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


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.


CONCLUSIONS
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.
De Bruin
M L
ML
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), PO Box 80082, 3508 TB Utrecht, The Netherlands. m.l.debruin@pharm.uu.nl
Pettersson
M
M
Meyboom
R H B
RH
Hoes
A W
AW
Leufkens
H G M
HG
D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016208:Databases, Factual; D003645:Death, Sudden / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005783:Gender Identity; D006352:Heart Ventricles; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D012306:Risk; D014944:World Health Organization
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated