title: Pharmacodynamic equivalence of two flecainide acetate formulations in patients with paroxysmal atrial fibrillation by QRS analysis of ambulatory electrocardiogram.
abstract: The pharmacodynamic equivalence of flecainide acetate immediate-release (IR) and controlled-release (CR) formulations was assessed from QRS duration in patients currently treated with the IR formulation. Patients were blindly assigned randomly to the IR (100 mg BID, n = 25) or to the CR group (200 mg OD, n = 23). Electrocardiographic parameters were measured at baseline and at week 8 from 24-h Holter monitoring. Mean (SD) normalized flecainide trough plasma concentration (measured 12 h after last intake) at week 8 was 381.3 ng/ml (104.8) with the IR and 381.4 ng/ml (123.8) with the CR formulation. Hodges-Lehmann estimate (95% CI) of the difference between IR and CR for change in QRS duration between baseline and week 8 was 1.6% (-0.1; 3.7), indicating that the formulations were pharmacodynamically equivalent. Median QRS values (102 vs 100.1 ms at baseline; 103.15 vs 99 ms at week 8) as well as first and third quartiles were very similar in both groups. The correlation between QRS duration and RR classes at baseline was highly significant (P < 0.0001). Correlation coefficient at week 8 was statistically significant for > 50% of the patients and was significant in a greater proportion of patients under the IR compared with the CR formulation. Circadian hourly variations of QRS duration as determined by harmonic analysis showed the occurrence of a peak of QRS widening following each intake of the IR, whereas this pattern was not observed with the CR formulation. The latter results are consistent with a greater occurrence of frequency-dependent QRS variations over the 24-h period with the IR compared with the CR formulation.
authors.affiliation: Department of Cardiology, Hôpital Lariboisière, Laboratoires 3M Santé, Cergy Pontoise Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Coumel
authors.forename: Pierre
authors.initials: P
authors.lastname: Maison-Blanche
authors.forename: Eliane
authors.initials: E
authors.lastname: Tarral
authors.forename: Antoine
authors.initials: A
authors.lastname: Périer
authors.forename: Paul
authors.initials: P
authors.lastname: Milliez
authors.forename: Antoine
authors.initials: A
authors.lastname: Leenhardt
mesh_terms: D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D002940:Circadian Rhythm; D004304:Dosage Forms; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory; D005260:Female; D005424:Flecainide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency
chemical_list: D000889:Anti-Arrhythmia Agents; D004304:Dosage Forms; D005424:Flecainide