Jan Beyer-Westendorf

BACKGROUND: Andexanet reduces hematoma expansion compared with usual care for acute FXa (factor Xa) inhibitor-associated intracerebral hemorrhage but is associated with a risk of thrombotic events (TE). We pooled data from andexanet-treated trial participants to determine baseline predictors of TE. METHODS: Secondary analyses of andexanet-treated participants in ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulant Effects of Factor Xa Inhibitors in ICH) and ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors), which included adults with acute life-threatening hemorrhage on FXa inhibitors. Stratified Cox proportional hazards models were used to examine associations between baseline variables and arterial or all TE and mortality. A stratified Cox regression model with arterial events as time-dependent covariates was used to examine associations of arterial events with mortality, adjusted for clinical covariates. RESULTS: Of 741 participants (mean age, 78.5 years; 54.5% male), 593 (80.0%) had intracranial hemorrhage and 109 (14.7%) had gastrointestinal hemorrhage. Seventy-seven (10.4%) participants had ≥1 TE, and 147 (19.8%) died. Arterial and venous thromboembolism events occurred a median of 3.5 days (interquartile range, 2.0–12.0) and 14.0 days (interquartile range, 10.0–20.0), respectively, after randomization. No baseline factors were associated with all TE. Arterial TE were associated with prior myocardial infarction (hazard ratio [HR], 2.64 [95% CI, 1.33–5.26]), high-dose eligibility (HR, 2.44 [95% CI, 1.33–4.48]), female sex (HR, 1.78 [95% CI, 1.00–3.16]), and age (HR per year, 1.04 [95% CI, 1.00–1.08]). Mortality was associated with arterial TE (HR, 2.68 [95% CI, 1.64–4.36]), prior congestive heart failure (HR, 2.53 [95% CI, 1.76–3.63]), intracerebral hemorrhage or intraventricular hemorrhage (HR, 1.90 [95% CI, 1.20–3.01]), and age (HR per year, 1.06 [95% CI, 1.03–1.08]). The initiation of anticoagulation after randomization was associated with a reduction in TE. CONCLUSIONS: In FXa inhibitor-associated hemorrhage treated with andexanet, baseline factors are associated with arterial TE and can be used to inform treatment decisions. Initiation of anticoagulation reduces the occurrence of TE. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.

Background - Anticoagulant therapy is the cornerstone of treatment for deep vein thrombosis (DVT) but does not directly dissolve clots. In contrast, alpha-2-antiplasmin (α2AP), the principal endogenous inhibitor of plasmin, is a novel target for enhancing endogenous fibrinolysis. Inclocibart (BAY 3018250) is a first-in-class monoclonal antibody that inhibits α2AP and has demonstrated thrombolytic activity without increasing bleeding in preclinical studies. Here, we describe the study design and validation of the quantitative ultrasound method. Methods - SIRIUS is a randomized, double-blind, placebo-controlled, multicenter Phase II trial evaluating the efficacy and safety of inclocibart in patients with acute symptomatic proximal DVT. Patients were randomized 1:1:1 to receive a single intravenous infusion of inclocibart 750 mg, inclocibart 250 mg, or placebo, in addition to therapeutic anticoagulation. The primary efficacy outcome is the weighted average of thrombus size score ratios relative to baseline, assessed by quantitative compression ultrasonography at 6 hours, 24 hours, Day 7, and Day 30. The primary safety outcome is the incidence of major and clinically relevant non-major bleeding through Day 15. Secondary outcomes include recurrent venous thromboembolism (VTE), changes in leg pain, and post-VTE functional status. Pharmacokinetic and pharmacodynamic evaluations were conducted. Results - The study randomized 262 patients at 61 sites across 13 countries. Patient follow-up was completed in December 2025. Independent, blinded experts centrally adjudicated the thrombus size score, recurrent VTEs, and key safety outcomes. A reproducibility analysis of quantitative compression ultrasound assessments demonstrated good agreement, supporting the reliability of the primary efficacy measure. Conclusion - The SIRIUS trial (NCT06149520) is the first randomized study evaluating α2AP inhibition as a thrombolytic strategy in patients with acute proximal DVT. The study will provide important information on the efficacy and safety of inclocibart and help define the therapeutic potential of α2AP inhibition as a novel approach to enhancing endogenous fibrinolysis in thromboembolic disease.

