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Background: Sudden cardiac death is responsible for 10% to 20% of all deaths in Europe. The current study investigates how well the risk of sudden cardiac death can be predicted. To this end, we validated a previously developed prediction model for sudden cardiac death from the Atherosclerosis Risk in Communities study (USA). Methods: Data from participants of the Copenhagen City Heart Study (CCHS) (n=9988) was used to externally validate the previously developed prediction model for sudden cardiac death. The model's performance was assessed through discrimination (C-statistic) and calibration by the Hosmer-Lemeshow goodness-of-fit (HL) statistics suited for censored data and visual inspection of calibration plots. Additional validation was performed using data from the Hoorn Study (N=2045), employing the same methods. Results: During ten years of follow-up of CCHS participants (mean age: 58.7 years, 56.2% women), 425 experienced SCD (4.2%). The prediction model showed good discrimination for sudden cardiac death risk (C-statistic: 0.81, 95% CI: 0.79-0.83). Calibration was robust (HL statistic: P=0.8). Visual inspection of the calibration plot showed that the calibration could be improved. Sensitivity was 89.8%, and specificity was 60.6%. The positive and negative predictive values were 10.1% and 99.2%. Model performance was similar in the Hoorn Study (C-statistic: 0.81, 95% CI: 0.77-0.85 and the HL statistic: 1.00). Conclusion: Our study showed that the previously developed prediction model in North American adults performs equally well in identifying those at risk for sudden cardiac death in a general North-West European population. However, the positive predictive value is low.

Patient-reported outcomes (PROs) are valuable for shared decision making and research. Patient-reported outcome measures (PROMs) are questionnaires used to measure PROs, such as health-related quality of life (HRQL). Although core outcome sets for trials and clinical practice have been developed separately, they, as well as other initiatives, recommend different PROs and PROMs. In research and clinical practice, different PROMs are used (some generic, some disease-specific), which measure many different things. This is a threat to the validity of research and clinical findings in the field of diabetes. In this narrative review, we aim to provide recommendations for the selection of relevant PROs and psychometrically sound PROMs for people with diabetes for use in clinical practice and research. Based on a general conceptual framework of PROs, we suggest that relevant PROs to measure in people with diabetes are: disease-specific symptoms (e.g. worries about hypoglycaemia and diabetes distress), general symptoms (e.g. fatigue and depression), functional status, general health perceptions and overall quality of life. Generic PROMs such as the 36-Item Short Form Health Survey (SF-36), WHO Disability Assessment Schedule (WHODAS 2.0), or Patient-Reported Outcomes Measurement Information System (PROMIS) measures could be considered to measure commonly relevant PROs, supplemented with disease-specific PROMs where needed. However, none of the existing diabetes-specific PROM scales has been sufficiently validated, although the Diabetes Symptom Self-Care Inventory (DSSCI) for measuring diabetes-specific symptoms and the Diabetes Distress Scale (DDS) and Problem Areas in Diabetes (PAID) for measuring distress showed sufficient content validity. Standardisation and use of relevant PROs and psychometrically sound PROMs can help inform people with diabetes about the expected course of disease and treatment, for shared decision making, to monitor outcomes and to improve healthcare. We recommend further validation studies of diabetes-specific PROMs that have sufficient content validity for measuring disease-specific symptoms and consider generic item banks developed based on item response theory for measuring commonly relevant PROs. Graphical Abstract

Depolarization-blocking drugs (DB drugs) used for cardiac disease increase the risk of cardiac arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]) and out-of-hospital cardiac arrest (OHCA) in specific patient groups. However, it is unknown whether drugs for non-cardiac disease that block cardiac depolarization as the off-target effect increase the risk of OHCA on a population level. Therefore, we aimed to investigate OHCA risk of non-cardiac, DB drugs in the community. We conducted a population-based case-control study. We included OHCA cases from an emergency-medical-services-attended OHCA registry in the Netherlands (ARREST:2009–2018), and age/sex/OHCA-date matched non-OHCA controls. We calculated adjusted odds ratios (ORadj) of use of non-cardiac DB drugs for OHCA using conditional logistic regression. Stratified analyses were performed according to first-registered rhythm (VT/VF or non-VT/VF), sex, and age (≤50, 50–70, or ≥70 years). We included 5473 OHCA cases of whom 427 (7.8%) used non-cardiac, DB drugs and 21,866 non-OHCA controls of whom 835 (3.8%) used non-cardiac, DB drugs and found that non-cardiac, DB-drug use was associated with increased OHCA-risk when compared to no use (ORadj1.6[95%-CI:1.4–1.9]). Stratification by first-recorded rhythm revealed that this applied to OHCA with non-VT/VF (asystole) (ORadj2.5[95%-CI:2.1–3.0]) but not with VT/VF (ORadj1.0[95%-CI:0.8–1.2]; p-value interaction < 0.001). The risk was higher in women (ORadj1.8[95%-CI:1.5–2.2] than in men (ORadj1.5[95%-CI:1.2–1.8]; p-value interaction = 0.030) and at younger ages (ORadj≥70yrs1.4[95%-CI:1.2–1.7]; ORadj50–70yrs1.7[95%-CI:1.4–2.1]; ORadj≤50yrs3.2[95%-CI:2.1–5.0]; p-value interaction < 0.001). Use of non-cardiac, DB drugs is associated with increased OHCA risk. This increased risk occurred in patients in whom non-VT/VF was the first-registered rhythm, and it occurred in both sexes but more prominently among women and more strongly in younger patients (≤50 years).

