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European Review for Medical and Pharmacological Sciences 2012; 16: 242-253 Atrial fibrillation and the pharmacological treatment: the role of propafenone A. SESTITO, E. MOLINA* Department of Cardiology, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy) *Department of Pharmacology, School of Medicine, University of Parma (Italy) Abstract. – Background: Atrial fibrillation is the most frequent cardiac rhythm disturbance, with prevalence increasing with age. This disease is a major risk factor for ischaemic stroke. The costs resulting from atrial fibrillation are really impressive. Pharmacological agents are the first line therapy for the management of atrial fibrillation. Antiarrhythmic drugs are used to terminate arrhythmias, as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. Among antiarrhythmic agents, drugs that inhibit early sodium current (as propafenone) are proven effective in atrial fibrillation. In this review, the most relevant data on propafenone are provided. Discussion: The development of a sustainedrelease formulation of propafenone allowed to reduce the wide fluctuations in plasma levels observed with the immediate release preparation, improving compliance and adherence to therapy, by simplifying the dosing regimen from 3 to 2 daily doses. Propafenone resulted an effective measure as acute treatment for conversion of recent onset atrial fibrillation, and to maintain sinus rhythm, as chronic therapy for prevention of atrial fibrillation recurrences. In several clinical studies, strong increases of arrhythmia-free periods as well as marked increases in time to recurrence of symptomatic atrial fibrillation, such as paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation were observed. In particular, well-designed clinical studies demonstrated in large patient populations the efficacy of propafenone at several doses. At the suggested doses propafenone is usually well tolerated. Conclusion: The risk of increased occurrence of regular supraventricular arrhythmia or paroxysmal supraventricular tachycardia has been overestimated for propafenone, because this adverse event was seen in all treatment groups, including placebo, with the same (and low) frequency. Key Words: Atrial fibrillation (AF), Acute onset AF, Prevention of AF recurrences, Antiarrhythmic drugs, Propafenone. 242 Introduction Atrial fibrillation is a major clinical problem and the most frequently occurring cardiac rhythm disturbance1-6. Its prevalence increases with age: 2-3‰ between 25 and 35 years, 30-40‰ between 55 and 65 years, 50-90‰ between 62 and 90 years1-3,5. The prevalence of atrial fibrillation is expected to increase for several factors, first of all for the progressive increase in longevity of worldwide populations1,2,6. According to a 2005 estimate6, in USA there were 3.03 millions of atrial fibrillation patients and this figure could reach 7.56 millions in 2050. Atrial fibrillation is a strong risk factor for ischaemic stroke (approximately 3- to 5-fold excess risk), with associated clinical problems and increased mortality rates (1.5- to 1.9-fold mortality risk)2-4,6. Together with its complications, atrial fibrillation is a major cause of health care consumption, costs and poor quality of life6,7. The costs resulting from atrial fibrillation are really impressive2,3,5. In USA it has been estimated that this disease is responsible for more than 1 million days of hospitalization per year5. Even if the pathophysiology of atrial fibrillation is not yet completely understood, there is evidence that the cardiac remodeling plays a major role in the disease process4. A high number of factors responsible for onset of atrial fibrillation, usually indicated as “triggers”, has been recognized8-10. Among them, sympathetic or parasympathetic stimulation, bradycardia, atrial premature beats, tachycardia, accessory atrio-ventricular pathways, and acute atrial stretch are included8. In particular, it has been demonstrated that a wide part of atrial premature beats, involved in paroxysms of atrial fibrillation, originate in the pulmonary veins9. The intrinsic cardiac autonomic nervous system is thought to play a crucial role in the atrial remodeling process10. Corresponding Author: Alfonso Sestito, MD; e-mail: [email