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Objective Patients with sleep apnea (SA) are at increased cardiovascular risk. However, little is known about the risk of out-of-hospital cardiac arrest (OHCA) in patients with SA. Therefore, we studied the relation between SA patients who did and did not receive continuous positive airway pressure (CPAP) therapy with OHCA in the general population. Methods Using nationwide databases, we conducted a nested case-control study with OHCA-cases of presumed cardiac causes and age/sex/OHCA-date matched non-OHCA-controls from the general population. Conditional logistic regression models with adjustments for well-known OHCA risk factors were performed to generate odds ratio (OR) of OHCA comparing patients with SA receiving and not receiving CPAP therapy with individuals without SA. Results We identified 46,578 OHCA-cases and 232,890 matched non-OHCA-controls [mean: 71 years, 68.8% men]. Compared to subjects without SA, having SA without CPAP therapy was associated with increased odds of OHCA after controlling for relevant confounders (OR:1.20, 95%-Cl:1.06–1.36), while having SA with CPAP therapy was not associated with OHCA (OR:1.04, 95%-Cl:0.93–1.36). Regardless of CPAP therapy, age and sex did not significantly influence our findings. Our findings were confirmed in: (I) patients with neither ischemic heart disease nor heart failure (untreated SA, OR:1.24, 95%-CI:1.04–1.47; SA with CPAP, OR:1.08, 95%-CI:0.93–1.25); and (II) in patients without cardiovascular disease (untreated SA, OR:1.33, 95%-CI:1.07–1.65; SA with CPAP, OR:1.14, 95%-CI:0.94–1.39). Conclusion SA not treated with CPAP was associated with OHCA, while no increased risk of OHCA was found for SA patients treated with CPAP. Keywords Sudden cardiac arrestSleep apneaCardiac electrophysiologyCPAP, Objective: Patients with sleep apnea (SA) are at increased cardiovascular risk. However, little is known about the risk of out-of-hospital cardiac arrest (OHCA) in patients with SA. Therefore, we studied the relation between SA patients who did and did not receive continuous positive airway pressure (CPAP) therapy with OHCA in the general population. Methods: Using nationwide databases, we conducted a nested case-control study with OHCA-cases of presumed cardiac causes and age/sex/OHCA-date matched non-OHCA-controls from the general population. Conditional logistic regression models with adjustments for well-known OHCA risk factors were performed to generate odds ratio (OR) of OHCA comparing patients with SA receiving and not receiving CPAP therapy with individuals without SA. Results: We identified 46,578 OHCA-cases and 232,890 matched non-OHCA-controls [mean: 71 years, 68.8% men]. Compared to subjects without SA, having SA without CPAP therapy was associated with increased odds of OHCA after controlling for relevant confounders (OR:1.20, 95%-Cl:1.06–1.36), while having SA with CPAP therapy was not associated with OHCA (OR:1.04, 95%-Cl:0.93–1.36). Regardless of CPAP therapy, age and sex did not significantly influence our findings. Our findings were confirmed in: (I) patients with neither ischemic heart disease nor heart failure (untreated SA, OR:1.24, 95%-CI:1.04–1.47; SA with CPAP, OR:1.08, 95%-CI:0.93–1.25); and (II) in patients without cardiovascular disease (untreated SA, OR:1.33, 95%-CI:1.07–1.65; SA with CPAP, OR:1.14, 95%-CI:0.94–1.39). Conclusion: SA not treated with CPAP was associated with OHCA, while no increased risk of OHCA was found for SA patients treated with CPAP.

