Drug-Induced QTc Prolongation: What We Know and Where We Are Going

: Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorizes medications into three risk categories: “known,” “possible,” and “conditional risk” of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

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Effect of Replacing Vendor QTc Alerts with a Custom QTc Risk Alert in Inpatients

Applied Clinical Informatics ◽

10.1055/s-0041-1740483 ◽

2022 ◽

Vol 13 (01) ◽

pp. 019-029

Author(s):

Steven Stettner ◽

Sarah Adie ◽

Sarah Hanigan ◽

Michael Thomas ◽

Kristen Pogue ◽

...

Keyword(s):

Odds Ratio ◽

Clinical Decision ◽

Qtc Interval ◽

Intervention Period ◽

Qtc Prolongation ◽

Post Intervention ◽

Medication Knowledge ◽

Quasi Experimental ◽

Risk Scoring ◽

Scoring Tool

Abstract Objective The aim of the study is to implement a customized QTc interval clinical decision support (CDS) alert strategy in our electronic health record for hospitalized patients and aimed at providers with the following objectives: minimize QTc prolongation, minimize exposure to QTc prolonging medications, and decrease overall QTc-related alerts. A strategy that was based on the validated QTc risk scoring tool and replacing medication knowledge vendor alerts with custom QTc prolongation alerts was implemented. Methods This is a retrospective quasi-experimental study with a pre-intervention period (August 2019 to October 2019) and post-intervention period (December 2019 to February 2020). The custom alert was implemented in November 2019. Results In the pre-implementation group, 361 (19.3%) patients developed QTc prolongation, and in the post-implementation group, 357 (19.6%) patients developed QTc prolongation (OR: 1.02, 95% CI: 0.87–1.20, p = 0.81). The odds ratio of an action taken post-implementation compared with pre-implementation was 18.90 (95% CI: 14.03–25.47, p <0. 001). There was also a decrease in total orders for QTc prolonging medications from 7,921 (5.5%) to 7,566 (5.3%) with an odds ratio of 0.96 (95% CI: 0.93–0.99, p = 0.01). Conclusion We were able to decrease patient exposure to QTc prolonging medications while not increasing the rate of QTc prolongation as well as improving alert action rate. Additionally, there was a decrease in QTc prolonging medication orders which illustrates the benefit of using a validated risk score with a customized CDS approach compared with a traditional vendor-based strategy. Further research is needed to confirm if an approach implemented at our organization can reduce QTc prolongation rates.

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Reflex sympatho-vagal coactivation and concealed QTc prolongation: Lessons from hERG-blockers and long QT syndromes type 1 and type 2

10.22541/au.161383229.97822546/v1 ◽

2021 ◽

Author(s):

Pascal Champéroux ◽

Raafat Fares ◽

Sebastien Jude ◽

Vincent Maleysson ◽

Serge Richard ◽

...

Keyword(s):

Stroke Volume ◽

High Frequency ◽

Torsades De Pointes ◽

Pulse Contour ◽

Contour Method ◽

Qtc Prolongation ◽

Compensatory Mechanisms ◽

Drug Induced ◽

Vagal Reflex ◽

Pulse Contour Method

Background and Purposes: Several hERG blocking molecules known for their propensity in triggering Torsades de Pointes (TdP) were reported as increasing High Frequency QT oscillations (HFQT). This effect was found as reflecting a sympatho-vagal coactivation. The present work aims to characterise the mechanism(s) leading to this particular state of the autonomic nervous system. Experimental approach: Effects of 20 hERG blockers including 15 torsadogenic molecules were assessed by telemetry in beagle dogs. Electrocardiogram and stroke volume modelled from the pulse contour method were analysed at the first dose level causing either QTc prolongation and/or HFQT increase. Cardiac autonomic control was analysed using the High Frequency Autonomic Modulation (HFAM) model in dogs and in untreated genotyped LQT1 and LQT2 individuals, for comparison. Key results: The sympatho-vagal coactivation induced by torsadogenic molecules is elicited by reflex compensatory mechanisms in response to changes in stroke volume or cardiac output related to hemodynamic off-targets and/or QT prolongation. QTc prolongation was concealed or markedly blunted by the sympathetic component activation in a large proportion of tested torsadogenic drugs. Sympathetic reflex mechanisms in LQT patients similar to that found for dofetilide was also revealed in both patients exhibiting QTc prolongation and concealed QTc prolongation, irrespective to LQT type. Conclusions and implications: QTc prolongation and/or drug-induced hemodynamic side effects enhance beat to beat ventricular repolarisation variability via sympatho-vagal reflex compensatory mechanisms. Considering the sympathetic reflex component via analysis of HFQT oscillations dramatically improves prediction, sensitivity and specificity of drug induced Torsades de pointes risk assessment.

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QTc Prolongation and Torsades de Pointes

Cardiothoracic Critical Care ◽

10.1093/med/9780190082482.003.0013 ◽

2020 ◽

pp. 137-142

Author(s):

Ankur Srivastava ◽

James E. Littlejohn

Keyword(s):

Qt Interval ◽

Torsades De Pointes ◽

Hemodynamic Instability ◽

Polymorphic Ventricular Tachycardia ◽

Stable Patient ◽

Qtc Prolongation ◽

Preventative Measures ◽

Drug Classes ◽

Alternative Medications ◽

Primary Management

This chapter looks at QTc prolongation and torsades de pointes (Tdp). In cases of recurrent polymorphic ventricular tachycardia, Tdp should be an immediate consideration. Tdp appears like a “twisting of points” of the cardiac axis, which is most often due to acquired QTc prolongation. The QT interval is inversely related to heart rate; therefore, it is corrected (QTc) using formulas such as Bazett's, Fridericia, and Framingham. There are several congenital and acquired causes of QTc prolongation. The congenital long QT syndrome, Romano-Ward syndrome, and Jervell and Lange-Nielsen syndrome are commonly associated with QTc prolongation and Tdp. Drug classes such as anti-arrhythmics, antidepressants, antipsychotics, antibiotics, and antihistamines are the other common cause of acquired QTc prolongation. Primary management of QTc prolongation and Tdp consists of minimizing risk factors like alternative medications and correcting electrolyte abnormalities. In a hemodynamically stable patient with QTc prolongation, treatment should focus on discontinuing the possible offending medications and correcting electrolyte levels. Meanwhile, patients with Tdp and hemodynamic instability require emergent electrical cardioversion in conjunction with preventative measures.

