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European Heart Journal Advance Access first published online on January 6, 2005
This version published online on January 11, 2005
European Heart Journal, doi:10.1093/eurheartj/ehi092
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European Heart Journal © The European Society of Cardiology 2005; all rights reserved

Clinical research

Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

M. L. De Bruin 1*, M. Pettersson 2, R. H.B. Meyboom 3, A. W. Hoes 4, and H. G.M. Leufkens 5

1 Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands
2 The Uppsala Monitoring Centre, Uppsala, Sweden
3 Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, The Netherlands; The Uppsala Monitoring Centre, Uppsala, Sweden
4 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands
5 Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, PO Box 80082, 3508 TB Utrecht, The Netherlands

* To whom correspondence should be addressed.
M. L. De Bruin, E-mail: m.l.debruin{at}pharm.uu.nl


  Abstract

Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice.

Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database.

Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.

Keywords: Adverse drug reaction reporting systems; Arrhythmia; Potassium channels; Pre-clinical drug evaluation; Sudden death; Torsades de pointes.
The originally published version of this paper was incorrect. In the equation within the Methods section, 'IC50' and 'ETCPunbound' were transposed throughout the equation. The author apologizes that this error was not identified earlier.
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