Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.

BACKGROUND: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. OBJECTIVES: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. METHODS: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. RESULTS: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. CONCLUSIONS: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

Comparison of the prophylactic antithrombotic effect of indobufen and warfarin in patients with nephrotic syndrome: a randomized controlled trial.

PURPOSE: The risk of thromboembolic events is elevated in patients with nephrotic syndrome, and warfarin use has been associated with an increased risk of bleeding. Indobufen, a selective cyclooxygenase-1 inhibitor, is currently being evaluated for the prevention of thromboembolic events in nephrotic syndrome. This study aimed to compare the efficacy and safety of indobufen with that of warfarin in patients with nephrotic syndrome. MATERIALS AND METHODS: This multicenter, randomized, three-arm, open-label, parallel controlled trial involved a total of 180 adult patients with nephrotic syndrome from four centers in China. Patients were randomly assigned to receive 100 mg indobufen (bid), 200 mg indobufen (bid), and 3 mg warfarin (qd) daily for 12 weeks. The primary endpoints included thromboembolic and bleeding events, while laboratory results and adverse events constituted secondary endpoints. RESULTS: No thromboembolic events occurred in the high-/low-dose indobufen and warfarin groups. Moreover, the use of a low dose of indobufen significantly reduced the risk of minor bleeding events compared with warfarin use (2% versus 18%, p < .05). Finally, adverse events were more frequent in warfarin-treated patients. CONCLUSIONS: This study found that indobufen therapy provided equivalent effects in preventing thromboembolic events compared with warfarin therapy, while low dose of indobufen was associated with a reduced risk of bleeding events, thus it should be recommended for the prevention of thromboembolic events in clinical practice in patients with nephrotic syndrome. TRIAL REGISTRATION NUMBER: ChiCTR-IPR-17013428.

Second-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland.

We investigated thrombocytopenic, thromboembolic and hemorrhagic events following a second dose of ChAdOx1 and BNT162b2 using a self-controlled case series analysis. We used a national prospective cohort with 2.0 million(m) adults vaccinated with two doses of ChAdOx or 1.6 m with BNT162b2. The incidence rate ratio (IRR) for idiopathic thrombocytopenic purpura (ITP) 14-20 days post-ChAdOx1 second dose was 2.14, 95% confidence interval (CI) 0.90-5.08. The incidence of ITP post-second dose ChAdOx1 was 0.59 (0.37-0.89) per 100,000 doses. No evidence of an increased risk of CVST was found for the 0-27 day risk period (IRR 0.83, 95% CI 0.16 to 4.26). However, few (≤5) events arose within this risk period. It is perhaps noteworthy that these events all clustered in the 7-13 day period (IRR 4.06, 95% CI 0.94 to 17.51). No other associations were found for second dose ChAdOx1, or any association for second dose BNT162b2 vaccination. Second dose ChAdOx1 vaccination was associated with increased borderline risks of ITP and CVST events. However, these events were rare thus providing reassurance about the safety of these vaccines. Further analyses including more cases are required to determine more precisely the risk profile for ITP and CVST after a second dose of ChAdOx1 vaccine.

Thromboembolic events after Ad.26.COV2.S COVID-19 vaccine: Reports to the Vaccine Adverse Event Reporting System.

