Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE - COALITION VIII randomised clinical trial.

Background: COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting. Methods: We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857. Findings: Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47-69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38-1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group. Interpretation: On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution. Funding: COALITION COVID-19 Brazil and Bayer S.A.

Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII). / Rivaroxabana em Pacientes Ambulatoriais com COVID-19 Leve ou Moderada: Fundamentação e Desenho do Estudo CARE (CARE ­ Coalition COVID-19 Brazil VIII).

BACKGROUND: Previous studies have demonstrated a high risk of arterial and venous thromboembolic events as a consequence of direct viral damage to endothelial cells by SARS-CoV-2 and a procoagulant milieu due to increased biomarkers, such as D-dimer, fibrinogen, and factor VIII. Although randomized controlled trials of antithrombotic therapies have been conducted in hospitalized patients, few have evaluated the role of thromboprophylaxis in an outpatient setting. OBJECTIVE: To assess whether antithrombotic prophylaxis with rivaroxaban reduces the risk of venous or arterial thrombotic events, invasive ventilatory support, and death in COVID-19 outpatients. METHODS: The COVID Antithrombotic Rivaroxaban Evaluation (CARE) study, a multicenter, randomized, open-label, controlled trial of rivaroxaban 10 mg once daily for 14 days or local standard treatment alone to prevent adverse outcomes, is registered in clinicaltrials.gov (NCT04757857). The inclusion criteria are adults with confirmed or suspected SARS-CoV-2 infection and mild or moderate symptoms without indication for hospitalization, within 7 days of symptom onset, and 1 risk factor for COVID-19 complication (> 65 years, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease or other chronic lung diseases, smoking, immunosuppression, or obesity). The primary composite endpoint, which includes venous thromboembolism, invasive mechanical ventilation, major acute cardiovascular events, and mortality within 30 days of randomization, will be assessed according to the intention-to-treat principle. All patients will provide informed consent. A significance level of 5% will be used for all statistical tests. RESULTS: Major thrombotic and bleeding outcomes, hospitalizations, and deaths will be centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. CONCLUSION: The CARE study will provide relevant and contemporary information about the potential role of thromboprophylaxis in outpatients with COVID-19.

FUNDAMENTO: Estudos anteriores revelaram alto risco de eventos tromboembólicos arteriais e venosos como consequência de danos virais diretos do SARS-CoV-2 em células endoteliais e um meio procoagulante devido ao aumento de biomarcadores como o D-dímero, fibrinogênio, fator VIII. Foram realizados ensaios controlados randomizados de terapias antitrombóticas em pacientes internados, no entanto, poucos estudos avaliaram o papel da tromboprofilaxia no ambiente ambulatorial. OBJETIVO: Avaliar se a profilaxia antitrombótica com rivaroxabana reduz o risco de eventos trombóticos venosos ou arteriais, suporte ventilatório invasivo e morte em pacientes ambulatoriais com COVID-19. MÉTODOS: O estudo CARE é um ensaio randomizado, aberto, multicêntrico e controlado por rivaroxabana 10 mg uma vez por dia durante 14 dias ou tratamento local padrão isolado, para a prevenção de resultados adversos, registrado no Clinicaltrials.gov (NCT04757857). Os critérios de inclusão são adultos com infecção confirmada ou suspeita do SARS-CoV-2, com sintomas leves ou moderados, sem indicação de hospitalização, no prazo de 7 dias após o início dos sintomas e um fator de risco de complicação da COVID-19 (>65 anos, hipertensão, diabetes, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). O desfecho primário composto inclui tromboembolismo venoso, necessidade de ventilação mecânica invasiva, eventos cardiovasculares agudos maiores e mortalidade no prazo de 30 dias após a randomização, sendo avaliado segundo o princípio da intenção de tratar. Todos os pacientes assinaram termo de consentimento. Foi estabelecido um nível de significância de 5% para todos os testes estatísticos. RESULTADOS: Os principais desfechos trombóticos e hemorrágicos, hospitalizações e mortes serão avaliados centralmente por um comitê de eventos clínicos independente, sob a condição cega para a alocação dos grupos de tratamento. CONCLUSÃO: O estudo CARE fornecerá informação relevante e contemporânea sobre o possível papel da tromboprofilaxia em pacientes ambulatoriais com COVID-19.

