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Hospital Pedro Hispano - ULS Matosinhos, Department of Medicine, Faculty of Medicine, Porto University UnIC, Faculty of Medicine, Porto University, Portugal
Medical Affairs, Daiichi Sankyo Portugal Department of Medicine, Lisbon Medical School, Lisbon University Centro Cardiovascular Universidade Lisboa, Lisbon University, Portugal
Department of Community Medicine, Health Information and Decision, Faculty of Medicine, University of Porto Faculty of Health Sciences, Fernando Pessoa University MTG Research and Development Lab, Portugal
To reduce sex disparities in achieving lipid-lowering therapy (LLT) goals, a sex-focused assessment is essential.
•
Women have a lower likelihood of attaining LDL-C goals than men after adjustment for LLT intensity, age, CV risk category, presence of mental health disorder and social deprivation.
•
There is the need for further investigation and tailoring of LLT management strategies in women.
Abstract
Background and aims
Cardiovascular (CV) diseases show clear differences in clinical manifestation and treatment outcomes between men and women. To reduce sex disparities in achieving lipid-lowering therapy (LLT) goals, a sex-focused assessment is essential and more studies are needed to bring new evidence to clinicians. This study aims to assess the role of sex in attaining Low-density lipoprotein cholesterol (LDL-C) goals, after correction for age, CV risk category, LLT intensity, and presence of mental health disorder and social deprivation.
Methods
A retrospective cohort analysis of patients aged 40–85, followed in 1 hospital and 14 primary care centers in Portugal, using electronic health records from 1/1/2012 to 31/12/2020 was performed. The analysis considered an episode-based design, where exposure consists of any time when LLT was started or intensity changed. The likelihood of reaching the LDL-C goal according to contemporary ESC/EAS guidelines was modeled using multivariate cox regression. LDL-C goal achievement at 180 days was defined as the outcome. The analysis was repeated at 30-day follow-up intervals up to 360 days, and also stratified by CV risk category.
Results
We identified 40 032 exposure episodes (LLT initiation or intensity change) in 30 323 distinct patients. Male sex, older age, lower CV risk and increasing LLT intensity were associated with improved LDL-C control. Women were 22% less likely to reach the LDL-C goal than men (HR = 0.78, 95% CI:0.73, 0.82) independently of covariates.
Conclusions
Women have a lower likelihood of attaining LDL-C goals than men after adjustment for LLT intensity, age, CV risk category, presence of mental health disorder and social deprivation. This finding underscores the need for further investigation and tailoring of LLT management strategies in women.
Atherosclerotic cardiovascular disease (ASCVD) causes four million deaths in Europe each year, killing more women than men (2.2 million compared to 1.8 million in men), and is the leading cause of death and disability worldwide [
]. The European Society of Cardiology (ESC)/European Society of Atherosclerosis (EAS) has defined Low-density lipoprotein cholesterol (LDL-C) goals according to the patient's cardiovascular (CV) risk, with no specific recommendations concerning sex [
Although for many years it was thought that the prevalence of CVD in men was higher than in women, several studies concluded otherwise. Women with diabetes have a higher risk of cardiovascular complications than men, with a 50% higher risk of fatal coronary heart disease [
]. There has been a significant increase in the prevalence of ischemic heart disease in young women due to unfavorable lifestyle changes over the last decade [
Sex and gender differences in cardiovascular health and lipid control may be attributed to various factors. These differences may be biological (sex-related), such as hormonal factors like premature menopause, pregnancy-related risk factors, use of hormonal contraceptives and higher prevalence of thyroid dysfunction [
Office for Civil Rights (OCR) Guidance Regarding Methods for DE-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
], such as lower adherence and higher treatment dropout, associated depressive symptoms, and even lower perceived risk in women by patients and clinicians [
Given that lipid control, particularly LDL-C levels, is a key modifiable risk factor for the development and progression of CVD, it is crucial to understand sex differences in this area to address disparities in CVD outcomes [
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.
The aim of this study was to estimate the effect of sex upon LDL-C control regardless of age, LLT regimen, CV risk category, presence of mental health disorder and social deprivation.