BACKGROUND: Andexanet improves hemostatic efficacy in FXa (factor Xa) inhibitor–associated intracranial hemorrhage but carries a risk of thrombotic events. These secondary analyses of the ANNEXA-I trial (A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor) examined determinants of hematoma expansion (HE) and the corresponding response to andexanet. METHODS: ANNEXA-I enrolled patients aged ≥18 years with acute FXa inhibitor–associated intracranial hemorrhage within 6 hours of onset between June 6, 2019, and May 27, 2023, at 131 sites in 23 countries. Participants were randomized (1:1) to andexanet or usual care. Among 530 participants, 459 (87%) had a qualifying intracerebral hemorrhage and adequate brain imaging for these analyses. The primary outcome was HE (≥12.5-mL or ≥35% increase in baseline volume) at 12 hours. We report differences in the proportion of HE between treatment groups stratified by variables significantly associated with HE in regression models. RESULTS: HE occurred in 149 of 459 participants (32.5%). Symptom onset-to-treatment time (adjusted odds ratio per hour, 0.73 [95% CI, 0.63–0.85]), baseline hematoma volume (adjusted odds ratio per 10 mL, 1.11 [95% CI, 1.01–1.23]), and diastolic blood pressure (adjusted odds ratio per 10 mm Hg, 1.15 [95% CI, 1.02–1.29]) were associated with HE but not thrombotic events. In a separate multivariable model replacing volume and onset-to-treatment time with prescan hematoma growth rate, growth rate was also associated with HE (adjusted odds ratio per mL/h, 1.02 [95% CI, 1.01–1.04]). Patients in the highest risk quartiles (baseline volume >22.4 mL, growth rate >11.4 mL/h, diastolic blood pressure >95.0 mm Hg, and onset-to-treatment time ≤3.3 hours) had ≈50% to 60% absolute risk of HE with usual care. Numerically greater absolute risk reductions with andexanet (≈25%; number needed to treat: 4) were observed in the highest quartiles of baseline volume and growth rate. CONCLUSIONS: Shorter onset-to-treatment time, larger baseline hematoma volume, higher diastolic blood pressure, and higher prescan hematoma growth rate predict HE but not thrombotic events in FXa inhibitor–associated intracerebral hemorrhage. Andexanet benefit is observed across these ranges and may be amplified through patient selection using these metrics. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03661528.

BACKGROUND: ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors) was a randomized trial that demonstrated that andexanet compared with usual care in patients with intracranial hemorrhage associated with FXa (factor Xa) inhibitor treatment reduces the risk of hematoma expansion and increases the risk of arterial thromboembolic events. METHODS: In a secondary analysis of the ANNEXA-I trial, we compared the effects of andexanet with usual care on change in anti-FXa activity and endogenous thrombin potential (ETP) using Wilcoxon rank-sum test. We examined the associations between 1-hour reduction in anti-FXa and 1-hour increase in ETP and hematoma expansion at 12 hours (≥12.5 mL or percentage volume change ≥35%) using logistic regression, both unadjusted and adjusted for time from symptom onset to baseline scan, baseline diastolic blood pressure, hematoma volume, baseline biomarker level and time from baseline scan to treatment, and association with arterial thromboembolic events (ischemic stroke, myocardial infarction, and systemic embolism) during 30 days of follow-up using Cox regression, both unadjusted and adjusted for age, baseline biomarker level, prior myocardial infarction, and eligibility for treatment with high-dose andexanet. RESULTS: ANNEXA-I enrolled 530 patients. Among 438 patients with baseline anti-FXa results, andexanet compared with usual care reduced anti-FXa activity at 1 hour (median, 8.6 versus 97.5 ng/mL; median reduction from baseline, 98.3 versus 10.9 ng/mL; P P P =0.010), and increase in ETP at 1 hour was associated with reduced hematoma expansion (per 100 nmol/L-min: odds ratio, 0.94 [95% CI, 0.90–0.99]; P =0.019) and risk of thromboembolic events (per 100 nmol/L-min: odds ratio, 1.08 [95% CI, 1.00–1.16]; P =0.047). CONCLUSIONS: In patients with apixaban- or rivaroxaban-associated intracranial hemorrhage, andexanet compared with usual care produces greater reduction in anti-FXa and greater increase in ETP at 1 hour. Reduction in anti-FXa from baseline to 1 hour is independently associated with reduced hematoma expansion, and increase in ETP from baseline to 1 hour is independently associated with both reduced hematoma expansion and increase of thromboembolic events. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03661528.

