Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. METHODS: We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. RESULTS: A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. CONCLUSIONS: Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).

Predictors of bleeding and thrombotic events among patients admitted to the hospital with COVID-19 and elevated D-dimer: insights from the ACTION randomized clinical trial.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. METHODS: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. FINDINGS: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. INTERPRETATION: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. FUNDING: Coalition COVID-19 Brazil, Bayer SA.

The Role of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Diagnosis of Left-sided Endocarditis: Native vs Prosthetic Valves Endocarditis.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has emerged as a useful diagnostic tool for suspected infective endocarditis (IE) in patients with prosthetic valves or implantable devices. However, there is limited evidence regarding use of 18F-FDG-PET/CT for the diagnosis of native valve endocarditis (NVE). METHODS: Between 2014 and 2017, 303 episodes of left-sided suspected IE (188 prosthetic valves/ascending aortic prosthesis and 115 native valves) were studied. 18F-FDG-PET/CT accuracy was determined in the subgroups of patients with NVE and prosthetic valve endocarditis (PVE)/ascending aortic prosthesis infection (AAPI). Associations between inflammatory infiltrate patterns and 18F-FDG-PET/CT uptake were investigated in an exploratory ad hoc histological analysis. RESULTS: Among 188 patients with PVE/AAPI, the sensitivity, specificity, and positive and negative predictive values of 18F-FDG-PET/CT focal uptake were 93%, 90%, 89%, and 94%, respectively, while among 115 patients with NVE, the corresponding values were 22%, 100%, 100%, and 66%. The inclusion of abnormal 18F-FDG cardiac uptake as a major criterion at admission enabled a recategorization of 76% (47/62) of PVE/AAPI cases initially classified as "possible" to "definite" IE. In the histopathological analysis, a predominance of polymorphonuclear cell inflammatory infiltrate and a reduced extent of fibrosis were observed in the PVE group only. CONCLUSIONS: Use of 18F-FDG-PET/CT at the initial presentation of patients with suspected PVE increases the diagnostic capability of the modified Duke criteria. In patients who present with suspected NVE, the use of 18F-FDG-PET/CT is less accurate and could only be considered a complementary diagnostic tool for a specific population of patients with NVE.

Integration of transthoracic focused cardiac ultrasound in the diagnostic algorithm for suspected acute aortic syndromes.

AIMS: The diagnosis of acute aortic syndromes (AASs) is challenging and requires integrated strategies. Transthoracic focused cardiac ultrasound (FoCUS) is endorsed by guidelines as a first-line/triage tool allowing rapid bedside assessment of the aorta. However, the performance of FoCUS in the European Society of Cardiology-recommended workup of AASs awaits validation. METHODS AND RESULTS: This was a prespecified subanalysis of the ADvISED multicentre prospective study. Patients with suspected AAS underwent FoCUS for detection of direct/indirect signs of AAS. Clinical probability assessment was performed with the aortic dissection detection risk score (ADD-RS). Case adjudication was based on advanced imaging, surgery, autopsy, or 14-day follow-up. An AAS was diagnosed in 146 (17.4%) of 839 patients. Presence of direct FoCUS signs had a sensitivity and specificity of 45.2% [95% confidence interval (CI) 37-53.6%] and 97.4% (95% CI 95.9-98.4%), while presence of any FoCUS sign had a sensitivity and specificity of 89% (95% CI 82.8-93.6%) and 74.5% (95% CI 71-77.7%) for AAS. The additive value of FoCUS was most evident within low clinical probability (ADD-RS ≤1). Herein, direct FoCUS signs were identified in 40 (4.8%) patients (P < 0.001), including 29 with AAS. ADD-RS ≤1 plus negative FoCUS for AAS rule-out had a sensitivity of 93.8% (95% CI 88.6-97.1%) and a failure rate of 1.9% (95% CI 0.9-3.6%). Addition of negative D-dimer led to a failure rate of 0% (95% CI 0-1.2%). CONCLUSION: FoCUS has additive value in the workup of AASs. Direct FoCUS signs can rapidly identify patients requiring advanced imaging despite low clinical probability. In integrated bundles, negative FoCUS is useful for rule-out of AASs.

Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes: The ADvISED Prospective Multicenter Study.

BACKGROUND: Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown. METHODS: In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0-3) per current guidelines. DD was considered negative (DD-) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD- or ADD-RS ≤1/DD-. RESULTS: A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6-98.6) and a specificity of 64% (95% CI, 61.6-66.4) for the diagnosis of AAS; 8 patients with AAS had DD-. In 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1.9) and an efficiency of 15.9% (95% CI, 14.3-17.6) for the ADD-RS=0/DD- strategy. In 924 patients with ADD-RS ≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1) and an efficiency of 49.9% (95% CI, 47.7-52.2) for the ADD-RS ≤1/DD- strategy. CONCLUSIONS: Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.

Preprocedural statin therapy, inflammation, and myocardial injury in low-risk stable coronary artery disease patients submitted to coronary stent implantation.

OBJECTIVE: Evaluate if statin therapy prior to elective coronary stent implantation (CSI) reduces the plasma levels of markers of inflammation and of myocardial necrosis in low-risk stable coronary artery disease patients (CAD). BACKGROUND: The elevation of markers of inflammation and of myocardial necrosis after percutaneous coronary intervention may interfere with clinical outcome. Among acute coronary syndrome patients, statins improve clinical outcomes when used before CSI-mostly due to reduction of CSI-related myocardial infarction. However, little is known concerning preprocedural statin therapy on the reduction of these markers in stable patients at low-risk. METHODS: In this prospective, observational study, 100 patients (n = 50 on statin therapy vs. n = 50 not on statin) with stable coronary artery disease underwent elective CSI. Inflammatory (C-reactive protein [CRP], interleukin [IL]-6, tumor necrosis factor-α and matrix metalloproteinase-9) and myocardial necrosis markers (troponin I and CK-MB) were determined before and 24 hr after CSI. RESULTS: All patients presented a significant increase of CRP and IL-6 after CSI. However, this increase was attenuated in patients on statin therapy prior to CSI than those without statin therapy: 75% vs. 150% (P < 0.001) and 192% vs. 300% (P < 0.01). The other pro-inflammatory markers were similar for both sets of patients. Troponin I and CK-MB did not change after CSI regardless of previous statin therapy or not. CONCLUSIONS: Pretreatment with statin attenuates procedural inflammation, denoted by markedly lower increases of CRP and IL-6 levels, in elective CSI within low-risk stable CAD patients. Periprocedural myocardial injury was irrelevant and was not affected by preprocedural statin therapy in this population.

Diagnosis of acute aortic syndromes with ultrasound and d-dimer: the PROFUNDUS study.

BACKGROUND: In patients complaining common symptoms such as chest/abdominal/back pain or syncope, acute aortic syndromes (AAS) are rare underlying causes. AAS diagnosis requires urgent advanced aortic imaging (AAI), mostly computed tomography angiography. However, patient selection for AAI poses conflicting risks of misdiagnosis and overtesting. OBJECTIVES: We assessed the safety and efficiency of a diagnostic protocol integrating clinical data with point-of-care ultrasound (POCUS) and d-dimer (single/age-adjusted cutoff), to select patients for AAI. METHODS: This prospective study involved 12 Emergency Departments from 5 countries. POCUS findings were integrated with a guideline-compliant clinical score, to define the integrated pre-test probability (iPTP) of AAS. If iPTP was high, urgent AAI was requested. If iPTP was low and d-dimer was negative, AAS was ruled out. Patients were followed for 30 days, to adjudicate outcomes. RESULTS: Within 1979 enrolled patients, 176 (9 %) had an AAS. POCUS led to net reclassification improvement of 20 % (24 %/-4 % for events/non-events, P < 0.001) over clinical score alone. Median time to AAS diagnosis was 60 min if POCUS was positive vs 118 if negative (P = 0.042). Within 941 patients satisfying rule-out criteria, the 30-day incidence of AAS was 0 % (95 % CI, 0-0.41 %); without POCUS, 2 AAS were potentially missed. Protocol rule-out efficiency was 48 % (95 % CI, 46-50 %) and AAI was averted in 41 % of patients. Using age-adjusted d-dimer, rule-out efficiency was 54 % (difference 6 %, 95 % CI, 4-9 %, vs standard cutoff). CONCLUSIONS: The integrated algorithm allowed rapid triage of high-probability patients, while providing safe and efficient rule-out of AAS. Age-adjusted d-dimer maximized efficiency. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04430400.

The Impact of Sonothrombolysis on Left Ventricular Diastolic Function and Left Atrial Mechanics Preventing Left Atrial Remodeling in Patients With ST Elevation Acute Myocardial Infarction.

BACKGROUND: The diagnostic ultrasound-guided high mechanical index impulses during an intravenous microbubble infusion (sonothrombolysis) improve myocardial perfusion in acute ST segment elevation myocardial infarction, but its effect on left ventricular diastolic dysfunction (DD), left atrial (LA) mechanics and remodeling is unknown. We assessed the effect of sonothrombolysis on DD grade and LA mechanics. METHODS: One hundred patients (59 ± 10 years; 34% women) were randomized to receive either high mechanical index impulses plus percutaneous coronary intervention (PCI) (therapy group) or PCI only (control group) (n = 50 in each group). Diastolic dysfunction grade and LA mechanics were assessed immediately before and after PCI and at 48 to 72 hours, 1 month, and 6 months of follow-up. Diastolic dysfunction grades were classified as grades I, II, and III. The LA mechanics was obtained by two-dimensional speckle-tracking echocardiography-derived global longitudinal strain (GLS). RESULTS: As follow-up time progressed, increased DD grade was observed more frequently in the control group than in the therapy group at 1 month and 6 months of follow-up (all P < .05). The LA-GLS values were incrementally higher in the therapy group when compared with the control group at 48 to 72 hours, 24.0% ± 7.3% in the therapy group versus 19.6% ± 7.2% in the control group, P = .005; at 1 month, 25.3% ± 6.3% in the therapy group versus 21.5% ± 8.3% in the control group, P = .020; and at 6 months, 26.2% ± 8.7% in the therapy group versus 21.6% ± 8.5% in the control group, P = .015. The therapy group was less likely to experience LA remodeling (odds ratio, 2.91 [1.10-7.73]; P = .03). LA-GLS was the sole predictor of LA remodeling (odds ratio, 0.79 [0.67-0.94]; P = .006). CONCLUSION: Sonothrombolysis is associated with better DD grade and LA mechanics, reducing LA remodeling.

The association of myocardial strain with cardiac magnetic resonance and clinical outcomes in patients with acute myocarditis.

Introduction: The role of myocardial strain in risk prediction for acute myocarditis (AMC) patients, measured by cardiac magnetic resonance (CMR), deserves further investigation. Our objective was to evaluate the association between myocardial strain measured by CMR and clinical events in AMC patients. Material and methods: This was a prospective single-center study of patients with AMC. We included 100 patients with AMC with CMR confirmation. The primary outcome was the composite of all-cause mortality, heart failure and AMC recurrence in 24 months. A subgroup analysis was performed on a sample of 36 patients who underwent a second CMR between 6 and 18 months. The association between strain measures and clinical events or an increase in left ventricular ejection fraction (LVEF) was explored using Cox regression analysis. Global peak radial, circumferential and longitudinal strain in the left and right ventricles was assessed. ROC curve analysis was performed to identify cutoff points for clinical event prediction. Results: The mean follow-up was 18.7 ± 2.3 months, and the composite primary outcome occurred in 26 patients. The median LVEF at CMR at baseline was 57.5% (14.6%). LV radial strain (HR = 0.918, 95% CI: 0.858-0.982, p = 0.012), LV circumferential strain (HR = 1.177, 95% CI: 1.046-1.325, p = 0.007) and LV longitudinal strain (HR = 1.173, 95% CI: 1.031-1.334, p = 0.015) were independently associated with clinical event occurrence. The areas under the ROC curve for clinical event prediction were 0.80, 0.79 and 0.80 for LV radial, circumferential, and longitudinal strain, respectively. LV longitudinal strain was independently correlated with prognosis (HR = 1.282, CI 95%: 1.022-1.524, p = 0.007), even when analyzed together with ejection fraction and delayed enhancement. LV and right ventricle (RV) strain were not associated with an increase in LVEF. Finally, when the initial CMR findings were compared with the follow-up CMR findings, improvements in the measures of LV and RV myocardial strain were observed. Conclusion: Measurement of myocardial strain by CMR can provide prognostic information on AMC patients. LV radial, circumferential and longitudinal strain were associated with long-term clinical events in these patients.

Potential performance of a 0 h/1 h algorithm and a single cut-off measure of high-sensitivity troponin T in a diverse population: main results of the IN-HOPE study.

AIMS: Chest pain is a major cause of medical evaluation at emergency department (ED) and demands observation to exclude the diagnosis of acute myocardial infarction (AMI). High-sensitivity cardiac troponin assays used as isolated measure and by 0- and 1-h algorithms are accepted as a rule-in/rule-out strategy, but there is a lack of validation in specific populations. METHODS AND RESULTS: The IN-HOspital Program to systematizE Chest Pain Protocol (IN-HOPE study) is a multicentre study that prospectively included patients admitted to the ED due to suspected symptoms of AMI at 16 sites in Brazil. Medical decisions of all patients followed the standard approach of 0 h/3 h protocol, but, in addition, blood samples were also collected at 0 and 1 h and sent to a central laboratory (core lab) to measure high-sensitivity cardiac troponin T (hs-cTnT). To assess the theoretical performance of 0 h/1 h algorithm, troponin < 12 ng/L with a delta < 3 was considered rule-out while a value ≥ 52 or a delta ≥ 5 was considered a rule-in criterion (the remaining were considered as observation group). The main objective of the study was to assess, in a population managed by the 0 h/3 h protocol, the accuracy of 0 h/1 h algorithm overall and in groups with a higher probability of AMI. All patients were followed up for 30 days, and potential events were adjudicated. In addition to the prospective cohort, a retrospective analysis was performed assessing all patients with hs-cTnT measured during the year of 2021 but not included in the prospective cohort, regardless of the indication of the test. A total of 5.497 patients were included (583 in the prospective and 4.914 in the retrospective analysis). The prospective cohort had a mean age of 57.3 (± 14.8) and 45.6% of females with a mean HEART score of 4.0 ± 2.2. By the core lab analysis, 74.4% would be eligible for a rule-out approach (45.3% of them with a HEART score > 3) while 7.3% would fit the rule-in criteria. In this rule-out group, the negative predictive value for index AMI was 100% (99.1-100) overall and regardless of clinical scores. At 30 days, no death or AMI occurred in the rule-out group of both 0/1 and 0/3 h algorithms while 52.4% of the patients in the rule-in group (0 h/1 h) were considered as AMI by adjudication. In the observation group (grey zone) of 0 h/1 h algorithm, GRACE discriminated the risk of these patients better than HEART score. In the retrospective analysis, 1.091 patients had a troponin value of <5 ng/L and there were no cardiovascular deaths at 30 days in this group. Among all 4.914 patients, the 30-day risk of AMI or cardiovascular death increased according to the level of troponin: 0% in the group < 5 ng/L, 0.6% between 5 and 14 ng/L, 2.2% between 14 and 42 ng/L, 6.3% between 42 and 90 ng/L, and 7.7% in the level ≥ 90 ng/L. CONCLUSION: In this large multicentre study, a 0 h/1 h algorithm had the potential to classify as rule-in or rule-out in almost 80% of the patients. The rule-out protocol had high negative predictive value regardless of clinical risk scores. Categories of levels of hs-cTn T also showed good accuracy in discriminating risk of the patients with a very favourable prognosis for cardiovascular death in the group with value < 5 ng/L. CLINICALTRIALS.GOV: NCT04756362.

[Rheumatoid arthritis and cardiovascular disease: what is known about this relationship and what can currently be done for affected patients?]. / Artrite reumatóide e doença cardiovascular: o que sabemos e o que podemos fazer pelo paciente na atualidade?

There is increasing interest in autoimmune diseases, especially their relationship with cardiovascular disease. Rheumatoid arthritis in particular has been considered an independent risk factor for coronary artery disease in recent years. Various studies have aimed to clarify important aspects of risk stratification and treatment options in patients with rheumatoid arthritis, and specific therapies are being studied that promise to reduce their long-term cardiovascular risk. We performed a wide-ranging review of the literature to highlight the importance of atherosclerotic and inflammatory mechanisms in coronary artery disease. We also suggest strategies for risk stratification and treatment of cardiovascular disease in patients with rheumatoid arthritis.

Sonothrombolysis Promotes Improvement in Left Ventricular Wall Motion and Perfusion Scores after Acute Myocardial Infarction. / A Sonotrombólise Promove Melhora dos Índices de Motilidade e Perfusão do Ventrículo Esquerdo após o Infarto Agudo do Miocárdio.

BACKGROUND: It has recently been demonstrated that the application of high-energy ultrasound and microbubbles, in a technique known as sonothrombolysis, dissolves intravascular thrombi and increases the angiographic recanalization rate in patients with ST-segment-elevation myocardial infarction (STEMI). OBJECTIVE: To evaluate the effects of sonothrombolysis on left ventricular wall motion and myocardial perfusion in patients with STEMI, using real-time myocardial perfusion echocardiography (RTMPE). METHODS: One hundred patients with STEMI were randomized into the following 2 groups: therapy (50 patients treated with sonothrombolysis and primary coronary angioplasty) and control (50 patients treated with primary coronary angioplasty). The patients underwent RTMPE for analysis of left ventricular ejection fraction (LVEF), wall motion score index (WMSI), and number of segments with myocardial perfusion defects 72 hours after STEMI and at 6 months of follow-up. P < 0.05 was considered statistically significant. RESULTS: Patients treated with sonothrombolysis had higher LVEF than the control group at 72 hours (50% ± 10% versus 44% ± 10%; p = 0.006), and this difference was maintained at 6 months of follow-up (53% ± 10% versus 48% ± 12%; p = 0.008). The WMSI was similar in the therapy and control groups at 72 hours (1.62 ± 0.39 versus 1.75 ± 0.40; p = 0.09), but it was lower in the therapy group at 6 months (1.46 ± 0.36 versus 1.64 ± 0.44; p = 0.02). The number of segments with perfusion defects on RTMPE was similar in therapy and control group at 72 hours (5.92 ± 3.47 versus 6.94 ± 3.39; p = 0.15), but it was lower in the therapy group at 6 months (4.64 ± 3.31 versus 6.57 ± 4.29; p = 0.01). CONCLUSION: Sonothrombolysis in patients with STEMI resulted in improved wall motion and ventricular perfusion scores over time.

FUNDAMENTO: Demonstrou-se recentemente que a aplicação de ultrassom de alta energia com microbolhas, técnica conhecida como sonotrombólise, causa a dissolução de trombos intravasculares e aumenta a taxa de recanalização angiográfica no infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAM-CSST). OBJETIVO: Avaliar o efeito da sonotrombólise nos índices de motilidade e perfusão miocárdicas em pacientes com IAM-CSST, utilizando a ecocardiografia com perfusão miocárdica em tempo real (EPMTR). MÉTODO: Uma centena de pacientes com IAM-CSST foram randomizados em dois grupos: Terapia (50 pacientes tratados com sonotrombólise e angioplastia coronária primária) e Controle (50 pacientes tratados com angioplastia coronária primária). Os pacientes realizaram EPMTR para analisar a fração de ejeção do ventrículo esquerdo (FEVE), o índice de escore de motilidade segmentar (IEMS) e o número de segmentos com defeito de perfusão miocárdica, 72 horas após o IAM-CSST e com 6 meses de acompanhamento. Foi considerado significativo p < 0,05. RESULTADOS: Pacientes tratados com sonotrombólise apresentaram FEVE mais alta que o grupo Controle em 72 horas (50 ± 10% vs. 44 ± 10%; p = 0,006), e essa melhora foi mantida em seis meses (53 ± 10% vs. 48 ± 12%; p = 0,008). O IEMS foi similar nos grupos Terapia e Controle em 72 horas (1,62 ± 0,39 vs. 1,75 ± 0,40; p = 0,09), mas tornou-se menor no grupo Terapia em 6 meses (1,46 ± 0,36 vs. 1,64 ± 0,44; p = 0,02). O número de segmentos com defeito de perfusão não foi diferente entre os grupos em 72 horas (5,92 ± 3,47 vs. 6,94 ± 3,39; p = 0,15), mas ficou menor no grupo Terapia em 6 meses (4,64 ± 3,31 vs. 6,57 ± 4,29; p = 0,01). CONCLUSÃO: A sonotrombólise em pacientes com IAM-CSST resulta na melhora dos índices de motilidade e perfusão ventricular ao longo do tempo.

Diagnostic Performance of Coronary Tomography Angiography and Serial Measurements of Sensitive Cardiac Troponin in Patients With Chest Pain and Intermediate Risk for Cardiovascular Events. / Desempenho Diagnóstico da Angiotomografia Computadorizada e da Avaliação Seriada de Troponina Cardíaca Sensível em Pacientes com Dor Torácica e Risco Intermediário para Eventos Cardiovasculares.

BACKGROUND: Coronary tomography angiography (CTA) has been mainly used for chest pain evaluation in low-risk patients, and few data exist regarding patients at intermediate risk. OBJECTIVE: To evaluate the performance of serial measures of sensitive troponin and CTA in intermediate-risk patients. METHODS: A total of 100 patients with chest pain, TIMI risk scores of 3 or 4, and negative troponin were prospectively included. All patients underwent CTA and those with coronary stenosis ≥ 50% were referred to invasive coronary angiography. Patients with coronary lesions <50% were discharged and contacted 30 days later by a telephone call to assess clinical outcomes. Outcomes were hospitalization, death, and myocardial infarction at 30 days. The comparison between methods was performed by Kappa agreement test. The performance of troponin measures and CTA for detecting significant coronary lesions and clinical outcomes was calculated. Results were considered statistically significant when p < 0.05. RESULTS: Coronary stenosis ≥ 50% on CTA was found in 38% of patients and significant coronary lesions on coronary angiography were found in 31 patients. Two clinical events were observed. Kappa agreement analysis showed low agreement between troponin measures and CTA in the detection of significant coronary lesions (kappa = 0.022, p = 0.78). The performance of CTA for detecting significant coronary lesions on coronary angiography or for predicting clinical events at 30 days was better than sensitive troponin measures (accuracy of 91% versus 60%). CONCLUSION: CTA performed better than sensitive troponin measures in the detection of significant coronary disease in patients with chest pain and intermediate risk for cardiovascular events.

FUNDAMENTO: A angiotomografia coronária (ATC) tem sido usada para avaliação de dor torácica principalmente em pacientes de baixo risco, e poucos dados existem com pacientes em risco intermediário. OBJETIVO: Avaliar o desempenho de medidas seriadas de troponinas sensíveis e de ATC em pacientes de risco intermediário. MÉTODOS: Um total de 100 pacientes com dor torácica, TIMI score 3 ou 4 e troponina negativa foram prospectivamente incluídos. Todos os pacientes foram submetidos à ATC, e aqueles com obstruções ≥ 50% foram encaminhados à cineangiocoronariografia. Pacientes com lesões < 50% recebiam alta hospitalar, receberam alta e foram contatados 30 dias depois por telefonema para avaliação dos desfechos clínicos. Os desfechos foram hospitalização, morte, e infarto agudo do miocárdio em 30 dias. A comparação entre os métodos foi realizada pelo teste de concordância kappa. O desempenho das medidas de troponina e da ATC na detecção de lesões coronárias significativas e desfechos clínicos foi calculado. Os resultados foram considerados estatisticamente significativos quando p <0,05. RESULTADOS: Estenose coronária ≥ 50% na ATC foi encontrada em 38% dos pacientes e lesões coronárias significativas na angiografia coronária foram encontradas em 31 pacientes. Dois eventos clínicos foram observados. A análise de concordância Kappa mostrou baixa concordância entre as medidas de troponina e ATC na detecção de lesões coronárias significativas (kappa = 0,022, p = 0,78). O desempenho da ATC para detectar lesões coronárias significativas na angiografia coronária ou para prever eventos clínicos em 30 dias foi melhor que as medidas de troponina sensível (acurácia de 91% versus 60%). CONCLUSÃO: ATC teve melhor desempenho que as medidas seriadas de troponina na detecção de doença coronariana significativa em pacientes com dor torácica e risco intermediário para eventos cardiovasculares.

Quality improvement program in Latin America decreases mortality after cardiac surgery: a before-after intervention study.

BACKGROUND: The current challenge of cardiac surgery (CS) is to improve outcomes in adverse scenarios. The aim of this study was to assess the impact of a quality improvement program (QIP) on hospital mortality in the largest CS center in Latin America. METHODS: Patients were divided into two groups: before (Jan 2013-Dec 2015, n = 3534) and after establishment of the QIP (Jan 2017-Dec 2019, n = 3544). The QIP consisted of the implementation of 10 central initiatives during 2016. The procedures evaluated were isolated coronary artery bypass grafting surgery (CABG), mitral valve surgery, aortic valve surgery, combined mitral and aortic valve surgery, and CABG associated with heart valve surgery. Propensity Score Matching (PSM) was used to adjust for inequality in patients' preoperative characteristics before and after the implementation of QIP. A multivariate logistic regression model was built to predict hospital mortality and validated using discrimination and calibration metrics. RESULTS: The PMS paired two groups using 5 variables, obtaining 858 patients operated before (non-QIP) and 858 patients operated after the implementation of the QIP. When comparing the QIP versus Non-QIP group, there was a shorter length of stay in all phases of hospitalization. In addition, the patients evolved with less anemia (P = 0.001), use of intra-aortic balloon pump (P = 0.003), atrial fibrillation (P = 0.001), acute kidney injury (P < 0.001), cardiogenic shock (P = 0.011), sepsis (P = 0.046), and hospital mortality (P = 0.001). In the multiple model, among the predictors of hospital mortality, the lack of QIP increased the chances of mortality by 2.09 times. CONCLUSION: The implementation of a first CS QIP in Latin America was associated with a reduction in length of hospital stay, complications and mortality after the cardiac surgeries analyzed.

Development and Validation of a Simplified Probability Assessment Score Integrated With Age-Adjusted d-Dimer for Diagnosis of Acute Aortic Syndromes.

Background When acute aortic syndromes (AASs) are suspected, pretest clinical probability assessment and d-dimer (DD) testing are diagnostic options allowing standardized care. Guidelines suggest use of a 12-item/3-category score (aortic dissection detection) and a DD cutoff of 500 ng/mL. However, a simplified assessment tool and a more specific DD cutoff could be advantageous. Methods and Results In a prospective derivation cohort (n=1848), 6 items identified by logistic regression (thoracic aortic aneurysm, severe pain, sudden pain, pulse deficit, neurologic deficit, hypotension), composed a simplified score (AORTAs) assigning 2 points to hypotension and 1 to the other items. AORTAs≤1 and ≥2 defined low and high clinical probability, respectively. Age-adjusted DD was calculated as years/age × 10 ng/mL (minimum 500). The AORTAs score and AORTAs≤1/age-adjusted DD rule were validated in 2 patient cohorts: a high-prevalence retrospective cohort (n=1035; 22% AASs) and a low-prevalence prospective cohort (n=447; 11% AASs) subjected to 30-day follow-up. The AUC of the AORTAs score was 0.729 versus 0.697 of the aortic dissection detection score (P=0.005). AORTAs score assessment reclassified 16.6% to 25.1% of patients, with significant net reclassification improvement of 10.3% to 32.7% for AASs and -8.6 to -17% for alternative diagnoses. In both cohorts, AORTAs≥2 had superior sensitivity and slightly lower specificity than aortic dissection detection ≥2. In the prospective validation cohort, AORTAs≤1/age-adjusted DD had a sensitivity of 100%, a specificity of 48.6%, and an efficiency of 43.3%. Conclusions AORTAs is a simplified score with increased sensitivity, improved AAS classification, and minor trade-off in specificity, amenable to integration with age-adjusted DD for diagnostic rule-out.

Tocilizumab in SARS-COVID19 following postoperative laparoscopic transhiatal esophagectomy for the adenocarcinoma of esophagogastric tumor: A case report.

INTRODUCTION AND IMPORTANCE: Esophagectomy for esophageal cancer is one of the most challenging surgical procedures, with high rates of morbidity, especially from respiratory complications. SARS-COVID19 represents a health threat nowadays. Peri-operative SARS-COVID19 infection after esophagectomy might negatively affect the postoperative outcomes. The use of tocilizumab as an alternative to reduce the inflammatory response in SARS-COVID19 is an option that has not been described in the literature after esophagectomy. CASE PRESENTATION: A SARS-COVID19-vaccinated (CORONAVAC) 73-year-old man with pulmonary emphysema, coronary artery disease, previous asymptomatic pulmonary embolism, and adenocarcinoma of the esophagogastric junction tumor was submitted to laparoscopic transhiatal esophagectomy (ypT2N0M0) after perioperative neoadjuvant chemotherapy. He was also infected with SARS-COVID19, confirmed by PCR test at the 14th postoperative day. During follow-up, mild hypoxemia persisted without evidence of infection except for SARS-COVID19, and a high-flow cannula was required to maintain oxygenation. Tocilizumab was administered following high parameters of a high-flow cannula, and invasive mechanical ventilation was avoided. DISCUSSION: Besides of the risk of secondary infection, after administration of tocilizumab, the parameters of oxygen supplementation were systematically reduced, and he stayed in the ICU for seven days. He was discharged from the ward six days later. He developed late cervical anastomotic leakage, which was treated with conservative therapy. CONCLUSION: Although the patient had high-risk comorbidities, esophagectomy, and SARS-COVID19 infection, the use of tocilizumab was safe and improved the pulmonary recovery.

