Factor Xa Inhibitors In Patients Research Articles

Perioperative Management in Patients with Atrial Fibrillation Treated with Non-Vitamin K Antagonist Oral Anticoagulants Undergoing Minor Bleeding Risk Procedure: Rationale and Protocol for the PERIXa Study.

While treatment interruption of non-vitamin K antagonist oral anticoagulants (NOACs) for elective surgery or procedures among patients with atrial fibrillation (AF) is becoming more prevalent, there remains insufficient evidence regarding the optimal perioperative management of NOACs, particularly procedures with minor bleeding risks. This study aims to evaluate the safety and effectiveness of a simplified, standardized protocol for perioperative management of direct factor Xa inhibitors in patients, with AF undergoing procedures associated with minor bleeding risk. This multicenter, prospective single-arm registry study plans to enroll patients undergoing procedures with minor bleeding risk who were prescribed direct factor Xa inhibitors for AF. The procedures with minor bleeding risk will include gastrointestinal endoscopy for diagnostic purposes, selected dental procedures, and ocular surgery for cataracts or glaucoma. For apixaban, patients will withhold the last evening dose and resume either from the evening dose of the procedure day or the following morning, depending on the bleeding risk of the patient. For edoxaban or rivaroxaban, patients will withhold only a single dose on the procedure day. The primary outcome is the occurrence of major bleeding events within 30 days. Secondary outcomes include systemic thromboembolism, all-cause mortality, and a composite of major and clinically relevant non-major bleeding events. This study has the potential to generate evidence regarding the safety of perioperative management for patients, with AF undergoing procedures associated with minor bleeding risk. Clinicaltrials.gov: NCT05801068.

Factor Xa inhibitors vs. warfarin in patients with Hughes syndrome: a systematic review and meta-analysis of randomized controlled trials.

The optimal treatment regimen for patients with Hughes syndrome remains unclear. Therefore, the authors sought to compare the outcomes of warfarin vs. factor Xa inhibitors in patients with Hughes syndrome. MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) comparing 8 efficacy and safety of warfarin and factor Xa inhibitors in patients with Hughes syndrome. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among 10 outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate 11 relative risks (RRs) with 95% CIs. The analysis included 625 patients from four RCTs and one post-hoc analysis. Meta-analysis showed a statistically non-significant difference between factor Xa inhibitors and warfarin in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P=0.11, I2=50%]. Consistent results were revealed among patients with a previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P=0.75, I2=0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P=0.31, I2=15%] and patients who were triple antiphospholipid antibodies (aPL) positive [RR 4.12 (95% CI 0.46, 37.10); 21 P=0.21, I2=58%]. Factor Xa inhibitors were significantly associated with an increased risk of stroke [RR 8.51 (95% CI 2.35, 13.82); P=0.47, I2=0%]. Factor Xa inhibitors exhibited an increased risk of stroke among patients with Hughes syndrome. In addition, although not significant, the higher RRs among patients on factor Xa inhibitors may indicate a higher risk of thrombotic events associated with factor Xa inhibitors.

Reversal of pre-injury factor-Xa inhibitors with prothrombin complex concentrates in patients following traumatic brain injury

IntroductionThere is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC). Material and methodsConsecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed. ResultsThere were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 – 40.9)]. ConclusionPCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.

Low-molecular-weight heparin is associated with lower venous thromboembolism events than factor Xa inhibitors in patients with severe blunt trauma: a cohort study from the Trauma Quality Improvement Program.

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common complication of major trauma. Pharmacological VTE prophylactics are widely used, and low-molecular-weight heparin (LMWH) is recommended. Factor Xa inhibitors are increasingly being used for VTE prophylaxis in both medical and surgical patients. Evidence comparing LMWH and factor Xa inhibitors as VTE prophylactics for severe blunt trauma is lacking. This study aims to compare the efficacy and safety of factor Xa inhibitors and LMHW in VTE prophylaxis. Patients with severe blunt trauma who received LMWH or a factor Xa inhibitor for VTE prophylaxis in the Trauma Quality Improvement Program between 2017 and 2019 were included. The comparison was performed after using propensity score matching. The outcomes included mortality and incidence of DVT, PE, post-prophylactics haemorrhage control procedures and length of stay. After 2:1 propensity score matching, 1128 patients ( n =752, LMHW group; n =376, factor Xa inhibitor group) were included in the analysis. Patients in the LMWH group had fewer VTE events than those in the factor Xa inhibitor group (DVT, 3.7% vs. 7.2%, P =0.013; PE, 0.4% vs. 3.2%, P <0.001). VTE risk was higher in the factor Xa group (DVT: odds ratio, 1.97; 95% CI, 1.12-3.44; P =0.018 and PE: odds ratio, 9.65; 95% CI, 2.91-44.12; P =0.001). The mortality rate was higher in the LMWH group; however, there was no significant difference (4.0% vs. 1.9%; P =0.075). The difference in the risk of undergoing haemorrhage control surgery after VTE prophylaxis between both groups was insignificant (0.3% vs. 0.0%; P =0.333). LMWH was associated with a lower risk of VTE than factor Xa inhibitors in patients with severe blunt trauma. The mortality rate was higher in the LMWH group; however, there was no statistically significant difference observed.