protected] Atrial fibrillation and the pharmacological treatment: the role of propafenone The clinical relevance and the high costs of atrial fibrillation account for the need of effective drug treatment5. As for the management of atrial fibrillation, the main therapeutic strategies include: • • • • Rate control; Termination of arrhythmia; Prevention of recurrences; Prevention of thromboembolic events11. Pharmacological agents are the first line therapy for rhythm management in atrial fibrillation1,6. Antiarrhythmic drugs are used to terminate arrhythmias and maintain sinus rhythm6,11. Efficacy and safety profiles are extremely important issues in the choice of an antiarrhythmic agent, but also the dosing convenience (allowing high patient compliance) should be taken in due account11. According to current guidelines, it is suggested to select an antiarrhythmic drug considering some main factors, in order to identify the best therapeutic strategy: • • • • • Symptoms presentation; Atrial fibrillation characteristics; Presence of cardiovascular diseases; Patient age and medical conditions; Treatment goals6. Among antiarrhythmic agents, drugs that inhibit early sodium current (as propafenone and flecainide) are proven effective in atrial fibrillation1,5,12,13. The most widely used antiarrhythmic drugs6 are listed in Table I. According to most recent guidelines and updated meta-analyses, as well as to the Author’s personal caseload, it is possible to anticipate some general considerations on the pharmacological approach to atrial fibrillation. As for other chronic treatments, also for antiarrhythmic drugs the choice of the proper therapy should balance at the best efficacy and safety. The group of antiarrhythmic drugs includes different molecules showing each a typical pro- file of efficacy, safety and convenience. Table II reports some observations on main antiarrhythmic agents6,14-16. We can state, therefore, that propafenone, thanks to its clinical efficacy associated to a good safety (in particular to a reduced risk of proarrhythmic effect), can represent an important measure in the management of atrial fibrillation patients not showing cardiac structural alterations. In addition, this drug, due to the availability of vials for intravenous use, immediate release tablets, and sustained release capsules, allows to develop various treatment schedules and to adapt the therapy according to different needs. Focus on Propafenone Propafenone is a powerful Ic class antiarrhythmic agent, with demonstrated effectiveness against a variety of cardiac arrhythmias12-14. This agent shows a marked inhibitory effect on the sodium channel and some beta-blocking activity5,14-17. The original formulation of oral propafenone immediate release was rapidly absorbed by gastrointestinal tract and metabolized by liver, needing a 3 times daily administration 13,17 . Propafenone 150-300 mg tid is associated to a half-life of 5-7 hours, wide fluctuations in peaktrough plasma concentrations, and a marked interindividual variability17,19. To solve these problems, a sustained-release preparation (SR) has been subsequently developed, improving compliance, efficacy, and safety12,13,17,18. Thank to its prolonged half-life (12 hours), this latter propafenone formulation allows a twice daily administration, with better compliance and adherence to therapy12,13,17,18. In addition, based on the official data on propafenone pharmacokinetics derived from SPC, we underline the importance of the curves reported in Figure 1. Propafenone undergoes extensive hepatic metabolization: the main products of oxidative metabolism are 5-hydroxy-propafenone and hydroxy-methoxy-propafenone5,17. In particular, 5hydroxy-propafenone shows a pharmacodynamic Table I. Main antiarrhythmics drugs. Sodium channel blockers Class Ia Class Ic Disopyramide, procainamide, quinidine Flecainide, propafenone Potassium channel blockers Class III Amiodarone, dofetilide*, ibutilide, sotalol *USA only. (Adapted from 6). 