Aims Automated external defibrillators (AEDs) are placed in public, but the majority of out-of-hospital cardiac arrests (OHCA) occur at home. Methods and results In residential areas, 785 AEDs were placed and 5735 volunteer responders were recruited. For suspected OHCA, dispatchers activated nearby volunteer responders with text messages, directing two-thirds to an AED first and one-third directly to the patient. We analysed survival (primary outcome) and neurologically favourable survival to discharge, time to first defibrillation shock, and cardiopulmonary resuscitation (CPR) before Emergency Medical Service (EMS) arrival of patients in residences found with ventricular fibrillation (VF), before and after introduction of this text-message alert system. Survival from OHCAs in residences increased from 26% to 39% {adjusted relative risk (RR) 1.5 [95% confidence interval (CI): 1.03–2.0]}. RR for neurologically favourable survival was 1.4 (95% CI: 0.99–2.0). No CPR before ambulance arrival decreased from 22% to 9% (RR: 0.5, 95% CI: 0.3–0.7). Text-message-responders with AED administered shocks to 16% of all patients in VF in residences, while defibrillation by EMS decreased from 73% to 39% in residences (P < 0.001). Defibrillation by first responders in residences increased from 22 to 40% (P < 0.001). Use of public AEDs in residences remained unchanged (6% and 5%) (P = 0.81). Time from emergency call to defibrillation decreased from median 11.7 to 9.3 min; mean difference –2.6 (95% CI: –3.5 to –1.6). Conclusion Introducing volunteer responders directed to AEDs, dispatched by text-message was associated with significantly reduced time to first defibrillation, increased bystander CPR and increased overall survival for OHCA patients in residences found with VF. Key Question The Emergency Medical Service introduced a text-message alert system to alert volunteers close to an out-of-hospital cardiac arrest patient. In addition, 785 automated external defibrillators (AEDs) were added and made available in the community. Does adding this system result in more basic life support (BLS), earlier defibrillation, and better survival? Key Finding We found that BLS increased from 78% to 91%, the time from emergency call to the first defibrillation shock decreased by 2.6 min and survival for patients at home, and found in ventricular fibrillation, increased from 26% to 39%. Take Home Message For patients with a cardiac arrest at home, an alert system that includes nearby volunteers activated by the ambulance dispatch centre and many easily accessible AEDs really saves lives. Implementation is an effective community effort.

Background: The burden of sudden cardiac death (SCD) in the general population is substantial and SCD frequently occurs among people with few or no known risk factors for cardiac disease. Reported incidences of SCD vary due to differences in definitions and methodology between cohorts. This study aimed to develop a method for adjudicating SCD cases in research settings and to describe uniform case definitions of SCD in an international consortium harmonizing multiple longitudinal study cohorts. Methods: The harmonized SCD definitions include both case definitions using data from multiple sources (eg, autopsy reports, medical history, eyewitnesses) as well as a method using only information from registers (eg, cause of death registers, ICD-10 codes). Validation of the register-based method was done within the consortium using the multiple sources definition as gold standard and presenting sensitivity, specificity, accuracy and positive predictive value. Results: Consensus definitions of “definite,” “possible” and “probable” SCD for longitudinal study cohorts were reached. The definitions are based on a stratified approach to reflect the level of certainty of diagnosis and degree of information. The definitions can be applied to both multisource and register-based methods. Validation of the method using register-information in a cohort comprising 1335 cases yielded a sensitivity of 74%, specificity of 88%, accuracy of 86%, and positive predictive value of 54%. Conclusions: This study demonstrated that a harmonization of SCD classification across different methodological approaches is feasible. The developed classification can be used to study SCD in longitudinal cohorts and to merge cohorts with different levels of information.

Jetty A Overbeek,1– 3 Karin MA Swart,1– 3 Emma YM van der Pal,2,3 Marieke T Blom,2,3 Joline WJ Beulens,3– 5 Giel Nijpels,2,3 Petra JM Elders,2,3 Ron MC Herings1,3,4 1Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands; 2Department of General Practice, Amsterdam UMC - Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands; 3Health Behaviors & Chronic Diseases, Amsterdam Public Health, Amsterdam, Netherlands; 4Department of Epidemiology and Data Science, Amsterdam UMC - Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands; 5Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, NetherlandsCorrespondence: Jetty A Overbeek, Department Research, PHARMO Institute for Drug Outcomes Research, Van Deventerlaan 30-40, Utrecht, 3528 AE, Netherlands, Tel +3130 7440 800, Email jetty.overbeek@pharmo.nlIntroduction: The increasing number of people with diabetes and the unclear long-term safety and effectiveness of newer and older blood-glucose-lowering treatments emphasize the need for more pharmaco-epidemiological studies in this field. A prospective, regularly updated cohort of people with diabetes would provide quick and up-to-date information regarding prevalence, treatment, safety and effectiveness. The current aim was to describe the design of the DIAbetes MANagement and Treatment (DIAMANT) cohort.Methods: The DIAMANT cohort is a population-based, dynamic, prospective cohort of persons with diabetes. It contains real-world data (RWD) from general practitioners (GP), including diagnoses, symptoms, examinations, communication to/from specialists and medication. Diabetes is defined as a recorded diabetes diagnosis or a prescription of drugs used in diabetes. The cohort is part of the national infrastructure of “Stichting Informatievoorziening voor Zorg en Onderzoek” (STIZON) and is linked to other data sources.Results: Currently, the cohort enables access to information of 89,883 patients in 2004 to 344,914 in 2020 (6% T1D, 84% T2D and 10% unclassified type of diabetes), with 193,931 participants still registered as being present in the GP practice (active) in 2020. The frequency of follow-up of persons with diabetes is practice dependent. The Dutch guidelines advise 2– 4 contacts per year with a more extensive yearly check-up. The DIAMANT cohort is updated several times a year. Anonymised data from the DIAMANT cohort are available to researchers.Discussion: The DIAMANT cohort provides the opportunity to gain RWD insights into the treatment and outcomes among people with diabetes in daily general practice. The data can be enriched by established linkages to other data sources (eg, hospital data, the Perinatal Registry, the Cancer Registry). The DIAMANT cohort serves as a start of a national infrastructure to study, manage and provide personalised care in order to ultimately improve care and outcomes for people with diabetes.Keywords: diabetes, type 2 diabetes, epidemiology, follow-up, prospective cohort, real-world data

