Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

BACKGROUND: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. RESULTS: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. CONCLUSION: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Does Neighborhood Crime Mediate the Relationship Between Neighborhood Socioeconomic Status and Birth Outcomes? An Application of the Mediational G-Formula.

While the link between living in a low-socioeconomic status (SES) neighborhood and higher risk of adverse birth outcomes has been well established, the underlying mechanisms remain poorly understood. Using the parametric g-formula, we assessed the role of neighborhood crime as a potential mediator of the relationship between neighborhood SES and birth outcomes using data on singleton births occurring in the Netherlands between 2010 and 2017 (n = 1,219,470). We estimated total and mediated effects of neighborhood SES on small-for-gestational-age (SGA) birth, low birth weight (LBW), and preterm birth (PTB) for 3 types of crime (violent crimes, crimes against property, and crimes against public order). The g-formula intervention settings corresponded to a hypothetical improvement in neighborhood SES. A hypothetical improvement in neighborhood SES resulted in a 6.6% (95% CI: 5.6, 7.5) reduction in the proportion of SGA birth, a 9.1% (95% CI: 7.6, 10.6) reduction in LBW, and a 5.8% (95% CI: 5.7, 6.2) decrease in PTB. Neighborhood crime jointly accounted for 28.1% and 8.6% of the total effects on SGA birth and LBW, respectively. For PTB, we found no evidence of mediation. The most relevant pathways were crimes against property and crimes against public order. The results indicate that neighborhood crime mediates a meaningful share of the relationship between neighborhood SES and birth outcomes.

The Contribution of Health Behaviors to Depression Risk Across Birth Cohorts.

BACKGROUND: More recent birth cohorts are at a higher depression risk than cohorts born in the early 20th century. We aimed to investigate to what extent changes in alcohol consumption, smoking, physical activity, and obesity contribute to these birth cohort variations. METHODS: We analyzed panel data from US adults born 1916-1966 enrolled in the Health and Retirement Study (N = 163,760 person-years). We performed a counterfactual decomposition analysis by combining age-period-cohort models with g-computation. We thereby compared the predicted probability of elevated depressive symptoms (CES-D 8 score ≥3) in the natural course to a counterfactual scenario where all birth cohorts had the health behaviors of the 1945 birth cohort. We stratified analyses by sex and race-ethnicity. RESULTS: We estimated that depression risk of the 1916-1949 and 1950-1966 birth cohort would be on average 2.0% (-2.3 to -1.7) and 0.5% (-0.9 to -0.1) higher with the alcohol consumption levels of the 1945 cohort. In the counterfactual with the 1945 BMI distribution, depression risk is on average 2.1% (1.8 to 2.4) higher for the 1916-1940 cohorts and 1.8% (-2.2 to -1.5) lower for the 1950-1966 cohorts. We find no cohort variations in depression risk for smoking and physical activity. The contribution of alcohol is more pronounced for Whites than for other race-ethnicity groups, and the contribution of BMI more pronounced for women than for men. CONCLUSION: Increased obesity levels were associated with exacerbated depression risk in recent birth cohorts in the United States, while drinking patterns only played a minor role.

Mechanisms of action of the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin on tubular inflammation and damage: A post hoc mediation analysis of the CANVAS trial.

AIMS: To test the hypothesis that the reduction in urinary kidney injury molecule-1 (KIM-1) observed with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin is mediated through its effects on urine albumin to creatinine ratio (UACR) and monocyte chemoattractant protein-1 (MCP-1) by assessing the proportion of the effect of canagliflozin on KIM-1 that is mediated through its effects on MCP-1 and UACR in patients with type 2 diabetes and albuminuric kidney disease. MATERIAL AND METHODS: We measured KIM-1 and MCP-1 levels in urine samples from the CANVAS trial at baseline and Week 52 with the Mesoscale QuickPlex SQ 120 platform. KIM-1 and MCP-1 were standardized by urinary creatinine (Cr). The proportion of the effect of canagliflozin that is mediated through UACR and MCP-1/Cr on KIM-1/Cr was estimated with G-computation. RESULTS: In total, 763 patients with micro- or macroalbuminuria (17.6% of the total cohort) were included. Baseline characteristics were well balanced between the canagliflozin and placebo group. At Year 1, canagliflozin compared to placebo reduced UACR, MCP-1/Cr and KIM-1/Cr by 40.4% (95% CI 31.0, 48.4), 18.1% (95% CI 8.9, 26.4) and 30.9% (95% CI 23.0, 38.0), respectively. The proportion of the effect of canagliflozin on KIM-1/Cr mediated by its effect on UACR and in turn on MCP-1/Cr was 15.2% (95% CI 9.4, 24.5). CONCLUSION: Canagliflozin reduces urinary KIM-1, suggesting decreased tubular damage. This effect was partly mediated through a reduction in MCP-1, indicative of reduced tubular inflammation, which was in turn mediated by a reduction in UACR. This post hoc analysis suggests that urinary albumin leakage may lead to tubular inflammation and induction of injury, and provide mechanistic insight for how canagliflozin may ameliorate tubular damage, but further research is required to confirm these findings.

The Impact of Unemployment on Antidepressant Purchasing: Adjusting for Unobserved Time-constant Confounding in the g-Formula.

BACKGROUND: The estimated effect of unemployment on depression may be biased by time-varying, intermediate, and time-constant confounding. One of the few methods that can account for these sources of bias is the parametric g-formula, but until now this method has required that all relevant confounders be measured. METHODS: We combine the g-formula with methods to adjust for unmeasured time-constant confounding. We use this method to estimate how antidepressant purchasing is affected by a hypothetical intervention that provides employment to the unemployed. The analyses are based on an 11% random sample of the Finnish population who were 30-35 years of age in 1995 (n = 49,753) and followed until 2012. We compare estimates that adjust for measured baseline confounders and time-varying socioeconomic covariates (confounders and mediators) with estimates that also include individual-level fixed-effect intercepts. RESULTS: In the empirical data, around 10% of person-years are unemployed. Setting these person-years to employed, the g-formula without individual intercepts found a 5% (95% confidence interval [CI] = 2.5%, 7.4%) reduction in antidepressant purchasing at the population level. However, when also adjusting for individual intercepts, we find no association (-0.1%; 95% CI = -1.8%, 1.5%). CONCLUSIONS: The results indicate that the relationship between unemployment and antidepressants is confounded by residual time-constant confounding (selection). However, restrictions on the effective sample when using individual intercepts can compromise the validity of the results. Overall our approach highlights the potential importance of adjusting for unobserved time-constant confounding in epidemiologic studies and demonstrates one way that this can be done.

An Assessment and Extension of the Mechanism-Based Approach to the Identification of Age-Period-Cohort Models.

Many methods have been proposed to solve the age-period-cohort (APC) linear identification problem, but most are not theoretically informed and may lead to biased estimators of APC effects. One exception is the mechanism-based approach recently proposed and based on Pearl's front-door criterion; this approach ensures consistent APC effect estimators in the presence of a complete set of intermediate variables between one of age, period, cohort, and the outcome of interest, as long as the assumed parametric models for all the relevant causal pathways are correct. Through a simulation study mimicking APC data on cardiovascular mortality, we demonstrate possible pitfalls that users of the mechanism-based approach may encounter under realistic conditions: namely, when (1) the set of available intermediate variables is incomplete, (2) intermediate variables are affected by two or more of the APC variables (while this feature is not acknowledged in the analysis), and (3) unaccounted confounding is present between intermediate variables and the outcome. Furthermore, we show how the mechanism-based approach can be extended beyond the originally proposed linear and probit regression models to incorporate all generalized linear models, as well as nonlinearities in the predictors, using Monte Carlo simulation. Based on the observed biases resulting from departures from underlying assumptions, we formulate guidelines for the application of the mechanism-based approach (extended or not).

Estimating time-varying drug adherence using electronic records: extending the proportion of days covered (PDC) method.

PURPOSE: Accurate measurement of drug adherence is essential for valid risk-benefit assessments of pharmacologic interventions. To date, measures of drug adherence have almost exclusively been applied for a fixed-time interval and without considering changes over time. However, patients with irregular dosing behaviour commonly have a different prognosis than patients with stable dosing behaviour. METHODS: We propose a method, based on the proportion of days covered (PDC) method, to measure time-varying drug adherence and drug dosage using electronic records. We compare a time-fixed PDC method with the time-varying PDC method through detailed examples and through summary statistics of 100 randomly selected patients on statin therapy. RESULTS: We demonstrate that time-varying PDC method better distinguishes an irregularly dosing patient from a stably dosing patient and demonstrate how the time-fixed method can result in a biassed estimate of drug adherence. Furthermore, the time-varying PDC method may be better used to reduce certain types of confounding and misclassification of exposure. CONCLUSIONS: The time-varying PDC method may improve longitudinal and time-to-event studies that associate adherence with a clinical outcome or (intervention) studies that seek to describe changes in adherence over time.