Aim Conflicting results have been reported regarding the association between fluoroquinolones (FQs) and the risk of out-of-hospital cardiac arrest (OHCA). In particular, it has not become clear whether OHCA in FQ users is related to the inherent comorbidities or whether there is a direct pro-arrhythmic effect of FQs. Therefore, we studied the relation between FQs and OHCA in the general population. Methods Through Danish nationwide registries, we conducted a nested case–control study with OHCA cases of presumed cardiac causes and age/sex/OHCA date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the OR with 95% CI of OHCA comparing FQs with amoxicillin. Results The study population consisted of 46 578 OHCA cases (mean: 71 years (SD: 14.40), 68.8% men) and 232 890 matched controls. FQ was used by 276 cases and 328 controls and conferred no increase in the odds of OHCA compared with amoxicillin use after controlling for the relevant confounders (OR: 0.91 (95% CI: 0.71 to 1.16)). The OR of OHCA associated with FQ use did not vary significantly by age (OR≤65: 0.96 (95% CI: 0.53 to 1.74), OR>65: 0.88 (95% CI: 0.67 to 1.16), p value interaction=0.7818), sex (ORmen: 0.96 (95% CI: 0.70 to 1.31), ORwomen: 0.80 (95% CI: 0.53 to 1.20), p value interaction=0.9698) and pre-existing cardiovascular disease (ORabsent: 1.02 (95% CI: 0.57 to 1.82), ORpresent: 0.98 (95% CI: 0.75 to 1.28), p value interaction=0.3884), including heart failure (ORabsent: 0.93 (95% CI: 0.72 to 1.22), ORpresent: 1.11 (95% CI: 0.61 to 2.02), p value interaction=0.7083) and ischaemic heart disease (ORabsent: 0.85 (95% CI: 0.64 to 1.12), ORpresent: 1.38 (95% CI: 0.86 to 2.21), p value interaction=0.6230). Conclusion Our findings do not support an association between FQ exposure and OHCA in the general population. This lack of association was consistent in me, Aim Conflicting results have been reported regarding the association between fluoroquinolones (FQs) and the risk of out-of-hospital cardiac arrest (OHCA). In particular, it has not become clear whether OHCA in FQ users is related to the inherent comorbidities or whether there is a direct pro-arrhythmic effect of FQs. Therefore, we studied the relation between FQs and OHCA in the general population. Methods Through Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the OR with 95% CI of OHCA comparing FQs with amoxicillin. Results The study population consisted of 46 578 OHCA cases (mean: 71 years (SD: 14.40), 68.8% men) and 232 890 matched controls. FQ was used by 276 cases and 328 controls and conferred no increase in the odds of OHCA compared with amoxicillin use after controlling for the relevant confounders (OR: 0.91 (95% CI: 0.71 to 1.16)). The OR of OHCA associated with FQ use did not vary significantly by age (OR ≤65: 0.96 (95% CI: 0.53 to 1.74), OR >65: 0.88 (95% CI: 0.67 to 1.16), p value interaction=0.7818), sex (OR men: 0.96 (95% CI: 0.70 to 1.31), OR women: 0.80 (95% CI: 0.53 to 1.20), p value interaction=0.9698) and pre-existing cardiovascular disease (OR absent: 1.02 (95% CI: 0.57 to 1.82), OR present: 0.98 (95% CI: 0.75 to 1.28), p value interaction=0.3884), including heart failure (OR absent: 0.93 (95% CI: 0.72 to 1.22), OR present: 1.11 (95% CI: 0.61 to 2.02), p value interaction=0.7083) and ischaemic heart disease (OR absent: 0.85 (95% CI: 0.64 to 1.12), OR present: 1.38 (95% CI: 0.86 to 2.21), p value interaction=0.6230). Conclusion Our findings do not support an association between FQ exposure and OHCA in the general population. This lack of association was consistent in men and women, i

Mikkel Porsborg Andersen,1,2 Rikke Wiingreen,3 Talip E Eroglu,4,5 Helle Collatz Christensen,6 Laura Bech Polcwiartek,7,8 Stig Nikolaj Fasmer Blomberg,6,9 Kristian Kragholm,10,11 Christian Torp-Pedersen,1,12 Kathrine Kold Sørensen1 1Department of Cardiology, Nordsjællands Hospital, Hillerød, Denmark; 2The Prehospital Center, Region Zealand, Denmark; 3Department of Pediatrics, Nordsjællands Hospital, Hillerød, Denmark; 4Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, Denmark; 5Department of Experimental and Clinical Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 6Copenhagen Emergency Medical Services, Copenhagen, Denmark; 7Department of Pediatrics, Randers Regional Hospital, Randers, Denmark; 8Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark; 9Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 10Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; 11Unit of Clinical Biostatistics and Epidemiology, Aalborg University Hospital, Aalborg, Denmark; 12Department of Public Health, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Mikkel Porsborg Andersen, Department of Cardiology, Nordsjællands Hospital, Dyrehavevej 29, Hillerød, 3400, Denmark, Tel +45 92 43 22 99, Email mikkel.porsborg.andersen@regionh.dkAim of the Database: The aim of the National Child Health Registry is to provide comprehensive insight into children’s health and growth on a national scale by continuously monitoring the health status of Danish children. Through this effort, the registry assists the health authorities in prioritizing preventive efforts to promote better child health outcomes.Study Population: The registry includes all Danish children, however, incomplete coverage persists.Main Variables: The National Child Health Registry contains informat

