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: 15.2). 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.

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Available from: Sabine Straus, Mar 11, 2015
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    • "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: Introduction: The comprehensive in vitro proarrhythmia assay (CiPA) is a nonclinical, mechanism-based paradigm for assessing drug proarrhythmic liability. Topics covered: The first CiPA assay determines effects on cloned human cardiac ion channels. The second investigates whether the latter study-generated metrics engender proarrhythmic markers on a computationally reconstructed human ventricular action potential. The third evaluates conclusions from, and searches possibly missed effects by in silico analysis, in human stem cell-derived cardiomyocytes (hSC-CMs). CiPA ad hoc Expert-Working Groups have proposed patch clamp protocols for seven cardiac ion channels, a modified O'Hara-Rudy model for in silico analysis, detailed procedures for field (MEA) and action potential (VSD) measurements in hSC-CMs, and 29 reference drugs for CiPA assay testing and validation. Discussion: CiPA adoption as drug development tool for identifying electrophysiological mechanisms conferring proarrhythmic liability to candidate drugs is a complex, multi-functional task requiring significant time, reflection, and efforts to be fully achieved.
    Journal of pharmacological and toxicological methods 07/2015; 76. DOI:10.1016/j.vascn.2015.06.004 · 2.39 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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