The effect of adherence to statin therapy on cardiovascular mortality: quantification of unmeasured bias using falsification end-points.

BACKGROUND: To determine the clinical effectiveness of statins on cardiovascular mortality in practice, observational studies are needed. Control for confounding is essential in any observational study. Falsification end-points may be useful to determine if bias is present after adjustment has taken place. METHODS: We followed starters on statin therapy in the Netherlands aged 46 to 100 years over the period 1996 to 2012, from initiation of statin therapy until cardiovascular mortality or censoring. Within this group (n = 49,688, up to 16 years of follow-up), we estimated the effect of adherence to statin therapy (0 = completely non-adherent, 1 = fully adherent) on ischemic heart diseases and cerebrovascular disease (ICD10-codes I20-I25 and I60-I69) as well as respiratory and endocrine disease mortality (ICD10-codes J00-J99 and E00-E90) as falsification end points, controlling for demographic factors, socio-economic factors, birth cohort, adherence to other cardiovascular medications, and diabetes using time-varying Cox regression models. RESULTS: Falsification end-points indicated that a simpler model was less biased than a model with more controls. Adherence to statins appeared to be protective against cardiovascular mortality (HR: 0.70, 95 % CI 0.61 to 0.81). CONCLUSIONS: Falsification end-points helped detect overadjustment bias or bias due to competing risks, and thereby proved to be a useful technique in such a complex setting.

Brief Report: Association Between Statin Use and Cardiovascular Mortality at the Population Level: An Ecologic Study.

BACKGROUND: We assessed the contribution of statin use to the decline in cardiovascular mortality for The Netherlands over the period 1994-2010. METHODS: We combined aggregated mortality data from Statistics Netherlands with dispensing data from a representative drug dispensing database. We estimated mortality as if prevalence of statin use had remained at its observed 1994 levels throughout the period 1994-2010 for acute myocardial infarction, other ischemic heart disease, and cerebrovascular disease using Poisson models adjusted for various confounders. RESULTS: We estimated that keeping prevalence of statin use at observed 1994 levels would have resulted in 6.3 (95% confidence interval [CI] = 4.9, 7.8), 1.6 (95% CI = 0.8, 2.6), and 3.4 (95% CI = 2.2, 4.6) more acute myocardial infarction, ischemic heart disease, and cerebrovascular deaths per 10,000 person-years, respectively. CONCLUSION: The findings indicate that statin therapy was associated with decreasing national cardiovascular mortality rates in the period 1994 to 2010.

Genetic propensity to depression and the role of partnership status.

Social relationships and genetic propensity are known to affect depression risk, but their joint effects are poorly understood. This study examined the association of a polygenic index for depression with time to antidepressant (AD) purchasing and the moderating role of partnership status. We analysed data from 30,192 Finnish individuals who participated in the FINRISK and Health 2000 and 2011 surveys and had register and medication data available. We measured genetic risk with a polygenic index (PGI) for depression. Depression was assessed through antidepressant purchases. We estimated an accelerated failure time model with partnership status as time-varying and different sets of confounder adjustments. The predicted cumulative hazard of antidepressant purchasing varied across PGI and partnership status. At follow-up year 10, being widowed was associated with the largest cumulative hazard of 0.34 (95%CI: 0.28-0.39) in the 80th and 0.20 (95%CI: 0.17-0.23) in the 20th PGI percentile, followed by divorced, single, married and cohabiting. Cohabiting was associated with a cumulative hazard of 0.19 (95%CI: 0.16-0.23) in the 80th and 0.11 (95%CI: 0.1-0.13) in the 20th PGI percentile. We found no evidence for an interaction between the PGI and partnership status. Results were robust to different model specifications, gender stratification, and the choice of PGI. Although antidepressant purchasing correlated with both PGI and partnership status, we found no evidence that partnership status could partially offset or amplify the association between the PGI for depression and antidepressant purchasing incidence.

Comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events-a real-world longitudinal inception cohort study.

