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Aims  Drugs that prolong the QT interval, either by design (cardiac QT‐prolonging drugs: anti‐arrhythmics) or as off‐target effect (non‐cardiac QT‐prolonging drugs), may increase the risk of ventricular arrhythmias and out‐of‐hospital cardiac arrest (OHCA). Risk mitigation measures were instituted, in particular, surrounding prescription of cardiac QT‐prolonging drugs. We studied OHCA risk of both drug types in current clinical practice.    Methods  Using data from large population‐based OHCA registries in the Netherlands and Denmark, we conducted two independent case–control studies. OHCA cases with presumed cardiac causes were matched on age/sex/index date with up to five non‐OHCA controls. We calculated odds ratios (ORs) for the association of cardiac or non‐cardiac QT‐prolonging drugs with OHCA risk using conditional logistic regression analyses.    Results  We identified 2503 OHCA cases and 10 543 non‐OHCA controls in the Netherlands, and 35 017 OHCA cases and 175 085 non‐OHCA controls in Denmark. Compared to no use of QT‐prolonging drugs, use of non‐cardiac QT‐prolonging drugs (Netherlands: cases: 3.0%, controls: 1.9%; Denmark: cases: 14.9%, controls: 7.5%) was associated with increased OHCA risk (Netherlands: OR 1.37 [95% CI: 1.03–1.81]; Denmark: OR 1.63 [95% CI: 1.57–1.70]). The association between cardiac QT‐prolonging drugs (Netherlands: cases: 4.0%, controls: 2.5%; Denmark: cases: 2.1%, controls: 0.9%) and OHCA was weaker (Netherlands: OR 1.17 [95% CI: 0.92–1.50]; Denmark: OR 1.21 [95% CI: 1.09–1.33]), although users of cardiac QT‐prolonging drugs had more medication use and comorbidities associated with OHCA risk than users of non‐cardiac QT‐prolonging drugs.    Conclusion  In clinical practice, cardiac QT‐prolonging drugs confer lower OHCA risk than non‐cardiac QT‐prolonging drugs, although users of the former have higher a priori risk. This is likely due to risk mitigation measures surrounding prescription of cardiac QT‐prolonging drugs.

Out‐of‐hospital cardiac arrest and differential risk of cardiac and non‐cardiac QT‐prolonging drugs in 37 000 cases