Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study.

BACKGROUND AND AIMS: The benefit of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) and intermediate stroke risk is debated. In a nationwide Norwegian cohort with a non-sex CHA2DS2-VASc risk score of one, this study aimed to investigate (i) stroke and bleeding risk in AF patients with and without OAC treatment, and (ii) the risk of stroke in non-anticoagulated individuals with and without AF. METHODS: A total of 1 118 762 individuals including 34 460 AF patients were followed during 2011-18 until ischaemic stroke, intracranial haemorrhage, increased CHA2DS2-VASc score, or study end. One-year incidence rates (IRs) were calculated as events per 100 person-years (%/py). Cox regression models provided adjusted hazard ratios (aHRs [95% confidence intervals]). RESULTS: Among AF patients, the ischaemic stroke IR was 0.51%/py in OAC users and 1.05%/py in non-users (aHR 0.47 [0.37-0.59]). Intracranial haemorrhage IR was 0.28%/py in OAC users and 0.19%/py in non-users (aHR 1.23 [0.88-1.72]). Oral anticoagulant use was associated with an increased risk of major bleeding (aHR 1.37 [1.16-1.63]) but lower risk of the combined outcome of ischaemic stroke, major bleeding, and mortality (aHR 0.57 [0.51-0.63]). Non-anticoagulated individuals with AF had higher risk of ischaemic stroke compared to non-AF individuals with the same risk profile (aHR 2.47 [2.17-2.81]). CONCLUSIONS: In AF patients at intermediate risk of stroke, OAC use was associated with overall favourable clinical outcomes. Non-anticoagulated AF patients had higher risk of ischaemic stroke compared to the general population without AF with the same risk profile.

Comparative Safety of Antiseizure Medication Monotherapy for Major Malformations.

OBJECTIVE: This study was undertaken to examine the comparative safety of antiseizure medication (ASM) monotherapy in pregnancy with respect to risk of major congenital malformations (MCMs), overall and by MCM subtype. METHODS: We conducted a population-based cohort study using national health register data from Denmark, Finland, Iceland, Norway, and Sweden (1996-2020). We compared pregnancies with first trimester exposure to lamotrigine monotherapy to ASM-unexposed, carbamazepine, valproate, oxcarbazepine, levetiracetam, and topiramate to lamotrigine monotherapy, and stratified monotherapy groups by dose. The outcome was nongenetic MCM and specific subtypes. We estimated adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) with log-binomial regression and propensity score weights. RESULTS: There was a higher crude risk of any MCM in pregnancies exposed to lamotrigine monotherapy (n = 8,339) compared to ASM-unexposed pregnancies (n = 4,866,362), but not after confounder adjustment (aRR = 0.97, 95% CI = 0.87-1.08). Compared to lamotrigine, there was an increased risk of malformations associated with valproate (n = 2,031, aRR = 2.05, 95% CI = 1.70-2.46) and topiramate (n = 509, aRR = 1.81, 95% CI = 1.26-2.60), which increased in a dose-dependent manner. We found no differences in malformation risk for carbamazepine (n = 2,674, aRR = 0.91, 95% CI = 0.72-1.15), oxcarbazepine (n = 1,313, aRR = 1.09, 95% CI = 0.83-1.44), or levetiracetam (n = 1,040, aRR = 0.78, 95% CI = 0.53-1.13). Valproate was associated with several malformation subtypes, including nervous system, cardiac, oral clefts, clubfoot, and hypospadias, whereas lamotrigine and carbamazepine were not. INTERPRETATION: Topiramate is associated with an increased risk of MCM similar to that associated with valproate, but lower doses may mitigate the risks for both drugs. Conversely, we found no increased risks for lamotrigine, carbamazepine, oxcarbazepine, or levetiracetam, which is reassuring. ANN NEUROL 2023;93:551-562.

Treatment patterns of antidepressants in children and adolescents in Scandinavia.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.

Stroke After SARS-CoV-2 mRNA Vaccine: A Nationwide Registry Study.

