Control of paroxysmal atrial fibrillation recurrence using combined administration of propafenone and quinidine

The frequent recurrence of paroxysmal atrial fibrillation (PAF) despite the use of standard antiarrhythmic agents prompted the use of new therapeutic approaches. There are few data on systematic assessment of PAF control with stepwise dose escalation and the use of a drug combination. Low-dose quinidine may promote the efficacy of propafenone by inhibiting its degradation through the cytochrome P450 pathway (CYP2D6). We prescribed propafenone 300 to 450 mg/day to 60 patients with PAF for 8 weeks, and 62% were symptomatically controlled. The 19 refractory patients were randomized in a double-blinded fashion to receive either a higher dose of propafenone (450 to 675 mg/day) or the standard dose of propafenone with low-dose quinidine 150 mg/day, each for an 8-week study period, and subsequently crossed over to the alternative treatment. The resulting serum propafenone concentrations were 259 ± 208 and 336 ± 237 mg/day (p >0.5), respectively. Both treatment arms prolonged the time to the first symptomatic atrial fibrillation (AF) recurrence and the interval between attacks, and AF was controlled in 37% of patients. However, the higher dose of propafenone was associated with gastrointestinal side effects not present with the low-dose quinidine combination. Of the 10 refractory patients, 7 were further controlled with a standard dose of propafenone plus quinidine (600 mg/day). Overall, control of PAF was achieved in 85% of patients at the end of 8 months; adverse effects necessitating withdrawal were observed in 6%, and uncontrolled AF in 5% of patients. There was no difference in the mean AF rate during recurrences in all phases, and ventricular proarrhythmia was not seen. This study documents the role of stepwise antiarrhythmic treatment of PAF. The use of a standard dose of propafenone, followed by low-dose quinidine combination to reduce propafenone degradation, and the combined standard dose of propafenone and quinidine may be used to maximize efficacy and tolerability.     

Control of paroxysmal atrial fibrillation recurrence using combined administration of propafenone and quinidine

The frequent recurrence of paroxysmal atrial fibrillation (PAF) despite the use of standard antiarrhythmic agents prompted the use of new therapeutic approaches. There are few data on systematic assessment of PAF control with stepwise dose escalation and the use of a drug combination. Low-dose quinidine may promote the efficacy of propafenone by inhibiting its degradation through the cytochrome P450 pathway (CYP2D6). We prescribed propafenone 300 to 450 mg/day to 60 patients with PAF for 8 weeks, and 62% were symptomatically controlled. The 19 refractory patients were randomized in a double-blinded fashion to receive either a higher dose of propafenone (450 to 675 mg/day) or the standard dose of propafenone with low-dose quinidine 150 mg/day, each for an 8-week study period, and subsequently crossed over to the alternative treatment. The resulting serum propafenone concentrations were 259 ± 208 and 336 ± 237 mg/day (p >0.5), respectively. Both treatment arms prolonged the time to the first symptomatic atrial fibrillation (AF) recurrence and the interval between attacks, and AF was controlled in 37% of patients. However, the higher dose of propafenone was associated with gastrointestinal side effects not present with the low-dose quinidine combination. Of the 10 refractory patients, 7 were further controlled with a standard dose of propafenone plus quinidine (600 mg/day). Overall, control of PAF was achieved in 85% of patients at the end of 8 months; adverse effects necessitating withdrawal were observed in 6%, and uncontrolled AF in 5% of patients. There was no difference in the mean AF rate during recurrences in all phases, and ventricular proarrhythmia was not seen. This study documents the role of stepwise antiarrhythmic treatment of PAF. The use of a standard dose of propafenone, followed by low-dose quinidine combination to reduce propafenone degradation, and the combined standard dose of propafenone and quinidine may be used to maximize efficacy and tolerability.     

New onset atrial flutter termination by overdrive transoesophageal pacing: effects of different protocols of stimulation.