243 A. Sestito, E. Molina Table II. Selected data on main antiarrhythmics. Some drugs, relatively more recent (as propafenone, flecainide, procainamide and sotalol), are at least as effective as some less recent agents, as quinidine and disopyramide. At the same time, propafenone, flecainide, procainamide and sotalol are better tolerated than quinidine and disopyramide. Among the most active agents, the proarrhythmic effect is less frequent with propafenone and amiodarone. As for proarrhythmic effect, no statistically significant differences were found when comparing propafenone and amiodarone with placebo. In particular, in the Ic class propafenone shows a lower frequency of proarrhythmic effects as compared with flecainide. Propafenone is a powerful Ic antiarrhythmic agent, widely used for sinus rhythm restoration and maintenance. In meta- and mixed-analyses, sotalol and propafenone were evaluated as for the safety profile in the widest patients populations (more than 1,000 patients), as compared with amiodarone (n = 437) or flecainide (n = 114). (Adapted from 6, 14, 15, 16). profile similar to the parent drug, thus contributing to the therapeutic efficacy5,17. As for pharmacodynamics, the principal activities of propafenone are arrhythmia suppression, intracardiac conduction and beta-adrenergic blockade5,17. Propafenone Clinical Efficacy Propafenone resulted an effective measure as acute treatment, for conversion of recent onset atrial fibrillation 5,11,20-30 and to maintain sinus rhythm, as chronic therapy, for prevention of atrial fibrillation recurrences11-13,31-35. Figure 1. Propafenone plasma levels following repeated oral doses of slow-release formulation (325 and 425 mg) and immediate-release (150 and 300 mg). 244 Atrial fibrillation and the pharmacological treatment: the role of propafenone Acute Treatment: Conversion to Sinus Rhythm The objectives of acute treatment of atrial fibrillation are: • To reduce atrial fibrillation duration; • To avoid the need for anticoagulants, required for atrial fibrillation that lasts more than 48 h; • To reduce hospital stay5. • At ≤ 1 hour, only intravenous propafenone was effective; • At ≤ 3 hours, all treatments were effective, except amiodarone; • At ≤ 8 hours, all comparisons vs placebo were statistically significant5. Figure 2. Efficacy of propafenone (PFN) or placebo (PLA) in acute-onset atrial fibrillation: cumulative results of 7 clinical studies. (Adapted from 5). These data5 are shown in Figure 3. The early onset of therapeutic action induced by propafenone has been demonstrated also in a shortterm study in comparison with quinidine in patients with recent-onset atrial fibrillation (≤ 48 h)28. 81 patient have been randomized to the following treatments: • Propafenone 300 mg bolus per os, followed by further 300 mg after 8 hours, if the sinus rhythm was not reached (n = 43); Sinus rhythm (%) The acute treatment is usually required in atrial fibrillation of recent onset, such as an arrhythmia of <48 to 72 hours duration5. Propafenone as intravenous formulation resulted effective in converting atrial fibrillation to sinus rhythm in several studies5,21,22. The dosing scheme was an intravenous single bolus (2 mg/kg) or an intravenous bolus (2 mg/kg) followed by an intravenous infusion5. After an intravenous bolus, the efficacy rates were of 51% to 88%, increasing up to 91% with intravenous infusion5. When considering efficacy, also the time of sinus rhythm restoration must be considered: in a meta-analysis of clinical trials, the proportions of patients attaining sinus rhythm with intravenous propafenone were: at 1 hour 57%; at 2 hours 66%; at 4 hours 51%; at 8 hours 69%5. The use of propafenone as oral loading doses (450 mg to 600 mg) appears a useful alternative to the intravenous route, producing therapeutic plasma levels of propafenone and its active metabolite, 5-hydroxy-propafenone5,11,20, 22-29. At doses of 450 mg to 600 mg, propafenone resulted associated with a success rate between 66% and 76% at 8-12 hours from administration5. The efficacy of oral loading with propafenone in converting atrial fibrillation to sinus rhythm has been demonstrated versus placebo and active treatments in several studies5,11,20, 22-29. Figure 2 shows the cumulative results of 7 comparative studies versus placebo in 934 patients5. A comparison of different drug protocols, including intravenous and oral loading propafenone, intravenous amiodarone, oral flecainide, and placebo, with assessments made at different times, showed that: Figure 3. Efficacy of intravenous amiodarone, intravenous propafenone, oral propafenone, flecainide, and placebo: conversion rate for sinus rhythm (SR) at ≤ 8 hours. (Adapted from 5). 