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.

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.

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.

Abstract Objective: To describe insulin use and postoperative glucose control in patients undergoing coronary artery bypass graft (CABG) surgery. Methods: We examined 2,390 patients with and without diabetes enrolled in the Contemporary Analysis of Perioperative Cardiovascular Surgical Care (CAPS-Care) Study who underwent CABG surgery (01/2004 - 06/2005) to describe postoperative insulin use, variation in insulin use across different hospitals, and associated in-hospital complications and clinical outcomes. Logistic regression was used to assess the adjusted relationship between insulin use and clinical outcomes. Results: Overall, insulin was used in 82% (n=1,959) of patients, including 95% (n=1,203) with diabetes (n=1,258) and 67% (n=756) without diabetes (n=1,132). Continuous insulin was used in 35.5% of patients in the operating room and in 56% in the intensive care unit. Continuous insulin use varied significantly among centers from 8-100% in patients with diabetes. When compared with all patients not receiving insulin, insulin use in patients without diabetes was associated with a higher rate of death or major complication (adjusted odds ratio [OR]=1.54; 95% confidence interval [CI] 1.15-2.04; P=0.003). In patients with diabetes, insulin use was not associated with a higher risk of adverse outcomes (adjusted OR=1.01; 95% CI 0.52-1.98; P=0.98). Conclusion: The postoperative use of insulin is high among CABG patients in the United States of America. Insulin use in patients without diabetes was associated with worse clinical outcomes compared to patients (both with and without diabetes) who did not receive insulin. Further investigation is needed to determine the optimal use of postoperative insulin after CABG.

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Abstract Introduction: Antiplatelet therapy after coronary artery bypass graft (CABG) has been used. Little is known about the predictors and efficacy of clopidogrel in this scenario. Objective: Identify predictors of clopidogrel following CABG. Methods: We evaluated 5404 patients who underwent CABG between 2000 and 2009 at Duke University Medical Center. We excluded patients undergoing concomitant valve surgery, those who had postoperative bleeding or death before discharge. Postoperative clopidogrel was left to the discretion of the attending physician. Adjusted risk for 1-year mortality was compared between patients receiving and not receiving clopidogrel during hospitalization after undergoing CABG. Results: At hospital discharge, 931 (17.2%) patients were receiving clopidogrel. Comparing patients not receiving clopidogrel at discharge, users had more comorbidities, including hyperlipidemia, hypertension, heart failure, peripheral arterial disease and cerebrovascular disease. Patients who received aspirin during hospitalization were less likely to receive clopidogrel at discharge (P≤0.0001). Clopidogrel was associated with similar 1-year mortality compared with those who did not use clopidogrel (4.4% vs. 4.5%, P=0.72). There was, however, an interaction between the use of cardiopulmonary bypass and clopidogrel, with lower 1-year mortality in patients undergoing off-pump CABG who received clopidogrel, but not those undergoing conventional CABG (2.6% vs 5.6%, P Interaction = 0.032). Conclusion: Clopidogrel was used in nearly one-fifth of patients after CABG. Its use was not associated with lower mortality after 1 year in general, but lower mortality rate in those undergoing off-pump CABG. Randomized clinical trials are needed to determine the benefit of routine use of clopidogrel in CABG.

