Risk stratification of drug-induced long QT syndrome caused by class III antiarrhythmic drugs

Abstract

Aim. To develop a personalized risk assessment score for the development of drug-induced QT interval prolongation while taking class III antiarrhythmic drugs (AAD).Methods. We studied data from 110 patients with coronary artery disease and/or hypertension, who had heart arrhythmias and were taking class III AAD (amiodarone or sotalol) in a cardiology department. All patients underwent clinical, laboratory and instrumental studies, including history taking, 12-lead electricardiography recording, biochemical blood test, determination of the levels of neuronal NO-synthase (NOS1) and adapter protein of neuronal NO-synthase (NOS1AP) in blood plasma by ELISA, as well as the determination of polymorphisms G84A of the NOS1 gene using polymerase chain reaction. In order to stratify the risk of drug-induced QT interval prolongation, the method of linear discriminant analysis with stepwise inclusion was applied. The training sample consisted of 70 patients (63.6%), the test sample of 40 patients (36.4%). The score was developed on a training sample, and the testing was performed on a test sample with the construction of an ROC curve, calculation of AUC, sensitivity, and specificity.Results. The training and test samples were comparable in terms of the main clinical and anamnestic parameters and features of the pharmacological history. Patients with QT interval prolongation had significantly lower levels of magnesium (p=0.001), NOS1 (p=0.015) and NOS1AP (p=0.035). The discriminant analysis algorithm was stopped at the fourth step, as a result of which four statistically significant predictors were included in the model: thiazide or loop diuretic intake, blood serum magnesium level, plasma NOS1 and NOS1AP levels, each of which was assigned a certain number of points according to the received standardized coefficients. When conducting an ROC analysis on the initial sample, a threshold value of the scale of 6 points was obtained (AUC 0.848 (0.759 0.937, p=0.002), sensitivity 73.81%, specificity 85.71%). The use of the scale on the test sample showed sensitivity of 77.27%, specificity of 77.77% and AUC of 0.834 (0.721 0.965, p=0.001), which corresponds to the good quality of the prognostic model.Conclusion. Patients with a total score of ≥6 points have a high risk of drug-induced QT interval prolongation while taking class III AAD.