Showing papers by "Raul D. Santos published in 2017"

Cardiovascular efficacy and safety of bococizumab in high-risk patients

Abstract: BackgroundBococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. MethodsIn two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10...

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

Abstract: BackgroundBococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin–kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. MethodsWe conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment. The patients were assessed for lipid changes over time, stratified according to the presence or absence of antidrug antibodies detected during the treatment period. ResultsAt 12 weeks, patients who received bococizumab had a reduction of 54.2% in the LDL cholesterol level from baseline, as compared with an increase of 1.0% among those who received placebo (absolute between-group difference, −55.2 percentage points). Significant between-group diffe...

Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study).

Abstract: Background:Although risk factors for atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH) have been described, models for predicting incident ASCVD have not been rep

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia.

Abstract: Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low-density lipoprotein cholesterol, as well as reductions in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long-term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid-modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia.

World Heart Federation Cholesterol Roadmap.

Abstract: Background The World Heart Federation has undertaken an initiative to develop a series of Roadmaps. Objectives The aim of these is to promote development of national policies and health systems approaches and identify potential roadblocks on the road to effective prevention, detection and management of cardiovascular disease (CVD) in low-and middle-income countries (LMIC), and strategies for overcoming these. This Roadmap focuses on elevated blood cholesterol, a leading risk factor for myocardial infarction, stroke, and peripheral arterial disease. Methods Through a review of published guidelines and research papers, and consultation with a committee composed of experts in clinical management of cholesterol and health systems research in LMIC, this Roadmap identifies (1) key interventions for primordial, primary and secondary prevention of CVD through detection, treatment, and management of elevated cholesterol and familial hypercholesterolemia (FH); (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMIC; and (4) potential strategies for overcoming these. Results Despite strong evidence of the importance of cholesterol levels in primary or secondary prevention of CVD, and the effectiveness of statin therapy for cholesterol lowering and reduction of CVD risk, gaps exist in the detection, treatment, and management of high cholesterol globally. Some potential roadblocks include poor access to laboratory facilities or trained professionals for cholesterol management, low awareness of FH among the general population and health professionals, unaffordability of statins for patient households, and low awareness of the importance of persistent adherence to lipid-lowering medication. Potential solutions include point-of-care testing, provision of free or subsidized lipid-lowering medication, and treatment adherence support using text message reminders. Conclusions Known effective strategies for detection, treatment, and management of elevated cholesterol and FH exist, but there are barriers to their implementation in many low-resource settings. Priorities for health system intervention should be identified at the national level, and the feasibility and effectiveness of proposed solutions should be assessed in specific contexts. Many solutions proposed in this Roadmap may apply to other cardiovascular conditions and present opportunities for integration of CVD care in LMIC.

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM).

Abstract: Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Positioning about the Flexibility of Fasting for Lipid Profiling.

Abstract: Justificativas A revisao da necessidade do jejum para determinacao do perfil lipidico (colesterol total, LDL-C, HDL-C, nao-HDL-C e triglicerides [TG]) baseia-se nas seguintes justificativas: […] Posicionamento sobre a Flexibilizacao do Jejum para o Perfil Lipidico

Relation of Fasting Triglyceride-Rich Lipoprotein Cholesterol to Coronary Artery Calcium Score (from the ELSA-Brasil Study).

Abstract: 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 had higher levels of LDL-C, non–high-density lipoprotein cholesterol, and lower high-density lipoprotein cholesterol (all p 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.

Statin-associated muscle symptoms: position paper from the Luso-Latin American Consortium.

Abstract: In the last two decades, statin therapy has proved to be the most potent isolated therapy for attenuation of cardiovascular risk. Its frequent use has been seen as one of the most important elements for the reduction of cardiovascular mortality in developed countries. However, the recurrent incidence of muscle symptoms in statin users raised the possibility of causal association, leading to a disease entity known as statin associated muscle symptoms (SAMS). Mechanistic studies and clinical trials, specifically designed for the study of SAMS have allowed a deeper understanding of the natural history and accurate incidence. This set of information becomes essential to avoid an unnecessary risk of severe forms of SAMS. At the same time, this concrete understanding of SAMS prevents overdiagnosis and an inadequate suspension of one of the most powerful prevention strategies of our times. In this context, the Luso-Latin American Consortium gathered all available information on the subject and presents them in detail in this document as the basis for the identification and management of SAMS.

Self-Reported High-Cholesterol Prevalence in the Brazilian Population: Analysis of the 2013 National Health Survey.

Abstract: Background: Data on the prevalence of dyslipidemia in Brazil are scarce, with surveys available only for some towns. Objective: To evaluate the prevalence of the self-reported medical diagnosis of high cholesterol in the Brazilian adult population by use of the 2013 National Health Survey data. Methods: Descriptive study assessing the 2013 National Health Survey data, a household-based epidemiological survey with a nationally representative sample and self-reported information. The sample consisted of 60,202 individuals who reported a medical diagnosis of dyslipidemia. The point prevalence and 95% confidence interval (95%CI) for the medical diagnosis of high cholesterol/triglyceride by gender, age, race/ethnicity, geographic region and educational level were calculated. Adjusted odds ratio was calculated. Results: Of the 60,202 participants, 14.3% (95%CI=13.7-14.8) never had their cholesterol or triglyceride levels tested, but a higher frequency of women, white individuals, elderly and those with higher educational level had their cholesterol levels tested within the last year. The prevalence of the medical diagnosis of high cholesterol was 12.5% (9.7% in men and 15.1% in women), and women had 60% higher probability of a diagnosis of high cholesterol than men. The frequency of the medical diagnosis of high cholesterol increased up to the age of 59 years, being higher in white individuals or those of Asian heritage, in those with higher educational level and in residents of the Southern and Southeastern regions. Conclusion: The importance of dyslipidemia awareness in the present Brazilian epidemiological context must be emphasized to guide actions to control and prevent coronary heart disease, the leading cause of death in Brazil and worldwide.

Phenotype vs. genotype in severe familial hypercholesterolemia: what matters most for the clinician?

Abstract: Purpose of review Familial hypercholesterolemia is associated with a high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is variable. This review evaluates recent evidence related to ASCVD risk stratification in familial hypercholesterolemia considering aspects of phenotype and genotype. Recent findings The heterogeneity in clinical, laboratory characteristics, and in ASCVD risk in both homozygous and heterozygous familial hypercholesterolemia individuals in part can be attributed to the type of molecular defect. In most individuals with LDL cholesterol more than 190 mg/dl, a familial hypercholesterolemia-causing variant is not encountered, however, when present, a variant implicates an even higher ASCVD risk for such individuals. Previous ASCVD events, elevated blood lipoprotein(a), cutaneous markers of cholesterol deposit are among other factors that indicate a higher ASCVD risk in familial hypercholesterolemia individuals underlying a more severe form of the phenotype. Summary Both clinical and genetic parameters help identify higher ASCVD risk among severe familial hypercholesterolemia individuals.

Persistent Depressive Symptoms are Independent Predictors of Low-Grade Inflammation Onset Among Healthy Individuals

Abstract: Resumo Fundamento: Sintomas depressivos estao associados de forma independente ao risco aumentado de doenca cardiovascular (DCV) em individuos com DCV nao diagnosticada Os mecanismos subjacentes a essa associacao, entretanto, nao estao claros Inflamacao tem sido indicada como um possivel elo mecanicista entre depressao e DCV Objetivos: Este estudo avaliou a associacao entre sintomas depressivos persistentes e o inicio de inflamacao de baixo grau Metodos: De um banco de dados de 1508 individuos jovens (idade media: 41 anos) sem diagnostico de []

Cardiovascular Risk Stratification and Statin Eligibility Based on the Brazilian vs. North American Guidelines on Blood Cholesterol Management

Abstract: Resumo Fundamento: Existe controversia sobre a melhor forma de selecionar individuos para tratamento hipolipemiante na populacao Objetivos: Em individuos saudaveis em prevencao primaria: Metodos: Em individuos de 40 a 75 anos submetidos consecutivamente a avaliacao rotineira de saude em um unico centro, quatro criterios de elegibilidade para estatina foram definidos: BR-1, BR-2 (LDL-c acima ou pelo menos 30 mg/dL acima da meta preconizada pela diretriz brasileira, respectivamente), EUA-1 e EUA-2 (risco estimado pelas PCE em 10 anos ≥ 5,0% ou []

Self-initiated changes in physical activity levels improve cardiometabolic profiles: A longitudinal follow-up study

Abstract: Background and aims While studies have described the importance of higher physical activity levels (PAL) in weight loss, the impact of self-initiated PAL on health status warrants further study. We aimed to prospectively examine the effects of self-initiated longitudinal PAL changes on body mass index (BMI) and cardiometabolic parameters in normal weight, overweight and obese adults. Methods and results We included 4840 adults (mean age 41.6 ± 7.9 years, 79% male) undergoing routine health screening examinations. Self-reported PAL, height, weight, blood pressure and blood samples were collected at baseline and after a mean (95% confidence interval) follow up of 536 (531–541) days. Subjects were stratified according to BMI [39.8% normal weight ( 2 ), 45.1% overweight (25.0–29.9 kg/m 2 ), and 19.1% obese (≥30 kg/m 2 )]. In normal weight individuals, BMI increased from baseline to follow-up, irrespective of PAL changes. On the other hand, overweight and obese individuals that increased PAL experienced a decrease in BMI by −0.9% and −3.1%, respectively (p Conclusions In a large cohort of screening patients, longitudinal self-initiated PAL is associated with improved BMI and cardiometabolic profile in overweight and obese individuals.

