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Objectives To analyze the frequency of the different clinical presentations of the disease in women with HELLP syndrome and the most important factors that can predict a different maternal and fetal outcome. Study design This is a cross-sectional, consecutive, case-series study, the subjects being all patients with HELLP syndrome admitted to our Hospital within the last decade (1999-2009). Results The rate of maternal complications was 43.0% and perinatal mortality 14.1%. The severity of the syndrome, measured by The Mississippi Classification, influenced the rate of maternal complications but not fetal mortality: the rate of maternal complications among women in class 1 HELLP syndrome was 67.6%, compared to 49.3% in class 2 and 24.0% in class 3 HELLP syndrome, p<0.0001. In a 21.8% of women, the onset of the disease was after delivery. We highlight the fact that those cases with an early puerperium onset of the disease were those with a higher number of maternal complications (odds ratio: 2.38; CI: 1.05-5.44). Conclusions These results suggest the possibility of an increased complication rate when the onset of the syndrome appears after delivery and the necessity of having a high grade of suspicion in every case to diagnose the disease, even when the gestation and delivery were normal. [ABSTRACT FROM AUTHOR]

Background and Aims: Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT)., Methods: Retrospective cohort study using data (2010-2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD., Results: 266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%-47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3-272.0) than CAD (92.9; 95%CI 92.5-93.4) or PAD cohorts (97.2; 95%CI 94.6-99.8). MALE incidence rate was 195.9 (95%CI 192.2-199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate., Conclusions: Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AJVV: personal fees for consulting from Bayer, during the conduct of the study; current or past participation in research grants to Imperial College London from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron, outside the submitted work; and personal fees for consulting from Regeneron and honoraria for lectures from Amgen, Mylan, Akcea, and Ferrer, outside the submitted work. KID: personal fees for consulting from Bayer, during the conduct of the study; grants from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron, outside the submitted study; and personal fees from Regeneron, outside the submitted work. NN,CCand STF:Bayer plc employees. MJF,ETand CL: none to report. KKR: personal fees for consulting from Bayer, during the conduct of the study; grants and personal fees from Aegerion, Amgen, Daiichi Sankyo, MSD, Pfizer, and Sanofi/Regeneron, and personal fees from Abbvie, Akcea, Algorithm, Astra Zeneca, Bayer, Boehringer Ingelheim, Cerenis Therapeutcics, Cipla, Dr Reddy's Laboratories, Esperion, Kowa, Lilly, Novartis, Silence Therapeutics, Takeda, and Zuellig Pharma, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: The global prevalence of mental health disorders has risen significantly since the beginning of the COVID-19 pandemic. The pandemic has additionally caused disruption to mental health services, leading to a shift from in-person to remote service delivery. Given its long-term impact, it has become critical to evaluate whether changes in health delivery during the pandemic have had an effect on prescribing patterns for commonly prescribed psychotropic drugs. This study aims to assess the impact of the COVID-19 pandemic on changes in psychotropic prescribing patterns in adults, as well as differences in prescribing in different healthcare delivery approaches across various geographical contexts., Design and Eligibility Requirements: Systematic review of cohort, interrupted time-series and cross-sectional studies examining prescribing trends for at least one commonly prescribed psychotropic drug during and after COVID-19 in accessing care remotely or face to face between 1 January 2020 and 17 June 2022., Data Sources: MEDLINE, EMBASE, CINAHL, HMIC and PsycINFO databases were searched in addition to citation chaining of relevant reviews., Extraction and Analysis: Study screening, data extraction and quality assessment were completed by two independent reviewers. The PECO strategy was used to devise the systematic review and findings were synthesised narratively., Results: 16 studies were eligible for inclusion. Studies documenting changes in psychotropic prescribing trends provided very conflicting findings. There were no stark differences in prescribing outcomes between different healthcare delivery methods (ie, face-to-face consultations vs remote consultations). A noteworthy finding was that the prescribing rate of benzodiazepines was higher in women than men. No particular trends were observed for the prescription rates of hypnotics, antidepressants or antipsychotics., Conclusions: Findings support mixed trends in the prescription of psychotropic medications in a range of settings, hindering conclusive statements on COVID-19's impact on prescribing. In areas where remote consultations are in use, more comprehensive research is required to assess the safety of prescribing in these settings to inform public health policy and assess if the observed trends in our systematic review persist over time (given the increased consideration of remote and telehealth care in delivering services), particularly the safe and effective deployment of these services., Competing Interests: Competing interests: RI and NM are employees of Oracle UK, a health technology organisation. AJV-V reports past or current participation in investigator-initiated research grants to Imperial College London from Pfizer, Amgen, Sanofi, MSD, Daiichi Sankyo and Regeneron, honoraria for lectures from Amgen, Mylan and Akcea, and steering committee/consulting fees from Radcliffe Cardiology and Bayer, all outside the submitted work. KID reports past or current participation in investigator-initiated research grants to Imperial College London from Amgen, Sanofi, MSD, Daiichi Sankyo and Regeneron and consulting fees from Bayer, all outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia., Methods: SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with ClinicalTrials.gov, NCT02693548., Findings: Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [54·1%] female and 1608 [45·9%] male participants) met the inclusion criteria and were included in the current study. Mean age was 46·1 years (SD 15·5) and median follow-up was 10·3 years (IQR 6·4-13·0). Mean on-treatment LDL-cholesterol at follow-up was 3·1 mmol/L (SD 1·4) in females and 3·0 mmol/L (1·5) in males. LDL-cholesterol reductions over time were similar in both sexes (1·39 mmol/L [95% CI 1·30-1·47] absolute reduction in females vs 1·39 mmol/L [1·29-1·48] in males; p=0·98). At enrolment, 130 (6·8%) females and 304 (18·9%) males (p<0·0001) had cardiovascular disease. During follow-up, 134 (7·1%) females and 222 (13·8%) males (p<0·0001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 61·6 years (IQR 50·0-71·4) in females and 50·6 years (42·0-58·6) in males (p<0·0001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 1·90 (95% CI 1·49-2·42) and for cardiovascular death was 1·74 (1·11-2·73). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 3·52 [95% CI 2·98-4·16]; p<0·0001). Median MACE-free survival time was 90·1 years (95% CI 86·5-not estimable) in females and 71·0 years (69·2-74·6) in males. The age at which 25% of female participants have had a MACE event was 74·9 years, this figure was 55·5 years in male participants., Interpretation: Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia., Funding: Fundación Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AJV-V reports current or past participation as an investigator in research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi Sankyo, and Regeneron; consultancy fees from Bayer and Regeneron; and honoraria for lecturers from Ferrer, European Atherosclerosis Society, and USA National Lipid Association; all outside the submitted work. GFW reports current or past participation in research grants to his institution; contracts or grants from Amgen, Novartis, Arrowhead, Silence Therapeutics, and the National Health and Medical Research Council (Australia); consulting fees from Esperion, CSL Sequiris, and Novartis; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen and Novartis; and support for attending meetings or travel from Arrowhead and Silence Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations., Methods and Results: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR , APOB , or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227)., Conclusions: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Background: Pneumocytis jirovecii infection in preterm newborns has recently been associated with neonatal respiratory distress syndrome and bronchopulmonary dysplasia. Changes in the bacterial microbiota of the airways have also been described in infants with bronchopulmonary dysplasia. However, until now there has been no information on the airway mycobiota in newborns. The purpose of this study was to describe the airway mycobiota in term and preterm newborns and its possible association with respiratory distress syndrome., Methods: Twenty-six matched preterm newborns with and without respiratory distress syndrome were studied, as well as 13 term babies. The identification of the fungal microbiota was carried out using molecular procedures in aspirated nasal samples at birth., Results: The ascomycota phylum was identified in 89.7% of newborns, while the basidiomycota phylum was found in 33.3%. Cladosporium was the predominant genus in both term and preterm infants 38.4% vs. 73% without statistical differences. Candida sake and Pneumocystis jirovecii were only found in preterm infants, suggesting a potential relationship with the risk of prematurity., Conclusions: This is the first report to describe the fungal microbiota of the airways in term and preterm infants with and without respiratory distress syndrome. Although no differences have been observed, the number of cases analyzed could be small to obtain conclusive results, and more studies are needed to understand the role of the fungal microbiota of the airways in neonatal respiratory pathology., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Friaza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated., Methods: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated., Results: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively., Conclusion: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach., (© 2022. The Author(s).)