Objetivo: la fibrilación auricular (FA) y la enfermedad coronaria (EC) son comunes en los pacientes añosos. En este estudio nos propusimos describir el uso de agentes antiarrítmicos (AAA) y los resultados clínicos en estos pacientes. Métodos y resultados: se analizó el tratamiento con AAA y los resultados observados en 1.738 pacientes mayores (edad ³65) con FA y EC registrados en el Banco de Datos para Enfermedad Cardiovascular de Duke. Los resultados primarios fueron mortalidad y rehospitalización al año y a los cinco años. En términos generales, 35% de los pacientes recibían un AAA al inicio, 43% eran mujeres y 85% eran blancos. Fueron frecuentes los antecedentes de infarto de miocardio (IM, 31%) e insuficiencia cardíaca (41%). La amiodarona era el AAA más frecuente (21%), seguida de agentes de Clase III pura (sotalol 6,3%, dofetilida 2,2%). La persistencia de los AAA fue baja (35% al año). Luego del ajuste, el uso de AAA al inicio no se asoció con la mortalidad al año (cociente de riesgo ajustado (HR) 1,23, intervalo de confianza (IC) 95%: 0,94-1,60) o con la mortalidad cardiovascular (HR ajustado 1,27, IC 95% 0,90-1,80). Sin embargo, el uso de AAA sí se asoció con un aumento de la rehospitalización por todas las causas (HR ajustado 1,20, IC 95%: 1,03-1,39) y rehospitalización cardiovascular (HR ajustado 1,20, IC 95% 1,01-1,43) al año. Esta asociación no se mantiene a los cinco años; sin embargo, estos pacientes tuvieron un elevado riesgo de muerte (55% para los >75 años y que recibían AAA) y rehospitalización (87% para aquellos >75 años que recibían AAA) a los cinco años. Conclusiones: en pacientes añosos que padecen FA y EC, la terapia antiarrítmica se acompañó de aumento de la rehospitalización al año. En términos generales, estos pacientes presentan un alto riesgo de internación y muerte a largo plazo. Se necesitan desarrollar terapias más seguras, mejor toleradas y que brinden un control de los síntomas más eficaz en esta población de alto riesgo.

OBJECTIVES: To correlate the importance of the ankle-brachial index in terms of cardiovascular morbimortality and the extent of coronary arterial disease amongst elderly patients without clinical manifestations of lower limb peripheral arterial disease. METHODS: We analyzed prospective data from 100 patients over 65 years of age with coronary arterial disease, as confirmed by coronary angiography, and with over 70% stenosis of at least one sub-epicardial coronary artery. We measured the ankle-brachial index immediately after coronary angiography, and a value of <0.9 was used to diagnose peripheral arterial disease. RESULTS: The patients' average age was 77.4 years. The most prevalent risk factor was hypertension (96%), and the median late follow-up appointment was 28.9 months. The ankle-brachial index was <0.9 in 47% of the patients, and a low index was more prevalent in patients with multiarterial coronary disease compared to patients with uniarterial disease in the same group. Using a bivariate analysis, only an ankle-brachial index of <0.9 was a strong predictive factor for cardiovascular events, thereby increasing all-cause deaths and fatal and non-fatal acute myocardial infarctions two- to three-fold. CONCLUSION: In elderly patients with documented coronary disease, a low ankle-brachial index (<0.9) was associated with the severity and extent of coronary arterial disease, and in late follow-up appointments, a low index was correlated with an increase in the occurrence of major cardiovascular events.

OBJECTIVES: N-3 polyunsaturated fatty acids have been proposed as a novel treatment for preventing postoperative atrial fibrillation due to their potential anti-inflammatory and anti-arrhythmic effects. However, randomized studies have yielded conflicting results. The objective of this study is to review randomized trials of N-3 polyunsaturated fatty acid use for postoperative atrial fibrillation. METHODS: Using the CENTRAL, PUBMED, EMBASE, and LILACS databases, a literature search was conducted to identify all of the studies in human subjects that reported the effects of N-3 polyunsaturated fatty acids on the prevention of postoperative atrial fibrillation in cardiac surgery patients. The final search was performed on January 30, 2011. There was no language restriction, and the search strategy only involved terms for N-3 polyunsaturated fatty acids (or fish oil), atrial fibrillation, and cardiac surgery. To be included, the studies had to be randomized (open or blinded), and the enrolled patients had to be >18 years of age. RESULTS: Four randomized studies (three double-blind, one open-label) that enrolled 538 patients were identified. The patients were predominantly male, the mean age was 62.3 years, and most of the patients exhibited a normal left atrial size and ejection fraction. N-3 polyunsaturated fatty acid use was not associated with a reduction in postoperative atrial fibrillation. Similar results were observed when the open-label study was excluded. CONCLUSIONS: There is insufficient evidence to suggest that treatment with N-3 polyunsaturated fatty acids reduces postoperative atrial fibrillation. Therefore, their routine use in patients undergoing cardiac surgery is not recommended.