AIM: We evaluated the effect of different stimulation protocols on atrial flutter interruption by transoesophageal pacing. METHODS AND RESULTS: Eighty patients with new onset atrial flutter were randomized into four groups. Pacing was attempted under the following conditions: with short bursts (5 s), without treatment (group A) and after oral administration of propafenone 600 mg (group B); with prolonged bursts (30 s), without treatment (group C) and after oral administration of propafenone 600 mg (group D). Pacing interrupted atrial flutter in 20% of patients in A, 55% in B, 50% in C and 85% in D. The use of longer bursts gave better results both in patients without treatment (P < 0.05: C vs A) and in patients with propafenone (P < 0.05: D vs B). Comparing groups with the same stimulation protocol, we observed a better response in patients treated with propafenone (P < 0.05: B vs A and D vs C). In the groups without treatment the use of shorter bursts was associated with a lower induction of stable atrial fibrillation (three vs nine episodes), in the groups on propafenone no differences were observed (one vs one episode). CONCLUSIONS: We conclude that the association of propafenone with long bursts gives the best result for interruption of new onset atrial flutter by transoesophageal pacing.     

Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation.

HYPOTHESIS: KCB-328 is a new potassium channel blocker, which prolongs action potential duration with exhibition of minimal reverse use dependence. We tested the efficacy and proarrhythmic potential of KCB-328, dofetilide and propafenone in the pacing induced canine model of atrial fibrillation (AF). METHODS: Mongrel dogs in complete heart block were paced for 1-6 weeks to produce AF, and given KCB-328 or dofetilide. A subset then received propafenone 14+/-3 days after testing the first drug. RESULTS: KCB-328 prolonged right and left atrial (RA and LA) activation times and AF cycle length (CL), terminating AF in 3 of 6 dogs. RA effective refractory period (ERP) and ventricular ERP and QT interval were prolonged. Dofetilide terminated AF in 1/6 dogs, and increased AF CL and ventricular ERP and QT interval. Dofetilide's reverse use dependency on the QT interval was greater than KCB-328. Propafenone prolonged RA and LA activation times and AF CL and terminated AF in 8 of 9 dogs. One death occurred with dofetilide, none with KCB-328 or propafenone. CONCLUSION: The spectrum of effect of the three drugs differed significantly: propafenone showed the greatest success in AF termination, and both propafenone and KCB-328 appeared less proarrhythmic than dofetilide in this model.     

Propafenone-mexiletine combination for the treatment of sustained ventricular tachycardia.

OBJECTIVES. The purpose of this study was to explore the efficacy of combined therapy with propafenone and mexiletine for control of sustained ventricular tachycardia. BACKGROUND. Combination antiarrhythmic drug therapy may enhance efficacy and lead to control of ventricular arrhythmias in some patients. Few reports have studied the combination of class IB and class IC drugs. Thus, this study was designed to investigate a combination of mexiletine and propafenone in patients with refractory ventricular tachycardia. METHODS. Sixteen patients with sustained ventricular tachycardia had their clinical arrhythmia induced by programmed stimulation. Procainamide and propafenone alone failed to prevent reinduction of tachycardia in all. Mexiletine was subsequently added to propafenone and programmed stimulation was repeated. RESULTS. With combination therapy ventricular tachycardia was noninducible in three patients (19%). A fourth who had presented with polymorphic ventricular tachycardia had slow bundle branch reentry (cycle length 500 ms) induced. In the other 12, tachycardia cycle length increased from 262 +/- 60 ms at baseline to 350 +/- 82 ms with propafenone and to 390 +/- 80 ms with propafenone plus mexiletine (p less than 0.0001 compared with baseline). Hemodynamic deterioration requiring defibrillation occurred in six patients at baseline study, in five taking propafenone and in two taking both drugs. CONCLUSIONS. The combination of propafenone and mexiletine is effective in suppressing the induction of ventricular tachycardia in some patients refractory to procainamide and propafenone alone. In those in whom ventricular tachycardia could still be induced, the rate was slower and hemodynamically tolerated.     

