Impact of atrial fibrillation and anticoagulation on the risk of death, thromboembolic disease and bleeding in patients with COVID-19: the ACO-VID Registry.

OBJECTIVE: To describe the clinical profile, risk of complications and impact of anticoagulation in COVID-19 hospitalized patients, according to the presence of atrial fibrillation (AF). METHODS: Multicenter, retrospective, and observational study that consecutively included patients >55 years admitted with COVID-19 from March to October 2020. In AF patients, anticoagulation was chosen based on clinicians' judgment. Patients were followed-up for 90 days. RESULTS: A total of 646 patients were included, of whom 75.2% had AF. Overall, mean age was 75 ± 9.1 years and 62.4% were male. Patients with AF were older and had more comorbidities. The most common anticoagulants used during hospitalization in patients with AF were edoxaban (47.9%), low molecular weight heparin (27.0%), and dabigatran (11.7%) and among patients without AF, these numbers were 0%, 93.8% and 0%. Overall, during the study period (68 ± 3 days), 15.2% of patients died, 8.2% of patients presented a major bleeding and 0.9% had a stroke/systemic embolism. During hospitalization, patients with AF had a higher risk of major bleeding (11.3% vs 0.7%; p < .01), COVID-19-related deaths (18.0% vs 4.5%; p = .02), and all-cause deaths (20.6% vs 5.6%; p = .02). Age (HR 1.5; 95% CI 1.0-2.3) and elevated transaminases (HR 3.5; 95% CI 2.0-6.1) were independently associated with all-cause mortality. AF was independently associated with major bleeding (HR 2.2; 95% CI 1.1-5.3). CONCLUSIONS: Among patients hospitalized with COVID-19, patients with AF were older, had more comorbidities and had a higher risk of major bleeding. Age and elevated transaminases during hospitalization, but not AF nor anticoagulant treatment increased the risk of all-cause death.

Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study.

OBJECTIVES: To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal. DESIGN: A nationwide, register based cohort study. SETTING: All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included. PARTICIPANTS: 2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded. INTERVENTIONS: SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days). MAIN OUTCOME MEASURES: Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95). RESULTS: 2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses. CONCLUSIONS: Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.

Hemorrhage, Disseminated Intravascular Coagulopathy, and Thrombosis Complications Among Critically Ill Patients with COVID-19: An International COVID-19 Critical Care Consortium Study.

OBJECTIVES: To determine the prevalence and outcomes associated with hemorrhage, disseminated intravascular coagulopathy, and thrombosis (HECTOR) complications in ICU patients with COVID-19. DESIGN: Prospective, observational study. SETTING: Two hundred twenty-nine ICUs across 32 countries. PATIENTS: Adult patients (≥ 16 yr) admitted to participating ICUs for severe COVID-19 from January 1, 2020, to December 31, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: HECTOR complications occurred in 1,732 of 11,969 study eligible patients (14%). Acute thrombosis occurred in 1,249 patients (10%), including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial ischemia, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic strokes. Hemorrhagic complications were reported in 579 patients (4.8%), including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, 77 (13%) with pulmonary hemorrhage, and 68 (12%) with hemorrhage associated with extracorporeal membrane oxygenation (ECMO) cannula site. Disseminated intravascular coagulation occurred in 11 patients (0.09%). Univariate analysis showed that diabetes, cardiac and kidney diseases, and ECMO use were risk factors for HECTOR. Among survivors, ICU stay was longer (median days 19 vs 12; p < 0.001) for patients with versus without HECTOR, but the hazard of ICU mortality was similar (hazard ratio [HR] 1.01; 95% CI 0.92-1.12; p = 0.784) overall, although this hazard was identified when non-ECMO patients were considered (HR 1.13; 95% CI 1.02-1.25; p = 0.015). Hemorrhagic complications were associated with an increased hazard of ICU mortality compared to patients without HECTOR complications (HR 1.26; 95% CI 1.09-1.45; p = 0.002), whereas thrombosis complications were associated with reduced hazard (HR 0.88; 95% CI 0.79-0.99, p = 0.03). CONCLUSIONS: HECTOR events are frequent complications of severe COVID-19 in ICU patients. Patients receiving ECMO are at particular risk of hemorrhagic complications. Hemorrhagic, but not thrombotic complications, are associated with increased ICU mortality.