Introduction: Antihypertensive drugs are used preventatively to lower the risk of cardiovascular disease events. Comparative effectiveness studies on angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and thiazides have yielded inconsistent results and given little consideration to patient adherence. Using a longitudinal cohort and considering time-varying adherence and confounding factors, we aimed to estimate the real-world effectiveness of five major antihypertensive drug monotherapies in the primary prevention of cardiovascular events. Methods: Eligible patients for a retrospective inception cohort study were selected using information obtained from the University of Groningen IADB.nl pharmacy prescription database. Cohort 1 comprised adherent patients with a follow-up time exceeding 1 year, and cohort 2 comprised all patients independent of adherence. The exposures were ACEIs, ARBs, BBs, CCBs, and thiazides. The primary outcome was the time to the first prescription for an acute cardiac drug therapy (CDT) measured using valid drug proxies to identify the first major cardiovascular event. A per-protocol analytical approach was adopted with inverse probability of treatment weighted (IPTW), time-varying Cox regression analysis to obtain the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In cohort 1 (n = 22,441), 1,294 patients (5.8%) were prescribed an acute CDT with an average follow-up time of 4.2 ± 2.8 years. Following IPTW, the hazard measures of ARBs and thiazides were lower than those of BBs (HRs: 0.79 and 0.80, respectively; 95% CIs: 0.64-0.97 and 0.69-0.94, respectively). Among drug-treated diabetic patients, the hazard measures were even lower, with HR point estimates of 0.43 (CI: 0.19-0.98) for ARBs and 0.32 (CI: 0.13-0.82) for thiazides. In cohort 2 (n = 33,427) and sensitivity analysis, the comparative effectiveness results for thiazides and BBs were similar to those for cohort 1. Conclusion: The findings of this real-world analysis suggest that the incidence of CDT associated with long-term thiazide or ARB monotherapy is lower than the incidence of CDT with BBs, notably among high-risk patients. Incidences of CDT associated with ACEIs and CCBs were comparable relative to those associated with BBs.

Childhood obesity's influence on socioeconomic disparities in young adolescents' mental health.

PURPOSE: We investigated whether socioeconomic inequalities in young adolescents' mental health are partially due to the unequal distribution of childhood obesity across socioeconomic positions (SEP), i.e. differential exposure, or due to the effect of obesity on mental health being more detrimental among certain SEPs, i.e. differential impact. METHODS: We studied 4660 participants of the Generation R study, a population-based study in the Netherlands. SEP was estimated by mother's education and household income at age five of the child. We estimated the contribution of the mediating and moderating effects of high body fat percentage to the disparity in mental health. This was done through a four-way decomposition using marginal structural models with inverse probability of treatment weighting. RESULTS: Comparing children with the least to most educated mothers and the lowest to highest household income, the total disparity in emotional problems was 0.98 points (95%CI:0.35-1.63) and 1.68 points (95%CI:1.13-2.19), respectively. Of these total disparities in emotional problems, 0.50 points (95%CI:0.15-0.85) and 0.24 points (95%CI:0.09-0.46) were due to the differential exposure to obesity. Obesity did not contribute to disparities in behavioural problems. CONCLUSION: Addressing the heightened obesity prevalence among children in low SEP families may reduce inequalities in emotional problems in early adolescence.

Assessing the effect of a guideline change on drug use prevalence by including the birth cohort dimension: the case of benzodiazepines.

PURPOSE: The aim of this study was to investigate whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the (long-term) effect of a guideline change on the trend of benzodiazepine use. METHODS: We calculated age-specific (20-84 years) and sex-specific prevalence of benzodiazepine use per 1000 population per quarter year (1998 to 2008) using a prescription database set in the Netherlands. We studied the prevalence over time by age group and within birth cohorts through interrupted time series analyses to estimate the effect of the guideline change in 2001. RESULTS: From 1998 to 2008, the overall age-standardized prevalence of benzodiazepine use per 1000 population declined from ~54 for men and ~107 for women to ~45 for men and ~85 for women. The relative change increased significantly after 2001 for both sexes and for the majority of age groups. Within birth cohorts, the prevalence increased with age until the year 2001 and leveled thereafter. The age-period approach overall had worse model fit indicators than the within-cohort approach and predicted larger long-term effects than the within-cohort approach. The age-period projection estimated 36% decline in benzodiazepine use relative to 2008, whereas the birth-cohort projection estimated 8% decline. CONCLUSION: Explicitly following birth cohort trajectories led to models with better fit; the conventional approach estimated a stronger long-term guideline effect. This has important implications for professional practice.