Are Factor Xa Inhibitors Efficacious for Ischemic Stroke Prevention in Patients Without Atrial Fibrillation? Evidence From Randomized Clinical Trials.

Clinical trials provide conflicting evidence regarding oral factor Xa inhibitors for prevention of ischemic stroke in patients without a history of atrial fibrillation (AF). We performed a critical appraisal of randomized clinical trials that tested oral factor Xa inhibitors in patients without AF that reported ischemic stroke. Considering the 11 trials that reported > 10 ischemic strokes during follow-up (97,578 participants, 1195 ischemic strokes), 1 tested apixaban (57 strokes), 1 betrixaban (52 strokes), and 9 rivaroxaban (1086 strokes). In 7 trials with placebo comparisons, numerically fewer ischemic strokes occurred among those assigned factor Xa inhibitors in 7 of 8 randomized comparisons (range of hazard ratios [HRs], 0.89-0.51), including statistically significant reductions in 2 trials that compared rivaroxaban 2.5 mg twice daily vs placebo on a background of aspirin in patients with cardiovascular disease, COMPASS (HR, 0.51; 95% confidence interval [CI], 0.38-0.68) and COMMANDER-HF (HR, 0.64; 95% CI, 0.43-0.95). Compared with aspirin in 4 trials, oral factor Xa inhibitors were associated with fewer ischemic strokes in 2, with statistically significant reduction in 1 (rivaroxaban 5 mg twice daily in COMPASS; HR, 0.69; 95% CI, 0.53-0.90). Major bleeding was increased by oral factor Xa inhibitors in all 7 placebo-controlled trials (HR range, 1.42-4.08), with statistically significant increases reported in 5 trials, and in all 4 aspirin-controlled trials (all statistically significant increases; HR range, 1.52-2.72). Aggregate evidence on the basis of placebo comparisons from randomized trials supports the potential for oral factor Xa inhibitors to reduce ischemic stroke in patients without AF, but major bleeding is increased.

779: FACTOR XA INHIBITORS IN PATIENTS WITH ACUTE KIDNEY INJURY

Introduction: Data is lacking regarding the safety and efficacy of factor Xa inhibitors in patients with acute kidney injury (AKI). The goal of this study is to compare bleeding and thromboembolic events in patients receiving therapeutic doses of apixaban or rivaroxaban versus unfractionated heparin (UFH) in patients with AKI. Methods: This retrospective, observational study evaluated hospitalized adult patients who received therapeutic doses of either apixaban, rivaroxaban, or UFH for at least 24 hours in the setting of AKI as defined by AKIN criteria. Patients were excluded if they met any of the following criteria: non-FDA approved factor-Xa inhibitor indication; COVID admission; major bleeding or clinically relevant non-major bleeding (CRNMB) on admission, embolic event within 30 days of admission; coagulopathy; receipt of a contraindicated medication, or ESRD. Bleeding events were evaluated in accordance with International Society on Thrombosis and Hemostasis criteria. The primary outcome was defined as composite major and clinically relevant non-major bleeding events. Secondary outcomes included comparison of the individual components of the composite bleeding endpoint and thromboembolic events. Results: A total of 500 patients met inclusion criteria, with 250 patients included in the UFH group and factor Xa inhibitor group. AKIN Stage I was most prevalent in the overall study population; patients with AKIN stage III were more likely to be transitioned to UFH (p< 0.01). Surgical patients were more likely to be transitioned to UFH (p< 0.01). Patients transitioned to IV heparin were more likely to undergo a procedure (p< 0.01). After adjusting for confounding factors, patients who received a factor Xa inhibitor experienced a lower risk of composite major bleeding and CRNMB events as compared to UFH (OR: 0.57, 95% CI: 0.34-0.94; p = 0.03). This was driven by a decreased risk of CRNMB in the factor Xa inhibitor group (OR: 0.55, 95% CI: 0.33-0.91, p = 0.02). No significant differences in major bleeding or VTE were noted. Conclusions: Continuation of factor Xa inhibitor therapy in the setting of AKI was associated with a reduced incidence of bleeding events compared to patients transitioned to UFH in accordance with package insert recommendations.

