Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study

Salem, Joe‐Elie; Bretagne, Marie; Lebrun‐Vignes, Bénédicte; Waintraub, Xavier; Gandjbakhch, Estelle; Hidden‐Lucet, Françoise; Gougis, Paul; Bachelot, Anne; Funck‐Brentano, Christian

doi:10.1016/j.acvd.2019.06.008

Cited by 21 publications

(13 citation statements)

References 46 publications

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“…Our results provide evidence for the first time that a significant proportion of patients developing TdP (~15% of males) were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals (Salem et al, 2018;Salem et al, 2019a;Salem et al, 2019b). These data further support an important physiological role for testosterone in preserving ventricular repolarization in males (Salem et al, 2016), and emphasize the clinical impact of ADTinduced hypogonadism in promoting TdP, particularly in the presence of other concomitant QT-prolonging risk factors.…”

Section: Discussionsupporting

confidence: 81%

“…Recently, in seven male patients with TdP, hypogonadism was diagnosed in all cases, and after correction for low testosterone levels, QTc shortened with no TdP recurrence (Salem et al, 2018). Moreover, by analyzing international pharmacovigilance databases, the same authors found that androgen-deprivation therapy (ADT) was associated with higher reporting odds-ratios for drug-induced-LQTS/TdP when compared to testosterone-replacement therapy (Salem et al, 2018;Salem et al, 2019a;Salem et al, 2019b). Although interesting, these pharmacovigilance data are limited as derived from uncontrolled sources.…”

Section: Introductionmentioning

confidence: 99%

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Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes

et al. 2020

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Background: Men 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.Objective: To 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 Results: We 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). Conclusion:We 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.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes

et al. 2020

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“…The mean "delta" in group A was 32.6 ± 43.6 ms. In the literature, the mean prolongation of QTc reported with androgen deprivation therapy is 10-20 ms [32]. We interpreted that patients in group A had a more pronounced QTc prolongation in comparison with the data reported in the literature due to the association of two classes of antiandrogens, whose cardiac effects may enhance each other.…”

Section: Discussionsupporting

confidence: 62%

Evolution of Electrocardiographic Repolarization Parameters During Antiandrogen Therapy in Patients with Prostate Cancer and Hypogonadism

et al. 2020

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We assessed the effects of antiandrogen therapy on ECG parameters of ventricular repolarization related to arrhythmic risk in 35 patients aged 70.3 ± 7 years with advanced prostate cancer treated with degarelix associated with enzalutamide (group A, 26 patients) or degarelix monotherapy (group B, 9 patients). We analyzed Fridericia corrected Q-T interval (QTc), Q-T dispersion (QTd), J-Tpeak interval (JTp), mean and maximum Tpeak-Tend interval (Tpe) and Tpe/QT ratio, Tpeak-Tend dispersion (Tped), index of cardio-electrophysiological balance (iCEB) from ECG tracings, and occurrence of ventricular premature beats (VPB) recorded by Holter ECG, before initiation of medication (M0) and after 6 months of treatment (M1). The groups had similar demographics except for a higher prevalence of prior myocardial infarction in group B (p = 0.01). All patients had low serum testosterone at M1. Baseline QTc, QTd, maxTpe/QT, meanTpe, maxTpe, Tped values were higher in B compared to A. They had a significant prolongation at M1 only in A. 20 patients in A and 6 in B had a 10% prolongation or decrease of iCEB (p = 0.66). In 5 patients, VPB severity increased from non-complex to complex: 3 in A and 2 in B (p = 0.31), but no sustained ventricular arrhythmia was registered. In conclusion, after 6 months of treatment, patients with hypogonadism on degarelix associated with enzalutamide had significant prolongation of QTc, QTd, maxTpe, meanTpe/ QT, maxTpe/QT, Tped compared to patients on degarelix alone. The proportion of patients with 10% iCEB variation was similar between groups. There was no record of severe arrhythmias during the first 6 months of treatment.

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“…We previously reported an independent association between HIV infection and longer QTc [4–5] but did not assess the influence of testosterone usage (T‐use). In the general population, low testosterone levels (T‐levels) are associated with 4–11 ms QTc prolongation [6–9], whereas high T‐levels are associated with lower SCD risk in men [10–11]. Evidence suggests that androgen deprivation therapy is associated with QTc prolongation and arrhythmic risk [12–13].…”

Section: Introductionmentioning

confidence: 99%

Testosterone use and shorter electrocardiographic QT interval duration in men living with and without HIV

et al. 2020

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Objectives Testosterone usage (T‐use) may alter risk factors for sudden cardiac death in men living with HIV (MLWH). Electrocardiographic QT interval prolongation, which could potentiate ventricular arrhythmias, has previously been associated with HIV infection and, separately, with low testosterone levels. We investigated whether T‐use shortens the QT interval duration in MLWH and HIV‐uninfected men. Methods We utilized data from the Multicenter AIDS Cohort Study, a prospective, longitudinal study of HIV infection among men who have sex with men. Multivariable linear regression analyses were used to evaluate associations between T‐use and corrected QT interval (QTc) duration. Results Testosterone usage was more common in MLWH compared with HIV‐uninfected men (19% vs. 9%). In a multivariable regression analysis, T‐use was associated with a 5.7 ms shorter QT interval [95% confidence interval (CI): −9.5 to −1.9; P = 0.003). Furthermore, stronger associations were observed for prolonged duration of T‐use and recent timing of T‐use. Conclusions This study is the first known analysis of T‐use and QTc interval in MLWH. Overall, our data demonstrate that recent T‐use is associated with a shorter QTc interval. Increased T‐use duration above a threshold of ≥ 50% of visits in the preceding 5 years was associated with a shorter QTc interval while lesser T‐use duration was not.

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Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study

Cited by 21 publications

References 46 publications

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes

Evolution of Electrocardiographic Repolarization Parameters During Antiandrogen Therapy in Patients with Prostate Cancer and Hypogonadism

Testosterone use and shorter electrocardiographic QT interval duration in men living with and without HIV

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