Safety and efficacy of prophylactic anticoagulation versus therapeutic anticoagulation in hospital-admitted COVID-19 patients: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: COVID-19 disease-related coagulopathy and thromboembolic complication, an important aspect of the disease pathophysiology, are frequent and associated with poor outcomes, particularly significant in hospitalized patients. Undoubtedly, anticoagulation forms a cornerstone for the management of hospitalized COVID-19 patients, but the appropriate dosing has been inconclusive and a subject of research. We aim to review existing literature and compare safety and efficacy outcomes of prophylactic and therapeutic dose anticoagulation in such patients. METHODS: We did a systematic review and meta-analysis to compare the efficacy and safety of prophylactic dose anticoagulation when compared with therapeutic dosing in hospitalized COVID-19 patients. We searched PubMed, Google Scholar, EMBASE and COCHRANE databases from 2019 to 2021, without any restriction by language. We screened records, extracted data and assessed the risk of bias in the studies. RCTs that directly compare therapeutic and prophylactic anticoagulants dosing and are not placebo-controlled trials were included. Analyses of data were conducted using the Mantel-Haenszel random-effects model (DerSimonian-Laird analysis). The study is registered with PROSPERO (CRD42021265948). RESULTS: We included three studies in the final quantitative analysis. The incidence of thromboembolic events in therapeutic anticoagulation was lower in comparison with prophylactic anticoagulation in hospitalized COVID-19 patients and reached statistical significance [RR 1·45, 95% CI (1.07, 1.97) I2 -0%], whereas major bleeding as an adverse event was found lower in prophylactic anticoagulation in comparison with therapeutic anticoagulation that was statistically significant [RR 0·42, 95% CI(0.19, 0.93) I2 -0%]. CONCLUSION: Our study shows that therapeutic dose anticoagulation is more effective in preventing thromboembolic events than prophylactic dose but significantly increases the risk of major bleeding as an adverse event. So, the risk-benefit ratio must be considered while using either of them.

Impact of COVID-19 on the Prescribing Pattern of Oral Anticoagulants for Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Because of logistic challenges associated with the COVID-19 pandemic, direct oral anticoagulants (DOAC) were favored over warfarin in patients presenting postoperative atrial fibrillation (AF) after cardiac surgery in our institution. Considering the limited evidence supporting the use of DOAC in this context, we sought to evaluate the safety and efficacy of this practice change. METHODS: A retrospective study was performed with patients from the Quebec City metropolitan area who were hospitalized at the Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval following cardiac surgery and who required oral anticoagulant (OAC) for postoperative AF. The primary objective was to compare the pre- and peri-COVID-19 period for OAC prescribing patterns and the incidence of thrombotic and bleeding events at 3 months post-surgery. The secondary objective was to compare DOAC to warfarin in terms of thrombotic events and bleeding events. RESULTS: A total of 233 patients were included, 142 from the pre-COVID-19 and 91 from the peri-COVID-19 period, respectively. Both groups had equivalent proportions of preoperative AF (48%) and new-onset postoperative AF (52%). The proportion of patients treated with a DOAC increased from 13% pre-COVID-19 to 82% peri-COVID-19. This change in practice was not associated with a significant difference in the incidence of thrombotic or bleeding events 3 months postoperatively. However, compared to DOAC, warfarin was associated with a higher incidence of major bleeding. Only 1 thrombotic event was reported with warfarin, and none were reported with DOAC. CONCLUSION: This study suggests that DOAC are an effective and safe alternative to warfarin to treat postoperative AF after cardiac surgery and that this practice can be safely maintained.

Incidence & outcomes of clinically significant bleeding events in critically ill COVID-19 patients receiving Therapeutic dose AntiCoagulanTs: A retrospective cohort study (INTerACT study).

