Oral Factor Xa Research Articles

When and How to Use Reversal Agents for Direct Oral Anticoagulants?

Our objective is to describe currently available reversal agents for direct oral anticoagulants (DOACs), their target population, the available clinical practice recommendations and future directions. Specific (idarucizumab for dabigatran and andexanet alfa for direct factor Xa inhibitors) and non-specific (prothrombin complex concentrates) reversal agents are effective in neutralizing the anticoagulant effect of DOACs. New investigational antidotes such as ciraparantag and VMX-C001 offer an alternative to andexanet alfa in reversing the anticoagulant activity of direct oral factor Xa inhibitors, but more clinical data are needed before they could be licensed for use. Specific reversal agents are recommended for use in clinical situations within their licensed indications (i.e.: reversal of DOACs in patients with severe uncontrolled or life-threatening bleeding or in need of emergency surgery or other invasive procedures), while non-specific reversal agents may be used when specific antidotes are not available or indicated.

Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach

PurposeWe assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose.MethodsIn an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods.ResultsTherapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001).ConclusionClarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature.Trial RegistrationEudraCT Number: 2018-002490-22

Four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-associated bleeding: a meta-analysis of fixed versus variable dosing

BackgroundThe optimal dosing strategy of four-factor prothrombin complex concentrate (4F-PCC) to treat oral factor Xa (FXa) inhibitor-associated bleeding has not been established. ObjectivesTo evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of FXa inhibitor-associated bleeding. MethodsA systematic literature search and meta-analysis of clinical studies was performed using PubMed, Embase, and Cochrane databases from inception to January 2022. The primary outcomes included hemostatic effectiveness, mortality, and thromboembolic events. Secondary outcomes included 4F-PCC usage, total length of stay in hospital and in intensive care units, and time to 4F-PCC administration. The pooled incidence or mean was calculated using a random-effects model and compared between the 2 dosing strategies. ResultsTwenty-five studies were included and data from 1,760 patients (fixed dosing, n = 228; variable dosing, n = 1,532) were analyzed. There were no significant differences in hemostatic effectiveness, thromboembolic events, or mortality rates between the dosing strategies. Hospital length of stay was significantly longer in the fixed-dosing group, with a mean stay of 7.4 days (95% CI: 3.6-11.1) compared to 5.9 days (95% CI: 5.5-6.3) in the variable-dosing group (P < 0.001). The mean initial 4F-PCC dose was significantly higher with variable dosing than fixed dosing (38 IU/kg; 95% CI: 32-44 vs. 27 IU/kg; 95% CI: 26-28, P < 0.001). ConclusionsA fixed-dosing strategy appears to be a safe and effective alternative to variable weight-based dosing and was associated with lower 4F-PCC usage. However, direct comparative studies are needed to confirm these results.

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.

Practical Nomogram Predicting Apixaban or Rivaroxaban Concentrations from Low-Molecular-Weight Heparin Anti-Xa Values: Special Interest in Acute Ischemic Stroke Patients

In patients with acute ischemic stroke (AIS) using a direct oral factor-Xa anticoagulant (DOAC) during the last 48 hours, a fixed plasma heparin-calibrated anti-Xa activity (0.5 IU/mL) was proposed as a threshold below which patients could be eligible for thrombolysis and/or thrombectomy. Besides, specific DOAC-calibrated anti-Xa thresholds up to 50 ng/mL have been proposed. However, specific DOAC assays are not widely available contrarily to low-molecularweight heparin (LMWH) anti-Xa activity. We developed and validated a nomogram for predicting apixaban and rivaroxaban concentrations based on LMWH anti-Xa assay. Our prospective study included apixaban (n=325) and rivaroxaban (n=276) patients. On the same sample, we systematically measured specific DOAC concentration and LMWH anti-Xa activity, using STA®-Liquid-Anti-Xa (Stago) and specific DOAC- or LMWH-calibrators, respectively. The nomogram was built using quantifiable values for both assays on the derivation cohorts with a log-linear regression model. Model performances including sensitivity, specificity, and true positive rate for different thresholds were checked on the validation cohorts. The models built from the derivation cohorts predicted that values <30 ng/mL and <50 ng/ mL DOAC thresholds corresponded to LMWH-anti-Xa values <0.10 IU/mL and <0.64 IU/mL for apixaban; <0.10 IU/mL and <0.71 IU/mL for rivaroxaban. The model accurately predicted apixaban/ rivaroxaban concentrations in the validation cohort. This easy-to-use nomogram, developed with our reagent, allowed accurately predicting DOAC concentrations based on LMWH-anti-Xa results in emergency situations such as AIS when drug-specific assessments are not rapidly available. Using DOAC <50 ng/mL equivalent threshold, instead of the fixed LMWH <0.5 IU/mL one, would allow proposing thrombolysis to more patients.

Clinical and Economic Outcomes in Low-risk Pulmonary Embolism Patients Treated with Rivaroxaban versus Standard of Care

BackgroundL Rivaroxaban, a fixed-dose oral direct factor Xa inhibitor, does not require continuous monitoring and thus reduces the hospital stay and economic burden in low-risk pulmonary embolism (LRPE) patients. Study Question: What is the effectiveness of rivaroxaban versus the standard of care (SOC; low-molecular-weight heparin, unfractionated heparin, warfarin) among LRPE patients in the Veterans Health Administration? Study Design: Adult patients with continuous health plan enrollment for ≥12 months pre- and 3 months post-inpatient PE diagnosis (index date=discharge date) between October 1, 2011- June 30, 2015 and an anticoagulant claim during the index hospitalization were included. Measures and Outcomes Patients scoring 0 points on the simplified Pulmonary Embolism Stratification Index were considered low-risk and were stratified into SOC and rivaroxaban cohorts. Propensity score matching (PSM) was used to compare hospital-acquired complications (HACs), PE-related outcomes (recurrent venous thromboembolism, major bleeding, and death), and healthcare utilization and costs between the rivaroxaban and SOC cohorts. Results: Among 6746 PE patients, 1918 were low-risk; of these, 73 were prescribed rivaroxaban, 1546 were prescribed SOC, and 299 were prescribed other anticoagulants during the index hospitalization. After 1:3 PSM, 64 rivaroxaban and 192 SOC patients were included. During the index hospitalization, rivaroxaban users (versus SOC) had similar inpatient length of stay (LOS; 7.0 vs 6.7 days, standardized difference [STD]=1.8) but fewer HACs (4.7% vs 10.4%; STD: 21.7). In the 90-day post-discharge period, PE-related outcome rates were similar between the cohorts (all p&gt;0.05). However, rivaroxaban users had fewer outpatient (15.9 vs 20.4; p=0.0002) visits per patient as well as lower inpatient ($765 vs $2,655; p&lt;0.0001), pharmacy ($711 vs $1,086; p=0.0033), and total costs ($6,270 vs $9,671; p=0.0027). Conclusions: LRPE patients prescribed rivaroxaban had similar index LOS and PE-related outcomes, but fewer HACs, and lower total costs than those prescribed SOC.

The 5 most frequently asked questions about factor Xa inhibitors.

Direct oral anticoagulants (DOACs) are commonly used oral factor Xa inhibitors in recent years. However, in some special clinical situations, the appropriate use of these anticoagulants may be of concern. In this article, we address the 5 commonly asked questions regarding their use for the treatment of venous thromboembolism, including in the setting of obesity, renal impairment, gastrointestinal (GI) malignancy, catheter-related thrombosis, and drug-drug interactions. Data on the use of DOACs in the presence of significant obesity or renal failure are mainly observational. Some DOACs are shown to have an increased risk of bleeding in patients with unresected luminal GI malignancy but not others, so selection of appropriate patients is the key. Furthermore, literature on the use of DOACs for catheter-related thrombosis or when drug-drug interactions are of concern is limited, and more research is welcome.

An Evaluation of Time to Therapeutic Range of Intravenous Unfractionated Heparin After Transitioning From Direct Oral Factor Xa Inhibitors.

