Validation of the ARIC prediction model for sudden cardiac death in the European population: The ESCAPE-NET project.

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.

Harmonization of the definition of sudden cardiac death in longitudinal cohorts of the European Sudden Cardiac Arrest network - towards Prevention, Education, and New Effective Treatments (ESCAPE-NET) consortium.

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.

The impact of modifiable risk factors in the association between socioeconomic status and sudden cardiac death in a prospective cohort study: equal access to healthcare, unequal outcome.

AIMS: Low socioeconomic status is associated with all-cause mortality and cardiac risk factors. Furthermore, sudden cardiac death (SCD) is among the leading causes of death in the general population, and an identification of high-risk subgroups is needed. The aim of this study was to investigate the association between income and education level and incidence of SCD and to calculate the impact of modifiable mediating risk factors. METHODS AND RESULTS: Participants in the Copenhagen City Heart Study were followed up from 1993 to 2016. Sudden cardiac death was identified using high-quality death certificates, autopsy reports, discharge summaries, and national registry data. Hazard ratios were calculated using Cox proportional hazards regression, and adjusted cumulative incidences were predicted using cause-specific Cox models. Mediation analyses were performed using a marginal structural model approach. During 24 years of follow-up, 10 006 people participated, whereof 5514 died during the study period with 822 SCDs. Compared with long education, persons with elementary school level education had an SCD incidence rate ratio (IRR) of 2.48 [95% confidence interval (CI) 1.86-3.31], and low income was likewise associated with an SCD IRR of 2.34 (95% CI 1.85-2.96) compared with high income. In the association between education and SCD, the combined mediating effect of smoking, physical activity, and body mass index accounted for ∼20% of the risk differences. CONCLUSION: We observed an inverse association between both income and education and the risk of SCD, which was only in part explained by common cardiac risk factors, implying that further research into the competing causes of SCD is needed and stressing the importance of targeted preventive measures.

Low socioeconomic status (e.g. education and income) has previously been found associated with an increased risk of death and with different heart diseases. Sudden cardiac death (SCD) is among the leading causes of death in the general population, and predicting who is at high risk is difficult. Finding people or groups at high risk is important to improve prevention. That is why we decided to investigate whether socioeconomic status is also associated with the risk of SCD and to calculate the impact of modifiable lifestyle factors on this risk. We followed ∼10 000 people from a general population cohort for 24 years and observed 822 sudden cardiac deaths. The lowest income and education groups had more than twice the risk of SCD compared with the high groups. Differences in smoking, physical activity, and body mass index explained ∼20% of this increase.

Temporal trends and sex differences in sudden cardiac death in the Copenhagen City Heart Study.

OBJECTIVE: More knowledge about the development of sudden cardiac death (SCD) in the general population is needed to develop meaningful predictors of SCD. Our aim with this study was to estimate the incidence of SCD in the general population and examine the temporal changes, demographics and clinical characteristics. METHODS: All participants in the Copenhagen City Heart Study were followed from 1993 to 2016. All death certificates, autopsy reports and national registry data were used to identify all cases of SCD. RESULTS: A total of 14 562 subjects were included in this study. There were 8394 deaths with all information available, whereof 1335 were categorised as SCD. The incidence of SCD decreased during the study period by 41% for persons aged 40-90 years, and the standardised incidence rates decreased from 504 per 100 000 person-years (95% CI 447 to 569) to 237 per 100 000 person-years (95% CI 195 to 289). The incidence rate ratio of SCD between men and women ≤75 years was 1.99 (95% CI 1.62 to 2.46). The proportion of SCD of all cardiac deaths decreased during the observation period and decreased with increasing age. Men had more cardiovascular comorbidities (OR 1.34, 95% CI 1.07 to 1.68, p<0. 01), and SCD was the first registered manifestation of cardiac disease in 50% of all cases. CONCLUSION: The incidence of SCD in the general population has declined significantly during the study period but should be further investigated for more recent variations as well as novel risk predictors for persons with low to medium risk of SCD.

Low Birth Weight Increases the Risk of Sudden Cardiac Death in the Young: A Nationwide Study of 2.2 Million People.

Background Sudden cardiac death (SCD) constitutes a major health problem worldwide. We investigated whether birth weight (BW), small for gestational age (SGA), and large for gestational age are associated with altered risk of SCD among the young (aged 1-36 years). Methods and Results We included all people born in Denmark from 1973 to 2008 utilizing the Danish Medical Birth Register. All SCDs in Denmark in 2000 to 2009 have previously been identified. We defined 5 BW groups, SGA, and large for gestational age as exposure and SCD as the outcome. We estimated the age-specific relative risk of SCD with 95% CI. Additionally, we investigated if SGA and large for gestational age are associated with pathological findings at autopsy. The study population for the BW analyses comprised 2 234 501 people with 389 SCD cases, and the SGA and large for gestational age analyses comprised 1 786 281 people with 193 SCD cases. The relative risk for SCD was 6.69 for people with BW between 1500 and 2499 g (95% CI, 2.38-18.80, P<0.001) and 5.89 for people with BW ≥4500 g (95% CI, 1.81-19.12, P=0.003) at age 5 years. BW 2500 to 3400 g was the reference group. Compared with an appropriate gestational age, the relative risk for SGA was 2.85 (95% CI, 1.35-6.00, P=0.006) at age 10 years. For the autopsied cases, the relative risk of sudden arrhythmic death syndrome at age 5 years was 4.19 for SGA (95% CI, 1.08-16.22, P=0.038). Conclusions We found an association between BW and SCD in the young, with an increased risk among SGA infants. In addition, we found an association between SGA and sudden arrhythmic death syndrome.