Reversal of apixaban and rivaroxaban with andexanet alfa prior to invasive or surgical procedures.

Outcomes following andexanet alfa reversal of factor Xa inhibitors in patients requiring urgent or emergent invasive procedures are lacking. This study aimed to describe efficacy and safety outcomes following andexanet alfa administration within 24h of an invasive procedure. This single-center, observational, retrospective study included patients who received andexanet alfa within 24h of an invasive or surgical procedure. The primary outcome was hemostatic efficacy graded as excellent, good, or poor using similar definitions to the ANNEXA-4 criteria. Secondary outcomes included hospital discharge disposition, intensive care unit (ICU) and hospital length of stay, 30-day mortality, 30-day thromboischemic event rates, and serum coagulation assay changes pre- and postreversal. Forty-four patients met inclusion criteria; of these, 27 (62.8%) received apixaban and 16 (37.2%) were treated with rivaroxaban prior to admission. The indications for reversal were categorized as intracranial (n=20 [45.5%]) or extracranial (n=24 [54.5%]) sites. Majority of patients required emergent operative procedures (18 [40.9%]), followed by invasive device placement (10 [22.7%]) or arterial embolization (9 [20.5%]). Thirty-eight (86.4%) patients were able to be adequately graded for hemostatic efficacy. Overall, 30 (78.9%) patients achieved excellent or good hemostasis within 24h after periprocedural administration of andexanet alfa (19 [82.6%] apixaban vs. 11 [78.6%] rivaroxaban; 12 [80.0%] intracranial events vs. 18 [78.3%] extracranial events). Discharge disposition was most often to a short- or long-term care facilities (27 [61.4%]). Thirty-day mortality and thromboischemic complications occurred in 15 (34.1%) and 12 (27.3%) patients, respectively. Prothrombin time and antifactor Xa assay results were significantly decreased after andexanet alfa administration (p < 0.05) while thromboelastogram assay values (reaction time, kinetic time, and activated clotting time) showed nonsignificant changes pre- versus postreversal. Andexanet alfa may be used for urgent or emergent reversal of apixaban and rivaroxaban peri-procedurally with promising hemostatic outcomes. Further prospective, comparative clinical research is warranted.

Pharmacological Difference Between Platelet Aggregations in Cardioembolic Stroke Patients with Direct Oral Anticoagulants: A Pilot Study

Background Selecting the appropriate direct oral anticoagulants (DOACs) for embolic ischemic stroke patients, especially on concurrent antiplatelet therapy, is important. However, a limited number of studies have reported on the pharmacological differences in platelet aggregation of each DOAC. We aimed to evaluate the antiplatelet effects of selected DOACs, by comparing dabigatran (a direct oral thrombin inhibitor) and factor Xa (FXa) inhibitors (apixaban and rivaroxaban) in patients who had suffered a cardioembolic stroke.Methods We retrospectively evaluated 12 patients diagnosed with a cardioembolic stroke who took any DOAC without an antiplatelet drug and underwent platelet aggregation tests within 60 days from the onset of symptoms. The platelet aggregation tests were analyzed by both light transmission aggregometry and VerifyNow®.Results Six patients (50%) took dabigatran, while the other six (50%) took an FXa inhibitor (n = 4 for apixaban and n = 2 for rivaroxaban). From the light transmission aggregometry analysis, it was found that the maximal extent of aggregation for adenosine diphosphate (ADP) was significantly higher with dabigatran than with FXa inhibitors, and the ED50 value of ADP on platelet aggregation was significantly lower with dabigatran than with FXa inhibitors. Moreover, the VerifyNow® analyses revealed that P2Y12 reaction units were significantly higher with dabigatran than with FXa inhibitors.Conclusions Dabigatran had little impact on platelet aggregation compared to FXa inhibitors in patients who had suffered a cardioembolic stroke with atrial fibrillation, and who took DOACs for secondary prevention within 60 days from the onset.

