Drug-induced proarrhythmia: Discussion and considerations for clinical practice.

Clinical practice includes contributions from physicians, pharmacists, NPs, and physician assistants. Drug safety considerations are of considerable importance. This article discusses drug-induced proarrhythmia, with a specific focus on torsades de pointes, a polymorphic ventricular tachycardia that typically occurs in self-limiting bursts that can lead to dizziness, palpitations, syncope, and seizures, but on rare occasions can progress to ventricular fibrillation and sudden cardiac death. A dedicated clinical pharmacology study conducted during a drug's clinical development program has assessed its propensity to induce torsades using prolongation of the QT interval as seen on the ECG as a biomarker.Identification of QT-interval prolongation does not necessarily prevent a drug from receiving marketing approval if its overall benefit-risk balance is favorable, but, if approved, a warning is placed in its prescribing information. This article explains why drugs can have a proarrhythmic propensity.

How to Prescribe Drugs With an Identified Proarrhythmic Liability.

This is an article in the Journal of Clinical Pharmacology's Core Entrustable Professional Activities in Clinical Pharmacology series that discusses drug-induced proarrhythmia and is offered as a teaching aid for medical students and residents. Drugs from diverse pharmacological classes can lead to multiple types of arrhythmias including the polymorphic ventricular tachycardia torsades de pointes (TdP). Although typically occurring in self-limiting bursts with or without associated symptoms, which can range from mild lightheadedness and palpitations to syncope and seizures, TdP can also occasionally progress to ventricular fibrillation and sudden cardiac death. To provide patients with the optimal therapeutic benefits of potentially proarrhythmic drugs, prescribers are responsible for obtaining a good understanding of the compound's benefit-risk properties and perform a judicious assessment of the patient's clinical characteristics and individual risk factors. Dose adjustments and/or additional monitoring of electrocardiograms and electrolyte balances may be appropriate in some cases. This article explains the pharmacological mechanism of action of drug-induced proarrhythmia associated with compounds that prolong the repolarization period, illustrates how this liability is conveyed in a drug's prescribing information (label), details the clinical characteristics of patients most susceptible to this type of proarrhythmia, and describes interventions that can be made if TdP occurs. Three clinical vignettes are provided at the end of the article to highlight the relevance of the preceding discussions.

Identification of Risk of QT Prolongation by Pharmacists When Conducting Medication Reviews in Residential Aged Care Settings: A Missed Opportunity?

QT interval prolongation is associated with torsade de pointes and sudden cardiac death. QT prolongation can be caused by many drugs that are commonly prescribed in elderly residential aged care populations. The aim of this study was to investigate the prevalence of use of QT-prolonging drugs and to identify interventions made by pharmacists to reduce the risk of QT prolongation when conducting medication reviews in aged care. A retrospective analysis of 400 medication reviews undertaken by Australian pharmacists in aged care settings was conducted. The assessment included the risk of QT prolongation due to prescribed medications and other risk factors and the recommendations made by pharmacists to reduce the risk of QT prolongation. There was a high prevalence of the use of QT-prolonging medication, with 23% of residents (92 out of 400) taking at least one medication with a known risk of QT prolongation. Amongst the 945 prescribed drugs with any risk of QT prolongation, antipsychotics were the most common (n = 246, 26%), followed by antidepressants (19%) and proton pump inhibitors (13%). There appeared to be low awareness amongst the pharmacists regarding the risk of QT prolongation with drugs. Out of 400 reviews, 66 residents were categorised as high risk and were taking at least one medication associated with QT prolongation; yet pharmacists intervened in only six instances (9%), mostly when two QT-prolonging medications were prescribed. There is a need to increase awareness amongst pharmacists conducting medication reviews regarding the risk factors associated with QT prolongation, and further education is generally needed in this area.

Restricted mean survival time for the analysis of cardiovascular outcome trials assessing non-inferiority: Case studies from antihyperglycemic drug development.

