Spotlight on real-world evidence for the treatment of DVT: XALIA

2016 ◽  
Vol 116 (S 02) ◽  
pp. S41-S49 ◽  
Author(s):  
Alexander Turpie ◽  
Walter Ageno
Keyword(s):  
Venous Thromboembolism ◽  
Real World ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Standard Of Care ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
Real World Evidence ◽  
Recurrent Vte

SummaryVenous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

scholarly journals New anticoagulants for the treatment of venous thromboembolism

2016 ◽  
Vol 42 (2) ◽  
pp. 146-154 ◽  
Author(s):  
Caio Julio Cesar dos Santos Fernandes ◽  
José Leonidas Alves Júnior ◽  
Francisca Gavilanes ◽  
Luis Felipe Prada ◽  
Luciana Kato Morinaga ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
New Anticoagulants ◽  
Acute Pulmonary Thromboembolism ◽  
Deep Vein

Worldwide, venous thromboembolism (VTE) is among the leading causes of death from cardiovascular disease, surpassed only by acute myocardial infarction and stroke. The spectrum of VTE presentations ranges, by degree of severity, from deep vein thrombosis to acute pulmonary thromboembolism. Treatment is based on full anticoagulation of the patients. For many decades, it has been known that anticoagulation directly affects the mortality associated with VTE. Until the beginning of this century, anticoagulant therapy was based on the use of unfractionated or low-molecular-weight heparin and vitamin K antagonists, warfarin in particular. Over the past decades, new classes of anticoagulants have been developed, such as factor Xa inhibitors and direct thrombin inhibitors, which significantly changed the therapeutic arsenal against VTE, due to their efficacy and safety when compared with the conventional treatment. The focus of this review was on evaluating the role of these new anticoagulants in this clinical context.

scholarly journals Direct oral anticoagulants and venous thromboembolism

2016 ◽  
Vol 25 (141) ◽  
pp. 295-302 ◽  
Author(s):  
Massimo Franchini ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
Direct Anticoagulants ◽  
Deep Vein

Venous thromboembolism (VTE), consisting of deep vein thrombosis and pulmonary embolism, is a major clinical concern associated with significant morbidity and mortality. The cornerstone of management of VTE is anticoagulation, and traditional anticoagulants include parenteral heparins and oral vitamin K antagonists. Recently, new oral anticoagulant drugs have been developed and licensed, including direct factor Xa inhibitors (e.g. rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g. dabigatran etexilate). This narrative review focusses on the characteristics of these direct anticoagulants and the main results of published clinical studies on their use in the prevention and treatment of VTE.

Efficacy and Safety of Fondaparinux (ARIXTRA®) in the Initial Treatment of Venous Thromboembolism in Obese Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 706-706 ◽  
Author(s):  
Harry R. Buller ◽  
Keyword(s):  
Venous Thromboembolism ◽  
Initial Treatment ◽  
Oral Anticoagulants ◽  
Safety Data ◽  
Factor Xa ◽  
Obese Patients ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Vein Thrombosis ◽  
Recurrent Vte

