Non-cardiovascular drugs that inhibit hERG-encoded potassium channels and risk of sudden cardiac death

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.

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