Better health literacy can make the difference when control of risk factors for cardiovascular disease and quality of life are concerned.

Abstract: Limited information, especially when coronary heart disease is concerned, suggests that lower health literacy has been associated with worse patient prognosis and quality of life. In this issue of the EJPC, Anna Aaby and colleagues show in a cross-sectional evaluation performed in 3116 Danish individuals who had previously suffered an atherosclerotic cardiovascular event (ASCVD) that higher health literacy and a greater capacity to engage with healthcare providers are associated not only with more healthy behaviours but also with a higher self-reported health status. More health-literate individuals had 52%, 36%, 53% and 21% lower odds, respectively, of being sedentary, eating an unhealthy diet, or being underweight or obese. The ability to engage with the healthcare provider was associated with 36%, 21% and 19%, respectively, lower odds for physical inactivity, eating a less than healthy diet and smoking. Greater patient literacy had a direct and continuous relation with better quality of life as measured by the robust adjusted beta coefficients shown in the study. The strengths of the study were the robust sample size, the use of validated health questionnaires and measures, and the ability to adequately adjust for confounding factors such as age, educational level, ethnic background (actually, most individuals had a Danish background) and cohabitation (i.e. whether or not a person lived alone). The main limitations of this study were: 1) the lack of prospective follow-up to really prove that the findings would change patients’ prognosis and 2) the possible lack of generalization of the findings to the rest of the world, mainly developing countries, where educational standards are much lower than those in Denmark. However, this does not reduce the merit of this elegant investigation at all. Indeed, healthier lifestyles such as non-smoking and exercising, which were associated with higher literacy in the current study, have been clearly shown to improve the prognosis of individuals who have had an ASCVD event. Importantly, the results of the current study do suggest that greater literacy can indeed improve quality of life and, with some good, sensible extrapolation, even make it longer. It would have been interesting if the authors, as a corollary of their study, could have tested how literacy and health professional engagement could influence adherence to medical treatments; mainly to lipid lowering therapy with statins, which can make a lot of difference for patients with previous cardiovascular disease and receives a very bad and unfair reputation nowadays in lay media and on the internet. One of the components of medical literacy is education. Another important question to be tested based on the authors’ work would be where patients get their health information, for example from their healthcare provider or from the nowadays ubiquitous internet, where one can have difficulty in distinguishing good from bad and scientifically unproven health information. Indeed, one of the greatest challenges nowadays is how to provide good health information about ASCVD prevention in overburdened healthcare systems. Certainly, a multi-professional approach is extremely important, and healthy behaviours must be considered very early on. To conclude, the study of Aaby et al. strongly suggests that health literacy is important for the success of preventive programmes that aim to reduce ASCVD and

Genetics and molecular biology controversies on Mendelian randomization and proprotein convertase subtilisin-kexin type 9 inhibitor clinical trials: more data still necessary.

Abstract: DOI:10.1097/MOL.0000000000000460 Mendelian randomization is a robust genetic epidemiology tool that is less subject to the limitations of classical epidemiological studies like short-time exposure, reverse causality, and influence of unmeasured confounders [1]. It has been used not only to understand potential causality of a given biomarker, that is, LDL cholesterol (LDL-C) and atherosclerosis, but also to signal the development of potential preventive therapies. However, it might also have its own methodological restrictions and some controversies have emerged from recent studies. Observational evidence shows independent and continuous association of LDL-C with coronary heart disease (CHD) as well as atherothrombotic ischemic stroke risks. Causality has been proven by statin studies that reduced cholesterol and prevented CHD and ischemic stroke in similar proportions [2]. Hopewell et al. [3 && ] have shown association of loss of function variants in the proprotein convertase subtilisin–kexin type 9 (PCSK9) gene that lower LDL-C with lower CHD risk, however, not with ischemic stroke risk in 200 000 individuals. This suggests that impact of the PCSK9 gene on ischemic stroke might not be so straightforward. The results are, however, in controversy with recent PCSK9 inhibitor intervention studies showing that both evolocumab [4 & ] and bococizumab [5 & ] that reduced LDL-C prevented myocardial infarction and ischemic stroke occurrence in similar proportions. Another controversy between the PCSK9 Mendelian genetics and intervention studies is in the possible causal role of low LDL-C on diabetes onset. Statins that inhibit hydroxyl methyl glutaryl CoA reductase (HMGCR) may increase the risk of diabetes in predisposed individuals. What about PCSK9 inhibitors? Mendelian randomization suggests that this might be the case. Ference et al. [6 && ] have tested loss of function variants in HMGCR and PCSK9 genes and found that genetic scores comprising variants in both genes were associated with lower LDL-C and

Subclinical carotid vascular disease and risk factors for atherosclerosis in type 1 and type 2 diabetes.