Comparative hemostatic efficacy of 4F-PCC in patients with intracranial hemorrhage on factor Xa inhibitors versus warfarin

ObjectivePatients experiencing an intracranial hemorrhage (ICH) on oral anticoagulants often require rapid reversal. This study evaluated patients taking factor Xa inhibitors or warfarin that received reversal with 4-factor prothrombin complex concentrate (4F-PCC) for an ICH. The objective of the study was to determine if the efficacy of 4F-PCC for the reversal of factor Xa inhibitors is noninferior to its use in warfarin reversal in patients with ICH. MethodsThis was a retrospective, single center, noninferiority trial. Patients presenting to the emergency department with ICH were divided into two cohorts: those taking factor Xa inhibitors versus those taking warfarin. In each cohort, patients received anticoagulation reversal with weight-based 4F-PCC. The primary endpoint was hemostatic efficacy defined as ≤20% expansion in hematoma volume on repeat computed tomography imaging. A pre-specified noninferiority margin of −10% was selected to evaluate the difference between groups for the primary endpoint. ResultsA total of 221 patients were included in the study (factor Xa inhibitors, n = 87; warfarin, n = 134). Effective hemostasis was achieved in 70 patients (81%) on factor Xa inhibitors compared to 111 patients (83%) on warfarin, (−2.4% difference, [95% confidence interval, −12.87 to 8.12]; p = 0.654). There was no statistically significant difference between groups with regards to the primary outcome; however, the use of 4F-PCC in factor Xa inhibitor reversal was not noninferior when compared to 4F-PCC use for warfarin reversal. Hospital length of stay and discharge disposition were similar between cohorts. ConclusionsThe efficacy of 4F-PCC in reversing factor Xa inhibitor-related ICH compared to warfarin-related ICH was not significantly different between groups; however, these results did not prove noninferiority. Further study is warranted to delineate 4F-PCC's role in reversing factor Xa inhibitors in patients with ICH.

Abstract WP203: Effects Of Oral Factor Xa Inhibitors On Ischemic Stroke In Patients Without Atrial Fibrillation: Systematic Review Of Randomized Clinical Trials

Background and Purpose: To assess the effects of oral factor Xa inhibitors for prevention of ischemic stroke in patients without a history of atrial fibrillation. Methods: Systematic review of randomized clinical trials (RCTs) testing oral factor Xa inhibitors in patients without a history of atrial fibrillation that reported ischemic stroke. Results: Twenty-two RCTs reported 1194 ischemic strokes: five RCTs testing apixaban (75 ischemic strokes), one RCT each testing betrixaban (52 ischemic strokes) and edoxaban (1 ischemic stroke), and 15 RCTs testing rivaroxaban (1066 ischemic strokes). Three double-blinded RCTs reported statistically significant reductions in ischemic stroke: Two comparing rivaroxaban 2.5mg twice daily versus placebo in patients with cardiovascular disease (COMPASS, hazard ratio (HR) 0.51, 95%CI 0.38-0.68 and COMMANDER-HF, HR 0.64, 95%CI 0.43-0.95), and a third trial compared betrixaban 80mg daily with enoxaparin followed by placebo in patients hospitalized for acute medical illness (APEX, relative risk 0.53, 95%CI 0.30-0.94). Compared with aspirin, rivaroxaban 5mg twice daily significantly reduced ischemic stroke in patients with chronic atherosclerosis in COMPASS (HR 0.69, 95%CI 0.53-0.90), but in contrast rivaroxaban 15mg daily vs. aspirin showed no reduction in ischemic stroke in patients with recent embolic stroke in the large NAVIGATE ESUS trial (HR 1.01, 95%CI 0.81-1.26). Comparisons from 18 other RCTs were inconclusive, although trends consistently showed numerically fewer ischemic strokes among those assigned oral fXa inhibitors compared with placebo. Conclusions: There is convincing evidence that oral factor Xa inhibitors reduce ischemic stroke in patients without a history of atrial fibrillation. The strongest evidence was for rivaroxaban 2.5mg twice daily when given with aspirin in patients with cardiovascular disease. Reduction in ischemic stroke by other dosages, by other factor Xa inhibitors, and when given without antiplatelet agents is less certain. The contribution of atrial fibrillation-related stroke unlikely accounts for the observed reductions.

Effect on Plasma Protein S Activity in Patients Receiving the Factor Xa Inhibitors.

