European Review for Medical and Pharmacological Sciences 2012; 16: 242-253 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 Introduction is the most frequent cardiac rhythm disturbance, with prevalence increasing with age. This disease Atrial fibrillation is a major clinical problem is a major risk factor for ischaemic stroke. The and the most frequently occurring cardiac rhythm costs resulting from atrial fibrillation are really 1-6 impressive. Pharmacological agents are the first disturbance . Its prevalence increases with age: line therapy for the management of atrial fibrilla- 2-3‰ between 25 and 35 years, 30-40‰ be- tion. Antiarrhythmic drugs are used to terminate tween 55 and 65 years, 50-90‰ between 62 and , as acute treatment for conversion of 90 years1-3,5. The prevalence of atrial fibrillation recent onset atrial fibrillation, and to maintain si- is expected to increase for several factors, first of nus rhythm, as chronic therapy for prevention of all for the progressive increase in longevity of atrial fibrillation recurrences. Among antiarrhyth- 1,2,6 mic agents, drugs that inhibit early sodium cur- worldwide populations . According to a 2005 6 rent (as propafenone) are proven effective in atri- estimate , in USA there were 3.03 millions of al fibrillation. In this review, the most relevant da- atrial fibrillation patients and this figure could ta on propafenone are provided. reach 7.56 millions in 2050. Discussion: The development of a sustained- Atrial fibrillation is a strong risk factor for is- release formulation of propafenone allowed to chaemic stroke (approximately 3- to 5-fold ex- reduce the wide fluctuations in plasma levels ob- served with the immediate release preparation, cess risk), with associated clinical problems and improving compliance and adherence to therapy, increased mortality rates (1.5- to 1.9-fold mortal- by simplifying the dosing regimen from 3 to 2 ity risk)2-4,6. daily doses. Propafenone resulted an effective Together with its complications, atrial fibrilla- measure as acute treatment for conversion of re- tion is a major cause of health care consumption, cent onset atrial fibrillation, and to maintain si- costs and poor quality of life6,7. The costs result- nus rhythm, as chronic therapy for prevention of ing from atrial fibrillation are really impres- atrial fibrillation recurrences. In several clinical 2,3,5 studies, strong increases of -free peri- sive . In USA it has been estimated that this ods as well as marked increases in time to recur- disease is responsible for more than 1 million rence of symptomatic atrial fibrillation, such as days of hospitalization per year5. paroxysmal supraventricular tachycardia and Even if the pathophysiology of atrial fibrillation paroxysmal atrial fibrillation were observed. In is not yet completely understood, there is evidence particular, well-designed clinical studies demon- that the cardiac remodeling plays a major role in the strated in large patient populations the efficacy of 4 propafenone at several doses. At the suggested disease process . A high number of factors respon- doses propafenone is usually well tolerated. sible for onset of atrial fibrillation, usually indicated Conclusion: The risk of increased occurrence as “triggers”, has been recognized8-10. Among them, of regular supraventricular arrhythmia or paroxys- sympathetic or parasympathetic stimulation, brady- mal supraventricular tachycardia has been over- cardia, atrial premature beats, tachycardia, accesso- estimated for propafenone, because this adverse ry atrio-ventricular pathways, and acute atrial event was seen in all treatment groups, including stretch are included8. In particular, it has been placebo, with the same (and low) frequency. demonstrated that a wide part of atrial premature Key Words: beats, involved in paroxysms of atrial fibrillation, originate in the pulmonary veins9. The intrinsic car- Atrial fibrillation (AF), Acute onset AF, Prevention of diac autonomic nervous system is thought to play a AF recurrences, Antiarrhythmic drugs, Propafenone. crucial role in the atrial remodeling process10.