BACKGROUND: Previous studies have observed a higher out-of-hospital cardiac arrest (OHCA) risk among lower socioeconomic groups. However, due to the cross-sectional and ecological designs used in these studies, the magnitude of these inequalities is uncertain. This study is the first to assess the individual-level association between income and OHCA using a large-scale longitudinal study. Methods: This retrospective cohort study followed 1 688 285 adults aged 25 and above, living in the catchment area of an OHCA registry in a Dutch province. OHCA cases (n=5493) were linked to demographic and income registries. Cox proportional hazard models were conducted to determine hazard ratios of OHCA for household and personal income quintiles, stratified by sex and age. Results: The total incidence of OHCA per 100 000 person years was 30.9 in women and 87.1 in men. A higher OHCA risk was observed with lower household and personal income. Compared with the highest household income quintile, the adjusted hazard ratios from the second highest to the lowest household income quintiles ranged from 1.24 (CI=1.01–1.51) to 1.75 (CI=1.46–2.10) in women and from 0.95 (CI=0.68–1.34) to 2.30 (CI=1.74–3.05) in men. For personal income, this ranged from 0.95 (CI=0.68–1.34) to 2.30 (CI=1.74–3.05) in women and between 1.28 (CI=1.16–1.42) and 1.68 (CI=1.48–1.89) in men. Comparable household and personal income gradients were found across age groups except in the highest (>84 years) age group. For example, household income in women aged 65 to 74 ranged from 1.25 (CI=1.02–1.52) to 1.65 (CI=1.36–2.00). Sensitivity analyses assessing the prevalence of comorbidities at baseline and different lengths of follow-up yielded similar estimates. Conclusions: This study provides new evidence for a substantial increase in OHCA risk with lower income in different age and sex groups. Low-income groups are likely to be a suitable target for intervention strategies to reduce OHCA risk.

Background Current out-of-hospital cardiac arrest (OHCA) prevention strategies are suboptimal due to the inability to identify subgroups at high risk. Insight into the occurrence of OHCA within general populations may help to target prevention strategies. Case registries suggest that there may be substantial differences in emergency medical service (EMS)-attended OHCA incidence between men and women. However, due to a lack of individual-level prospective data, relative sex differences across ethnic groups and socioeconomic (SES) groups have not been studied. Purpose We investigated sex differences in OHCA incidence, overall and across ethnic groups and SES groups. Methods We performed a retrospective population-based cohort study, combining individual-level data on ethnicity and income (as SES measure) from Statistics Netherlands of all men and women aged ≥25 years living in one study region in the Netherlands on 01–01–2009 (n=1,688,285) with prospectively collected EMS-attended OHCA cases (n=5,676) from the ARREST registry until 31-12-2015. We calculated age-standardised incidence rates of OHCA. Sex differences were assessed with Cox proportional hazards regression analyses, adjusted for age, ethnicity and income, in the overall population, and across ethnic and SES groups. Results Overall, the age-standardised incidence rate of OHCA was lower in women than in men (30.9 versus 87.3 per 100,000 person-years), corresponding with a hazard ratio (HR) of 0.33 (95% confidence interval [CI] 0.31–0.35). While incidence rates varied across subgroups (range: 22.6–104.6 per 100,000 person-years), the sex differences in hazard for OHCA existed in all income quintiles (HR range: 0.30–0.35) and ethnic groups (HR range: 0.19–0.40), except among Moroccans (HR 0.89, 95% CI 0.51–1.57). Conclusion In most ethnic groups and all SES groups, women have a substantial, yet lower OHCA incidence rate than men. This confirms that men are an important target group for OHCA prevention strategies across social strata. Nevertheless, considering potentially differential aetiology as well as the lower survival rates among women, women will also benefit from targeted prevention strategies. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation programme under acronym ESCAPE-NET (grant number 733381) and the COST Action PARQ (grant agreement number CA19137).ZonMw Gender and Health (grant number 8492ehab724.06458) and Gender and Prevention (grant number 555003016) programmes.

