Response to “Digoxin or digoxin prescribed patient? Randomized trials are essential to discriminate the principal risk factor for the association of digoxin and increased mortality”

ReplyWe thank Dr Yildiz and Dr Soydinc for their interest and commentsonourrecentworkregardingtheassociationbetweentheuseofdigox-in and increased mortality in patients affected by atrial fibrillation (AF)[1].IntheirLettertotheEditor[2],Authorsraisemanyinterestingques-tions, suggesting that other factors, in addition to those reported in ourobservational study, may influence the incidence of cardiovascularoutcome in AF digoxin-treated patients.A crucialpointraisedby theAuthorsconcernsthe dosageof digoxinand blood concentrations, as these two factors contribute to the in-creasedriskofmortality[3].Digoxinserumlevelsabovethetherapeuticrangecanbefoundinapercentageofpatientsrangingfrom4to10%[4],and are known to be associated with cardiac toxicity and increasedmortality [5]. However, in a large cohort of 5100 patients in whichblood concentration of digoxin was measured, clinical toxicity attribut-ed to thepro-arrhythmic effectof digoxin havebeensuspected for only0.25% of total patients treated with digitalis [3].Renal dysfunction is another critical issue, which requires digoxintailoring to avoid toxicity; thus, 50%–70% of digitalis is excreted un-changed by the kidney [6].Noteworthy, in the large RIKS-HIA trial [7] including 1493 patientswith and 5540 without digoxin, the relative risk for death betweenpatients discharged with and without digoxin, after adjustment forpropensity score, was independent from baseline serum creatinine.Recent findings from the TREAT-AF study [8] confirmed that, in avery large cohort of 122,465 AF patients (353,168 person-years), theincreased mortality by digoxin was apparently independent from theestimated glomerular filtration rate (eGFR), the effect persisting alsoin the propensity-matched cohort.Inourpopulation,wefoundnodifferencesinrenalfunctionbetweenAF patients treated (n = 90, eGFR calculated by MDRD formula, 69.5[56.4–88.9] ml/min) or not (n = 426, eGFR 73.6 [59.5–87.3] ml/min,p = 0.601) with digoxin.Body mass composition did not apparently influence results fromour study, as at baseline no differences of body mass index (27.4 ±5.0 vs. 27.4 ± 4.7 kg/m