Addressing persistent evidence gaps in cardiovascular sex differences research – the potential of clinical care data

Women have historically been underrepresented in cardiovascular clinical trials, resulting in a lack of sex-specific data. This is especially problematic in two situations, namely those where diseases manifest differently in women and men and those where biological differences between the sexes might affect the efficacy and/or safety of medication. There is therefore a pressing need for datasets with proper representation of women to address questions related to these situations. Clinical care data could fit this bill nicely because of their unique broad scope across both patient groups and clinical measures. This perspective piece presents the potential of clinical care data in sex differences research and discusses current challenges clinical care data-based research faces. It also suggests strategies to reduce the effect of these limitations, and explores whether clinical care data alone will be sufficient to close evidence gaps or whether a more comprehensive approach is needed

Addressing persistent evidence gaps in cardiovascular sex differences research – the potential of clinical care data

Women have historically been underrepresented in cardiovascular clinical trials, resulting in a lack of sex-specific data. This is especially problematic in two situations, namely those where diseases manifest differently in women and men and those where biological differences between the sexes might affect the efficacy and/or safety of medication. There is therefore a pressing need for datasets with proper representation of women to address questions related to these situations. Clinical care data could fit this bill nicely because of their unique broad scope across both patient groups and clinical measures. This perspective piece presents the potential of clinical care data in sex differences research and discusses current challenges clinical care data-based research faces. It also suggests strategies to reduce the effect of these limitations, and explores whether clinical care data alone will be sufficient to close evidence gaps or whether a more comprehensive approach is needed

Myocarditis and pericarditis associated with SARS-CoV-2 vaccines: A population-based descriptive cohort and a nested self-controlled risk interval study using electronic health care data from four European countries

COVID-19 vaccine; Adverse drug reaction; MyocarditisVacuna contra el COVID-19; Reacció adversa a fàrmacs; MiocarditisVacuna contra el COVID-19; Reacción adversa a medicamentos; MiocarditisBackground: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39–49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed.The project received support from the European Medicines Agency (EMA/2018/23/PE)

Sex Differences in Reported Adverse Drug Reactions to Angiotensin-Converting Enzyme Inhibitors

Sex differences in adverse drug reactions (ADRs) associated with angiotensin-converting enzyme inhibitors (ACEIs) remain poorly understood owing to a lack of sex-specific ADR data from clinical trials. 1 Postmarketing pharmacovigilance data, containing structured and detailed ADR information, may play an important role in such analyses. However, these data are often not corrected for prescription numbers and therefore cannot separate sex differences in ADR risk from sex differences in prescription rates. To investigate whether women report more ACEI-related ADRs than men after correction for sex-specific prescription and describe sex differences in reported ADR types, we combined data from the global pharmacovigilance database VigiBase and the prescription-corrected Dutch pharmacovigilance database Lareb

Sex Differences in Reported Adverse Drug Reactions to Angiotensin-Converting Enzyme Inhibitors

This cross-sectional study investigates differences by sex in reporting of adverse drug reactions associated with angiotensin-converting enzyme inhibitors combining global and prescription-corrected databases

Statins are associated with a large reduction in all-cause mortality in women from a cardiac outpatient population

OBJECTIVES: Uncertainty about the benefit of (high-intensity) statins for women remains due to under-representation of women in primary prevention trials and scarcity of sex-stratified data. This study evaluates the sex-specific relation between statin treatment and survival and the additional benefit of high-intensity statins. METHODS: Electronic health record data from 47 801 patients (17 008 statin users and 30 793 non-users) without prior cardiovascular disease were extracted from thirteen Dutch outpatient cardiology clinics. Patients prescribed statins at baseline were propensity-score matched to those eligible for statin therapy (low-density lipoprotein >2.5 mmol/L) without a statin prescription. Statins were divided into low-intensity and high-intensity according to Dutch guidelines. Mortality data were obtained via linkage to the national mortality registry. Cox regression was used to evaluate the relationship between statin prescription and intensity and all-cause and cardiovascular mortality. RESULTS: Propensity score matching created a cohort of 8631 statin users and 8631 non-users. 35% of women and 28% of men received a low-intensity statin. The beneficial effect of statins on both all-cause and cardiovascular mortality was stronger in women (HR 0.66, 95% CI 0.58 to 0.74 and HR 0.55, 95% CI 0.39 to 0.71, respectively) than in men (HR 0.89, 95% CI 0.81 to 0.95 and HR 0.93, 95% CI 0.77 to 1.08, respectively). High-intensity statins conferred modest protection against all-cause mortality (HR 0.94, 95% CI 0.88 to 1.00) and cardiovascular mortality (HR 0.86, 95% CI 0.74 to 0.98) in both sexes. CONCLUSIONS: The protective effect of primary prevention statins was stronger in women than men for both all-cause and cardiovascular mortality. High-intensity statins conferred a modest additional benefit in both sexes. Statins seem to be effective regardless of treatment intensity, especially in women