The role of labor market inequalities in explaining the gender gap in depression risk among older US adults.

We aim to investigate to what extent gender inequality at the labor market explains higher depression risk for older US women compared to men. We analyze data from 35,699 US adults aged 50-80 years that participated in the Health and Retirement Study. The gender gap is calculated as the difference in prevalence in elevated depressive symptoms (score ≥ 3 on the 8-item Center for Epidemiological Studies Depression Scale) between women and men. We employ a dynamic causal decomposition and simulate the life course of a synthetic cohort from ages 50-80 with the longitudinal g-formula and introduce four nested interventions by assigning women the same probabilities of A) being in an employment category, B) occupation class, C) current income and D) prior income group as men, conditional on women's health and family status until age 70. The gender gap in depression risk is 2.9%-points at ages 50-51 which increases to 7.6%-points at ages 70-71. Intervention A decreases the gender gap over ages 50-71 by 1.2%-points (95%CI for change: 2.81 to 0.4), intervention D by 1.64%-points (95%CI for change: 3.28 to -0.15) or 32% (95%CI: 1.39 to 62.83), and the effects of interventions B and C are in between those of A and D. The impact is particularly large for Hispanics and low educated groups. Gender inequalities at the labor market substantially explain the gender gap in depression risk in older US adults. Reducing these inequalities has the potential to narrow the gender gap in depression.

Long-term comparative effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events: a population-based retrospective inception cohort study in the Netherlands.

OBJECTIVE: To determine the long-term effectiveness of antihypertensive monotherapies in primary prevention of cardiovascular events. DESIGN: Retrospective inception cohort study covering a 25-year study period. SETTING: University Groningen IADB.nl pharmacy prescription database with data from 1996 to 2020. PARTICIPANTS: Patients aged 18 years or older, free of any cardiovascular disease (CVD) drug therapies prior to initiation of a preventive antihypertensive monotherapy (ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs) and thiazides). OUTCOME MEASURES: Primary outcome was the time to first prescription of acute cardiac drug therapy (CDT) measured by valid drug proxies to identify a first major CVD event in patients without a history of CVD. RESULTS: Among 33 427 initiators, 5205 (15.6%) patients experienced an acute CDT. The average follow-up time was 7.9±5.5 years. The 25-year incidence rate per 1000 person-years were 25.3, 22.4, 18.2, 24.4 and 22.0 for ACEI, ARB, BB, CCB and thiazide starters, respectively. Inverse probability of treatment-weighted Cox regression showed that thiazide starters had lower hazards than the reference BB starters (HR: 0.88, 95% CI: 0.81 to 0.95). Among patients on diabetes drugs, risks were lower (HR: 0.49, 95% CI: 0.28 to 0.85). CCB starters had higher hazards than reference BB (HR: 1.21, 95% CI: 1.07 to 1.36). The overall estimated number needed to treat for thiazides compared with BBs to prevent one acute CDT in 25 years was 26, and four among patients on diabetes drugs. CONCLUSIONS: After adjustments for confounders, patients starting on monotherapy with thiazides had a lower incidence of CDT compared with those starting on BBs, notably among patients on diabetes drugs. Conversely, patients who began CCB monotherapy had a higher incidence of CDT compared with those starting on BBs. Other monotherapies had comparable incidence of cardiovascular disease compared with BBs.

Association Between Alcohol Use Disorders and Dementia in 262,703 Dementia-free Finnish Adults: Is Cardiovascular Disease a Mediator?

BACKGROUND: The possible mediating role of cardiovascular disease (CVD) in the relationship between alcohol use disorders (AUD) and the risk of early-onset (

Real-World Dispensing Patterns of Inhalation Medication in Young Adult Asthma: An Inception Cohort Study.