Hepatic toxicity of propafenone: a case description

A case of acute liver injury associated with the use of the antiarrhythmic drug propafenone in a 62-year-old woman undergoing clinical observation for recurrent atrial fibrillation is reported. Propafenone hydrochloride, a class 1C antiarrhythmic drug widely used in the clinical practice for the treatment of supraventricular and ventricular arrhythmias, rarely (0.1-0.2% of incidence) causes liver injury characterized by a rise in hepatic cell enzymes or cholestatic enzymes or both. Within 2 months of the discontinuation of therapy the liver function tests return to normal, therefore there are no known fatalities secondary to propafenone liver injury including fulminant hepatitis and death. The close temporal relationship between the administration of the drug and the acute onset of signs of liver injury, the marked rise in liver function tests following the increase of the drug dosage and their gradual normalization after its withdrawal strongly suggest that propafenone is involved in the pathogenesis of this syndrome. Although rare, hepatotoxicity due to this widely used antiarrhythmic drug should be borne in mind in the differential diagnosis of sudden hepatocellular or cholestatic syndrome of obscure origin. It seems prudent to obtain baseline liver function before starting therapy with propafenone and then follow up laboratory tests some months later at least in patients with known liver disease.     

Efficacy of oral propafenone in chronic ventricular arrhythmias: a placebo controlled cross-over exercise study

The efficacy of propafenone, a new class I C antiarrhythmic drug, on ventricular premature contractions (VPCs) during rest and exercise was assessed during a two-phase protocol: phase 1, an initial two week placebo controlled double blind cross-over assessment; phase 2, an open 3 month follow-up. Twelve consecutive patients with symptomatic chronic ventricular arrhythmias and fulfilling other inclusion criteria underwent an exercise test and were allocated to either propafenone or placebo. During the double blind phase, oral propafenone significantly reduced the number of VPCs at rest with the patient supine or sitting, during the bicycle ergometer test, and after the exercise test. After 3 months of treatment a 90 to 100% reduction of VPCs was achieved in 11 patients continuing on 600 to 900 mg of propafenone daily. Treatment was stopped in one patient during the double blind phase because of drug induced LBBB. A prolongation of the PR interval and QRS duration occurred in all patients with propafenone doses exceeding 450 mg day-1. Subjective side effects were slight and consisted of abnormal taste sensations and minor central nervous symptoms. The results suggest that propafenone is an effective drug for the treatment of ventricular arrhythmias in selected patients. A-V or intraventricular conduction disturbances contraindicate its use.     

Propafenone: A New Anti arrhythmic for Treatment of Chronic Ventricular Arrhythmias

Propafenone is a new anti arrhythmic agent with primarily membrane-stabilizing action. Three U.S. controlled double-blind cross-over studies demonstrated the efficacy of propafenone in suppressing ventricular premature complexes (VPCs), including repetitive forms: 67–83% of patients had greater than 80% reduction of VPCs, 62% achieved greater than 90% reduction of couplets and 80%–100% achieved 200% abolition of ventricular tachycardia runs. Other studies showed that propafenone is effective in controlling ventricular arrhythmias refractory to conventional anti arrhythmic agents. Propafenone is at least as effective as these agents. Long-term sustained efficacy of propafenone was shown in some preliminary studies. Because of the variation in individual response to the drug, therapy should be individualized for each patient. Propafenone is well tolerated: side effects of propafenone are few and involve mostly the cardiac conduction system. Propafenone would be a significant addition to the anti arrhythmic armamentarium.     

Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation

The objective of this randomized, double-blind, placebo-controlled clinical trial was to test the efficacy and safety of a new sustained-release preparation of the antiarrhythmic drug propafenone (propafenone SR) in reducing the frequency of symptomatic arrhythmia recurrences in patients with atrial fibrillation (AF). Patients with a history of symptomatic AF who were in sinus rhythm were randomly assigned to receive placebo or propafenone SR 425, 325, or 225 mg, all twice daily. Recurrent symptomatic arrhythmias were documented using transtelephone electrocardiographic monitoring. Electrocardiograms were reviewed by an event committee that was blinded to treatment assignment. In the primary efficacy analysis, propafenone SR significantly lengthened the time to first symptomatic atrial arrhythmia recurrence at all 3 doses compared with placebo as assessed by log-rank test: propafenone SR 425 mg twice daily versus placebo twice daily, p <0.001; 325 mg twice daily versus placebo twice daily, p <0.001; and 225 mg twice daily versus placebo twice daily, p = 0.014. The median time to recurrence was 41 days in the placebo twice daily group, >300 days in the propafenone SR 425-mg group, 291 days in the 325-mg group, and 112 days in the 225-mg group. Adverse effects leading to withdrawal were higher in the propafenone SR 425-mg twice daily group than in any other group. Thus, propafenone SR has important and statistically significant antiarrhythmic effects in patients with AF.     