2. Patients and methods
2.1 Study design
This is an observational cohort study using electronic health records (EHR) of patients followed at the Unidade Local de Saúde de Matosinhos (ULSM). ULSM is a large healthcare institution that includes 14 primary care centers supported by 1 hospital that provides secondary and tertiary care services to the region of Matosinhos, reflecting the activity of more than 1 000 doctors from different background specialties. An 8-year time window from 01/01/2012 to 31/12/2020 to scan EHRs for eligible patients was considered, encompassing the 2011, 2016 and 2019 revisions of the ESC/EAS Guidelines [
Others, ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European society of Cardiology (ESC) and the European Atherosclerosis society (EAS).
]. The index date was defined as the first time upon which LLT was initiated or changed. In order for a patient to be included and analyzed in the study, the following criteria had to be met at the same point in time: i) age between 40 and 85 years; ii) at least one appointment with a ULSM primary care physician in the three years preceding the index date, in line with the official government indicator used to determine whether a patient is routinely followed or not; iii) at least one record in the last year before the index date and iv) enough information to categorize the patient according to the contemporary ESC/EAS Guidelines. These inclusion criteria maximize the overlap of the study population with the resident population, which accounts for approximately 90% of the resident population of Matosinhos within the selected age group, according to the 2021 Portuguese Census. Matosinhos is the eighth most inhabited municipality in the country and the fourth in the northern region.
Only patients aged between 40 and 85 years old were included in the analysis because the evidence upon which the ESC/EAS guidelines were built to recommend usage of the Systematic Coronary Risk Estimation (SCORE), CV risk category calculation and LLT initiation are not as widely accepted outside this age group and thus allow greater room for clinician discretion regarding patient assessment and treatment.
This study was approved by the Ethical Committee of ULSM (translated from Comissão de Ética para a Saúde da Unidade Local de Saúde de Matosinhos). All data processing and analysis were performed exclusively by analytic programs developed for this purpose and sent for execution at ULSM datacenter. No data was extracted outside ULSM, and no direct access to the data took place. As an additional degree of security, processed data were de-identified by the ULSM Information Technology Department prior to the analytic code execution according to the Health Insurance Portability and Accountability Act (HIPAA) safe harbor standard [
Office for Civil Rights (OCR) Guidance Regarding Methods for DE-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
CV risk categories were constructed considering the contemporary ESC/EAS Guidelines for Dyslipidemia from 2011, 2016 and 2019 at the index date. Firstly, risk categories were decomposed in independent risk criteria sufficient to classify the patient in a given CV risk category. Then, each criteria was broken down into smaller sub-criteria, and then further refined into the most granular EHR data available among clinical measurements, laboratory results and conditions recorded at ULSM.
Relevant conditions at primary care were originally coded using International Classification of Primary Care, version 2 (ICPC-2), and inpatient and outpatient hospital appointments coded using International Classification of Disease, 9th Revision (ICD-9) and International Classification of Disease, 10th Revision (ICD-10) codes. Laboratory and clinical measurements were coded using ad-hoc vocabularies that were standardized to the systematized nomenclature of medicine clinical terms (SNOMED CT). In order to compute family history of relevant diseases, familial relationships were reconstructed from primary care family information.
Neither carotid or coronary imaging data, nor ankle brachial index, were used to assert the presence of ASCVD as these were not retrievable from the EHR at the time of this study. Furthermore, familial hypercholesterolemia was classified as definite or possible according to Simon and Broome criteria [
] and corresponding dosage information were used in order to compute LLT regimens. The statin intensity group, considering both the drug and the dosage, was attributed according to the classification of the American College of Cardiology and the American Heart Association [
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology ….
]. A total of 6 groups for LLTs were defined according to statin intensity (low, moderate, high) and the addition of ezetimibe. Prescriptions of fixed or single-pill combinations of the LLTs were considered. In case a patient switched statins or doses within the same intensity range it would remain in the same LLT category.
To account for socioeconomic and mental health factors, the presence of mental health disorders and social deprivation was defined using ICPC-2, ICD-9 and ICD-10 codes (Supplementary Table S5 provides further details on these definitions). The patient's sex was determined from the administrative record available in the EHR.
Prior to analysis, the source data was harmonized according to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) version 5.3 [
]. A detailed definition for all study variables is present as supplementary material (Tables S1–S5).
