Abiraterone Acetate-Induced Life-Threatening Torsade de Pointes

Abstract

Abiraterone acetate (AA) was approved in 2011 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). AA selectively inhibits the CYP17 enzyme, resulting in the suppression of testosterone production and an increase in ACTH levels, and hence in mineralocorticoid production. Prednisone coadministration is warranted to suppress the adrenocorticotropic feedback loop and reduce the most common adverse effects of AA, including hypokalemia, hypertension, and fluid retention. Hypokalemia still affects up to 28% of patients taking AA.We report the first case of life-threatening torsade de pointes (TdP) associated with a prolonged QT interval in a patient taking AA. Case PresentationA 74-year-old patient, without any personal or family history of cardiac disease, but known for hypertension, diabetes, anxiety disorder, and mCRPC, was admitted for a cardiac arrest. First observed rhythm was TdP alternating with ventricular fibrillation (Figure 1). After resuscitation, the electrocardiogram showed a prolonged QTc interval (620 ms). Laboratory results showed severe hypokalemia (2.5 mEq/L) and mild hypocalcemia (4.1 mEq/L). Other blood electrolyte levels, including magnesium (1.32 mEq/L); liver enzymes (aspartate aminotransferase, 75 IU/L; alanine aminotransferase, 43 IU/L); renal function (serum creatinine 0.87 mg/dL); thyroid function (thyroid-stimulating hormone 2.5 mIU/L); and complete blood count (hemoglobin 100 g/L; platelet count 123 × 10 9 /L; white blood cell count 7.8 × 10 9 /L) were in the normal range. Myocardial infarction was excluded.The only concomitant medications were enalapril 20 mg once a day, metformin 850 mg thrice a day, and zolpidem 10 mg once a day, which the patient had been taking for 10 years. He had begun AA, 250 mg 4 times a day, 6 months earlier, which was decreased to 250 mg thrice a day because of diarrhea, and prednisone 5 mg twice a day for a mCRPC. Adherence was good, except for prednisone because its usefulness was not clear for the patient.AA was stopped. The other medications were continued. Serum potassium was corrected and was in the normal range on day 2. Calcium levels normalized within 48 hours without supplementation. The QTc interval gradually decreased and was 440 ms on day 6. The patient was confused and agitated because of postanoxic encephalopathy. He slowly recovered and was discharged home 2 weeks later. DiscussionThe imputability of AA in our patient's life-threatening TdP is supported by chronology and the exclusion of other potential causes of long-QT syndrome, including no other drugs known to prolong the QT interval. Based on the Naranjo probability scale, the score for AA-induced TdP in this case was 5, indicating a probable causal relation between the reaction and AA.1 Poor adherence to prednisone treatment explains the severity of the hypokalemia and might be the direct link between AA and TdP. In phase 3 clinical trials, AA was not associated with cardiac arrhythmia or a prolongation of QT interval. 2,3 Contrary to most drugs prolonging the QT ...

Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation

“…In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11,12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.…”

“…In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5,8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11,12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13,14].…”

Abiraterone-induced refractory hypokalaemia and torsades de pointes in a patient with metastatic castration-resistant prostate carcinoma: a case report

“…Rodieux et al . 10 reported a patient with mCRPC on abiraterone and prednisone and no prior cardiac history who presented as a cardiac arrest and was found to have TdP, hypokalemia and prolonged QTc. In 2010, a science advisory from the American Heart Association, American Cancer Society, and American Urological Association concluded that Androgen deprivation therapy (ADT) is associated with increased cardiovascular events.…”

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

“…Nevertheless, the evidence of an association between ADT and TdP/SCD is currently limited to single case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases (Salem et al, 2019b). In fact, to date only three published cases of TdP occurring in prostatic cancer patients under ADT can be found in PubMed-Medline, two with abiraterone and one with the combined treatment leuprolide/bicaluatimde (Rodieux et al, 2015;Khan and Kneale, 2016;Hasegawa et al, 2019). In an effort to fill this knowledge gap, we here analyzed a large prospective cohort of consecutive, unselected patients with marked QTc prolongation complicated with TdP, and demonstrated that ongoing ADT was an unexpectedly common finding.…”