US) propafenone therapy has demonstrated termination of PAF, PSVT, or tachycardia associated with WPW syndrome in 73, 57, or 45%, respectively, of patients. However, 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 for acute conversion of PSVT.
The safety and efficacy of propafenone hydrochloride as immediate-release tablets or extended-release capsules have not been established in patients with chronic atrial fibrillation, and the manufacturer states that the drug should not be used to control ventricular rate in patients with atrial fibrillation.
Because of the risk of proarrhythmia, propafenone should not be used in patients with structural heart disease or ischemic heart disease.
Paroxysmal Atrial Fibrillation/Flutter and Paroxysmal Supraventricular Tachyarrhythmias
Immediate-release Propafenone Hydrochloride
Controlled and uncontrolled clinical studies have shown that propafenone (immediate-release tablets) may prevent or delay recurrence of PAF or increase the interval between recurrences of PAF in 39-64% of patients monitored for 6-18 months. Preliminary analysis of combined data from clinical studies indicates that propafenone prevented or delayed recurrence of PAF in 51 or 33% of patients monitored for 1 or 2 years, respectively, and prevented or delayed recurrence of PSVT or AV reentrant tachycardia (WPW syndrome) syndrome in 63 or 83%, respectively, of patients treated during a 10-month period. Long-term therapy with oral propafenone also has been effective in some patients for suppression and prevention of atrial fibrillation refractory to other antiarrhythmic agents. It has been suggested that propafenone may be more effective than flecainide in patients with adrenergically mediated atrial fibrillation or flutter, possibly because of its β-adrenergic blocking activity.
Control of ventricular rate should be the first therapeutic step in most patients with hemodynamically stable, acute atrial fibrillation. The goal of therapy should be a reduction of ventricular rate to less than 80-90 beats/minute and prevention of inappropriately high ventricular rates during activity. The use of propafenone in patients with chronic atrial fibrillation has not been adequately evaluated to date, and the manufacturer states that the drug should not be used to control ventricular rate in patients with atrial fibrillation. However, some experts and clinicians suggest that propafenone may be useful in controlling ventricular response rate in patients with stable but rapid atrial fibrillation/flutter and ventricular preexcitation via an accessory pathway (e.g., WPW syndrome).
In a randomized, crossover clinical trial of approximately 2-3 months' duration, the median time to arrhythmia recurrence was greater than 98 days in patients with PAF or PSVT receiving propafenone and 8 or 12 days in patients with PAF or PSVT, respectively, receiving placebo. Recurrences of PAF or PSVT were completely prevented in 53 or 47%, respectively, of patients receiving propafenone and in 13 or 16%, respectively, of those receiving placebo. In another randomized, crossover clinical trial of 2-3 months' duration, the median time to arrhythmia recurrence in patients with PAF or PSVT was 62 or 31 days, respectively, with propafenone therapy and 5 or 8 days, respectively, with placebo. Recurrences of PAF or PSVT were completely prevented in 67 or 38%, respectively, of patients receiving propafenone and in 22 or 7%, respectively, of those receiving placebo. Patients enrolled in these 2 trials had a mean age of 57.3 years; 50% of patients were male, and 80% received a daily propafenone hydrochloride dosage of 600 mg. Patients with PSVT or PAF were equally represented in the 2 studies.
Propafenone has been used orally for the long-term management of AV nodal reentrant tachycardia; however, the drug is generally reserved for patients in whom other therapies (e.g., catheter ablation, β-adrenergic blocking agents, diltiazem, verapamil) are ineffective or contraindicated.
In a randomized crossover study, the rate of recurrence of tachycardia with propafenone therapy was approximately one-fifth that with placebo. Propafenone may be particularly effective and may be considered first-line therapy in patients with atrial fibrillation/flutter associated with ventricular preexcitation and WPW syndrome; in these patients, the drug may slow the ventricular rate and possibly restore and maintain normal sinus rhythm. However, in patients with WPW syndrome whose condition is unstable (e.g., those with hypotension or heart failure), immediate cardioversion may be required. In studies in patients with recurrent episodes of supraventricular tachyarrhythmia associated with WPW syndrome, administration of oral propafenone hydrochloride (300-1200 mg daily prevented arrhythmia recurrence in 38-100% of patients during 7-36 months of follow-up. Propafenone therapy also has been effective for arrhythmias associated with WPW syndrome and a short anterograde refractory period of the accessory pathway, although radiofrequency catheter ablation of the accessory pathway may be preferred for the long-term management of this condition.