Abstract: The association of diabetes mellitus, both type 1 (T1DM) and type 2 (T2DM), with increased cardiovascular risk is well known (), but growing evidence has shown a wide heterogeneity in the risk of cardiovascular events in diabetics. Besides clinical evaluation, assessment of subclinical vascular disease, such as screening for coronary artery calcium (CAC), a surrogate marker of atherosclerosis in those with normal renal function, and carotid intimal-media thickness (CIMT), can further stratify risk in diabetics, identifying higher and lower risk [...]

The Expected Cardiovascular Benefit of Plasma Cholesterol Lowering with or Without LDL-C Targets in Healthy Individuals at Higher Cardiovascular Risk.

Abstract: Resumo Fundamentos: Ha controversias sobre se o controle do colesterol plasmatico deve ou nao se basear em metas de concentracao de colesterol LDL (LDL-c) Objetivos: Comparar o impacto estimado de diferentes estrategias hipolipemiantes, baseadas ou nao em metas de LDL-c, sobre o risco de eventos cardiovasculares maiores em uma populacao de risco cardiovascular mais elevado Metodos: Foram incluidos individuos consecutivamente submetidos a uma avaliacao rotineira de saude em um unico centro e que apresentavam um risco em 10 anos de []

Metabolic syndrome, diabetes and inadequate lifestyle in first-degree relatives of acute myocardial infarction survivors younger than 45 years old.

Abstract: A premature myocardial infarction (PMI) is usually associated with a familial component. This study evaluated cardiovascular risk factors in first-degree relatives (FDR) of patients with PMI not presenting the familial hypercholesterolemia phenotype. A cross-sectional study comprising FDR of non-familial hypercholesterolemia patients who suffered a myocardial infarction <45-years age matched for age and sex with individuals without family history of cardiovascular disease. Subjects were evaluated for presence of the metabolic syndrome and its components, lifestyle, statin therapy, and laboratory parameters. The sample was composed of 166 FDR of 103 PMI patients and 111 controls. The prevalence of smoking (29.5 vs. 6.3%; p < 0.001), prediabetes (40.4 vs. 27%; p < 0.001), diabetes (19.9 vs. 1.8%; p < 0.001), metabolic syndrome (64.7 vs. 36%; p < 0.001), and dyslipidemia (84.2 vs. 31.2%; p = 0.001) was greater in FDR. There was no difference on the prevalence of abdominal obesity between groups. In addition, FDR presented higher triglycerides (179.0 ± 71.0 vs. 140.0 ± 74.0 mg/dL; p = 0.002), LDL-cholesterol (122.0 ± 36.0 vs. 113.0 ± 35 mg/dL; p = 0.031), non-HDL-cholesterol (157.0 ± 53.0 vs. 141.0 ± 41.0 mg/dL; p = 0.004), and lower HDL-cholesterol (39.0 ± 10.0 vs. 48.0 ± 14.0 mg/dL; p < 0.001) than controls. Thyrotropin levels (2.4 ± 1.6 vs. 1.9 ± 1.0 mUI/L; p = 0.002) were higher in FDR. The risk factor pattern was like the one of index cases. Only 5.9% (n = 10) of FDR were in use of statins. FDR of non-familial hypercholesterolemia patients with PMI presented an elevated prevalence of metabolic abnormalities, inadequate lifestyle and were undertreated for dyslipidemia.

Abstract 14877: Familial Hypercholesterolemia in Children and Safety of Early Lipid-Lowering Treatment

Abstract: Introduction: The safety of lipid lowering therapy (LLT) in familial hypercholesterolemia (FH) children ≤ 10-years-old, is unclear. Hypothesis: To show that LLT is safe in children and adolescents ...

Abstract 15477: Association Between TSH Levels and Hepatic Steatosis is Mediated by Metabolic Syndrome Factors

Abstract: Introduction: Thyroid hormones are involved in the regulation of body composition, lipid metabolism and insulin resistance. Thus, they might play a role in the pathogenesis of non-alcoholic fatty l...