Rivaroxabana em Pacientes Ambulatoriais com COVID-19 Leve ou Moderada: Fundamentação e Desenho do Estudo CARE (CARE - Coalition COVID-19 Brazil VIII) / Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE - Coalition COVID-19 Brazil VIII)

Resumo Fundamento Estudos anteriores revelaram alto risco de eventos tromboembólicos arteriais e venosos como consequência de danos virais diretos do SARS-CoV-2 em células endoteliais e um meio procoagulante devido ao aumento de biomarcadores como o D-dímero, fibrinogênio, fator VIII. Foram realizados ensaios controlados randomizados de terapias antitrombóticas em pacientes internados, no entanto, poucos estudos avaliaram o papel da tromboprofilaxia no ambiente ambulatorial. Objetivo Avaliar se a profilaxia antitrombótica com rivaroxabana reduz o risco de eventos trombóticos venosos ou arteriais, suporte ventilatório invasivo e morte em pacientes ambulatoriais com COVID-19. Métodos O estudo CARE é um ensaio randomizado, aberto, multicêntrico e controlado por rivaroxabana 10 mg uma vez por dia durante 14 dias ou tratamento local padrão isolado, para a prevenção de resultados adversos, registrado no Clinicaltrials.gov (NCT04757857). Os critérios de inclusão são adultos com infecção confirmada ou suspeita do SARS-CoV-2, com sintomas leves ou moderados, sem indicação de hospitalização, no prazo de 7 dias após o início dos sintomas e um fator de risco de complicação da COVID-19 (>65 anos, hipertensão, diabetes, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). O desfecho primário composto inclui tromboembolismo venoso, necessidade de ventilação mecânica invasiva, eventos cardiovasculares agudos maiores e mortalidade no prazo de 30 dias após a randomização, sendo avaliado segundo o princípio da intenção de tratar. Todos os pacientes assinaram termo de consentimento. Foi estabelecido um nível de significância de 5% para todos os testes estatísticos. Resultados Os principais desfechos trombóticos e hemorrágicos, hospitalizações e mortes serão avaliados centralmente por um comitê de eventos clínicos independente, sob a condição cega para a alocação dos grupos de tratamento. Conclusão O estudo CARE fornecerá informação relevante e contemporânea sobre o possível papel da tromboprofilaxia em pacientes ambulatoriais com COVID-19.

Abstract Background Previous studies have demonstrated a high risk of arterial and venous thromboembolic events as a consequence of direct viral damage to endothelial cells by SARS-CoV-2 and a procoagulant milieu due to increased biomarkers, such as D-dimer, fibrinogen, and factor VIII. Although randomized controlled trials of antithrombotic therapies have been conducted in hospitalized patients, few have evaluated the role of thromboprophylaxis in an outpatient setting. Objective To assess whether antithrombotic prophylaxis with rivaroxaban reduces the risk of venous or arterial thrombotic events, invasive ventilatory support, and death in COVID-19 outpatients. Methods The COVID Antithrombotic Rivaroxaban Evaluation (CARE) study, a multicenter, randomized, open-label, controlled trial of rivaroxaban 10 mg once daily for 14 days or local standard treatment alone to prevent adverse outcomes, is registered in clinicaltrials.gov (NCT04757857). The inclusion criteria are adults with confirmed or suspected SARS-CoV-2 infection and mild or moderate symptoms without indication for hospitalization, within 7 days of symptom onset, and 1 risk factor for COVID-19 complication (> 65 years, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease or other chronic lung diseases, smoking, immunosuppression, or obesity). The primary composite endpoint, which includes venous thromboembolism, invasive mechanical ventilation, major acute cardiovascular events, and mortality within 30 days of randomization, will be assessed according to the intention-to-treat principle. All patients will provide informed consent. A significance level of 5% will be used for all statistical tests. Results Major thrombotic and bleeding outcomes, hospitalizations, and deaths will be centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups. Conclusion The CARE study will provide relevant and contemporary information about the potential role of thromboprophylaxis in outpatients with COVID-19.

Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial.

Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]). Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. Funding: COALITION COVID-19 Brazil and EMS.

Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. / Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados.