Direct oral anticoagulants such as edoxaban are standard of care in current treatment of venous thromboembolism (VTE). However, phase III trial data need confirmation in real-world settings.We extracted data from the prospective, noninterventional multiple-indication DRESDEN NOAC REGISTRY to evaluate outcome rates during VTE treatment with edoxaban. Patients were included in this analysis, if they had acute VTE and if patient enrolment and edoxaban initiation occurred within 30 days after VTE diagnosis. Patient characteristics, treatment persistence, and clinical outcomes were centrally adjudicated using standard definitions.Until December 31, 2023, 323 acute VTE patients (median age 67 years, 56.7% male) were enrolled and initiated edoxaban within 7.8 ± 4.9 days (mean) for isolated deep vein thrombosis (DVT) (57.6%) or pulmonary embolism (PE) ± DVT (42.4%). Mean duration of follow-up was 3.9 ± 1.9 years with a mean duration of edoxaban exposure of 1.5 ± 1.7 years. During ongoing edoxaban therapy, 3/323 patients (0.9%) experienced recurrent VTE (0.6/100 patient-years); 141/323 (43.7%) patients reported clinically relevant International Society on Thrombosis and Haemostasis (ISTH) nonmajor bleeding and 16 reported ISTH major bleeding (5.0%; 3.2/100 patient-years). Death was observed in 53 patients (4.1/100 patient-years). At 6 months, 78.2% were still taking edoxaban, 2% were electively switched to dose-reduced secondary prophylaxis with apixaban 2.5 mg twice a day or rivaroxaban 10 mg once daily. The remaining patients had a scheduled end of VTE treatment (11.4%) or were switched to nonedoxaban therapeutic anticoagulation (6.2%).Our results indicate effectiveness of edoxaban in acute VTE treatment with excellent persistence in the treatment and low rates of unplanned discontinuation. Bleeding was frequently observed, but rates of major bleeding were low and comparable to phase III data.

Background: Major bleeding or emergency surgery are the most frequently observed emergency situations in patients anticoagulated with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). The restart of anticoagulation after these situations is a therapeutic dilemma. Methods: The prospective RADOA registry is an observational, noninterventional multicenter registry that documents the management of severe bleeding or emergency surgery in patients treated with VKAs or DOACs. In this substudy, we analyzed time point, type, and dosage of anticoagulant resumption after emergency situations. Results: Overall, 78 emergency surgery patients and 193 major bleeding patients were analyzed. Median age was similar in the VKA- and DOAC-treated groups (emergency surgery: 77 years, major bleeding: 79 years). Anticoagulants were restarted significantly earlier after emergency surgery compared to major bleeding, with no difference between the VKA and DOAC groups. While patients after cardiothoracic surgery received UFH intravenously, patients with trauma or having received abdominal surgery were mainly treated with prophylactic LMWH s.c.. After major bleeding, the majority of patients were treated with prophylactic LMWH. None of the patients in the emergency surgery group and 17% (4/24) of the major bleeding group with recurrent bleeding (12%, 24/193) experienced recurrent bleeding after restart of anticoagulation. Thromboembolism occurred rarely in both patient groups (emergency surgery: 3%, major bleeding 4%). Conclusions: Time points of restart, type, and dosage of anticoagulants are highly diverse in this high-risk patient population. Resumption of prophylactic anticoagulation is associated with a low risk of thrombosis and should be initiated as soon as possible.

