Proarrhythmic drugs, drug levels, and polypharmacy in victims of sudden arrhythmic death syndrome: An autopsy-based study from Denmark

Background Sudden arrhythmic death syndrome (SADS), characterized by an unknown or inconclusive cause of death at autopsy, together with a negative or non-lethal toxicology screening, is the most common cause of sudden cardiac death (SCD) in victims under the age of 35. The complete causality of SADS remains unclear, with drugs being a potential risk factor. Objective To describe the toxicological profiles of SADS victims, focusing on proarrhythmic drugs, drug levels, and polypharmacy. Methods All deaths in Denmark from 2000–2019 aged 1–35 years and 2007–2019 aged 36–49 years were examined through death certificates, national registries, and autopsy reports with toxicology screenings. We investigated all sudden unexpected death victims with an autopsy performed, and where cause of death was unknown or inconclusive, including negative or non-lethal drug findings (SADS). Results We identified 477 SADS victims; 313 (66%) had a positive toxicology screening (adjudicated non-lethal), with an average of 2.8 drugs/case. More than half of the SADS victims with a positive toxicology screening had QT-prolonging or brugadogenic drugs present. Polypharmacy was present in 66%, psychotropic polypharmacy in 37%, and QT-prolonging polypharmacy in 22%, with the most frequent overall and QT-prolonging drug combination being an antipsychotic and a psychoanaleptic drug. QT-prolonging drugs were more often present at suprapharmacological levels than non-QT-prolonging drugs. Conclusion A majority of the SADS population had a positive toxicology, with a notably large proportion having proarrhythmic drugs and polypharmacy. This highlights the need for future focus on drugs as a risk factor for SADS.