PURPOSE: The Food and Drug Administration (FDA) has identified a potential safety concern for thromboembolic events (TEEs) after Ad.26.COV2.S COVID-19 Vaccine. We sought to characterize the frequency, severity, type, and anatomic location of TEEs reported to the Vaccine Adverse Event Reporting System (VAERS) following Ad.26.COV2.S. METHODS: Reports of TEEs after Ad.26.COV2.S were identified in VAERS, and demographics, clinical characteristics, and relevant medical history were summarized. For a subset of reports, physicians reviewed available medical records and evaluated clinical presentation, diagnostic evaluation, risk factors, and treatment. The crude reporting rate of TEEs was estimated based on case counts in VAERS and vaccine administration data. RESULTS: Through February 28, 2022, FDA identified 3790 reports of TEEs after Ad.26.COV2.S. Median age was 56 years, and 1938 individuals (51.1%) were female. Most reports, 2892 (76.3%), were serious, including 421 deaths. Median time to onset was 12 days post-vaccination. Obesity and ischemia were among the most commonly documented risk factors. Thrombocytopenia (platelet count less than 150 000/µl) was documented in 63 records (11.5%) and anti-platelet 4 antibodies in 25 (4.6%). Medical review identified cases of severe clot burden (e.g., bilateral, saddle, or other massive pulmonary embolism with or without cor pulmonale; lower extremity thrombus involving the external iliac, common femoral, popliteal, posterior tibial, peroneal, and gastrocnemius veins). The crude reporting rate was ~20.7 cases of TEE per 100 000 doses of Ad.26.COV2.S administered. CONCLUSIONS: Life-threatening or fatal TEEs have been reported after Ad.26.COV2.S, including bilateral massive pulmonary embolism or other severe clot burden.

The prognostic role of anticoagulants in COVID-19 patients: national COVID-19 cohort in South Korea.

BACKGROUND: There currently exists a paucity of data on whether pre-admission anticoagulants use may have benefits among COVID-19 patients by preventing COVID-19 associated thromboembolism. The aim of this study was to assess the association between pre-admission anticoagulants use and COVID-19 adverse outcomes. METHODS: We conducted a population-based cohort studying using the Health Insurance Review and Assessment Service (HIRA) claims data released by the South Korean government. Our study population consisted of South Koreans who were aged 40 years or older and hospitalized with COVID-19 between 1 January 2020 through 15 May 2020. We defined anticoagulants users as individuals with inpatient and outpatient prescription records in 120 days before cohort entry. Our primary endpoint was a composite of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Individual components of the primary endpoint were secondary endpoints. We compared the risk of endpoints between the anticoagulants users and non-users by logistic regression models, with the standardized mortality ratio weighting (SMRW) adjustment. RESULTS: In our cohort of 4,349 patients, for the primary endpoint of mortality, mechanical ventilation and ICU admission, no difference was noted between anticoagulants users and non-users (SMRW OR 1.11, 95% CI: 0.60-2.05). No differences were noted, among individual components. No effect modification was observed by age, sex, history of atrial fibrillation and thromboembolism, and history of cardiovascular disease. When applying the inverse probability of treatment weighting (IPTW) and SMRW with doubly robust methods in sensitivity analysis, anticoagulants use was associated with increased odds of the primary endpoint. CONCLUSIONS: Pre-admission anticoagulants were not determined to have a protective role against severe COVID-19 outcomes.

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.

Predicted and Observed Incidence of Thromboembolic Events among Koreans Vaccinated with ChAdOx1 nCoV-19 Vaccine.

We used the nationwide claims database to calculate the incidence of thrombotic events and predict their overall 2-week incidence. From 2006 to 2020, the incidence of deep vein thrombosis (DVT), pulmonary embolism (PE), and disseminated intravascular coagulation (DIC) tended to increase. Unlike intracranial venous thrombosis (ICVT) and intracranial thrombophlebitis (ICTP), which showed no age difference, other venous embolism, and thrombosis (OVET), DIC, DVT, and PE were significantly more common in over 65 years. The overall 2-week incidence of ICVT was 0.21/1,000,000 (95% confidence interval [CI], 0.11-0.32). ICTP, OVET, DIC, DVT and PE were expected to occur in 0.08 (95% CI, 0.02-0.14), 7.66 (95% CI, 6.08-9.23), 5.95 (95% CI, 4.88-7.03), 13.28 (95% CI, 11.92-14.64), 14.09 (95% CI, 12.80-15.37) per 1,000,000, respectively. To date, of 8,548,231 patients vaccinated with ChAdOx1 nCoV-19 in Korea, two had confirmed thrombosis with thrombocytopenia syndrome within 2 weeks. The observed incidence of ICVT after vaccination was 0.23/1,000,000.