Propafenone

Observational studies

Of 87 patients with atrial fibrillation who were given propafenone 2 mg/kg intravenously over 10 minutes, four had hypotension at 8–45 minutes after the start of infusion [ ]. In two cases this was accompanied by sinus bradycardia, nausea, and slight malaise. In all cases the hypotension resolved rapidly with saline infusion; the drug was withdrawn in only one case. In two cases atrial fibrillation was transformed to asymptomatic atrial flutter with 2:1 atrioventricular conduction.

Quinidine has been added to propafenone with the intention of inhibiting propafenone metabolism via CYP2D6 in the hope of improving outcome [ ]. Of 60 patients with paroxysmal atrial fibrillation given propafenone 300–450 mg/day for 8 weeks there were 19 refractory cases, who were then randomized double-blind to receive either a higher dose of propafenone (450–675 mg/day) or the standard dose of propafenone with extra low-dose quinidine (150 mg/day), each for 8 weeks, with subsequent crossover to the alternative. Patients who even then were not adequately controlled were given the standard dose of propafenone plus a standard dose of quinidine (600 mg/day) for a further 8 weeks. The plasma propafenone concentrations during the four phases were as follows:

• 1.

  standard-dose propafenone alone 128 ng/ml;

• 2.

  standard-dose propafenone plus low-dose quinidine 259 ng/ml;

• 3.

  high-dose propafenone alone 336 ng/ml;

• 4.

  standard-dose propafenone plus standard-dose quinidine 490 ng/ml.

The beneficial effects were related to these plasma concentrations, as were the time to the first bout of atrial fibrillation, the frequency of bouts of atrial fibrillation, and the time between episodes. However, when atrial fibrillation occurred there was no difference in the ventricular rate in the different groups. Adverse reactions necessitated drug withdrawal in four patients; one had heart failure and two who took the higher dose of propafenone had gastrointestinal symptoms. The authors suggested that this stepwise approach, with increasing doses of propafenone and increasing doses of quinidine could be beneficial in the treatment of paroxysmal atrial fibrillation.

Comparative studies

Placebo-controlled studies

In controlled trials in patients with recent-onset atrial fibrillation without heart failure, oral propafenone (450–600 mg as a single dose) had a relatively quick effect (within 3–4 hours) and a high rate of efficacy (72–78% within 8 hours) [ ].

Adverse reactions to propafenone in placebo-controlled trials in patients with atrial tachydysrhythmias have been reviewed [ ]. The following reactions were reported after single intravenous oral doses to produce conversion of atrial fibrillation to sinus rhythm. Non-cardiac adverse reactions included mild dizziness. Mild hypotension was also noted, but only required withdrawal of propafenone in one of 29 patients in one study. There have been prodysrhythmic effects in several studies, including atrial flutter with a broad QRS complex, which can occur in up to 5% of cases; in some cases atrial flutter can have a rapid ventricular response due to 1:1 atrioventricular conduction, which has been attributed to slowing of atrial conduction and reduced refractoriness of the atrioventricular node. Other prodysrhythmic effects in a few patients included sinus bradycardia with sinus pauses and effects on atrioventricular conduction.

In patients taking long-term propafenone for supraventricular dysrhythmias adverse reactions were more common and have been reported in 14–60% of cases. Cardiac adverse reactions were more common in patients with structural heart disease. The non-cardiac reactions were either gastrointestinal (nausea, vomiting, taste disturbances) or neurological (dizziness). In one large study there was no difference between propafenone and placebo in the risk of death.

The use of propafenone in atrial fibrillation has been studied in a randomized, double-blind, placebo-controlled trial in 55 patients [ ]. The dose of propafenone was chosen according to body weight: 450, 600, and 750 mg for those weighing 50–64, 65–80, and over 80 kg respectively. Propafenone converted atrial fibrillation to sinus rhythm significantly more quickly than placebo, and most patients given propafenone had converted by 6 hours. However, by 24 hours there was no significant difference between the two groups. Four patients had hypotension after propafenone, in three cases transiently. The patient with sustained hypotension had poor left ventricular systolic function, but it responded promptly to the administration of fluids and electrical cardioversion. In one patient with transient hypotension there was a brief episode of sinus bradycardia and in another an isolated sinus pause.

In a randomized, double-blind, placebo-controlled study of a modified-release formulation of propafenone (propafenone SR) patients with a history of symptomatic atrial fibrillation who were in sinus rhythm were randomized to placebo or propafenone SR 225, 325, 425 or mg, all twice daily [ ]. In the primary efficacy analysis, propafenone SR significantly prolonged the time to first symptomatic recurrence of atrial dysrhythmia at all three doses compared with placebo. The median time to recurrence was 41 days with placebo, 112 days with propafenone 225 mg, 291 days with 325 mg, and over 300 days with 425 mg. The numbers of patients who reported at least one adverse event were 91 (72%) with placebo, 97 (77%) with propafenone 225 mg, 113 (84%) with propafenone 325 mg, and 113 (83%) with propafenone 425 mg. Adverse events that led to withdrawal occurred in 17 (14%), 16 (13%), 19 (14%), and 34 (25%) patients in each of the four groups respectively. In all of the propafenone treatment groups, the most commonly reported adverse events that also exceeded the percent reported by patients taking placebo by at least 5% were dizziness, dyspnea, taste disturbances, fatigue, and constipation. Propafenone increased the PR interval and QRS duration dose-relatedly but did not change the QT _c interval. The average changes from baseline in PR interval were 1.0 ms with placebo, 9.1 ms with propafenone 225 mg, 12 ms with propafenone 325 mg, and 21 ms with propafenone 425 mg. The changes in QRS duration were ?1.6 ms with placebo, 4.0 ms with propafenone 225 mg, 6.3 ms with propafenone 325 mg, and 6.3 ms with propafenone 425 mg. There were no deaths during treatment or within 30 days of withdrawal. There were no cases of ventricular tachycardia.

Cardiovascular

Cardiovascular adverse reactions have been reported in 13–27% of patients taking propafenone and ventricular dysrhythmias in 8–19% in small studies. However, in large studies the risk has been reported to be about 5%.

Conduction disturbances are common with propafenone and can result in sinus bradycardia, sinoatrial block, sinus arrest, any degree of atrioventricular block, and right or left bundle-branch block [ ].

Left bundle branch block during exercise has been attributed to propafenone [ ].

• A 66-year-old man took propafenone 450 mg/day for 3 months for paroxysmal atrial fibrillation and underwent maximal symptom-limited exercise testing to rule out the presence of coronary artery disease. His resting heart rate was 74/minute and the QRS duration was 124 ms with no repolarization abnormalities. He exercised according to the Bruce protocol for 10 minutes. During exercise his heart rate rose to 144/minute and his blood pressure rose from 130/80 to 190/90 mmHg. During the test there was gradual prolongation of the QRS duration culminating in left bundle branch block (LBBB) morphology with a QRS duration of 165 ms and left axis deviation at peak exercise. During recovery the LBBB morphology disappeared and the QRS duration gradually returned to the pre-exercise value.

Adverse reactions to a single oral dose of propafenone for cardioversion of recent-onset atrial fibrillation have been evaluated in a systematic review [ ]. The adverse reactions were transient dysrhythmias (atrial flutter, bradycardia, pauses, and junctional rhythm), reversible widening of the QRS complex, transient hypotension, and mild non-cardiac reactions (nausea, headache, gastrointestinal disturbances, dizziness, and paresthesia).

Dysrhythmias can occur; these include ventricular tachycardia, ventricular flutter, and atrial fibrillation [ , , ]. Hypotension and worsening of heart failure have occasionally been reported [ ].

• Wide-complex tachycardias occurred in two elderly patients (a 74-year-old man and an 80-year-old woman) who had taken propafenone for atrial fibrillation [ ]. In the first case the dysrhythmia was due to atrial flutter with 1:1 conduction.

Although drugs of class Ic, such as propafenone, can slow atrial and atrioventricular nodal conduction in patients with atrial fibrillation or atrial flutter, they do not alter the refractoriness of the atrioventricular node, and this allows 1:1 atrioventricular conduction as the atrial rate slows. This happens despite prolongation of the PR interval.

Class Ic drugs can also convert atrial fibrillation to atrial flutter, reportedly in 3.5–5% of patients. Of 187 patients with paroxysmal atrial fibrillation who were treated with flecainide or propafenone, 24 developed atrial flutter, which was typical in 20 cases [ ]. These patients underwent radiofrequency ablation, which failed in only one case. All the patients continued to take their pre-existing drugs, and during a mean follow-up period of 11 months, the incidence of atrial fibrillation was higher in patients who were taking combined therapy than in those taking monotherapy. The authors suggested that in patients with atrial fibrillation who developed typical atrial flutter due to class Ic antidysrhythmic drugs, combined catheter ablation and continued drug treatment is highly effective in reducing the occurrence and duration of atrial tachydysrhythmias. They did not report adverse reactions.

In controlled trials of oral propafenone (450–600 mg as a single dose) in patients with recent-onset atrial fibrillation without heart failure, atrial flutter with 1:1 atrioventricular conduction occurred in only two of 709 patients (0.3%) who received propafenone [ ].

Propafenone and ibutilide have been compared in 40 patients with atrial flutter [ ]. Ibutilide was superior to propafenone for treating atrial flutter (90% versus 30%) and the respective mean conversion times were 11 and 35 minutes. Bradycardia (2/20) and hypotension (4/20) were more common adverse reactions to propafenone.

In 100 consecutive patients with persistent atrial fibrillation pharmacological cardioversion was carried out using either intravenous ibutilide (1 mg plus an additional 1 mg, if required; n = 51) or oral propafenone (600 mg) plus the same dose of intravenous ibutilide (n = 49). The QT _c interval increased in both groups and there was one case of sustained torsade de pointes, requiring electrical cardioversion, in those who were given propafenone plus ibutilide [ ].

“Cardiac memory” is the phenomenon whereby T wave changes persist after aberrant ventricular activation. Propafenone toxicity has been reported to cause cardiac memory after QRS widening and markedly abnormal ventricular activation in a 74-year-old woman [ ].

Propafenone can cause Brugada-like changes on the electrocardiogram [ ], which can be mistaken for acute myocardial infarction [ ].

Respiratory

Since propafenone is a beta-adrenoceptor antagonist it can cause shortness of breath or worsening of asthma [ ].

Nervous system

Adverse reactions in the nervous system are common with propafenone and include somnolence, weakness and disorientation, global amnesia [ ], dizziness and vertigo, tremor, visual disturbances, and convulsions [ ].

• Ataxia has been reported in patients taking propafenone [ ].

• An 80-year-old man taking propafenone 150 mg tds for paroxysmal atrial fibrillation developed progressive generalized ataxia and weakness 4 days after starting treatment. He had a bilateral symmetrical ataxia, unclear speech, impairment of gait, altered hand coordination, and tremor. The ataxia resolved completely within 3 days of withdrawal.

• A 73-year-old woman taking propafenone 150 mg tds for paroxysmal atrial tachycardia underwent cardioversion during an attack, and the dose of propafenone was increased to 300 mg tds. After 5 days she developed severe ataxia and progressive weakness. The ataxia was symmetrical and there was severe impairment of gait, altered hand coordination, and tremor. The dose of propafenone was reduced to 600 mg/day and the ataxia resolved completely within 6 days. A year later, when the dose of propafenone was increased to 900 mg/day, progressive ataxia again developed after 2 days and became severe within 1 week. Propafenone was withdrawn and the ataxia resolved within a few days.

• An 85-year-old woman took propafenone 150 mg tds for paroxysmal atrial fibrillation and 2 months later developed a progressive ataxia and recurrent falls. The ataxia was symmetrical and there was altered hand coordination, impairment of gait, and tremor. The propafenone was withdrawn and the ataxia resolved completely within 4 days.