Background: The COVID-19 pandemic has a large impact worldwide and is known to particularly affect the older population. This paper outlines the protocol for external validation of prognostic models predicting mortality risk after presentation with COVID-19 in the older population. These prognostic models were originally developed in an adult population and will be validated in an older population (≥70 years of age) in three healthcare settings: the hospital setting, the primary care setting, and the nursing home setting. Methods: Based on a living systematic review of COVID-19 prediction models, we identified eight prognostic models predicting the risk of mortality in adults with a COVID-19 infection (five COVID-19 specific models: GAL-COVID-19 mortality, 4C Mortality Score, NEWS2+ model, Xie model, and Wang clinical model and three pre-existing prognostic scores: APACHE-II, CURB65, SOFA). These eight models will be validated in six different cohorts of the Dutch elder population, three hospital cohorts, two primary care cohorts, and a nursing home cohort. All prognostic models will be validated in hospital setting while the GAL-COVID-19 mortality model will be validated in hospital, primary care, and nursing home settings. The study will include individuals ≥70 years of age with a highly suspected or PCR-confirmed COVID-19 infection from March 2020 to December 2020 (and up to December 2021 in a sensitivity analysis). The predictive performance will be evaluated in terms of discrimination, calibration, and decision curves for each of the COVID-19 prognostic models in each cohort individually. For prognostic models with indications of miscalibration, an intercept update will be performed after which predictive performance will be re-evaluated. Discussion:Insight into the performance of existing prognostic models in one of the most vulnerable populations clarifies the extent to which tailoring of COVID-19 prognostic models is needed when models are applied to the older population. Such insight will be important for possible future waves of the COVID-19 pandemic or future pandemics.

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 by differential effects on APD.

BackgroundThe incidence of out-of-hospital cardiac arrest (OHCA) differs consistently between women and men. Besides sex-related (biological) factors, OHCA risk may relate to gender-related (sociocultural) factors. We explored the association of selected gender-related factors with OHCA incidence in women and men.MethodsWe combined data on emergency medical services-attended OHCA with individual-level data from all women and men aged ≥25 years living in North Holland, the Netherlands. We estimated the associations between employment status, primary earner status, living with children and marital status and the OHCA incidence with Cox proportional hazards models stratified by sex and adjusted for age and socioeconomic status. To determine if metabolic factors explain the associations, we added hypertension, diabetes mellitus and dyslipidaemia to the models. Population attributable fractions (PAF) for all gender-related factors were calculated.ResultsAll four gender-related factors were associated with OHCA incidence (eg, unemployed vs employed; HR 1.98, 95% CI 1.67 to 2.35 in women; HR 1.60, 95% CI 1.44 to 1.79 in men). In both sexes, those unemployed, those who are not primary earners, those living without children, and married or divorced individuals had an increased OHCA risk. The PAF ranged from 4.9 to 40.3 in women and from 4.4 to 15.5 in men, with the highest PAF for employment status in both sexes. Metabolic risk factors did not explain the observed associations.ConclusionGender-related factors were associated with risk of OHCA and contributed substantially to the OHCA burden at the population level, particularly in women. Employment status contributed most to the OHCA burden.

Background This study investigated whether raised chronic stress in low education groups contributes to education differences in cardiovascular disease by altering sympathovagal balance. Methods This study included cross-sectional data of 10,202 participants from the multi-ethnic, population-based HELIUS-study. Sympathovagal balance was measured by baroreflex sensitivity (BRS), the standard deviation of the inter-beat interval (SDNN) and the root mean square of successive differences between normal heartbeats (RMSSD). The associations between chronic stressors (work, home, psychiatric, financial, negative life events, lack of job control and perceived discrimination) in a variety of domains and BRS, SDNN and RMSSD were assessed using linear regression, adjusted for age, ethnicity, waist-to-hip ratio and pack-years smoked. Mediation analysis was used to assess the contribution of chronic stress to the association between education and sympathovagal balance. Results Modest but significant associations were observed between financial stress and BRS and SDNN in women, but not in RMSSD nor for any outcome measure in men. Women with the highest category of financial stress had 0.55% lower BRS (ms/mmHg; β = -0.055; CI = -0.098, -0.011) and 0.61% lower SDNN (ms; β = -0.061; CI = -0.099, -0.024) than those in the lowest category. Financial stress in women contributed 7.1% to the association between education and BRS, and 13.8% to the association between education and SDNN. Conclusion No evidence was found for the hypothesized pathway in which sympathovagal balance is altered by chronic stress, except for a small contribution of financial stress in women.