Purpose: Direct oral factor Xa inhibitors (Xa inhibitor) may falsely elevate anti-Xa assays, creating a challenge when patients transition from Xa inhibitors to intravenous unfractionated heparin (IV UFH). This study compared the time to therapeutic anti-Xa range in patients transitioning from Xa inhibitors to IV UFH to those not previously anticoagulated and initiated on IV UFH. Methods: This single-center, retrospective study included adults receiving IV UFH from August 2018 through August 2019. The study group received apixaban or rivaroxaban prior to the initiation of IV UFH, and the control group was not previously anticoagulated. The primary outcome was the time to reach therapeutic range. Secondary outcomes included the number of anti-Xa levels drawn to reach therapeutic range, incidence of treatment failure, and incidence of major bleeding episodes. Categorical and continuous data were analyzed with chi-square and Mann-Whitney U tests, respectively. Results: The time to reach therapeutic range was a median of 18.5 hours in the study group (IQR 14.9-26.9) compared to 7.3 hours (IQR 5.9-14.7) in the control group (P < .001). Two anti-Xa levels were drawn in the study group (IQR 1-4) compared to 1 (IQR 1-2) in the control group (P < .001). There was no difference in the incidence of treatment failures (P = .981) or major bleeding episodes (P = .972). Conclusions: In patients transitioning from Xa inhibitors to IV UFH, the time to therapeutic range was longer and required additional laboratory tests compared to those not previously anticoagulated. Further research is needed to examine the incidence of treatment failures or major bleeding episodes.

Meta-Analysis and Meta-Regression to Assess Four-Factor Prothrombin Complex Concentrate's Ability to Achieve Hemostatic Effectiveness in Patients with Oral Factor Xa Inhibitor-Associated Intracranial Hemorrhage

Background: Four-factor prothrombin complex concentrates (4FPCCs), both non-activated and activated products, are commonly used off-label to manage oral factor Xa (FXa) inhibitor-associated severe or life-threatening bleeds including intracranial hemorrhage (ICH). Available evidence supporting 4FPCC use in the management of oral FXa inhibitor-associated ICH patients come from small-to-modest sized studies or case series. These studies or case series often differed in key inclusion and exclusion criteria employed and definition of hemostatic effectiveness utilized. We performed a systematic review and meta-analysis including multivariable meta-regression to assess the proportion of oral FXa inhibitor-associated ICH patients achieving hemostatic effectiveness with 4FPCC and the effect of key methodological decisions on this estimate. Methods: We searched PubMed and Embase from the earliest date possible through May 31, 2022. Studies or case series were included if: 4FPCC was administered for the management of oral FXa inhibitor-associated bleeding; reported solely on ICH patients (or a subgroup of); evaluated ≥10 patients; was performed within the United States; and provided data on the proportion of patients achieving hemostatic effectiveness. Meeting abstracts were not included. We performed a random-effects meta-analysis to calculate the pooled arcsine square root transformation weighted proportion of patients achieving hemostatic effectiveness with 95% confidence intervals (CIs). Multivariable meta-regression was used to determine the impact of studies’ inclusion or exclusion of severe ICH; requirement that the oral FXa inhibitor was taken within 24-hours and/or drug concentration or FXa levels were drawn; handling of patients with missing repeat imaging; and use (or non-use) of an accepted definition of hemostatic effectiveness on our pooled estimate. Results: We identified 36 studies or case series reporting on 38 unique study arms and including 1,732 oral FXa inhibitor-associated ICH patients managed with 4FPCC. Nearly 16% of study arms excluded patients with severe ICH (i.e., those with a hematoma volume >60 mL and/or Glasgow Coma Scale score <7) and fewer than 8% required the last oral intake of FXa inhibitor be within 24 hours or drug or FXa levels be drawn prior to 4FPCC administration. More than half (55.3%) of study arms excluded patients due to missing repeat imaging and 21.1% of arms failed to use an accepted definition to assess hemostatic effectiveness. The weighted pooled proportion of ICH patients achieving hemostatic effectiveness was 79.7% (95% CI 76.5, 82.8) (Figure). Upon multivariable meta-regression, study arms that excluded severe ICH patients reported a significant 8.5% increase in in the proportion achieving hemostatic effectiveness compared to those who retained these patients (p<0.001). Moreover, study arms that did not require oral FXa inhibitor intake within 24 hour or drug concentration/FXa levels reported a 12.5% (95% CI 4.0, 21.0, p=0.004) higher incidence of achieving hemostatic effectiveness. Exclusion of patients with missing repeat imaging and the use of an accepted definition of hemostatic effectiveness were not shown in this meta-regression analysis to significantly impact hemostatic effectiveness estimates. Conclusions: Studies’ and case series’ exclusion of patients with severe ICH and lack of implementation of inclusion criteria to increase the likelihood of therapeutic anticoagulation being present at time of treatment may result in the overestimation of 4FPCC's hemostatic effectiveness in oral FXa inhibitor-associated ICH. Readers of these (and future) studies should consider these methodological decisions when using them in clinical decision-making. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thrombin Generation Is Differentially Affected By Anticoagulants in Patients with Acute Lymphoblastic Leukemia - an Ex-Vivo Study

Background: Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). Low molecular weight heparin (LMWH) reduces the risk of VTE in ALL, but is not well tolerated in children. VTE rates remain unacceptably high in adults despite LMWH prophylaxis. Thus, novel strategies for VTE prevention are warranted. In the primary analysis of the PREVAPIX-ALL trial there was no statistically significant reduction in VTE among children treated with the oral factor Xa inhibitor, apixaban, compared to no anticoagulation (AC). Comparative data on activity of different anticoagulants are needed to guide planning of VTE prophylaxis trials. Aims: To characterize and compare the ex-vivo effect of LMWH (enoxaparin), oral direct factor Xa inhibitors (apixaban, rivaroxaban) and oral direct thrombin inhibitor (dabigatran etexilate) in ALL patients' samples using thrombin generation (TG). Methods: A prospective observational cohort study of 46 children with newly-diagnosed ALL, treated with the L-asparaginase (ASP)-based BFM protocol, at a tertiary medical center. Patients on therapeutic-dose AC at baseline were excluded. Blood samples were drawn before ASP treatment (ALL-Day0) and 7 days after (ALL-Day7). Normal pooled plasma (NP) was collected from healthy adult volunteers. Samples were spiked ex-vivo with enoxaparin [0.2 U/mL], apixaban [39 ng/mL], rivaroxaban [39 ng/mL] and dabigatran [150 ng/mL] or vehicle (i.e., control). AC concentrations chosen based on 50% peak reduction (for Xa inhibitors) or 200% LT prolongation (for dabigatran) in NP. Subsequently, TG was performed initiated using 5 pM tissue factor in the presence of 4 µM phospholipids using Calibrated Automated Thrombogram method in these samples. Results are expressed as peak height (PH) and lag time (LT) and relative reduction or prolongation (% difference in PH or LT, respectively) in plasma samples spiked with anticoagulants compared to control. Reduction in PH reflects enoxaparin, apixaban and rivaroxaban activity, while LT prolongation indicates dabigatran activity. This report focuses on measures reflecting the activity of each drug. Descriptive statistics were used to show the median [interquartile range (IQR)] for continuous variables and percentages for categorical data. T-Test / Mann-Whitney U test and paired T-test / Wilcoxon test used to compare between paired and non-paired samples, respectively. Results: Selected sample characteristics are as follows: median age, 7.75 years [IQR 3.73-11.93]; 19 (41%) females; median BMI, 16.8 [IQR 15.5-19.9]; B-cell precursor immunophenotype in 33 (71.7%) and T-cell in 13 (28.3%); prior VTE in 1 (2%). Median PH [IQR] in control samples (without AC) was 256.6 [252.6-265.3] nmol/l, 396.0 [347.2-464.7] nmol/l and 354.4 [307.1-407.4] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median LT [IQR] in control samples was 2.7 [2.5-2.83] nmol/l, 1.8 [1.7-2.3] nmol/l and 1.7 [1.6-2] nmol/l in NP, ALL-Day0 and ALL-Day7 respectively. Median % differences in PH and LT between samples spiked with different anticoagulants and controls are shown in Figure 1A and Figure 1B, respectively. Enoxaparin, apixaban and rivaroxaban reduced PH in NP, ALL-Day0 and ALL-Day7 samples (p<0.0005). There was less reduction in PH with enoxaparin, apixaban and rivaroxaban in ALL-Day0 samples than in NP (p=0.029, p<0.0005, p<0.0005 respectively), suggesting reduced anticoagulant activity in ALL patients compared to subjects without ALL. LT was prolonged with dabigatran in NP, ALL-Day0 and ALL-Day7 samples (p<0.05). Dabigatran resulted in a similar LT prolongation in ALL-Day0 and NP (p=0.677), suggesting a preserved AC effect in ALL. There was less LT prolongation in ALL-Day7 (134% [123-175%] than in ALL-Day0 (180% [134-238]; p=0.031). This reflects an ongoing dabigatran effect after ASP, albeit to a lesser degree. Conclusions: Our ex-vivo results suggest limited anticoagulant activity of enoxaparin and lack of anticoagulant activity of apixaban and rivaroxaban (both factor Xa inhibitors) in preventing VTE in ALL, in line with prior clinical data. In contrast, dabigatran etexilate, an oral direct thrombin inhibitor not previously tested in ALL, exhibited preserved anticoagulant activity in ALL patients, even after exposure to ASP. This may suggest that dabigatran should be investigated in clinical studies for the unmet need of VTE prophylaxis in ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hereditary Antithrombin Deficiency Pilot Project Registry from the American Thrombosis and Hemostasis Network (ATHN)