(1) Background: The clinical management of anticoagulated patients treated with direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA) needing emergency surgery is challenging. (2) Methods: The prospective German RADOA registry investigated treatment strategies in DOAC- or VKA-treated patients needing emergency surgery within 24 h after admission. Effectiveness was analysed by clinical endpoints including major bleeding. Primary observation endpoint was in hospital mortality until 30 days after admission. (3) Results: A total of 78 patients were included (DOAC: 44; VKA: 34). Median age was 76 years. Overall, 43% of the DOAC patients and 79% of the VKA patients were treated with prothrombin complex concentrates (PCC) (p = 0.002). Out of the DOAC patients, 30% received no hemostatic treatment compared to 3% (1/34) of the VKA patients (p = 0.002), and 7% of the DOAC patients and 21% of the VKA patients developed major or clinically relevant non-major bleeding at the surgical site (p = 0.093). In-hospital mortality was 13% with no significant difference between the two treatment groups (DOAC: 11%, VKA: 15%; p > 0.20). (4) Conclusions: The 30-day in-hospital mortality rate was comparable between both patient groups. VKA patients required significantly more hemostatic agents than DOAC patients in the peri- and postoperative surgery period.

Background Edoxaban is a non-vitamin K dependent oral anticoagulant (NOAC) licensed for venous thromboembolism (VTE) treatment or stroke prevention in atrial fibrillation. Major surgical procedures are not uncommon in anticoagulated patients but data on perioperative edoxaban management are scarce. Patients and Methods Using data from the prospective DRESDEN NOAC REGISTRY, we extracted data on major surgical procedures in edoxaban patients. Periinterventional edoxaban management patterns and rates of outcome events were evaluated until day 30 after procedure. Results Between 2011 and 2021, 3,448 procedures were identified in edoxaban patients, including 287 (8.3%) major procedures. A scheduled interruption of edoxaban was observed in 284/287 major procedures (99%) with a total median edoxaban interruption time of 11.0 days (25–75th percentile: 5.0–18.0 days). Heparin bridging was documented in 183 procedures (46 prophylactic dosages, 111 intermediate and 26 therapeutic dosages). Overall, 7 (2.4%; 95% CI: 1.2–4.9%) major cardiovascular events (5 VTE, 2 arterial thromboembolic events) and 38 major bleedings (13.2%; 95% CI: 9.8–17.7%) were observed and 6 patients died (2.1%; 95% CI: 1.0–4.5%). Rates of major cardiovascular events with or without heparin bridging were comparable (4/137; 2.9%; 95% CI: 1.1–7.3% vs. 3/82; 3.7%; 95% CI: 1.3–10.2%). Major bleedings occurred numerically more frequent in patients receiving heparin bridging (23/137; 16.8%; 95% CI: 11.5–23.9%) versus procedures without heparin bridging (9/82; 11.0%; 95% CI: 5.9–19.6%). Conclusion Within the limitations of our study design, real-world periprocedural edoxaban management seems effective and safe. Use of heparin bridging seems to have limited effects on reducing vascular events but may increase bleeding risk. The DRESDEN NOAC REGISTRY is registered at ClinicalTrials.gov (NCT01588119). The study protocol of the Dresden NOAC registry was approved by the local ethics committee at the Technical University Dresden (AZ EK 349092011). All patients gave their written informed consent and signed a data protection waiver before enrolment. J.B.-W. and L.T. conceived the present analysis and performed the statistical analyses. C.K. wrote the first draft of the manuscript. S.M., C.N. C.K. and J.B.-W. performed the central event adjudication. All authors contributed to the data collection and to the written presentation. All authors critically reviewed the manuscript and approved submission. Received: 29 March 2023 Accepted: 26 June 2023 Article published online: 22 September 2023 © 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany