Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death

Pharmaco-Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
European Heart Journal (Impact Factor: 14.72). 11/2005; 26(19):2007-12. DOI: 10.1093/eurheartj/ehi312
Source: PubMed

ABSTRACT To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death.
A population-based case-control study was performed in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500,000 persons. All deaths between 1 January 1995 and 1 September 2003 were reviewed. Sudden cardiac death was classified based on the time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, gender, date of sudden death, and general practice. The exposure of interest was the use of non-cardiac QTc-prolonging drugs. Exposure at the index date was categorized into three mutually exclusive groups of current use, past use, and non-use. The study population comprised 775 cases of sudden cardiac death and 6297 matched controls. Current use of any non-cardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted OR: 2.7; 95% CI: 1.6-4.7). The risk of death was highest in women and in recent starters.
The use of non-cardiac QTc-prolonging drugs in a general population is associated with an increased risk of sudden cardiac death.

    • "Additionally, in the case of successful development , a precaution-free regulatory approval would have been virtually impossible to obtain, even in the absence of clinical evidence of proarrhythmic danger (e.g., ranolazine). Available human data demonstrate that only compounds producing a marked blockade of the cardiac hERG channel accompanied by excessive prolongation of ventricular repolarization (QTc interval prolongation N 500 ms) portend a potentially lethal TdP risk in people generally carrying additional cardiac risks (Straus et al., 2005). Small to moderate QTc prolongations are unlikely to elicit TdP events, particularly when produced by drugs (e.g.; fluoxetine , ranolazine and verapamil) which concurrently block cardiac depolarization currents (I NaL and I Ca ), that have the ability to constrain hERG blockade-mediated QTc prolongation to non-dangerous levels (Antzelevitch et al., 2014; Moreno and Clancy, 2012). "
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    ABSTRACT: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is being evaluated as nonclinical, mechanism-based in vitro and in silico paradigm for assessing the proarrhythmic liability of candidate drugs. The first of the three core assays of CiPA determines candidate drug effects on cloned human ventricular ion channels. The second investigates whether metrics from the latter study engenders proarrhythmic markers on the computationally reconstructed human ventricular action potential. The third assay evaluates conclusions from, and searches possibly missed effects, by in silico analysis in the human stem cell-derived cardiomyocytes (hSC-CMs). Since launching the CiPA project, Expert Working Groups have endeavored to define means and prepare ad hoc protocols for a fit-to-purpose evaluation of each CiPA component. Henceforth, the Clinical Translational Working Group selected (and allocated into low, intermediate, and high-proarrhythmic risk groups) twenty-nine established drugs for testing and validating CiPA. The Ion Channel Working Group prepared detailed patch clamp protocols to evaluate candidate drug effects on seven cardiac ion channels of potential interest for the first tier CiPA assay. The In Silico Working-Group selected and modified the O'Hara-Rudy model for computationally reconstructing the human ventricular action potential contour. Ongoing pilot assays test various ion channel metrics to identify the ones best predicting, and ranking, in relation to a reference panel of established drugs, the proarrhythmic risk of a candidate drug. The Myocyte Working Group has prepared, and runs studies using protocols for assessing which electrophysiological parameters obtained from field (MEA technology) and action (VSD technology) potential measurements in spontaneously beating hSC-CMs best uncover candidate drug proarrhythmic liability. Ongoing testing and the following-up qualification processes of CiPA as a drug development tool for identifying electrophysiological mechanisms that may confer ventricular proarrhythmic risk to clinical candidates is a complex and multi-functional task that will require significant efforts and time to be entirely achieved. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of pharmacological and toxicological methods 07/2015; 76. DOI:10.1016/j.vascn.2015.06.004 · 2.15 Impact Factor
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    • "Two case-control studies from the Netherlands [46] [47] examined the relation of SCD or in-hospital cardiac arrest to exposure to noncardiac QTc-prolonging medications. One study found an almost four-fold increased risk of out-of-hospital SCD among current users of domperidone [46]. "
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    ABSTRACT: Domperidone, a dopamine antagonist that does not easily cross the blood-brain barrier, is considered the gold standard for treating gastrointestinal symptoms in patients with Parkinson´s disease (PD) because the risk of developing extrapyramidal adverse effects is considered minimal. On the other hand, cardiotoxicity related to domperidone is not a new issue. In fact, arrhythmias, sudden death and cardiac arrest were reported with high intravenous doses in the 80s. Concern about the cardiotoxicity of oral domperidone has arisen more recently after the publication of two case-control studies which have questioned domperidone´s safety even further, especially in patients > 60 years and in doses >30 mg/day. Very little is known about domperidone´s cardiac effects in patients with PD. In addtion, pharmacoepidemiological data about specific antiemetic use in these patients is scarce, with almost anecdotal reports of inappropriate centrally acting antidopaminergic drugs like metoclopramide in the hospital setting. As a result, and even no cases of serious arrhythmias or sudden cardiac death ssociated with domperidone concerning patients with PD have been reported, no definitive conclusions can be drawn about its safety. In conclusion, despite domperidone is still recognized as the first choice for treating gastrointestinal symptoms PD, doses above 30 mg/daily should only be considered with special caution taking into account its potential cardiotoxic effects.
    05/2013; DOI:10.2174/1574886311308010009
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    • "E14, 2005). Drugs that prolong or shorten the QT interval in the ECG are considered to have pro-arrhythmic consequences (Straus et al., 2005; Kowey and Malik, 2007; Lu et al., 2008; Pugsley et al., 2008), and their development is generally discontinued. "
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    ABSTRACT: Background and Purpose Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential. Experimental Approach We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC50 value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions. Key Results Introducing a 50% hERG-channel current block results in 8% prolongation of the APD90 and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD90 is not affected. Conclusions and Implications Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.
    British Journal of Pharmacology 09/2012; 168(3). DOI:10.1111/j.1476-5381.2012.02200.x · 4.99 Impact Factor
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