Background: Familial hypercholesterolemia (FH) is common, but underdiagnosed, and few systematic early screening programs exist., Objective: To assess health outcomes among those with a recorded diagnosis of FH and potential cases of FH with no recorded diagnosis., Methods: Retrospective cohort study using the UK Clinical Practice Research Datalink. Records of adults were classified as diagnosed FH (FH Coded ), or via accepted algorithms using LDL-C and clinical characteristics as potential FH (FH Potential ) or unlikely FH (FH Unlikely ) using the DLCN or EUROASPIRE criteria (but no record of FH). Outcomes assessed were premature cardiovascular (CV) events, premature deaths and life expectancy., Results: Among 1,729,046 individuals free from CV events, a record of FH Coded before the age of 40 was 0.3/1000 (IQR 0.3-0.4) and increased with age. Where LDL-C levels were available, 1.8/1000 (IQR 1.6-2.0) could be classified as FH Potential . LDL-C was higher for both FH Coded and FH Potential vs FH Unlikely (185.6 and 216.6 vs 116 mg/dL, respectively, p <0.001). Compared to FH Unlikely both FH Coded and FH Potential cohorts had a higher risk of premature cardiovascular events (both p <0.001) with highest rates among FH Coded . Risk of premature deaths did not differ between FH Coded and FH Unlikely, but was 1.88 (95% CI 1.27-2.78, p  = 0.002) for FH Potential vs FH Coded and 2.40 (95% CI 1.57-3.67, p <0.001) for FH Potential vs FH Unlikely . At age 18, the FH Potential cohort had a life expectancy 16 years lower than the FH Coded cohort ( p <0.001)., Conclusions: Potential cases of FH had a doubling in risk of premature death and a large reduction in life expectancy compared to individuals with a recorded diagnosis of FH. These findings strengthen the critical importance of identifying potential cases of FH early and early treatment., Competing Interests: Professor Kausik K. Ray reports the following; Unrestricted research grants to Imperial College London from Amgen, Daiichi Sankyo, Regeneron, Sanofi, SC, EC or advisory boards honoraria from Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, Cargene, Honoria for CME and non CME from Novartis, Novo Nordisk, BI, AZ, Viatris, Daiichi Sankyo, Amgen, Sanofi and stock options PEMI-31. Dr. Demetris Pillas provided consultancy services to Amgen Ltd. Dr. Savvas Hadjiphilippou has no disclosures. Professor Kamlesh Khunti has received research grants from Lilly, Sanofi-Aventis, Boehringer Ingelheim, Merck, Sharpe & Dohme, and Novo Nordisk, has provided consultancy services to Amgen, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Servier, and Merck, Sharpe & Dohme, has served in non-remunerative positions of influence at Lilly, Sanofi-Aventis, Merck, Sharpe & Dohme, and Novo Nordisk and has participated in Speakers Bureau for Lilly, Sanofi-Aventis, Merck, Sharpe & Dohme, and Novo Nordisk. Dr. Sreenivasa Rao Kondapally Seshasai has provided consultancy services to Amgen. Dr. Antonio J. Vallejo-Vaz reports current or past participation in research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi Sankyo, and Regeneron; personal fees for consulting from Bayer and Regeneron; and honoraria for lectures from Amgen, Mylan, Akcea, and Ferrer; all outside the submitted work. Dr David Neasham is employed at Amgen Ltd. Ms. Janet Addison was previously employed at Amgen Ltd., (© 2023 The Authors. Published by Elsevier B.V.)