Based on findings from the Cardiac Arrhythmia Suppression (CAST) study of substantial risk associated with flecainide or encainide therapy in certain patients with ventricular arrhythmias, some experts currently caution that use of class Ic antiarrhythmic agents 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 propafenone for the management of such arrhythmias in patients with structural heart disease remain to be elucidated, and assessment of the possible risks and potential benefits in such patients must be individualized. Current evidence indicates that initiation of antiarrhythmic therapy in patients with atrial fibrillation is associated with a notable risk for adverse cardiac events, particularly in geriatric patients or those with structural heart disease (e.g., heart failure); initiation of antiarrhythmic therapy in such patients should be performed in a hospital setting with ECG monitoring for the initial 24-48 hours. 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.
Extended-release Propafenone Hydrochloride
The FDA-labeled indication for extended-release propafenone hydrochloride in prolonging the time to first recurrence of symptomatic paroxysmal atrial fibrillation is based principally on the results of 2 multicenter, randomized, double-blind, placebo-controlled trials in patients with a history of ECG-documented recurrent episodes of this arrhythmia. Patients had a median duration of paroxysmal atrial fibrillation of 13 months and ECG-documented symptomatic atrial fibrillation within 12 months in one trial, and a median duration of paroxysmal atrial fibrillation of 39.6 months and ECG-documented symptomatic atrial fibrillation within 28 days in the second trial. In the first trial, the median time to first recurrence of atrial fibrillation from day 1 of randomization (primary efficacy variable) was 112, 291, or 41 days in patients receiving extended-release propafenone hydrochloride 225 or 325 mg twice daily or placebo, respectively, for up to 39 weeks. Additional analysis indicated that extended-release propafenone hydrochloride 425 mg twice daily also increased the interval to first recurrence of symptomatic atrial fibrillation. A dose-response relationship was observed with respect to time to first recurrence of ECG-documented symptomatic atrial fibrillation. The time to first recurrence of atrial fibrillation from day 5 of randomization (primary efficacy variable) also was increased in patients receiving extended-release propafenone hydrochloride (325 or 425 mg twice daily) for 91 days in the second trial.
IV† Propafenone Hydrochloride
Propafenone has been administered IV with some success in the acute treatment of supraventricular reentrant tachycardias. In a randomized, crossover, placebo-controlled study in patients with AV nodal reentrant tachycardia, intraatrial orthodromic reentrant tachycardia, or tachycardia associated with WPW syndrome, conversion to normal sinus rhythm occurred in 75% of patients receiving 1 or 2 rapid IV injections of propafenone hydrochloride (2 mg/kg) and in no patients receiving placebo. However, an IV dosage form is not commercially available in the US and other therapies (e.g., vagal maneuvers, IV adenosine, calcium-channel blocking agents, β-adrenergic blocking agents, synchronized cardioversion) are recommended for acute conversion of PSVT.
Conversion of Atrial Fibrillation or Flutter to Normal Sinus Rhythm
Propafenone has been used for pharmacologic cardioversion of atrial fibrillation or flutter. Both oral (immediate-release tablets) and IV propafenone (IV dosage form currently not commercially available in the US) have been effective for conversion of recent-onset atrial fibrillation, including atrial fibrillation occurring after open-heart surgery, to normal sinus rhythm, and some clinicians suggest that propafenone may be considered first-line therapy for this use. Conversion rates are inversely related to both duration of atrial fibrillation, number of previous drug treatment failures, and degree of atrial enlargement. Some patients with atrial flutter receiving propafenone (immediate-release tablets) may develop 1:1 AV conduction and a rapid ventricular response; therefore, concomitant therapy with drugs that prolong the functional AV refractory period (e.g., cardiac glycoside, β-adrenergic blocking agent) is recommended in such patients.
In acute, hemodynamically stable atrial fibrillation of less than 48 hours' duration, antiarrhythmic drug therapy may result in conversion to sinus rhythm in about 60-90% of patients; however, such therapy is effective in only 15-30% or less of patients with atrial fibrillation of longer duration. 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.
Propafenone hydrochloride also has been administered orally (150-600 mg as immediate-release tablets) or IV (2 mg/kg over 10 minutes) as a single dose for restoration of sinus rhythm in patients with infrequent episodes of paroxysmal atrial fibrillation when it is desirable to avoid potential adverse effects of long-term antiarrhythmic drug therapy. Limited data suggest that oral propafenone therapy (immediate-release tablets) initiated 48 hours prior to electrical cardioversion of patients with chronic atrial fibrillation may decrease the recurrence rate of this arrhythmia without an untoward effect on defibrillation threshold or electrical cardioversion rates.
Self-administration for Conversion of Paroxysmal Atrial Fibrillation
Limited evidence suggests that out-of-hospital self-administration (''pill-in-the-pocket'' approach) of a single oral loading dose of propafenone hydrochloride (immediate-release tablets) or flecainide 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 propafenone hydrochloride (immediate-release tablets) or flecainide 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 propafenone hydrochloride (immediate-release tablets) or flecainide (according to clinician preference) to restore normal sinus rhythm. Patients weighing 70 kg or more received 600 mg of propafenone hydrochloride (immediate-release tablets) or 300 mg of flecainide acetate and those weighing less than 70 kg received 450 mg of propafenone hydrochloride (immediate-release tablets) or 200 mg of flecainide acetate. 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 propafenone hydrochloride (immediate-release tablets) or flecainide 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 propafenone hydrochloride (immediate-release tablets) or flecainide 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 a period of 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 hydrochloride 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 (immediate-release tablets) (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 propafenone or flecainide hydrochloride terminated all such episodes in 84% of patients. Self-administration of oral propafenone (immediate-release tablets) or flecainide 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.
Other Atrial Tachycardias
Propafenone 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.
Supraventricular Tachyarrhythmias in Children
Although controlled studies generally are lacking, oral (immediate-release tablets) or IV propafenone (IV dosage form currently not commercially available in the US) has been used successfully for the management of supraventricular tachyarrhythmias (e.g., PSVT, postoperative or congenital junctional ectopic tachycardia, atrial ectopic tachycardia, chaotic atrial tachycardia, atrial fibrillation or flutter) in children. Oral propafenone (immediate-release tablets) reportedly has been effective in treating refractory atrial flutter in children; however, experience is limited and the drug cannot currently be recommended as first-line therapy for this use.
Propafenone hydrochloride (immediate-release tablets) is used orally to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation). Based on the results of the Cardiac Arrhythmia Suppression Trial (CAST) (), FDA, the manufacturer, and many clinicians recommend that therapy with antiarrhythmic agents, including propafenone, be reserved for the suppression and prevention of documented ventricular tachyarrhythmias that, in the clinician's judgment, are considered life-threatening.
Because of propafenone's arrhythmogenic potential and the associated risk of death identified with other class Ic antiarrhythmic drugs (encainide, flecainide) in CAST, use of propafenone for less severe ventricular arrhythmias (e.g., asymptomatic ventricular premature complexes [VPCs]), is not 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 40%), and asymptomatic or mildly symptomatic ventricular arrhythmias (mean baseline VPCs of 127/hour as evidenced by 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 non-life-threatening ventricular arrhythmias (e.g., patients with arrhythmias in the absence of ventricular dysfunction, myocardial ischemia, or recent myocardial infarction) or to other antiarrhythmic drugs (e.g., propafenone). 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 antiarrhythmic therapy substantial and currently do not recommend use of propafenone in any patient with non-life-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 non-life-threatening manifestations. 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 propafenone (immediate-release tablets) in the suppression and prevention of ventricular arrhythmias remains to be clearly determined. In addition, it remains to be determined whether antiarrhythmic agents, including propafenone, have a beneficial effect on mortality or sudden death. Although propafenone (immediate-release tablets) has been used for chronic suppression and prevention of ventricular arrhythmias in carefully selected patients, further study is needed to evaluate the long-term efficacy and safety and the relative role of the drug in such patients. Therefore, it is recommended that propafenone (immediate-release tablets) 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 propafenone's negative inotropic 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 and/or substantial ventricular dysfunction (e.g., left ventricular ejection fraction less than 30%). 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.