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Faculty Opinions recommendation of Improved Prediction of Drug-Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726198630.793523964 ◽

2016 ◽

Author(s):

John Jeremy Rice

Keyword(s):

Machine Learning ◽

Learning Algorithms ◽

Torsades De Pointes ◽

Machine Learning Algorithms ◽

Drug Induced

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An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2021.104281 ◽

2021 ◽

Vol 131 ◽

pp. 104281

Author(s):

Alaa Alahmadi ◽

Alan Davies ◽

Jennifer Royle ◽

Leanna Goodwin ◽

Katharine Cresswell ◽

...

Keyword(s):

At Risk ◽

Heart Rate ◽

Torsades De Pointes ◽

Qt Prolongation ◽

Drug Induced ◽

T Wave ◽

Wave Morphology

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Developing a scoring tool to estimate the risk of deterioration for normotensive patients with acute pulmonary embolism on admission

Respiratory Research ◽

10.1186/s12931-020-01602-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yizhuo Gao ◽

Chao Ji ◽

Hongyu Zhao ◽

Jun Han ◽

Haitao Shen ◽

...

Keyword(s):

Pulmonary Embolism ◽

Acute Pulmonary Embolism ◽

Clinical Laboratory ◽

Systolic Pressure ◽

Adverse Outcomes ◽

Web Based ◽

Derivation Cohort ◽

Risk Scoring ◽

Scoring Tool ◽

Acute Pe

Abstract Background It is important to identify deterioration in normotensive patients with acute pulmonary embolism (PE). This study aimed to develop a tool for predicting deterioration among normotensive patients with acute PE on admission. Methods Clinical, laboratory, and computed tomography parameters were retrospectively collected for normotensive patients with acute PE who were treated at a Chinese center from January 2011 to May 2020 on admission into the hospital. The endpoint of the deterioration was any adverse outcome within 30 days. Eligible patients were randomized 2:1 to derivation and validation cohorts, and a nomogram was developed and validated by the aforementioned cohorts, respectively. The areas under the curves (AUCs) with 95% confidence intervals (CIs) were calculated. A risk-scoring tool for predicting deterioration was applied as a web-based calculator. Results The 845 eligible patients (420 men, 425 women) had an average age of 60.05 ± 15.43 years. Adverse outcomes were identified for 81 patients (9.6%). The nomogram for adverse outcomes included heart rate, systolic pressure, N-terminal-pro brain natriuretic peptide, and ventricle/atrial diameter ratios at 4-chamber view, which provided AUC values of 0.925 in the derivation cohort (95% CI 0.900–0.946, p < 0.001) and 0.900 in the validation cohort (95% CI 0.883–0.948, p < 0.001). A risk-scoring tool was published as a web-based calculator (https://gaoyzcmu.shinyapps.io/APE9AD/). Conclusions We developed a web-based scoring tool that may help predict deterioration in normotensive patients with acute PE.

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Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

Italian Journal of Medicine ◽

10.4081/itjm.2010.127 ◽

2013 ◽

pp. 127-136

Author(s):

Gianluca Airoldi

Keyword(s):

Heart Rate ◽

Qt Interval ◽

Physical Restraint ◽

Safety Data ◽

Surrogate Marker ◽

Diagnostic Procedures ◽

Torsades De Pointes ◽

Long Qt ◽

Drug Induced ◽

Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

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Drug-Induced Restless Legs Syndrome

Annals of Pharmacotherapy ◽

10.1177/1060028018760296 ◽

2018 ◽

Vol 52 (7) ◽

pp. 662-672 ◽

Cited By ~ 9

Author(s):

Edna Patatanian ◽

Melanie K. Claborn

Keyword(s):

Restless Legs Syndrome ◽

English Language ◽

Case Reports ◽

Data Extraction ◽

Case Series ◽

Predisposing Factors ◽

Drug Induced ◽

Restless Legs ◽

Drug Classes ◽

Study Selection

Objective: To review the literature on drug-induced restless legs syndrome (DI-RLS). Data Sources: The review included a search for English-language literature from 1966 to December 2017 in the MEDLINE, PubMed, and Ovid databases using the following search terms: restless legs syndrome (RLS), periodic limb movement, adverse effects, and drug-induced. In addition, background articles on the pathophysiology, etiology, and epidemiology of RLS were retrieved. Bibliographies of relevant articles were reviewed for additional citations. Study Selection and Data Extraction: All case reports, case series, and review articles of DI-RLS were identified and analyzed. There were only a small number of controlled clinical trials, and most data were from case reports and case series. Results: Several drugs and drug classes have been implicated in DI-RLS, with antidepressants, antipsychotics, and antiepileptics having the most evidence. In addition, RLS may be linked with a number of disorders or underlying predisposing factors as well. Conclusions: The prevalence of RLS is variable and ranges from 3% to 19% in the general population. There are many predisposing factors to RLS, but an emerging body of evidence suggests that there is an association between numerous drugs and RLS.

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