Aims: Measurement of protein S (PS) activity in patients taking direct oral anticoagulants (DOACs) using reagents based on a clotting assay results in falsely high PS activity, thus masking inherited PS deficiency, which is most frequently seen in the Japanese population. In this study, we investigated the effect of factor Xa (FXa) inhibitors on PS activity using the reagent on the basis of the chromogenic assay, which was recently developed in Japan. Methods: The study enrolled 152 patients (82 males and 70 females; the average age: 68.5±14.0 years) receiving three FXa inhibitors (rivaroxaban, edoxaban, and apixaban). PS activity was measured using the reagents on the basis of the clotting and chromogenic assays. Results: PS activity measured by the clotting assay reagents exhibited falsely high values depending on the plasma concentrations of FXa inhibitors in patients taking either rivaroxaban or edoxaban. However, none of the three FXa inhibitors affected PS activity when measured using the chromogenic assay. Conclusion: In patients taking rivaroxaban or edoxaban, inherited PS deficiency is likely missed because the levels of PS activity measured using the reagents based on the clotting assay are falsely high. However, we report that three FXa inhibitors do not affect PS activity measured by the chromogenic assay. When measuring the levels of PS activity in patients undergoing DOACs, the principles of each reagent should be understood. Furthermore, plasma samples must be collected at the time when plasma concentrations of DOACs are lowest or the DOAC-Stop reagent should be used.

Oral Factor Xa (FXa) Inhibitors for Treatment of Heparin-induced Thrombocytopenia (HIT)

Background:: Heparin is the most commonly used injectable anticoagulant for many indications, ranging from the treatment of atrial fibrillation to the prevention of clotting in patients undergoing surgery. Currently, only argatroban and bivalirudin are FDA approved for the management of heparin induced thrombocytopenia (HIT) in the United States, both of which are direct thrombin inhibitors. The agents being reviewed, apixaban and rivaroxaban, are oral direct factor Xa (FXa) inhibitors. Currently, neither has FDA approval for use in HIT. The objective of this review is to summarize the current evidence available regarding the use of oral factor Xa inhibitors for the treatment of HIT. Methods:: A literature search was conducted using Medline and Ovid Embase. Search terms included heparin-induced thrombocytopenia, HIT, apixaban, rivaroxaban, Xa Inhibitor, direct thrombin inhibitor, NOAC, and DOAC. Studies and case reports were included if they evaluated the efficacy and safety of oral FXa inhibitors for the treatment of HIT. Additional literature and case reports were found through bibliographic review. Results and Discussion: Currently, available literature includes an in vitro study with apixaban, case reports, and retrospective and prospective cohort studies. The in vitro study evaluated the interaction between apixaban and platelets in the presence of HIT antibodies, which assessed its potential for use in HIT management. Fourteen case reports and one case series were also identified, of which six described treatment with apixaban and eight with rivaroxaban. Lastly, four cohort studies were published evaluating the use of direct acting oral anticoagulants (DOACs), including oral factor Xa inhibitors in patients with HIT. Although there are no published randomized control trials evaluating the use of FXa inhibitors in the management of HIT, there are several findings that may guide clinicians on the use of these agents in practice. Conclusion:: As indicated by the case reports, case series and cohort studies detailing clinical use and described in this manuscript, there are data and positive patient outcomes that support the potential use of these agents for HIT, and are an impetus for future studies.

An 18-month single-center observational study of real-world use of andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage

ObjectiveIntracranial hemorrhage is a life threatening complication of factor Xa inhibitors. Except for results of the open-label, single-arm ANNEXA-4 study, published real-world utilization of andexanet alfa is limited. We present our experience with andexanet alfa use in factor Xa inhibitor associated intracranial hemorrhage. The objective of this study was to assess the hemostatic efficacy and safety following early implementation of andexanet alfa use in factor Xa inhibitor associated intracranial hemorrhage. MethodsSingle center, retrospective, observational study at a large community teaching hospital and Comprehensive Stroke Center. Consecutive patients with factor Xa inhibitor associated intracranial hemorrhage, spontaneous or traumatic, treated with andexanet alfa. Primary outcome was hemostatic efficacy established by categories of hematoma growth between baseline and follow-up head computerized tomography after andexanet alfa treatment. Safety outcomes included inpatient mortality and 30-day readmission due to a thromboembolic event. Consecutive factor Xa inhibitor associated intracranial hemorrhage treated with andexanet alfa presenting between June 2018 and December 2019 were included. ResultsThirty-nine patients with mean age of 81.9 years and median baseline Glasgow Coma Score of 14 were evaluated. Median (IQR) baseline intracerebral hematoma volume was 7.1 mL (2.3-28.5), while baseline thickness for subdural hemorrhage was 12.5 mm (8.0-19.3). In 35 of 39 patients with repeat computerized tomography prior to surgical intervention, excellent/good hemostatic efficacy was seen in 29 (82.9%). Excluded from the hemostatic efficacy estimate were four trauma patients who underwent hematoma evacuation prior to repeat head computerized tomography, nevertheless they had excellent hemostatic effectiveness without perioperative complications or rebleeding. Four (10.3%) patients died during hospitalization and two (5.1%) thrombotic events were observed. ConclusionsIn this cohort of a real-world utilization of andexanet alfa for reversal of factor Xa inhibitors in patients presenting with intracranial hemorrhage, we observed a high excellent/good hemostatic efficacy rate and lower than reported inpatient mortality and 30-day readmission due to thromboembolism consistent with the findings reported in ANNEXA-4 study. Despite the lack of comparative group, our outcomes, most noticeably hemostatic efficacy and inpatient mortality are consistent with those reported in the literature.