Background & objectives: The high mortality associated with the thrombotic events in hospitalized COVID-19 patients resulted in the usage of anticoagulants in varying doses. Whether high-dose anticoagulants have led to better outcomes or higher incidence of clinically significant bleeding events is debatable. Thus, this study was conducted to find the incidence of clinically significant bleeding events in moderate-to-severe COVID-19 ARDS (acute respiratory distress syndrome) patients on therapeutic anticoagulation and their outcomes. Methods: In this retrospective, single-centre study of 155 critically ill COVID-19 patients, the incidence of clinically significant bleeding was observed. Multivariate regression models were used to evaluate the association between anticoagulant regimen, coagulation and inflammatory markers with the incidence of bleeding and thrombotic events. Results: The incidence of clinically relevant non-major bleeding was 33.54 per cent (26.17-41.46%) and major bleeding was 9.03 per cent (5.02-14.69%). The anticoagulation intensity at baseline had a high odds of major bleeding when enoxaparin and dual antiplatelet therapy were used together [adjusted odds ratio OR of 434.09 (3.81-49502.95), P<0.05]. At admission, bleeders had a poorer PaO2/FiO2 ratio with more patients on invasive ventilation. At the time of bleeding, the bleeders had a higher D-dimer, ferritin, C-reactive protein and procalcitonin compared to non-bleeders. The subhazard ratio for death in bleeders was 3.35 (95% confidence interval, 1.97-5.65; P<0.001). Interpretation & conclusions: The incidence of bleeding in critically ill COVID-19 patients on therapeutic anticoagulation may increase with the severity of the disease as well as with concurrent use of dual antiplatelets. Major bleeding may also contribute to higher mortality.

Impact of apixaban treatment discontinuation on the risk of hospitalization among patients with nonvalvular atrial fibrillation and COVID-19.

INTRODUCTION: This study evaluated the risk of hospitalization among nonvalvular atrial fibrillation (NVAF) patients with an outpatient COVID-19 diagnosis who discontinued vs continued apixaban treatment. METHODS: Adult patients with NVAF with an apixaban prescription prior to an outpatient COVID-19 diagnosis were identified from Optum Clinformatics claims database (1 April 2020-31 March 2021). Continuers were those who continued apixaban as of the index date (date of initial outpatient COVID-19 diagnosis) and discontinuers were those who had the last day of apixaban supply on or before index. Patients were followed from COVID-19 diagnosis to change of continuation/discontinuation status, switch, death, end of continuous coverage or study end, whichever occurred first. Inverse probability treatment weighting (IPTW) was performed to balance cohorts. Cox proportional hazard models were used to compare the risk of all-cause hospitalization and hospitalization for ischemic stroke (IS), venous thromboembolism (VTE), myocardial infarction (MI), bleeding and mortality. RESULTS: A total of 7869 apixaban patients with COVID-19 were included: 6676 continuers (84.8%) and 1193 discontinuers (15.2%). Compared with continuers, discontinuers had a higher risk of all-cause hospitalization (hazard ratio [HR]: 1.23; 95% confidence interval [CI]: 1.08-1.40), IS (HR: 2.00; 95% CI: 1.03-3.87), VTE (HR: 2.37; 95% CI: 1.06-5.27) and mortality (HR: 2.28; 95% CI: 1.85-2.80). There were no significant differences in the risk of MI (HR: 1.01; 95% CI: 0.54-1.90) or bleeding-related hospitalization (HR: 1.13; 95% CI: 0.73-1.76). CONCLUSION: NVAF patients with COVID-19 who discontinued apixaban had a higher risk of hospitalization and thrombotic events vs those who continued apixaban, with no significant difference in bleeding-related hospitalization.

Thromboembolic events in COVID-19 ambulatory patients: An observational study about incidence, and thromboprophylaxis outcomes.