BACKGROUND: Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. OBJECTIVE: To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. METHODS: The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. RESULTS: Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. CONCLUSION: This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

FUNDAMENTO: Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. OBJETIVO: Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. MÉTODOS: O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. RESULTADOS: Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. CONCLUSÃO: Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados / Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Resumo Fundamento Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. Objetivo Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. Métodos O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. Resultados Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. Conclusão Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Abstract Background Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. Objective To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. Methods The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. Results Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. Conclusion This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

Survival curve identifies critical period for postoperative mortality in cardiac patients undergoing emergency general surgery.

The number of non-cardiac major surgeries carried out has significantly increased in recent years to around 200 million procedures carried out annually. Approximately 30% of patients submitted to non-cardiac surgery present some form of cardiovascular comorbidity. In emergency situations, with less surgery planning time and greater clinical severity, the risks become even more significant. The aim of this study is to determine the incidence and clinical outcomes in patients with cardiovascular disease submitted to non-cardiac surgical procedures in a single cardiovascular referral center. This is a prospective cohort study of patients with cardiovascular disease submitted to non-cardiovascular surgery. All procedures were carried out by the same surgeon, between January 2006 and January 2018. 240 patients included were elderly, 154 were male (64%), 8 patients presented two diagnoses. Of the resulting 248 procedures carried out, 230 were emergency (92.8%). From the data obtained it was possible to estimate the day from which the occurrence of mortality is less probable in the postoperative phase. Our research evaluated the epidemiological profile of the surgeries and we were able to estimate the survival and delimit the period of greatest risk of mortality in these patients. The high rate of acute mesenteric ischemia was notable, a serious and frequently fatal condition.

Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study.

BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

High-density lipoprotein-cholesterol functionality and metabolic syndrome: Protocol for review and meta-analysis.

INTRODUCTION: The prevalence of metabolic syndrome (MetS) and MetS-related stroke is set to increase dramatically in coming decades. MetS is a complex disease that includes endothelial dysfunction, insulin resistance, diabetes, hypertension, ectopic obesity, and dyslipidaemia and an increased risk of cardiovascular events. One function of high-density lipoprotein (HDL) cholesterol (HDL-C) is the cholesterol-efflux pathway, which is the pathway where cholesterol is removed from macrophages within the arterial walls back into the bloodstream and out to the liver. As one of the key functions of HDL, their hypothesis was that if they could measure HDL-C-efflux capacity, they would have a better handle on the role of HDL in atherosclerosis. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between HDL-C functionality and MetS. The aim of this study is to examine this association of HDL-C functionality with MetS in different ages and sex. METHODS AND ANALYSIS: The update systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (i.e., PubMed, EMBASE, Web of Science, and Google Scholar). Studies that examined the association between HDL-C functionality and MetS; focused on cohort, case-control, and cross-sectional studies; were conducted among in adults aged 40 to 70 years; provided sufficient data for calculating odds ratio or relative risk with a 95% confidence interval; were published as original articles written in English or other languages; and have been published until January 2018 will be included. Study selection, data collection, quality assessment, and statistical syntheses will be conducted based on discussions among investigators. ETHICS AND DISSEMINATION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42018083465).

Epicardial adipose tissue and carotid artery disease: Protocol for systematic review and meta-analysis.

BACKGROUND: Atherosclerosis is now widely recognized as a multifactorial disease with outcomes that arise from complex factors such as plaque components, blood flow, and inflammation. Epicardial adipose tissue (EAT) is a metabolically active fat depot, abundant in proinflammatory cytokines, and has been correlated with the extent and severity of carotid artery disease (CD). The locations most frequently affected by carotid atherosclerosis are the proximal internal carotid artery (ie, the origin) and the common carotid artery bifurcation. Progression of atheromatous plaque at the carotid bifurcation results in luminal narrowing, often accompanied by ulceration. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between EAT and CD. The aim of this study is to examine this association of EAT with CD in different ages and sex. METHODS: This systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (ie, PubMed, EMBASE, Web of Science, and Google Scholar. Studies that (1) examined the association between EAT and CD, (2) focus on cohort, case-control and cross-sectional studies, (3) will conducted among in adults aged 40 to 70 years, (4) provided sufficient data for calculating ORs or relative risk with a 95% CI, (5) will published as original articles written in English or other languages, and (6) have been published until January 2018 will be included. Study selection, data collection, quality assessment and statistical syntheses will be conducted based on discussions among investigators. RESULTS: We propose the current protocol to evaluate the evaluation of EAT with ED. CONCLUSION: This systematic review will not need ethical approval, because it does not involve human beings. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. ETHICS AND DISSEMINATION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42018083458).