Factor Xa inhibitors in patients with continuous-flow left ventricular assist devices.

Warfarin is standard anticoagulation therapy for patients with a continuous-flow left ventricular assist device (CF-LVAD). However, warfarin requires regular monitoring and dosage adjustments and fails for many patients, causing thromboembolic and bleeding events. Factor Xa inhibitors have been shown to be noninferior to warfarin in preventing strokes and are associated with less intracranial hemorrhage in patients with atrial fibrillation. We evaluated treatment safety and effectiveness in CF-LVAD patients who switched from warfarin to a factor Xa inhibitor (apixaban or rivaroxaban) after warfarin failure. This was a retrospective, single-center study of patients treated between 2008 and 2018. We assessed the occurrence of stroke, non-central nervous system (CNS) embolism, pump thrombosis, and major gastrointestinal bleeding and intracranial hemorrhage during therapy. We identified seven patients: five were male, the average body mass index was 30kg/m2, and average age was 56years. Preimplantation comorbidities included hypertension (all patients) and diabetes mellitus, ischemic cardiomyopathy, atrial fibrillation, and previous myocardial infarction (fourpatients each). Overall, patients received warfarin for 3968days and apixaban/rivaroxaban for 1459days. The warfarin group was within the therapeutic INR range (2.0-3.0) 30% of the time. Complication rates did not differ between warfarin and apixaban/rivaroxaban: strokes, 0.20 vs none, non-CNS embolism, 0.54 vs none; pump thrombosis, 0.27 vs none; major gastrointestinal bleeding, 0.20 vs 0.50; intracranial hemorrhage, 0.13 vs none. Factor Xa inhibitors may be viable treatment options for CF-LVAD patients for whom warfarin therapy has failed. Large prospective studies are necessary to confirm these results.

Comparison of Anti-factor Xa Activity Among Three Different Factor Xa Inhibitors in Non-valvular Atrial Fibrillation Patients with Renal Impairment.

Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated. Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30-49mL/min] and 17 patients with severe RI (CrCl 15-29mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed. In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban. Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.

Ischemic stroke and dose adjustment of oral Factor Xa inhibitors in patients with atrial fibrillation

BackgroundOral Factor Xa inhibitors for the prevention of stroke in atrial fibrillation require dose adjustment based on certain clinical criteria, but the off-label use of the reduced doses is common.MethodsData from an observational registry including patients admitted with acute cerebral ischemia while taking oral Factor Xa inhibitors for atrial fibrillation between April 2016 and December 2018 were investigated. The dose regimen of the Xa inhibitor was classified as “appropriate”, “underdosed” and “overdosed” in conformity with the European Medicines Agency labelling. The effect of underdosing on the functional factor Xa plasma level on admission, the clinical stroke severity and the functional outcome after 3 months were investigated.Results254 patients with cerebral ischemia while on Factor Xa inhibitors were included. The dose regimen of the Factor Xa inhibitor was appropriate in 166 patients (65%), underdosed in 67 patients (26%) and overdosed in 21 patients (8%). Underdosing was associated with female sex, diabetes mellitus and higher CHA2DS2–Vasc scores. Underdosing independently predicted lower anti-Xa plasma levels on admission [median 69.4 ng/ml (IQR 0.0–121.6) vs. 129.2 ng/ml (65.5–207.2); p < 0.001], was associated with higher NIHSS scores on admission [median 5 (IQR 1–10) vs. 3 (1–7); p = 0.041] and worse functional outcome after 3 months (favorable outcome 26.9% vs. 46.9%; p = 0.025).ConclusionOne in three patients with ischemic stroke during treatment with oral Xa inhibitors used inappropriate dose regimens. Underdosing was associated with lower functional plasma levels, higher clinical stroke severity and worse functional outcome.

