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In acutely ill patients, 10 days of rivaroxaban was noninferior to 10 days of enoxaparin for thromboprophylaxis. Extended-duration rivaroxaban treatment (35 days) reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding. Patients with active cancer, stroke, myocardial infarction, or acute exacerbations of a variety of medical conditions are at increased risk for venous thromboembolism. 1 Prolonged immobilization and risk factors such as an age older than 75 years, chronic heart failure, a history of venous thromboembolism, and obesity can increase this risk further. 2 , 3 Randomized, controlled trials involving hospitalized patients at increased risk for venous thromboembolism have shown the benefits of administering anticoagulant agents for up to 14 days, 4 – 8 and guidelines recommend the use of unfractionated heparin, low-molecular-weight heparins, or fondaparinux in such patients. 9 There is some evidence that the risk . . .

Thromboembolic events contribute to morbidity and mortality in coronavirus disease 2019 (COVID-19). As a result, thromboprophylaxis using low-molecular-weight heparin (LMWH) is universally recommended for hospitalized patients based on multiple guidelines. However, ethnic differences with respect to thrombogenicity have been reported and the incidence of thromboembolic events is considered to be lower in the Asian population. Despite the importance of thromboprophylaxis, bleeding is also a side effect that should be considered. We examine the data relating to potential ethnic differences in thrombosis and bleeding in COVID-19. Although sufficient data is not yet available, current evidence does not oppose routine anticoagulant use and thromboprophylaxis using a standard dose of LMWH for admitted patients regardless of ethnicity based on our review.

INTRODUCTION The coronavirus disease 2019 (COVID‐19), first identified in December 2019 in Wuhan, China, is a major public health crisis with new infections increasing exponentially worldwide. 1 COVID‐19 is an acute infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) and has contributed to significant morbidity and mortality, including the development of coagulopathy. 2 Similar thrombotic and thromboembolic events have occurred during other viral outbreaks, including severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome, and influenza A H1N1. 3–7 Venous thromboembolism (VTE) (ie, deep vein thrombosis or pulmonary embolism [PE]) is a common complication of acute infectious diseases, which increase VTE risk 2‐fold to 32‐fold. 8–10 Survival among patients with incident and recurrent VTE is significantly reduced, especially after PE. 11 Hospitalized patients with acute medical illness, including infections such as pneumonia, are at increased risk of VTE, both in‐hospital and for an extended period of time (up to 45 days) after hospital discharge. 8,9,12–16 Despite this well‐established association, 8–10 there are few data specifically addressing VTE in patients recently hospitalized with COVID‐19 infections. 17,18 Indeed, infection‐associated VTE might account for a substantial burden of incident or recurrent VTE among those with COVID‐19. 25,26 Common laboratory abnormalities include lymphopenia and increase in lactate dehydrogenase and inflammatory markers such as C‐reactive protein, D‐dimer, ferritin, interleukin (IL)‐6, and fibrinogen. 27,28 Thrombocytopenia 29 and increased D‐dimer levels 30 are the most consistent laboratory abnormalities associated with a higher risk of developing severe COVID‐19. [...]several protocols suggest measuring D‐dimers, prothrombin time, and platelet counts to help assess COVID‐19 severity. 41 Empiric evidence supports use of treatment dose unfractionated heparin (UFH) as improving thrombosis‐free survival in acute respiratory distress syndrome with influenza A H1N1 but not coronavirus. 42 There is also recent evidence that prophylactic doses of LMWH (namely, enoxaparin at 40‐60 mg subcutaneous [s.c.] daily) or UFH (10 000‐15 000 units/d) appears to be associated with better prognosis in COVID‐19 patients with serious illness meeting sepsis‐induced coagulopathy score of ≥4 or with markedly elevated D‐dimer (>6× ULN) compared to non–heparin users. 43 The World Health Organization interim guidance statement as well as a recent guidance statement from ISTH recommends prophylactic use of daily LMWH over twice‐daily subcutaneous UFH. 44,45 Obese patients with body mass index (BMI) >30 kg/m2 have increased risk of VTE, 46 recurrent VTE, 47 and postthrombotic syndrome 48; however, prior studies have mainly focused VTE prophylaxis on extreme obesity defined by BMI >40 kg/m2. In‐ and outpatients Inpatients In‐ and outpatients Outpatients In‐ and outpatients Inpatients and elderly in establishment ICU patients Thrombotic risk assessment Yes Yes Yes Yes Yes Not mentioned Not mentioned Criteria for VTE risk Use of Wells’ Criteria IMPROVE VTE score D‐dimer Use of ISTH DIC score IMPROVE VTE score D‐dimer Use of ISTH DIC score Immobilization > 48 h, cancer, recent surgery, personal history of VTE, BMI > 30 kg/m2, age > 70 y old Thrombotic risk and ISTH DIC score NA NA Hemostasis surveillance Not mentioned Not mentioned Yes Not mentioned Yes Yes Yes Assessment of bleeding risk Yes Yes Not mentioned Not mentioned Yes Yes Not mentioned Proposed prophylactic treatments Patients hospitalized with suspected or confirmed COVID‐19, VTE prophylaxis with enoxaparin at prophylactic or intermediate doses (ie, 40 mg s.c. daily or 40 mg s.c. twice daily, especially for BMI > 40 kg/m2) as the preferred agent over UFH, unless patients have acute renal failure or chronic kidney disease (CrCl < 15 mL/min); if CrCl < 15 mL/min, then UFH 5000 IU s.c. 3 times daily for BMI < 40 kg/m2 or 7500 IU s.c. twice daily for BMI

Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause‐specific mortality in global reports. We analyzed global PE‐related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age‐sex–specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE‐related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization. We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper‐middle income, 14 (12.1%) lower‐middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE‐related mortality rate increased with age in most countries. The reporting of PE‐related deaths was heterogeneous, with an age‐standardized mortality rate ranging from 0 to 24 deaths per 100 000 population‐years. Income status only partially explained this heterogeneity. Reporting of PE‐related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE‐related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.

Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.

The Management of Anticoagulation in the Periprocedural Period (MAPPP) app is a free tool providing up-to-date guidelines on the periprocedural management of patients on long-term anticoagulants. After validating its effectiveness in the post-procedural period, we aimed to study its overall cost-effectiveness. SF-12 surveys were sent to eligible patients, converted into SF-6D forms, and subsequently into quality-adjusted life years (QALYs) to calculate the incremental cost-effectiveness ratio (ICER). The number of 30-day readmissions was used to calculate hospitalization costs, utilizing publicly available data. From 1/1/2018 to 1/31/2019, 642 patients were screened for enrollment, with an overall response rate of 94% (164/175) among the consented and 49% (164/336) among all eligible patients. The average QALY score was 0.7134 (95% CI [0.6836, 0.7431]) for the patients whose treatment plan followed the MAPPP app recommendations (acceptance group) and 0.7104 (95% CI [0.6760, 0.7448]) for those who did not (rejection group), without statistically significant differences. The difference in ICER scores was −$429 866.67, with the negative sign demonstrating that acceptance was the dominant strategy. By utilizing QALYs and ICER scores we have shown that the acceptance of MAPPP app recommendations is the dominant strategy for the periprocedural management of patients on long-term anticoagulation.

Purpose: To assess costs and healthcare resource utilization (HCRU) associated with the use of idarucizumab for the reversal of dabigatran and andexanet alfa for the reversal of direct oral Factor Xa inhibitors. Methods: This retrospective study utilizing Premier Healthcare Database (PHD) included patients aged ≥18 years on direct oral anticoagulants (DOACs) who experienced life-threatening bleeds, discharged from the hospital during 5/1/2018–6/30/2019, and received idarucizumab or andexanet alfa. Inverse of treatment probability weighting (IPTW) method was used to balance patient and clinical characteristics between treatment cohorts. Results: Idarucizumab patients were older than andexanet alfa patients (median age 81 vs 77 years; p < 0.001), and less likely to experience intracranial hemorrhage (ICH) (37.1%vs 73.8%; p  =  0.001). After IPTW adjustment, idarucizumab patients incurred lower mean total hospital costs ($30,413  ±  $33,028 vs $44,477  ±  $30,036; p < 0.001),and mean intensive care unit (ICU) cost ($25,114  ±  $30,433 vs $43,484  ±  $29,335; p < 0.001). Conclusions: Anticoagulant reversal therapy with idarucizumab was associated with significantly lower adjusted mean total hospital and ICU costs compared with andexanet alfa. However, a higher prevalence of ICH bleeds was noted in the andexanet alfa group. Trial Registration: Not applicable.