ObjectiveArea-level socioeconomic factors are known to associate with chances to survive out-of-hospital cardiac arrest (OHCA survival). However, the relationship between individual-level socioeconomic factors and OHCA survival in men and women is less established. This study investigated the association between individual-level income and OHCA survival in men and women, as well as its contribution to outcome variability and mediation by resuscitation characteristics.MethodsA cross-sectional cohort study using data from a Dutch community-based OHCA registry was performed. We included 5395 patients aged≥25 years with OHCA from a presumed cardiac cause. Household income, derived from Statistics Netherlands, was stratified into quartiles. The association between survival to hospital discharge and household income was analysed using multivariable logistic regression adjusting for age, sex and resuscitation characteristics.ResultsOverall women had lower household income than men (median €18 567 vs €21 015), and less favourable resuscitation characteristics. Increasing household income was associated with increased OHCA survival in both men and women in a linear manner (Q4 vs Q1: OR 1.63 95% CI (1.24 to 2.16) in men, and 2.54 (1.43 to 4.48) in women). Only initial rhythm significantly changed the ORs for OHCA survival with>10% in both men and women. Household income explained 3.8% in men and 4.3% in women of the observed variance in OHCA survival.ConclusionBoth in men and women, higher individual-level household income was associated with a 1.2-fold to 2.5-fold increased OHCA survival to hospital discharge, but explained only little of outcome variability. A shockable initial rhythm was the most important resuscitation parameter mediating this association. Our results do not support the need for immediate targeted interventions on actionable prehospital resuscitation care characteristics.

BackgroundThe European resuscitation council have highlighted emergency medical dispatch centres as an important key player for early recognition of Out-of-Hospital Cardiac Arrest (OHCA) and in providing dispatcher assisted cardiopulmonary resuscitation (CPR) before arrival of emergency medical services. Early recognition is associated with increased bystander CPR and improved survival rates. The aim of this study is to describe OHCA call handling in emergency medical dispatch centres in Copenhagen (Denmark), Stockholm (Sweden) and Oslo (Norway) with focus on sensitivity of recognition of OHCA, provision of dispatcher-assisted CPR and time intervals when CPR is initiated during the emergency call (NO-CPRprior), and to describe OHCA call handling when CPR is initiated prior to the emergency call (CPRprior).MethodsBaseline data of consecutive OHCA eligible for inclusion starting January 1st 2016 were collected from respective cardiac arrest registries. A template based on the Cardiac Arrest Registry to Enhance Survival definition catalogue was used to extract data from respective cardiac arrest registries and from corresponding audio files from emergency medical dispatch centres. Cases were divided in two groups: NO-CPRpriorand CPRpriorand data collection continued until 200 cases were collected in the NO-CPRprior-group.ResultsNO-CPRpriorOHCA was recognised in 71% of the calls in Copenhagen, 83% in Stockholm, and 96% in Oslo. Abnormal breathing was addressed in 34, 7 and 98% of cases and CPR instructions were started in 50, 60, and 80%, respectively. Median time (mm:ss) to first chest compression was 02:35 (Copenhagen), 03:50 (Stockholm) and 02:58 (Oslo). Assessment of CPR quality was performed in 80, 74, and 74% of the cases. CPRpriorcomprised 71 cases in Copenhagen, 9 in Stockholm, and 38 in Oslo. Dispatchers still started CPR instructions in 41, 22, and 40% of the calls, respectively and provided quality assessment in 71, 100, and 80% in these respective instances.ConclusionsWe observed variations in OHCA recognition in 71–96% and dispatcher assisted-CPR were provided in 50–80% in NO-CPRpriorcalls. In cases where CPR was initiated prior to emergency calls, dispatchers were less likely to start CPR instructions but provided quality assessments during instructions.

Diese Ethikleitlinien des Europäischen Rats für Wiederbelebung enthalten evidenzbasierte Empfehlungen für die ethische, routinemäßige Praxis der Wiederbelebung und für die Betreuung von Erwachsenen und Kindern am Lebensende. Die Leitlinie konzentriert sich in erster Linie auf wichtige Maßnahmen in Bezug auf ethische Praktiken (d. h. Patientenverfügung, vorausschauende Behandlungsplanung* und gemeinsame Entscheidungsfindung), die Entscheidungsfindung in Bezug auf Wiederbelebung, Ausbildung und Forschung. Diese Bereiche stehen in engem Zusammenhang mit der Anwendung der Prinzipien der Bioethik in der Praxis der Wiederbelebung und der Betreuung am Lebensende.

Background Consent for data research in acute and critical care is complex as patients become at least temporarily incapacitated or die. Existing guidelines and regulations in the European Union are of limited help and there is a lack of literature about the use of data from this vulnerable group. To aid the creation of a patient-centred framework for responsible data research in the acute setting, we explored views of patients and next-of-kin about the collection, storage, sharing and use of genetic and health-related data for observational research. Methods We conducted qualitative interviews (n = 19) with Dutch sudden cardiac arrest survivors who donated clinical and socio-economic data and genetic samples to research. We also interviewed their next-of-kin. Topics were informed by ethics literature and we used scenario-sketches to aid discussion of complex issues. Results Sudden cardiac arrest survivors displayed limited awareness of their involvement in health data research and of the content of their given consent. We found that preferences regarding disclosure of clinically actionable genetic findings could change over time. When data collection and use were limited to the medical realm, patients trusted researchers to handle data responsibly without concern for privacy or other risks. There was no consensus as to whether deferred consent should be explicitly asked from survivors. If consent is asked, this would ideally be done a few months after the event when cognitive capacities have been regained. Views were divided about the need to obtain proxy consent for research with deceased patients’ data. However, there was general support for the disclosure of potentially relevant post-mortem genetic findings to relatives. Conclusions Sudden cardiac arrest patients’ donation of data for research was grounded in trust in medicine overall, blurring the boundary between research and care. Our findings also highlight questions about the acceptability of a one-time consent and about responsibilities of patients, researchers and ethics committees. Finally, further normative investigation is needed regarding the (continued) use of participants’ data after death, which is of particular importance in this setting. Our findings are thought to be of relevance for other acute and life-threatening illnesses as well.