245 A. Sestito, E. Molina • 1 mg digoxin iv, followed by oral quinidine loading dose: 400 mg per os and additional 200 mg every 2 hours (n = 38)28. The length of treatment was not exceeding 24 hours28. At 8 hours propafenone was associated with a success rate of 83.3% versus 53% of quinidine (p = 0.01)28. Also the time to restore sinus rhythm was significantly shorter with propafenone than quinidine: 165 minutes versus 360 minutes (p = 0.05)28. Figure 4 shows the number of patients with atrial fibrillation in this study28. Naccarelli et al11 carried out an overview of clinical trials on efficacy of antiarrhythmic drugs in converting and maintaining sinus rhythm. In this analysis the best pharmacological strategies for acute control of atrial fibrillation were evaluated. Comparative efficacy of oral quinidine, sotalol, oral bolus propafenone, and intravenous amiodarone versus and placebo, estimated as conversion rates for recent-onset atrial fibrillation, is reported in Figure 5. According to the data shown in Figure 5, in atrial fibrillation11 of recent onset the highest efficacy was observed for propafenone 300 mg bid. In the management of paroxysmal atrial fibrillation, propafenone and flecainide resulted the most effective agents in order to obtain the conversion to sinus rhythm29. Some differences were observed, however, when considering the control exerted by these two drugs on heart rate in patients who failed cardioversion29. In fact, flecainide induced a reduction of heart rate from 9% to 13%, a result comparable to that observed with placebo, while propafenone was associated with a reduction of heart rate from 15% to 31%29. Very likely, this result is related with the beta-blocking properties typical of propafenone29. The marked activity of propafenone, as acute treatment by oral route, and the quick onset of therapeutic action led to the “pill in the pocket” strategy, implying the drug is taken per os shortly after a symptomatic recurrence appears: this approach was described by Alboni et al30 in 2004. Obviously, the “pill in the pocket” approach, which can be performed out of hospital, should be adopted only in selected patients, who already experienced the safety of such a treatment during a hospital stay. Chronic treatment: Sinus Rhythm Maintenance and Prevention of Atrial Fibrillation Recurrences Several benefits are associated to sinus rhythm maintenance: • Prevention of atrial electrical remodelling, slowing disease progression; • Improvement of hemodynamics by restoring atrial transport function; • Enhancement of exercise capacity; • Relief of symptoms, with quality of life improvement; • Reduction of thromboembolic events. Figure 4. % of patients with atrial fibrillation who received propafenone or quinidine per os. (Adapted from 28). 246 % cardioversion Atrial fibrillation and the pharmacological treatment: the role of propafenone Figure 5. Antiarrhythmic conversion of recent-onset atrial fibrillation: comparative efficacy of different pharmacological agents. (Adapted from 9). According to International Guidelines, in order to prevent recurrences of atrial fibrillation, it is often suggested a pharmacological treatment that can be performed by antiarrhythmic agents, able to maintain sinus rhythm36. Among antiarrhythmic agents, propafenone resulted an effective measure in several clinical studies, allowing strong increases of arrhythmia-free periods as well as marked increases in time to recurrence of symptomatic atrial fibrillation: thus propafenone is of value in the prophylaxis of both paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation11-13,31-35. The efficacy of immediate release propafenone formulation was already demonstrated as soon as the drug became available in Europe and USA in the 80’s12. ERAFT and his sister trial from North America RAFT have been designed to definitely assess the effectiveness of the SR (Sustained Release) formulation in the prophylaxis of atrial fibrillation recurrences12,13. Therefore, for the most recent SR propafenone formulation, these two large and well-conducted studies are described12,13. The ERAFT (the European Rythmol/Rytmonorm Atrial Fibrillation Trial) was a multicenter prospective, randomized