Abstract WP113: Impact of Apixaban on Clinical Outcome of the Patients With Large Vessel Occlusion or Stenosis (alvo) Study

Background: Efficacy and safety of direct oral factor Xa inhibitor in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) were questionable because recombinant tissue plasminogen activator (rt-PA) and endovascular therapy (EVT) became the standard therapy. Methods: We conducted historical and prospective multicenter registry from July 2016 to Feb 2018 at 38 centers in Japan. The eligible criteria were 20-year old or elder and patients with NVAF and acute LVO who received apixaban within 14 days from the onset. The primary endpoint was a composite of all-cause death, International Society of Thrombosis and Hemostasismajor bleedings, and ischemic events. Ischemic events included ischemic stroke, acute coronary syndrome, acute myocardial infarction and systemic embolism. The secondary endpoints were each component of primary composite endpoint. Results: We registered 713 patients but 27 patients were excluded due to logical error or ineligibility. The mean age was 78 (SD 10) years and 52% were male among 686 enrolled patients. The median NIHSS and ASPECTS on admission were 14 (range 0-38) and 8 (range 0-10), respectively. The use of rt-PA and EVT were 39.1% and 52.3% of patients, respectively. The median time from onset to the start of apixaban was 2.5 days (range 0-14). The cumulative incidence of primary composite endpoint at 90 days and 365 days were 9.6% (95%CI 7.4-11.9) and 17.5% (95%CI 14.4-20.5), respectively. The cumulative incidence of primary composite endpoint were 15.6% and 12.2% in those with and without EVT at 365 days (p=0.20) The cumulative incidences of ISTH major bleedings and ischemic events at 365 days were 9.0% (95%CI 6.7-11.2) and 4.4% (95%CI 2.8-6.0), respectively. Conclusions: We estimated the cumulative incidences of bleeding and ischemic events as well as all-cause mortality in patients on apixaban for NVAF and acute LVO. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02818868.)

Efficacy and Safety of Direct Oral Factor Xa Inhibitors in Patients after Bariatric Surgery

Background: Over 200,000 people underwent weight loss surgery in the United States in 2017. The absorption of numerous drugs has been shown to be altered in patients after bariatric procedures, as gastrointestinal absorptive surface, food volume, and gastric pH all affect bioavailability. Dosing of warfarin, which is commonly used for the treatment of venous thromboembolism (VTE), often needs to be adjusted, based on INR, after bariatric surgery. Since direct oral anticoagulants (DOACs), which are rapidly replacing warfarin as standard anticoagulant therapy, are not monitored, there is concern regarding their efficacy and safety in patients who have had bariatric surgery, particularly rivaroxaban, which is absorbed primarily in the stomach and must be taken with food at therapeutic doses. One study found that 9 out of 9 apixaban patients (but only 2 of 7 rivaroxaban patients) had levels that fell within the expected range after bariatric surgery. Effects of bariatric surgery on DOACs may be further complicated by baseline obesity and subsequent weight loss of the patients. The goal of our current study is to determine whether DOACs are safe and effective in preventing recurrent VTE in patients who have undergone bariatric surgery. Methods: Using our institutional database, we identified all adult patients (age ≥18 years) with a history of bariatric surgery (gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass) who were started on anticoagulation with apixaban or rivaroxaban for VTE, between July 1, 2013 and June 30, 2018. We performed retrospective chart review to obtain information on patient demographics, BMI and type of bariatric surgery. We documented clinical outcomes of recurrent VTE and bleeding from the first prescription date to the earliest of a thrombotic event, discontinuation of medication, death, or the end of study period, June 30, 2018. VTE events were confirmed by a review of imaging studies (compression ultrasonography, ventilation/perfusions scans, and CT scans). Bleeding events were included if they met criteria for clinically relevant non-major bleeding and/or major bleeding according to the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Safety outcomes included major bleeding (MB) and clinically relevant non-major bleeding (CRNMB). We also compared VTE recurrence and bleeding rates between the post-bariatric surgery patients and patients with BMI &gt;40 from our prior study. Chi- squared tests were used to assess statistical significance of the differences in recurrent VTE and bleeding rates between anticoagulant cohorts. Results: Data on 102 patients were collected: 42 patients on apixaban and 60 patients on rivaroxaban. Our population was predominantly female (82.4%) with a mean age of 48.5 years and a median BMI of 35.7 at initiation of anticoagulation. Gastric bypass was the most common bariatric procedure (51%), followed by sleeve gastrectomy (37.3%), and gastric banding (11.8%). There were no recurrent VTE events in the apixaban cohort with a median follow-up duration of 137 days. Among patients on rivaroxaban, with a median follow-up of 232 days, there was one recurrent VTE (1.7%) in a patient with a BMI of 54 at the time of event. When we compared VTE recurrence rates of our combined DOAC cohort (apixaban + rivaroxaban) between our general morbidly obese population, from a prior study at our institution, and post-bariatric surgery patients, there was no statistically significant difference (2.0% vs. 1.0%, respectively, p=0.5). In bariatric surgery patients, one CRNMB event was recorded in apixaban group (2.4%) while 4 major bleeding events occurred on rivaroxaban (6.7%), p=0.3. There was no significant difference in the rate of composite MB and CRNMB between the general obesity and bariatric surgery patients (8.0% vs. 4.9%, respectively, p=0.3). Conclusions: In a review of post-bariatric surgery patients on anticoagulation for VTE, we found low rates of recurrent VTE for patients on DOACs. Although we had a relatively small sample size, the incidence of VTE recurrence was not higher in this cohort than was found in our previously published study of general obesity population. Prospective studies are needed to further investigate the efficacy and safety of direct oral anticoagulants in patients after bariatric surgery. Table. Disclosures Kushnir: Janssen Pharmaceuticals: Research Funding. Billett:Janssen: Research Funding.

Andexanet alfa is an effective reversal agent for factor Xa inhibitors in patients that develop intracranial hemorrhage

&lt;p&gt;A critical appraisal and clinical application of Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. &lt;em&gt;N Engl J Med&lt;/em&gt;. 2016;375(12):1131-1141. doi: &lt;a href="https://doi.org/10.1056/NEJMoa1607887"&gt;10.1056/NEJMoa1607887&lt;/a&gt;.&lt;/p&gt;

Effectiveness and safety of selective and non - selective factor Xa inhibitors in antiphospholipid syndrome and systemic lupus erythematosus: anti - Xa - activity range

Clinical and laboratory data were analyzed retrospectively in SLE and APS patients who protractedly received low weight molecular heparins (LWMH) and selective factor Xa inhibitors fondaparinux and rivaroxaban. The study included 70 patients in the middle age 39 [31; 43] years: 15/70 (21%) - with SLE, 10/70 (14%) - with APS and 45/70 (65%) - with SLE and APS (SLE+APS). All the patients received anticoagulants: 29 patients - nadroparin (98.3 [67.8; 129.5] IU/kg/day), 29 patients - fondaparinux (5 [5; 7.5] mg/day), 3 patients - enoxaparin (1.2 [0.8; 1.5] mg/day) and 9 patients - rivaroxaban (20 mg/day). All the patients signed informed consents. aXa therapeutic range of 0.1-1.5 IU/ml was found in 43/70 (61%) patients, low aXa - in 14/70 (20%) and high aXa - in 13/70 (19%) patients. Patients with low aXa underwent anticoagulant dose correction. There were not any major bleedings and thrombosis relapses in the study. Increased aXa was more common in patients, who took fondaparinux (31%), than in those, who took nadroparin (7%) and rivaroxaban (23%), p=0.02. Patients with enoxaparin had normal aXa range. In the absence of bleeding in SLE and APS patients, received anticoagulants in standardized therapeutic dose, the next factors influenced the aXa range excess: valvular heart disease (VHD) with the 3rd stage of mitral valve insufficiency as a result of aseptic Libman-Sacks endocarditis (odds ratio - OR 9.02, 95% confidential interval - CI [1.53; 53.12], p=0.015), peripheral artery disease in analogy with arteritis obliterans (AO) (OR 6.86, 95% CI [1.25; 37.71], p=0.027), and also triple - positivity of all types of antiphospholipid antibodies (OR 4.93, 95% CI [1.11; 21.99], p=0.036). According to found logistic regression model, aXa range excess risk can be prognosticated by the next formula: Z = -3.98 + 2.2 × VHD (yes-1/no-0) + 1.9 × AO (yes-1/no-0) + 1.6 × Triple - positivity (yes-1/no-0). Classified function value Z=0.39 defines the patients group with aXa range excess. Thus the value Z>0.39 indicates aXa range excess in the absence of bleeding, herewith sensibility is of 77% and specificity is 86%, positive prognostic value is 84.3%. In SLE and APS patients the next clinical and immunologic manifestations influenced the aXa therapeutic range excess: peripheral artery disease in analogy with AO, earlier aseptic Libman-Sacks endocarditis with the 3rd stage of mitral valve insufficiency and triple - positivity of all types of antiphospholipid antibodies, that does not need LWMH and fondaparinux dose correction. In contrast, anticoagulant dose reduction can cause clinical symptoms progression. Therapeutic aXa range in such patients should be extended.