In 2020, Spain ranked fourth among European countries with the highest excess mortality due to COVID-19 disease. This study evaluates the impact of the COVID-19 pandemic on non-COVID patients in a tertiary hospital during the second pandemic wave in Spain (22 June 2020-6 December 2020). Data from Virgen del Rocío University Hospital in Seville during that timeframe were compared with the data from the same period in the preceding two years (2018-2019). Between-group comparisons were performed using the Chi-squared test, Student's t -test, or Mann-Whitney U tests, as appropriate. A total of 63,137 non-COVID patients were included in this study. During the second pandemic wave, a 19% decrease was observed in the annual number of non-COVID admissions overall (18,260 vs. 22,439, p < 0.001), but a 10% increase in the proportion of emergency admissions (60.6% vs. 54.93%, p < 0.001), a higher severity level of patients (1.79 vs. 1.72, p < 0.001), a longer in-hospital stay (7.02 vs. 6.74 days, p < 0.001), a 26% increase in non-COVID mortality (4.9% vs. 3.9%, p < 0.001), and a 50% increase in global mortality (5.9 vs. 3.9, p < 0.001) were also observed. In terms of both medical and surgical diagnoses, a significant reduction in the number of admissions and an increase in in-hospital mortality were observed. These results demonstrate the significant impact of the pandemic on hospital care, similar to what was previously observed during the initial wave in the same hospital. Our findings emphasize the need to include non-COVID patients when assessing the broad impact of the pandemic on healthcare, beyond its direct effects on COVID-19 patients.

Background: The impact of the stepwise implementation of the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) treatment algorithm on low-density lipoprotein cholesterol (LDL-C) goal attainment was simulated in patients from the DA VINCI study., Methods: Monte Carlo simulation was used to evaluate treatment optimisation scenarios, based on a patient's risk category: statin intensification (step 1), addition of ezetimibe (step 2), and addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (step 3). Residual cardiovascular risk and predicted relative and absolute risk reduction (RRR and ARR) in cardiovascular events were assessed., Findings: In DA VINCI, 2482 patients did not achieve their 2019 ESC/EAS LDL-C goals and were included in the simulation. In patients without atherosclerotic cardiovascular disease (ASCVD) ( n  = 962), 27.0% ( n  = 259) and 57.0% ( n  = 548 ) are likely to achieve their LDL-C goals at step 1 and step 2, respectively. Of those at very high risk without ASCVD ( n  = 74), 88.1% ( n  = 65) are likely to achieve their LDL-C goals at step 3. In patients with ASCVD ( n  = 1520), 12.0% ( n  = 183), 42.1% ( n  = 641) and 93.2% ( n  = 1416) are likely to achieve their LDL-C goals at steps 1, 2 and 3, respectively. In patients with and without ASCVD, treatment optimisation may result in mean simulated RRR of 24.0% and 17.7%, respectively, and ARR of 8.1% and 2.6%, respectively., Interpretation: Most patients at high cardiovascular risk are unlikely to achieve LDL-C goals through statin optimisation and ezetimibe, and will require a PCSK9 inhibitor, leading to greater reduction in cardiovascular risk., Funding: Amgen., Competing Interests: JB has received speaker fees from Amgen and research grant support from AstraZeneca. SB is an employee of Amgen Ltd and holds stock in Amgen. GV is an employee of Amgen (Europe) GmbH and holds stock in Amgen. ALC has received research grant(s)/support from Amgen, Eli Lilly, Menarini, Mylan, Sanofi, and Sanofi-Regeneron; and has served as a consultant for or received fees from Aegerion, Akcea, Amgen, Amryt, AstraZeneca, Daiichi Sankyo, Esperion, Genzyme, Ionis Pharmaceuticals, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, and Sanofi. NP has received consultancy fees and financial support for research projects from Amgen and Pfizer, and financial support for arranging and speaking at educational meetings from Amgen, MSD and Pfizer. He holds no stocks and shares in any such companies. NP is supported by the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. He has received financial support from several pharmaceutical companies which manufacture lipid lowering agents, for consultancy fees (Pfizer and Amgen), research projects and staff (Pfizer and Amgen) and for arranging and speaking at educational meetings (MSD, Amgen and Pfizer). He holds no stocks and shares in any such companies. AJV-V has participated, or is currently participating, in research grants to Imperial College London from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron, and Sanofi-Aventis; has received personal fees for consulting from Bayer and Regeneron; and has received fees for lectures from Akcea, Amgen, Mylan and Ferrer; all outside the submitted work. KKR reports grants from Amgen, Daiichi Sankyo, MSD, Pfizer, Regeneron and Sanofi; and has received personal fees from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Beren Therapeutics, Biologix Pharma, Boehringer Ingelheim, Cargene, CSL Behring, CRISPR, Eli Lilly Esperion, Kowa, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Resverlogix, Sanofi, Silence Therapeutics, SCRIBE Therapeutics, Vaxxinity and Viatris., (© 2023 The Author(s).)

