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], Pinteraction  < .0001; Denmark: OR 2.3 [95% CI: 2.0-2.5], Pinteraction  < .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.

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

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.

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, ß1-selective beta-blockers, or α-ß-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 ß1-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-ß-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 ß1-selective beta-blockers, are associated with non-shockable rhythm in OHCA.

Influence of psychopathology and metabolic parameters on quality of life in patients with first-episode psychosis before and after initial antipsychotic treatment.

The impact of psychological and physical health on quality of life (QoL) in patients with early psychosis remain relatively unexplored. We evaluated the predictive value of psychopathological and metabolic parameters on QoL in antipsychotic-naïve patients with first-episode psychosis before and after initial antipsychotic treatment. At baseline, 125 patients underwent assessments of psychopathology, prevalence of metabolic syndrome (MetS), and QoL. After 6 weeks of antipsychotic monotherapy, 89 patients were re-investigated. At baseline, the prevalence of MetS was 19.3% (n = 22). After 6 weeks, body weight (1.3 kg, p < 0.001) and body mass index (0.4 kg/m2, p < 0.001) increased, and four additional patients developed MetS. Multivariate linear regression revealed that positive and negative symptoms, and to some degree waist circumference, were predictors of QoL at both time points. Our findings suggest that in the earliest stages of antipsychotic treatment, metabolic side-effects may be less influential on QoL than psychopathological severity.

Differential effects on out-of-hospital cardiac arrest of dihydropyridines: real-world data from population-based cohorts across two European countries.

AIMS: 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. METHODS AND RESULTS: 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 (ORadj) 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. CONCLUSION: 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.

Out-of-hospital cardiac arrest in patients with psychiatric disorders - Characteristics and outcomes.

AIMS: To investigate whether the recent improvements in pre-hospital cardiac arrest-management and survival following out-of-hospital cardiac arrest (OHCA) also apply to OHCA patients with psychiatric disorders. METHODS: We identified all adult Danish patients with OHCA of presumed cardiac cause, 2001-2015. Psychiatric disorders were defined by hospital diagnoses up to 10 years before OHCA and analyzed as one group as well as divided into five subgroups (schizophrenia-spectrum disorders, bipolar disorder, depression, substance-induced mental disorders, other psychiatric disorders). Association between psychiatric disorders and pre-hospital OHCA-characteristics and 30-day survival were assessed by multiple logistic regression. RESULTS: Of 27,523 OHCA-patients, 4772 (17.3%) had a psychiatric diagnosis. Patients with psychiatric disorders had lower odds of 30-day survival (0.37 95% confidence interval 0.32-0.43) compared with other OHCA-patients. Likewise, they had lower odds of witnessed status (0.75 CI 0.70-0.80), bystander cardiopulmonary resuscitation (CPR) (0.77 CI 0.72-0.83), shockable heart rhythm (0.37 95% CI, 0.33-0.40), and return of spontaneous circulation (ROSC) at hospital arrival (0.66 CI 0.59-0.72). Similar results were seen in all five psychiatric subgroups. The difference in 30-day survival between patients with and without psychiatric disorders increased in recent years: from 8.4% (CI 7.0-10.0%) in 2006 to 13.9% (CI 12.4-15.4%) in 2015 and from 7.0% (4.3-10.8%) in 2006 to 7.0% (CI 4.5-9.7%) in 2015, respectively. CONCLUSION: Patients with psychiatric disorders have lower survival following OHCA compared to non-psychiatric patients and the gap between the two groups has widened over time.