Torsade de Pointes Publications (4160)


Torsade de Pointes Publications

The purpose of this investigation was to identify and characterize post-marketing reports of cardiotoxicity, including torsades de pointes (TdP), associated with loperamide use.
We searched the U.S. Read More

Food and Drug Administration Adverse Event Reporting System (FAERS) database for post-marketing reports of serious cardiac adverse events associated with loperamide use from December 28, 1976 (U.S. drug approval date), through December 14, 2015. We also conducted a Pubmed and Google Scholar search to identify additional published reports of cardiotoxicity associated with loperamide in the medical literature through February 11, 2016.
Forty-eight cases of serious cardiac adverse events associated with loperamide use composed the case series. The most frequently reported cardiac adverse events were syncope (n = 24), cardiac arrest (n = 13), QT-interval prolongation (n = 13), ventricular tachycardia (n = 10), and TdP (n = 7). There were 10 cases that resulted in death. Of the 48 cases, the most commonly reported reasons for use can be characterized as drug abuse (n = 22) and diarrhea treatment (n = 17). More than one-half of the 48 cases were reported after 2010. Of the 22 drug abuse cases, the median daily dose was 250 mg (range 70 mg to 1600 mg) and events occurred as early as 6 hours after a dose and as long as 18 months after initiation of loperamide. Thirteen of the 22 cases reported using loperamide for euphoric or analgesic effects, and 9 reported use to prevent opioid withdrawal symptoms.
The FAERS case reports provide evidence to suggest that high doses of loperamide are associated with TdP and other serious cardiac adverse events. The majority of cases in this series occurred in the setting of drug abuse for the purpose of preventing opioid withdrawal or to produce euphoric effects. It is important for both clinicians and patients to be aware of this potential risk, because prompt therapy and discontinuation of the offending agent are often essential to management and prevention of loperamide-induced cardiac arrhythmias.

QJM 2017 Jan 5. Epub 2017 Jan 5.
Department of Medicine and Cardiology, Maimonides Medical Center, Brooklyn, NY, USA
PLoS One 2016 30;11(12):e0163619. Epub 2016 Dec 30.
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Read More

Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.
In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).
Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.
NCT02308748 and NCT01873950.

PLoS One 2016 30;11(12):e0166925. Epub 2016 Dec 30.
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.

Prolongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-Tpeakc (J-Tpeakc) and Tpeak-Tend intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the "CiPA" initiative).
In this work, we describe an automated measurement methodology for assessment of the J-Tpeakc and Tpeak-Tend intervals using the vector magnitude lead. Read More

The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial.
Comparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas <1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead to the same conclusions about the electrophysiological mechanisms of the studied drugs.
We have developed an automated algorithm for assessment of J-Tpeakc and Tpeak-Tend intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. The algorithm is being released as open-source software.
NCT02308748 and NCT01873950.

JAAPA 2017 Jan;30(1):11-13
S. Scott Sutton is a professor in the Department of Clinical Pharmacy and Outcomes Sciences in the South Carolina College of Pharmacy at the University of South Carolina in Columbia, S.C. The author has disclosed no potential conflicts of interest, financial or otherwise.

The FDA has updated azithromycin package labeling to include the risk of prolonged cardiac repolarization and QT prolongation, which increase the possibility of cardiac dysrhythmias and torsades de pointes, especially in older adults. The update was initiated by a study that found an increased risk of death in patients taking azithromycin compared with those taking amoxicillin. However, cardiovascular results of other azithromycin studies have demonstrated discordant results, and more research is needed. Read More

In the meantime, providers should recognize that azithromycin has a role in the management of bacterial infections and should prescribe the antibiotic when warranted.

Oxf Med Case Reports
Oxf Med Case Reports 2016 Dec 1;2016(12):omw086. Epub 2016 Dec 1.
Department of Cardiology, Centro Hospitalar do Porto.

We describe the case of a teenager with a structurally normal heart that presented with torsades de pointes and cardiac arrest. He had a history of epilepsy in childhood, mild cognitive impairment and cognitive visual dysfunction. The baseline electrocardiogram had prominent J waves and a marked early repolarization pattern in all the leads, with normal QT interval. Read More

We discuss the differential diagnosis for this interesting case, as well as the patient's management.

A systematic review was performed to categorize the hERG (human ether-a-go-go-related gene) liability of antihistamines, antipsychotics, and anti-infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half-minimal inhibitory concentrations (IC50). A "hERG safety margin" was calculated from the IC50 divided by the peak human plasma concentration (free Cmax ). Read More

A margin below 30 defined hERG liability. Each drug was assigned an "uncertainty score" based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk ( Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty-one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti-infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/Cmax data, or other patient/drug-specific factors that contribute to real-life TdP risk.

J Pediatr Pharmacol Ther
J Pediatr Pharmacol Ther 2016 Nov-Dec;21(6):476-485
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.