Aim of the Database: The aim of the National Child Health Registry is to provide comprehensive insight into children’s health and growth on a national scale by continuously monitoring the health status of Danish children. Through this effort, the registry assists the health authorities in prioritizing preventive efforts to promote better child health outcomes. Study Population: The registry includes all Danish children, however, incomplete coverage persists. Main Variables: The National Child Health Registry contains information on exposure to secondhand smoking, breastfeeding duration, and anthropometric measurements through childhood. The information in the registry is divided into three datasets: Smoking, Breastfeeding, and Measurements. Beside specific information on the three topics, all datasets include information on CPR-number, date of birth, sex, municipality, and region of residence. Database Status: The National Child Health Registry was established in 2009 and contains health information on children from all Danish municipalities, collected through routinely performed health examinations conducted by general practitioners and health nurses. Conclusion: The National Child Health Register is an asset to epidemiological and health research with nationwide information on children’s health and growth in Denmark. Due to the unique Danish Civil Registration System, it is possible to link data from the National Child Health Register to information from several other national health and social registers which enables longitudinal unambiguous follow-up., Aim of the Database: The aim of the National Child Health Registry is to provide comprehensive insight into children’s health and growth on a national scale by continuously monitoring the health status of Danish children. Through this effort, the registry assists the health authorities in prioritizing preventive efforts to promote better child health outcomes. Study Population: The registry includes all Danish children, however, incomplete coverage persists. Main Variables: The National Child Health Registry contains information on exposure to secondhand smoking, breastfeeding duration, and anthropometric measurements through childhood. The information in the registry is divided into three datasets: Smoking, Breastfeeding, and Measurements. Beside specific information on the three topics, all datasets include information on CPR-number, date of birth, sex, municipality, and region of residence. Database Status: The National Child Health Registry was established in 2009 and contains health information on children from all Danish municipalities, collected through routinely performed health examinations conducted by general practitioners and health nurses. Conclusion: The National Child Health Register is an asset to epidemiological and health research with nationwide information on children’s health and growth in Denmark. Due to the unique Danish Civil Registration System, it is possible to link data from the National Child Health Register to information from several other national health and social registers which enables longitudinal unambiguous follow-up.

Objective Patients with stress-related disorders and anxiety are at increased risk of developing cardiovascular disease. However, the risk of out-of-hospital cardiac arrest (OHCA) is scarcely investigated. We aimed to establish whether long-term stress (post-traumatic stress disorder, adjustment disorder) or anxiety is associated with OHCA in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. Cases were OHCA patients with presumed cardiac causes. Each case was matched by age, sex and date of OHCA with 10 non-OHCA controls from the general population. HRs for OHCA were derived from Cox models after controlling for common OHCA risk factors. Stratified analyses were performed according to sex, age and pre-existing cardiovascular disease. Results We included 35 195 OHCAs and 351 950 matched controls (median age 72 years; 66.8% male). Long-term stress conditions were diagnosed in 324 (0.92%) OHCA cases and 1577 (0.45%) non-OHCA controls, and were associated with higher rate of OHCA (HR 1.44, 95% CI 1.27 to 1.64). Anxiety was diagnosed in 299 (0.85%) OHCA cases and 1298 (0.37%) controls, and was associated with increased rate of OHCA (HR 1.56, 95% CI1.37 to 1.79). We found no interaction with sex, age or history of cardiovascular diseases. Conclusion Patients with stress-related disorders or anxiety have an increased rate of OHCA. This association applies equally to men and women and is independent from the presence of cardiovascular disease. Awareness of the higher risks of OHCA in patients with stress-related disorders and anxiety is important when treating these patients.

Objective Sarcoidosis is over-represented among victims of cardiac arrest. We aimed to establish whether sarcoidosis is associated with out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case-control study in a nationwide cohort of individuals between 1 June 2001 and 31 December 2015 in Denmark. OHCA cases from presumed cardiac causes were matched 1:10 by sex and age on OHCA date with non-OHCA controls from the general population. The association between sarcoidosis and OHCA was assessed using Cox regression by calculating HR and 95% CIs. Models were adjusted for cardiovascular disease. Finally, stratified analyses were performed according to sex, heart failure and ischaemic heart disease. 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 (HR heart failure: 2.59, 95% CI 1.42 to 4.73; HR no 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.

Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population. Methods and results Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate. The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62–81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of OHCA compared with non-users {OR: 1.78 [95% confidence interval (CI): 1.32–2.40]}. The OR was highest in recent starters (OR≤180 days: 2.59, 95% CI: 1.28–5.23). The OR of OHCA associated with methylphenidate use did not vary significantly by age (P-value interaction: 0.37), sex (P-value interaction: 0.94), and pre-existing cardiovascular disease (P-value interaction: 0.27). Furthermore, the ORs remained elevated when we repeated the analyses in individuals without registered hospital-based ADHD (OR: 1.85, 95% CI: 1.34–2.55), without severe psychiatric disorders (OR: 1.98, 95% CI: 1.46–2.67), without depression (OR: 1.93, 95% CI: 1.40–2.65), or in non-users of QT-prolonging drugs (OR: 1.79, 95% CI: 1.27–2.54). Conclusion Methylphenidate use is associated with an increased risk of OHCA in the general population. This increased risk applies to both sexes and is independent of age and the presence of cardiovascular disease., Aim Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population.Methods and results Using Danish nationwide registries, we conducted a nested case-control study with OHCA cases of presumed cardiac causes and age/sex/OHCA-date-matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA by comparing methylphenidate use with no use of methylphenidate. The study population consisted of 46 578 OHCA cases [median: 72 years (interquartile range: 62–81), 68.8% men] and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with an increased OR of OHCA compared with non-users {OR: 1.78 [95% confidence interval (CI): 1.32–2.40]}. The OR was highest in recent starters (OR≤180 days: 2.59, 95% CI: 1.28–5.23). The OR of OHCA associated with methylphenidate use did not vary significantly by age (P-value interaction: 0.37), sex (P-value interaction: 0.94), and pre-existing cardiovascular disease (P-value interaction: 0.27). Furthermore, the ORs remained elevated when we repeated the analyses in individuals without registered hospital-based ADHD (OR: 1.85, 95% CI: 1.34–2.55), without severe psychiatric disorders (OR: 1.98, 95% CI: 1.46–2.67), without depression (OR: 1.93, 95% CI: 1.40–2.65), or in non-users of QT-prolonging drugs (OR: 1.79, 95% CI: 1.27–2.54).Conclusion Methylphenidate use is associated with an increased risk of OHCA in the general population. This increased risk applies to both sexes and is independent of age and the presence of cardiovascular disease.

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: 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 We studied the effect of discontinuing beta-blockers following myocardial infarction in comparison to continuous beta-blocker use in optimally treated, stable patients without heart failure. Methods and results Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography. The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21 220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; −4.19% [−8.95%; 0.57%], −1.18% [−4.11%; 1.75%], and −0.37% [−4.56%; 3.82%]). Further, beta-blocker discontinuation within 2 years after myocardial infarction was associated with an increased risk of the composite outcome (landmark year 2; absolute risk [95% confidence interval] 19.87% [17.29%; 22.46%]) compared with continued beta-blocker use (landmark year 2; absolute risk [95% confidence interval] 17.10% [16.34%; 17.87%]), which yielded an absolute risk difference [95% confidence interval] at −2.8% [−5.4%; −0.1%], however, there was no risk difference associated with discontinuation hereafter. Conclusion Discontinuation of beta-blockers 1 year or later after a myocardial infarction without heart failure was not associated with increased serious adverse events, AIMS: We studied the effect of discontinuing beta-blockers following myocardial infarction in comparison to continuous beta-blocker use in optimally treated, stable patients without heart failure.METHODS AND RESULTS: Using nationwide registers, we identified first-time myocardial infarction patients treated with beta-blockers following percutaneous coronary intervention or coronary angiography. The analysis was based on landmarks selected as 1, 2, 3, 4, and 5 years after the first redeemed beta-blocker prescription date. The outcomes included all-cause death, cardiovascular death, recurrent myocardial infarction, and a composite outcome of cardiovascular events and procedures. We used logistic regression and reported standardized absolute 5-year risks and risk differences at each landmark year. Among 21 220 first-time myocardial infarction patients, beta-blocker discontinuation was not associated with an increased risk of all-cause death, cardiovascular death, or recurrent myocardial infarction compared with patients continuing beta-blockers (landmark year 5; absolute risk difference [95% confidence interval]), correspondingly; -4.19% [-8.95%; 0.57%], -1.18% [-4.11%; 1.75%], and -0.37% [-4.56%; 3.82%]). Further, beta-blocker discontinuation within two years after myocardial infarction was associated with an increased risk of the composite outcome (landmark year 2; absolute risk [95% confidence interval] 19.87% [17.29%; 22.46%]) compared with continued beta-blocker use (landmark year 2; absolute risk [95% confidence interval] 17.10% [16.34%; 17.87%]), which yielded an absolute risk difference [95% confidence interval] at -2.8% [-5.4%; -0.1%], however, there was no risk difference associated with discontinuation hereafter.CONCLUSION: Discontinuation of beta-blockers one year or later after a myocardial infarction without heart failure was not associated with increased serious adverse events.