242 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 file of efficacy, safety and convenience. Table II atrial fibrillation account for the need of effective reports some observations on main antiarrhyth- drug treatment5. mic agents6,14-16. As for the management of atrial fibrillation, We can state, therefore, that propafenone, the main therapeutic strategies include: thanks to its clinical efficacy associated to a good safety (in particular to a reduced risk of proar- • Rate control; rhythmic effect), can represent an important mea- • Termination of arrhythmia; sure in the management of atrial fibrillation pa- • Prevention of recurrences; tients not showing cardiac structural alterations. • Prevention of thromboembolic events11. In addition, this drug, due to the availability of vials for intravenous use, immediate release Pharmacological agents are the first line thera- tablets, and sustained release capsules, allows to py for rhythm management in atrial fibrillation1,6. develop various treatment schedules and to adapt Antiarrhythmic drugs are used to terminate ar- the therapy according to different needs. rhythmias and maintain sinus rhythm6,11. Efficacy and safety profiles are extremely im- Focus on Propafenone portant issues in the choice of an antiarrhythmic Propafenone is a powerful Ic class antiarrhyth- agent, but also the dosing convenience (allowing mic agent, with demonstrated effectiveness high patient compliance) should be taken in due against a variety of cardiac arrhythmias12-14. This account11. According to current guidelines, it is agent shows a marked inhibitory effect on the suggested to select an antiarrhythmic drug con- and some beta-blocking activi- sidering some main factors, in order to identify ty5,14-17. the best therapeutic strategy: The original formulation of oral propafenone immediate release was rapidly absorbed by gas- • Symptoms presentation; trointestinal tract and metabolized by liver, • Atrial fibrillation characteristics; needing a 3 times daily administration13,17. • Presence of cardiovascular diseases; Propafenone 150-300 mg tid is associated to a • Patient age and medical conditions; half-life of 5-7 hours, wide fluctuations in peak- • Treatment goals6. trough plasma concentrations, and a marked in- terindividual variability17,19. To solve these prob- Among antiarrhythmic agents, drugs that in- lems, a sustained-release preparation (SR) has hibit early sodium current (as propafenone and been subsequently developed, improving compli- ) are proven effective in atrial fibrilla- ance, efficacy, and safety12,13,17,18. Thank to its tion1,5,12,13. The most widely used antiarrhythmic prolonged half-life (12 hours), this latter drugs6 are listed in Table I. propafenone formulation allows a twice daily ad- According to most recent guidelines and up- ministration, with better compliance and adher- dated meta-analyses, as well as to the Author’s ence to therapy12,13,17,18. In addition, based on the personal caseload, it is possible to anticipate official data on propafenone some general considerations on the pharmaco- derived from SPC, we underline the importance logical approach to atrial fibrillation. of the curves reported in Figure 1. As for other chronic treatments, also for an- Propafenone undergoes extensive hepatic me- tiarrhythmic drugs the choice of the proper thera- tabolization: the main products of oxidative me- py should balance at the best efficacy and safety. tabolism are 5-hydroxy-propafenone and hy- The group of antiarrhythmic drugs includes droxy-methoxy-propafenone5,17. In particular, 5- different molecules showing each a typical pro- hydroxy-propafenone shows a pharmacodynamic

Table I. Main antiarrhythmics drugs.

Sodium channel blockers blockers

Class Ia , , Class III , *, , Class Ic Flecainide, propafenone

*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 amio- darone 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 , 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 popu- lations (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 contribut- Propafenone Clinical Efficacy ing to the therapeutic efficacy5,17. Propafenone resulted an effective measure as As for pharmacodynamics, the principal activ- acute treatment, for conversion of recent onset ities of propafenone are arrhythmia suppression, atrial fibrillation5,11,20-30 and to maintain sinus intracardiac conduction and beta- rhythm, as chronic therapy, for prevention of atri- blockade5,17. al fibrillation recurrences11-13,31-35.

Figure 1. Propafenone plasma levels following repeated oral doses of slow-release formulation (325 and 425 mg) and imme- diate-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 fib- rillation 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.

