What causes some patients with drug-induced QT interval prolongation to develop torsades de pointes but not others? The elusive missing link.

Cardiac arrest due to torsades de pointes (TdP) is an uncommon but potentially catastrophic event associated with QT interval-prolonging drugs [1]. Numerous medications that may cause TdP are available for use in clinical practice, and include drugs for management of cardiovascular diseases, primarily arrhythmias, but also noncardiovascular agents from multiple classes, including antiinfectives, antipsychotics, antidepressants, methadone, and many more [2]. The risk of TdP increases as the heart ratecorrected QT (QTc) interval increases [3–6], particularly when it exceeds 500 ms [5, 6]. Numerous independent risk factors for QTc interval prolongation and TdP have been identified, and include female sex, hypokalemia, hypomagnesemia, acute myocardial infarction, sepsis, supratherapeutic concentrations of QTc interval-prolonging drugs, rapid intravenous infusion of QTc interval-prolonging drugs, concomitant administration of two or more QTc interval-prolonging drugs, concomitant administration of a loop diuretic, bradycardia, heart failure with reduced ejection fraction (HFrEF), pretreatment QTc interval prolongation, and ion channel polymorphisms [7, 8]. Some evidence indicates that older age is also a risk factor for prolonged QTc interval [8–10] and TdP [11]. In the Third National Health and Nutrition Examination Survey (NHANES III), age was associated with prolonged QTc interval in men [8]. In a study of hospitalized patients, age [60 years was reported to be a risk factor for druginduced QT interval prolongation [9]. In another study of hospitalized patients, age C68 years was shown to be an independent risk factor for QTc interval prolongation in patients in cardiac care units [10]. Age C65 years is an independent risk factor for TdP associated with azimilide [11]. Mechanisms underlying an increased risk of druginduced QTc interval prolongation and TdP in older patients are unclear, but could include declining serum testosterone concentrations in older men [12, 13] and reduced serum progesterone concentrations in postmenopausal women [14]. QTc interval-prolonging medications are prescribed commonly to older patients [15]; therefore, awareness of the degree of risk and strategies for mitigating the risk of QTc interval prolongation and TdP in this population are desirable. Although it is known that the risk of TdP increases as the QTc interval increases, there is a missing link; only a small portion of patients that develop drug-induced QTc interval prolongation experience TdP. It is unknown why some patients with drug-induced QTc interval prolongation experience TdP and some do not, and whether there are risk factors that predispose patients with drug-induced QT interval prolongation to develop TdP. Information that could shed light on this mystery would advance the field and contribute important knowledge regarding mitigation of TdP risk. In this issue of Drugs and Aging [16], Goutelle and colleagues attempt to identify factors that predispose elderly patients with drug-associated long QTc interval to development of TdP. In this retrospective, case–control study, the investigators queried the national French pharmacovigilance database for cases of long QTc interval and This comment refers to the article available at doi:10.1007/s40266-014-0188-y.