926-27 Probucol-associated Arrhythmic Events: Further Evidence for Increased Female Predisposition to Acquired Long QT Syndromes

Recent data suggest an increased female susceptibility to torsade de pointes (TdP) during exposure to cardiac drugs that prolong the QT interval. We investigated possible gender differences in the occurrence of arrhythmic events in pts taking Probucol (P), a lipid lowering agent that prolongs QTc. A MED-LINEsearch along with data obtained from the Food and Drug Administration, identified a total of 16 reported pts with arrhythmic events (TdP-10, VF-2, VT-2, cardiac arrest-2) during P therapy (median P dose 1000 mg/day, for median duration 1 yr). Of these 16 pts, 15 (94%) were female; yet, during approximately the same time period of these reports (from 1979–1991), nationwide P exposure, according to a large pharmacological database (IMS America), was only 60% female (p l 0.01). Among 10 of the reported pts having known QT interval data, 8 (80%) exhibited marked QTc prolongation ( g 0.60 sec)on P. Nine of the 16 pts had additional potential causes of QT prolongation (Class IA agents-3, hypokalemia-2, prolonged baseline QTc-2, prolonged baseline QT/hypokalemia-1, Class IA agent/hypokalemia-1). In the 3 reported cases of TdP withoutconcomitant causes of QT prolongation, all were female. From pooled studies, we also analyzed a total of 357 asymptomatic pts (64% female) with normalbaseline QTc ( ≤ 0.44 sec) in whom QTc intervals were obtained both prior to and during P therapy (median P dose 500 mg/day, for both men and women). On P, QTc was g 0.45 sec in 16% of women (up to 0.51 sec) vs 3% men (up to 0.49 sec) [p l 0.001] and was ≥ 0.47 sec in 8% of women vs 2% men [p l 0.03]; logistic regression revealed pre-P QTc (p = 0.0001) and female gender (p = 0.01) to be significant predictors of P-induced QTc prolongation ( g 0.45 sec). Conclusions (1) Women appear to have increased susceptibility to Probucol-associated arrhythmic events (primarily TdP); (2) Probucol-associated arrhythmic events occur mainly, but not exclusively, in pts with additional conditions which may prolong QTc; (3) Even in the absence of Tdp, women are more likely to exhibit significant Probucol-induced QTc prolongation, suggesting a clinical continuum in the differential QT interval response of women to the drug.