Background: Hereditary antithrombin deficiency (HAD) is a severe rare thrombophilia with an estimated prevalence of 0.02% to 0.2% in the general population. Patients with HAD have a high risk of developing arterial and venous thromboembolism (VTE). The purpose of ATHN 12: HAD Pilot Project is to collect data on participants diagnosed with HAD across the United States to better understand this rare thrombophilia and to develop guidelines regarding timing of screening for HAD, type of antithrombotic therapy, and indications for using antithrombin concentrate. The ATHN 12 study is sponsored by the American Thrombosis and Hemostasis Network (ATHN). ATHN will leverage its existing data collection infrastructure and its ATHN-affiliated network of 146 hemostasis and thrombosis treatment centers in the United States to identify a cohort of approximately 100 patients with HAD who are receiving care in these centers. Methods: We designed a national HAD registry to collect clinical, laboratory, and treatment data for participants with HAD with the goal of optimizing their management. The ongoing prospective HAD registry project (ATHN 12) was created in 2020 to identify a cohort of 100 adult and pediatric participants with HAD receiving care at thrombosis centers affiliated with ATHN. We collected information on demographics, laboratory data, thrombotic events, risk factors, antithrombotic therapy, and use of antithrombin (AT) concentrate during pregnancy and procedures. Results: 71 participants have been enrolled, 47 (66.2%) are female; mean age is 35 years (1-82); the majority 58 (82%) are White and 31 (43.6%) have type 1 HAD; 62 (87.32%) had a known diagnosis of HAD; 45 (63.38%) had a history of VTE (Table 1). The most common VTE locations included: lower extremity deep vein thrombosis 51 events (57%) and pulmonary embolisms 23 events (26%). 23 participants (51%) had recurrent VTEs. 4 participants (5.5%) had history of arterial thrombosis (AT) and 1 (25%) had a recurrent event. Of 45 participants, 17 (38%) had no other known risk factors for VTE; 21 (46.5%) were estrogen-related; 11 (24.4%) occurred after surgery, prolonged immobilization, hospitalization, travel, or trauma (Table 1). A total of 173 anticoagulants were prescribed on 45 (63.38%) participants (Table 2) There were 87 pregnancies in 37 women. Low molecular weight heparin (LMWH) was administered in 46% of the pregnancies and in 3 women LMWH was switched to UFH between 36 to 38 weeks of gestation. AT concentrate was administered in 22 (25%) of the pregnancies before delivery and in 14 pregnancies 24 hours post-delivery. 31 women (36%) restarted anticoagulation post-delivery. The earliest initiation of anticoagulation was 6 hours after delivery. Overall, there were 34 (39%) pregnancy complications: 23 pregnancy losses mainly in first trimester, 4 thrombosis, 4 pre-eclampsia, and 6 other complications (Table 2). 59 participants (83%) had a total of 171 surgeries or procedures. The most frequent surgeries were gastrointestinal, and the most common procedures were vascular (Table 2). Overall, 28 (39.4%) have received AT concentrate without adverse events. Conclusions: VTE was the most frequent clinical manifestation with DVT accounting for 57% of events and PE 26%. Oral factor Xa inhibitors were the most common anticoagulants prescribed. LMWH was administered in almost half of the pregnancies and AT concentrates in 25% of the pregnancies before delivery, and in 39.4% overall in pregnancies and procedures without reported adverse events. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of Venous Thromboembolism After Hip Arthroscopy Is Low With or Without Prophylaxis but Risk Factors Include Oral Contraceptive Use, Obesity, and Malignancy