Background: Electronic health records provide the opportunity to identify undiagnosed individuals likely to have a given disease using machine learning techniques, and who could then benefit from more medical screening and case finding, reducing the number needed to screen with convenience and healthcare cost savings. Ensemble machine learning models combining multiple prediction estimates into one are often said to provide better predictive performances than non-ensemble models. Yet, to our knowledge, no literature review summarises the use and performances of different types of ensemble machine learning models in the context of medical pre-screening., Method: We aimed to conduct a scoping review of the literature reporting the derivation of ensemble machine learning models for screening of electronic health records. We searched EMBASE and MEDLINE databases across all years applying a formal search strategy using terms related to medical screening, electronic health records and machine learning. Data were collected, analysed, and reported in accordance with the PRISMA scoping review guideline., Results: A total of 3355 articles were retrieved, of which 145 articles met our inclusion criteria and were included in this study. Ensemble machine learning models were increasingly employed across several medical specialties and often outperformed non-ensemble approaches. Ensemble machine learning models with complex combination strategies and heterogeneous classifiers often outperformed other types of ensemble machine learning models but were also less used. Ensemble machine learning models methodologies, processing steps and data sources were often not clearly described., Conclusions: Our work highlights the importance of deriving and comparing the performances of different types of ensemble machine learning models when screening electronic health records and underscores the need for more comprehensive reporting of machine learning methodologies employed in clinical research., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Christophe AT Stevens (CATS) is an employee of Imperial College London and reports grants from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron, during the conduct of the study. Alexander RM Lyons (ARML) is an employee of Imperial College London and reports grants from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron, during the conduct of the study. Kanika I Dharmayat (KID) is an employee of Imperial College London and receives grants from Daiichi Sankyo, Amgen and Regeneron, and personal fees from Bayer and Regeneron; all outside of the submitted work. Alireza Mahani (AM) is an employee of Davidson Kempner Capital Management and has no conflict of interest to disclose. Kausik K Ray (KKR) is an employee of Imperial College London and reports grants and personal fees from Amgen, Sanofi–Regeneron, Pfizer, Merck Sharp & Dohme, and Daiichi Sankyo; and personal fees from AstraZeneca, The Medicines Company, Kowa, Novartis, Lilly, Algorithm, Boehringer Ingelheim, AbbVie, Silence Therapeutics, Bayer, Esperion, Abbott, New Amsterdam, and Resverlogix, outside the submitted work. Antonio J Vallejo-Vaz (AJV-V) is an employee of the University of Seville and acknowledges past or current participation in research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi Sankyo and Regeneron, outside the submitted work; and received personal fees for consulting from Bayer and Regeneron and honoraria for lectures from Amgen, Mylan, Akcea and Ferrer, all outside the submitted work. Mansour TA Sharabiani (MTAS) is an employee of Imperial College London and has no conflict of interest to disclose., (© The Author(s) 2023.)

We assessed the impact of the first wave of COVID-19 pandemic on non-COVID hospital admissions, non-COVID mortality, factors associated with non-COVID mortality, and changes in the profile of non-COVID patients admitted to hospital. We used the Spanish Minimum Basic Data Set with diagnosis grouped according to the Diagnostic Related Groups. A total of 10,594 patients (3% COVID-19; 97% non-COVID) hospitalised during the first wave in 2020 (27-February/07-June) were compared with those hospitalised within the same dates of 2017-2019 (average annual admissions: 14,037). We found a decrease in non-COVID medical (22%) and surgical (33%) hospitalisations and a 25.7% increase in hospital mortality among non-COVID patients during the first pandemic wave compared to pre-pandemic years. During the officially declared sub-period of excess mortality in the area (17-March/20-April, in-hospital non-COVID mortality was even higher (58.7% higher than the pre-pandemic years). Non-COVID patients hospitalised during the first pandemic wave (compared to pre-pandemic years) were older, more frequently men, with longer hospital stay and increased disease severity. Hospitalisation during the first pandemic wave in 2020, compared to hospitalisation during the pre-pandemic years, was an independent risk factor for non-COVID mortality (HR 1.30, 95% CI 1.07-1.57, p = 0.008), reflecting the negative impact of the pandemic on hospitalised patients., (© 2023. The Author(s).)