Statins in adult patients with HIV: Protocol for a systematic review and network meta-analysis.

BACKGROUND: Patients with HIV have been found to suffer from lipid abnormalities, including elevated levels of total and LDL-cholesterol as well as triglyceride levels. Abnormal lipid levels are associated with an increased risk of developing cardiovascular diseases, which are significant causes of mortality among the general population. Therefore, the objective of the current study is to conduct a systematic review with network meta-analysis to compare the effects of statins classes on HIV patients. METHODS: Randomized clinical trials (RCTs) and observational studies published in English up to 31 December 2017, and which include direct and/or indirect evidence, will be included. Studies will be retrieved by searching four electronic databases and cross-referencing. Dual selection and abstraction of data will occur. The primary outcome will all-cause mortality, new event of acute myocardial infarction, stroke (hemorrhagic and ischemic), hospitalization for acute coronary syndrome and urgent revascularization procedures and cardiovascular mortality. Secondary outcomes will be assessment of the differences in change of total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (ApoB), high density lipoprotein (HDL-C). Risk of bias will be assessed using the Cochrane Risk of Bias assessment instrument for RCTs and the Strengthening the Reporting of Observational Studies in Epidemiology instrument for observational studies. Network meta-analysis will be performed using multivariate random-effects meta-regression models. The surface under the cumulative ranking curve will be used to provide a hierarchy of statins that reduce cardiovascular mortality in HIV patients. A revised version of the Cochrane Risk of Bias tool (RoB 2.0) will be used to assess the risk of bias in eligible RCTs. Results will be synthesized and analyzed using network meta-analysis (NMA). Overall strength of the evidence and publication bias will be evaluated. Subgroup and sensitivity analysis will also be performed. RESULTS AND CONCLUSION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. The evidence will determine which combination of interventions are most promising for current practice and further investigation. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42017072996).

Epicardial adipose tissue and metabolic syndrome: An update protocol for systematic review and meta-analysis.

BACKGROUND: The prevalence of metabolic syndrome (MetS) and MetS-related stroke is set to increase dramatically in coming decades. MetS is a complex disease that includes endothelial dysfunction, insulin resistance, diabetes, hypertension, ectopic obesity, and dyslipidaemia, and an increased risk of cardiovascular events. However, there are no systematic analyses, or well-conducted meta-analyses to evaluate the relationship between epicardial adipose tissue (EAT) and (MetS). The aim of this study is to examine this association of EAT with MetS in different ages and sex. METHODS: The update systematic review, and meta-analysis will be conducted using published studies that will be identified from electronic databases (ie, PubMed, EMBASE, Web of Science, and Google Scholar. Studies that firstly, examined the association between EAT and MetS, secondly, focus on cohort, case-control, and cross-sectional studies, thirdly, were conducted among in adults aged between 40 and 70 years, fourth, provided sufficient data for calculating ORs or relative risk with a 95% CI, fifth, were published as original articles written in English or other languages, and sixth, have been published until January year 2018 will be included. Study selection, data collection, quality assessment, and statistical syntheses will be conducted based on discussions among investigators. RESULTS: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. This study will provide a high quality synthesis on the association of EAT and MetS. CONCLUSION: This systematic review will provide evidence to assess whether there is a strong association of EAT and MetS, and its components.

Metabolic syndrome and risk of stroke: Protocol for an update systematic review and meta-analysis.

INTRODUCTION: The metabolic syndrome is composed of several cardiovascular risk factors and has a high prevalence throughout the world. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between metabolic syndrome and stroke. The aim of this study is to examine this association of metabolic syndrome with stroke in different ages and sex. METHODS AND ANALYSIS: The update systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (i.e., PubMed, EMBASE, Web of Science, and Google Scholar. Studies that examined the association between metabolic syndrome and stroke, had a longitudinal or prospective cohort design, were conducted among in adults aged 40 to 70 years, provided sufficient data for calculating ORs or relative risk with a 95% CI, were published as original articles written in English or other languages, and have been published until December 2017 will be included. Study selection, data collection, quality assessment, and statistical syntheses will be conducted based on discussions among investigators. ETHICS AND DISSEMINATION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. The findings from this study could be useful for assessing metabolic syndrome risk factors in stroke, and determining approaches for prevention of stroke in the future.