Cardiovascular outcome trials (CVOTs) have been employed in multiple therapeutic areas to explore whether a noncardiovascular drug increases the risk for cardiovascular events. These studies are now a central part of drug development programs for antihyperglycemic drugs. These programs are expected to demonstrate that new antihyperglycemic drugs for patients with Type 2 diabetes do not have unacceptable cardiovascular risk. The hazard ratio, which is usually provided as evidence that patients receiving the investigational treatment are not at statistically significantly greater cardiovascular risk than patients on the control treatment, can be difficult to interpret for various reasons. Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Additionally, detailed considerations are given on how to design a non-inferiority CVOT using the RMST approach. The RMST methodology is shown to be a practical alternative to the hazard ratio methodology for designing a non-inferiority CVOT.

Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting.

A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell-derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.

Individual-Specific QT Interval Correction for Drugs With Substantial Heart Rate Effect Using Holter ECGs Extracted Over a Wide Range of Heart Rates.

Although fixed QT correction methods are typically used to adjust for the effect of heart rate on the QT interval in thorough QT/QTc studies, individual-specific QT correction (QTcI = QT/RRI ) is advisable for drugs that increase the heart rate by >5 to 10 beats/minute (bpm). QTcI is traditionally derived using resting drug-free electrocardiograms (ECGs) collected at prespecified times. However, the resting heart rate range in healthy individuals is narrow, and extrapolation of inferences from these data to higher heart rates could be inappropriate. Accordingly, the QTcI derived from triplicate ECGs extracted at prespecified times (the traditional [T] method, yielding QTcIT) was compared with QTcIs obtained using ECGs with a wider heart rate range (alternative Holter [H] method, yielding QTcIH) from 24-hour Holter recordings from 40 healthy individuals selected from a central ECG laboratory database. For QTcIH, 10-second ECGs were extracted at stable heart rates in the ranges of 51-60, 61-70, 71-80, and 81-90 bpm (9 ECGs in each bin = 36 ECGs). An independent set of 40 ECGs with heart rates from 51 to 90 bpm was extracted from each individual to validate the accuracy of QTcI by the 2 methods. For the validation set, the QTcIH was a better QT correction method (slope of QTc vs heart rate closer to zero) than QTcIT. The mean difference between QTcIT and QTcIH increased from 3.1 milliseconds at 65 bpm to 10.0 milliseconds at 90 bpm (P < 0.01). The QTcIT exceeded QTcIH at heart rates > 60 bpm. Employment of the QTcIH may be more appropriate for studies involving drugs that increase heart rate.

Drug-induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy.

Multiple marketing withdrawals due to proarrhythmic concerns occurred in the United States, Canada, and the United Kingdom in the late 1980s to early 2000s. This primer reviews the clinical implications of a drug's identified proarrhythmic liability, the issues associated with these safety-related withdrawals, and the actions taken by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and by regulatory agencies in terms of changing drug development practices and introducing new nonclinical and clinical tests to asses proarrhythmic liability. ICH Guidelines S7B and E14 were released in 2005. Since then, they have been adopted by many regional regulatory authorities and have guided nonclinical and clinical proarrhythmic cardiac safety assessments during drug development. While this regulatory paradigm has been successful in preventing drugs with unanticipated potential for inducing the rare but potentially fatal polymorphic ventricular arrhythmia torsade de pointes from entering the market, it has led to the termination of drug development programs for other potentially useful medicines because of isolated results from studies with limited predictive value. Research efforts are now exploring alternative approaches to better predict potential proarrhythmic liabilities. For example, in the domain of human electrocardiographic assessments, concentration-response modeling conducted during phase 1 clinical development has recently become an accepted alternate primary methodology to the ICH E14 "thorough QT/QTc" study for defining a drug's corrected QT interval prolongation liability under certain conditions. When a drug's therapeutic benefit is considered important at a public health level but there is also an identified proarrhythmic liability that may result from administration of the single drug in certain individuals and/or drug-drug interactions, marketing approval will be accompanied by appropriate directions in the drug's prescribing information. Health-care professionals in the fields of medicine and pharmacy need to consider the prescribing information in conjunction with individual patients' clinical characteristics and concomitant medications when prescribing and dispensing such drugs.

Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.