INTRODUCTION: There are no clear data about the incidence and the prophylactic strategies of arterial and venous thromboembolic events (TE) in COVID-19 ambulatory patients. Thus, we conducted this study to analyze thromboembolic complications in this setting and to assess thromboprophylaxis management and outcomes in the real life. PATIENTS AND METHODS: This is an observational study including Covid-19 ambulatory patients. We assessed incidence of venous and arterial TE events as well as thromboprophylaxis outcomes and hemorrhagic complications. We defined high risk thrombo-embolic factor according to the Belgian guidelines which are the only guidelines that described thromboprophylaxis in COVID-19 ambulatory patients. RESULTS: We included 2089 patients with a mean age of 43±16 years. The incidence of 30 days venous and arterial TE complications in our cohort was 1%. Venous thromboembolic complications occurred in 0.8% and arterial thromboembolic complications occurred in 0.3%.We noted at least one high-risk TE factor in 18.5% of patients but thromboprophylaxis was prescribed in 22.5% of the cases, LMWH in 18.1%, and Rivaroxaban in 3.7%. Hemorrhagic events occurred in eight patients (0.3%): five patients showed minor hemorrhagic events and three patients showed major ones (0.14%). CONCLUSIONS: Our study showed that the incidence of thromboembolic complications is very low in COVID-19 ambulatory patients. Paradoxically, there is an over prescription of thrombo-prophylaxis in this population.

Effect of intermediate/high versus low dose heparin on the thromboembolic and hemorrhagic risk of unvaccinated COVID-19 patients in the emergency department.

BACKGROUND: The optimal prophylactic dose of heparin in patients with coronavirus-associated disease 2019 (COVID-19) in the emergency department (ED) is debated. This study aimed to analyze different thromboprophylaxis approaches in unvaccinated COVID-19 patients admitted to ED without initial venous thromboembolism. METHODS: Retrospectively, the effect of intermediate/high versus low dose heparin treatment was evaluated from December 2020 to July 2021 in a tertiary Academic Hospital in northeast Italy. The primary outcome comprised arterial or venous thromboembolism or all-cause death within 30 days. Secondary outcomes comprised each single primary outcome component or major hemorrhagic event. Cox regression was used to determine predictors of the primary outcome and propensity score weights to balance the effect of heparin treatment on all outcomes. RESULTS: Data of 144 consecutive patients (age 70 ± 13, 33% females) were included in the study. High-dose prophylactic heparin was used in 69%, intermediate in 15%, and low in 17% of patients. The primary outcome occurred in 48 patients. Independent predictors of the primary outcome were COVID-19 severity (hazards ratio (HR) 1.96, 95% confidence interval (CI) 1.05-3.65, p = 0.035) and D-dimer levels (HR each log ng/dl 1.38, 95% CI 1.04-1.84, p = 0.026). Intermediate/high dose heparin did not affect the risk of the primary outcome compared with the low dose (weighted HR 1.39, 95% CI 0.75-2.56, p = 0.292). Intermediate/high heparin increased the risk of major hemorrhagic events (weighted HR 5.92, 95% CI 1.09-32, p = 0.039). CONCLUSIONS: In unvaccinated COVID-19 patients admitted to ED, prophylaxis with heparin at the intermediate/high dose did not reduce primary outcome compared with the low dose but increased the risk of major hemorrhagic events.

Venous thromboembolism (VTE) prevention and diagnosis in COVID-19: Practice patterns and outcomes at 33 hospitals.

