New Developments in Anticoagulation Therapy: Oral Direct Thrombin Inhibitors

2004 ◽  
Vol 24 (10 Part 2) ◽  
pp. 165S-165S
Author(s):  
Edith A. Nutescu ◽  
Jerry L. Bauman
Keyword(s):  
Anticoagulation Therapy ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
New Developments

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.

Anticoagulation Monitoring Part 1: Warfarin and Parenteral Direct Thrombin Inhibitors

2005 ◽  
Vol 39 (6) ◽  
pp. 1049-1055 ◽  
Author(s):  
Sarah A Spinler ◽  
Edith A Nutescu ◽  
Maureen A Smythe ◽  
Ann K Wittkowsky
Keyword(s):  
Clinical Application ◽  
Web Sites ◽  
English Language ◽  
Point Of Care ◽  
Anticoagulation Therapy ◽  
Thrombin Inhibitors ◽  
Care Utilization ◽  
Direct Thrombin Inhibitors ◽  
Reference Laboratory ◽  
Medline Search

OBJECTIVE: To review the availability, mechanisms, limitations, and clinical application of point-of-care (POC) devices used in the management of warfarin and parenteral direct thrombin inhibitors. DATA SOURCES: Scientific articles were identified through a MEDLINE search (1966–August 2004), manufacturer Web sites, additional references listed in articles and Web sites, and abstracts from scientific meetings. STUDY SELECTION AND DATA EXTRACTION: English-language literature from clinical trials was reviewed to evaluate the accuracy, reliability, and clinical application of POC monitoring devices. DATA SYNTHESIS: The prothrombin time expressed as the international normalized ratio (PT—INR) is a well-established test for monitoring warfarin anticoagulation. Multiple devices are available for POC testing. Because there is no universally accepted standard, the performance of each device is typically tested against a standard test performed in a reference laboratory. Performance of currently available devices, as measured by correlations to a standard reference laboratory PT—INR, may be considered very good and acceptable for use in patient care. Utilization of patient self-testing and patient self-monitoring of warfarin anticoagulation using POC devices is increasing. Parenteral direct thrombin inhibitors are typically monitored using a standard laboratory activated partial thromboplastin time. Some research has shown that POC monitoring of direct thrombin inhibitors using the ecarin clotting time is helpful for patients undergoing cardiopulmonary bypass surgery, although that test is not readily available. CONCLUSIONS: POC testing for anticoagulation therapy has been available for >20 years. Multiple POC devices are available to monitor warfarin. There is some variability in results between devices and between reagents used in the same device. Despite these limitations, POC monitoring of warfarin via the PT—INR is an integral part of clinical practice. Additional research evaluating POC monitoring of direct thrombin inhibitors is necessary.

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.

High Incidence of Thromboembolic Complications and PF4 Positivity in Patients with Ventricular Assist Devices.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4083-4083
Author(s):  
Brandon J. McMahon ◽  
Jainulabdeen J. Ifthikharuddin ◽  
Elie Dib ◽  
Leway Chen ◽  
Charles W. Francis ◽  
...  
Keyword(s):  
Anticoagulation Therapy ◽  
High Rate ◽  
Thrombin Inhibitors ◽  
Ventricular Assist Devices ◽  
Direct Thrombin Inhibitors ◽  
Thromboembolic Complications ◽  
Ventricular Assist ◽  
Full Dose ◽  
Assist Devices ◽  
High Incidence

Abstract Patients with ventricular assist devices (VAD) are at high risk for thromboembolic complications (TEC) probably due to platelet activation and excessive thrombin generation once the device is implanted. This warrants prophylactic use of full dose anticoagulation, usually with unfractionated heparin (UFH), which increases the risk for development of heparin-induced thrombocytopenia (HIT). We retrospectively evaluated the incidence of TEC and PF4 positivity in 50 sequential patients who underwent VAD placement for severe ventricular dysfunction between November 2002 and April 2005. Median age at VAD placement was 52 years (range 18–72), 68% were men, and all patients were on full dose UFH post-VAD insertion. TEC were observed in 22/50 patients (44%), with 8 patients experiencing >1 event. CNS embolic phenomena occurred in 11/22 (50% of TEC), with watershed/non-embolic CNS infarcts being identified in 2 additional patients. Splenic infarcts were identified in 6/22 (27%). Two patients had lower extremity deep vein thromboses (DVT), and two patients had pulmonary emboli. One patient died from complications of multiple infarcts involving his spleen and gut that were attributed to HIT. All patients became thrombocytopenic (<150K) at some point during VAD/UFH use. 44 patients (88%) dropped the platelet count below 100K with an average nadir of 56K. Antibodies to the PF4/heparin complex were checked using a standard enzyme immunoassay (EIA) in 38 (76%) patients, and found to be positive in 17 (44.7%). PF4 antibodies were detected using the EIA in 50% of patients with TEC and in 25% of patients with no documented TEC. A functional antibody assay was checked in a total of 17 patients, the serotonin release assay (SRA) in 13 and heparin-induced agglutination (HIA) in 4 cases. The SRA was only positive in 2/13 cases, and concordant with the PF4 result both times. The HIA was positive once, and concordant with the PF4 result. These results highlight the high incidence of TEC in patients with a VAD, despite anticoagulation therapy. There is a particularly high rate of embolic stroke in this patient population, and better ways of preventing this complication need to be explored. Thrombocytopenia is also extremely common post-VAD placement, prompting evaluation of HIT in over ¾ of the patients, often necessitating use of direct thrombin inhibitors. The frequent detection of PF4 antibodies in this patient group and lack of correlation with functional assays illustrates the need for more specific laboratory means to quickly confirm those patients with HIT.

