Extended thromboprophylaxis with betrixaban in acutely ill medical patients

BACKGROUND: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. METHODS: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. RESULTS: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). CONCLUSIONS: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.)

Asymptomatic and symptomatic deep venous thrombosis in hospitalized acutely ill medical patients: risk factors and therapeutic implications

Background Acutely ill medical patients experience deep venous thrombosis (DVT) during the hospitalization, however the time course of DVT is still unclear. Objectives To evaluate risk factors in acutely ill hospitalized medical patients for proximal asymptomatic DVT (ADVT) and symptomatic DVT (SDVT) at admission and discharge. Patients/Methods In this prospective observational study, consecutive acutely ill medical patients (hospitalized mainly for acute medical disease as infections, neoplasm, anemia, heart failure) underwent compression ultrasonography (CUS) of proximal lower limb veins within 48 h from admission and at discharge to diagnose ADVT and SDVT. Covid-19 patients, anticoagulant therapy, surgical procedures, acute SDVT, and acute pulmonary embolism, were exclusion criteria. Biographical characteristics at hospitalization, D-Dimer (assessed by ELISA)) and DD-improve score. Results Of 2,100 patients (1002 females, 998 males, age 71 +/- 16 years) 58 (2.7%) had proximal ADVT at admission. Logistic regression analysis showed that age, and active cancer were independently associated with ADVT at admission. The median length of hospitalization was 10 days [interquartile range: 6-15]. During the hospital stay, 6 patients (0.3%) with a negative CUS at admission experienced DVT (2 SDVT and 4 ADVT). In the subgroup of patients (n = 1118), in whom D-dimer was measured at admission, D-Dimer and IMPROVE-DD score were associated with ADVT at admission (n = 37) and with all DVT (n = 42) at discharge. ROC curve defined an IMPROVE-DD score of 2.5 as the optimal cut-off for discriminating patients with and without thrombotic events. Conclusions We provide evidence of early development of ADVT in unselected acutely ill medical patients suggesting the need of investigating patients by CUS immediately after hospital admission (within 48 h). Advanced age, active cancer, known thrombophilia and increased IMPROVE-DD score may identify patients at risk. The benefit of anticoagulation needs to be investigated in patients with these specific risk factors and negative CUS at admission

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Prognostic Value of Fibrinogen among COVID-19 Patients Admitted to an Emergency Department: An Italian Cohort Study

Introduction: A highly pathogenic human coronavirus able to induce severe acute respiratory syndrome (SARS) has been recently recognized as the cause of the coronavirus disease 2019 (COVID-19); the disease became pandemic after a few months. Little is still known about the laboratory prognostic markers in COVID-19 patients. The aim of our study was to describe the prognostic value of clotting parameters for the prediction of severe form of COVID-19 characterized by acute respiratory distress syndrome (ARDS) at hospital admission. Material and Methods: From a large cohort of 152 patients consecutively admitted from February to March 2020 for fever and dyspnea to the emergency departments (ED) of three Italian hospitals, we evaluated 85 patients with confirmed diagnosis of COVID-19 and 67 patients with acute illness. All patients underwent medical history checks, physical examination, and laboratory evaluation. Prothrombin time (PT), activated thromboplastin time (aPTT), fibrinogen and D-dimer tests were performed and compared, first, between COVID-19 and control groups, and then between COVID-19 patients with or without ARDS. Results: COVID-19 patients were more likely to show abnormal baseline levels of PT, aPTT, D-dimer, and fibrinogen at admission compared to the control group. COVID-19 patients with ARDS showed a statistically significant increase in levels of fibrinogen compared to those without ARDS (720 (621-833) vs. 490 (397.5-601.5); p= 1.8653 x 10(-9) (0.0765). A cut-off value of 617 mg/dL had a sensitivity of 76% and a specificity of 79% in identifying COVID-19 patients with ARDS. Conclusion: A serum level of fibrinogen of 617 mg/dL in COVID-19 patients admitted to emergency department may help to identify early those with ARDS

Clinical experience with fondaparinux in antiaggregate patients undergoing total hip and knee arthroplasty

Patients undergoing total hip arthroplasty or total knee arthroplasty have a high risk for post-operative venous thromboembolism. The current study addressed the use of fondaparinux post-operatively in 556 patients with antiplatelet therapy in order to prevent deep vein thrombosis as well as demonstrate efficacy in preventing arterial thrombotic events. Results provided evidence for a safe and effective prophylaxis strategy, involving the change from low molecular weight heparin pre-operatively to fondaparinux postoperatively. Also, fondaparinux proved effective as a unique post-operative therapy in the prevention of venous thromboembolism with no adverse effects, such as major bleeding or arterial thrombosis in patients with pre-operative antiplatelet therapy

Clinical experience with fondaparinux in antiaggregate patients undergoing total hip and knee arthroplasty

Patients undergoing total hip arthroplasty or total knee arthroplasty have a high risk for post-operative venous thromboembolism. The current study addressed the use of fondaparinux post-operatively in 556 patients with antiplatelet therapy in order to prevent deep vein thrombosis as well as demonstrate efficacy in preventing arterial thrombotic events. Results provided evidence for a safe and effective prophylaxis strategy, involving the change from low molecular weight heparin pre-operatively to fondaparinux postoperatively. Also, fondaparinux proved effective as a unique post-operative therapy in the prevention of venous thromboembolism with no adverse effects, such as major bleeding or arterial thrombosis in patients with pre-operative antiplatelet therapy

Clotting Factors in COVID-19: Epidemiological Association and Prognostic Values in Different Clinical Presentations in an Italian Cohort

Introduction: A novel highly pathogenic human coronavirus able to induce severe acute respiratory syndrome (SARS) has been recently recognized as the cause of the coronavirus disease 2019 (COVID-19) outbreak, which has spread rapidly from China to other countries. Little is known about laboratory prognostic markers in COVID-19 patients. The aim of our study was to describe the basic clotting parameters in COVID-19 patients and their prognostic role in different clinical forms of the disease. Material and Methods: We enrolled 67 COVID-19 patients admitted to the Emergency Department. A cohort of 67 age- and sex-matched non-COVID-19 patients with acute respiratory illness was used as a control group. For all patients, platelet count (PLT), prothrombin time (PT), activated thromboplastin time (aPTT), C-reactive protein (PCR), fibrinogen, and D-dimer were determined. The COVID-19 population was divided in two groups according to the presence or absence of SARS. The clotting factors values were compared between the groups. Results: At admission, the COVID-19 patients showed statistically significant increased levels of fibrinogen (601.5 (480-747) vs. 455 (352.5-588.5) mg/dL; p = 0.0000064), and a higher percentage of patients had fibrinogen levels &gt;400 mg/dL (86% vs.58%; p = 0.0054) compared to the control group. The levels of fibrinogen were higher in COVID-19 patients with SARS compared to those without SARS (747 (600.0-834.0) vs. 567 (472.5-644.50); p = 0.0003). Conclusion: Fibrinogen seems to increase early in COVID-19 patients and may be used as a risk stratification marker for the early detection of a subgroup of COVID-19 patient at increased risk to develop SARS, who might benefit from a different and thorough clinical surveillance and treatment