Development of a Pipeline for Adverse Drug Reaction Identification in Clinical Notes: Word Embedding Models and String Matching

BACKGROUND: Knowledge about adverse drug reactions (ADRs) in the population is limited because of underreporting, which hampers surveillance and assessment of drug safety. Therefore, gathering accurate information that can be retrieved from clinical notes about the incidence of ADRs is of great relevance. However, manual labeling of these notes is time-consuming, and automatization can improve the use of free-text clinical notes for the identification of ADRs. Furthermore, tools for language processing in languages other than English are not widely available. OBJECTIVE: The aim of this study is to design and evaluate a method for automatic extraction of medication and Adverse Drug Reaction Identification in Clinical Notes (ADRIN). METHODS: Dutch free-text clinical notes (N=277,398) and medication registrations (N=499,435) from the Cardiology Centers of the Netherlands database were used. All clinical notes were used to develop word embedding models. Vector representations of word embedding models and string matching with a medical dictionary (Medical Dictionary for Regulatory Activities [MedDRA]) were used for identification of ADRs and medication in a test set of clinical notes that were manually labeled. Several settings, including search area and punctuation, could be adjusted in the prototype to evaluate the optimal version of the prototype. RESULTS: The ADRIN method was evaluated using a test set of 988 clinical notes written on the stop date of a drug. Multiple versions of the prototype were evaluated for a variety of tasks. Binary classification of ADR presence achieved the highest accuracy of 0.84. Reduced search area and inclusion of punctuation improved performance, whereas incorporation of the MedDRA did not improve the performance of the pipeline. CONCLUSIONS: The ADRIN method and prototype are effective in recognizing ADRs in Dutch clinical notes from cardiac diagnostic screening centers. Surprisingly, incorporation of the MedDRA did not result in improved identification on top of word embedding models. The implementation of the ADRIN tool may help increase the identification of ADRs, resulting in better care and saving substantial health care costs

Cardiovascular imaging of women and men visiting the outpatient clinic with chest pain or discomfort: design and rationale of the ARGUS Study

INTRODUCTION: Chest pain or discomfort affects 20%-40% of the general population over the course of their life and may be a symptom of myocardial ischaemia. For the diagnosis of obstructive macrovascular coronary artery disease (CAD), algorithms have been developed; however, these do not exclude microvascular angina. This may lead to false reassurance of symptomatic patients, mainly women, with functionally significant, yet non-obstructive coronary vascular disease. Therefore, this study aims to estimate the prevalence of both macrovascular and microvascular coronary vascular disease in women and men presenting with chest pain or discomfort, and to subsequently develop a decision-support tool to aid cardiologists in referral to cardiovascular imaging for both macrovascular and microvascular CAD evaluation. METHODS AND ANALYSIS: Women and men with chest pain or discomfort, aged 45 years and older, without a history of cardiovascular disease, who are referred to an outpatient cardiology clinic by their general practitioner are eligible for inclusion. Coronary CT angiography is used for anatomical imaging. Additionally, myocardial perfusion imaging by adenosine stress cardiac MRI is performed to detect functionally significant coronary vascular disease. Electronic health record data, collected during regular cardiac work-up, including medical history, cardiovascular risk factors, physical examination, echocardiography, (exercise) ECG and blood samples for standard cardiovascular biomarkers and research purposes, are obtained. Participants will be classified as positive or negative for coronary vascular disease based on all available data by expert panel consensus (a cardiovascular radiologist and two cardiologists). After completion of the clinical study, all collected data will be used to develop a decision support tool using predictive modelling and machine-learning techniques. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht. Results will be disseminated through national and international conferences and in peer-reviewed journals in cardiovascular disease. TRIAL REGISTRATION NUMBER: Trialregister.nl Registry NL8702

Myocarditis and pericarditis associated with SARS-CoV-2 vaccines: A population-based descriptive cohort and a nested self-controlled risk interval study using electronic health care data from four European countries

Background: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39-49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms