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Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study.

ABSTRACT: Background: Intracranial hemorrhage (ICH) is associated with high mortality and morbidity, especially in patients under anticoagulative treatment. Andexanet alfa (AA) is a modified recombinant form of human factor Xa (FXa) developed for reversal of FXa-inhibitors, e.g., in the event of ICH, but experience is still limited. Methods: This monocentric retrospective observational cohort study included 46 patients with acute FXa-inhibitor-associated non-traumatic ICH (FXa-I-ICH) of whom 23 were treated with AA within 12 h after symptom onset, compared to 23 patients with usual care (UC). Volumetrically analyzed hematoma expansion (HE) in brain imaging, clinical outcome and incidence of adverse events were analyzed. Results: All patients (mean age 79.8 ± 7.2 years) were effectively anticoagulated. The cohort included severely ill patients with large hematoma volumes (median 20.4, IQR 7.8−39.0 mL). Efficacy, as assessed by HE in imaging, was very good in the AA-group. There was no (0.0%) relevant HE (>33%) in contrast to UC-group (26.1%). Nevertheless, we observed a high incidence of thromboembolic events (30.4% vs. 4.4%) and non-favorable outcomes (death/palliative condition) in 43.5% vs. 26.1%. Conclusions: There was no HE in the volumetric neuroimaging assessment in the AA-group, but clinical outcomes remained often worse. Large randomized trials for the use of AA in patients with acute FXa-inhibitor-associated ICH are needed to investigate the clinical outcome in consideration of the rates of thromboembolism.

SUBMITTER: Rauch S

PROVIDER: S-EPMC9224862 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study.

Rauch Sebastian S Müller Hans-Peter HP Dreyhaupt Jens J Ludolph Albert C AC Kassubek Jan J Althaus Katharina K

Journal of clinical medicine 20220613 12

Background: Intracranial hemorrhage (ICH) is associated with high mortality and morbidity, especially in patients under anticoagulative treatment. Andexanet alfa (AA) is a modified recombinant form of human factor Xa (FXa) developed for reversal of FXa-inhibitors, e.g., in the event of ICH, but experience is still limited. Methods: This monocentric retrospective observational cohort study included 46 patients with acute FXa-inhibitor-associated non-traumatic ICH (FXa-I-ICH) of whom 23 were treat ...[more]

PMID: 35743469

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Project description:Background/objectiveThere are limited data on the risks and benefits of using andexanet alfa (AA) in comparison with four-factor prothrombin complex concentrate (4F-PCC) to reverse factor Xa inhibitors (FXi) associated intracranial hemorrhage (ICH). We sought to describe our experience with AA or 4F-PCC in patients with oral FXi-related traumatic and spontaneous ICH.MethodsWe conducted a retrospective review of consecutive adult patients with FXi-related ICH who received AA or 4F-PCC. FXi-related ICH cases included traumatic and spontaneous intracranial hemorrhages. Our primary analysis evaluated ICH stability on head computed tomography scan (CT), defined as a similar amount of blood from the initial scan at the onset of ICH to subsequent scans, at 6-h and 24-h post-administration of AA or 4F-PCC. For the subset of spontaneous intraparenchymal hemorrhages, volume was measured at 6-h and 24-h post-reversal. In secondary analyses, we evaluated good functional outcome at discharge, defined as a Modified Rankin Score of less than 3, and the incidence of thrombotic events after AA or 4F-PCC adminstration, during hospitalization.ResultsA total of 44 patients (16 traumatic and 28 spontaneous ICH) with median age of 79 years [72-86], 36% females, with a FXi-related ICH, were included in this study. The majority of spontaneous ICHs were intraparenchymal 19 (68%). Twenty-eight patients (64%) received AA and 16 patients (36%) received 4F-PCC. There was no difference between AA and 4F-PCC in terms of CT stability at 6 h (21 [78%] vs 10 [71%], p = 0.71) and 24 h (15 [88%] vs 6 [60%], p = 0.15). In a subgroup of patients with spontaneous intraparenchymal hemorrhage, there was no difference in the degree of achieved hemostasis based on hematoma volume between AA and 4F-PCC at 6 h (9.3 mL [6.9-26.4] vs 10 mL [9.4-22.1], adjusted p = 0. 997) and 24-h (9.2 mL [6.1-18.8] vs 9.9 [9.4-21.1], adjusted p = 1). The number of patients with good outcome based on mRS on discharge were 10 (36%) and 6 (38%) in the AA and 4F-PCC groups, respectively (adjusted p = 0.81). The incidence of thromboembolic events was similar in the AA and 4F-PCC groups (2 [7%] vs 0, p = 0.53).ConclusionIn this limited sample of patients, we found no difference in neuroimaging stability, functional outcome and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since our analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