The acute treatment is usually required in atri- al fibrillation of recent onset, such as an arrhyth- mia of <48 to 72 hours duration5. Propafenone as intravenous formulation re- sulted effective in converting atrial fibrillation to sinus rhythm in several studies5,21,22. The dosing scheme was an intravenous single bolus (2 Figure 2. Efficacy of propafenone (PFN) or placebo (PLA) mg/kg) or an intravenous bolus (2 mg/kg) fol- in acute-onset atrial fibrillation: cumulative results of 7 clin- lowed by an intravenous infusion5. ical studies. (Adapted from 5). After an intravenous bolus, the efficacy rates were of 51% to 88%, increasing up to 91% with intravenous infusion5. These data5 are shown in Figure 3. When considering efficacy, also the time of si- The early onset of therapeutic action induced by nus rhythm restoration must be considered: in a propafenone has been demonstrated also in a short- meta-analysis of clinical trials, the proportions of term study in comparison with quinidine in patients patients attaining sinus rhythm with intravenous with recent-onset atrial fibrillation (≤ 48 h)28. propafenone were: at 1 hour 57%; at 2 hours 81 patient have been randomized to the fol- 66%; at 4 hours 51%; at 8 hours 69%5. lowing treatments: The use of propafenone as oral loading doses (450 mg to 600 mg) appears a useful alternative • Propafenone 300 mg bolus per os, followed by to the intravenous route, producing therapeutic further 300 mg after 8 hours, if the sinus plasma levels of propafenone and its active rhythm was not reached (n = 43); 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 com- parative studies versus placebo in 934 patients5. A comparison of different drug protocols, in- cluding intravenous and oral loading propafenone, intravenous amiodarone, oral fle- Sinus rhythm (%) cainide, and placebo, with assessments made at different times, showed that:

• At ≤ 1 hour, only intravenous propafenone was effective; • At ≤ 3 hours, all treatments were effective, ex- Figure 3. Efficacy of intravenous amiodarone, intravenous cept amiodarone; propafenone, oral propafenone, flecainide, and placebo: • At ≤ 8 hours, all comparisons vs placebo were conversion rate for sinus rhythm (SR) at ≤ 8 hours. (Adapt- statistically significant5. ed from 5).

245 A. Sestito, E. Molina

• 1 mg iv, followed by oral quinidine in patients who failed cardioversion29. In fact, loading dose: 400 mg per os and additional flecainide induced a reduction of heart rate from 200 mg every 2 hours (n = 38)28. 9% to 13%, a result comparable to that ob- served with placebo, while propafenone was as- The length of treatment was not exceeding 24 sociated with a reduction of heart rate from hours28. 15% to 31%29. Very likely, this result is related At 8 hours propafenone was associated with a with the beta-blocking properties typical of success rate of 83.3% versus 53% of quinidine (p propafenone29. = 0.01)28. The marked activity of propafenone, as acute Also the time to restore sinus rhythm was sig- treatment by oral route, and the quick onset of nificantly shorter with propafenone than quini- therapeutic action led to the “pill in the pocket” dine: 165 minutes versus 360 minutes (p = strategy, implying the drug is taken per os shortly 0.05)28. after a symptomatic recurrence appears: this ap- Figure 4 shows the number of patients with proach was described by Alboni et al30 in 2004. atrial fibrillation in this study28. Obviously, the “pill in the pocket” approach, Naccarelli et al11 carried out an overview of which can be performed out of hospital, should clinical trials on efficacy of antiarrhythmic drugs be adopted only in selected patients, who already in converting and maintaining sinus rhythm. In experienced the safety of such a treatment during this analysis the best pharmacological strategies a hospital stay. for acute control of atrial fibrillation were evalu- ated. Comparative efficacy of oral quinidine, so- Chronic treatment: Sinus Rhythm talol, oral bolus propafenone, and intravenous Maintenance and Prevention of amiodarone versus and placebo, estimated as Atrial Fibrillation Recurrences conversion rates for recent-onset atrial fibrilla- Several benefits are associated to sinus rhythm tion, is reported in Figure 5. maintenance: According to the data shown in Figure 5, in atrial fibrillation11 of recent onset the highest effi- • Prevention of atrial electrical remodelling, cacy was observed for propafenone 300 mg bid. slowing disease progression; In the management of paroxysmal atrial fib- • Improvement of hemodynamics by restoring rillation, propafenone and flecainide resulted atrial transport function; the most effective agents in order to obtain the • Enhancement of exercise capacity; conversion to sinus rhythm29. Some differences • Relief of symptoms, with quality of life im- were observed, however, when considering the provement; control exerted by these two drugs on heart rate • Reduction of thromboembolic events.

Figure 4. % of patients with atrial fibrillation who received propafenone or quinidine per os. (Adapted from 28).

246 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 or- symptomatic paroxysmal atrial fibrillation12. The der to prevent recurrences of atrial fibrillation, it primary efficacy analysis was based on the ar- is often suggested a pharmacological treatment rhythmia-free period form 5th day from random- that can be performed by antiarrhythmic agents, ization to first recurrence of symptoms of atrial able to maintain sinus rhythm36. Among antiar- fibrillation (primary endpoint)12. A total of 293 rhythmic agents, propafenone resulted an effec- patients were randomized to the 3 treatment tive measure in several clinical studies, allowing arms: strong increases of arrhythmia-free periods as well as marked increases in time to recurrence of • 111 to propafenone 325 mg bid; symptomatic atrial fibrillation: thus propafenone • 89 to propafenone 425 mg bid; is of value in the prophylaxis of both paroxysmal • 93 to placebo bid12. supraventricular tachycardia and paroxysmal atrial fibrillation11-13,31-35. The results of the trial showed, as primary ef- The efficacy of immediate release propafenone ficacy analysis, that the most frequent diagnosis formulation was already demonstrated as soon as of symptomatic arrhythmia observed after 5 days the drug became available in Europe and USA in was atrial fibrillation12. the 80’s12. It has been evidenced a significant increase in ERAFT and his sister trial from North Amer- the arrhythmia-free period from 5th day from ran- ica RAFT have been designed to definitely as- domization to first recurrence in the 2 sess the effectiveness of the SR (Sustained Re- propafenone groups compared with placebo: 325 lease) formulation in the prophylaxis of atrial mg bid p = 0.004 and 425 mg bid p = 0.003 fibrillation recurrences12,13. Therefore, for the (Table III)12. most recent SR propafenone formulation, these The median duration of arrhythmia-free peri- two large and well-conducted studies are de- od was 9 days for the placebo group, 35 days scribed12,13. for the propafenone SR 325 mg bid group, and The ERAFT (the European Rythmol/Rytmo- 44 days for the propafenone SR 425 mg bid norm Atrial Fibrillation Trial) was a multicenter group (p < 0.001 in favour of propafenone in prospective, randomized double-blind, placebo- both comparisons versus placebo)12. These dif- controlled parallel group study, that compared ferences resulted even greater wen adopting the propafenone 325 mg bid, propafenone 425 mg per-protocol analysis, such as when the analy- bid, and placebo in a large patient population12. sis was restricted to patients adherent to study The objective of the trial was to demonstrate the protocol, instead of performing the full data drug efficacy in the prevention of recurrences of 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 325 mg (n 107) (%) 425 mg (n 83) (%) Placebo (n 88) (%)