Purpose: The Global Initiative for Asthma (GINA) suggests a step-wise approach for pharmacological treatment of asthma. Valid study of real-world treatment patterns using dispensing databases includes proper measurement of medication adherence. We aim to explore such patterns by applying a time-varying proportion of days covered (tPDC)-based algorithm. Patients and Methods: We designed a retrospective inception cohort study using the University of Groningen IADB.nl community pharmacy dispensing database. Included were 19,184 young adults who initiated asthma medication anywhere between 1994 and 2021, in the Netherlands. Main treatment steps were defined as: 1 - SABA/ICS-formoterol as needed, 2 - low dose ICS, 3 - low dose ICS + LABA or tiotropium, or intermediate dose ICS, 4 - intermediate to high dose ICS + LABA or tiotropium, triple therapy, or high dose ICS, 5 - treatment prescribed by a specialist. Changes in treatment steps were determined using a time-varying proportion of days covered (tPDC)-based algorithm. Individual drug treatment trajectories were visualized over time using a lasagna plot. Results: At initiation, of the 19,184 included individuals, 52%, 7%, 15%, 16%, and 10% started treatment in steps 1 to 5, respectively. The median (IQR) follow-up time was 3 (1-7) years. Median (IQR) number of switches was 1 (0-3). Comparing starting step to last observed step, 37% never switched between treatment steps, 20% of individuals stepped down and 22% stepped up. Conclusion: The low proportion of treatment switches between steps indicates that tailoring of treatment to patients' needs might be suboptimal. The tPDC-based algorithm functions well in translating dispensing data into continuous drug-utilization data, enabling a more granular assessment of treatment patterns among asthma patients.

Association between Incidence of Prescriptions for Alzheimer's Disease and Beta-Adrenoceptor Antagonists: A Prescription Sequence Symmetry Analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, with a growing number of patients worldwide. The association between AD and treatment with drugs targeting the beta-adrenergic receptor is controversial. The aim of this study is to assess the association between the initiation of AD medication and beta-adrenoceptor antagonists (beta-blockers) in adults. MATERIALS AND METHODS: We conducted a prescription sequence symmetry analysis using the University of Groningen IADB.nl prescription database. We determined the order of the first prescription for treating AD and the first prescription for beta-blockers, with the dispensing date of the first prescription for AD defined as the index date. Participants were adults over 45 years old starting any AD medication and beta-blockers within two years. We calculated adjusted sequence ratios with corresponding 95% confidence intervals. RESULTS: We identified 510 users of both AD and beta-blockers, and 145 participants were eligible. The results were compatible with either a significant decrease in the incidence of AD after using beta-blockers (adjusted sequence ratio (aSR) = 0.52; 95% CI: 0.35-0.72) or, conversely, an increase in beta-blockers after AD medication (aSR = 1.96; 95% CI: 1.61-2.30). CONCLUSIONS: There is a relationship between the use of beta-blockers and AD medications. Further research is needed with larger populations to determine whether drug therapy for AD increases the risk of hypertension or whether beta-blockers have potential protective properties against AD development.

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis.

OBJECTIVE: Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults. DESIGN: Systematic review. ELIGIBILITY: Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease. DATA SOURCE: PubMed and Embase (1 January 2020-28 September 2022). RISK OF BIAS: Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies. DATA ANALYSIS: Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available. RESULTS: In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I2=48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I2=96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies. CONCLUSIONS: Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection. PROSPERO REGISTRATION NUMBER: CRD42021292797.

Impact of the COVID-19 pandemic on breast cancer incidence and tumor stage in the Netherlands and Norway: A population-based study.

BACKGROUND: Comparing the impact of the COVID-19 pandemic on the incidence of newly diagnosed breast tumors and their tumor stage between the Netherlands and Norway will help us understand the effect of differences in governmental and social reactions towards the pandemic. METHODS: Women newly diagnosed with breast cancer in 2017-2021 were selected from the Netherlands Cancer Registry and the Cancer Registry of Norway. The crude breast cancer incidence rate (tumors per 100,000 women) during the first (March-September 2020), second (October 2020-April 2021), and Delta COVID-19 wave (May-December 2021) was compared with the incidence rate in the corresponding periods in 2017, 2018, and 2019. Incidence rates were stratified by age group, method of detection, and clinical tumor stage. RESULTS: During the first wave breast cancer incidence declined to a larger extent in the Netherlands than in Norway (27.7% vs. 17.2% decrease, respectively). In both countries, incidence decreased in women eligible for screening. In the Netherlands, incidence also decreased in women not eligible for screening. During the second wave an increase in the incidence of stage IV tumors in women aged 50-69 years was seen in the Netherlands. During the Delta wave an increase in overall incidence and incidence of stage I tumors was seen in Norway. CONCLUSION: Alterations in breast cancer incidence and tumor stage seem related to a combined effect of the suspension of the screening program, health care avoidance due to the severity of the pandemic, and other unknown factors.