Correlation of Ventricular Arrhythmias With Peak and Trough Levels of Oral Digoxin: A Prospective Ambulatory Electrocardiographic Study.

INTRODUCTION: Digoxin is an affordable medication with a narrow therapeutic window and is widely used globally, particularly in resource-constrained areas. Once-daily oral digoxin produces intraday fluctuations in plasma concentration, as expected from its established pharmacokinetic profile. Whether these fluctuations translate into a time-dependent increase in arrhythmia frequency has not previously been examined in a prospective setting. Given its narrow therapeutic index, there is always concern about digoxin's proarrhythmic potential. We postulated that ectopic arrhythmia density would be greatest during the period of highest drug exposure and least during the pre-dose nadir.

METHODS: This prospective observational study included 50 patients with indications for digoxin therapy, including heart failure with reduced ejection fraction (HFrEF) or rheumatic heart disease (RHD), who underwent 24-hour Holter monitoring. Digoxin 0.25 mg was administered four hours after the Holter was attached, under direct physician supervision. The 24-hour recording was segmented into six four-hour intervals relative to drug intake. The period before ingestion was considered the trough phase. The two- to six-hour post-ingestion interval was identified as the pharmacokinetic peak phase, based on existing digoxin pharmacokinetics data. The main goal was to compare ventricular ectopic beat (VEB) burden across these intervals using the Friedman test with Nemenyi post-hoc correction.

RESULTS: The cohort had a mean age of 50.6±13.4 years; 58% were male. Underlying diagnoses were non-ischaemic dilated cardiomyopathy (n=28, 56%), ischaemic cardiomyopathy (n=7, 14%), and RHD (n=15, 30%). Atrial fibrillation was present in 48%. The median VEB count during the designated peak phase (hours 2-6) did not differ significantly from that in any other four-hour interval (Friedman χ²=3.3, p=0.767). Pairwise comparisons of all intervals with the peak phase showed no significant difference (all p>0.05, Nemenyi correction). No sustained ventricular tachycardia was recorded in any participant.

CONCLUSIONS: In patients on stable oral digoxin therapy, ventricular ectopic burden does not correlate with the drug's peak or trough pharmacokinetic levels. These findings suggest that the proarrhythmic risk of digoxin at therapeutic doses is less likely to be driven by intra-day fluctuations in drug levels. Larger controlled studies with concurrent serum level monitoring are needed to confirm this observation.