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38)., Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society., Competing Interests: Declaration of interests SB declares no competing interests. DJB reports research grants from Amgen, Amryt, AstraZeneca, Sanofi, and Regeneron; lecture fees and personal fees from Amgen, Sanofi-Aventis and Novartis; participation in advisory board for Amryt (Chair of the LOWER study steering committee); and being member of the executive committee of the Lipid and Atherosclerosis Society of South Africa. MC reports institutional support for the conduction of clinical trials from Regeneron Pharmaceuticals, Akcea, and Regenxbio; consulting fees from Amryt Pharma; and support from NIH/NHLBI grant (P01HL059407). TF reports personal fees from Novartis, Sanofi, and Amgen; and that he was partly supported by the Ministry of Health, Czech Republic, grant number NU20-02-00261. MH-S reports research grants from Recordati and Kaneka; personal fees from Amgen, Astellas, Recordati, Merck Sharp & Dohme, and Sanofi; being on the advisory board for New Amsterdam Pharma and Medicine Company and Scilence Therapeutics; being chairperson Primary Hyperlipidemia, Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labor, and Welfare; being chairperson of the Working Group by Japan Atherosclerosis Society for Making Guidance of Familial Hypercholesterolemia; and owning stock options of Liid Pharma. MLH reports lecture fees from Sanofi, outside the submitted work. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, EU, and the Klinkerpad fonds; institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment at Novo Nordisk, Denmark since April, 2019. FJR reports consulting fees, lecturing fees, and advisory board fees from Amgen, Sanofi-Aventis, Regeneron, Novartis and Lib Therapeutics outside the submitted work; and being member of the International Atherosclerosis Society. KKR reports institutional research grants from Amgen, Sanofi, Daiichi Sankyo, Regeneron, and Pfizer; consulting fees and lecturing fees from Amgen, Sanofi, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Kowa, Silence Therapeutics, New Amsterdam, Esperion, Daiichi Sankyo, Bayer, Abbott, Resverlogix, Medicines Company, Eli Lilly, Algorithm, Merck, Sharp & Dohme, AbbVie, and Viatris, outside the submitted work. HS reports research grants from Amgen, Merck, Sharp & Dohme, Synageva, Amryt, Alexion, and Akcea; consulting fees from Amgen, Alexion, Daiichi Sankyo, Pfizer, and Akcea; and speaker fees from Amgen, Daiichi Sankyo, Sanofi, and Akcea. TRT declares no competing interests. AJV-V reports participation in research grants to Imperial College London or European Atherosclerosis Society, or both, from Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron; personal fees for consulting from Bayer and Regeneron; and honoraria for lectures from Amgen, Mylan, and Akcea; outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Chronic diseases are the leading cause of disability globally. Most chronic disease management occurs in primary care with outcomes varying across primary care providers. Computerised clinical decision support systems (CDSS) have been shown to positively affect clinician behaviour by improving adherence to clinical guidelines. This study provides a summary of the available evidence on the effect of CDSS embedded in electronic health records on patient-reported and clinical outcomes of adult patients with chronic disease managed in primary care., Design and Eligibility Criteria: Systematic review, including randomised controlled trials (RCTs), cluster RCTs, quasi-RCTs, interrupted time series and controlled before-and-after studies, assessing the effect of CDSS (vs usual care) on patient-reported or clinical outcomes of adult patients with selected common chronic diseases (asthma, chronic obstructive pulmonary disease, heart failure, myocardial ischaemia, hypertension, diabetes mellitus, hyperlipidaemia, arthritis and osteoporosis) managed in primary care., Data Sources: Medline, Embase, CENTRAL, Scopus, Health Management Information Consortium and trial register clinicaltrials.gov were searched from inception to 24 June 2020., Data Extraction and Synthesis: Screening, data extraction and quality assessment were performed by two reviewers independently. The Cochrane risk of bias tool was used for quality appraisal., Results: From 5430 articles, 8 studies met the inclusion criteria. Studies were heterogeneous in population characteristics, intervention components and outcome measurements and focused on diabetes, asthma, hyperlipidaemia and hypertension. Most outcomes were clinical with one study reporting on patient-reported outcomes. Quality of the evidence was impacted by methodological biases of studies., Conclusions: There is inconclusive evidence in support of CDSS. A firm inference on the intervention effect was not possible due to methodological biases and study heterogeneity. Further research is needed to provide evidence on the intervention effect and the interplay between healthcare setting features, CDSS characteristics and implementation processes., Prospero Registration Number: CRD42020218184., Competing Interests: Competing interests: RI and NM are employees of Cerner UK, a health technology organisation. AJV-V reports past or current participation in investigator-initiated research grants to Imperial College London from Pfizer, Amgen, Sanofi, MSD, Daiichi Sankyo and Regeneron, honoraria for lectures from Amgen, Mylan and Akcea, and steering committee/consulting fees from Radcliffe Cardiology and Bayer, all outside the submitted work. KID reports past or current participation in investigator-initiated research grants to Imperial College London from Amgen, Sanofi, MSD, Daiichi Sankyo and Regeneron and consulting fees from Bayer, all outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment., Competing Interests: LBR reports past participation in investigator-initiated research grants to Hospital Universitario La Paz from MSD; personal fees for consulting/advisory committee from Sanofi-Aventis, Amgen and Bayer; honoraria for lectures from Pfizer, MSD, Novartis, Sanofi-Aventis and Amgen; all outside the submitted work. AV-V reports current or past participation in investigator-initiated research grants to Imperial College London and/or European Atherosclerosis Society from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo and Regeneron; personal fees for consulting/advisory committee from Bayer, Regeneron and Radcliffe Cardiology; honoraria for lectures from Amgen, Mylan and Akcea; all outside the submitted work. OMG reports current or past participation in investigator-initiated research grants to Hospital Universitario Virgen del Rocío from MSD, Astra-Zeneca and Sanofi-Aventis; personal fees for consulting/advisory committee from MSD, Ackcea, Sanofi-Aventis, Novartis and Daiichi-Sankyo; honoraria for lectures from MSD, Astra-Zeneca, Sanofi-Aventis, Daiichi-Sankyo, Novartis, Amgen, Ferrer, Esteve, Mylan-Viatris and Pfizer; all outside the submitted work., (Copyright © 2021 Beltrán Romero, Vallejo-Vaz and Muñiz Grijalvo.)

Background and Aims: We aimed to assess the prevalence of familial hypercholesterolaemia (FH) and to determine the incidence of cardiovascular events during a 10-year follow up in individuals with FH, compared to unaffected individuals in a working, middle-aged/young population., Methods and Results: 576,724 active workers (36 ± 10 years-old, 70% men) without cardiovascular disease were given regular health check-ups and followed for a median of 8.5 years (i.e., 4,123,927 person-years). The FH phenotype was defined according to validated low-density lipoprotein-cholesterol thresholds, adjusted for age and sex. The primary outcome was a first cardiovascular event, whether fatal or non-fatal. We found that 707 workers (0.12% or 1 in 816 individuals) met the criteria for a heterozygous FH phenotype. During the follow-up, cardiovascular events occurred in 23 of 707 (3.25%) subjects with the FH phenotype and in 3297 of 576,017 (0.57%) subjects without the FH phenotype (p<0.001). The hazard ratio (HR, assessed with a Cox regression model) for the primary outcome was 5.7 (99% CI 3.33-9.78), before adjustments, and 4.7 (99% CI 2.62-8.58) after adjusting for sex, age, smoking, blood pressure, and diabetes. The HRs were significant for both men and women, but the magnitude of the effect was greater for men than for women., Conclusions: Our findings confirmed the high incidence of cardiovascular disease in individuals with untreated FH. We showed that regular health check-ups in an active, and mostly young, working population could contribute to the early identification of FH. Therefore, this approach may provide an opportunity for early treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant., Methods: We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity., Results: Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (Q M  = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (Q M  = 8.3, df = 4, p = 0.08)., Conclusions: Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype., Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype., Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH)., Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control ( n  = 4983)., Methods: Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles., Results: Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides ( p  < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment., Conclusion: Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.

Background: Contemporary studies suggest that familial hypercholesterolemia (FH) is more frequent than previously reported and increasingly recognized as affecting individuals of all ethnicities and across many regions of the world. Precise estimation of its global prevalence and prevalence across World Health Organization regions is needed to inform policies aiming at early detection and atherosclerotic cardiovascular disease (ASCVD) prevention. The present study aims to provide a comprehensive assessment and more reliable estimation of the prevalence of FH than hitherto possible in the general population (GP) and among patients with ASCVD., Methods: We performed a systematic review and meta-analysis including studies reporting on the prevalence of heterozygous FH in the GP or among those with ASCVD. Studies reporting gene founder effects and focused on homozygous FH were excluded. The search was conducted through Medline, Embase, Cochrane, and Global Health, without time or language restrictions. A random-effects model was applied to estimate the overall pooled prevalence of FH in the general and ASCVD populations separately and by World Health Organization regions., Results: From 3225 articles, 42 studies from the GP and 20 from populations with ASCVD were eligible, reporting on 7 297 363 individuals/24 636 cases of FH and 48 158 patients/2827 cases of FH, respectively. More than 60% of the studies were from Europe. Use of the Dutch Lipid Clinic Network criteria was the commonest diagnostic method. Within the GP, the overall pooled prevalence of FH was 1:311 (95% CI, 1:250-1:397; similar between children [1:364] and adults [1:303], P =0.60; across World Health Organization regions where data were available, P =0.29; and between population-based and electronic health records-based studies, P =0.82). Studies with ≤10 000 participants reported a higher prevalence (1:200-289) compared with larger cohorts (1:365-407; P <0.001). The pooled prevalence among those with ASCVD was 18-fold higher than in the GP (1:17 [95% CI, 1:12-1:24]), driven mainly by coronary artery disease (1:16; [95% CI, 1:12-1:23]). Between-study heterogeneity was large ( I 2 >95%). Tests assessing bias were nonsignificant ( P >0.3)., Conclusions: With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP, similarly present across different regions of the world, and is more frequent among those with ASCVD. The present results support the advocacy for the institution of public health policies, including screening programs, to identify FH early and to prevent its global burden.

Purpose of Review: This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice., Recent Findings: Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia., Summary: Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.

Purpose of Review: To review the recent evidence from observational/genetic/interventional studies addressing triglycerides and residual cardiovascular risk (CVRisk)., Recent Findings: Large population-based and secondary prevention studies consistently show an association of higher triglycerides with increased CVRisk. This is compounded by genetic studies demonstrating an independent relationship between triglyceride raising or lowering genetic variants affecting triglyceride-rich lipoproteins (TRL) metabolism and CVRisk. Mendelian randomization analysis suggests the benefit of genetic lowering of triglycerides and LDL-cholesterol is similar per unit change in apolipoprotein-B. Among cholesterol-lowering trials, more intensive statin therapy produced greater CVRisk reductions in patients with higher TRL-cholesterol or triglycerides; proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition led to similar triglycerides reduction but greater non-HDL-C or apolipoprotein-B reductions than fibrates or fish oils. Regarding n-3 fatty acids, A Study of Cardiovascular Events in Diabetes (ASCEND) and Vitamin D and Omega-3 Trial (VITAL) primary prevention trials with eicosapentaenoic acid (EPA) and docosahexaenoic acid failed to demonstrate cardiovascular benefits, Conversely, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) using high-dose icosapent-ethyl (purified EPA) in primary (diabetes) and secondary prevention with hypertriglyceridemia showed significant cardiovascular events reductions (greater than expected by the observed triglycerides or apolipoprotein-B reductions, suggesting potential benefits through non-lipid pathways)., Summary: Evidence suggests higher triglycerides are a marker of CVRisk and may help identify patients who benefit from intensification of therapy. Moreover, genetic studies support a causal link between TRL/triglycerides and cardiovascular disease. Treatment with high-dose EPA may be of benefit in high-risk patients with hypertriglyceridemia to reduce CVRisk.

Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH., Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created., Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

Background and Aims: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups., Methods: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared., Results: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities., Conclusions: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE., Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies., Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549)., Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Management of familial hypercholesterolaemia (FH) may vary across different settings due to factors related to population characteristics, practice, resources and/or policies. We conducted a survey among the worldwide network of EAS FHSC Lead Investigators to provide an overview of FH status in different countries., Methods: Lead Investigators from countries formally involved in the EAS FHSC by mid-May 2018 were invited to provide a brief report on FH status in their countries, including available information, programmes, initiatives, and management., Results: 63 countries provided reports. Data on FH prevalence are lacking in most countries. Where available, data tend to align with recent estimates, suggesting a higher frequency than that traditionally considered. Low rates of FH detection are reported across all regions. National registries and education programmes to improve FH awareness/knowledge are a recognised priority, but funding is often lacking. In most countries, diagnosis primarily relies on the Dutch Lipid Clinics Network criteria. Although available in many countries, genetic testing is not widely implemented (frequent cost issues). There are only a few national official government programmes for FH. Under-treatment is an issue. FH therapy is not universally reimbursed. PCSK9-inhibitors are available in ∼2/3 countries. Lipoprotein-apheresis is offered in ∼60% countries, although access is limited., Conclusions: FH is a recognised public health concern. Management varies widely across countries, with overall suboptimal identification and under-treatment. Efforts and initiatives to improve FH knowledge and management are underway, including development of national registries, but support, particularly from health authorities, and better funding are greatly needed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Familial hypercholesterolaemia (FH) is a genetic disorder affecting the metabolism of low-density lipoprotein (LDL) particles, leading to high LDL-cholesterol levels maintained over time and higher risk of cardiovascular disease (CVD) early in life. Contemporary studies have challenged prior estimations of FH prevalence and suggest this condition to be more frequent than previously considered, with an overall prevalence rate of 1:200-300 individuals in the general population (1:160,000-300,000 for homozygous FH). However, prevalence of FH varies around the world. In part this is due to an artefact of approaches of detection and methods used to diagnose FH (e.g. lack of gold standard for diagnosis of FH, different criteria applied, availability of genetic testing). But also due to intrinsic characteristic of different populations, e.g. higher presence of founder effects or rates of consanguinity. Additionally, results from many regions are lacking and it is estimated that only a small percentage of subjects with FH would have been diagnosed overall. FH entails a significantly higher risk of CVD, reported to be higher than that estimated by conventional risk assessment tools for the general population. This risk is mainly driven by coronary heart disease. Despite this evidence, low rates of patients meet therapeutic targets for cardiovascular prevention, and implementation of therapy (high intensity statins, combination therapy) is needed. The introduction of novel lipid-lowering therapies may improve this situation. In the present review, we discuss the epidemiology of FH overall, with special attention to different aspects related to prevalence, cardiovascular risk and prognosis, and treatment of FH., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low-density lipoprotein cholesterol ( LDL -C) reduction. We explored whether lower LDL -C levels and greater LDL -C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL -C and percentage LDL -C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL -C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL -C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL -C <50 mg/dL. Each 39 mg/dL lower LDL -C was associated with a 33% and 22% lower risk of MACE in women ( P=0.0209) and men ( P=0.0307), respectively, with no significant between-sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL -C reduction, 24% ( P=0.1094) and 29% ( P=0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL -C lowering. Although women had slightly higher on-treatment LDL -C than men, both sexes showed a similar lower MACE risk with lower LDL -C.

Background: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets)., Methods: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression., Results: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008)., Conclusions: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

Background: Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL., Methods: We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up., Results: Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% ( P =0.002) and major adverse cardiovascular events by 25% ( P =0.004) consistently among those with and without LDL-C ≥190 mg/dL ( P -interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% ( P =0.033) and major adverse cardiovascular events by 25% ( P =0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% ( P =0.020), 25% ( P =0.009), and 18% ( P =0.004), respectively, over a total of 20 years of follow-up., Conclusions: The present analyses provide robust novel evidence for the short- and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL., (© 2017 American Heart Association, Inc.)

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by hypertension and proteinuria. The HELLP syndrome is the most severe form of PE. The aim of the present study was to determine different potential biomarkers that may help us perform an early diagnosis of the disease, assess on the severity of the disease, and/or predict maternal or fetal adverse outcomes., Methods: We measured serum levels of total and fetal circulating cell-free DNA (cfDNA), soluble endoglin, soluble form of vascular endothelial growth factor receptor, and placental growth factor in a healthy control group of pregnant women (n = 26), patients with mild (n = 37) and severe PE (n = 25), and patients with HELLP syndrome (n = 16)., Results: We observed a gradual and strong relationship between all the biomarkers mentioned and the range of severity of PE, with the highest levels in patients with HELLP syndrome. Nevertheless, only the values of total cfDNA were able to significantly differentiate severe PE and HELLP syndrome (20957 ± 2784 vs. 43184 ± 8647 GE/ml, P = 0.01). Receiver operating characteristic (ROC) curves were constructed (i) for the healthy group with respect to the groups with PE and (ii) for patients with PE with respect to the group with HELLP syndrome; sensitivity and specificity values at different cutoff levels were calculated in each case. The maximum ROC area under the curve value for PE and HELLP syndrome (with respect to controls) was 0.91 (P < 0.001)., Conclusions: The measured biomarkers of cell damage, angiogenesis, and antiangiogenesis may reflect the severity of PE, with higher levels in patients who develop HELLP syndrome. In addition, these biomarkers may also help predict adverse fetal and maternal outcomes., (© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Although low-density lipoprotein cholesterol (LDL-C) is widely accepted as the principal lipid fraction associated with atherosclerosis, emerging evidence suggests a causal relation between lifelong elevations in triglyceride-rich lipoprotein cholesterol (TRL-C) and cardiovascular disease (CVD) in genetic studies. To provide further evidence for the potential relevance of TRL-C and atherosclerosis, we have evaluated the relation between TRL-C and coronary artery calcium (CAC) score. We included 3,845 subjects (49.9 ± 8.4 years, 54% women) who had no history of CVD, were not using lipid-lowering medications, and underwent CAC evaluation. We assessed the relation between increasing fasting TRL-C and the graded increase in CAC and to what extent TRL-C were independently associated with CAC over and above LDL-C using logistic regression models. Overall, 973 (25%) of the participants had a CAC >0 and 308 (8%) had a CAC >100. The median TRL-C level was 22 mg/dL (IQR 16 to 32). Subjects with CAC >0 had higher TRL-C levels than those with CAC = 0 (p <0.001). Similarly, subjects with CAC >0 had higher levels of LDL-C, non-high-density lipoprotein cholesterol, and lower high-density lipoprotein cholesterol (all p <0.001). After multivariate adjustment, log-transformed TRL-C remained associated with the presence and severity of CAC (all p <0.05). When TRL-C was added to models that contained demographic factors and conventional lipids, it significantly improved the model to predict the presence of CAC >0 (p = 0.01). In conclusion, in a large cohort of asymptomatic subjects, TRL-C was associated with subclinical atherosclerosis supporting a potentially causal role in CVD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide., Methods: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects., Conclusions: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Flow-mediated dilation (FMD) of the brachial artery reflects endothelium-dependent vasodilator function; since it correlates with coronary endothelial function, its reduction could predict cardiovascular events. Several studies have investigated the potential impact of fibrates therapy on endothelial function, but clinical findings have not been fully consistent. We aimed to conduct a meta-analysis of randomized placebo-controlled trials in order to clarify whether fibrate therapy could improve endothelial function. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of fibrates on endothelial function as estimated by FMD. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk of bias evaluation, and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. Fifteen trials with a total of 556 subjects met the eligibility criteria. Fibrate therapy significantly improves FMD (weighted mean difference [WMD]: 1.64%, 95% CI: 1.15, 2.13, p<0.001) and the result was confirmed in both subgroups with treatment durations ≤8 weeks (WMD: 1.35%, 95% CI: 0.85, 1.86, p<0.001) and >8 weeks (WMD: 2.55%, 95% CI: 1.21, 3.89, p<0.001). When the analysis was stratified according to the fibrate type, a significant effect was observed with fenofibrate but not with gemfibrozil, though difference between the two subgroups was not significant. Meta-analysis of data from trials where nitrate mediated dilation (NMD) was available did not suggest a significant change in NMD following treatment with fibrates. The results of this meta-analysis suggest that fibrates may exert beneficial effects on endothelial function, even over a short-term treatment course., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and "trim and fill" tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: -15.72 ng/ml, 95 % confidence interval [CI]: -25.01, -6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: -21.32 ng/ml, 95 % CI: -32.73, -9.91, I²=99 %) and particularly atorvastatin (WMD: -20.88 ng/mL, 95 % CI: -28.79, -12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.

Aims: Whether adverse effect of statins on glycaemic indices is common to all statins remains controversial and as yet data for pitavastatin are limited. We sought to assess the effects of pitavastatin on glycaemia and new-onset diabetes (NOD) in non-diabetic individuals using data from RCT pooled together by means of a meta-analysis., Materials and Methods: We searched Medline, Cochrane, Embase and clinical trials registries websites until November-2014 for ≥12-week follow-up placebo or statin-controlled RCT of pitavastatin that included participants without diabetes and reported on fasting blood glucose (FBG), HbA1c or NOD. We additionally sought studies by consulting with Kowa Ph. Ltd. The association of pitavastatin with the outcomes were estimated by random-effects meta-analyses. Heterogeneity was assessed by the I(2) statistic and sensitivity and subgroup analyses, and publication bias with funnel plots and Egger and Harbord Tests., Results: 15 studies (approx. 1600 person-years) were included. No significant differences associated with pitavastatin (vs. control) were observed for FBG (MD -0.01 mg/dL [95%CI -0.77, 0.74], I(2) = 0%), HbA1c (MD -0.03% [95%CI -0.11, 0.05], I(2) = 43%) or NOD (RR 0.70 [95%CI 0.30, 1.61]; RD 0.0 [95%CI -0.004, 0.003]; I(2) = 0%). Sensitivity and subgroup analyses (including type of control [placebo or other statin], pitavastatin dose or follow-up] did not yield significant results. Potential publication bias may occur for NOD., Conclusions: In the present meta-analysis pitavastatin did not adversely affect glucose metabolism or diabetes development compared with placebo or other statins., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL)., Methods and Results: Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal <1.8 and non-HDL-C goal <2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0-2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0-2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61-0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38-0.61, for non-HDL-C goal attainment)., Conclusion: Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most marked at higher triglyceride levels, possibly due to higher levels of TRL., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)

Despite more effective management of heart failure over the past few decades, its burden as a chronic disease has grown and is expected to continue to rise, representing a major health problem for years to come. Having reliable tools for early diagnosis and risk stratification can help managing the condition more efficiently. In this context, the interest for biomarkers has increased considerably in the last years following the useful clinical role of B-type natriuretic peptides. These biomarkers have been extensively studied and have become established diagnostic and prognostic biomarkers in heart failure. Despite their usefulness, limitations still remain a problem in clinical practice and the search for new biomarkers has therefore continued. Amongst the most promising newer biomarkers, soluble ST2 deserves further consideration. The present review will focus on the role of this new biomarker in the context of heart failure., Competing Interests: Disclosure: The author has no conflicts of interest to declare.