BACKGROUND: Early reports of increased thrombosis risk with SARS-CoV-2 infection led to changes in venous thromboembolism (VTE) management. Real-world data on the prevalence, efficacy and harms of these changes informs best practices. OBJECTIVE: Define practice patterns and clinical outcomes related to VTE diagnosis, prevention, and management in hospitalized patients with coronavirus disease-19 (COVID-19) using a multi-hospital US sample. METHODS: In this retrospective cross-sectional study of 1121 patients admitted to 33 hospitals, exposure was dose of anticoagulant prescribed for VTE prophylaxis (standard, intensified, therapeutic), and primary outcome was VTE (pulmonary embolism [PE] and deep vein thrombosis [DVT]); secondary outcomes were PE, DVT, arterial thromboembolism (ATE), and bleeding events. Multivariable logistic regression models accounting for clustering by site and adjusted for risk factors were used to estimate odds ratios (ORs). Inverse probability weighting was used to account for confounding by indication. RESULTS: 1121 patients (mean age 60 ± 18, 47% female) admitted with COVID-19 between February 2, 2020 and December 31, 2020 to 33 US hospitals were included. Pharmacologic VTE prophylaxis was prescribed in 86%. Forty-seven patients (4.2%) had PE, 51 (4.6%) had DVT, and 23 (2.1%) had ATE. Forty-six patients (4.1%) had major bleeding and 46 (4.1%) had clinically relevant non-major bleeding. Compared to standard prophylaxis, adjusted odds of VTE were 0.67 (95% CI 0.21-2.1) with no prophylaxis, 1.0 (95% CI 0.06-17) with intensified, and 3.0 (95% CI 0.89-10) with therapeutic. Adjusted odds of bleeding with no prophylaxis were 5.6 (95% CI 3.0-11) and 5.3 (95% CI 3.0-10) with therapeutic (no events on intensified dosing). CONCLUSIONS: Therapeutic anticoagulation was associated with a 3-fold increased odds of VTE and 5-fold increased odds of bleeding. While higher bleeding rates with high-intensity prophylaxis were likely due to full-dose anticoagulation, we conclude that high thrombosis rates were due to clinical concern for thrombosis before formal diagnosis.

Thrombosis and hemorrhage experienced by hospitalized children with SARS-CoV-2 infection or MIS-C: Results of the PICNIC registry.

INTRODUCTION: Coagulopathy and thrombosis associated with SARS-CoV-2 infection are well defined in hospitalized adults and leads to adverse outcomes. Pediatric studies are limited. METHODS: An international multicentered (n = 15) retrospective registry collected information on the clinical manifestations of SARS-CoV-2 and multisystem inflammatory syndrome (MIS-C) in hospitalized children from February 1, 2020 through May 31, 2021. This sub-study focused on coagulopathy. Study variables included patient demographics, comorbidities, clinical presentation, hospital course, laboratory parameters, management, and outcomes. RESULTS: Nine hundred eighty-five children were enrolled, of which 915 (93%) had clinical information available; 385 (42%) had symptomatic SARS-CoV-2 infection, 288 had MIS-C (31.4%), and 242 (26.4%) had SARS-CoV-2 identified incidentally. Ten children (1%) experienced thrombosis, 16 (1.7%) experienced hemorrhage, and two (0.2%) experienced both thrombosis and hemorrhage. Significantly prevalent prothrombotic comorbidities included congenital heart disease (p-value .007), respiratory support (p-value .006), central venous catheter (CVC) (p = .04) in children with primary SARS-CoV-2 and in those with MIS-C included respiratory support (p-value .03), obesity (p-value .002), and cytokine storm (p = .012). Comorbidities prevalent in children with hemorrhage included age >10 years (p = .04), CVC (p = .03) in children with primary SARS-CoV-2 infection and in those with MIS-C encompassed thrombocytopenia (p = .001) and cytokine storm (p = .02). Eleven patients died (1.2%), with no deaths attributed to thrombosis or hemorrhage. CONCLUSION: Thrombosis and hemorrhage are uncommon events in children with SARS-CoV-2; largely experienced by those with pre-existing comorbidities. Understanding the complete spectrum of coagulopathy in children with SARS-CoV-2 infection requires ongoing research.

Thrombosis and coagulopathy in COVID-19 patients rceiving ECMO: A narrative review of current literature.

Extracorporeal membrane oxygenation (ECMO) is an established part of the treatment algorithm for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. An intense inflammatory response may cause an imbalance in the coagulation cascade making both thrombosis and bleeding common and notable features of the clinical management of these patients. Large observational and retrospective studies provide a better understanding of the pathophysiology and management of bleeding and thrombosis in COVID-19 patients requiring ECMO. Clinically significant bleeding, including intracerebral hemorrhage, is an independent predictor of mortality, and thrombosis (particularly pulmonary embolism) is associated with mortality, especially if occurring with right ventricular dysfunction. The incidence of heparin-induced thrombocytopenia is higher than the general patient cohort with acute respiratory distress syndrome or other indications for ECMO. The use of laboratory parameters to predict bleeding or thrombosis has a limited role. In this review, the authors discuss the complex pathophysiology of bleeding and thrombosis observed in patients with COVID-19 during ECMO support, and their effects on outcomes.