Independent predictors of effective blood pressure control in patients with hypertension on drug treatment in Brazil.

Population assessment of effective blood pressure (BP) control is fundamental for reducing the global burden of hypertension, especially in low- and middle-income countries. The authors evaluated the effectiveness of BP control and determined independent predictors associated with effective control among patients with hypertension on drug treatment in a large cross-sectional study performed in two metropolitan areas in Brazil's southeast region. A total of 43 647 patients taking antihypertensive treatment were identified. Less than half of the patients (40.9%) had controlled BP (systolic BP <140 mm Hg and diastolic BP <90 mm Hg). Independent predictors of BP control were age, eating fruit daily, physical activity, previous cardiovascular disease, male sex, diabetes mellitus, ethnicity, and obesity. Simple variables associated with BP control may be utilized for knowledge translation strategies aiming to reduce the burden of hypertension.

Secondary CV Prevention in South America in a Community Setting: The PURE Study.

BACKGROUND: Despite the availability of evidence-based therapies, there is no information on the use of medications for the secondary prevention of cardiovascular disease in urban and rural community settings in South America. OBJECTIVES: This study sought to assess the use, and its predictors, of effective secondary prevention therapies in individuals with a history of coronary heart disease (CHD) or stroke. METHODS: In the PURE (Prospective Urban Rural Epidemiological) study, we enrolled 24,713 individuals from South America ages 35 to 70 years from 97 rural and urban communities in Argentina, Brazil, Chile, and Colombia. We assessed the use of proven therapies with standardized questionnaires. We report estimates of drug use at national, community, and individual levels and the independent predictors of their utilization through a multivariable analysis model. RESULTS: Of 24,713 individuals, 910 had a self-reported CHD event (at a median of 5 years earlier) and 407 had stroke (6 years earlier). The proportions of individuals with CHD who received antiplatelet medications (30.1%), beta-blockers (34.2%), angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers (36.0%), or statins (18.0%) were low; with even lower proportions among stroke patients (antiplatelets 24.3%, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers 37.6%, statins 9.8%). A substantial proportion of patients did not receive any proven therapy (CHD 31%, stroke 54%). A minority of patients received either all 4 (4.1%) or 3 proven therapies (3.3%). Male sex, age >60 years, better education, more wealth, urban location, diabetes, and obesity were associated with higher rates of medication use. In a multivariable model, markers of wealth had the largest impact in secondary prevention. CONCLUSIONS: There are large gaps in the use of proven medications for secondary prevention of cardiovascular disease in South America. Strategies to improve the sustained use of these medications will likely reduce cardiovascular disease burden substantially.

Cardiovascular Disease Burden: Evolving Knowledge of Risk Factors in Myocardial Infarction and Stroke through Population-Based Research and Perspectives in Global Prevention.

Current knowledge and research perspectives on the top ranking causes of mortality worldwide, i.e., ischemic heart disease and cerebrovascular diseases have developed rapidly. In fact, until recently, the evidence describing the incidence of acute myocardial infarction, the underlying risk factors, and the clinical outcomes of those who have this acute ischemic coronary event has largely been based on studies conducted in developed countries, with limited data for women and usually of low-ethnic diversity. Recent reports by the WHO have provided striking public health information, i.e., the global burden of cardiovascular mortality for the next decades is expected to predominantly occur among developing countries. Therefore, multiethnic population-based research including prospective cohorts and, when appropriate, case-control studies, is warranted. These studies should be specifically designed to ascertain key public health measures, such as geographic variations in non-communicable diseases, diagnosis of traditional and potential newly discovered risk factors, causes of death and disability, and gaps for improvement in healthcare prevention (both primary and secondary) and specific treatments. As an example, a multinational, multiethnic population-based cohort study is the Prospective Urban and Rural Epidemiology study, which is the largest global initiative of nearly 200,000 adults aged 35-70 years, looking at environmental, societal, and biological influences on obesity and chronic health conditions, such as ischemic heart disease, stroke, and cancer among urban and rural communities in low-, middle-, and high-income countries, with national, community, household, and individual-level data. Implementation of population-based strategies is crucial to optimizing limited health system resources while improving care and cardiovascular morbidity and mortality.

