Effect Of Apixaban Research Articles

Comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban in dogs.

Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown. Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation. Six University-owned, purpose-bred, middle-aged, mixed-breed dogs (4 male, 2 female). Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14-day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti-Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D-dimers, thrombin-antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation. Plasma drug concentrations and anti-Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti-Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D-dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation. Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary.

Effectiveness and Safety of Anticoagulants in Cancer Patients with VTE and Kidney Disease

Introduction: Cancer patients with kidney disease are at increased risk for having venous thromboembolism (VTE) and bleeding than those without kidney disease. There is a lack of evidence about the effectiveness and safety of anticoagulants in cancer patients with VTE and kidney disease. Purpose: To evaluate the effectiveness and safety of different anticoagulants among VTE cancer patients with or without kidney disease. Methods: Adult VTE patients with any active cancer identified between 01SEP2014 and 29SEP2020 who initiated apixaban, low molecular weight heparin (LMWH), or warfarin within 30-days following a VTE were identified from 4 commercial databases and Medicare database. Cancer status was identified in the 6-months prior through 30-days post VTE. Kidney disease (chronic kidney disease plus acute kidney disease) was defined based on diagnosis codes and was identified in the 6-months prior to VTE. Stabilized inverse probability treatment weighting (IPTW) was used to balance patient characteristics between treatment cohorts. After IPTW, VTE cancer patients were stratified by those with and without kidney disease. Incidence rates (IRs) were determined for major bleeding (MB), clinically relevant non-major (CRNM) bleeding and recurrent VTE events within the first 6-months of follow-up. Cox proportional hazard models were used to evaluate interactions between treatments (apixaban or warfarin or LMWH) and kidney disease status on the risk of MB, CRNM bleeding and recurrent VTE events. Interactions with P<0.10 were considered statistically significant. Results: Among the 30,586 VTE cancer patients who met all study criteria 8,858 (29.0%) had kidney disease. Use of warfarin, LMWH and apixaban was similar between those with kidney disease (40.2%, 31.6%, and 28.1%) and without kidney disease (36.9%, 38.6%, and 24.4%, respectively). After IPTW, patient characteristics were balanced between treatment cohorts. Analyses stratified by kidney disease status showed that treatment effects were not significantly different for patients with and without kidney disease (figure). The incidence rates of major bleeding, CRNM bleeding and recurrent VTE events trended lower in the apixaban cohort compared to warfarin or LMWH for both kidney disease and no kidney disease patients (figure). Generally, there were no significant interactions between kidney disease status and treatments on any of the outcomes (figure). Conclusion: Effects of apixaban, LMWH and warfarin on recurrent VTE and bleeding were generally consistent in VTE cancer patients with or without kidney disease. Additional research is needed to identify optimal anticoagulant treatment strategy for VTE cancer patients with kidney disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 12512: Antithrombotic Strategies According to Age in Patients With Atrial Fibrillation and a Recent Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the Augustus Trial

Background: In AUGUSTUS, apixaban led to lower rates of bleeding and hospitalization than VKA, and aspirin caused more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor. We evaluated the safety and efficacy of different antithrombotic strategies by age in this population. Methods: Patients were stratified into 3 age groups: &lt;65, 65-74, and ≥75 years. Outcomes of interest were adjudicated ISTH major or clinically relevant nonmajor (CRNM) bleeding, ISTH major bleeding, death or rehospitalization, and death or ischemic events. The treatment effects of apixaban vs. VKA and aspirin vs. placebo were assessed across age categories using Cox models. Results: Of 4614 patients, 1267 (27.5%) were &lt;65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. All events, including bleeding, rehospitalization, and ischemic events, were more common with older age. Compared with VKA, apixaban was associated with lower rates of ISTH major or CRNM bleeding, ISTH major bleeding, and death or hospitalization, regardless of age (Fig). Apixaban was associated with greater absolute reduction in ISTH major bleeding than VKA in the older age groups, reflecting the higher bleeding risk in these groups. No differences were observed in rates of death or ischemic events between apixaban and VKA according to age. Patients who received aspirin had higher rates of bleeding than those receiving placebo in all age groups. Rates of death or rehospitalization and death or ischemic events were similar among patients receiving aspirin or placebo in different age categories. Conclusions: The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of age. Aspirin compared with placebo increased ISTH major or CRNM bleeding in all age groups. Our findings support the use of apixaban plus a P2Y12 inhibitor without aspirin as the standard therapy for this patient population, regardless of age. Figure: Outcomes by Age

Effectiveness and safety of apixaban vs warfarin among older venous thromboembolism patients: a subgroup analysis of age