Atrial fibrillation: choice of the method of pharmacological cardioversion

The paper considers circumstances under which it is expedient or not expedient to perform cardioversion in patients with paroxysmal or persistent atrial fibrillation. It contains discussion of benefits, limitations and drawbacks of electrical and pharmacological methods of cardioversion. American College of Cardiology/American Heart Association/European Society of Cardiology Guidelines for the Management of Patients With Atrial Fibrillation are presented. These guidelines suggest amiodarone, dofetilide, ibutilide, propafenone, flecainide, and quinidine as first line therapy because of their proven efficacy. Efficacy of intravenous disopyramide and procainamide in some patients with recent onset atrial fibrillation is recognized with certain reservations. The use of azimilide and dronedarone is considered promising. In Russia nibentan and ethacizine can be also used. Special emphasis is made on the possibility of wide use (including self-administration) of loading doses of oral propafenone for cardioversion in some categories of patients with atrial fibrillation of recent onset.     

Efficacy of Propafenone When Used in Combination Antiarrhythmic Therapy

Propafenone is a new antiarrhythmic agent that has been classified as a type IC agent. Combination therapy using propafenone with either procainamide or quinidine was undertaken in this study. The addition of propafenone to procainamide or quinidine in 30 patients with more than 30 VPDs per hour resulted in a mean suppression of VPD frequency of 80%; 8 of 11 patients with runs of ventricular tachycardia had greater than 90% reduction of these events during combination therapy. During combination therapy, only two patients had proarrhythmic effects. Thus, this study demonstrates that combination of propafenone with either quinidine or procainamide is effective in suppressing ventricular arrhythmias.     

Effects of acute and prolonged administration of propafenone on internal defibrillation in the pig.

Some antiarrhythmic sodium channel blocking drugs have been found to increase the energy necessary for internal defibrillation. Propafenone is a new drug that has been shown to be efficacious in the therapy of supraventricular and ventricular arrhythmias, and is of potential use in patients with defibrillators. The effects of short-term and prolonged propafenone administration on the internal defibrillation threshold (DFT) were determined in 43 pigs randomized to one of four groups: saline infusion (n = 10); propafenone infusion (n = 10); placebo administration for 8 days (n = 10); or propafenone administration for 8 days (n = 13). Two mesh electrodes were sutured on the right lateral and left lateral epicardial surface and current was delivered from the right electrode to the left electrode. Triplicate DFTs were obtained before and at 40 and 80 minutes after infusion of drug or placebo. In pigs receiving long-term administration, after baseline DFTs were obtained the electrodes were removed and the chest was closed. Following 8 days of drug or placebo administration, DFTs were redetermined. No changes were observed in the short- or long-term control groups. DFTs were lower after propafenone administration: either short-term infusion (20 +/- 6.2 joules at baseline; 15.6 +/- 5 joules at 40 minutes, p less than 0.05; 10.2 +/- 6 joules at 80 minutes, p less than 0.001) or long-term administration (17.8 +/- 2.6 joules at baseline versus 12 +/- 3.2 joules on drug, p less than 0.002). Decreased ventricular cycle lengths were found with acute administration of propafenone. Three pigs died during long-term administration of propafenone.(ABSTRACT TRUNCATED AT 250 WORDS)     

小剂量三磷酸腺苷治疗阵发性室上性心动过速临床观察

目的观察小剂量三磷酸腺苷（ATP）治疗阵发性室上性心动过速（PSVT）的疗效及不良反应,探讨小剂量ATP治疗PSVT的价值。方法82例急诊PSVT患者,随机分成2组。小剂量ATP组45例,给予ATP0．1mg／kg快速静脉注射,随即给予20ml生理盐水快速静脉注射。普罗帕酮组37例,给予70懈普罗帕酮静脉注射。结果小剂量ATP组复律38例,普罗帕酮组复律31例,两组比较差异无统计学意义（P〉0．05）,但前者复律时间明显短于后者（P〈0．01）。ATP组7例未复律者,经使用普罗帕酮复律。普罗帕酮组6例未复律者,2例经刺激迷走神经而复律,另4例经重复使用普罗帕酮而复律。ATP组不良反应发生率高于普罗帕酮组（P〈0．05）,但不良反应短暂而轻微。结论小剂量ATP治疗PSVT的有效率与普罗帕酮相当,虽然不良反应发生率较高,但短暂而轻微,具有复律时间短、不影响后续抗心律失常药物使用的优点。     

