Abstract
BackgroundMen normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases.ObjectiveTo better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period.Methods and ResultsWe found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available).ConclusionWe provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.
Highlights
Congenital long-QT syndrome (LQTS) results from genetically determined channelopathies directly or indirectly affecting the function of specific potassium, sodium, or calcium channels critically involved in regulating ventricular action potential duration (APD) (El-Sherif et al, 2017)
It should be noted that this percentage was ~7-times higher than that observed in a control population of 123 elderly males comparable for age, consecutively admitted in our Internal Medicine Unit at the University Hospital of Siena, during the last 2 years within the ASTEROID study [2.4%, 3 patients under androgen-deprivation therapy (ADT) (2 leuprolide, 1 abiraterone) for prostatic cancer; relative risk 6.83, 95% confidence interval 1.63–28.61; two-sided Fisher’s exact test: p=0.014]
Our results provide evidence for the first time that a significant proportion of patients developing Torsades de Pointes (TdP) (~15% of males) were under treatment with ADT for prostatic cancer, confirming the clinical relevance of previous pharmacovigilance signals (Salem et al, 2018; Salem et al, 2019a; Salem et al, 2019b)
Summary
Torsades de Pointes (TdP) is a polymorphic ventricular tachycardia occurring in patients with congenital or acquired long-QT syndrome (LQTS), which can degenerate to ventricular fibrillation (VF) and sudden cardiac death (SCD) (Drew et al, 2010). Congenital LQTS results from genetically determined channelopathies (inherited channelopathies) directly or indirectly affecting the function of specific potassium (loss of function), sodium, or calcium (gain of function) channels critically involved in regulating ventricular action potential duration (APD) (El-Sherif et al, 2017). Mainly hERG-potassium channel blockers, and electrolyte imbalances (hypokalemia, hypocalcaemia, hypomagnesemia) represent the most frequent causes of acquired LQTS (Drew et al, 2010; El-Sherif et al, 2018). The evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases
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