Objective: Alterations in sympathovagal balance are associated with cardiovascular disease. If sympathovagal balance differs across socioeconomic groups, it may reflect a mechanism through which disparities in cardiovascular disease occur. We therefore assessed the association between education and occupation with measures of sympathovagal balance in a large multiethnic sample. Methods: We included cross-sectional data of 10,202 South Asian Surinamese, African Surinamese, Ghanaian, Turkish, Moroccan, and Dutch-origin participants from the Healthy Life in an Urban Setting study. Sympathovagal balance was measured by baroreflex sensitivity (BRS) and the standard deviation of the interbeat interval, calculated fromchanges in blood pressure and interbeat intervals, from5-minute recordings.We calculated geometric means and estimated the relative index of inequality, using age- and ethnicity-adjusted linear regression, to quantify the association between education and occupation and sympathovagal balance. In addition, we assessed whether the association was consistent across ethnic groups. Results: The geometric means of BRS ranged from 8.16 ms/mm Hg (confidence interval [CI] = 7.91-8.43 ms/mm Hg) in low-educated to 14.00 ms/mm Hg (CI = 13.53-14.48 ms/mm Hg) in highly educated women, and from 8.32 ms/mm Hg (CI, 7.97-8.69 ms/mm Hg) in low-educated to 12.25 ms/mm Hg (CI = 11.86-12.66 ms/mm Hg) in highly educated men. High education and occupation were statistically significantly associated with higher BRS and standard deviation of the interbeat interval. Compared with the participants of Dutch origin, a pattern of weaker associations was found in the Surinamese and Ghanaian ethnic groups, but not the Turkish and Moroccan groups. Conclusions: There is a clear socioeconomic gradient in measures of sympathovagal balance, indicating that sympathovagal balance may play a role in socioeconomic disparities in cardiovascular morbidity and mortality.

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],PinteractionPinteraction 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.

Introduction: Out-of-hospital cardiac arrest (OHCA) at home is associated with lower rates of shockable initial rhythm and survival than OHCA in a public location. We determined whether medical history and medication use explain the association between OHCA location and presence of shockable initial rhythm and survival rate. Methods: Data from ARREST, an OHCA registry in the Netherlands, were used (January 2009December 2012). We assessed if OHCA location remained associated with a) presence of shockable initial rhythm and b) survival when taking medical history, medication use, resuscitation characteristics and demographics into account in a multivariable regression analysis. The relative contributions of the above mentioned variables to variance in both outcome measures was estimated using the Nagelkerke test. Results: We included 1404 patients (1034 [73.6%] home OHCA, 370 [26.4%] public OHCA). OHCA location remained significantly associated with shockable initialrhythm(home42.7%,public78.1%;P < 0.01)andsurvivaltohospitaldischarge(home14.0%,public45.7%;P < 0.01).Addingresuscitationcharacteristics to models of shockable initial rhythm and survival rate resulted in an increase in explained variance (13.0%23.6%), whereas adding medical history or medication use to these models resulted in only a limited increase in explained variance (medical history to 27.6%, medication use to 30.0%). Conclusions: Comorbidity and medication use do not substantially contribute in explaining the poor outcome from out-of-hospital cardiac arrest occurring at home. Even when adjusted for medical history, medication use, resuscitation characteristics, and demographics, a large gap of unexplained variance in shockable initial rhythm and survival remains. Keywords: Out-of-hospital, cardiac arrest, location, shockable rhythm, survival

Background: Ventricular fibrillation (VF) waveform analyses are considered a reliable proxy for OHCA characteristics in out-of-hospital cardiac arrest (OHCA), but patient characteristics such as cardiovascular medication use might also be associated with changes in VF waveform measures. Objectives: To assess associations between cardiovascular medication use and amplitude spectrum area (AMSA) of VF, while correcting for the presence of cardiovascular disease (CVD), CVD risk factors, and OHCA characteristics. Methods: We included 990 VF patients from an OHCA registry in the Netherlands, with available information on medical history and cardiovascular medication use. Associations between cardiovascular medication use and AMSA were tested in a multivariate linear regression model, adjusting for CVD, CVD risk factors, and OHCA characteristics. Model performance was shown using R-square and R-change. We also calculated whether medication use was associated with faster dissolution of AMSA to lower values with increasing time delay. Results: In the multivariate analysis, when corrected for CVD, CVD risk factors and OHCA characteristics, only potassium-sparing agents were associated with a lower AMSA when compared to patients using other cardiovascular medications (OR 0.46 [95% CI 0.100.81]; P < 0.012). The decrease in AMSA with increasing EMS-call-to-ECG delay was the same for patients with and without cardiovascular medication use (all P > 0.05). Only a small part of the variance in AMSA could be explained by medication use (R-square 0.003 0.026). Adding OHCA characteristics to the model resulted in the largest R square change (0.090.15). Conclusions: It is unlikely that there is a strong and clinically relevant independent pharmacologic effect of cardiovascular medication use on AMSA. In OHCA, AMSA might be used as patient management tool without considering cardiovascular medication use.: It is unlikely that there is a strong and clinically relevant independent pharmacologic effect of cardiovascular medication use on AMSA. In OHCA, AMSA might be used as patient management tool without considering cardiovascular medication use.

