SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents.

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged. Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age. Design, Setting, and Participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23 122 522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden. Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2. Main Outcomes and Measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals. Results: Among 23 122 522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar. Conclusions and Relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

Using multiple random index dates with the reverse waiting time distribution improves precision of estimated prescription durations.

PURPOSE: To improve the precision of prescription duration estimates when using the reverse waiting time distribution (rWTD). METHODS: For each patient we uniformly sampled multiple random index dates within a sampling window of length δ . For each index date, we identified the last preceding prescription redemption, if any, within distance δ . Based on all pairs of last prescription and index date, we estimated prescription durations using the rWTD with robust variance estimation. In simulation studies with increasing misspecification we investigated bias, root mean square error (RMSE) and coverage probability of the rWTD using multiple index dates (1, 5, 10, and 20). We applied the method to Danish data on warfarin prescriptions from 2013 to 2014 stratifying by and adjusting for sex and age. RESULTS: In simulation scenarios without misspecification, the relative bias was negligible (-0.04% to 0.01%) and nominal coverage probabilities almost retained (93.8%-95.4%). RMSE decreased with the number of random index dates (e.g., from 1.3 with 1 index date to 0.6 days with 5). With misspecification, the relative bias was higher irrespective of the number of index dates. Precision increased with the number of index dates, and hence coverage probabilities decreased. When estimating durations of warfarin prescriptions in Denmark, precision increased with number of index dates, in particular in strata with few patients (e.g., men 90+ years: width of 95% confidence interval was 16.2 days with 5 index dates versus 35.4 with 1). CONCLUSIONS: Increasing the number of random index dates used with the rWTD improved precision without affecting bias.

Change in cardiovascular risk assessment tool and updated Norwegian guidelines for cardiovascular disease in primary prevention increase the population proportion at risk: the Tromsø Study 2015-2016.

AIMS: To compare the population proportion at high risk of cardiovascular disease (CVD) using the Norwegian NORRISK 1 that predicts 10-year risk of CVD mortality and the Norwegian national guidelines from 2009, with the updated NORRISK 2 that predicts 10-year risk of both fatal and non-fatal risk of CVD and the Norwegian national guidelines from 2017. METHODS: We included participants from the Norwegian population-based Tromsø Study (2015-2016) aged 40-69 years without a history of CVD (n=16 566). The total proportion eligible for intervention was identified by NORRISK 1 and the 2009 guidelines (serum total cholesterol ≥8 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg) and NORRISK 2 and the 2017 guidelines (serum total cholesterol ≥7 mmol/L, low density lipoprotein (LDL) cholesterol ≥5 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg). RESULTS: The total proportion at high risk as defined by a risk score was 12.0% using NORRISK 1 and 9.8% using NORRISK 2. When including single risk factors specified by the guidelines, the total proportion eligible for intervention was 15.5% using NORRISK 1 and the 2009 guidelines and 18.9% using NORRISK 2 and the 2017 guidelines. The lowered threshold for total cholesterol and specified cut-off for LDL cholesterol stand for a large proportion of the increase in population at risk. CONCLUSION: The population proportion eligible for intervention increased by 3.4 percentage points from 2009 to 2017 using the revised NORRISK 2 score and guidelines.

Occupational physical activity and longevity in working men and women in Norway: a prospective cohort study.

BACKGROUND: Studies suggest that high occupational physical activity increases mortality risk. However, it is unclear whether this association is causal or can be explained by a complex network of socioeconomic and behavioural factors. We aimed to examine the association between occupational physical activity and longevity, taking a complex network of confounding variables into account. METHODS: In this prospective cohort study, we linked data from Norwegian population-based health examination surveys, covering all parts of Norway with data from the National Population and Housing Censuses and the Norwegian Cause of Death Registry. 437 378 participants (aged 18-65 years; 48·7% men) self-reported occupational physical activity (mutually exclusive groups: sedentary, walking, walking and lifting, and heavy labour) and were followed up from study entry (between February, 1974, and November, 2002) to death or end of follow-up on Dec 31, 2018, whichever came first. We estimated differences in survival time (death from all causes, cardiovascular disease, and cancer) between occupational physical activity categories using flexible parametric survival models adjusted for confounding factors. FINDINGS: During a median of 28 years (IQR 25-31) from study entry to the end of follow-up, 74 203 (17·0%) of the participants died (all-cause mortality), of which 20 111 (27·1%) of the deaths were due to cardiovascular disease and 29 886 (40·3%) were due to cancer. Crude modelling indicated shorter mean survival times among men in physically active occupations than in those with sedentary occupations. However, this finding was reversed following adjustment for confounding factors (birth cohort, education, income, ethnicity, prevalent cardiovascular disease, smoking, leisure-time physical activity, body-mass index), with estimates suggesting that men in occupations characterised by walking, walking and lifting, and heavy labour had life expectancies equivalent to 0·4 (95% CI -0·1 to 1·0), 0·8 (0·3 to 1·3), and 1·7 (1·2 to 2·3) years longer, respectively, than men in the sedentary referent category. Results for mortality from cardiovascular disease and cancer showed a similar pattern. No clear differences in survival times were observed between occupational physical activity groups in women. INTERPRETATION: Our results suggest that moderate to high occupational physical activity contributes to longevity in men. However, occupational physical activity does not seem to affect longevity in women. These results might inform future physical activity guidelines for public health. FUNDING: The Norwegian Research Council (grant number 249932/F20).

Validation of the cardiovascular risk model NORRISK 2 in South Asians and people with diabetes.

OBJECTIVES: To evaluate the predictive ability of the previously published NORRISK 2 cardiovascular risk model in Norwegian-born and immigrants born in South Asia living in Norway, and to add information about diabetes and ethnicity in an updated model for South Asians and diabetics (NORRISK 2-SADia). Design. We included participants (30-74 years) born in Norway (n = 13,885) or South Asia (n = 1942) from health surveys conducted in Oslo 2000-2003. Cardiovascular disease (CVD) risk factor information including self-reported diabetes was linked with information on subsequent acute myocardial infarction (AMI) and acute cerebral stroke in hospital and mortality registry data throughout 2014 from the nationwide CVDNOR project. We developed an updated model using Cox regression with diabetes and South Asian ethnicity as additional predictors. We assessed model performance by Harrell's C and calibration plots. Results. The NORRISK 2 model underestimated the risk in South Asians in all quintiles of predicted risk. The mean predicted 13-year risk by the NORRISK 2 model was 3.9% (95% CI 3.7-4.2) versus observed 7.3% (95% CI 5.9-9.1) in South Asian men and 1.1% (95% CI 1.0-1.2) versus 2.7% (95% CI 1.7-4.2) observed risk in South Asian women. The mean predictions from the NORRISK 2-SADia model were 7.2% (95% CI 6.7-7.6) in South Asian men and 2.7% (95% CI 2.4-3.0) in South Asian women. Conclusions. The NORRISK 2-SADia model improved predictions of CVD substantially in South Asians, whose risks were underestimated by the NORRISK 2 model. The NORRISK 2-SADia model may facilitate more intense preventive measures in this high-risk population.

Risk of cardiovascular disease after preventive salpingo-oophorectomy.

INTRODUCTION: Breast cancer susceptibility gene (BRCA) mutation carriers are recommended to undergo early oophorectomy to prevent ovarian cancer. Premature loss of ovarian hormones may increase the risk of cardiovascular disease. Because women with preventive oophorectomy are mainly young and healthy, they rarely undergo specialized cardiological surveillance. We compared the risk of cardiovascular disease in women after preventive oophorectomy with reference women. METHODS: In an historical cohort study, we included 134 women aged ≤52 years after preventive oophorectomy and 268 age matched premenopausal reference women, aged 52 years or less, from the general population, excluding participants with diabetes or cardiovascular disease. The Norwegian risk assessment tool (NORRISK 2) was used to estimate 10 year cardiovascular risk. This algorithm was validated in a large Norwegian population and is based on age, smoking, systolic blood pressure, total and high density lipoprotein cholesterol, antihypertensive medication, and family history of cardiovascular disease. We also examined cardiometabolic factors (levels of triglycerides and high sensitivity C reactive protein, as well as body mass index and waist circumference) not included in the NORRISK 2 calculation. RESULTS: Median age in the preventive oophorectomy and reference groups were 47 (range 33-52) and 46 (31-52) years, respectively. Mean time since surgery in the preventive oophorectomy group was 4.2 years (standard deviation (SD) 2.8). Ten year cardiovascular risk was similar in women after preventive oophorectomy and reference women (mean 1.15% (SD 1.00) vs 1.25 (1.09), respectively, p=0.4). Women in the preventive oophorectomy group had a lower body mass index (24.7 kg/m2 (4.0) vs 26.2 (4.8), p=0.003) and waist circumference (86 cm vs 89, p=0.006). The overall cardiovascular risk estimation was comparable among hormone therapy users and non-users, but hormone therapy users had lower total cholesterol and waist circumference. DISCUSSION: Women who underwent preventive oophorectomy had a similar risk of cardiovascular disease as population based reference women, estimated according to risk factors easily measured in general practice. Cardiometabolic risks were not increased in the preventive oophorectomy group.

Performance of a Framingham cardiovascular risk model among Indians and Europeans in New Zealand and the role of body mass index and social deprivation.