OBJECTIVES: The purpose of this study was to evaluate the difference between education via written materials alone and written materials enhanced with hands-on simulation. METHODS: A simulation case, educational module, and assessment regarding torsades de pointes (TdP) in an adolescent patient were designed. The written educational module was given to all study participants. Read More

A total of 92 third-year pharmacy students and 26 pharmacists participated in the study. RESULTS: When approximately half of the participants had been to simulation, an anonymous assessment was given. Responses from those who had been to simulation and those who had not, and whether they had read, skimmed or not read the educational material were compared. A non-paired Student t-test compared the percentage correct and responses of individual questions between groups. Mean participant scores of those who went to simulation (70% ± 16%) were statistically significantly higher than mean scores of those who had not attended simulation (54% ± 21%; p<0.0001). Furthermore, those who attended simulation and read the module (72% ± 3%), skimmed (68% ± 13%), or did not read the module (66% ± 16%) had higher scores than those who did not attend simulation and read the module (62% ± 26%), skimmed the module (54 ± 17%) or did not read the module (51% ± 20%). CONCLUSIONS: Hands-on simulation significantly improved assessment scores. Overall, reading the educational module and participating in simulation yielded the best scores. Participants who attended the simulation and did not read the module had higher average scores than participants who read the educational module and did not go to simulation.

Pacing Clin Electrophysiol
Pacing Clin Electrophysiol 2016 Dec 24. Epub 2016 Dec 24.
Department of Thoracic and Cardiovascular Surgery, Kyungpook National University Hospital, Daegu, Republic of Korea.

Left cardiac sympathetic denervation (LCSD) has been underutilized in patients with hereditary ventricular arrhythmia syndromes such as congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The purpose of this study was to investigate the safety and efficacy of video-assisted thoracoscopic (VATS) LCSD in such patients.
Fifteen patients (4 men, 24. Read More

6 ± 10.5 years old) who underwent VATS-LCSD between November 2010 and January 2015 for hereditary ventricular arrhythmia syndromes at Kyungpook National University Hospital were enrolled in this study. The safety and efficacy of VATS-LCSD were evaluated by periprocedural epinephrine tests and assessing the development of complications and cardiac events during follow-up.
Fourteen patients with LQTS and one patient with CPVT underwent VATS-LCSD. Six and one patients developed ventricular tachyarrhythmia during pre-procedural and post-procedural epinephrine test, respectively (p = 0.063). No serious complications such as Horner syndrome, pneumothorax, or bleeding developed after LCSD. Mean hospital stay after VATS-LCSD was 3.7 ± 1.5 days. During a mean follow-up of 927 ± 350 days, one LQTS patient and one CPVT patient, neither of whom manifested tachyarrhythmia during post-LCSD epinephrine test, developed torsades de pointes and syncope, respectively. The annual event rates of 6 patients who were symptomatic during the period preceding LCSD decreased from 0.97 to 0.19 events/year (p = 0.045).
VATS-LCSD was a safe, and probably effective procedure for patients with hereditary ventricular tachycardia syndrome, with no serious adverse events and with short hospital stay. This article is protected by copyright. All rights reserved.

Int J Clin Pharm
Int J Clin Pharm 2016 Dec 23. Epub 2016 Dec 23.
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, O&N2, Box 521, 3000, Leuven, Belgium.

Background QTc-interval prolongation has been associated with serious adverse events, such as Torsade de Pointes and sudden cardiac death. In the prevention of QTc-prolongation, special attention should go to high-risk patients. Aim of the review The aim of this review is to summarize and assess the evidence for different risk factors for QTc-prolongation (demographic factors, comorbidities, electrolytes, QTc-prolonging medication). Read More

Methods Potential studies were retrieved based on a systematic search of articles published until June 2015 in the databases Medline and Embase. Both terms about QTc-prolongation/Torsade de Pointes and risk factors were added in the search strategy. The following inclusion criteria were applied: randomized controlled trials and observational studies; inclusion of ≥500 patients from a general population (not limited to specific disease states); assessment of association between QTc-interval and risk factors. For the articles that met the inclusion criteria, the following data were extracted: study design, setting and study population, number of patients and cases of QTc-prolongation, method of electrocardiogram-monitoring, QTc-correction formula, definition of QTc-prolongation, statistical methods and results. Quality assessment was performed using the GRADE approach (for randomized controlled trials) and the STROBE-recommendations (for observational studies). Based on the number of significant results and the level of significance, a quotation of the evidence was allocated. Results Ten observational studies could be included, with a total of 89,532 patients [prospective cohort design: N = 6; multiple regression analyses: N = 5; median STROBE score = 17/22 (range 15-18)]. Very strong evidence was found for hypokalemia, use of diuretics, antiarrhythmic drugs and QTc-prolonging drugs of list 1 of CredibleMeds. Little or no evidence was found for hyperlipidemia, the use of digoxin or statins, neurological disorders, diabetes, renal failure, depression, alcohol abuse, heart rate, pulmonary disorders, hormone replacement therapy, hypomagnesemia, history of a prolonged QTc-interval/Torsade de Pointes, familial history of cardiovascular disease, and the use of only QTc-prolonging drugs of list 2 or 3 of CredibleMeds. Conclusion This systematic review gives a clear overview of the available evidence for a broad range of risk factors for QTc-prolongation.