2.3 Exposure and outcome definitions
Exposure was defined as any time point in which an LLT regimen was initiated or its intensity was changed. Upon cohort entry date, baseline CV risk category was computed according to the current version of the ESC/EAS Guidelines [
Others, ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European society of Cardiology (ESC) and the European Atherosclerosis society (EAS).
]. The outcome of interest was defined as the attainment of the LDL-C target according to baseline CV risk category and contemporary version of the ESC/EAS Guidelines 180 days after exposure. This time frame was chosen considering that in the Portuguese National Health System it is recommended that patients are reevaluated 60–180 days after LLT regimen is initiated or its intensity is changed. Additional sensitivity analyses were performed for each 30-day period from baseline until 360 days, and repeated for LLT events occurring after entering each CV risk category.
To compensate for the delay in implementing the latest version of the guidelines in clinical practice, the goals set out in the guidelines were assumed to take effect from January 1st of the year following the publication.
A patient may become eligible for multiple cohorts as their LLT changes over time. When a patient already being followed in one cohort becomes eligible for another cohort, they will begin to be followed in the new cohort while still keeping follow-up in the former cohort. A graphical representation of the cohort identification and follow-up strategy, illustrating examples of different patient's trajectory scenarios with respect to the exposure and the outcome is available in the Supplementary Material (Fig. S1).
2.4 Statistical analysis
Continuous variables were reported as median and interquartile range (IQR). Categorical variables were presented as absolute and relative frequencies. In order to estimate the risk for LDL-C control, we modeled cohorts using a Cox proportional hazards model adjusted at baseline for age, sex, CV risk category, mental health condition and social deprivation, and LLT intensity. To correct for the dependent observations resulting from having a patient in more than one cohort at different points in time, the standard errors of the estimated hazard ratios (HR) were adjusted to account for correlations between the same patient by applying the cluster method available in the Survival package. The resulting variance is what is known as the working independence variance in a generalized estimating equation. Overall, this design ensures that risk estimates are kept as conservative as possible.
To further account for potential differences in LDL-C target achievement between age groups and between primary care and hospital settings, we conducted additional subanalyses focused on patients categorized by age group and by their outpatient appointment history. Specifically, we examined whether or not they had attended any Cardiology, Endocrinology, or Internal Medicine outpatient appointments within the 365 days prior to the index date.
We used Apache Spark Framework version 2.4.5 for engineering the source data into the final dataset, R version 4.0.3 to perform the statistical analysis using the Survival package [
30 323 distinct patients were eligible for the study, which contributed to 40 032 episodes of LLT initiation or intensity changes which means that, on average, each distinct patient contributed with 1.3 eligible episodes of LLT initiation or intensity changes.
The median age at the time of entering the cohort was 63 years (IQR = 14). There was a predominance of females in the low-intensity statin (57.3%), moderate-intensity statin (53.2%) and low intensity statin associated with ezetimibe (55.2%) cohorts. Further detail on CV risk level distribution and context covariates by LLT use at the time of entry into the cohort are depicted in Table 1.
Table 1Cohort characteristics at baseline for the time-to-event analysis to estimate the effect of sex in LDL-C achievement after starting or switching LLT.
4 437 (11.1%) episodes were identified for low intensity statin use, 22 944 (57.3%) episodes for moderate intensity statin, 6 491 (16.2%) episodes for high intensity statin, 1 108 (2.8%) episodes for low intensity statin associated with ezetimibe, 3 546 (8.9%) episodes for moderate-intensity statin associated with ezetimibe, and 1506 (3.8%) episodes for high-intensity statin associated with ezetimibe.
3.2 Achievement of LDL-C target at 180 days
For the analysis at 180 days of follow-up, LDL-C control was reached for 7 349 episodes (18%) across all cohorts. The median time to reach LDL-C control varied between 52 and 84 days.
Regression results indicate that women had a 22% lower likelihood of reaching their LDL-C goal (HR = 0.78, 95% CI = [0.73, 0.82]) when compared to men (Fig. 1), independently of age, LLT intensity, CV risk category, and social or mental health status. The likelihood of reaching LDL-C control increased with age and LLT intensity and reduced with increased CV risk category. Further details for this model are available in the Supplementary Material (Table S6).
Fig. 1Forest plot of the likelihood of reaching LDL-C target 180 days after LLT start or intensity change, based on adjusted hazard ratios (HRs) derived from the constructed multivariate model.