To determine the incidence of and risk factors for symptomatic venous thromboembolism (VTE) after hip arthroscopy (HA) and thromboprophylaxis prescription utilization for this procedure. The PearlDiver Mariner database was queried using Current Procedural Terminology codes to identify adult patients (aged ≥ 18 years) who underwent HA between 2010 and 2020. Patient demographic information, including age, oral contraceptive use, and medical comorbidities, as well as perioperative thromboprophylaxis utilization, was recorded using International Classification of Diseases codes and National Drug Codes. The incidence of postoperative VTE within 90 days was determined. Multivariate logistic regression was used to identify predictors of perioperative thromboprophylaxis utilization and risk factors for VTE. The queried records identified 60,181 patients who met the inclusion criteria. Of these patients, 367 (0.6%) experienced VTE, including deep venous thrombosis (0.5%) and/or pulmonary embolism (0.2%). Approximately 2.1% of patients used thromboprophylaxis, including aspirin (1.1%), low-molecular-weight heparin (0.9%), and oral factor Xa inhibitors (0.1%). Oral contraceptive pill use (adjusted odds ratio [aOR], 2.16; 95% confidence interval [CI], 1.34-3.46), obesity (aOR, 1.37; 95% CI, 1.05-1.79), and a history of malignancy (aOR, 1.69; 95% CI, 1.12-2.54) were associated with increased odds of experiencing VTE. Perioperative thromboprophylaxis (aOR, 0.52; 95% CI, 0.19-1.39) was not significantly associated with decreased odds of experiencing VTE. However, obesity (aOR, 1.17; 95% CI, 1.00-1.38) and hypertension (aOR, 1.17; 95% CI, 1.02-1.36) were associated with increased odds of thromboprophylaxis prescription utilization. Although the overall risk of symptomatic VTE after HA remains low, oral contraceptive use, obesity, and a history of malignancy are associated with increased odds of thromboembolic events within 90 days. Routine thromboprophylaxis after HA may not be indicated in all patients but can be considered based on patient-specific risk factors. Level III, retrospective prognostic comparative trial.

55 Andexanet Alfa Is Associated With Reduced In-hospital Mortality Compared to 4-Factor Prothrombin Complex Concentrate Among Patients With Intracranial or Gastrointestinal Bleeding

There are limited data on real-world effectiveness of the specific factor Xa (FXa) inhibitor reversal agent andexanet alfa (AA) in comparison with 4-factor prothrombin complex concentrates (4F-PCC). We compared in-hospital mortality in patients hospitalized with oral FXa inhibitor- or enoxaparin- related intracranial hemorrhage (ICH) or gastrointestinal (GI) bleeds who were treated with AA or 4F-PCC.

Cancer-associated coagulation disorders

Diagnosis and treatment of paraneoplastic coagulation disorders are achallenge in daily practice. While prophylactic anticoagulation to prevent venous thromboembolism (VTE) is standard of care in all surgical and acutely ill medical cancer patients, particularly careful evaluation of risks and benefits using validated risk assessment models is required during outpatient chemotherapy. Low-molecular-weight heparin and direct oral factor Xa inhibitors are available to treat established cancer-associated VTE, adhering to algorithms for bleeding risk stratification. In patients with overt disseminated intravascular coagulation, therapeutic measures should strictly follow clinical symptoms. An acquired von Willebrand syndrome may evoke asevere bleeding tendency in patients with myeloproliferative neoplasms or plasma cell dyscrasias. In 15% of cases, acquired hemophiliaA, due to the formation of inhibitory autoantibodies against coagulation factor VIII, is associated with malignancy.

Direct oral to parenteral anticoagulant transitions: Role of factor Xa inhibitor-specific anti-Xa concentrations.

The increasing use of oral factor Xa inhibitors (FXaI) has led to a growing interest in the clinical utility of laboratory monitoring to enhance safety and effectiveness. Particularly, the use of FXaI-specific anti-Xa concentrations has gained traction and been advocated for several indications, but limited studies have explored the role of anti-Xa concentrations in guiding inpatient transitions from oral to parenteral anticoagulants. Therefore, additional data on such approaches are warranted to help balance bleeding and thrombotic risks in the higher acuity inpatient setting. This study sought to compare two strategies for oral-to-parenteral anticoagulant transitions: FXaI anti-Xa concentration-guided versus standard of care (i.e., per-package insert). This was an observational, single-center, retrospective cohort study conducted from May 2016 to May 2021. Hospitalized patients converted from an oral FXaI (apixaban or rivaroxaban) to therapeutic parenteral anticoagulation with or without FXaI anti-Xa concentration guidance were reviewed. The primary outcome of major bleeding, according to the International Society on Thrombosis and Hemostasis criteria, was compared between groups. Cox proportional hazard modeling was used to evaluate patient characteristics associated with major bleeding events. A total of 845 patients (388 in the concentration-guided group and 457 in the non-concentration-guided group) met the inclusion criteria. Major bleeding was significantly lower in the concentration-guided versus the non-concentration-guided group (2.2% vs. 11.3%; p < 0.001, respectively). There were no differences between the groups in thromboembolic complications (1.8% concentration guided vs. 1.5% non-concentration guided; p=0.72) despite a significantly longer time from last oral FXaI dose to parenteral anticoagulant initiation in the concentration-guided group (27.9 h vs. 15.1 h; p < 0.01). The concentration-guided group had an 80% lower risk of major bleeding compared with the non-concentration-guided group (adjusted hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.10-0.39; p < 0.01). This analysis suggests using FXaI anti-Xa concentrations to guide the transition from oral to parenteral anticoagulants may be beneficial in reducing major bleeds in select patient populations.

A Description of Apixaban Dosing Patterns for Treatment or Prevention of Thrombotic Events in Hospitalized Patients on Dialysis.

Introduction: Apixaban is currently the only oral direct factor Xa inhibitor approved for treatment and prevention of venous thromboembolism (VTE) in patients on hemodialysis. Exclusion of dialysis patients from major clinical trials results in prescriber uncertainty regarding the optimal dose of apixaban for VTE treatment in this population. This study sought to characterize the variance in apixaban prescribing patterns for thrombotic indications other than atrial fibrillation. Methods: This retrospective, multi-center, descriptive study analyzed apixaban dosing patterns for hospitalized chronic dialysis patients with history of thrombosis. The primary outcome was incidence of deviation from manufacturer recommendations for dosing, assessed for either a new start or receipt prior to hospitalization. Secondary outcomes included observation of recurrent thrombotic and bleeding event rates during subsequent hospitalizations. Patients were analyzed into subgroups according to type of thrombotic indication for treatment. Data are reported with descriptive statistics. Results: A total of 101 patients were included. Deviations in recommended dosing were observed in 53 of 80 (66.2%) patients receiving apixaban for treatment of acute or chronic thrombosis. Of 44 patients started on apixaban during hospitalization for the indication of acute VTE, a dose deviation was observed in 79.5% of patients. Rates of rehospitalization for recurrent thrombotic events and bleeding were 11.8% and 9.9%, respectively. Conclusion: Variation in apixaban prescribing practices for the treatment of VTE in dialysis patients is common, suggesting an urgent need for prospective studies and updated dosing guidance to optimize safety with apixaban use in this population.

Application of plasma metabolome for monitoring the effect of rivaroxaban in patients with nonvalvular atrial fibrillation.

Rivaroxaban, an oral factor Xa inhibitor, has been used to treating a series of thromboembolic disorders in clinical practice. Measurement of the anticoagulant effect of rivaroxaban is important to avoid serious bleeding events, thus ensuring the safety and efficacy of drug administration. Metabolomics could help to predict differences in the responses among patients by profiling metabolites in biosamples. In this study, plasma metabolomes before and 3 hours after rivaroxaban intake in 150 nonvalvular atrial fibrillation (NVAF) patients and 100 age/gender-matched controls were analyzed by liquid chromatography coupled with mass spectrometry (LC–MS/MS). When compared with controls, a total of thirteen plasma metabolites were differentially expressed in the NVAF patients. Pathway analysis revealed that purine and lipid metabolism were dysregulated. A panel of three metabolites (17a-ethynylestradiol, tryptophyl-glutamate and adenosine) showed good predictive ability to distinguish nonvalvular atrial fibrillation with an area under the receiver operating characteristic curve (AUC) of 1 for the discovery phase and 1 for validation. Under rivaroxaban treatment, a total of seven metabolites changed, the lipid and glycosylphosphatidylinositol biosynthesis pathways were altered and the panel consisting of avocadene, prenyl glucoside and phosphatidylethanolamine showed predictive ability with an AUC of 0.86 for the discovery dataset and 0.82 for the validation. The study showed that plasma metabolomic analyses hold the potential to differentiate nonvalvular atrial fibrillation and can help to monitor the effect of rivaroxaban anticoagulation.

