JTc prolongation with d,l-sotalol in women versus men

Women are at increased risk for torsades de pointes associated with a variety of drugs that prolong ventricular repolarization, but few data exist regarding possible sex differences in extent of repolarization changes with these medications.We sought to compare JTc interval responses in women and men during treatment with d,l-sotalol. The study cohort consisted of 1,897 patients (26% women) with available baseline and ≥1 on-drug electrocardiogram from a database involving patients exposed to oral d,l-sotalol without developing torsades de pointes. The mean lowest and highest daily d,l-sotalol dose, normalized for weight, was not significantly different between sexes. At each dosing extreme, on-drug JTc was significantly longer in women (p ≤0.0002). Statistically independent predictors of on-drug JTc included gender (p = 0.003), baseline JTc (p = 0.0001), dose (p = 0.0001), serum creatinine (p ≤0.03), and history of sustained ventricular tachyarrhythmias (p = 0.01). In both men and women, as baseline JTc increased, the drug-induced increment in JTc became progressively smaller. Thus, in response to d,l-sotalol, JTc intervals become longer in women than in men. This sex difference is independent of dose and not solely attributable to the known gender disparity in baseline JTc. The greater propensity of women to drug-induced torsades de pointes may represent the most extreme expression of a basic sex difference in the response to medications that prolong ventricular repolarization.