The subanalyses exploring LLT events among distinct age groups and outpatient appointment categories are presented in Figs. S2 and S3 within the Supplementary Material. The sex disparity in reaching LDL-C control remained true for most of these groups.
3.3 LDL-C target achievement at additional time points and CV risk category
Women are significantly less likely than men to reach LDL-C goal for all follow-up times and for LLT events within all CV risk categories (Fig. 2). The sex disparity found for the likelihood of reaching LDL-C goals was greater among patients with low CV risk compared to those with high CV risk. Tables in the supplementary material provide baseline cohort characteristics (Tables S7–S10) and model estimates for each CV risk group (Tables S11–S14).
Fig. 2Likelihood of reaching LDL-C target after LLT start or intensity change at 30-day intervals by CV risk group.
The results of this study show relevant sex differences on the management of hypercholesterolemia. In fact, women are 22% less likely to achieve the LDL-C target, 180 days after starting or changing LLT, regardless of the intensity of the LLT used, CV risk category, age, mental health condition or social deprivation. This study focused specifically on patients who were prescribed LLT and, by using an episode-based approach to model multiple changes in LLT over time, is able to estimate the likelihood of achieving the LDL-C goals. In addition, this study also considered the CV risk definitions and LDL-C goals of contemporary guidelines, minimizing potential bias resulting from guideline changes over time.
Our results are in agreement with other studies. A cross-sectional study of primary care patients aged 40–79 years in Switzerland found that women had higher LDL-C values than men in both primary and secondary prevention and lower LDL-C assessment rates [
Inferior control of low-density lipoprotein cholesterol in women is the primary sex difference in modifiable cardiovascular risk: a large-scale, cross-sectional study in primary care.
]. The EUROASPIRE III study concluded that women are less likely to achieve their LDL-C target in secondary prevention than men under the same treatment [
EUROASPIRE Study Group EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22 European countries.
Eur. J. Cardiovasc. Prev. Rehabil.2009; 16: 121-137
EUROASPIRE Investigators, EUROASPIRE IV: a European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.
]. The DISGEN-LIPID study, conducted in Portugal, analyzed a total of 368 patients, of whom 73% had a high or very high CV risk SCORE. Women had higher TC (p<0.001), LDL-C (not significant) and HDL-C (p<0.001), and lower TG (p=0.002); 57% of men and 63% of women had LDL-C>100 mg/dL (p=0.28), and 58% of men and 47% of women had LDL-C>70 mg/dL (p=0.933) [
DISGEN-LIPID study Investigators, Suboptimal lipid levels in clinical practice among Portuguese adults with dyslipidemia under lipid-lowering therapy: data from the DISGEN-LIPID study.
]. Other 2 studies showed different results, although they were not designed specifically to estimate the likelihood of control of LDL-C after LLT initiation or change, which may partially explain the differences from our study [
Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials.
These differences in reaching the LDL-C target between women and men may have several reasons, most of them gender-related.
One often proposed is lower adherence to therapy and higher therapy abandonment by women, which this study could not account for. In the study by Cangemi et al., response to therapy was comparable between sexes, with slightly more abandonment of therapy in women due to adverse events [
Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study.
]. In the study by Nanna et al., women more often reported discontinuing their statin because of a side effect (7.9% vs 3.6%; p<0.001) and less often believed that statins were safe (47.9% vs 55.2%; p<0.001) or effective (68.0% vs 73.2%; p<0.001). This study also concluded that women were more likely to discontinue and to decline statin therapy when offered and less likely to report having been offered statin therapy [
]. In a more recent study by Brown et al., women were more likely than men to not accept the initial statin therapy recommendation and to never initiate a statin during the study. Female sex was found to be an independent risk factor associated with a longer time to achieve LDL cholesterol control, and women were less likely to achieve LDL cholesterol control within 12 months [
Assessment of sex disparities in nonacceptance of statin therapy and low-density lipoprotein cholesterol levels among patients at high cardiovascular risk.
Other possibilities are psychosocial differences, such as associated depressive symptoms and socioeconomic status, conditioning the sense of responsibility and health care seeking in women [
Inferior control of low-density lipoprotein cholesterol in women is the primary sex difference in modifiable cardiovascular risk: a large-scale, cross-sectional study in primary care.
