Prolongation of the heart rate-corrected QT (QTc) interval increases the risk for torsade de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors that include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of two or more QTc interval-prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP. Investigators have utilized the field of predictive analytics, which generates predictions using techniques including data mining, modeling, machine learning, and others, to develop methods of risk quantification and prediction of QTc interval prolongation. Predictive analytics have also been incorporated into clinical decision support (CDS) tools to alert clinicians regarding patients at increased risk of developing QTc interval prolongation. The objectives of this article are to assess the effectiveness of predictive analytics for identification of patients at risk of drug-induced QTc interval prolongation and to discuss the efficacy of incorporation of predictive analytics into CDS tools in clinical practice. A systematic review of English-language articles (human subjects only) was performed, yielding 57 articles, with an additional 4 articles identified from other sources; a total of 10 articles were included in this review. Risk scores for QTc interval prolongation have been developed in various patient populations including those in cardiac intensive care units (ICUs) and in broader populations of hospitalized or health system patients. One group developed a risk score that includes information regarding genetic polymorphisms; this score significantly predicted TdP. Development of QTc interval prolongation risk prediction models and incorporation of these models into CDS tools reduce the risk of QTc interval prolongation in cardiac ICUs and identify health system patients at increased risk for mortality. The impact of these QTc interval prolongation predictive analytics on overall patient safety outcomes, such as TdP and sudden cardiac death relative to the cost of development and implementation, requires further study.

While female sex is a risk factor for torsades de pointes, 1 29-44% of drug-induced cases occur in men. 2,3 Older age is also a risk factor. 1 Preclinical studies have shown that testosterone and progesterone protect against drug-induced prolongation of ventricular repolarization, early afterdepolarizations and arrhythmias. 4 Oral progesterone shortens QT intervals and attenuates drug-induced QT lengthening in young women. 5 We hypothesized that transdermal testosterone and oral progesterone attenuate drug-induced QT interval lengthening in older men. This prospective, randomized, double-blind, placebo-controlled three-way crossover-design study was approved by the Indiana University IRB and conducted from July 2015 -October 2017 (ClinicalTrial.gov Identifier: ). Exclusion criteria: history of prostate or breast cancer; benign prostatic hyperplasia; weight <60 or >135 kg; potassium <3.6 mEq/L; magnesium <1.8 mg/dL; hematocrit <26%; hepatic transaminases >3x ULN; baseline Bazett's-corrected QTc >450 ms; heart failure (LVEF <40%); family/personal history of long QT syndrome, arrhythmias or sudden cardiac death; permanently paced ventricular rhythm; taking QTprolonging drugs or strong CYP3A inhibitors. Subjects provided written informed consent.Men ≥ 65 years of age received, for 7 days, in randomized order: a) Transdermal testosterone 100mg (1% Androgel ® ) every morning and 2 placebo capsules every evening,

Study Objective Methadone is associated with QT interval prolongation and torsades de pointes. The objective of this study was to (a) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), (b) compare characteristics of patients who developed methadone‐associated QT prolongation with those who did not develop QT prolongation, and (c) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP)] concentrations. Design Prospective study. Setting Urban opioid treatment program (OTP). Patients n = 93 patients on maintenance methadone therapy in an urban OTP. Intervention Patients underwent a 12‐lead electrocardiogram (ECG) prior to initiating methadone and again during steady‐state maintenance methadone therapy. In a subset (n = 43), blood was obtained to determine serum (S)‐ and (R)‐methadone and (S)‐ and (R)‐EDDP concentrations, which were compared in patients who developed Bazett’s‐corrected QT (QTc) prolongation [≥470 ms (men) or ≥480 ms (women) and/or ≥60 ms lengthening from pretreatment value] with those who did not have QTc prolongation. Measurements and Main Results Mean [± standard deviation (SD)] age was 36 ± 12 years; 73% were female, and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41 ± 13 vs. 35 ± 9 years, p = 0.03) and had a longer pre‐methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs. 420 ± 20 ms, respectively, p = 0.02). Serum (S)‐methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199 ± 81 vs. 128 ± 68 ng/ml, respectively, p = 0.01), whereas the difference in serum (R)‐methadone concentrations between the groups did not reach significance (189 ± 68 vs. 125 ± 60 ng/ml, respectively, p = 0.08). Serum (R)‐methadone concentrations correlated with QTc intervals [R2 = 0.15 (95% confidence interval (CI) 0.11–0.62, p = 0.0009)]. The correlation between serum (S)‐methadone concentrations and QTc did not reach significance [R2 = 0.08 (95% CI −0.01 to 0.54, p = 0.06)]. Serum (S)‐and (R)‐EDDP concentrations were not significantly different between the groups and did not significantly correlate with QTc intervals. Conclusions Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)‐ and (R)‐methadone concentrations, but not (S)‐ or (R)‐EDDP, contribute to methadone‐associated QT prolongation.