BACKGROUND: Whether the SARS-CoV-2 mRNA vaccines may cause a transient increased stroke risk is uncertain. METHODS: In a registry-based cohort of all adult residents at December 27, 2020, in Norway, we linked individual-level data on COVID-19 vaccination, positive SARS-CoV-2 test, hospital admissions, cause of death, health care worker status, and nursing home resident status extracted from the Emergency Preparedness Register for COVID-19 in Norway. The cohort was followed for incident intracerebral bleeding, ischemic stroke, and subarachnoid hemorrhage within the first 28 days after the first/second or third dose of mRNA vaccination until January 24, 2022. Stroke risk after vaccination relative to time not exposed to vaccination was assessed by Cox proportional hazard ratio, adjusted for age, sex, risk groups, health care personnel, and nursing home resident. RESULTS: The cohort included 4 139 888 people, 49.8% women, and 6.7% were ≥80 years of age. During the first 28 days after an mRNA vaccine, 2104 people experienced a stroke (82% ischemic stroke, 13% intracerebral hemorrhage, and 5% subarachnoid hemorrhage). Adjusted hazard ratios (95% CI) after the first/second and after the third mRNA vaccine doses were 0.92 (0.85-1.00) and 0.89 (0.73-1.08) for ischemic stroke, 0.81 (0.67-0.98) and 1.05 (0.64-1.71) for intracerebral hemorrhage, and 0.64 (0.46-0.87) and 1.12 (0.57-2.19) for subarachnoid hemorrhage, respectively. CONCLUSIONS: We did not find increased risk of stroke during the first 28 days after an mRNA SARS-CoV-2 vaccine.

Smoking history and all-cause, ischaemic heart disease and lung cancer mortality: follow-up study of 358 551 men and women aged 40-43 years.

AIMS: We studied the health consequences of quitting smoking before age 43 by time since quitting, number of years smoked and cigarettes smoked per day. The outcomes were all-cause, ischaemic heart disease and lung cancer mortality. DESIGN: Prospective study. SETTING: Norwegian counties. PARTICIPANTS: Men and women aged 40-43 years who participated in a national cardiovascular screening programme and who were followed from 1985 to 2018. MEASUREMENTS: Self-reports from questionnaire on time since quitting smoking, years smoked and number of cigarettes per day, and measurements of height, weight and blood pressure, and a blood sample where serum was analysed for total serum cholesterol and triglycerides. FINDINGS: The all-cause mortality rate was 30% higher among quitters less than 1 year ago compared with never smokers (adjusted HR=1.30, 95% CI 1.18-1.43 in men and HR=1.31, 95% CI 1.16 to 1.50 in women). Quitters who had smoked longer than 20 years had 23% higher mortality in men (HR=1.23, 95% CI 1.14 to 1.34) and 32% higher mortality in women (HR=1.32, 95% CI 1.18 to 1.49). Past smoking of more than 20 cigarettes/day was associated with HR=1.14 (1.05-1.23) in men and HR=1.16 (1.01-1.32) in women. The HR for lung cancer was 6.77 (95% CI 4.86 to 9.45) for quitting men who had smoked for more than 20 years compared with never smokers. The corresponding figure for women was 5.75 (95% CI 4.08 to 8.09). CONCLUSIONS: The mortality among quitters was close to that of never smokers, except for a higher mortality for lung cancer, which on the other hand was much lower than the lung cancer mortality in current smokers.

Investigating the association between prenatal exposure to folic acid and risk of neonatal diabetes/hyperglycemia and type 1 diabetes: A Norwegian register-based study.

BACKGROUND: Experimental animal studies suggest a novel role for the folate receptor 1 in ß-cell differentiation in the pancreas, with potential implications for glycemic control. We tested the hypothesis of a protective association between prenatal folic acid use and neonatal diabetes or hyperglycemia and type 1 diabetes in an observational cohort study using data from the national population health registers in Norway. METHODS: All singleton pregnancies resulting in live births from 2005 to 2018 were identified. Prenatal exposure to folic acid was determined based on maternal report at antenatal care in early pregnancy. Diagnoses of neonatal diabetes, hyperglycemia, and type 1 diabetes for the children were identified. Associations were estimated with logistic regression or Cox proportional hazard model and included crude and adjusted estimates. RESULTS: Among 781,567 children, 69% had prenatal exposure to folic acid, 264 were diagnosed with neonatal diabetes or hyperglycemia, and 1390 with type 1 diabetes. Compared to children with no prenatal exposure to folic acid, children with prenatal exposure to folic acid had similar odds of having a neonatal diabetes or hyperglycemia diagnosis (adjusted odds ratio 0.95, 95% confidence interval [CI] 0.72, 1.25) and similar risk of being diagnosed with type 1 diabetes (adjusted hazard ratio 1.05, 95% CI 0.93, 1.18). CONCLUSIONS: No association between prenatal folic acid exposure and neonatal diabetes/hyperglycemia or type 1 diabetes was found. These findings do not rule out a translational effect of the experimental results and future studies with longer follow-up and more precise information on the window of prenatal exposure are needed.

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.

Alcohol Consumption, HDL-Cholesterol and Incidence of Colon and Rectal Cancer: A Prospective Cohort Study Including 250,010 Participants.

AIMS: Alcohol consumption has been linked to colorectal cancer (CRC) and also to the high-density lipoprotein cholesterol level (HDL-C). HDL-C has been associated with the incidence of CRC. The aim of this study was to investigate the association between self-reported alcohol consumption, HDL-C and incidence of CRC, separately for the two sites. METHODS: Altogether, 250,010 participants in Norwegian surveys have been followed-up for an average of 18 years with respect to a first-time outcome of colon or rectal cancer. During follow-up, 3023 and 1439 colon and rectal cancers were registered. RESULTS: For men, the HR per 1 drink per day was 1.05 with 95% confidence interval (0.98-1.12) for colon and 1.08 (1.02-1.15) for rectal cancer. The corresponding figures for women were 1.03 (0.97-1.10) and 1.05 (1.00-1.10). There was a positive association between alcohol consumption and HDL-C. HDL-C was inversely associated with colon cancer in men (0.74 (0.62-0.89) per 1 mmol/l) and positively associated with rectal cancer, although not statistically significant (1.15 (0.92-1.44). A robust regression that assigned weights to each observation and exclusion of weights ≤ 0.1 increased the HRs per 1 drink per day and decreased the HR per 1 mmol/l for colon cancer. The associations with rectal cancer remained unchanged. CONCLUSION: Our results support a positive association between alcohol consumption and colon and rectal cancer, most pronounced for rectal cancer. Considering the positive relation between alcohol consumption and HDL-C, the inverse association between HDL-C and colon cancer in men remains unsettled.

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.

Cannabis Use during Pregnancy and Risk of Adverse Birth Outcomes: A Longitudinal Cohort Study.

BACKGROUND: With recent changes in legislation regulating recreational and medical cannabis use around the globe, increased use in pregnancy is to be expected. OBJECTIVES: To investigate the association between cannabis use during pregnancy and birth outcomes. METHOD: Data from the Norwegian Mother and Child Cohort Study (MoBa), a prospective pregnancy cohort, were used. Participants were recruited from all over Norway between 1999 and 2008: 9,312 women with 10,373 pregnancies who reported use of cannabis before or in pregnancy. Women reported on their illegal drug use before pregnancy and at pregnancy weeks 17/18 and 30 and at 6 months postpartum. Linear regression was used to estimate crude and adjusted effects of prenatal cannabis exposure on birth outcomes. RESULTS: In 10,101 pregnancies, women had used cannabis before pregnancy but not during pregnancy. In 272 pregnancies, women had used cannabis during pregnancy, and among these, in 63 pregnancies, women had used cannabis in at least 2 periods. In adjusted analyses for potential confounders, only cannabis use during at least 2 periods of pregnancy showed statistically significant effects on birth weight. The effect was observed in the complete cohort (B = -228 g, 95% CI = -354 to -102, p < 0.001) and for the subgroup where information about the child's father was available (B = -225 g, 95% CI = -387 to -63, p = 0.01). Our results may indicate that prolonged use causes more harm, whereas short-term use did not indicate adverse effects on birth outcomes. CONCLUSIONS: There was a statistically significant and clinically relevant association between the use of cannabis during pregnancy and reduced birth weight. Clinicians should screen not only for cannabis use but also for the length and intensity of use as part of a comprehensive substance use screening.

Interrupted time series analysis to assess changes in prescription filling around conception and implications for exposure misclassification.

PURPOSE: Medication exposures in pregnancy are often defined by one or more prescription fills. Harmful effects could be underestimated if rapid discontinuation of use after pregnancy recognition is common. We used conception, a critical biological period, as an intervention in a novel application of interrupted time series analysis (ITSA). METHODS: Among 645 049 pregnancies from the Medical Birth Registry (2005-2015) linked to the Norwegian Prescription Database, we modeled the total number of prescription fills in the 12 weeks before and after estimated conception date with ITSA. We examined psychostimulants, antidepressants, antipsychotics, and antiepileptics (AEDs; separated by use for epilepsy or other indications). We used relative measures (%) to compare model coefficients. We also compared number of pregnancies defined as exposed when the earliest fill considered was 30 days before the last menstrual period (LMP -30 days), LMP, or estimated conception date (LMP +14 days). RESULTS: We observed a sudden decline in prescription fills from 2 weeks after conception and decreasing fills thereafter for psychostimulants, antidepressants, AEDs for other indications, and antipsychotics excluding incident users. Fills for AEDs for epilepsy did not fall after conception. Only 77% of pregnancies with fills for psychostimulants from LMP and 58% with fills from LMP -30 days had fills from conception. Similar figures for AEDs for epilepsy were 99% and 96%. CONCLUSIONS: This application shows that ITSA can help researchers understand rapid changes in patient behavior around conception that have consequences for exposure misclassification in pregnancy drug safety studies. ITSA results can help pharmacoepidemiologists guide study exposure definitions.

In utero exposure to analgesic opioids and language development in 5-year old children.

PURPOSE: An increasing consumption of opioids has been reported. The primary aim of the present study was follow-up of neurocognitive development in children exposed to analgesic opioids during pregnancy, using three different validated instruments to assess language and communication development at 5 years. METHODS: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women 1999 to 2008. Participants reported medication use at pregnancy week 17/18 and 30, and 6 months after birth. Children's language competence and communication skills at 5 years were reported by mothers on three different validated scales; The Ages and Stages Questionnaire (ASQ), The Speech and Language Assessment Scale (SLAS) and The Twenty Statements about Language-Related Difficulties list (Language20Q). RESULTS: A total of 27 428 women with 33 407 singleton pregnancies were included. Use of analgesic opioids was reported in 584 pregnancies (1.7%). No associations between opioid use and lower language competence or communication skills were found. For ASQ, the OR of being in the lowest category vs the group with maximum mean score was 0.82 (95%CI 0.57, 1.17), for SLAS the OR of scoring worse than typical for age vs better than typical for age was 0.84 (0.61, 1.17) in children exposed to opioids in utero. For Language20Q using the best performance category as reference, the OR of scoring in the lower performance category was 0.57 (0.35, 0.91) with exposure to opioids. CONCLUSION: Use of analgesic opioids in pregnant women does not seem to negatively affect language development or communication skills in children at 5 years.

Using the waiting time distribution with random index dates to estimate prescription durations in the presence of seasonal stockpiling.

PURPOSE: A pervasive problem in registry-based pharmacoepidemiological studies is what exposure duration to assign to individual prescriptions. The parametric waiting time distribution (WTD) has been proposed as a method to estimate such durations. However, when prescription durations vary due to seasonal stockpiling, WTD estimates will vary with choice of index date. To counter this, we propose using random index dates. METHODS: Within a calendar period of a given length, δ, we randomly sample individual index dates. We include the last prescription redemption prior to the index date in the analysis. Only redemptions within distance δ of the index date are included. In a simulation study with varying types and degrees of stockpiling at the end of the year, we investigated bias and precision of the reverse WTD with fixed and random index dates, respectively. In addition, we applied the new method to estimate durations of Norwegian warfarin prescriptions in 2014. RESULTS: In simulation settings with stockpiling, the reverse WTD with random index dates had low relative biases (-0.65% to 6.64%) and high coverage probabilities (92.0% to 95.3%), although when stockpiling was pronounced, coverage probabilities decreased (2.7% to 85.8%). Using a fixed index date was inferior. The estimated duration of warfarin prescriptions in Norway using random index dates was 131 (130; 132) days. CONCLUSIONS: In the presence of seasonal stockpiling, the WTD with random index dates provides estimates of prescription durations, which are more stable, less biased and with better coverage when compared to using a fixed index date.

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006-2016: A study in the five Nordic countries, United States, and Australia.

