Review article Oral antiarrhythmic drugs in converting recent onset atrial fibrillation • Vera H.M. Deneer, Marieke B.I. Borgh, J. Herre Kingma, Loraine Lie-A-Huen and Jacobus R.B.J. Brouwers Introduction Pharm World Sci 2004; 26: 66–78. © 2004 Kluwer Academic Publishers. Printed in the Netherlands. Atrial fibrillation is the most common arrhythmia. The incidence of atrial fibrillation depends on the age of V.H.M. Deneer (correspondence, e-mail: the study population. The incidence varies between 2 [email protected]), M.B.I. Borgh, L. Lie-A-Huen: Department of Clinical Pharmacy or 3 new cases per 1,000 population per year between J.H. Kingma: Department of Cardiology, St Antonius Hospital, the ages of 55 and 64 years to 35 new cases per 1,000 Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands population per year between the ages of 85 and 94 J.R.B.J. Brouwers: Groningen University Institute for Drug 1 Exploration (GUIDE), Section of Pharmacotherapy, University years . Treatment of an episode of paroxysmal atrial fi- of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, brillation consists of restoring sinus rhythm by DC- The Netherlands electrical cardioversion or by the intravenous adminis- Key words tration of an antiarrhythmic drug, but frequently the Atrial fibrillation arrhythmia spontaneously terminates1–3. After one or Amiodarone more episodes of atrial fibrillation chronic prophylac- Antiarrhythmic drugs Digoxin tic treatment with an antiarrhythmic drug is often Episodic treatment started for maintenance of sinus rhythm4–8. Another Flecainide treatment strategy consists of allowing the arrhythmia Propafenone Quinidine to exist in combination with pharmacological ven- Sotalol tricular rate control. A single oral loading dose in re- Verapamil storing sinus rhythm would be more convenient than Abstract the intravenous administration of an antiarrhythmic Aim: This article reviews clinical studies on oral antiarrhythmic drug. Due to its simplicity oral loading dosing could be drugs in converting recent onset atrial fibrillation. An oral an option both for patients admitted to outpatient de- loading dose of an antiarrhythmic drug for cardioversion of atrial fibrillation could be an option, due to its simplicity, both partments and for episodic treatment by self adminis- for patients admitted to outpatient departments and for tration outside the hospital9–13. This treatment strat- episodic treatment by self administration outside the hospital. egy has recently been pointed out by the American The latter treatment strategy has recently been pointed out by the American College of Cardiology, the American Heart College of Cardiology, the American Heart Association Association and the European Society of Cardiology as the ‘pill and the European Society of Cardiology as the ‘pill in in the pocket approach’. the pocket approach’14. Methods: Articles were identified by Medline 1966 to November 2001 and Embase 1966 to November 2001. Episodic treatment implies an early intervention. Randomized studies of oral antiarrhythmic drugs versus This seems attractive because in an animal model it placebo or comparative treatment, which are written in the was shown that within a few hours after its onset atrial English language, were selected. Non-randomized or non-comparative studies were selected if the results of an fibrillation leads to electrical remodelling which en- analysis to identify predictors for successful conversion are hances the persistence of atrial fibrillation15. An early described. The review of clinical trials is followed by a recovery of sinus rhythm may favour the maintenance description of pharmacokinetic parameters of the antiarrhythmic drugs. of sinus rhythm, gives an early relief of symptoms and Results: Studies meeting the inclusion criteria were on reduces the risk of thromboembolic complica- propafenone, flecainide, sotalol, amiodarone, quinidine, tions3, 15. Episodic on demand treatment of atrial fi- digoxin and verapamil. Conversion rates of a single oral loading dose of 600 mg propafenone varied between 37% brillation might be a useful alternative to chronic pro- and 41% at 4 h after ingestion. Propafenone was more phylactic treatment with antiarrhythmic drugs. It over- effective than quinidine, amiodarone and placebo. A single comes the problems of patient compliance and the oc- oral dose of 300 mg flecainide restored sinus rhythm in 59% and 68% of patients at 3 h. Flecainide was more effective than currence of side effects necessitating to change the amiodarone and placebo. Oral sotalol, digoxin and verapamil dosage or to discontinue the medication4, 16–18. Fre- were not effective in converting atrial fibrillation to sinus quent DC-electrical cardioversions or acute treatment