], all of which were accounted for in this study that still showed a sex gap regardless of these conditions.
In our study, there was a predominance of women in the low-intensity statin (57.3%), moderate-intensity statin (53.2%) and low intensity statin associated with ezetimibe (55.2%) cohorts. Many studies have shown that women, despite having higher LDL-C, less frequently receive statin therapy than men, particularly high-intensity therapy [
Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study.
]. Virani et al. showed that women with CVD (n = 13 371) were less likely than men to receive statins (57.6% vs 64.8%, p < 0.0001) or high-intensity statins (21.1% vs 23.6%, p < 0.001), although their mean LDL-C levels (99 vs 85 mg/dL) were higher (p < 0.0001) [
]. In the ESC-EORP EUROASPIRE V survey, after hospitalization for a coronary event women were treated less often with LLT (80.3% vs 85.6%) and received high-intensity LLT less often than men (46.0% vs 51.3%), even with higher levels of TC, LDL-C and non-HDL-C [
EUROASPIRE V collaboratorsWriting Committee Scientific Steering/Executive Committee, Coordinating centre, Diabetes centre, Data management centre, Statistical analysis centre, Central laboratory, Study centres, organisations, investigators and other research personnel (National Co-ordinators in each country are indicated by asterisk, Management of dyslipidaemia in patients with coronary heart disease: results from the ESC-EORP EUROASPIRE V survey in 27 countries.
]. These results are complementary to the ones in our study as only patients receiving LLT were studied. In another study by Peters et al., among patients following hospital discharge for myocardial infarction, women were less likely than men to fill high-intensity statins and the disparity was largest in the youngest and oldest adults and for those without comorbid conditions [
]. This is a factor that may contribute to explain these findings as the analysis focuses only on whether LLT was prescribed and not if it was actually filled.
The prescription differences between sexes are evident and deserve careful consideration. One reason for therapeutic inertia toward women may also be the biased belief that they have a lower risk of CVD and less need for preventive intervention [
There may also be sex-related issues justifying a differential response to LLT. In addition to the difference in the treatment of women, differences were also found in the response to statins compared to men. Mombelli et al. conducted an observational study to evaluate sex-related differences in statin responses and obtained, after adjusting the dose and statin intensity, a significantly greater reduction in total cholesterol and LDL-C after 1 year of treatment in men [
]. According to the BARI 2D trial, women with type 2 DM and established CAD, even when treated as aggressively as men, were less likely to achieve LDL-C targets, suggesting the existence of a sex-targeted response to lipid-lowering drugs [
BARI 2D study group, sex, prescribing practices and guideline recommended, blood pressure, and LDL cholesterol targets at baseline in the BARI 2D trial.
The fact that women more often have side effects such as muscle symptoms with statins than men may also condition a less interventionist medical attitude towards hypercholesterolemia [
]. The onset or worsening of muscle symptoms was reported in 31% of women compared with 26% of men (p<0.01). However, it is important to note that most reported side effects of statins are a result of the nocebo effect, as evidenced by recent studies [
]. Although some adverse effects of statins, such as toxic skeletal muscle damage and diabetes mellitus, appear to be more common in women, there is no mechanistic data to prove that statins may be more harmful to women than to men [
]. A better understanding of the nocebo effect and its implications on reported side effects could help improve the clinical management of muscle symptoms in patients taking statins, regardless of gender.
These disparities reflect the limited understanding of the physiology of sex differences, which is substantially related to the lack of female-specific data, especially in primary prevention trials [
]. The results of these studies are sometimes inconsistent, as women with ASCVD are typically older, with more comorbidities and risk factors than men, such as hypertension and DM [
]. Moreover, women are underrepresented in clinical trials, challenging the assessment of sex-related disparities in dyslipidemia and response to LLT [
In summary, despite documented efficacy of treatments in both sexes and international guidelines, women are less likely to receive guideline-based primary and secondary prevention and to be assessed for their CV risk, with the majority not adhering to adequate primary prevention care and instead resorting to non-evidence-based therapies [
]. In this regard, our study also showed that despite the LLT intensity, men were still more likely to attain the LDL-C treatment target.