Patients completing with terminating event* 66 (61.7) 41 (49.4) 65 (73.9) AEC diagnosis AF 65 (60.7) 39 (47.0) 65 (73.9) Atrial flutter 1 (0.9) 2 (2.4) 0 (0.0) Comparison of tachycardia-free periods Kaplan-Meier median 35.0 44.0 9.0 Range 0-105 0-101 0-106 p value† Log-rank 0.004 0.003 – Hazard ratio 0.60 0.55 _ 95% CI for hazard ratio‡ 0.43-0.86 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 A total of 523 patients were randomized to the in a large patient population the efficacy of 4 treatment arms: propafenone SR formulation12. The results of this trial, using propafenone SR 2 times daily, are • 126 to propafenone 225 mg bid; consistent with the results of other studies adopt- • 135 to propafenone 325 mg bid; ing the immediate release formulation 3 times • 136 to propafenone 425 mg bid; daily12. In particular, the PSVT (UK Propafenone • 126 to placebo bid. Paroxysmal Supraventricular Tachycardia) study, conducted on patients with two or more recur- The analysis of all patients showed a median rences of atrial fibrillation, compared time to the occurrence of a primary outcome propafenone 300 mg bid versus placebo, fol- event of 41 days in placebo group, of 112 days in lowed by 300 mg tid versus placebo in a the propafenone 225 mg group, 291 days in the crossover design12,32. The mean time to arrhyth- propafenone 325 mg group, and >300 days in the mia was 11 days in the placebo group vs > 98 propafenone 425 mg bid group (Table IV). days in the propafenone bid group12,32. In the primary efficacy analysis, statistically The RAFT (Rythmol Atrial Fibrillation Trial) significant differences between placebo and was a randomized double-blind, placebo-con- propafenone were recorded: trolled study, carried out in USA, that compared propafenone 225 mg bid, propafenone 325 mg • p < 0.001 for propafenone 425 mg; bid, propafenone 425 mg bid, and placebo in pa- • p < 0.001 for propafenone 325 mg; tients not previously exposed to this agent13. • p = 0.014 for propafenone 225 mg13. The objective of the trial was to demonstrate the propafenone efficacy in reducing sympto- These data are shown in Figure 713. matic arrhythmia recurrences in patients with The survey of Naccarelli at al11, already quot- atrial fibrillation13. ed for acute treatment of atrial fibrillation, in- The primary outcome event was the first of cluded also an evaluation of the efficacy of an- electrocardiograms coded as atrial fibrillation, tiarrhythmic drugs in the recurrence prevention. atrial flutter or paroxysmal supraventricular According to the results of 6 main studies, tachycardia. Patients completed the study if they comparing oral propafenone, flecainide, sotalol, had an outcome event or if they finished the 39 and quinidine, it can be evidenced that weeks of follow-up. propafenone was significantly more effective

248 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 randomiza- tion. (Adapted from 10).

than sotalol and quinidine (p < 0.01 and p < 0.05, placebo twice daily group and the two respectively), while propafenone and flecainide propafenone groups, 225 and 325 mg bid12. were equally effective. When comparing the safety profiles of propafenone and flecainide, it can be observed Safety that the frequency of side effects not requiring In the most clinical studies propafenone result- treatment withdrawal was significantly higher ed well tolerated, with only minor side-ef- with flecainide: 48% versus 8% of propafenone fects11,12,13,17,34-36. (p < 0.01)29. In the RAFT study, for instance, adverse Interestingly, in the RAFT study, propafenone events were generally comparable among the did not result associated with an increased occur-

249 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 225 mg 325 mg 425 mg Placebo

All randomized patients 126 135 136 126 Patients with symptomatic outcome 66 (52%) 56 (42%) 41 (30%) 87 (69%) arrhythmia documented by electrocardiogram Time to outcome arrhythmia 112 291 300 41 Kaplan-Meier, median (d) Range (d) 0-285 0-293 0-300 0-289 Log-rank p value vs placebo 0.014 0.001 0.001 – Hazard ratio (propafenone: placebo) 0.672 0.434 0.353 – 95% CI for hazard ratio (0.488-0.927) (0.309-0.609) (0.243-0.513) – Patients in sinus rhythm after loading period 124 132 131 124 Patients with symptomatic outcome 60 (48.4%) 54 (40.9%) 36 (27.5%) 84 (67.7%) arrhythmia documented by electrocardiogram Time to outcome arrhythmia Kaplan-Meier, 149 287 296 39 median (d) Range (d) 0-281 0-289 0-296 0-285 Log-rank p value vs placebo 0.002 0.001 0.001 – Hazard ratio (propafenone:placebo) 0.604 0.438 0.319 – 95% CI for hazard ratio (0.433-0.842) (0.310-0.619) (0.216-0.473) –

CI = confidence intervals. (Adapted from 11).

250 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 Collabora- tive Group on the use of antiarrhythmic agents in the maintenance therapy after cardioversion in atrial fibrillation.

Drugs Nr of studies Nr of patients Effect size° (95% IC)

Flecainide 3 149 5.97 (1.67-21.34) Propafenone 5 1098 1.52 (0.33-7.02) Peto method°

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