Delay to reperfusion in patients with acute myocardial infarction presenting to acute care hospitals: an international perspective.

AIMS: To examine the extent of delay from initial hospital presentation to fibrinolytic therapy or primary percutaneous coronary intervention (PCI), characteristics associated with prolonged delay, and changes in delay patterns over time in patients with ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: We analysed data from 5170 patients with STEMI enrolled in the Global Registry of Acute Coronary Events from 2003 to 2007. The median elapsed time from first hospital presentation to initiation of fibrinolysis was 30 min (interquartile range 18-60) and to primary PCI was 86 min (interquartile range 53-135). Over the years under study, there were no significant changes in delay times to treatment with either strategy. Geographic region was the strongest predictor of delay to initiation of fibrinolysis >30 min. Patient's transfer status and geographic location were strongly associated with delay to primary PCI. Patients treated in Europe were least likely to experience delay to fibrinolysis or primary PCI. CONCLUSION: These data suggest no improvements in delay times from hospital presentation to initiation of fibrinolysis or primary PCI during our study period. Geographic location and patient transfer were the strongest predictors of prolonged delay time, suggesting that improvements in modifiable healthcare system factors can shorten delay to reperfusion therapy even further.

Six-month follow-up of patients with in-hospital thrombocytopenia during heparin-based anticoagulation (from the Complications After Thrombocytopenia Caused by Heparin [CATCH] registry).

Thrombocytopenia is a predictor of adverse outcomes in patients with acute coronary syndromes and in critically ill patients. The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry was designed to explore the incidence, management, and clinical consequences of in-hospital thrombocytopenia occurring during heparin-based anticoagulation in diverse clinical settings. We conducted a prospective observational study of 37 United States hospitals participating in the CATCH registry to assess the relation of in-hospital thrombocytopenia to long-term outcomes. A total of 2,104 patients at increased risk of developing in-hospital thrombocytopenia or thrombosis were identified, and the 6-month mortality and rehospitalization rates were determined. Thrombocytopenia was not a significant predictor of 6-month mortality. In an adjusted model for in-hospital death in this cohort, thrombocytopenia had an odds ratio of 3.59 (95% confidence interval 2.24 to 5.77). The postdischarge mortality rate at 6 months was 9.7%. No significant difference was observed in the long-term mortality between patients who developed thrombocytopenia and those who did not. Thrombocytopenia was a weak, but statistically significant, predictor of a composite of mortality and rehospitalization at 6 months (hazards ratio 0.80, 95% confidence interval 0.65 to 0.98, p = 0.03). In conclusion, the 6-month mortality rate among heparin-treated patients with thrombocytopenia is high, although the risk independently related to thrombocytopenia appears to be restricted to the acute hospital phase.

Contribution of bleeding and thromboembolic events to in-hospital mortality among patients with thrombocytopenia treated with heparin.

In a population of patients experiencing thrombocytopenia while treated with heparin, bleeding and thromboses are well-appreciated complications, but their relative contributions to mortality have been less well described. In this population, the aims of this study were (1) to identify the independent predictors of bleeding and (2) to compare the incidence and the strength of association of bleeding and of new thromboses to in-hospital mortality. The independent predictors of bleeding and in-hospital mortality were identified using multivariate logistic regression models on the 1,478 patients who developed thrombocytopenia after their enrollment in the Complications After Thrombocytopenia Caused by Heparin (CATCH) study. The independent predictors of bleeding were chronic hematologic disorders, intra-aortic balloon pump, congestive heart failure, and platelet count nadir <120 x 10(9)/L. Although bleeding (n = 141 [10%]) and thromboembolic complications (n = 135 [9%]) were equally prevalent, the former was less strongly associated than the latter with in-hospital mortality (odds ratio 1.75, 95% confidence interval 1.01 to 3.03, and odds ratio 2.77, 95% confidence interval 1.67 to 4.61, respectively). In conclusion, medical management should be directed mainly at the prevention of thromboembolic complications, while additionally considering the risk for bleeding.