PURPOSE: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. METHODS: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. RESULTS: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). CONCLUSIONS: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.

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.

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies.

AIMS: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. METHODS AND RESULTS: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. CONCLUSION: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.

Ten-year prediction of cardiovascular disease in healthy Norwegian men, based on NORRISK-2. / Tiårsprediksjon av hjerte- og karsykdom hos friske norske menn basert på NORRISK-2.

BACKGROUND: Norwegian guidelines for primary prevention of cardiovascular disease recommend the use of the NORRISK-2 risk model, with some additions. We wished to investigate whether NORRISK-2 could predict cardiovascular disease in healthy Norwegian men who took part in the Oslo Ischaemia Study. MATERIAL: NORRISK-2 scores were calculated for 2 014 men in the age group 40-60 years who were included in the Oslo Ischaemia Study in 1972-75. Cox regression analyses were used to calculate the hazard ratio for death and cardiovascular disease within ten years of the participants' initial assessment. RESULTS: No participant was lost to follow-up of the 2 014 men, 125 died in the first ten years after inclusion, 61 of whom died from cardiovascular disease. Those who died were older than those who survived, with a larger proportion of daily smokers, and they had higher systolic blood pressure and resting pulse, increased total cholesterol and lower physical fitness. The majority of those who died from acute myocardial infarction and ischaemic stroke within ten years were classified in the high-risk group in NORRISK-2. INTERPRETATION: NORRISK-2 satisfactorily identified the high-risk persons in this cohort of healthy, middle-aged Norwegian men. This supports use of the Norwegian guidelines in the decision on possible primary protection against cardiovascular disease.

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Educational inequalities in midlife risk factors for non-communicable diseases in two Norwegian counties 1974-2002.

Background: The absolute educational differences in the mortality of Norwegian women and men increased during 1960-2000 and thereafter levelled off in men, but continued to widen in women. Which of the risk factors for non-communicable diseases (NCDs) might explain these trends? Aim: The aim of this study was to investigate trends in gender-specific, absolute educational differences in established risk factors during 1974-2002. Methods: We used cross-sectional data from 40-45-year-old women and men who participated in one of three health surveys in two counties, from the years 1974-1978, 1985-1988 and 2001-2002. To account for increasing educational attainment through the period we used a regression-based index of inequality (Slope Index of Inequality) to assess the educational gradients over time. Results: From 1974 to 2002, the mean levels of serum total cholesterol and blood pressure decreased and body mass index (BMI) increased in all subgroups by education in both sexes. In men, the educational gradient tended to diminish toward the null for serum total cholesterol and narrowed for systolic blood pressure, but increased for BMI. In women, the educational gradient increased to the double for smoking and increased for triglycerides. Conclusions: In two Norwegian counties, the NCD risk factors showed dynamic patterns during 1974-2002. For blood pressure and serum total cholesterol, the levels showed consistent beneficial changes in all educational subgroups, with a narrowing tendency for educational gradients in men. In women, the educational gradient for smoking increased markedly. Knowledge on midlife trends in the educational gradients of risk factors may help to explain recent and future NCD mortality.

ß-Blocker Use in Pregnancy and the Risk for Congenital Malformations: An International Cohort Study.

Background: ß-Blockers are a class of antihypertensive medications that are commonly used in pregnancy. Objective: To estimate the risks for major congenital malformations associated with first-trimester exposure to ß-blockers. Design: Cohort study. Setting: Health registries in the 5 Nordic countries and the U.S. Medicaid database. Patients: Pregnant women with a diagnosis of hypertension and their offspring. Measurements: First-trimester exposure to ß-blockers was assessed. Outcomes were any major congenital malformation, cardiac malformations, cleft lip or palate, and central nervous system (CNS) malformations. Propensity score stratification was used to control for potential confounders. Results: Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to ß-blockers in the first trimester. The pooled adjusted relative risk (RR) and risk difference per 1000 persons exposed (RD1000) associated with ß-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, -6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, -4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, -0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, -2.0 to 4.0) (based on U.S. cohort data only). Limitation: Analysis was restricted to live births, exposure was based on dispensed medication, and cleft lip or palate and CNS malformations had few outcomes. Conclusion: The results suggest that maternal use of ß-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders. Primary Funding Source: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Söderström König Foundation.