Available data suggest that the efficacy of propafenone (immediate-release tablets) for suppression and prevention of recurrent, life-threatening ventricular arrhythmias is comparable to that of other antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide), with propafenone considered effective in approximately 22-50% of patients. The decision to use propafenone therapy (immediate-release tablets) should be based on an analysis of each patient's risk profile, including consideration of the type and prognosis of the specific arrhythmia, presence of underlying heart disease, degree of ventricular dysfunction, and any other serious comorbidities (e.g., hepatic or renal impairment, conduction abnormalities). Additional studies, including comparative studies with other antiarrhythmic agents, are needed to evaluate the use of propafenone (immediate-release tablets) in the management of life-threatening ventricular arrhythmias.
In a cohort study, oral propafenone hydrochloride (750-900 mg daily) (immediate-release tablets) was effective in rendering arrhythmias noninducible in 26% of patients with documented sustained ventricular arrhythmias and/or ventricular fibrillation as determined by programmed ventricular stimulation. An analysis of 27 studies in a combined total of 684 patients with malignant ventricular arrhythmias receiving propafenone yielded overall efficacy rates of 61 and 71% as determined by invasive and noninvasive testing methods, respectively. In the invasive method efficacy studies, propafenone therapy (immediate-release tablets) was considered effective in 25% of patients whose arrhythmias became noninducible, 32% of patients whose arrhythmias remained inducible but who developed improved hemodynamic tolerance and prolongation of ventricular tachycardia cycle length (100 msec or greater), and 4% of patients whose inducible sustained ventricular tachycardia was improved to inducible nonsustained ventricular tachycardia. In the noninvasive method efficacy studies, short-term propafenone therapy (1-5 days) (immediate-release tablets) was considered effective in 53-92% (mean: 71%) of patients as determined by the complete elimination of ventricular tachycardia, greater than 90% reduction in frequency of ventricular coupled beats, or greater than 50% reduction in the total number of VPCs compared with baseline arrhythmia frequency. Overall long-term efficacy, defined as the absence of symptomatic recurrence of the baseline arrhythmia, was determined by evaluation of the 90% of patients who had a positive initial response to therapy (measured by invasive or noninvasive efficacy criteria) and who continued propafenone therapy (immediate-release tablets) after hospital discharge. Long-term propafenone therapy (immediate-release tablets) (mean duration of follow-up: 14 months; range: 1-57 months) was considered effective in 67% of patients discharged on the drug and in 36% of the combined total of patients enrolled in the studies.
Limited information is available on the use of propafenone (immediate-release tablets) in conjunction with other antiarrhythmic agents for the management of severe, refractory ventricular arrhythmias. In a limited number of patients, propafenone (immediate-release tablets) has been combined with procainamide, quinidine, or mexiletine with good results in selected patients.
(See Drug Interactions: Antiarrhythmic Agents.)
Concomitant use of 2 or more antiarrhythmic drugs requires extreme caution and generally is reserved for patients with life-threatening ventricular arrhythmias inadequately controlled by single-agent therapy with propafenone (immediate-release tablets) or another antiarrhythmic agent. Combination antiarrhythmic therapy for severe refractory ventricular arrhythmias generally is empiric and must be individualized.
Other Ventricular Arrhythmias
Controlled and uncontrolled clinical studies in patients with chronic stable ventricular arrhythmias have shown that propafenone (immediate-release tablets) is highly effective in suppressing and preventing nonsustained ventricular tachycardia and frequent VPCs, including complex VPCs. In short-term clinical studies, propafenone therapy (immediate-release tablets) produced approximately 66-98% suppression of VPCs in about 90% of patients; in approximately 75% of patients, ventricular tachycardia was abolished and ventricular couplets suppressed. However, despite such documented evidence of efficacy in suppressing and preventing these arrhythmias, there currently is no evidence of a 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 treated with other class Ic antiarrhythmic drugs (i.e., flecainide, encainide), there was evidence of substantial risk (including mortality and nonfatal cardiac arrest) associated with therapy. (.) Therefore, use of propafenone in non-life-threatening ventricular arrhythmias currently is not recommended by the manufacturer, FDA, and other experts.
Although controlled studies generally are lacking, both oral (immediate-release tablets) and IV propafenone (IV dosage form currently not commercially available in the US) have been used successfully in the management of ventricular arrhythmias (e.g., VPCs, coupled VPCs, nonsustained ventricular tachycardia) in children.