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.

Outcomes after out-of-hospital cardiac arrest in immigrants vs natives in Denmark.

AIMS: Ethnic disparities subsist in out-of-hospital cardiac arrest (OHCA) outcomes in the US, yet it is unresolved whether similar inequalities exist in European countries. This study compared survival after OHCA and its determinants in immigrants and non-immigrants in Denmark. METHODS: Using the nationwide Danish Cardiac Arrest Register, 37,622 OHCAs of presumed cardiac cause between 2001 and 2019 were included, 95% in non-immigrants and 5% in immigrants. Univariate and multiple logistic regression was used to assess disparities in treatments, return of spontaneous circulation (ROSC) at hospital arrival, and 30-day survival. RESULTS: Immigrants were younger at OHCA (median 64 [IQR 53-72] vs 68 [59-74] years; p < 0.05), had more prior myocardial infarction (15% vs 12%, p < 0.05), more diabetes (27% vs 19%, p < 0.05), and were more often witnessed (56% vs 53%; p < 0.05). Immigrants received similar bystander cardiopulmonary resuscitation and defibrillation rates to non-immigrants, but more coronary angiographies (15% vs 13%; p < 0.05) and percutaneous coronary interventions (10% vs 8%, p < 0.05), although this was insignificant after age-adjustment. Immigrants had higher ROSC at hospital arrival (28% vs 26%; p < 0.05) and 30-day survival (18% vs 16%; p < 0.05) compared to non-immigrants, but adjusting for age, sex, witness status, first observed rhythm, diabetes, and heart failure rendered the difference non-significant (odds ratios (OR) 1.03, 95% confidence interval (CI) 0.92-1.16 and OR 1.05, 95% CI 0.91-1.20, respectively). CONCLUSIONS: OHCA management was similar between immigrants and non-immigrants, resulting in similar ROSC at hospital arrival and 30-day survival after adjustments.

External validation of the simple NULL-PLEASE clinical score in predicting outcomes of out-of-hospital cardiac arrest in the Danish population - A nationwide registry-based study.

AIM: The NULL-PLEASE score (Nonshockable rhythm, Unwitnessed arrest, Long no-flow or Long low-flow period, blood pH < 7.2, Lactate > 7.0 mmol/L, End-stage renal disease on dialysis, Age ≥85 years, Still resuscitation, and Extracardiac cause) may identify patients with out-of-hospital cardiac arrest (OHCA) unlikely to survive. We aimed to validate the NULL-PLEASE score in a nationwide setting. METHODS: We used Danish nationwide registry data from 2001 to 2019 and identified OHCA survivors with return of spontaneous circulation (ROSC) or ongoing cardiopulmonary resuscitation at hospital arrival. The primary outcome was 1-day mortality. Secondary outcomes were 30-day mortality and the combined outcome of 1-year mortality or anoxic brain damage. The risks of outcomes were estimated using logistic regression with a NULL-PLEASE score of 0 as reference (range 0-14). The predictive ability of the score was examined using the area under the receiver operating characteristics (AUCROC) curve. RESULTS: A total of 3,881 patients were included in the analyses. One-day mortality was 35%, 30-day mortality was 61%, and 68% experienced the combined outcome. For a NULL-PLEASE score ≥9 (n = 244) the absolute risks were: 1-day mortality: 80.7% (95% confidence interval [CI]: 75.8-85.7%); 30-day mortality: 98.0% (95% CI: 96.2-99.7%); and the combined outcome: 98.4% (95% CI: 96.8-100.0%). Corresponding AUCROC values were 0.800 (95% CI: 0.786-0.814) for 1-day mortality, 0.827 (95% CI: 0.814-0.840) for 30-day mortality, and 0.828 (95% CI: 0.815-0.841) for the combined outcome. CONCLUSIONS: In a nationwide OHCA-cohort, AUCROC values for the predictive ability of NULL-PLEASE were high for all outcomes. However, some survived even with high NULL-PLEASE scores.

Association Between ECG Abnormalities and Fatal Cardiovascular Disease Among Patients With and Without Severe Mental Illness.

