Risk of out-of-hospital cardiac arrest in patients with epilepsy and users of antiepileptic drugs

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

Risk of out-of-hospital cardiac arrest in patients with rheumatoid arthritis:a nationwide study

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

Use of sodium-glucose cotransporter-2 inhibitors and the risk for sudden cardiac arrest and for all-cause death in patients with type 2 diabetes mellitus

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

Opioid use is associated with increased out-of-hospital cardiac arrest risk among 40,000-cases across two countries

AIMS: Opioid use has substantially increased in the last decade and is associated with overdose mortality, but also with increased mortality from cardiovascular causes. This finding may partly reflect an association between opioids and out‐of‐hospital cardiac arrest (OHCA). Therefore, we aimed to investigate OHCA‐risk of opioids in the community. METHODS: We conducted 2 population‐based case–control studies separately in the Netherlands (2009–2018) and Denmark (2001–2015). Cases were individuals who experienced OHCA of presumed cardiac cause. Each case was matched with up to 5 non‐OHCA‐controls according to age, sex and OHCA‐date. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 5473 OHCA‐cases matched with 21 866 non‐OHCA‐controls in the Netherlands, and 35 017 OHCA‐cases matched with 175 085 non‐OHCA‐controls in Denmark. We found that use of opioids (the Netherlands: cases: 5.4%, controls: 1.8%; Denmark: cases: 11.9%, controls: 4.4%) was associated with increased OHCA‐risk in both regions (the Netherlands: OR 2.1 [95% CI 1.8–2.5]; Denmark: OR 1.8 [95% CI 1.5–2.1]). The association was observed in both sexes, and in individuals with cardiovascular disease (the Netherlands: OR 1.8 [95% CI 1.5–2.1]; Denmark: OR 1.6 [95% CI 1.5–1.7]) or without (the Netherlands: OR 3.4 [95% CI: 2.4–4.8], P (interaction) < .0001; Denmark: OR 2.3 [95% CI: 2.0–2.5], P (interaction) < .0001). CONCLUSION: Use of opioids is associated with increased OHCA‐risk in both sexes, independently of concomitant cardiovascular disease. These findings should be considered when evaluating the harms and benefits of treatment with opioids

Risk of out-of-hospital cardiac arrest in antidepressant drug users

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

Association of beta-blockers and first-registered heart rhythm in out-of-hospital cardiac arrest: real-world data from population-based cohorts across two European countries

AIMS: Conflicting results have been reported regarding the effect of beta-blockers on first-registered heart rhythm in out-of-hospital cardiac arrest (OHCA). We aimed to establish whether the use of beta-blockers influences first-registered rhythm in OHCA. METHODS AND RESULTS: We included patients with OHCA of presumed cardiac cause from two large independent OHCA-registries from Denmark and the Netherlands. Beta-blocker use was defined as exposure to either non-selective beta-blockers, β1-selective beta-blockers, or α-β-dual-receptor blockers within 90 days prior to OHCA. We calculated odds ratios (ORs) for the association of beta-blockers with first-registered heart rhythm using multivariable logistic regression. We identified 23 834 OHCA-patients in Denmark and 1584 in the Netherlands: 7022 (29.5%) and 519 (32.8%) were treated with beta-blockers, respectively. Use of non-selective beta-blockers, but not β1-selective blockers, was more often associated with non-shockable rhythm than no use of beta-blockers [Denmark: OR 1.93, 95% confidence interval (CI) 1.48-2.52; the Netherlands: OR 2.52, 95% CI 1.15-5.49]. Non-selective beta-blocker use was associated with higher proportion of pulseless electrical activity (PEA) than of shockable rhythm (OR 2.38, 95% CI 1.01-5.65); the association with asystole was of similar magnitude, although not statistically significant compared with shockable rhythm (OR 2.34, 95% CI 0.89-6.18; data on PEA and asystole were only available in the Netherlands). Use of α-β-dual-receptor blockers was significantly associated with non-shockable rhythm in Denmark (OR 1.21; 95% CI 1.03-1.42) and not significantly in the Netherlands (OR 1.37; 95% CI 0.61-3.07). CONCLUSION: Non-selective beta-blockers, but not β1-selective beta-blockers, are associated with non-shockable rhythm in OHCA

Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current

Aim: To assess the risk of sudden cardiac arrest (SCA) associated with the use of carbamazepine (CBZ) and establish the possible underlying cellular electrophysiological mechanisms. Methods: The SCA risk association with CBZ was studied in general population cohorts using a case–control design (n = 5,473 SCA cases, 21,866 non-SCA controls). Effects of 1–100 µM CBZ on action potentials (APs) and individual membrane currents were determined in isolated rabbit and human cardiomyocytes using the patch clamp technique. Results: CBZ use was associated with increased risk of SCA compared with no use (adjusted odds ratio 1.90 [95% confidence interval: 1.12–3.24]). CBZ reduced the AP upstroke velocity of rabbit and human cardiomyocytes, without prominent changes in other AP parameters. The reduction occurred at ≥30 µM and was frequency-dependent with a more pronounced reduction at high stimulus frequencies. The cardiac sodium current (INa) was reduced at ≥30 μM; this was accompanied by a hyperpolarizing shift in the voltage-dependency of inactivation. The recovery from inactivation was slower, which is consistent with the more pronounced AP upstroke velocity reduction at high stimulus frequencies. The main cardiac K+ and Ca2+ currents were unaffected, except reduction of L-type Ca2+ current by 100 µM CBZ. Conclusion: CBZ use is associated with an increased risk of SCA in the general population. At concentrations of 30 µM and above, CBZ reduces AP upstroke velocity and INa in cardiomyocytes. Since the concentration of 30 µM is well within the therapeutic range (20–40 µM), we conclude that CBZ increases the risk of SCA by a reduction of the cardiac INa

Risk of out-of-hospital cardiac arrest in patients with sarcoidosis: a Danish nationwide nested case–control study

Results We identified 35 195 OHCA cases and 351 950 matched controls without OHCA (median age 72 years and 66.8% male). Patients with sarcoidosis had higher rate of OHCA compared with the general population after adjustments for common OHCA risk factors (HR 1.51, 95% CI 1.19 to 1.92). This increased OHCA rate occurred in women (HR 2.11, 95% CI 1.42 to 3.12) but not in men (HR 1.27, 95% CI 0.93 to 1.72; p value interaction=0.033), and was larger in patients with than without heart failure (HRheart failure: 2.59, 95% CI 1.42 to 4.73; HRno heart failure: 1.33, 95% CI 1.01 to 1.74; p value interaction: 0.007). The HR associated with sarcoidosis did not vary by the presence of ischaemic heart disease.Conclusion Patients with sarcoidosis have a higher OHCA rate than the general population. This increased OHCA rate occurred in women but not in men, and was larger in patients with than without heart failure