Abstract Background: The MATISSE trials demonstrated that once-daily subcutaneous fondaparinux, a synthetic selective factor Xa inhibitor, was at least as effective and as safe as standard therapies in the initial treatment of deep-vein thrombosis (DVT) or pulmonary embolism (PE). Since obesity is a risk factor for venous thromboembolism (VTE), we analyzed the MATISSE data from the subpopulation of obese patients (body-mass index, BMI ≥30 kg/m2). Methods: Fondaparinux was administered at a once-daily subcutaneous dose of 7.5 mg (5.0 mg and 10.0 mg in patients <50 kg and >100 kg, respectively). In the MATISSE-DVT trial, fondaparinux was compared with twice-daily subcutaneous enoxaparin (1 mg/kg) in patients with DVT. In the MATISSE-PE trial, it was compared with adjusted-dose intravenous unfractionated heparin (UFH) in patients with PE. All drugs were given for at least 5 days and until anticoagulation with oral anticoagulants was therapeutic. The primary efficacy and safety outcomes were recurrent VTE during 3 months’ follow-up and major bleeding (MB) and death during the initial treatment period. Results: The percentage of obese patients was 26.3% in MATISSE-DVT and 28.7% in MATISSE-PE (Tables). In both MATISSE-DVT and -PE, efficacy and safety data from obese patients were similar to those from non-obese patients (BMI <30kg/m2). The rates of recurrent VTE and MB in obese patients were not significantly different between fondaparinux and either enoxaparin (MATISSE-DVT) or UFH (MATISSE-PE). Conclusion: Once-daily fondaparinux is at least as effective and as safe as standard therapies in the initial treatment of DVT or PE in obese patients. MATISSE DVT BMI<30 kg/m2 BMI≥30 kg/m2 Enoxaparin Fondaparinux Enoxaparin Fondaparinux *As treated patients n 791 803 300 280 VTE, n/N 35/791 (4.4%) 31/803 (3.9%) 10/300 (3.3%) 10/280 (3.6%) MB*, n/N 10/788 (1.3%) 12/798 (1.5%) 3/297 (1.0%) 0/279 (0%) MATISSE PE BMI<30 kg/m2 BMI≥30 kg/m2 UFH Fondaparinux UFH Fondaparinux *As Treated Patients n 760 757 322 314 VTE, n/N 35/760 (4.6%) 30/757 (4.0%) 20/322 (6.2%) 12/314 (3.8%) MB*, n/N 8/752 (1.1%) 11/751 (1.5%) 4/314 (1.3%) 2/311 (0.6%)

Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement

2003 ◽  
Vol 89 (02) ◽  
pp. 288-296 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Alexander Cohen ◽  
Ola Dahl ◽  
Patrick Mouret ◽  
Nadia Rosencher ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Knee Replacement ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Double Blind Study ◽  
Double Blind ◽  
Total Hip ◽  
Vein Thrombosis ◽  
Major Orthopaedic Surgery

SummaryWe evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

Old and new anticoagulants

2011 ◽  
Vol 31 (01) ◽  
pp. 21-27 ◽  
Author(s):  
U. Harbrecht
Keyword(s):  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
New Oral Anticoagulants ◽  
Thrombin Inhibitors ◽  
Clotting Factor ◽  
Direct Thrombin Inhibitors ◽  
Self Monitoring ◽  
New Anticoagulants ◽  
Gastrointestinal Side Effects

SummaryVitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosure of the molecular basis of interaction with VKORC1, the target enzyme of VKA, has helped to better understand coumarin sensitivity and resistance. New oral anticoagulants have now been approved and stimulated expectations in patients and physicians to get rid of the burdening frequent controls of VKA without loss of efficacy and safety.This review will summarize the development and profile of the new substances. Main difference compared to VKA is their direct mode of action against one clotting factor which is factor IIa in dabigatran and factor Xa in rivaroxaban and other “xabanes” currently under intensive investigation. Half lifes of the new anticoagulants are much shorter than that of the mainly used coumarins (phenprocoumon, warfarin), making “anticoagulation bridging” unnecessary before surgery. Therapeutic width of direct thrombin inhibitors and factor Xa inhibitors is broader and they are given at fixed doses. Clinical studies in thromboprophylaxis, thromboembolism and atrial fibrillation indicate at least non-inferiority or even superior efficacy compared with enoxaparin and VKA at comparable safety outcomes. Limitations of the new substances may arise from gastrointestinal side effects, mode of metabolism and route of elimination. Specific antidots are not available for none of them.Undoubtedly, the new oral anticoagulants are very promising. But, although thousands of study patients already have been treated, there are questions to be answered such as treatment adherence in absence of monitoring, safety and efficacy in risk patients, dosage adjustment and interactions with other drugs, before conclusions can be drawn towards their potential to replace VKA.

Management consensus guidance for the use of rivaroxaban – an oral, direct factor Xa inhibitor

2012 ◽  
Vol 108 (11) ◽  
pp. 876-886 ◽  
Author(s):  
Reinhold Kreutz ◽  
Juan Llau ◽  
Bo Norrving ◽  
Sylvia Haas ◽  
Alexander Turpie
Keyword(s):  
Venous Thromboembolism ◽  
Large Scale ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Clinical Trial Data ◽  
Thrombin Inhibitor ◽  
Direct Factor ◽  
Replacement Surgery ◽  
Vein Thrombosis

SummaryA number of novel oral anticoagulants that directly target factor Xa or thrombin have been developed in recent years. Rivaroxaban and apixaban (direct factor Xa inhibitors) and dabigatran etexilate (a direct thrombin inhibitor) have shown considerable promise in large-scale, randomised clinical studies for the management of thromboembolic disorders, and have been approved for clinical use in specific indications. Rivaroxaban is licensed for the prevention of venous thromboembolism in patients undergoing elective hip or knee replacement surgery, the treatment of deep-vein thrombosis and prevention of recurrent venous thromboembolism, and for stroke prevention in patients with non-valvular atrial fibrillation. Based on the clinical trial data for rivaroxaban, feedback on its use in clinical practice and the authors’ experience with the use of rivaroxaban, practical guidance for the use of rivaroxaban in special patient populations and specific clinical situations is provided. Although most recommendations are in line with the European summary of product characteristics for the approved indications, additional and, in several areas, different recommendations are given based on review of the literature and the authors’ clinical experience.

Ximelagatran: A new type of oral anticoagulant

2005 ◽  
Vol 21 (4) ◽  
pp. 480-486
Author(s):  
Lisa Kwok ◽  
Dana Molckovsky ◽  
Michel Boucher
Keyword(s):  
Atrial Fibrillation ◽  
Venous Thromboembolism ◽  
Web Sites ◽  
Liver Toxicity ◽  
Oral Anticoagulants ◽  
Bleeding Risk ◽  
Thrombin Inhibitors ◽  
Cochrane Library ◽  
Direct Thrombin Inhibitors ◽  
Elevated Liver Enzymes

Objectives: This assessment sought to evaluate the comparative benefit and adverse effect profile of ximelagatran, as well as the clinical issues surrounding its potential use.Methods: We performed a Dialog OneSearch across BIOSIS Previews, EMBASE, MEDLINE, PASCAL, and ToxFile to identify published literature. PubMed and The Cochrane Library were also searched. Gray literature was identified by searching a variety of Web sites of health technology assessment and related agencies and their associated databases. The manufacturer's Canadian office, AstraZeneca, was invited to submit information.Results: Ximelagatran is the first oral agent from a new class of anticoagulants called direct thrombin inhibitors. Other oral anticoagulants require routine blood monitoring; ximelagatran does not. Ximelagatran has been evaluated in the areas of venous thromboembolism management, particularly after orthopedic surgery, and stroke prevention in patients with atrial fibrillation. Overall, ximelagatran's efficacy appears comparable to other anticoagulants in these clinical settings. Also, bleeding rates were generally similar between ximelagatran and comparators but, as for warfarin, bleeding risk increases with higher ximelagatran doses. In addition, there is no specific antidote to help manage ximelagatran-induced bleeding. Finally, significantly more patients exposed to long-term ximelagatran developed elevated liver enzymes more than three times the upper normal limit, compared with patients on comparator anticoagulants.Conclusions: Given its apparent simplicity of use, ximelagatran carries the potential to replace, at least in part, anticoagulants currently used in the management of venous thromboembolism or for preventing stroke in atrial fibrillation patients. However, the safety of ximelagatran will not be fully known without further evaluation and surveillance for potential liver toxicity. There is also a need to evaluate its use in special populations such as patients with renal failure and patients using several concurrent medications.

