Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a 'thorough QT/QTc' (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.

AIMTo study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODSContinuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTSRac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml −1 (range 1.1-2.8) vs. 1.4 μg ml −1 (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTcI relationship was steeper in women (30 ms per μg ml −1 vs. 23 ms per μg ml −1 in men; P = 0.0135). CONCLUSIONSThe study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Women have a longer QTc interval and an increased risk for pro-arrhythmias caused by drug-induced delayed cardiac repolarization.• This increased risk cannot be explained by gender differences in plasma concentration of the drug.• This study evaluated the QTc-plasma concentration relationship after dosing of rac-sotalol in men and women. WHAT THIS STUDY ADDS• When given a therapeutic dose of rac-sotalol, the slope of the relationship between rac-sotalol concentration and change in QTc interval was steeper in women.• This indicates a greater sensitivity in women as compared with men for rac-sotalol-induced QT prolongation, which may contribute to the greater pro-arrhythmic risk in women.

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In India, AF patients are younger and RHD is still the most frequent etiology. Almost two-third of the patients have persistent/permanent AF. At one-year follow-up, there is a significant mortality and morbidity in AF patients in India.

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