Perioperative Thromboprophylaxis Is Associated With Lower Risk of Venous Thromboembolism After Knee Arthroscopy

To determine the rate of symptomatic venous thromboembolism (VTE) among patients undergoing arthroscopic knee procedures, risk factors associated with postoperative VTE, and current perioperative thromboprophylaxis prescription patterns associated with this population in the United States. Medical records for patients ≥18 years of age were queried from the Mariner database using Current Procedural Terminology codes for knee arthroscopy performed in the United States from 2010 to 2020 in this cross-sectional study. Patients who received thromboprophylaxis and those diagnosed with VTE, including deep-vein thrombosis or pulmonary embolism, within 90 days of surgery were identified using International Classification of Diseases and National Drug Codes. Two multivariable logistic regression models were used to identify VTE risk factors and likelihood of perioperative thromboprophylaxis. Covariates included procedure type, age, oral contraceptive pill (OCP) use, and medical comorbidities. A total of 718,289 patients met inclusion criteria and 7,618 patients (1.06%) experienced VTE, including deep-vein thrombosis (n= 6,394, 0.9%) and/or pulmonary embolism (n= 2,211, 0.3%). A total of 10,769 patients (1.5%) filled perioperative thromboprophylaxis, including aspirin (n= 5,353, 0.7%), low-molecular-weight heparin (n= 4,563, 0.6%), and oral factor Xa inhibitors (n= 947, 0.1%). Perioperative thromboprophylaxis was associated with decreased odds of experiencing VTE (adjusted odds ratio [aOR] 0.65, 95% confidence interval [CI] 0.51-0.80). Procedure types categorized as moderate-to-greater risk were associated with increased odds of VTE (aOR 1.42, 95% CI 1.34-1.50). OCP use (aOR 1.63, 95% CI 1.38-1.91), obesity (aOR 1.17, 95% CI 1.11-1.24), renal disease (aOR 1.33, 95% CI 1.18-1.50) and congestive heart failure (aOR 1.30, 95% CI 1.13-1.50) were associated with increased odds of VTE. While the overall rate of symptomatic VTE following knee arthroscopy remains low, procedure types that are more complex and generally require restrictive rehabilitation protocols, OCP use, obesity, renal disease, and congestive heart failure are associated with increased odds of postoperative VTE. Conversely, the use of perioperative thromboprophylaxis is associated with significantly lower VTE risk. III, retrospective comparative prognostic trial.

EE391 Budget Impact of Andexanet ALFA for Gastrointestinal Bleeding Associated with Factor Xa Inhibitors from a US Hospital Perspective

Oral Factor Xa (FXa) inhibitors are used to treat and prevent thrombotic events but may exacerbate acute major bleeding. This analysis calculated the budget impact of using Andexanet alfa (andexanet), a novel specific reversal agent for FXa inhibitors, to treat FXa inhibitor-related major gastrointestinal bleeding from a US acute care hospital perspective.

Favorable effect of rivaroxaban against vascular dysfunction in diabetic mice by inhibiting NLRP3 inflammasome activation.

Cardiovascular disease (CVD) is the leading cause of death in various complications of type 2 diabetes mellitus (T2DM). Rivaroxaban (Xarelto; Bayer), an oral direct factor Xa (FXa) inhibitor, prevents the activation of the coagulation cascade in CVD. Considering its anticoagulant and anti-inflammatory effects, we assessed the hypothesis that rivaroxaban treatment may attenuate the vascular lesion and dysfunction in T2DM mice.C57BL/6, BKS-db/db, BKS-db/+, wild-type (WT), and NLRP3-/- mice were fed with standard chow or high-fat diet (HFD). Biochemical indexes, vascular lesions, and protein expression were evaluated using Western blot analysis, immunofluorescent staining, and RNA interference. Rivaroxaban presented favorable protection of vascular dysfunction in T2DM mice with significantly relieved vascular tension, intima-media thickness, and collagen deposition. Similar improvements in NLR family pyrin domain containing 3 (NLRP3) knockout groups and rivaroxaban pointed to the positive role of rivaroxaban against vascular dysfunction in diabetic mice by ameliorating NLRP3 inflammasome activation. Furthermore, the augmentation of inflammation and cell dysfunction in mice aortic endothelial cells (MAECs) and smooth muscle cells (MOVASs) induced by soluble FXa may be blocked by rivaroxaban via protease-activated receptors (PAR-1, PAR-2), mitogen-activated protein kinase (MAPK), and nuclear factor κ-B (NF-κB) pathway.The data indicate that the development of vascular dysfunction and inflammation in T2DM mice may be blocked by rivaroxaban in vivo and in vitro. Rivaroxaban treatment may also attenuate NLRP3 inflammasome activation via PARs, MAPK, and NF-κB pathway. This study provides mechanistic evidence of rivaroxaban therapies for vascular complications of T2DM.