rhythm. Conclusion: Propafenone and flecainide are effective in with intravenously administered antiarrhythmic drugs converting recent onset atrial fibrillation. No serious could also be an option in patients in whom chronic ventricular arrhythmia, other serious proarrhythmic effects or treatment is problematic. However, this treatment serious non cardiac adverse events were observed. Regular supraventricular tachyarrhythmias with 1:1 AV conduction strategy requiring hospitalisation or admittance to were rare and were also observed in placebo treated patients. emergency departments is both costly and inconven- Propafenone and flecainide are more effective in patients with ient for patients2. atrial fibrillation of less than 24 h. The association between cardioversion and patient characteristics are not consistent To determine the efficacy of oral antiarrhythmic between studies. The pharmacokinetics of flecainide, with drugs in converting short lasting atrial fibrillation rel- lower interindividual variability of absorption kinetics, no evant studies are reviewed. genetically determined formation of an active metabolite and a more rapid distribution to myocardial tissue, are more favourable for episodic treatment as compared to propafenone. Both flecainide and propafenone are safe in Methods hospitalized patients. Out of hospital self administration of antiarrhythmic drugs, also described as the ‘pill in the pocket Published clinical trials studying oral antiarrhythmic approach’, could be an option for selected patients, after the drugs in converting atrial fibrillation are reviewed. Ar- treatment has proven to be safe in hospital. ticles were identified by Medline 1966 to November Accepted July 2003 2001 and Embase 1966 to November 2001. Subse- 66 quently references were checked. Search terms were: atrial fibrillation, atrial tachycardia, supraventricular ar- Conversion rates were 3%23 and 15%25 at1h,was rhythmia, supraventricular tachyarrhythmias, su- 41% and 43% at 2 h28, 31, varied between 45 and praventricular tachycardia, conversion, cardioversion, 55% at 3 h21, 23, 24 and ranged from 37% to 71% at 4 antiarrhythmic drugs, flecainide, propafenone, amio- h after ingestion22, 25, 26, 31. Propafenone was more ef- darone, sotalol, quinidine, digoxin, disopyramide, ve- fective than placebo at 3 to 12 h21, 28. However, after rapamil, procainamide, dofetilide. an observation period of 24 h the difference between The efficacy of some intravenously administered an- propafenone and placebo disappeared and conversion tiarrhythmic drugs in converting atrial fibrillation was rates became similar31. In one study, after an initial highly dependent on the time of onset of the arrhyth- higher efficacy of propafenone, the difference be- mia. Efficacy decreased with increasing duration of tween the propafenone and the placebo group disap- atrial fibrillation19, 20. In episodic treatment patients peared at 6 h27. are expected to take their medication shortly after the A single oral dose of 450 mg propafenone was less onset of the arrhythmia. Therefore, studies were only effective than 600 mg at 2 h, while conversion rates at selected if patients with a duration of atrial fibrillation 4 to 24 h were not significantly different31. Mean con- of less than 24 h, were allowed to be included. Studies version times were 287 ± 352 min and 279 ± 237 min in which oral antiarrhythmic drugs were preceded by for the 600 mg dose and the lower dose respectively, the intravenous administration of the drug and studies while the observation period was 24 h. Propafenone on atrial fibrillation following cardiac surgery were ex- was equally effective as an oral loading dose of flecai- cluded. This review includes randomized studies of nide with mean conversion times of 165 ± 119 min oral antiarrhythmic drugs versus placebo or compara- and 158 ± 109 min respectively and an observation tive treatment, which are written in the English lan- period of 8 h21. Intravenously administered propaf- guage. Non-randomized or non-comparative studies enone was more effective than oral propafenone at 1 were selected if the results of an analysis to identify h. However, at 3 and 6 h conversion rates were simi- predictors for successful conversion are described. The lar23 with conversion times of 138 ± 140 min for intra- review of clinical trials is followed by a description of venous propafenone and 163 ± 114 min for oral pharmacokinetic parameters of the antiarrhythmic propafenone23. In a study of Botto et al.25 intravenous drugs. A meta-analysis was not performed because the propafenone also showed a higher conversion rate at study populations varied widely in the duration of 1 h after administration. At 4 and 8 h conversion rates atrial fibrillation which highly