BACKGROUND: Prior research suggests that the proportion of a shockable initial rhythm in out-of-hospital cardiac arrest (OHCA) declined during the last decades. This study aims to investigate if this decline is still ongoing and explore the relationship between location of OHCA and proportion of a shockable initial rhythm as initial rhythm.METHODS: We calculated the proportion of patients with a shockable initial rhythm between 2006-2015 using pooled data from the COSTA-group (Copenhagen, Oslo, Stockholm, Amsterdam). Analyses were stratified according to location of OHCA (residential vs. public).RESULTS: A total of 19,054 OHCA cases were included. Overall, the total proportion of cases with a shockable initial rhythm decreased from 42% to 37% (P CONCLUSION: We found a decline in the proportion of patients with a shockable initial rhythm in OHCAs at a residential location; this decline levelled off during the second half of the study period (2011-2015). In public locations, we observed no decline in shockable initial rhythm over time.

Background: A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit. Objective: Because DPP6 impacts both cardiomyocyte and neuronal function, we hypothesized that ventricular fibrillation (VF) in risk haplotype carriers arises from functional changes in both the heart and autonomic nervous system. Methods: We studied 6 risk haplotype carriers with previous VF (symptomatic), 8 carriers without VF (asymptomatic), and 7 noncarriers (controls). We analyzed supine and standing heart rate variability, baroreflex sensitivity, pre-VF heart rate changes, and myocardial 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. Results: Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P

Background: Lower survival chances after out-of-hospital cardiac arrest (OHCA) in women is associated with lower odds of a shockable initial rhythm (SIR). We hypothesized that sex differences in the prevalence of SIR are due to sex differences in comorbidities. We aimed to establish to what extent sex differences in the cumulative comorbidity burden, measured using the Charlson Comorbidity Index (CCI), or in individual comorbidities, account for the lower proportion of SIR in women. Methods: The association between CCI or its constituent comorbidities, and presence of SIR was studied using data (2010–2014) from a Dutch community-based OHCA registry, and included 2510 OHCA patients aged ≥18y with presumed cardiac cause. Results: The mean age was 67.8 ± 13.8y, 71% were men. Women were more often in high CCI categories than men. However, moderate or high disease burden was associated with lower odds of SIR compared to no disease burden only in men (OR 99 %CI 0.73 [0.53–1.00] and OR 0.54 [0.37–0.80] P-trend < 0.001), but not in women (1.00 [0.58–1.72] and 1.02 [0.57–1.84 P-trend 0.93). Adding CCI to a multivariable model did not alter the OR of sex with SIR. Of the individual comorbidities, only previous myocardial infarction was both differently distributed between sexes (men 22.7% vs. women 13.1%, p < 0.001) and associated with odds of SIR (higher in both sexes). Adding this variable to the model changed the association of sex with initial rhythm from 0.49 (0.38–0.64) to 0.53 (0.41–0.69). Conclusion: Sex differences in comorbidities explained lower odds of SIR in women only modestly: differences in previous myocardial infarction contributed little, and cumulative comorbidity not at all.

Aims Previous studies on sex differences in out-of-hospital cardiac arrest (OHCA) had limited scope and yielded conflicting results. We aimed to provide a comprehensive overall view on sex differences in care utilization, and outcome of OHCA. Methods and results We performed a population-based cohort-study, analysing all emergency medical service (EMS) treated resuscitation attempts in one province of the Netherlands (2006–2012). We calculated odds ratios (ORs) for the association of sex and chance of a resuscitation attempt by EMS, shockable initial rhythm (SIR), and in-hospital treatment using logistic regression analysis. Additionally, we provided an overview of sex differences in overall survival and survival at successive stages of care, in the entire study population and in patients with SIR. We identified 5717 EMS-treated OHCAs (28.0% female). Women with OHCA were less likely than men to receive a resuscitation attempt by a bystander (67.9% vs. 72.7%; P Conclusion In case of OHCA, women are less often resuscitated by bystanders than men. When resuscitation is attempted, women have lower survival rates at each successive stage of care. These sex gaps are likely explained by lower rate of SIR in women, which can only partly be explained by resuscitation characteristics.

Background Individuals with a low socioeconomic status (SES) may have a greater mortality rate from out of hospital cardiac arrest (OHCA) than those with a high SES. We explored whether SES disparities in OHCA mortality manifest in the incidence of OHCA, the chance of receiving bystander cardiopulmonary resuscitation (CPR) or in the chance of surviving an OHCA. We also studied whether sex and age differences exist in such SES disparities. Methods The Medline, Embase and Scopus databases were searched from 01-01-1993 until 31-01-2019. Studies utilising any study design or population were included. Studies were included if the exposure was SES of the OHCA victim or the OHCA location and the outcome was either OHCA incidence, CPR provision and/or survival rate after OHCA. Study selection and quality assessment were conducted by two reviewers independently. Descriptive data and measures of association were extracted, both in the total study population and in subgroups stratified by age and/or sex. This review was carried out following the PRISMA guidelines. Results Overall 32 studies were included. Twelve studies reported on OHCA incidence, thirteen on bystander CPR provision and fourteen on survival. Some evidence for SES differences was found in each identified stage. In all the studies on incidence, SES was measured over the area of the OHCA victims’ residence and was consistently associated with OHCA. In studies on bystander CPR, SES of the area in which the OHCA occurred was associated with bystander CPR, while evidence on individual SES was lacking. In studies on OHCA survival, SES of the victim measured at the individual level and SES of the area in which the OHCA occurred were associated, while SES of the victim, measured at the area of residence was not. Studies reporting age and sex differences in the SES trends were scarce. Conclusion SES disparities in OHCA mortality likely manifest in OHCA incidence, bystander CPR provision and survival rate after OHCA. However, there is a distinct lack of data on SES measured at the individual level and on differences within subgroups, e.g. by sex and age.