Abstract Background Venous thromboembolism (VTE) is the third most common cardiovascular condition in adult patients. Older patients are at an increased risk of VTE. However, they have been underrepresented in clinical trials and evidence on the safety and effectiveness of anticoagulants in older VTE patients, especially very elderly patients (≥80 years), is sparse. Purpose To evaluate the risk of recurrent VTE, major bleeding (MB), and clinically relevant non-major (CRNM) bleeding among older VTE patients initiating apixaban or warfarin according to two age sub-groups: 65–79 and ≥80 years. Methods Older VTE patients (aged ≥65 years) who initiated apixaban or warfarin were identified from the CMS Medicare database (September 2014–December 2017). To balance the characteristics between apixaban and warfarin patients, stabilized inverse probability treatment weighting (IPTW) was conducted. Post IPTW, a subgroup interaction analysis was conducted to evaluate if there was any difference in treatment effects between the two age subgroups (65–79 vs. ≥80) on recurrent VTE, MB, and CRNM bleeding. Cox proportional hazard models were used to conduct the interaction analysis, and the statistical significance of the interaction was set to p-value &amp;lt;0.10. Results A total of 22,135 apixaban and 45,840 warfarin patients with VTE aged ≥65 years were eligible for analysis. Post IPTW, patient characteristics were balanced between the apixaban and warfarin treatment cohorts. Apixaban patients had significantly lower risk of recurrent VTE, MB, and CRNM bleeding compared to warfarin patients (Figure). 42,551 (62.6%) were aged 65–79 years and 25,424 (37.4%) were aged ≥80 years. Among apixaban or warfarin patients, those aged 65–79 years had lower Charlson comorbidity index scores (mean 2.7 vs 3.2) and were less likely to have a diagnosis of anemia (34.7–34.9% vs 42.3–42.5%), cerebrovascular disease (14.7–15.7% vs 20.3–20.5%), or dementia (5.0–6.9% vs 20.4–24.6%) compared to patients aged ≥80 years. Across both age subgroups, incidence rates of recurrent VTE, MB and CRNM bleeding were lower for apixaban vs. warfarin. No significant interaction was observed between the treatment and age on recurrent VTE and MB (Figure). There was a significant interaction between treatment and age on CRNM bleeding. Apixaban trended towards a lower risk of CRNM bleeding across both age groups but the treatment effect on CRNM bleeding was larger for patients aged 65–79 years. Conclusion The treatment effects of apixaban vs. warfarin on recurrent VTE and MB were consistently observed across both older age groups in this analysis. More studies are needed to evaluate management of VTE in an older and especially the very elderly population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer Inc.

Effectiveness and safety of apixaban vs warfarin among venous thromboembolism patients using five US databases: a subgroup analysis of chronic liver disease

Abstract Background Venous thromboembolism (VTE) is a serious disease in the United States affecting approximately 1 in 1000 patients each year. Patients with chronic liver disease (CLD) are at an increased risk of VTE and major bleeding (MB). Currently, insufficient clinical and real-world evidence exists on the efficacy/effectiveness and safety of apixaban or warfarin in VTE patients with CLD. Purpose To evaluate the risk of recurrent VTE, MB, and clinically relevant non-major (CRNM) bleeding among VTE patients initiating apixaban or warfarin stratified by CLD status. Methods VTE patients ≥18 years of age (≥65 years for Medicare) initiating apixaban or warfarin were identified from CMS Medicare and four commercial claims databases. To balance the characteristics between apixaban and warfarin patients, stabilized inverse probability treatment weighting (IPTW) was conducted. Post-IPTW, subgroup interaction analysis was conducted to evaluate whether treatment effects of apixaban vs. warfarin were consistent across patients with and without a diagnosis of CLD. Cox proportional hazard models were used to evaluate the interaction of the treatment (apixaban vs. warfarin) and CLD on recurrent VTE, MB, and CRNM bleeding. The statistical significance of the interaction was set to p-value &amp;lt;0.10. Results A total of 60,786 apixaban and 94,333 warfarin patients with VTE were eligible for analysis. Post-IPTW, all patient characteristics were balanced between the apixaban and warfarin treatment cohorts. Apixaban treated patients had significantly lower risk of recurrent VTE, MB, and CRNM bleeding compared to warfarin patients (Figure). In the IPTW weighted population, 4,766 (7.8%) apixaban patients and 6,320 (6.7%) warfarin patients had a diagnosis of CLD. For the apixaban or warfarin patients, those with a diagnosis of CLD were generally younger (mean 64.0–65.2 vs 66.9 years), had higher Charlson comorbidity index scores (mean 3.8–3.9 vs 2.1) and were more likely to have an inpatient VTE event (67.8–69.5% vs 53.0–53.2%) or provoked VTE events (66.2–67.8% vs 55.4–55.5%) compared to patients without a diagnosis of CLD. The incidence rate of recurrent VTE, MB, and CRNM bleeding was higher among VTE patients with CLD than without CLD and was also higher for patients treated with warfarin compared to those treated with apixaban regardless of CLD status (Figure). There were no significant interactions observed between treatment and CLD status for recurrent VTE, MB or CRNM (Figure). Conclusion Treatment with apixaban had a lower risk of recurrent VTE, MB, and CRNM bleeding compared to treatment with warfarin. The benefits of apixaban were consistently observed among subgroups of VTE patients with and without CLD. Additional studies are needed to evaluate VTE patients with CLD. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer, Inc.

Plasma levels do not predict thrombin generation in patients taking direct oral anticoagulants.

The antithrombotic effect of direct oral anticoagulants (DOAC) in specific clinical scenarios is difficult to assess. This study aimed to evaluate the effect of DOAC on thrombin generation (TG) in relation to their plasma level. Eighty patients newly started on anticoagulation were included, 20 patients for each DOAC-apixaban, edoxaban, rivaroxaban, and dabigatran. Plasma was sampled before DOAC (baseline), at plasma peak time, 6 and 12hours after starting DOAC for quantification of drug levels and TG. The baseline TG before DOAC intake showed inter-individual variability. All DOACs significantly prolonged lag time (LT) and time to peak (TTP), but did not change endogenous thrombin potential (ETP). Anti-Xa inhibitors but not dabigatran reduced thrombin peak, but the effect of apixaban at plasma peak was less pronounced (factor 1.6). LT and TTP prolongation of dabigatran was lower compared to anti-Xa inhibitors. All DOACs showed a nonlinear dose-response relationship, with the greatest antithrombotic effect at lower DOAC plasma levels. The inhibition of TG parameters between baseline and peak was parallel between individual patients but the coefficient of variation of TG was lower compared to drug levels. The antithrombotic effect at DOAC peak plasma level measured by TG depends on the patient-specific baseline TG level and the drug-specific inhibition by the particular DOAC. Although peak plasma levels have a high variability, the variation of TG is lower compared to drug levels. Therefore, TG assays may be superior to plasma levels in the assessment of the intensity of anticoagulation.

Evaluation of the effect of apixaban using a viscoelastic coagulation assay with Russell\u2019s viper venom reagent

BackgroundConventional coagulation tests, such as prothrombin time and activated partial thromboplastin time, are not sensitive to anticoagulation by apixaban. We evaluated the antithrombotic effect of apixaban using a Russell viper venom (RVV) test for a patient who underwent posterior spine fusion surgery.Case presentationAn 84-year-old man was scheduled for percutaneous posterior spine fusion. He continued apixaban until the night before surgery and resumed it on the first day after surgery. We performed an RVV test as point-of-care coagulation monitoring in combination with chromogenic anti-activated factor X (anti-Xa) activity, prothrombin time, and activated partial thromboplastin time. Clotting time with the RVV test was prolonged according to the anti-Xa activity of apixaban, which was in the therapeutic range during surgery.ConclusionsAn RVV test might be useful as a point-of-care assay for estimation of the anti-Xa level induced by apixaban during the perioperative period.

Safety and efficacy of antithrombotic therapy according to stroke and bleeding risk in patients with atrial fibrillation and acute coronary syndrome or PCI: insights from AUGUSTUS

Abstract Background The AUGUSTUS trial showed that patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) and/or PCI treated with a P2Y12 inhibitor and apixaban resulted in less bleeding and comparable ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both. We assessed the effect of apixaban versus VKA and aspirin versus placebo according to patients' baseline risk of stroke and bleeding. Methods AUGUSTUS randomized 4614 patients in a two-by-two factorial design to open label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor (CRNM) bleeding over 6 months of follow-up. The effects were assessed stratified by baseline CHA2DS2-VASc and HAS-BLED score using Cox proportional hazards models. Results 4386 patients were included for this analysis. The median age was 71 (64–77) years, 29.4% were female, 81.7% had a CHA2DS2-VASc score≥3, and 66.8% a HAS-BLED score≥3. As shown in the table, rates of bleeding were lower with apixaban (vs VKA) irrespective of baseline bleeding risk (p-value interaction: 0.23). Aspirin (vs placebo) was associated with increased bleeding irrespective of baseline risk (p-value interaction: 0.88). Apixaban use was associated with a lower risk of death or hospitalization without a significant interaction with stroke risk (p-value of interaction=0.53). No differences were found for ischemic outcomes. Conclusion An antithrombotic regimen including a P2Y12 inhibitor and apixaban is associated with less bleeding and hospitalization compared to a regimen with VKA, aspirin, or both with results consistent across CHA2DS2-VASc, and HAS-BLED scores. Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients with AF and ACS and/or PCI, regardless of stroke and bleeding risk. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The Augustus trial was sponsored by Bristol-Myers Squibb and Pfizer, Inc

Thromboprophylaxis for Patients with Newly Diagnosed Vs. Recurrent Cancers: A Post-Hoc Analysis of the Avert Trial

Background: The risk of venous thromboembolism (VTE) is increased in cancer patients, which can result in significant increases in mortality, morbidity and healthcare expenditures. The recent AVERT trial (N Engl J Med 2019 Feb 21;380(8):711-719), showed that prophylactic apixaban lowered the rate of VTE when compared to placebo in cancer patients starting chemotherapy. However, the risk-benefit ratio of primary thromboprophylaxis in patients initiating chemotherapy for recurrent disease compared to those with newly diagnosed patients who are chemotherapy naïve is unknown. Methods: This is a post-hoc analysis of the AVERT trial. The AVERT trial assessed apixaban therapy vs. placebo for prophylaxis among patients with cancer who were intermediate-to-high risk for VTE (Khorana score ≥2; the Khorana score is ranged from 0 to 6 with higher scores reflecting an increased risk of VTE) and were initiating chemotherapy. It was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was VTE and the main safety outcomes were major bleeding episodes. Secondary outcome measures included clinically relevant non-major bleeding (CRNMB). The severity of major bleeding was stratified from category 1 to 4, with category 4 being the most severe type. We performed time-to-event analysis on the primary efficacy and main safety end-points in patients with recurrent and new diagnosed cancers. The hazard ratio (HR) for the outcomes were estimated using a Cox regression model controlling for age, gender, and center. Results: A total of 574 patients were randomized in the AVERT trial. 563 were included in the modified intention-to-treat analysis. 237 and 232 patients with newly diagnosed cancer were allocated to the apixaban and placebo groups, respectively. Similarly, 51 and 43 patients with recurrent cancer were allocated to the apixaban and placebo groups, respectively. Baseline demographics and clinical characteristics are depicted in Table 1A and Table 1B. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR: 0.45; 95% CI: 0.27-0.76; p = 0.002) and a higher rate of major bleeding complications (HR: 2.10; 95% CI: 1.09-4.08; p = 0.028) but not of CRNMB (HR: 1.06; 95% CI: 0.61-1.82) (Table 2A). A majority of the major bleeding complications were of category 2. In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR: 0.26; 95% CI: 0.13-0.53; p &amp;lt; 0.001) without an associated significant increased risk of major bleeding complication (HR: 1.82; 95% CI: 0.36-9.15; p = 0.466) but with a significant increase rate of CRNMB (HR: 2.78; 95% CI: 0.58-1.34; p = 0.006) (Table 2B). Major bleeding episodes were split evenly between severity category 1 and 2. Conclusion: The risk-benefit ratio of primary thromboprophylaxis with apixaban might differ between patients with recurrent or newly diagnosed cancers. Apixaban was associated with a lower rate of VTE compared to placebo in both groups. Patients with recurrent cancer initiating chemotherapy may potentially have a more favorable risk benefit profile, as shown through the HR and the prevalence of major bleeding episodes. However, more trials are required to confirm these findings to help tailor thromboprophylaxis in this patient population. (AVERT ClinicalTrials.gov number, NCT02048865.) Disclosures Wells: BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. This study will show whether the prophylactic effects of apixaban will be more effective when used with patients with recurrent cancer or patients with newly diagnosed cancer.

P4752Apixaban 2.5 mg twice daily is effective and safe for patients with atrial fibrillation and combinations of advanced age, low body weight, and elevated creatinine: insights from ARISTOTLE

Abstract Background In ARISTOTLE, patients with atrial fibrillation and ≥2 dose-reduction criteria [age ≥80 years, weight ≤60 kg, and creatinine ≥1.5 mg/dL (133 μmol/L)] were randomized to apixaban 2.5 mg twice daily (b.i.d) or warfarin. Purpose To determine whether the apixaban dose adjustment in ARISTOTLE resulted in similar efficacy and safety compared to warfarin. Methods The effects of apixaban 2.5 mg b.i.d versus warfarin on stroke or systemic embolism, major bleeding and death in ARISTOTLE patients with ≥2 dose-reduction criteria were compared with the effects of apixaban 5 mg b.i.d in patients with 0 or 1 dose-reduction criterion. Results Of 751 (4.1%) patients with ≥2 dose-reduction criteria, 386 were assigned to apixaban 2.5 mg b.i.d and 365 to warfarin. Compared to patients with 0 or 1 dose reduction criteria (n=17,322), these patients had a higher risks of stroke/systemic embolism (HR =1.78; 95% CI [1.24–2.57]), major bleeding (HR =1.73; 95% CI [1.28–2.32]) and death (HR=3.21; 95% CI [2.69–3.83]), irrespective of whether they were assigned to apixaban or warfarin. The benefits of apixaban 2.5 mg b.i.d compared with warfarin on stroke or systemic embolism, major bleeding, and death in patients with ≥2 dose-reduction criteria were consistent with that of apixaban 5 mg b.i.d in patients with either 0 or 1 dose-reduction criteria (Figure). Conclusions While they are at higher overall risk, patients with appropriate dose reduction criteria have consistent benefits with apixaban 2.5 mg b.i.d. over warfarin. Additional analyses investigating the relationship between apixaban dose and both apixaban plasma concentrations and levels of thrombosis biomarkers are underway. Acknowledgement/Funding Bristol-Myers Squibb and Pfizer, Inc.

Reversal of the Thrombin Generation Inhibitory Effect of Apixaban, Betrixaban, Edoxaban and Rivaroxaban by Andexanet Alpha may be Associated with Increased Thrombogenesis

IntroductionCoagulation factor Xa recombinant, inactivated – ZhZo also known as Andexanet Alpha (AA, Portola Pharmaceuticals) is a recombinant modified version of human activated factor Xa which is devoid of enzymatic activity and developed to neutralize factor Xa inhibitors such as Apixaban, Betrixaban, Edoxaban and Rivaroxaban. This agent acts as a decoy receptor with the same affinity as factor Xa rendering them ineffective. Although AA is not an active procoagulant its use has been reported to result in thromboembolic events. It was hypothesized that AA may enhance thrombin generation in human plasma which may contribute to the reported thrombotic complications. To validate this, the reversal effect of AA was studied in thrombin generation assays with different oral factor Xa inhibitors.MethodsCitrated plasma samples (n=10) with normal clotting profiles as measured by PT and APTT were pooled to obtain citrated pooled plasma (CPP). Individual aliquots of CPP were supplemented with either saline or AA at a final concentration of 100 ug/ml. They were also tested in plasma samples supplemented with 1 ug/ml of Apixaban, Betrixaban, Edoxaban and Rivaroxaban. Factor Xa activity was measured using an amidolytic method. Thrombin generation studies were carried out using a calibrated automated thrombogram (CAT) ‐ thrombin generation assay (Diagnostica Stago, Paris, France). Parameters as peak thrombin (PT), area under the curve (AUC) and lag time (LT) were measured. The inhibitory effects of each of these agents were calculated and the reversal by AA was also calculated.ResultsSupplementation of AA to normal plasma resulted in an increased generation of thrombin in comparison to saline control. The peak thrombin levels was higher (40%), the AUC was also increased (15%) whereas the lag time was decreased (17%). No anti Xa activity was observed in the saline supplemented system with AA. At 1 ug/ml level all of the factor Xa inhibitors produced varying levels of the inhibition of PT (&gt;75%) and AUC (&gt;35%) which was associated with an increase in the LT. AA at 100 ug/ml to various factor Xa supplemented systems resulted in a reversal of the inhibitory effects restoring the thrombin generation profile. Notably the thrombin generation profile was stronger in comparison to the saline supplemented plasma. In terms of the AUC the LT and PT levels were comparable to saline. The factor Xa activity reversal profile varied with the specific agents, apixaban (22%), betrixaban (56%), edoxaban (28%) and rivaroxaban (49%) decrease rate.ConclusionsThese results suggest that AA is capable reversing anti Xa activity of different anticoagulants, but also enhancing thrombogenesis in both the saline and factor Xa inhibitor supplemented systems as evident by increased generation of thrombin. The relative degree of enhancement in different Xa inhibitors supplemented systems was product specific.Support or Funding InformationNone.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series

BackgroundThe lack of an antidote against factor Xa inhibitors in case of major bleeding or need for urgent surgery is a concern to clinicians. Guidelines on managing major bleeding in patients under anticoagulation with a factor Xa inhibitor suggest several hemostatic agents to reverse the effect, but there is no consensus regarding the choice of drug or appropriate dose. The ability of prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa to reverse the effect of factor Xa inhibitors has been evaluated in animal studies, in vitro studies, and healthy volunteers, but not yet in randomized clinical studies.Case presentationWe report a consecutive case series of patients under factor Xa inhibitor (apixaban) treatment who received activated prothrombin complex concentrate to reverse the anticoagulation effect before emergency cardiovascular surgery. Patient 1, a 63-year-old white man, was operated with replacement of the aortic valve; patient 2, a 65-year-old white man, underwent heart transplantation; patient 3, a 68-year-old white man, was operated for acute type A aortic dissection. They all received activated prothrombin complex concentrate 25 IU/kg immediately before surgery. In two of the cases, the global coagulation assay thromboelastometry (ROTEM™) was performed before and after administering activated prothrombin complex concentrate. The ROTEM™ clotting time was reduced from 1900 seconds to 740 seconds and from 1482 to 807 seconds, respectively, after administering a dose of 25 IU/kg activated prothrombin complex concentrate. The apixaban concentration before reversal was within the range considered to be the therapeutic level in all cases. No bleeding complications occurred during surgery, but one case was complicated with bleeding postoperatively. No thromboembolic complications were observed during or after surgery.ConclusionsActivated prothrombin complex concentrate 25 IU/kg reversed the anticoagulation effect of apixaban effectively and safely before emergency cardiovascular surgery.

Apixaban attenuates ischemia-induced myocardial fibrosis by inhibition of Gq/PKC signaling

It was previously found that patients with symptom of myocardial dysfunction had increased levels of thrombin. Apixaban is one of the novel oral anticoagulant drugs widely used in clinic. As the inhibitor of FXa (prothrombin), it inhibits prothrombin conversion into thrombin leading to thrombin deficiency in vivo. However, the effects of apixaban on myocardial fibrosis were still unclear, and the concomitant molecular mechanisms remain to be investigated. Here, we showed that myocardial fibrosis-bearing mice induced by continuous myocardial ischemia (MI) had higher levels of thrombin. Orally administration of apixaban significantly abrogated fibrosis condition and thrombin levels. In vitro, thrombin induced collagen deposition in primary cardiac fibroblasts in a dose-dependent manner. Mechanistic experiments showed that thrombin induced collagen deposition by activation of the Par-1-coupled Gq/PKC signaling. Genetic ablation of Gq or pharmacological inhibition of PKC effectively blunted thrombin-induced collagen deposition in cardiac fibroblasts. Moreover, administration of PKC inhibitor or Gq antagonist obviously blocked MI-induced myocardial fibrosis in mice. To conclude, apixaban attenuates MI-induced myocardial fibrosis by inhibition of thrombin-dependent Par-1/Gq/PKC signaling axis.

Apixaban Enhances Vasodilatation Mediated by Protease-Activated Receptor 2 in Isolated Rat Arteries.

Apixaban (APX) is a direct inhibitor of factor X (FXa) approved for prophylaxis and treatment of deep venous thrombosis and atrial fibrillation. Because FXa activates protease-activated receptor 2 (PAR-2) in endothelium and vascular smooth muscle, inhibition of FXa by APX may affect vasomotor function. The effect of APX was assessed in vitro, by wire myography, in rat mesenteric resistance arteries (MRAs) and basilar arteries challenged with vasoconstrictors [phenylephrine (PE); 5-hydroxytryptamine (5-HT)], vasodilators [acetylcholine (ACh); sodium nitroprusside (SNP)] or with the PAR-2 peptide agonist SLIGRL. APX (10 μM) reduced the vasoconstriction to PE and 5-HT while did not change the vasodilatation to ACh or SNP. SLIGRL induced concentration-dependent vasodilation in pre-constricted arteries, that was reduced by incubation with the NO inhibitor NG-nitro-L-arginine (L-NNA) and abolished by endothelium removal. APX enhanced vasodilation to SLIGRL either in the presence or in the absence of L-NNA, but was ineffective in endothelium-denuded vessels. In preparations from heparin-treated rats (to inhibit FXa) APX did not change the vasodilation to SLIGRL. FXa enzymatic activity, detected in mesentery homogenates from controls, was inhibited by APX, whereas APX-sensitive enzymatic activity was undetectable in homogenates from heparin-treated rats. Immunoblot analysis showed that incubation of MRA or aorta with APX increased the abundance of PAR-2, an effect not seen in MRA from heparin-treated rats or in endothelium-denuded aortas. In conclusion, inhibition of FXa by APX increases vasodilatation mediated by PAR-2. APX may act by inhibiting PAR-2 desensitization induced by endogenous FXa. This effect could be useful in the context of endothelial dysfunction associated to cardiovascular diseases.

The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects.

PurposeApixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug–drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies.Patients and methodsThe digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2–10, followed by apixaban 20 mg and digoxin 0.25 mg once daily on days 11–20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of apixaban 10 mg, atenolol 100 mg, or apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration–time curve (AUCtau), with and without apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%–125% (digoxin) or 70%–143% (atenolol). A similar analysis was performed to assess the effect of atenolol on apixaban.ResultsApixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study.ConclusionApixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between apixaban and atenolol. Coadministration of digoxin or atenolol with apixaban in healthy subjects was generally well tolerated.

Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis

Background/Aims: Venous thromboembolism (VTE) is the most common complication after major joint surgery. VTE can easily develop into pulmonary embolism (PE), leading to cardiopulmonary dysfunction or sudden death. We aimed to comprehensively analyse the thromboprophylactic drugs that are used to prevent thrombosis and reduce bleeding risk. Methods: We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that evaluated the use of thromboprophylaxis after major joint surgery. The major outcomes were the numbers of all-cause VTE and bleeding events, and the secondary outcomes were major VTE and major bleeding/clinically relevant non-major bleeding events. A random-effects network meta-analysis was used to assess the effectiveness and tolerability of each anticoagulant after major joint surgery. Results: We included 104 trials that assessed 110,643 patients in our meta-analysis. The cluster ranking of major outcomes indicated that FXI-ASO, ardeparin, aspirin, and apixaban were ideal for preventing all-cause VTE and avoiding all bleeding events. Nadroparin, recombinant hirudin, and rivaroxaban effectively inhibited VTE but were associated with a high risk of bleeding. For secondary outcomes, we found that betrixaban, dalteparin, warfarin, and eribaxaban were ideal for preventing major VTE and reducing major bleeding, while rivaroxaban effectively inhibited major VTE but was associated with a high risk of major/clinically relevant non-major bleeding. A sensitivity analysis showed that the effect of apixaban was more robust for major outcomes, while aspirin was more robust for preventing all-cause bleeding events. In secondary outcomes, the effect of warfarin was more robust, while apixaban was still considered an ideal treatment to inhibit major VTE and bleeding events. Conclusion: Our study indicates that FXI-ASO, ardeparin, aspirin, and apixaban are ideal for preventing all-cause VTE and reducing all bleeding events, among which apixaban is the most reliable. Betrixaban, dalteparin, warfarin, and eribaxaban are ideal for preventing major VTE and reducing major/clinically relevant non-major bleeding events, among which warfarin is the most reliable.

The 2005 Caprini Score Predicts Both Baseline Venous Thromboembolism Risk and Effectiveness of Chemoprophylaxis: A Meta-Analysis of 13,412 Surgical Patien

Conclusions: Apixaban is less effective in reducing thrombus burden than enoxaparin at 2and 14-day time points in this nonstasis murine model of DVT. This may be due to anti-inflammatory pleiotropic effects of enoxaparin that apixaban may not have in acute DVT. Further study is ongoing to determine whether vein wall remodeling is affected by Xa inhibition and whether this is an effect of apixaban itself or a class effect of anti-Xa inhibitors.

Apixaban 5 mg Twice Daily and Clinical Outcomes in Patients With Atrial Fibrillation and Advanced Age, Low Body Weight, or High Creatinine: A Secondary Analysis of a Randomized Clinical Trial.

In the Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) trial, the standard dose of apixaban was 5 mg twice daily; patients with at least 2 dose-reduction criteria-80 years or older, weight 60 kg or less, and creatinine level 1.5 mg/dL or higher-received a reduced dose of apixaban of 2.5 mg twice daily. Little is known about patients with 1 dose-reduction criterion who received the 5 mg twice daily dose of apixaban. To determine the frequency of 1 dose-reduction criterion and whether the effects of the 5 mg twice daily dose of apixaban on stroke or systemic embolism and bleeding varied among patients with 1 or no dose-reduction criteria. Among 18 201 patients in the ARISTOTLE trial, 17 322 were included in this analysis. Annualized event rates of stroke or systemic embolism and major bleeding and hazard ratios (HRs) and 95% CIs were evaluated. Interactions between the effects of apixaban vs warfarin and the presence of 1 or no dose-reduction criteria were assessed. The first patient was enrolled in the ARISTOTLE trial on December 19, 2006, and follow-up was completed on January 30, 2011. Data were analyzed from January 2015 to May 30, 2016. Analysis of major bleeding included events during study drug treatment. Analysis of stroke or systemic embolism was based on intention to treat. Of the patients with 1 or no dose-reduction criteria assigned to receive the 5 mg twice daily dose of apixaban or warfarin, 3966 had 1 dose-reduction criterion; these patients had higher rates of stroke or systemic embolism (HR, 1.47; 95% CI, 1.20-1.81) and major bleeding (HR, 1.89; 95% CI, 1.62-2.20) compared with those with no dose-reduction criteria (n = 13 356). The benefit of the 5 mg twice daily dose of apixaban (n = 8665) compared with warfarin (n = 8657) on stroke or systemic embolism in patients with 1 dose-reduction criterion (HR, 0.94; 95% CI, 0.66-1.32) and no dose-reduction criterion (HR, 0.77; 95% CI, 0.62-0.97) were similar (P for interaction = .36). Similarly, the benefit of 5 mg twice daily dose of apixaban compared with warfarin on major bleeding in patients with 1 dose-reduction criterion (HR, 0.68; 95% CI, 0.53-0.87) and no dose-reduction criterion (HR, 0.72; 95% CI, 0.60-0.86) were similar (P for interaction = .71). Similar patterns were seen for each dose-reduction criterion and across the spectrum of age, body weight, creatinine level, and creatinine clearance. Patients with atrial fibrillation and isolated advanced age, low body weight, or renal dysfunction have a higher risk of stroke or systemic embolism and major bleeding but show consistent benefits with the 5 mg twice daily dose of apixaban vs warfarin compared with patients without these characteristics. The 5 mg twice daily dose of apixaban is safe, efficacious, and appropriate for patients with only 1 dose-reduction criterion. clinicaltrials.gov Identifier: NCT00412984.

Apixaban: An oral anticoagulant having unique mechanism of action with better safety and efficacy profile

Anticoagulants are routinely used in stroke, embolism, infarct, etc. Blood clotting profile in such patients needs to be monitored frequently. Anticoagulants which can be administered orally such as warfarin and dicoumarol are preferred in such patients. Injectable anticoagulants such as heparin are prescribed when anticoagulation therapy is required for short duration. Absence of oral form of heparin makes it impractical for long-term use. Currently, warfarin and coumarone derivatives are the best available oral anticoagulants in market. They act by inhibiting decarboxylation of blood clotting factors II, VII, IX, and X. Pharmacological response of warfarin and dicoumarol needs to be monitored by frequent assessments of prothrombin time (PT) and international normalized ratio (INR). There is a need for a drug which can overcome these limitations. Apixaban is an oral anticoagulant which acts by inhibiting factor Xa. It does not require laboratory monitoring of PT and INR. Hence, it overcomes the limitations of heparin and warfarin. It acts by selectively inhibiting the activated factor Xa in a reversible manner. Apixaban has an oral bioavailability of ~50%. It is administered as twice daily dose. It is excreted in urine and feces. Apixaban is useful in atrial fibrillation, venous thromboembolism, and pulmonary embolism. Bleeding is the major side effect of apixaban. It has been found that apixaban has superiority over warfarin and aspirin in terms of efficacy and safety. Further studies are required to monitor and assess the pharmacokinetics, efficacy, adverse effects, and drug interaction data in many populations and sub-populations throughout the world.

Abstract 10343: Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Peripheral Artery Disease and Non-valvular Atrial Fibrillation: Insights From the Aristotle Trial

Introduction: Vascular disease has been incorporated in the CHA2DS2-VASc risk tool to predict the risk of stroke/systemic embolism in patients with atrial fibrillation (AF). Hypothesis: This post hoc analysis of the ARISTOTLE trial aimed to determine the absolute rates of stroke/systemic embolism and bleeding associated with peripheral artery disease (PAD) as well as the efficacy and safety of apixaban vs warfarin in AF patients with and without PAD. Methods: ARISTOTLE randomized patients with AF and risk of stroke to apixaban and warfarin for the prevention of stroke/systemic embolism. Results: A total of 884 (4.9%) patients had PAD at baseline as defined by site investigators on the case report form. Patients with versus without PAD had non-significantly higher rates of stroke/systemic embolism [HR 1.32, 95% CI 0.93-1.88, p=0.12] and major or clinically relevant non-major (CRNM) bleeding [HR 1.12, 95% CI 0.90-1.39, p=0.31]. Those with PAD had an increased risk of all-cause death [HR 1.36, 95% CI 1.11-1.67, p=0.003] and CV death [HR 1.44, 95% CI 1.08-1.90, p=0.01] when compared with those without PAD. The effect of apixaban vs warfarin for the prevention of stroke/systemic embolism was similar in patients with PAD [HR 0.66, 95% CI 0.33- 1.31] and without PAD [HR 0.80, 95% CI 0.66-0.96, interaction p=0.61] [Table]. Patients with PAD appeared to have less reduction in major or CRNM bleeding with apixaban compared with warfarin [HR 1.04, 95% CI 0.69-1.57] versus those without PAD [HR 0.66, 95% CI 0.59-0.73, interaction p=0.03]. Conclusions: Patients with PAD in ARISTOTLE had non-significantly higher risk of stroke/systemic embolism when compared with patients without PAD. The benefits of apixaban versus warfarin on stroke and all-cause death are similar in patients with and without PAD. However, the reduction in bleeding with apixaban seemed to be greater in patients without PAD than in patients with PAD (interaction p=0.03).