Project description:Background and purposeAndexanet alfa is a recombinant modified human FXa (factor Xa) developed to reverse FXa inhibition from anticoagulants. Hemostatic efficacy and reversal of anti-FXa activity with andexanet were assessed in patients from the ANNEXA-4 study (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXa Inhibitors) with intracranial hemorrhage (ICrH).MethodsANNEXA-4 was a single-arm study evaluating andexanet in patients presenting with major bleeding ≤18 hours after taking an FXa inhibitor. Patients received a bolus plus 2-hour infusion of andexanet. Brain imaging in patients with ICrH was performed at baseline and at 1 and 12 hours postandexanet infusion. Coprimary efficacy outcomes were change in anti-FXa activity and hemostatic efficacy at 12 hours (excellent/good efficacy defined as ≤35% increase in hemorrhage volume/thickness). Safety outcomes included occurrence of thrombotic events and death at 30 days.ResultsA total of 227 patients with ICrH were included in the safety population (51.5% male; mean age 79.3 years) and 171 in the efficacy population (99 spontaneous and 72 traumatic bleeds). In efficacy evaluable patients, excellent/good hemostasis 12 hours postandexanet occurred in 77 out of 98 (78.6%) and in 58 out of 70 (82.9%) patients with spontaneous and traumatic bleeding, respectively. In the subanalysis by FXa inhibitor treatment group in the efficacy population, median of percent change in anti-FXa from baseline to nadir showed a decrease of 93.8% for apixaban-treated patients (n=99) and by 92.6% for rivaroxaban-treated patients (n=59). Within 30 days, death occurred in 34 out of 227 (15.0%) patients and thrombotic events occurred in 21 out of 227 (9.3%) patients (safety population).ConclusionsAndexanet reduced anti-FXa activity in FXa inhibitor-treated patients with ICrH, with a high rate of hemostatic efficacy. Andexanet may substantially benefit patients with ICrH, the most serious complication of anticoagulation.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02329327.

Project description:BackgroundAndexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.MethodsIn this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.ResultsThe mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.ConclusionsOn the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Project description:Background: Mortality of oral anticoagulation-associated ICH is around 60%, with oral anticoagulation increasing the risk of ICH seven to ten-fold compared to no anticoagulation. Current guidelines recommend DOACs (direct oral anticoagulants) as first-line therapy in the treatment of VTE (Venous Thromboembolism) due to their more favorable safety profile. There are two agents available for DOAC reversal, Coagulation Factor Xa (recombinant), inactivated-zhzo (andexanet alfa, Andexxa®) and 4-factor prothrombin complex concentrate (4FPCC). There is little data comparing the two agents in real-life clinical settings.ObjectiveThe primary objective of this study was to determine if there was a difference in hemostatic efficacy of andexanet alfa and 4FPCC in patients with a factor Xa inhibitor-related intracranial hemorrhage.MethodsThis was a retrospective, single-center study conducted in adult patients admitted at a quaternary academic medical center from September 2017 to March 2021. Adults with a diagnosis of intracranial hemorrhage (ICH) were included if they received either 4FPCC or andexanet alfa for reversal of apixaban or rivaroxaban. In addition to hemostatic efficacy per imaging, we assessed disposition location, cerebral performance score, blood product consumption, and the development of a new thrombus.ResultsA total of 46 patients were included in this study, 15 received 4FPCC (32%) and 31 received andexanet alfa (68%). There was no difference in the proportion of patients with excellent (4FPCC 9 [60%] vs. andexanet alfa 16 [51.6%], p = 0.61), good (4FPCC 2 [13.3%] vs. andexanet alfa 7 [22.6%]), or poor (4FPCC 1 [6.7%] vs. andexanet alfa 5 [16.1%]) hemostasis after administration of each agent. There were no significant differences in any secondary outcomes.Conclusion and relevanceOur study found no difference in hemostatic efficacy between andexanet alfa and 4FPCC. At this time, clinicians should choose an agent based on individual patient presentation and resource availability. Further research will help clarify the role of each agent in the management of DOAC-related intracranial hemorrhage.

Project description:BackgroundAndexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.MethodsWe evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).ResultsPatients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.ConclusionsIn patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).

Project description:BackgroundAndexanet alfa is approved (FDA "accelerated approval"; EMA "conditional approval") as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH).MethodsThis two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban < 24 h prior to the bleed were included. Patients with a Glasgow Coma Scale (GCS) score < 7, hematoma volume > 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression.ResultsThe study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16-6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13-0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC.ConclusionsIn this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Project description:BackgroundWell-designed studies with sufficient sample size comparing andexanet alfa vs 4-factor prothrombin complex concentrate (4F-PCC) in routine clinical practice to evaluate clinical outcomes are limited.ObjectivesTo compare in-hospital mortality in patients hospitalized with rivaroxaban- or apixaban-related major bleeding who were treated with andexanet alfa or 4F-PCC.MethodsAn observational cohort study (ClinicalTrials.gov identifier: NCT05548777) was conducted using electronic health records between May 2018 and September 2022 from 354 U.S. hospitals. Inclusion criteria were age ≥18 years, inpatient admission with diagnosis code D68.32 (bleeding due to extrinsic anticoagulation), a record of use of the factor Xa inhibitors rivaroxaban or apixaban, andexanet alfa or 4F-PCC treatment during index hospitalization, and a documented discharge disposition. Multivariable logistic regression on in-hospital mortality with andexanet alfa vs 4F-PCC was performed. The robustness of the results was assessed via a supportive propensity score-weighted logistic regression.ResultsThe analysis included 4395 patients (andexanet alfa, n = 2122; 4F-PCC, n = 2273). There were 1328 patients with intracranial hemorrhage (ICH), 2567 with gastrointestinal (GI) bleeds, and 500 with critical compartment or other bleed types. In the multivariable analysis, odds of in-hospital mortality were 50% lower for andexanet alfa vs 4F-PCC (odds ratio [OR], 0.50; 95% CI, 0.39-0.65; P < .01) and were consistent for both ICH (OR, 0.55; [0.39-0.76]; P < .01) and GI bleeds (OR, 0.49 [0.29-0.81]; P = .01). Similar results were obtained from the supporting propensity score-weighted logistic regression analyses.ConclusionIn this large observational study, treatment with andexanet alfa in patients hospitalized with rivaroxaban- or apixaban-related major bleeds was associated with 50% lower odds of in-hospital mortality than 4F-PCC. The magnitude of the risk reduction was similar in ICH and GI bleeds.

Dataset Information

Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study.

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Andexanet Alfa for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage: Observational Cohort Study.

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