Overall rates of venous thromboembolism, including in-situ pulmonary thrombosis, are approximately three-times higher than historical matched controls of hospitalised populations, whereas rates of arterial thromboembolism, including acute coronary syndromes and stroke, although still elevated, are lower than previously described. 1 Microvascular thrombotic mechanisms have been implicated in progression to acute respiratory distress syndrome and subsequent need for organ support, and autopsy studies have identified unsuspected pulmonary embolism or in-situ pulmonary arterial thrombosis in nearly 60% of patients, suggesting that thrombosis has an important role in mortality. 2,3 Proposed mechanisms for these microvessel thrombotic and intravascular coagulopathic mechanisms and classic macrovessel thromboembolism are complex and include patient-related risk factors seen in medical patients hospitalised with pneumonia and sepsis, as well as more SARS-CoV-2-dependent mechanisms, including endothelial dysfunction, hyperinflammation and cytokine storm, formation of neutrophil-extracellular traps, complement-system activation, hypofibrinolysis, and platelet-derived and coagulation-derived mechanisms of thrombin generation leading to thromboinflammation. 4 Given this tendency for thrombotic complications with COVID-19, several multicentre randomised trials of antithrombotic therapies were launched globally as a logical next step to test whether the addition or escalated dosing of antithrombotic agents would provide further benefit to existing standards of care, and to understand the risk–benefit in terms of bleeding risk. 5 These trials have included anticoagulants with escalated or therapeutic doses being compared with standard prophylactic doses, anti-platelet agents, and fibrinolytic agents, as well as more novel approaches. 6 Trial designs have included adaptive, multiplatform, and Bayesian design frameworks, and the endpoints have included all-cause mortality, or composites including freedom from organ support or other surrogates of disease severity, and finally thrombosis. 5 For the most part, randomised trials to date have not shown benefits of add-on or escalated antithrombotic therapy over usual standard of care. The reason why the HEP-COVID trial 12 yielded a clear result despite its modest size in answering the trial hypothesis was that it used a traditional antithrombotic clinical trial design. 12 HEP-COVID used an agent with established efficacy in thromboembolic disease at an optimal dose (therapeutic low molecular weight heparin), selected a highly enriched population using a validated strategy (elevated D dimers), and used an endpoint that was specific to the mechanism of intervention (a composite of major thromboembolism and mortality). Burger/Phanie/Science Photo Library ACS declares research grants and consulting fees from Janssen Research & Development LLC, Bayer, Portola, Boehringer Ingelheim, Bristol-Meyers Squibb, and the ATLAS group, unrelated to the area of work commented on here.

Antithrombotic guidance statements for hospitalized patients with coronavirus disease 2019 (COVID‐19) suggest a universal thromboprophylactic strategy with potential to escalate doses in high‐risk patients. To date, no clear approach exists to discriminate patients at high risk for venous thromboembolism (VTE). The objective of this study is to externally validate the IMPROVE‐DD risk assessment model (RAM) for VTE in a large cohort of hospitalized patients with COVID‐19 within a multihospital health system. This retrospective cohort study evaluated the IMPROVE‐DD RAM on adult inpatients with COVID‐19 hospitalized between March 1, 2020, and April 27, 2020. Diagnosis of VTE was defined by new acute deep venous thrombosis or pulmonary embolism by Radiology Department imaging or point‐of‐care ultrasound. The receiver operating characteristic (ROC) curve was plotted and area under the curve (AUC) calculated. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using standard methods. A total of 9407 patients were included, with a VTE prevalence of 2.9%. The VTE rate was 0.4% for IMPROVE‐DD score 0‐1 (low risk), 1.3% for score 2‐3 (moderate risk), and 5.3% for score ≥ 4 (high risk). Approximately 45% of the total population scored high VTE risk, while 21% scored low VTE risk. IMPROVE‐DD discrimination of low versus medium/high risk showed sensitivity of 0.971, specificity of 0.218, PPV of 0.036, and NPV of 0.996. ROC AUC was 0.702. The IMPROVE‐DD VTE RAM demonstrated very good discrimination to identify hospitalized patients with COVID‐19 as low, moderate, and high VTE risk in this large external validation study with potential to individualize thromboprophylactic strategies.