Background Virtually all QTc-prolonging drugs act by blocking the human ether a go-go-related gene (hERG)-encoded potassium channels (hERG channels), whereas not all QTc-prolonging drugs are associated with an increased risk of serious cardiac arrhythmias. This study assessed whether non-cardiovascular hERG channel blockers are associated with an increased risk of sudden cardiac death (SCD) and whether hERG-channel-inhibiting capacity is an indicator of the risk of SCD.
Methods and results The risk of SCD was studied in the Integrated Primary Care Information database, a longitudinal general practice research database. A case-control study was performed, matched for age, gender and calendar time. Odds ratios were calculated with conditional logistic regression, multivariably adjusted. In addition, the hERG-channel-inhibiting capacity of the different drugs was compared, defined as the effective free therapeutic plasma concentration (ETCPunbound) divided by the concentration that inhibits 50% of the potassium channels (IC50), with the risk of SCD. 1424 cases of SCD and 14 443 controls were identified. Current use of hERG channel blockers was associated with an increased risk of SCD. The risk of SCD was significantly increased in users of antipsychotic drugs. Patients using hERG channel blockers with a high ETCPunbound/IC50 ratio (≥0.033) had a higher risk of SCD than patients using drugs with a low ETCPunbound/IC50 ratio (<0.033).
Conclusions The current use of hERG channel blockers was associated with an increased risk of SCD in the general population. In addition, drugs with a high hERG-channel-inhibiting capacity had a higher risk of SCD than drugs with a low hERG-channel-inhibiting capacity.
- hERG-encoded potassium channel-inhibiting capacity
- non-cardiovascular hERG-encoded potassium channel-inhibiting drugs
- sudden cardiac death
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Competing interests As an employee of Erasmus MC, MCJMS has been involved as project leader and in analyses contracted by various pharmaceutical companies and received unconditional research grants from Pfizer, Merck, Johnson & Johnson, Amgen, Roche, GSK, Boehringer, Yamanouchi and Altana, none of which are related to the subject of this study. MCJMS has been a consultant to Pfizer, Servier, Celgene, Novartis and Lundbeck on issues not related to this paper. CvN works with the Dutch national registration authorities; BHCS is also senior medical officer at the Dutch Inspectorate for Health Care. Both authors have no bonds with the pharmaceutical industry.
Ethics approval This study was conducted with the approval of the Scientific and Ethical Advisory Board of the Integrated Primary Care Information project.
Provenance and peer review Not commissioned; externally peer reviewed.