Response - Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes.

Letter

We thank Chen et al. for their comments on our recently published study showing that androgen-deprivation therapies (ADT) can induce QT prolongation and Torsade de pointes (TdP). In the manuscript, we identified a clinical signal using the VigiBase pharmacovigilance database and then provided biological plausibility for our observations by performing electrophysiological studies in cardiomyocytes differentiated from induced pluripotent steam cells from healthy men.¹ Our work builds on previous reports from us and others showing that ADT use is associated with TdP risk, especially in prostate cancer patients. Together, these data suggest that in men treated with ADT, any risk factors for TdP should be sought and corrected, to avoid accumulation of risks.

We completely agree with Chen et al. that in men treated with ADT, the role of electrocardiographic monitoring to detect QT-prolongation requires further evaluation and that no firm guidelines can yet be drawn concerning timing of this monitoring. The pharmacovigilance part of our study relied on spontaneous physician reports, and these focuses generally on chronic ADT therapy and do not precisely establish the relationship between the initiation and duration of ADT therapy and QT prolongation. Further, available cohort studies evaluating the effects of ADT on QT are generally not well controlled and have focused on chronic effects over months rather than any possible acute effects over hours and days.² During ADT therapy, the incidence of QTc (QT corrected for heart rate) >450msec was up to 15% and QTc >500msec was up to 2% in patients having normal QTc prior to ADT initiation.²

Examining the effects of drugs in in-vitro systems is an established method to assess their arrhythmogenic potential, but generally cannot be used to inform the timing of any drug-induced arrhythmias. Interestingly, there are a number of case reports showing an acute effect (over hours or days) of androgen therapy on QTc in humans.^{3, 4} In men with intractable TdP and hypogonadism, administration of testosterone was associated with QT shortening and abolition of arrhythmias within 3 days and this effect was sustained.⁴ Moreover, ADTs are often combined with other anticancer drugs with variable mechanisms of action or with their own propensity to increase QT,⁵ so the problem of establishing temporal relationships or even causality between one drug or dosage and QT prolongation becomes even more complex. Thus, we agree with Chen and colleagues in calling for further prospective studies to better delineate the relationships among ADT intake, QT prolongation, and TdP risk.¹