Effects of Direct Oral Anticoagulants' Nonrecommended Dose in Atrial Fibrillation: A Meta-Analysis.

BACKGROUND: The efficacy and safety profiles of nonrecommended direct oral anticoagulant (DOAC) doses in patients with nonvalvular atrial fibrillation (NVAF) are still undefined. SUMMARY: We searched for randomized controlled trials and observational studies that compared nonrecommended versus recommended doses of DOACs, published up to December 2021. Primary study outcomes were ischemic stroke/transient ischemic attack/systemic embolism (IS/TIA/SE) and major bleeding (MB). All-cause mortality was a secondary outcome. We determined pooled odds ratios (ORs) between groups of patients with a random-effect model. Twenty-three studies with 175,801 patients were included. Nonrecommended doses were associated with a higher risk of IS/TIA/SE and all-cause mortality, but not of MB as compared to recommended doses of DOACs (OR 1.25 [95% CI: 1.14-1.38], OR 1.69 [95% CI: 1.31-2.18] and OR 1.10 [95% CI: 0.93-1.31], respectively). The nonrecommended low dose was associated with an increased risk of IS/TIA/SE and all-cause death (OR 1.21 [95% CI: 1.05-1.39] and OR 1.66 [95% CI: 1.18-2.35], respectively) but not of MB (OR 1.01 [95% CI: 0.83-1.22] as compared to recommended doses. Subgroup analysis of nonrecommended low doses of DOACs showed a nonsignificant increase in IS/TIA/SE in Asians (OR 1.17 [95% CI: 0.89-1.54] vs. non-Asian (OR 1.21 [95% CI: 1.07-1.36]). KEY MESSAGES: Compared with recommended doses, nonrecommended low doses of DOACs increase the risk of ischemic events without decreasing the risk of bleeding. For Asians, the efficacy of DOACs seemed preserved despite the nonrecommended low-dose prescription. Clinicians should carefully adhere to recommended DOAC prescription advice in managing NVAF patients.

Renal function and clinical outcome of patients with cancer-associated venous thromboembolism randomized to receive apixaban or dalteparin. Results from the Caravaggio trial

The effect of renal impairment (RI) on risk of bleeding and recurrent thrombosis in cancer patients treated with direct oral anticoagulants for venous thromboembolism (VTE) is undefined. We ran a prespecified analysis of the randomized Caravaggio study to evaluate the role of RI as a risk factor for bleeding or recurrence in patients treated with dalteparin or apixaban for cancerassociated VTE. RI was graded as moderate (creatinine clearance between 30-59 mL/minute; 275 patients) and mild (between 60- 89 mL/minute; 444 patients). In the 1142 patients included in this analysis, the incidence of major bleeding was similar in patients with moderate vs. no or mild RI (HR 1.06-95% CI: 0.53-2.11), with no difference in the relative safety of apixaban and dalteparin. Recurrent VTE was not different in moderate vs. no or mild RI (HR=0.67, 95% CI: 0.38-1.20); in moderate RI, apixaban reduced recurrent VTE compared to dalteparin (HR=0.27, 95% CI: 0.08-0.96; P for interaction 0.1085). At multivariate analysis, no association was found between variation of renal function over time and major bleeding or recurrent VTE. Advanced or metastatic cancer was the only independent predictor of major bleeding (HR=2.84, 95% CI: 1.20-6.71), with no effect of treatment with apixaban or dalteparin. In our study, in cancer patients treated with apixaban or dalteparin, moderate RI was not associated with major bleeding or recurrent VTE. In patients with moderate renal failure, the safety profile of apixaban was confirmed with the potential for improved efficacy in comparison to dalteparin. ClinicalTrials.gov identifier: NCT03045406.

Eltrombopag for refractory vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a life-threatening complication described after administration of recombinant adenoviral vector encoding the spike protein antigen of Severe Acute Respiratory Syndrome CoronaVirus-2. The syndrome is characterized by platelet consumption and thrombosis. High levels of antibodies to platelet factor 4 (PF4)-polyanion complexes were identified in many patients with VITT by enzyme-linked immunosorbent assay (ELISA). A 64-year-old woman presented with thrombocytopenia, right renal vein thrombosis with renal infarction, right intra-right atrium and intra-right ventricle thrombosis and pulmonary embolism after ChAdOx1-S vaccine administration. ELISA for antibodies to PF4-polyanion complexes tested positive, while functional tests were not. Thrombocytopenia was refractory to intravenous immunoglobulins and corticosteroids. Eltrombopag was introduced and platelet gradually rose to normal values. VITT is a novel complication yet to be understood. The clinical case we reported highlights the difficulties in the management of this disorder and discloses a new potential therapy in refractory conditions.

