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.