The role of factor Xa inhibitors in venous thromboembolism treatment.
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ABSTRACT:
SUBMITTER: Cabral KP
PROVIDER: S-EPMC4321604 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Publications
The role of factor Xa inhibitors in venous thromboembolism treatment.
Cabral Katherine P KP Ansell Jack E JE
Vascular health and risk management 20150130
Three factor Xa inhibitors have been studied in the treatment of venous thromboembolism, both for acute therapy and as extended therapy to prevent recurrent events. Rivaroxaban, apixaban, and edoxaban have all proven to be effective in Phase III clinical trials for this indication when compared to current standard of therapy with similar or less bleeding. Nevertheless, the agents all offer different pharmacological profiles, which have an impact on patient selection and potential advantages in c ...[more]
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Project description:BackgroundThere is considerable debate regarding the ideal agent for venous thromboembolism (VTE) prophylaxis after TKA. Numerous studies and meta-analyses have yet to provide a clear answer and often omit one or more of the commonly used agents such as aspirin, warfarin, enoxaparin, and factor Xa inhibitors.Questions/purposesUsing a large database analysis, we asked: (1) What are the differences in VTE incidence in primary TKA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors? (2) What are the differences in bleeding risk among these four agents? (3) How has use of these agents changed with time?MethodsWe queried a combined Humana and Medicare database between 2007 and Quarter 1 of 2016, and identified all primary TKAs performed using ICD-9 and Current Procedural Terminology codes. All patients who had any form of antiplatelet or anticoagulation prescribed within 1 year before TKA were excluded from our study cohort. We then identified patients who had either aspirin, warfarin, enoxaparin, or factor Xa inhibitors prescribed within 2 weeks of primary TKA. Each cohort was matched by age and sex. Elixhauser comorbidities and Charlson Comorbidity Index for each group were calculated. We identified 1016 patients with aspirin, and age- and sex-matched 6096 patients with enoxaparin, 6096 patients with warfarin, and 5080 patients with factor Xa inhibitors. Using ICD-9 codes, with the understanding that patients at greater risk may have had more-attentive surveillance, the incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications (bleeding requiring surgical intervention, hemorrhage, hematoma, hemarthrosis), postoperative anemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days postoperatively. A four-way chi-squared test was used to determine statistical significance. Utilization was calculated using compound annual growth rate.ResultsThere was a difference in the incidence of DVT at 90 days (p < 0.01). Factor Xa inhibitors (2.9%) had the lowest incidence of DVT followed by aspirin (3.0%) and enoxaparin (3.5%), and warfarin (4.8%). There was a difference in the incidence of PE at 90 days (p < 0.01). Factor Xa inhibitors (0.9%) had the lowest incidence of PE followed by enoxaparin (1.1%), aspirin (1.2%), and warfarin (1.6%). There was a difference in the incidence of postoperative anemia at 90 days (p < 0.01). Aspirin (19%) had the lowest incidence of postoperative anemia followed by warfarin (22%), enoxaparin (23%), and factor Xa inhibitors (23%). There was a difference in the incidence of a blood transfusion at 90 days (p < 0.01). Aspirin (7%) had the lowest incidence of a blood transfusion followed by factor Xa inhibitors (9%), warfarin (12%), and enoxaparin (13%). There were no differences in bleeding-related complications (p = 0.81) between the groups. Aspirin use increased at a compound annual growth rate of 30%, enoxaparin at 3%, and factor Xa inhibitors at 43%, while warfarin use decreased at a compound annual growth rate of -3%.ConclusionsFactor Xa inhibitors had the highest growth in utilization during our study period, followed by aspirin, when compared with enoxaparin and warfarin. When selected for the right patient, factor Xa inhibitors provided improved VTE prophylaxis compared with enoxaparin and warfarin, with a lower rate of blood transfusion. Aspirin provided comparable VTE prophylaxis compared with factor Xa inhibitors with improved VTE prophylaxis compared with enoxaparin and warfarin with the lowest risk of bleeding.Level of evidenceLevel III, therapeutic study.
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Project description:IntroductionGuidelines have endorsed non-vitamin K antagonist oral anticoagulants (NOACs), consisting of factor Xa inhibitors (xabans) and direct thrombin inhibitors, as the first line of treatment in venous thromboembolism (VTE) and atrial fibrillation. However, morbidly obese patients were under-represented in landmark trials of NOACs. Therefore, this study aimed to systematically review and perform a meta-analysis of studies on xabans versus vitamin K antagonist (VKA) in this high-risk population with VTE.MethodsPubMed, Embase, Medline, Cochrane library, and Google Scholar databases were searched to identify studies that compared xabans and VKA in treating morbidly obese patients with VTE. Morbid obesity was defined as body weight ≥ 120 kg or BMI ≥ 40 kg/m2. Outcomes of interest included recurrent VTE, major bleeding, and clinically relevant non-major bleeding (CRNMB).ResultsEight studies comprising 30,895 patients were included. A total of 12,755 patients received xabans while 18,140 received VKAs. No significant difference in the odds of recurrent VTE (OR 0.75, 95% CI 0.55-1.01) and CRNMB (OR 0.69, 95% CI 0.44-1.09) was observed between the xabans group and the VKA group. However, the xabans group was associated with lower odds of major bleeding (OR 0.70, 95% CI 0.59-0.83).ConclusionXabans have lower odds of major bleeding but similar odds of recurrent VTE when compared with VKAs in treating VTE in morbidly obese patients. Large registry analyses or future randomized controlled trials will be helpful in confirming these findings.
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Project description:Direct oral anti-activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end-stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose-finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small-molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter-directed, pharmacomechanical antithrombotic strategies have been developed for high- and intermediate-risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.
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Project description:Human factor XIIIa (FXIIIa) is a multifunctional transglutaminase with a significant role in hemostasis. FXIIIa catalyzes the last step in the coagulation process. It stabilizes the blood clot by cross-linking the α- and γ-chains of fibrin. It also protects the newly formed clot from plasmin-mediated fibrinolysis, primarily by cross-linking α2-antiplasmin to fibrin. Furthermore, FXIIIa is a major determinant of clot size and clot's red blood cells content. Therefore, inhibitors targeting FXIIIa have been considered to develop a new generation of anticoagulants to prevent and/or treat venous thromboembolism. Several inhibitors of FXIIIa have been discovered or designed including active site and allosteric site small molecule inhibitors as well as natural and modified polypeptides. This work reviews the structural, biochemical, and pharmacological aspects of FXIIIa inhibitors so as to advance their molecular design to become more clinically relevant.
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Project description:Long-term anticoagulation in the treatment of Cerebral Venous Sinus Thrombosis (CVST) has revolved around the use of warfarin. The relatively recent introduction of Direct Oral Anticoagulants (DOACs), such as Factor Xa inhibitors, in treating CVSTs promises to offer numerous patient benefits. We aimed to examine the efficacy of Factor Xa inhibitors in comparison to warfarin in the long-term treatment of CVSTs. A single-center retrospective analysis was conducted in which 49 eligible patients having presented with a first-time CVST were identified. Long-term anticoagulation was achieved with Warfarin (n = 23) or Factor Xa Inhibitors (n = 26; Apixaban or Rivaroxaban). Outcomes of interest were improvements in patient functional status, modified Ranking Scores (mRS), and radiographic improvement/resolution in sinus thromboses. Secondary comparisons included complication rates, particularly recurring venous thrombotic events. Patient mRS scores by 7-to-18-month follow-up all fell within the extremely favorable range of 0-1 regardless of the long-term anticoagulant (P-value = 0.3591). Proportion of patients with radiographic improvement/resolution of thrombosed sinuses trended towards being higher in the Factor Xa Inhibitor group at the <12-month period, 69.2%, compared to 33.3% with Warfarin (P-value = 0.0548). By the >12-month follow-up period, Warfarin and Factor Xa inhibitor groups had similar rates of radiographic sinus improvement - 76.9% versus 71.4%, respectively (P-value = 0.6298). No statistically significant differences were documented between groups regarding complications. Factor Xa inhibitors are equally as effective as Warfarin in the long-term treatment of CVSTs, whether it be restoring patient functional status, sinus thrombus burden reduction, or minimizing bleeding complications whilst preventing recurrent venous thrombosis.
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Project description:Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, is a common disorder with at least 250 000 new events occurring each year in the United States alone. Treatment of venous thromboembolism includes anticoagulation, which is achieved initially with the use of a parenterally administered agent followed by a more prolonged course of treatment with an oral vitamin K antagonist. The duration of treatment depends on the clinical assessment of the benefit-to-risk ratio of prolonged anticoagulation versus the risk of recurrent events. In this review, we discuss some of the issues that we believe are among the most critical unanswered questions in the management of venous thromboembolism in the present era.
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Project description:MicroRNAs (miRNAs) are non-coding RNAs that execute their function by targeted downregulation of gene expressions. There is growing evidence from epidemiological studies and animal models suggesting that the expression level of miRNAs is dysregulated in venous thromboembolism (VTE). In this review, we summarize the current knowledge on the role of miRNAs as biomarkers for VTE and provide general insight into research exploring the modulation of miRNA activity in animal models of venous thrombosis. Up to now, published studies have yielded inconsistent results on the role of miRNAs as biomarkers for VTE with most of the reports focused on diagnostic research. The limited statistical power of the individual studies, due to the small sample sizes, may substantially contribute to the poor reproducibility among studies. In animal models, over-expression or inhibition of some miRNAs appear to influence venous thrombus formation and resolution. However, there is an important gap in knowledge on the potential role of miRNAs as therapeutic targets in VTE. Future research involving large cohorts should be designed to clarify the clinical usefulness of miRNAs as biomarkers for VTE, and animal model studies should be pursued to unravel the role of miRNAs in the pathogenesis of VTE and their potential as therapeutic targets.
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Project description:The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme's B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.
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