Aims Adult congenital heart disease(ACHD) patients are at increased risk ofsudden cardiac deathandout-of-hospital cardiac arrest(OHCA). Currently, insufficient data exist on outcome, causes and circumstances ofOHCAof ACHD patients resuscitated for OHCA. We investigate these parameters in ACHD patients in comparison to OHCA in the general population. Methods and results We identified ACHD patients with OHCA by linking data from a Dutch nationwide registry of ACHD patients (CONCOR, n = 15,727), and ARREST, a cohort of OHCA cases (n = 17,868). 62 ACHD patients with OHCA were identified.Ventricular septal defect(n = 11),bicuspid aortic valve(n = 10) andatrial septal defect(n = 8) were the most common diagnoses. We included OHCA cases from the general population as controls. ACHD patients were younger than controls (n = 11,624) at the time of OHCA (47 (SD ± 17) years vs. 66 (SD ± 15) years, respectively, p ischemia. Survival was better in ACHD patients than in controls (44% vs. 19%, p resuscitation, public location and shockable rhythm. Conclusions OHCA in ACHD patients occurs at young age, is rarely caused by ischemia and occurs mainly in patients with simple congenital defects.Risk stratificationefforts should therefore not be restricted to ACHD patients with severe congenital defects.

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.

These European Resuscitation Council Ethics guidelines provide evidence-based recommendations for the ethical, routine practice of resuscitation and end-of-life care of adults and children. The guideline primarily focus on major ethical practice interventions (i.e. advance directives, advance care planning, and shared decision making), decision making regarding resuscitation, education, and research. These areas are tightly related to the application of the principles of bioethics in the practice of resuscitation and end-of-life care.

IntroductionEarly recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information.AimTo describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA.MethodsThe RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA.ConclusionThe RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.

Background: In Europe, survival-rates after out-of-hospital cardiac arrest (OHCA) vary widely between regions. Whether a system dispatching First Responders (FRs; main FR-types: firefighters, police officers, citizen-responders) is present or not may be associated with survival-rates. This study aimed to assess the association between having a dispatched FR-system and rates of return of spontaneous circulation (ROSC) and survival across Europe. Methods: Results of an inventory of dispatched FR-systems for OHCA in Europe were combined with aggregate ROSC and survival data from the EuReCa-TWO study and additionally collected data. Regression analysis (weighted on number of patients included per region) was performed to study the association between having a dispatched FR-system and ROSC and survival-rates to hospital discharge in the total population and in patients with shockable initial rhythm, witnessed OHCA and bystander cardiopulmonary resuscitation (CPR; Utstein comparator group). For regions without a dispatched FR-system, the theoretical survival-rate if a dispatched FR-system would have existed was estimated. Findings: We included 27 European regions. There were 15,859 OHCAs in the total group and 2,326 OHCAs in the Utstein comparator group. Aggregate ROSC and survival-rates were significantly higher in regions with an FR-system compared to regions without (ROSC: 36% [95%CI 35%-37%] vs. 24% [95%CI 23%–25%]; P

Aim:First responder (FR) programmes dispatch professional FRs (police and/or firefighters) or citizen responders to perform cardiopulmonary resuscitation (CPR) and use automated external defibrillators (AED) in out-of-hospital cardiac arrest (OHCA). We aimed to describe management of FR-programmes across Europe in response to the Coronavirus Disease 2019 (COVID-19) pandemic. Methods:In June 2020, we conducted a cross-sectional survey sent to OHCA registry representatives in 18 European countries with active FR-programmes. The survey was administered by e-mail and included questions regarding management of both citizen responder and FR-programmes. A follow-up question was conducted in October 2020 assessing management during a potential "second wave" of COVID-19. Results:All representatives responded (response rate = 100%). Fourteen regions dispatched citizen responders and 17 regions dispatched professional FRs (9 regions dispatched both). Responses were post-hoc divided into three categories: FR activation continued unchanged, FR activation continued with restrictions, or FR activation temporarily paused. For citizen responders, regions either temporarily paused activation (n = 7, 50.0%) or continued activation with restrictions (n = 7, 50.0%). The most common restriction was to omit rescue breaths and perform compression-only CPR. For professional FRs, nine regions continued activation with restrictions (52.9%) and five regions (29.4%) continued activation unchanged, but with personal protective equipment available for the professional FRs. In three regions (17.6%), activation of professional FRs temporarily paused. Conclusion:Most regions changed management of FR-programmes in response to the COVID-19 pandemic. Studies are needed to investigate the consequences of pausing or restricting FR-programmes for bystander CPR and AED use, and how this may impact patient outcome. Keywords:AED; CPR; Citizen responder; Corona; OHCA.

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 ( 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.