Association between pre-admission anticoagulation and in-hospital death, venous thromboembolism, and major bleeding among hospitalized COVID-19 patients in Japan.

PURPOSE: The coagulation activation leads to thrombotic complications such as venous thromboembolism (VTE) in patients with coronavirus disease-2019 (COVID-19). Prophylactic anticoagulation therapy has been recommended for hospitalized COVID-19 patients in clinical guidelines. This retrospective cohort study aimed to examine the association between pre-admission anticoagulation treatment and three outcomes: in-hospital death, VTE, and major bleeding among hospitalized COVID-19 patients in Japan. METHODS: Using a large-scale claims database built by the Medical Data Vision Co. in Japan, we identified patients hospitalized for COVID-19 who had outpatient prescription data at least once within 3 months before being hospitalized. Exposure was set as pre-admission anticoagulation treatment (direct oral anticoagulant or vitamin K antagonist), and outcomes were in-hospital death, VTE, and major bleeding. We conducted multivariable logistic regression analyses, adjusting for a single summarized score (a propensity score of receiving pre-admission anticoagulation) for VTE and major bleeding, due to the small number of outcomes. RESULTS: Among the 2612 analytic patients, 179 (6.9%) had pre-admission anticoagulation. Crude incidence proportions were 13.4% versus 8.5% for in-hospital death, 0.56% versus 0.58% for VTE, and 2.2% versus 1.1% for major bleeding among patients with and without pre-admission anticoagulation, respectively. Adjusted odds ratios (95% confidence intervals) were 1.25 (0.75-2.08) for in-hospital death, 0.21 (0.02-1.97) for VTE, and 2.63 (0.80-8.65) for major bleeding. Several sensitivity analyses did not change the results. CONCLUSIONS: We found no evidence that pre-admission anticoagulation treatment was associated with in-hospital death. However, a larger sample size may be needed to conclude its effect on VTE and major bleeding.

Four-factor prothrombin complex concentrate plus andexanet alfa for reversal of factor Xa inhibitor-associated bleeding: Case series.

PURPOSE: To manage factor Xa (FXa) inhibitor-associated bleeding, andexanet alfa or 4-factor prothrombin concentrate (4F-PCC) has been used to restore hemostasis. However, literature on the outcomes for patients who received both andexanet alfa and 4F-PCC is limited. SUMMARY: We report a case series of 5 patients who received andexanet alfa plus 4F-PCC for reversal of FXa inhibitor-associated bleeding. Patients were included in this case series if they received both andexanet alfa and 4F-PCC for reversal of FXa inhibitor-associated bleeding. They were followed to either discharge or death, and in-hospital complications related to concurrent use of andexanet alfa and 4F-PCC were documented. We report an incidence of thromboembolism of 40% (2 of 5 cases) and an in-hospital mortality rate of 60% (3 of 5 cases). Taking these cases together with those in the existing literature, we found a total of 23 reported cases of safety outcomes with andexanet alfa plus 4F-PCC. The overall incidence of thromboembolism was 35% (8 of 23 cases). CONCLUSION: This case series adds to the limited literature describing the outcomes for patients receiving andexanet alfa plus 4F-PCC. We encourage other institutions to report safety data on administering both agents.

Major Bleeding and Thrombosis Events in COVID-19 Versus Influenza Patients Requiring Extracorporeal Membrane Oxygenation.

Initial reports described a hypercoagulable state and an increased risk of thrombosis in patients who tested positive for SARS-CoV-2. Infected patients with severe acute respiratory distress syndrome in the setting of coronavirus disease 2019 (COVID-19) may require extracorporeal membrane oxygenation (ECMO), leading to coagulopathies and further increasing the risk for bleeding and thrombosis. We conducted a single-center retrospective cohort study to compare the incidence of major bleeding and thrombosis in COVID-19 versus influenza-positive patients requiring ECMO. There was no difference in the incidence of major bleeding (67.7% vs. 85.7%, p = 0.287) or major thrombosis (9.7% vs. 21.4%, p = 0.356) between COVID-19 and influenza patients, respectively. COVID-19 patients experienced significantly fewer major bleeding events per ECMO days compared with influenza (0.1 [interquartile range 0-0.2] vs. 0.2 [interquartile range 0.1-0.5], p = 0.026). Influenza patients may be at higher risk for developing coagulopathies that contribute to bleeding. Larger evaluations are needed to confirm these results and further assess bleeding and thrombosis risk in these populations.

Warfarin versus direct oral anticoagulants for patients needing distal deep vein thrombosis treatment.

OBJECTIVE: Great interest exists in standardizing the anticoagulant choice for patients requiring treatment of distal deep vein thrombosis (DDVT). In the present multicenter, retrospective cohort study, we evaluated the outcomes of patients with DDVT who had been treated with warfarin vs direct oral anticoagulants (DOACs; ie, rivaroxaban, apixaban, edoxaban, dabigatran). METHODS: Queries were built for the TriNetX database (TriNetX LLC, Cambridge, Mass), a federated network of healthcare organizations across the United States that provides de-identified patient data through aggregated counts and statistical summaries. International Classification of Diseases, 10th revision, diagnostic codes were used to identify eligible patients. Data from January 1, 2013 to January 1, 2020 were reviewed. Statistical analyses, including propensity matching, were performed using TriNetX's internal software. The inclusion criterion was treatment with either warfarin or a DOAC started within the first 24 hours of diagnosis of an isolated thrombosis of the following veins: anterior tibial, posterior tibial, peroneal, or calf muscular veins. The exclusion criteria were a history of an adverse reaction to anticoagulant agents, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, thrombophilia, mechanical heart valve, chronic proximal DVT (PDVT) and/or DDVT, and 6-month history of the following: acute PDVT, pulmonary embolism (PE), or anticoagulant usage. The outcomes measured included the incidence of mortality, PE, PDVT, stroke, myocardial infarction, and major bleeding within 6 months after initiating anticoagulation therapy. RESULTS: In a cohort of 6509 patients, 1570 were treated with warfarin and 4939 were treated with a DOAC drug. After propensity matching for age, sex, ethnicity, and comorbidities, the DOAC cohort had a significantly lower incidence of PE (1.795% vs 3.590%; P = .0020) and major bleeding (7.949% vs 10.513%; P = .0134). Differences in the incidence of mortality, PDVT, myocardial infarction, and stroke were not statistically significant. CONCLUSIONS: Before the present study, no strong evidence was available to suggest an optimal treatment modality for DDVT requiring anticoagulation therapy. The data from the present study suggest that patients receiving DOACs for the treatment of DDVT will have significantly lower rates of progression to PE and a lower incidence of major bleeding compared with patients receiving warfarin. This suggests that DOACs are superior to warfarin for treatment of DDVT.

Risk assessment of venous thromboembolism and bleeding in COVID-19 patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is a newly recognized illness that has spread rapidly all over the world. More and more reports highlight the risk of venous thromboembolism (VTE) in COVID-19. Our study aims to identify in-hospital VTE risk and bleeding risk in COVID-19 patients. METHODS: We retrospectively studied 138 consecutively enrolled patients with COVID-19 and identified in-hospital VTE and bleeding risk by Padua Prediction Score and Improve bleed risk assessment model. The clinical data and features were analyzed in VTE patients. RESULTS: Our findings identified that 23 (16.7%) patients with COVID-19 were at high risk for VTE according to Padua prediction score and 9 (6.5%) patients were at high risk of bleeding for VTE prophylaxis according to Improve prediction score. Fifteen critically ill patients faced double high risk from thrombosis (Padua score more than 4 points in all 15 [100%] patients) and hemorrhage (Improve score more than 7 points in 9 [60.0%] patients). Thrombotic events were identified in four patients (2.9%) of all COVID-19 patients. All of them were diagnosed with deep vein thrombosis by ultrasound 3 to 18 days after admission. Three (75.0%) were critically ill patients, which means that the incidence of VTE among critically ill patients was 20%. One major hemorrhage happened in critically ill patients during VTE treatment. CONCLUSION: Critically ill patients with COVID-19 suffered both a high risk of thrombosis and bleeding risks. More effective VTE prevention strategies based on an individual assessment of bleeding risks were necessary for critically ill patients with COVID-19.

Venous Thromboembolism and Major Bleeding in Patients With Coronavirus Disease 2019 (COVID-19): A Nationwide, Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS: Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. RESULTS: The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS: Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Validation of a Prognostic Score to Identify Hospitalized Patients with COVID-19 at Increased Risk for Bleeding.

INTRODUCTION: Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major bleeding. METHODS: We aimed to validate the score in a subsequent cohort of hospitalized patients with COVID-19 receiving standard-, intermediate- or therapeutic doses of VTE prophylaxis. We evaluated its capacity to predict major bleeding, non-major bleeding, and bleeding-related death. RESULTS: The cohort included 972 patients from 29 hospitals, of whom 280 (29%) received standard-; 412 (42%) intermediate-, 157 (16%) therapeutic doses of VTE prophylaxis and 123 (13%) other drugs. Median duration of prophylaxis was 14.7 ± 10.3 days. Major bleeding occurred in 65 patients (6.7%) and non-major bleeding in 67 (6.9%). Thirty patients with major bleeding (46%) died within the first 30 days after bleeding. The prognostic score identified 203 patients (21%) at very low risk, 285 (29%) at low risk, 263 (27%) intermediate-risk and 221 (23%) at high risk for bleeding. Major bleeding occurred in 1.0%, 2.1%, 8.7% and 15.4% of the patients, respectively. Non-major bleeding occurred in 0.5%, 3.5%, 9.5% and 14.2%, respectively. The c-statistics was: 0.74 (95% confidence intervals [CI]: 0.68-0.79) for major bleeding, 0.73 (95% CI: 0.67-0.78) for non-major bleeding and 0.82 (95% CI: 0.76-0.87) for bleeding-related death. CONCLUSIONS: In hospitalized patients with COVID-19, we validated that a prognostic score including 4 easily available items may identify those at increased risk for bleeding.

The effect of higher-intensity dosing of anticoagulation on the clinical outcomes in hospitalized patients with COVID-19: A meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to perform a meta-analysis to summarize the overall evidence from randomized controlled trials related to higher-intensity anticoagulation in hospitalized patients with COVID-19. METHODS: A systematic literature search was performed in electronic databases to identify randomized controlled trials comparing the clinical outcomes between intermediate/ therapeutic anticoagulation and prophylactic anticoagulation. Meta-analyses with random-effects models were used to estimate the pooled odds ratio (OR) for outcomes of interest at a 95% confidence interval (CI). RESULTS: Eight randomized controlled trials were included, with a total of 5405 hospitalized patients with COVID-19. The meta-analysis revealed no statistically significant difference in the odds of mortality (pooled OR = 0.92; 95% CI 0.71-1.19) but a statistically significant reduction in the odds of development of thrombotic events (pooled OR = 0.55; 95% CI 0.42-0.72), and significantly increased odds of development of major bleeding (pooled OR = 1.81; 95% CI 1.20-2.72) with the use of intermediate/therapeutic anticoagulation, relative to prophylactic anticoagulation. Subgroup analysis in patients with a severe course of COVID-19 observed a statistically significant reduction in the odds of development of thrombotic events (pooled OR = 0.66; 95% CI 0.45-0.98) but no significant difference in the odds of development of major bleeding events (pooled OR = 1.37; 95% CI 0.74-2.56), with the use of intermediate/therapeutic anticoagulation, relative to prophylactic anticoagulation. CONCLUSION: There could be net clinical benefits with higher-intensity dosing of anticoagulation relative to prophylactic-dosing of anticoagulation among hospitalized patients with severe COVID-19.