AIM: Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] increase the risk of out-of-hospital cardiac arrest (OHCA). Such drugs are categorized in multiple clinically widely used CredibleMeds.org lists. Category 1 ('known risk of Torsade de Pointes') and category 2 ('possible risk of Torsade de Pointes') are of particular clinical relevance. However, a category-stratified analysis of OHCA-risk is presently unavailable.METHODS AND RESULTS: We conducted a case-control study with OHCA-cases from presumed cardiac causes included from the ARREST registry in the Netherlands (2009-2018) that was specifically designed to study OHCA, and age/sex/OHCA-date matched non-OHCA-controls. Adjusted odds ratios for OHCA (ORadj) of QT-drugs from categories 1 or 2 were calculated, using conditional logistic regression. Stratified analysis was performed according to sex, age, and presence of cardiovascular drugs (proxy for cardiovascular disease). We included 5473 OHCA-cases (68.8 years, 69.9% men) and matched them to 20 866 non-OHCA-controls. Compared with no use of non-cardiac QT-drugs, drugs of both categories were associated with increased OHCA-risk, but seemingly weaker for category 2 {category 1: case 3.2%, control 1.4%, ORadj 1.7 [95% confidence interval (CI): 1.3-2.1]}; [category 2: case 7.3%, control 4.0%, ORadj 1.4 (95% CI: 1.2-1.6)]. The increased risk occurred in men and women, at all ages (highest in patients aged ≤50 years), and both in the presence or absence of cardiovascular drug use.CONCLUSION: Both category 1 and category 2 QT-drugs are associated with increased OHCA-risk in both sexes, at all ages, and in patients taking or not taking cardiovascular drugs.

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.

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.

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.

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.

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 dr

Aims: Out-of-hospital cardiac arrest (OHCA) mostly results from ventricular tachycardia/ventricular fibrillation (VT/VF), often triggered by acute myocardial infarction (AMI). Sulfonylurea (SU) antidiabetics can block myocardial ATP-regulated K+ channels (KATP channels), activated during AMI, thereby modulating action potential duration (APD). We studied whether SU drugs impact on OHCA risk, and whether these effects are related to APD changes. Methods: We conducted a population-based case–control study in 219 VT/VF-documented OHCA cases with diabetes and 697 non-OHCA controls with diabetes. We studied the association of SU drugs (alone or in combination with metformin) with OHCA risk compared to metformin monotherapy, and of individual SU drugs compared to glimepiride, using multivariable logistic regression analysis. We studied the effects of these drugs on APD during simulated ischaemia using patch-clamp studies in human induced pluripotent stem cell-derived cardiomyocytes. Results: Compared to metformin, use of SU drugs alone or in combination with metformin was associated with reduced OHCA risk (ORSUdrugs-alone 0.6 [95% CI 0.4–0.9], ORSUdrugs + metformin 0.6 [95% CI 0.4–0.9]). We found no differences in OHCA risk between SU drug users who suffered OHCA inside or outside the context of AMI. Reduction of OHCA risk compared to glimepiride was found with gliclazide (ORadj 0.5 [95% CI 0.3–0.9]), but not glibenclamide (ORadj 1.3 [95% CI 0.6–2.7]); for tolbutamide, the association with reduced OHCA risk just failed to reach statistical significance (ORadj 0.6 [95% CI 0.3–1.002]). Glibenclamide attenuated simulated ischaemia-induced APD shortening, while the other SU drugs had no effect. Conclusions: SU drugs were associated with reduced OHCA risk compared to metformin monotherapy, with gliclazide having a lower risk than glimepiride. The differential effects of SU drugs are not explained b

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 (

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, b1-selective beta-blockers, or a-b-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 b1-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 a-b-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 b1-selective beta-blockers, are associated with non-shockable rhythm in OHCA.