Early Variation of Respiratory Indexes to Predict Death or ICU Admission in Severe Acute Respiratory Syndrome Coronavirus-2-Related Respiratory Failure.

BACKGROUND: In severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-related respiratory failure, the prognostic value of clinically based or blood-gas-based respiratory indexes is unclear. OBJECTIVES: We aimed to assess the prognostic value of Respiratory Index (RI, oxygen saturation [SpO2]/respiratory rate [RR]), RR-oxygenation index (ROX, SpO2/fraction of inspired oxygen [FiO2]/RR), partial pressure of oxygen (PaO2)/FiO2 ratio (P/F), or standard PaO2/FiO2 ratio (STP/F) at admission and of their variation during hospitalization in SARS-CoV-2-related respiratory failure. METHODS: In 100 consecutive patients hospitalized due to SARS-CoV-2-related respiratory failure, we assessed the association of RI, ROX, P/F and STP/F, and death; secondary outcome was the composite of 7-day death or intensive care unit (ICU) admission. RESULTS: ROX <3.85 at admission (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.29-6.77) and decreasing RI or P/F during hospitalization (RI: HR 1.05, 95% CI: 1.00-1.09; P/F: HR 1.01, 95% CI: 1.00-1.02) were predictors of in-hospital death. RI ≤3.8, ROX <3.85, and P/F <100 at admission were predictors for death or ICU admission (RI: HR 3.77, 95% CI: 1.30-10.98; ROX: HR 4.56, 95% CI: 1.90-10.96; P/F: HR 7.37, 95% CI: 1.59-34.2). The decrease of RI (HR 1.14, 95% CI: 1.03-1.25), ROX (HR 1.45, 95% CI: 1.11-1.88), P/F (HR 1.08, 95% CI: 1.01-1.15), or STP/F (HR 1.05, 95% CI: 1.01-1.08) during hospitalization was associated with 7-day death or ICU admission. CONCLUSIONS: In patients with SARS-CoV-2-related respiratory failure, easy-to-calculate clinically based respiratory indexes at admission and their variation during hospital stay can be used to assess and monitor the risk for death or ICU admission.

Right ventricle assessment in patients with pulmonary embolism at low risk for death based on clinical models: an individual patient data meta-analysis.

AIMS: Patients with acute pulmonary embolism (PE) at low risk for short-term death are candidates for home treatment or short-hospital stay. We aimed at determining whether the assessment of right ventricle dysfunction (RVD) or elevated troponin improves identification of low-risk patients over clinical models alone. METHODS AND RESULTS: Individual patient data meta-analysis of studies assessing the relationship between RVD or elevated troponin and short-term mortality in patients with acute PE at low risk for death based on clinical models (Pulmonary Embolism Severity Index, simplified Pulmonary Embolism Severity Index or Hestia). The primary study outcome was short-term death defined as death occurring in hospital or within 30 days. Individual data of 5010 low-risk patients from 18 studies were pooled. Short-term mortality was 0.7% [95% confidence interval (CI) 0.4-1.3]. RVD at echocardiography, computed tomography or B-type natriuretic peptide (BNP)/N-terminal pro BNP (NT-proBNP) was associated with increased risk for short-term death (1.5 vs. 0.3%; OR 4.81, 95% CI 1.98-11.68), death within 3 months (1.6 vs. 0.4%; OR 4.03, 95% CI 2.01-8.08), and PE-related death (1.1 vs. 0.04%; OR 22.9, 95% CI 2.89-181). Elevated troponin was associated with short-term death (OR 2.78, 95% CI 1.06-7.26) and death within 3 months (OR 3.68, 95% CI 1.75-7.74). CONCLUSION: RVD assessed by echocardiography, computed tomography, or elevated BNP/NT-proBNP levels and increased troponin are associated with short-term death in patients with acute PE at low risk based on clinical models. RVD assessment, mainly by BNP/NT-proBNP or echocardiography, should be considered to improve identification of low-risk patients that may be candidates for outpatient management or short hospital stay.

Comparative study of venous thromboembolic prophylaxis strategies in hemorrhagic stroke: A systematic review and network meta-analysis.

BACKGROUND: Venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), are frequent complications in patients with intracerebral hemorrhage (ICH). Various prophylactic strategies have been employed to mitigate this risk, such as heparin, intermittent pneumatic compression (IPC), and graduated compression stockings (GCS). The optimal thromboembolic prophylaxis approach remains uncertain due to the lack of randomized controlled trials (RCTs) comparing all interventions. AIMS: We conducted a network meta-analysis and meta-analysis to systematically review and synthesize evidence from RCTs and non-randomized studies on the efficacy and safety of thromboembolic prophylaxis strategies in hospitalized ICH patients. SUMMARY OF FINDINGS: Our study followed a registered protocol (PROSPERO CRD42023489217) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines incorporating the extension for network meta-analyses. Search for eligible studies was performed up to December 2023. We considered the occurrence of DVT, PE, hematoma expansion (HE), and all-cause mortality as outcome measures. A total of 16 studies, including 7 RCTs and 9 non-randomized studies, were included in the analysis. Network meta-analysis revealed that IPC demonstrated the highest efficacy in reducing DVT incidence (odds ratios (OR) 0.30, 95% confidence interval (CI) 0.08-1.16), particularly considering only RCTs (OR 0.33, 95% CI 0.16-0.67). GCS showed the highest safety profile for HE (OR 0.67, 95% CI 0.14-3.13), but without efficacy. Chemoprophylaxis did not reduce the risk of PE events (OR 1.10, 95% CI 0.17-7.19) with a higher occurrence of HE (OR 1.33, 95% CI 0.60-2.96), but the differences were not significant. CONCLUSION: Our study supports the use of IPC as the primary thromboembolic prophylaxis measure in ICH patients. Further research, including head-to-head RCTs, is needed to strengthen the evidence base and optimize clinical decision-making for thromboembolic prophylaxis in this vulnerable patient population.

Arterial lactate as a risk factor for death in respiratory failure related to coronavirus disease 2019: an observational study.

BACKGROUND: Arterial lactate is a recognized biomarker associated with death in critically ill patients. The prognostic role of arterial lactate in acute respiratory failure due to the novel coronavirus disease 2019 (COVID-19) is unclear. OBJECTIVES: We aimed to investigate the prognostic role of arterial lactate levels at admission in patients with COVID-19-related acute respiratory failure. DESIGN AND METHODS: Cohorts of consecutive patients admitted to nonintensive care units (ICU) at study centers for COVID-19-related respiratory failure were merged into a collaborative database. The prognostic role of lactate levels at admission was assessed for continuous values and values ⩾2.0 mmol/l, and lactate clearance at 24 h through delta-lactate (ΔLac). The study outcome was 30-day in-hospital death. Cox proportional regression model was used to assess independent predictors of the study outcome. RESULTS: At admission, 14.6% of patients had lactate levels ⩾2 mmol/l. In-hospital death at 30 days occurred in 57 out of 206 patients; 22.3% and 56.7% with normal or ⩾ 2 mmol/l lactate at admission, respectively. The median lactate level was 1.0 [interquartile range (IQR) 0.8-1.3] mmol/l and 1.3 (IQR 1.0-2.1) mmol/l in survivors and nonsurvivors, respectively (p-value < 0.001). After adjusting for age, relevant comorbidities, acidemia, and the severity of respiratory failure, lactate ⩾2.0 mmol/l was associated with in-hospital death (HR 2.53, 95% CI 1.29-4.95, p-value 0.0066), while Δ Lac ⩾0 was not (HR 1.37, 95% CI 0.42-4.49). These results were confirmed in patients with a pO2/FiO2-ratio (P/F ratio) ⩽300 mmHg. CONCLUSIONS: In our study, increased arterial lactate at admission was independently associated with in-hospital death at 30 days in non-ICU patients with acute respiratory failure related to COVID-19.

Prognostic role of different findings at echocardiography in acute pulmonary embolism: a critical review and meta-analysis.

Background: Right ventricle dysfunction (RVD) at echocardiography predicts mortality in patients with acute pulmonary embolism (PE), but heterogeneous definitions of RVD have been used. We performed a meta-analysis to assess the role of different definitions of RVD and of individual parameters of RVD as predictors of death. Methods: A systematic search for studies including patients with confirmed PE reporting on right ventricle (RV) assessment at echocardiography and death in the acute phase was performed. The primary study outcome was death in-hospital or at 30 days. Results: RVD at echocardiography, regardless of its definition, was associated with increased risk of death (risk ratio 1.49, 95% CI 1.24-1.79, I2=64%) and PE-related death (risk ratio 3.77, 95% CI 1.61-8.80, I2=0%) in all-comers with PE, and with death in haemodynamically stable patients (risk ratio 1.52, 95% CI 1.15-2.00, I2=73%). The association with death was confirmed for RVD defined as the presence of at least one criterion or at least two criteria for RV overload. In all-comers with PE, increased RV/left ventricle (LV) ratio (risk ratio 1.61, 95% CI 1.90-2.39) and abnormal tricuspid annular plane systolic excursion (TAPSE) (risk ratio 2.29 CI 1.45-3.59) but not increased RV diameter were associated with death; in haemodynamically stable patients, neither RV/LV ratio (risk ratio 1.11, 95% CI 0.91-1.35) nor TAPSE (risk ratio 2.29, 95% CI 0.97-5.44) were significantly associated with death. Conclusion: Echocardiography showing RVD is a useful tool for risk stratification in all-comers with acute PE and in haemodynamically stable patients. The prognostic value of individual parameters of RVD in haemodynamically stable patients remains controversial.

The role of prone positioning in patients with SARS-CoV-2-related respiratory failure in non-intensive care unit.

BACKGROUND: Prone positioning (PP) is an established and commonly used lung recruitment method for intubated patients with severe acute respiratory distress syndrome, with potential benefits in clinical outcome. The role of PP outside the intensive care unit (ICU) setting is debated. OBJECTIVES: We aimed at assessing the role of PP in death and ICU admission in non-intubated patients with acute respiratory failure related to COronaVIrus Disease-19 (COVID-19) pneumonia. DESIGN: This is a retrospective analysis of a collaborative multicenter database obtained by merging local non-interventional cohorts. METHODS: Consecutive adult patients with COVID-19-related respiratory failure were included in a collaborative cohort and classified based on the severity of respiratory failure according to the partial arterial oxygen pressure to fraction of inspired oxygen ratio (PaO2/FiO2) and on clinical severity by the quick Sequential Organ Failure Assessment (qSOFA) score. The primary study outcome was the composite of in-hospital death or ICU admission within 30 days from hospitalization. RESULTS: PP was used in 114 of 536 study patients (21.8%), more commonly in patients with lower PaO2/FiO2 or receiving non-invasive ventilation and less commonly in patients with known comorbidities. A primary study outcome event occurred in 163 patients (30.4%) and in-hospital death in 129 (24.1%). PP was not associated with death or ICU admission (HR 1.17, 95% CI 0.78-1.74) and not with death (HR 1.01, 95% CI 0.61-1.67) at multivariable analysis; PP was an independent predictor of ICU admission (HR 2.64, 95% CI 1.53-4.40). The lack of association between PP and death or ICU admission was confirmed at propensity score-matching analysis. CONCLUSION: PP is used in a non-negligible proportion of non-intubated patients with COVID-19-related severe respiratory failure and is not associated with death but with ICU admission. The role of PP in this setting merits further evaluation in randomized studies.

Risk stratification to optimize the management of acute pulmonary embolism.

INTRODUCTION: Pulmonary embolism (PE) is a life-threatening disease. Risk stratification in patients with acute PE can guide clinical decisions. Clinical assessment, including hemodynamics, respiratory parameters, patient history, and right ventricle evaluation, has a pivotal role in this scope. AREAS COVERED: This review aims to describe: i) the role of individual tools for prognostic stratification, from simple clinical parameters to the models suggested by international guidelines; ii) the implications of risk stratification in terms of patient disposition and treatment. The bleeding risk assessment in acute PE was also reviewed. The literature search was performed in PubMed and Embase to address these issues. EXPERT OPINION: Prognostic assessment is essential to proceed with life-saving treatments in hemodynamically unstable patients and consider home treatment or short hospital stay in patients at low risk for death. In hemodynamically stable patients, risk stratification allows the implementation of personalized treatment pathways to reduce the risk of death, early PE recurrence, and bleeding. With the aim of optimizing healthcare resources, risk stratification may suggest appropriate patient disposition.