Comparative Investigation of the Antiarrhythmic Effect of Propafenone (Rytmonorm) and Lidocaine in Patients with Ventricular Arrhythmias during Acute Myocardial Infarction

ABSTRACT Propafenone, a new class I antiarrhythmic drug, given as a bolus injection followed by oral medication, or lidocaine were given to 20 consecutive patients admitted with chest pain suggesting acute myocardial infarction and showing high grades, i.e. multiform, pairs or R-on-T premature ventricular complexes or short runs of ventricular tachycardia. Before institution of therapy the mean number (±1 SD) of premature ventricular contractions (PVCs) per hour was 169±123 in the lidocaine group and 324±440 in the propafenone group. During the next 24 hours lidocaine reduced the numbers of PVCs by 73% and propafenone by 75%. The mean number (±1 SD) of 5-minute periods with high grade PVCs was 4.3±2.9 in the lidocaine group and 5.8±4.5 in the propafenone group. During therapy this number was equally reduced in both groups to 2.4. One patient in the lidocaine group developed ventricular fibrillation and three patients in the propafenone group were excluded because of increasing numbers of PVCs. One patient in the propafenone group showed a torsade-de-pointes ventricular tachycardia.     

Utility of adjunctive single oral bolus propafenone therapy in patients with atrial defibrillators.

AIMS: Previous studies have demonstrated that ambulatory atrial defibrillation shocks delivered by an implantable cardioverter-defibrillator (ICD) are safe and effective, but poorly tolerated. Separate studies have demonstrated the utility of single oral bolus propafenone for conversion of recent-onset atrial fibrillation (AF); however, most patients were hospitalized, had no structural heart disease, were taking no other antiarrhythmic drugs, and were not exposed to concomitant shock. We hypothesized that a single oral bolus dose of propafenone given early after onset would be a safe and effective adjunct to ICD-based AF therapy and improve overall therapy tolerance. METHODS AND RESULTS: A randomized three-way crossover study design was used to compare three strategies, deployed in the ambulatory setting early after AF episode onset in 35 ICD patients with advanced, drug refractory episodic/persistent syndromes, many of whom had structural heart disease and were taking other antiarrhythmic drugs: (i) single oral bolus propafenone (600 mg), followed by ICD shock if necessary; (ii) single oral bolus placebo, followed by ICD shock if necessary; and (iii) no oral bolus therapy and ICD shock if necessary (no bolus). Antiarrhythmic efficacy, defined by the restoration of sinus rhythm within 24 h, was similar during propafenone (81%) and no-bolus strategies (84%); both were significantly higher than during placebo strategy (62%). Propafenone was well tolerated and not associated with proarrhythmia. Shock use was significantly lower during propafenone strategy (19%) than during no-bolus strategy (55%); this was correlated with improved patient tolerance. CONCLUSION: Adjunctive use of single oral bolus propafenone is safe and effective in patients with an ICD and improves patient tolerance of device-based AF therapy.     

The Efficacy of Propafenone for Treatment of Ventricular Ectopic Depolarizations

Propafenone is an effective agent for suppression of chronic ventricular ectopic depolarizations. Complete elimination of nonsustained ventricular tachycardia is achieved in most patients treated with propafenone. The efficacy of propafenone is best correlated with its prolongation of the PR and QRS intervals whereas its plasma level is a poor predictor of therapeutic efficacy. Although serious side effects do occur with propafenone therapy and the drug must be discontinued in some patients, successful therapy of patients for up to four years has been reported.     