Sudden unexpected death caused by stroke: A nationwide study among children and young adults in Denmark.

Background Stroke is the fifth leading cause of death in young individuals globally. Data on the burden of sudden death by stroke are sparse in the young. Aims The aim of this study was to report mortality rates, cause of death, stroke subtype, and symptoms in children and young adults who suffered sudden death by stroke. Methods We conducted a retrospective, nationwide study including all deaths within Danish borders between 2000-2009 and 2007-2009 in persons aged 1-35 years and 36-49 years, respectively. Two physicians identified all sudden death cases through review of all death certificates. All available autopsy reports and records from hospitals and general practitioners were retrieved and a neurologist identified all sudden death by stroke cases. Results Of the 14,567 deaths in the 10-year period, there were 1,698 sudden death cases, of which 52 (3%) were sudden death by stroke. There was a male predominance (56%) and the median age was 33 years. The incidence of sudden death by stroke in individuals aged 1-49 years was 0.19 deaths per 100,000 person-years. Stroke was hemorrhagic in 94% of cases, whereof subarachnoid hemorrhage was the cause of death in 63% of cases. Seventeen (33%) cases contacted the healthcare system because of neurological symptoms, whereof one was suspected of having a stroke (6%). Conclusions Sudden death by stroke in children and young adults occurs primarily due to hemorrhagic stroke. We report a high frequency of neurological symptoms prior to sudden death by stroke. Increased awareness among healthcare professionals towards stroke symptoms in children and young adults may lead to earlier detection of stroke, and thereby potentially lowering the incidence of sudden death by stroke.

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine.

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies. For each study, the coefficient of variation was calculated for maximum plasma concentration and area under the plasma concentration-time curve, and we divided the drug variability into two categories; high variability, coefficient of variation >40%, or low or moderate variability, coefficient of variation <40%. Based on the area under the plasma concentration-time curve in steady-state studies, the following drugs have high pharmacokinetic variability: propranolol in 92% (33/36), metoprolol in 85% (33/39), and amitriptyline in 60% (3/5) of studies. The following drugs have low or moderate variability: atenolol in 100% (2/2), valproate in 100% (15/15), topiramate in 88% (7/8), and naproxen and candesartan in 100% (2/2) of studies. For drugs with low or moderate pharmacokinetic variability, treatment can start without initial titration of doses, whereas titration is used to possibly enhance tolerability of topiramate and amitriptyline. The very high pharmacokinetic variability of metoprolol and propranolol can result in very high plasma concentrations in a small minority of patients, and those drugs should therefore be titrated up from a low initial dose, depending mainly on the occurrence of adverse events.

Sudden cardiac death and coronary disease in the young: A nationwide cohort study in Denmark.

BACKGROUND: Sudden cardiac death caused by coronary artery disease (CAD-SCD) is the most frequent cause of SCD in persons <50years. The aim of this study was to examine differences in clinical characteristics and autopsy findings of the heart among 18-35 and 36-49year old CAD-SCD cases. METHODS: We have previously identified all sudden cardiac deaths in Denmark through review of death certificates and autopsy reports including all deaths between 2000 and 2006 in individuals aged 18-35years and all deaths between 2007 and 2009 in individuals aged 18-49years. In this study we included the 197 autopsied CAD-SCD cases. Full autopsy report and medical records from general practitioners and hospitals were obtained. RESULTS: There was a male predominance (n=151, 76%) and the median age was 42years. In witnessed cases, 51% had a shockable rhythm and 9 cases returned to spontaneous circulation briefly, CAD-SCD victims aged 36-49years had more severe atherosclerosis in all coronary arteries, more multi-vessel disease (29% vs. 15%, p=0.049) and less commonly (38% vs. 54%, p=0.039) acute coronary occlusion than victims <36years. Sixty-eight percent(n=133) of CAD-SCD victims had cardiac symptoms prior to death. CONCLUSION: This nationwide study found several differences in the pathologic lesions of the heart in victims aged 18-35 and 36-49years, which might be associated with different disease progression leading to death in these age groups. We also report a high frequency of cardiac symptoms prior to death in young CAD-SCD cases, which may enable clinicians to prevent these tragic deaths.