double-blind, placebocontrolled parallel group study, that compared propafenone 325 mg bid, propafenone 425 mg bid, and placebo in a large patient population12. The objective of the trial was to demonstrate the drug efficacy in the prevention of recurrences of symptomatic paroxysmal atrial fibrillation12. The primary efficacy analysis was based on the arrhythmia-free period form 5th day from randomization to first recurrence of symptoms of atrial fibrillation (primary endpoint)12. A total of 293 patients were randomized to the 3 treatment arms: • 111 to propafenone 325 mg bid; • 89 to propafenone 425 mg bid; • 93 to placebo bid12. The results of the trial showed, as primary efficacy analysis, that the most frequent diagnosis of symptomatic arrhythmia observed after 5 days was atrial fibrillation12. It has been evidenced a significant increase in the arrhythmia-free period from 5th day from randomization to first recurrence in the 2 propafenone groups compared with placebo: 325 mg bid p = 0.004 and 425 mg bid p = 0.003 (Table III)12. The median duration of arrhythmia-free period was 9 days for the placebo group, 35 days for the propafenone SR 325 mg bid group, and 44 days for the propafenone SR 425 mg bid group (p < 0.001 in favour of propafenone in both comparisons versus placebo)12. These differences resulted even greater wen adopting the per-protocol analysis, such as when the analysis was restricted to patients adherent to study protocol, instead of performing the full data analysis (Figure 6)12. 247 A. Sestito, E. Molina Table III. Results of the ERAFT Study: tachyarrhythmia-free periods (days) from day 5th of randomization in the 2 propafenone groups and placebo. Propafenone SR dose (twice daily) Variable Patients completing with terminating event* AEC diagnosis AF Atrial flutter Comparison of tachycardia-free periods Kaplan-Meier median Range p value† Log-rank Hazard ratio 95% CI for hazard ratio‡ 325 mg (n 107) (%) 425 mg (n 83) (%) Placebo (n 88) (%) 66 (61.7) 41 (49.4) 65 (73.9) 65 (60.7) 1 (0.9) 39 (47.0) 2 (2.4) 65 (73.9) 0 (0.0) 35.0 0-105 44.0 0-101 9.0 0-106 0.004 0.60 0.43-0.86 0.003 0.55 0.36-0.82 – _ _ *Patients had a terminating event if they had symptomatic AF or atrial flutter according to the AEC. †Value was based on the test of each propafenone SR dose versus placebo, and statistical significance was based on a closed testing procedure. ‡Hazard ratio was based on the proportional hazard model with propafenone SR dose versus placebo as single independent variable. AEC = Arrhythmia Events Committee; CI = confidence intervals. (Adapted from 12). In conclusion, the ERAFT study demonstrated in a large patient population the efficacy of propafenone SR formulation12. The results of this trial, using propafenone SR 2 times daily, are consistent with the results of other studies adopting the immediate release formulation 3 times daily12. In particular, the PSVT (UK Propafenone Paroxysmal Supraventricular Tachycardia) study, conducted on patients with two or more recurrences of atrial fibrillation, compared propafenone 300 mg bid versus placebo, followed by 300 mg tid versus placebo in a crossover design12,32. The mean time to arrhythmia was 11 days in the placebo group vs > 98 days in the propafenone bid group12,32. The RAFT (Rythmol Atrial Fibrillation Trial) was a randomized double-blind, placebo-controlled study, carried out in USA, that compared propafenone 225 mg bid, propafenone 325 mg bid, propafenone 425 mg bid, and placebo in patients not previously exposed to this agent13. The objective of the trial was to demonstrate the propafenone efficacy in reducing symptomatic arrhythmia recurrences in patients with atrial fibrillation13. The primary outcome event was the first of electrocardiograms coded as atrial fibrillation, atrial flutter or paroxysmal supraventricular tachycardia. Patients completed the study if they had an outcome event or if they finished the 39 weeks of follow-up. 248 A total of 523 patients were randomized to the 4 treatment arms: • • • • 126 to propafenone 225 mg bid; 135 to propafenone 325 mg bid; 136 to propafenone 425 mg bid; 126 to placebo bid. The analysis of all patients showed a median time to the occurrence of a primary outcome event of 41 days in placebo group, of 112 days in the propafenone 225 mg group, 291 days