Background ECG abnormalities are associated with adverse outcomes in the general population, but their prognostic significance in severe mental illness (SMI) remains unexplored. We investigated associations between no, minor, and major ECG abnormalities and fatal cardiovascular disease (CVD) among patients with SMI compared with controls without mental illness. Methods and Results We cross-linked data from Danish nationwide registries and included primary care patients with digital ECGs from 2001 to 2015. Patients had SMI if they were diagnosed with schizophrenia, bipolar disorder, or severe depression before ECG recording. Controls were required to be without any prior mental illness or psychotropic medication use. Fatal CVD was assessed using hazard ratios (HRs) with 95% CIs and standardized 10-year absolute risks. Of 346 552 patients, 10 028 had SMI (3%; median age, 54 years; male, 45%), and 336 524 were controls (97%; median age, 56 years; male, 48%). We observed an interaction between SMI and ECG abnormalities on fatal CVD (P<0.001). Severe mental illness was associated with fatal CVD across no (HR, 2.17; 95% CI, 1.95-2.43), minor (HR, 1.90; 95% CI, 1.49-2.42), and major (HR, 1.40; 95% CI, 1.26-1.55) ECG abnormalities compared with controls. Across age- and sex-specific subgroups, SMI patients with ECG abnormalities but no CVD at baseline had highest standardized 10-year absolute risks of fatal CVD. Conclusions ECG abnormalities conferred a poorer prognosis among patients with SMI compared with controls without mental illness. SMI patients with ECG abnormalities but no CVD represent a high-risk population that may benefit from greater surveillance and risk management.

Contacts With the Health Care System Before Out-of-Hospital Cardiac Arrest.

Background It remains challenging to identify patients at risk of out-of-hospital cardiac arrest (OHCA). We aimed to examine health care contacts in patients before OHCA compared with the general population that did not experience an OHCA. Methods and Results Patients with OHCA with a presumed cardiac cause were identified from the Danish Cardiac Arrest Registry (2001-2014) and their health care contacts (general practitioner [GP]/hospital) were examined up to 1 year before OHCA. In a case-control study (1:9), OHCA contacts were compared with an age- and sex-matched background population. Separately, patients with OHCA were examined by the contact type (GP/hospital/both/no contact) within 2 weeks before OHCA. We included 28 955 patients with OHCA. The weekly percentages of patient contacts with GP the year before OHCA were constant (25%) until 1 week before OHCA when they markedly increased (42%). Weekly percentages of patient contacts with hospitals the year before OHCA gradually increased during the last 6 months (3.5%-6.6%), peaking at the second week (6.8%) before OHCA; mostly attributable to cardiovascular diseases (21%). In comparison, there were fewer weekly contacts among controls with 13% for GP and 2% for hospital contacts (P<0.001). Within 2 weeks before OHCA, 57.8% of patients with OHCA had a health care contact, and these patients had more contacts with GP (odds ratio [OR], 3.17; 95% CI, 3.09-3.26) and hospital (OR, 2.32; 95% CI, 2.21-2.43) compared with controls. Conclusions The health care contacts of patients with OHCA nearly doubled leading up to the OHCA event, with more than half of patients having health care contacts within 2 weeks before arrest. This could have implications for future preventive strategies.

Electrocardiogram Characteristics and Their Association With Psychotropic Drugs Among Patients With Schizophrenia.

BACKGROUND: There are limited data on electrocardiogram (ECG) characteristics and their association with psychotropic drugs in schizophrenia. METHODS: Using a cross-sectional design, we included Danish primary care patients with first-time digital ECGs from 2001 to 2015. Patients diagnosed with schizophrenia before ECG recording were matched 1:5 on age, sex, and ECG recording year to controls without psychiatric disease. Multivariable logistic regression was used to compute odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: We included 4486 patients with schizophrenia matched with 22 430 controls (median age, 47 years; male, 55%). Between groups, the prevalence of abnormal ECGs was similar (54%, P = .536), but patients with schizophrenia demonstrated higher median heart rate (79 vs 69 beats per minute, P < .001) and Fridericia-corrected QT (QTc) interval (416 vs 412 ms, P < .001) than controls. QTc prolongation was also more prevalent among patients with schizophrenia (3.4% vs 1.1%, P < .001), and so were pathological Q waves (5.3% vs 3.9%, P < .001). Patients with schizophrenia less frequently demonstrated left ventricular hypertrophy (6.1% vs 9.6%, P < .001) and atrial fibrillation or flutter (0.7% vs 1.4%, P < .001). Among patients with schizophrenia only, particularly antipsychotics were associated with abnormal ECGs (OR, 1.20; 95% CI, 1.04-1.39). CONCLUSIONS: Patients with schizophrenia demonstrate a different cardiovascular risk profile than matched controls without psychiatric disease, with higher prevalence of elevated heart rate, QTc prolongation, and pathological Q waves, and lower prevalence of left ventricular hypertrophy and atrial fibrillation or flutter. Particularly antipsychotics were associated with abnormal ECGs. This underscores an integrated care approach when ECG abnormalities are detected in this group.