Thrombophilia and New Anticoagulant Drugs

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 424-438 ◽  
Author(s):  
Jeffrey I. Weitz ◽  
Saskia Middeldorp ◽  
William Geerts ◽  
John A. Heit
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Phase Ii ◽  
Anticoagulation Therapy ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
First Episode ◽  
Direct Thrombin Inhibitors ◽  
Risk Of Recurrence ◽  
Phase Ii And Iii

Abstract Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is the result of an imbalance among procoagulant, anticoagulant and profibrinolytic processes. This imbalance reflects a complex interplay between genetic and environmental or acquired risk factors. Genetic thrombophilic defects influence the risk of a first episode of thrombosis. How these defects influence the risk of recurrence in patients whose first episode of venous thromboembolism was unprovoked is less certain. Thus, when anticoagulants are stopped, patients with unprovoked venous thromboembolism have a risk of recurrence of at least 7% to 10% per year, even in the absence of an underlying thrombophilic defect. Consequently, there is a trend toward longer durations of anticoagulation therapy for these patients, which is problematic given the limitation of existing anticoagulants. This chapter provides an overview of the thrombophilic defects and how they influence the risk of venous thromboembolism. The chapter also details advances in anticoagulant therapy, focusing on new inhibitors of factor Xa and thrombin. In Section I, Dr. Saskia Middeldorp describes the various thrombophilic defects and reviews their relative importance in the pathogenesis of a first episode of venous thromboembolism. She then discusses the influence of these defects on the risk of recurrent thrombotic events in patients with unprovoked venous thromboembolism and in those whose thrombosis occurred in association with a known risk factor, such as surgery. In Section II, Dr. William Geerts reviews the pharmacology of new parenteral and oral factor Xa inhibitors and describes the results of the Phase II and III clinical trials with these agents. He then provides perspective on the potential advantages and drawbacks of these drugs for the prevention and treatment of venous thromboembolism. In Section III, Dr. John Heit focuses on direct thrombin inhibitors. He discusses their mechanism of action and compares and contrasts their pharmacological profiles prior to describing the results of Phase II and III clinical trials. Dr. Heit then provides perspective on the potential advantages and limitations of these drugs relative to existing anticoagulants.

Review of the Target-Specific Oral Anticoagulants in Development for the Treatment and Prevention of Venous Thromboembolism

2016 ◽  
Vol 29 (4) ◽  
pp. 392-405 ◽  
Author(s):  
Sandeep Devabhakthuni ◽  
Connie H. Yoon ◽  
Kathleen J. Pincus
Keyword(s):  
Venous Thromboembolism ◽  
Clinical Decision Making ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Bleeding Risk ◽  
Clinical Decision ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Treatment And Prevention

Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice.

scholarly journals Direct oral anticoagulant (DOAC) interference in hemostasis assays

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 129-133
Author(s):  
Karen A. Moser ◽  
Kristi J. Smock
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Sample Collection ◽  
Educational Materials ◽  
Direct Factor Xa Inhibitors ◽  
Testing Algorithms

Abstract Direct oral anticoagulants (DOACs) are a group of direct coagulation factor inhibitors including both direct thrombin inhibitors and direct factor Xa inhibitors. These medications may cause hemostasis assay interference by falsely increasing or decreasing measured values, depending on the analyte. Considering the potential for DOAC interference in a variety of hemostasis assays is essential to avoid erroneous interpretation of results. Preanalytic strategies to avoid DOAC interference include selecting alternatives to clot-based hemostasis assays in patients taking DOACs when possible and sample collection timed when the patient is off anticoagulant therapy or at the expected drug trough. Clinical laboratories may also provide educational materials that clearly describe possible interferences from DOAC, develop testing algorithms to aid in detection of DOAC in submitted samples, use DOAC-neutralizing agents to remove DOACs before continuing with testing, and write interpretive comments that explain the effects of DOAC interference in hemostasis tests. Using a combination of the described strategies will aid physicians and laboratorians in correctly interpreting hemostasis and thrombosis laboratory tests in the presence of DOACs.

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