伊布利特转复心房颤动和心房扑动的疗效观察

目的观察和比较伊布利特和普罗帕酮终止心房颤动(房颤)/心房扑动(房扑)的疗效及其不良反应。方法 268例发作持续时间<90 d的房颤/房扑患者,随机分组,分别静脉应用(1～2次,每次10 min推注)伊布利特(1.0 mg和1.0 mg)和普罗帕酮(70.0 mg和70.0 mg)。结果伊布利特转复房颤/房扑的成功率分别为67.6%(46/68)和92.4%(61/66),普罗帕酮转复房颤/房扑的成功率分别为32.5%(26/80)和29.6%(16/54)。伊布利特组平均转复时间(27±13)min,转复窦性心律时平均使用量为(1.5±0.4)mg。普罗帕酮组平均转复时间(39±7)min,转复窦性心律时平均使用量为(134.1±6.4)mg。房颤的转复率与左心房直径呈负相关,左心房直径<4.0 cm患者的转复率明显高了左心房直径≥4.0 cm患者的转复率;房扑持续时间可作为房扑终止的预测因子。扑动波周长延长是伊布利特终止房扑的主要特征。结论伊布利特作为一种Ⅲ类的抗心律失常药,在监测的条件下,能迅速、安全、有效地终止房颤/房扑。     

Propafenone for refractory ventricular arrhythmias: correlation with drug plasma levels during long-term treatment

The efficacy of propafenone, a new antiarrhythmic drug, was studied in 21 patients with ventricular arrhythmias refractory to previous antiarrhythmic medications. Group A included 10 patients with chronic ventricular premature complexes (VPCs), 6 of whom had nonsustained ventricular tachycardia (VT) and 4 of whom had recurrent, sustained VT; all received propafenone, 900 mg/day. Group B included 11 patients, all with chronic VPCs, 9 of whom had nonsustained VT and 5 of whom had sustained VT; all received propafenone, 450 mg/day. Drug efficacy was evaluated as a 70% or greater reduction in VPC frequency with complex VPC abolition in ambulatory monitoring and suppression of nonsustained VT and sustained VT during a follow-up period up to 154 +/- 58 days in group A and 96 +/- 42 days in group B. Drug plasma levels were measured during chronic therapy in pharmacologic steady state. In group A, propafenone reduced the frequency of chronic VPCs in 9 patients and abolished nonsustained VT in 4 of 6 and sustained VT in 3 of 4; in group B, propafenone reduced the frequency of chronic VPCs in 6 patients and abolished nonsustained VT in 6 of 9 and sustained VT in 3 of 5. Two patients with recurrences of sustained VT in this group were later successfully treated with propafenone, 900 mg/day; overall, 8 of 9 patients with recurrences of sustained VT were successfully treated with 900 mg/day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Torsade de pointes ventricular tachycardia in a hypothyroid patient treated with propafenone

A 31-year-old female had recurring palpitations and black-outs for 13 years. Hyperthyroidism was diagnosed and electrocardiogram suggested ventricular preexcitation. Despite being treated for hyperthyroidism (which rendered the patient hypothyroid) and receiving propranolol for the arrhythmia, the palpitations persisted. Electrophysiologic testing identified the patient's arrhythmia, and demonstrated that it improved with intravenous propafenone, a new type 1C antiarrhythmic medication. After two days of oral propafenone, this initially good response was followed by episodes of Torsade de pointes ventricular tachycardia with repeated cardiac arrest. Lidocaine and isoproterenol failed to control the rhythm, and the patient was stabilized by electrical cardioversions, atrial pacing and withdrawing the propafenone. Propafenone has been used to treat Torsade de pointes, but we show that it may also cause Torsade de pointes.     

胺碘酮与普罗帕酮转复心房颤动疗效对比研究的系统评价

目的比较胺碘酮与普罗帕酮转复心房颤动(简称房颤)的疗效,为临床用药提供参考。方法计算机检索Cochrane图书馆(2008年第3期)、PubMed、EMBASE(荷兰医学文摘),中国生物医学文献数据库和中国知网全文数据库,收集2000年1月～2008年6月公开发表的有关比较胺碘酮与普罗帕酮转复房颤效果的文献,并用RevMan5.0统计软件对这些文献进行统计分析。结果共纳入5个随机对照试验,累计胺碘酮治疗组262例,普罗帕酮治疗组255例。胺碘酮与普罗帕酮转复房颤效果的合并OR值为1.26,95%可信区间为0.83～1.91,P>0.05。结论胺碘酮与普罗帕酮转复房颤的效果没有差异。