Objectives: To evaluate a Framingham 5-year cardiovascular disease (CVD) risk score in Indians and Europeans in New Zealand, and determine whether body mass index (BMI) and socioeconomic deprivation were independent predictors of CVD risk. Methods: We included Indians and Europeans, aged 30-74 years without prior CVD undergoing risk assessment in New Zealand primary care during 2002-2015 (n=256 446). Risk profiles included standard Framingham predictors (age, sex, systolic blood pressure, total cholesterol/high-density lipoprotein ratio, smoking and diabetes) and were linked with national CVD hospitalisations and mortality datasets. Discrimination was measured by the area under the receiver operating characteristics curve (AUC) and calibration examined graphically. We used Cox regression to study the impact of BMI and deprivation on the risk of CVD with and without adjustment for the Framingham score. Results: During follow-up, 8105 and 1156 CVD events occurred in Europeans and Indians, respectively. Higher AUCs of 0.76 were found in Indian men (95% CI 0.74 to 0.78) and women (95% CI 0.73 to 0.78) compared with 0.74 (95% CI 0.73 to 0.74) in European men and 0.72 (95% CI 0.71 to 0.73) in European women. Framingham was best calibrated in Indian men, and overestimated risk in Indian women and in Europeans. BMI and deprivation were positively associated with CVD, also after adjustment for the Framingham risk score, although the BMI association was attenuated. Conclusions: The Framingham risk model performed reasonably well in Indian men, but overestimated risk in Indian women and in Europeans. BMI and socioeconomic deprivation could be useful predictors in addition to a Framingham score.

Impact of age on excess risk of coronary heart disease in patients with familial hypercholesterolaemia.

OBJECTIVE: The primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population. METHODS: Patients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001-2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates. RESULTS: SIRs for AMI (95% CIs) were highest in the age group 25-39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70-79 years. Similarly, SIRs for CHD were highest among patients 25-39 years old; 11.1 (7.1-17.5) in men and 17.3 (9.6-31.2) in women and decreased 2.4 (1.4-4.2) in men and 3.2 (1.5-7.2) in women at age 70-79. For all age groups, combined SIRs for CHD were 4.2 (3.6-5.0) in men and 4.7 (3.9-5.7) in women. CONCLUSION: Patients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25-39 years, in both sexes.

Smoking and risk of ovarian cancer by histological subtypes: an analysis among 300 000 Norwegian women.

BACKGROUND: We prospectively investigated the association between different measures of smoking exposure and the risk of serous, mucinous, and endometrioid ovarian cancers (OC) in a cohort of more than 300 000 Norwegian women. METHODS: We followed 300 398 women aged 19-67 years at enrolment until 31 December 2013 for OC incidence through linkage to national registries. We used Cox proportional hazards models with attained age as the underlying time scale to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for relevant confounders. RESULTS: During more than 5.9 million person-years and a median follow-up time of 19 years, 2336 primary invasive (1647, 71%) and borderline (689, 29%) OC were identified (53% serous, 19% mucinous). Compared with never smokers, current smokers who had smoked for ⩾10 years had a higher risk of mucinous OC (HR10-19 years vs never=1.73, 95% CI 1.24-2.42; HR⩾20 vs never=2.26, 95% CI 1.77-2.89, Ptrend <0.001). When stratified by invasiveness, current smokers had a higher risk of invasive mucinous OC (HR=1.78, 95% CI 1.20-2.64) and borderline mucinous OC (HR=2.26 95% CI, 1.71-2.97) (Pheterogeneity=0.34) than never smokers. Smoking was not associated with serous or endometrioid OC. CONCLUSIONS: Using a very large cohort of women, the current analysis provides an important replication for a similar risk of invasive and borderline mucinous OC related to smoking.

Height and body mass index in relation to total mortality.

BACKGROUND: The relation between body mass index (BMI) and mortality is not clear in the literature. An inverse relation between height and mortality has been suggested. We explore these relations in a very large cohort in Norway. METHODS: We studied two million men and women, age 20-74 years, who were measured during 1963-2000. These persons were followed for an average of 22.1 years. We used Cox proportional hazard models in the analyses. Also, the optimal BMI (the BMI at the time of measurement that was subsequently related to the lowest mortality) was estimated. RESULTS: Over the study period, 723,000 deaths were registered. The relative risk of death by BMI showed a J- or U-shaped curve, with the lowest rates of death at BMI between 22.5 and 25.0. In men, the optimal BMI increased from 21.6 when measured at age 20-29 to 24.0 when measured at age 70-74. In women, the optimal BMI was consistently higher, increasing from 22.2 to 25.7. Mortality decreased with increased height in men; in women, mortality decreased with height only up to heights of about 160-164 cm and then increased among the tallest women. CONCLUSIONS: The relation between BMI and mortality was J- or U-shaped, with the "optimal" BMI varying by age and sex. Height was inversely related to mortality in men and in women up to a height of 165 cm.