Nitazoxanide superiority to placebo to treat moderate COVID-19 - A Pilot prove of concept randomized double-blind clinical trial.

BACKGROUND: The absence of specific antivirals to treat COVID-19 leads to the repositioning of candidates' drugs. Nitazoxanide (NTZ) has a broad antiviral effect. METHODS: This was a randomized, double-blind pilot clinical trial comparing NTZ 600 mg BID versus Placebo for seven days among 50 individuals (25 each arm) with SARS-COV-2 RT-PCR+ (PCR) that were hospitalized with mild respiratory insufficiency from May 20th, 2020, to September 21st, 2020 (ClinicalTrials.gov NCT04348409). Clinical and virologic endpoints and inflammatory biomarkers were evaluated. A five-point scale for disease severity (SSD) was used. FINDINGS: Two patients died in the NTZ arm compared to 6 in the placebo arm (p = 0.564). NTZ was superior to placebo when considering SSD (p < 0001), the mean time for hospital discharge (6.6 vs. 14 days, p = 0.021), and negative PCR at day 21 (p = 0.035), whereas the placebo group presented more adverse events (p = 0.04). Among adverse events likely related to the study drug, 14 were detected in the NTZ group and 22 in placebo (p = 0.24). Among the 30 adverse events unlikely related, 21 occurred in the placebo group (p = 0.04). A decrease from baseline was higher in the NTZ group for d-Dimer (p = 0.001), US-RCP (p < 0.002), TNF (p < 0.038), IL-6 (p < 0.001), IL-8 (p = 0.014), HLA DR. on CD4+ T lymphocytes (p < 0.05), CD38 in CD4+ and CD8+ T (both p < 0.05), and CD38 and HLA-DR. on CD4+ (p < 0.01). INTERPRETATION: Compared to placebo in clinical and virologic outcomes and improvement of inflammatory outcomes, the superiority of NTZ warrants further investigation of this drug for moderate COVID-19 in larger clinical trials. A higher incidence of adverse events in the placebo arm might be attributed to COVID-19 related symptoms.

Morphomolecular Characterization of Serum Nanovesicles From Microbiomes Differentiates Stable and Infarcted Atherosclerotic Patients.

Microbial communities are considered decisive for maintaining a healthy situation or for determining diseases. Acute myocardial infarction (AMI) is an important complication of atherosclerosis caused by the rupture of atheroma plaques containing proinflammatory cytokines, reactive oxygen species, oxidized low-density lipoproteins (oxLDL), damaged proteins, lipids, and DNA, a microenvironment compatible with a pathogenic microbial community. Previously, we found that archaeal DNA-positive infectious microvesicles (iMVs) were detected in vulnerable plaques and in the sera of Chagas disease patients with heart failure. Now, we characterize and quantify the levels of serum microbiome extracellular vesicles through their size and content using morphomolecular techniques to differentiate clinical outcomes in coronary artery disease (CAD). We detected increased numbers of large iMVs (0.8-1.34 nm) with highly negative surface charge that were positive for archaeal DNA, Mycoplasma pneumoniae antigens and MMP9 in the sera of severe AMI patients, strongly favoring our hypothesis that pathogenic archaea may play a role in the worst outcomes of atherosclerosis. The highest numbers of EVs <100 nm (exosomes) and MVs from 100 to 200 nm in the stable atherosclerotic and control healthy groups compared with the AMI groups were indicative that these EVs are protective, entrapping and degrading infectious antigens and active MMP9 and protect against the development of plaque rupture. Conclusion: A microbiome with pathogenic archaea is associated with high numbers of serum iMVs in AMI with the worst prognosis. This pioneering work demonstrates that the morphomolecular characterization and quantification of iEVs in serum may constitute a promising serum prognostic biomarker in CAD.