An in-depth assessment, taking into account both biological sex and gender, is essential to adapt CVD prevention strategies. Further research is needed to explore factors influencing disparities in LLT goal attainment across sex and gender. Such studies may include investigating sex-specific pharmacokinetics and pharmacodynamics of LLT, examining the impact of sociocultural factors and gender roles on adherence to LLT, and exploring potential interactions between sex, gender, and other comorbidities in achieving LLT targets.
4.1 Strengths and limitations
This study yields important information on long-term trends of a large cohort with limited selection bias, loss to follow-up, and small amount of missing data. Considering the high usage rate of ULSM by the resident population, the low population migration rates, and the large data collection period, the authors believe that these findings can be generalized to the population served in this region, and to populations of comparable profile. This statistical analysis approach, allowing patients to be followed in more than one cohort, not censoring on new cohort inclusion, and including covariates that frequently account for competing risk of death, enabled a conservative estimation of risks, which were still shown to be of high clinical magnitude.
Still, there are limitations in this study. ULSM serves a predominantly urban population with broad primary healthcare coverage, and thus may not be representative of other regions of Portugal. This analysis was based on retrospective EHR data with their unavoidable potential for quality and completeness issues, and thus vulnerable to bias or residual confounding that hinders causal inference. Furthermore, the study only considers patients between 40 and 85 years, who started or changed their LLT intensity, and therefore does not account for differences in control among patients who did not use LLTs. This may limit the generalizability of the findings to the broader population of patients with dyslipidemia. Also, the patient's sex was determined from the administrative record available in the EHR, which did not allow for direct capture of any other aspects of gender identity. Consequently, it is likely that these results better reflect sex-related differences.
4.2 Conclusion
Women have a lower likelihood of attaining LDL-C goals than men after adjustment for LLT intensity, age, risk category, presence of mental health disorder and social deprivation. This finding underscores the need for further investigation and tailoring of LLT management strategies in women.
Financial support
This study was funded by Daiichi Sankyo Europe.
Data availability statement
All aggregate statistical results are incorporated into the article and its online supplementary material. Patient level data used in this study is not publicly available.
C.G. declares speaker and consulting fees from AstraZeneca, Bayer, BIAL, Boehringer-Ingelheim, Daiichi Sankyo, Lilly, MSD, Novartis and Novo Nordisk. F.A. declares speaker and consulting fees from AstraZeneca, Bayer, BIAL, Daiichi Sankyo, Ferrer, MSD, Novartis, Novo Nordisk and Servier. T.T.-G. declares speaker and consulting fees from AstraZeneca, BIAL, Daiichi Sankyo, MSD and Medinfar. T.T.-G. holds shares in MTG. C.T. and J.R. are employees of Daiichi Sankyo.
Acknowledgments
The authors would like to acknowledge the editorial support, namely the constructive review of the manuscript and raised comments. The authors also would like to acknowledge Pedro Hispano Hospital for granted permissions for this study and to Daniel Santos, Tiago Morais and José Castanheira from the Department of Information Technologies for conducting data extraction, and Anastassia Anastassopoulou for critical review of the manuscript.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis.
Others, ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European society of Cardiology (ESC) and the European Atherosclerosis society (EAS).
Guidance Regarding Methods for DE-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology ….
Inferior control of low-density lipoprotein cholesterol in women is the primary sex difference in modifiable cardiovascular risk: a large-scale, cross-sectional study in primary care.
EUROASPIRE Investigators, EUROASPIRE IV: a European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries.
DISGEN-LIPID study Investigators, Suboptimal lipid levels in clinical practice among Portuguese adults with dyslipidemia under lipid-lowering therapy: data from the DISGEN-LIPID study.
Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials.
Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study.
Assessment of sex disparities in nonacceptance of statin therapy and low-density lipoprotein cholesterol levels among patients at high cardiovascular risk.
Scientific Steering/Executive Committee, Coordinating centre, Diabetes centre, Data management centre, Statistical analysis centre, Central laboratory, Study centres, organisations, investigators and other research personnel (National Co-ordinators in each country are indicated by asterisk, Management of dyslipidaemia in patients with coronary heart disease: results from the ESC-EORP EUROASPIRE V survey in 27 countries.
BARI 2D study group, sex, prescribing practices and guideline recommended, blood pressure, and LDL cholesterol targets at baseline in the BARI 2D trial.
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