Various drugs increase the risk of out-of-hospital cardiac arrest (OHCA) in the general population by impacting cardiac ion channels, thereby causing ventricular tachycardia/fibrillation (VT/VF). Dihydropyridines block L-type calcium channels, but their association with OHCA risk is unknown. We aimed to study whether nifedipine and/or amlodipine, often-used dihydropyridines, are associated with increased OHCA risk, and how these drugs impact on cardiac electrophysiology. We conducted a case–control study with VT/VF-documented OHCA cases with presumed cardiac cause from ongoing population-based OHCA registries in the Netherlands and Denmark, and age/sex/index date-matched non-OHCA controls (Netherlands: PHARMO Database Network, Denmark: Danish Civil Registration System). We included 2503 OHCA cases, 10 543 non-OHCA controls in Netherlands, and 8101 OHCA cases, 40 505 non-OHCA controls in Denmark. To examine drug effects on cardiac electrophysiology, we performed single-cell patch-clamp studies in human-induced pluripotent stem cell-derived cardiomyocytes. Use of high-dose nifedipine (≥60 mg/day), but not low-dose nifedipine (<60 mg/day) or amlodipine (any-dose), was associated with higher OHCA risk than non-use of dihydropyridines [Netherlands: adjusted odds ratios (OR_adj) 1.45 (95% confidence interval 1.02–2.07), Denmark: 1.96 (1.18–3.25)] or use of amlodipine [Netherlands: 2.31 (1.54–3.47), Denmark: 2.20 (1.32–3.67)]. Out-of-hospital cardiac arrest risk of (high-dose) nifedipine use was not further increased in patients using nitrates, or with a history of ischaemic heart disease. Nifedipine and amlodipine blocked L-type calcium channels at similar concentrations, but, at clinically used concentrations, nifedipine caused more L-type calcium current block, resulting in more action potential shortening. High-dose nifedipine, but not low-dose nifedipine or any-dose amlodipine, is associated with increased OHCA risk in the general population. Careful titration of nifedipine dose should be considered.

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic agents that can have direct cardiac effects by impacting on cardiac ion transport mechanisms that control cardiac electrophysiology. We studied the association between SGLT-2i use and all-cause mortality and the risk of sudden cardiac arrest (SCA) in patients with type 2 diabetes. Methods: Using data from the UK Clinical Practice Research Datalink, a cohort study among patients initiating a new antidiabetic drug class on or after January 2013 through September 2020 was conducted. A Cox regression with time-dependent covariates was performed to estimate the hazard ratios (HRs) of SCA and all-cause mortality comparing SGLT-2is with other second- to third-line antidiabetic drugs. Stratified analyses were performed according to sex, diabetes duration (<5 or ≥5 years), and the presence of cardiovascular disease. Results: A total of 152 591 patients were included. Use of SGLT-2i was associated with a reduced HR of SCA when compared with other second- to third-line antidiabetic drugs after adjustment for common SCA risk factors, although this association marginally failed to reach statistical significance [HR: 0.62, 95% confidence interval (95% CI): 0.38–1.01]. The HR of all-cause mortality associated with SGLT-2i use when compared with other second- to third-line antidiabetics was 0.43 (95% CI: 0.39–0.48) and did not vary by sex, diabetes duration, or the presence of cardiovascular disease. SGLT-2i use remained associated with lower all-cause mortality in patients without concomitant insulin use (HR: 0.56, 95% CI: 0.50–0.63). Conclusion: SGLT-2i use was associated with reduced all-cause mortality in patients with type 2 diabetes. The association between use of SGLT-2i and reduced risk of SCA was not statistically significant.

Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA.Methods: We conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately.Results: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27–1.69], HR:1.43 [95% CI:1.16–1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high‐dose mirtazapine (>30; HR:1.59 [95% CI:1.18–2.14]) among the serotonin–norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05–1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors.Conclusion: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues.

Aims: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes. Methods: Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference). Results: The study population consisted of 3618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58–0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (P-value interaction: 0.461), pre-existing cardiac disease (P-value interaction: 0.762), heart failure (P-value interaction: 0.891), diabetes duration (P-value interaction: 0.101), and chronic kidney disease (P-value interaction: 0.894). Conclusion: Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.

Aims: A few studies suggested that epilepsy and antiepileptic drugs with sodium channel‐blocking properties were independently associated with out‐of‐hospital cardiac arrest (OHCA). However, these findings have not yet been replicated.Methods: Using Danish registries, we conducted a nested case–control study in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were defined as OHCA from presumed cardiac causes, and were matched with non‐OHCA‐controls based on sex, and age on the date of OHCA. Exposure of interest was epilepsy or antiepileptic drug use. To study the association between individual antiepileptic drug use and the rate of OHCA, we compared each antiepileptic drug with valproic acid. Cox regression with time‐dependent covariates was conducted to calculate hazard ratio (HR) and 95% confidence interval (CI).Results: We identified 35 195 OHCA‐cases and 351 950 matched non‐OHCA controls. Epilepsy (cases: 3.58%, controls: 1.60%) was associated with increased rate of OHCA compared with the general population (HR: 1.76, 95%CI: 1.64–1.88) when common OHCA risk factors were taken into account. When we studied antiepileptic drug use, we found that 2 antiepileptic drugs without sodium channel blockage, clonazepam (HR: 1.88, 95%CI: 1.45–2.44) and pregabalin (HR: 1.33, 95%CI: 1.05–1.69), were associated with OHCA, whereas none of the antiepileptic drugs with sodium channel blockage were associated with OHCA.Conclusion: Epilepsy is associated with increased rate of OHCA. Our findings do not support a possible association between antiepileptic drugs with sodium channel‐blocking properties and OHCA.

Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac electrophysiology by inhibiting cardiac potassium currents, leading to delay of cardiac repolarisation and QT-prolongation. This may result in lethal arrhythmias. We studied whether RA increases the rate of out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case–control in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were OHCA patients from presumed cardiac causes, and were matched with non-OHCA-controls based on age, sex and OHCA date. Cox-regression with time-dependent covariates was conducted to assess the association between RA and OHCA by calculating the HR and 95% CI. Stratified analyses were performed according to sex and presence of cardiovascular diseases. Also, the association between OHCA and use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with RA was studied. Results We included 35 195 OHCA cases of whom 512 (1.45%) had RA, and 351 950 non-OHCA controls of whom 3867 (1.10%) had RA. We found that RA was associated with increased rate of OHCA after adjustment for cardiovascular comorbidities and use of QT-prolonging drugs (HR: 1.22, 95% CI: 1.11 to 1.34). Stratification by sex revealed that increased OHCA rate occurred in women (HR: 1.32, 95% CI: 1.16 to 1.50) but not in men (HR: 1.12, 95% CI: 0.97 to 1.28; P value interaction=0.046). OHCA rate of RA was not further increased in patients with cardiovascular disease. Finally, in patients with RA, use of NSAIDs was not associated with OHCA. Conclusion In the general population, RA is associated with increased rate of OHCA in women but not in men.