in the propafenone 325 mg group, and >300 days in the propafenone 425 mg bid group (Table IV). In the primary efficacy analysis, statistically significant differences between placebo and propafenone were recorded: • p < 0.001 for propafenone 425 mg; • p < 0.001 for propafenone 325 mg; • p = 0.014 for propafenone 225 mg13. These data are shown in Figure 713. The survey of Naccarelli at al11, already quoted for acute treatment of atrial fibrillation, included also an evaluation of the efficacy of antiarrhythmic drugs in the recurrence prevention. According to the results of 6 main studies, comparing oral propafenone, flecainide, sotalol, and quinidine, it can be evidenced that propafenone was significantly more effective Atrial fibrillation and the pharmacological treatment: the role of propafenone Figure 6. Tachyarrhythmia-free period (absence of symptomatic atrial fibrillation or atrial flutter) from day 5 of randomization. (Adapted from 10). than sotalol and quinidine (p < 0.01 and p < 0.05, respectively), while propafenone and flecainide were equally effective. Safety In the most clinical studies propafenone resulted well tolerated, with only minor side-effects11,12,13,17,34-36. In the RAFT study, for instance, adverse events were generally comparable among the placebo twice daily group and the two propafenone groups, 225 and 325 mg bid 12 . When comparing the safety profiles of propafenone and flecainide, it can be observed that the frequency of side effects not requiring treatment withdrawal was significantly higher with flecainide: 48% versus 8% of propafenone (p < 0.01)29. Interestingly, in the RAFT study, propafenone did not result associated with an increased occur249 A. Sestito, E. Molina Figure 7. RAFT Study: efficacy analysis in all randomized patients. Time to first symptomatic arrhythmia recurrence. (Adapted from 11). Table IV. Results of RAFT study: efficacy of propafenone 225, 325, and 425 mg versus placebo. Propafenone SR dose or placebo (all twice daily) Parameter All randomized patients Patients with symptomatic outcome arrhythmia documented by electrocardiogram Time to outcome arrhythmia Kaplan-Meier, median (d) Range (d) Log-rank p value vs placebo Hazard ratio (propafenone: placebo) 95% CI for hazard ratio Patients in sinus rhythm after loading period Patients with symptomatic outcome arrhythmia documented by electrocardiogram Time to outcome arrhythmia Kaplan-Meier, median (d) Range (d) Log-rank p value vs placebo Hazard ratio (propafenone:placebo) 95% CI for hazard ratio CI = confidence intervals. (Adapted from 11). 250 225 mg 325 mg 425 mg Placebo 126 66 (52%) 135 56 (42%) 136 41 (30%) 126 87 (69%) 112 291 300 41 0-285 0.014 0.672 (0.488-0.927) 0-293 0.001 0.434 (0.309-0.609) 0-300 0.001 0.353 (0.243-0.513) 0-289 – – – 124 60 (48.4%) 132 54 (40.9%) 131 36 (27.5%) 124 84 (67.7%) 149 287 296 39 0-281 0.002 0.604 (0.433-0.842) 0-289 0.001 0.438 (0.310-0.619) 0-296 0.001 0.319 (0.216-0.473) 0-285 – – – Atrial fibrillation and the pharmacological treatment: the role of propafenone Table V. Risk of proarrhythmic effect with propafenone and flecainide, according to the analysis of the Cochrane Collaborative Group on the use of antiarrhythmic agents in the maintenance therapy after cardioversion in atrial fibrillation. Drugs Flecainide Propafenone Peto method° Nr of studies Nr of patients 3 5 149 1098 Effect size° (95% IC) 5.97 (1.67-21.34) 1.52 (0.33-7.02) (Adapted from 28). rence of supraventricular arrhythmia or paroxysmal supraventricular tachycardia, as well as of asymptomatic atrial fibrillation13. The increase in the occurrence of regular supraventricular arrhythmia with ECG, typical for atrial flutter or paroxysmal supraventricular tachycardia, was a supposed effect widely reported when the class Ic antiarrhythmic drugs was introduced on the market13. The Authors of RAFT report suggest that this problem has been possibly overestimated for propafenone, as it was seen in all treatment groups, including placebo, with the same and low frequency13. These data were recently confirmed by the Cochrane Collaborative Group, who carried out a systematic review on the efficacy and safety of antiarrhythmic agents in maintaining the sinus rhythm after cardioversion of atrial fibrillation16. 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