Advances in antithrombotic therapy as adjunct to reperfusion therapies for ST-segment elevation myocardial infarction

2008 ◽  
Vol 100 (08) ◽  
pp. 184-195 ◽  
Author(s):  
Paolo Marino ◽  
Giuseppe De Luca
Keyword(s):  
Myocardial Infarction ◽  
Antithrombotic Therapy ◽  
Anticoagulation Therapy ◽  
Primary Angioplasty ◽  
Thrombin Inhibitors ◽  
Bleeding Complications ◽  
Direct Thrombin Inhibitors ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
St Segment

SummaryThe treatment of ST-segment elevation myocardial infarction (STEMI) has improved over the past decades, mainly due to reperfusion therapies. The aim of this article is to provide an updated review of adjunctive antithrombotic therapy to reperfusion strategies for STEMI. As compared to unfractionated heparin (UFH), among patients treated with thrombolysis, low-molecular- weight heparins (LMWHs),mainly enoxaparin, fonda-parinux and clopidogrel have been shown to improve outcome in terms of death and reinfarction, whereas GP IIb-IIIa inhibitors, mainly abciximab, and direct thrombin inhibitors have reduced reinfarction, but not mortality. Among patients undergoing primary angioplasty, early UFH should still be regarded as the gold standard in anticoagulation therapy. In addition to ASA, early GP IIb-IIIa inhibitors, especially abciximab, should be considered since it has been shown to provide further benefits in terms of preprocedural recanalization. Despite the positive results observed in the HORIZONS trial, additional studies are needed to investigate the role of bivalirudin as compared to abciximab administration. In our opinion, bivalirudin may be considered instead of GP IIb-IIIa inhibitors among STEMI patients at high risk for bleeding complications. Due to the very low mortality currently achieved by primary angioplasty, a further reduction in short- or medium-term mortality would be quite improbable to be observed. Thus, additional endpoints, such as infarct size and myocardial perfusion, may be considered in future randomized trials among patients undergoing mechanical revascularization for STEMI.

scholarly journals Old and new oral anticoagulants for secondary stroke prevention in atrial fibrillation

2015 ◽  
Vol 9 (4) ◽  
pp. 314
Author(s):  
Tommaso Sacquegna ◽  
Anna Zaniboni ◽  
Andrea Rubboli ◽  
Gaetano Procaccianti ◽  
Michela Crisci ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Secondary Prevention ◽  
Stroke Prevention ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
New Oral Anticoagulants ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Significant Difference

Vitamin K antagonists, such as warfarin, used in oral anticoagulation therapy currently represent the standard drugs for the primary and secondary prevention of stroke in non-valvular atrial fibrillation (AF), with a relative risk reduction close to 70%. Newer oral anticoagulants, such as direct thrombin inhibitors (<em>i.e</em>., dabigatran) and direct factor Xa inhibitors (<em>i.e</em>., apixaban and rivaroxaban) have been recently compared with warfarin in large randomized trials for stroke prevention in AF. The new oral anticoagulants showed, compared with warfarin, no statistically significant difference in the rate of stroke or systemic embolism in secondary prevention (patients with previous transient ischemic attack or stroke) subgroups. With regard to safety, the risk of intracranial bleeding was reduced with new anticoagulants compared with warfarin. Indirect treatment comparisons of clinical trials on secondary prevention cohorts showed no significant difference in efficacy among apixaban, rivaroxaban, and dabigatran; but dabigatran 110 mg was associated with less intracranial bleedings than rivaroxaban.

scholarly journals Updates in Anticoagulation Therapy Monitoring

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 262
Author(s):  
Hannah L. McRae ◽  
Leah Militello ◽  
Majed A. Refaai
Keyword(s):  
Therapy Monitoring ◽  
Anticoagulation Therapy ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Low Molecular Weight Heparins ◽  
Reversal Agents ◽  
The Past ◽  
Clinical Scenarios ◽  
Do So

In the past six decades, heparin and warfarin were the primary anticoagulants prescribed for treatment and prophylaxis of venous thromboembolism worldwide. This has been accompanied by extensive clinical knowledge regarding dosing, monitoring, and reversal of these anticoagulants, and the resources required to do so have largely been readily available at small and large centers alike. However, with the advent of newer oral and parenteral anticoagulants such as low molecular weight heparins, factor Xa inhibitors, and direct thrombin inhibitors in recent years, new corresponding practice guidelines have also emerged. A notable shift in the need for monitoring and reversal agents has evolved as well. While this has perhaps streamlined the process for physicians and is often desirable for patients, it has also left a knowledge and resource gap in clinical scenarios for which urgent reversal and monitoring is necessary. An overview of the currently available anticoagulants with a focus on the guidelines and available tests for anticoagulant monitoring will be discussed in this article.

scholarly journals Antiphospholipid Syndrome (APS) - An Update on Clinical Features and Treatment Options

2015 ◽  
Vol 8 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Mamatha Katikaneni ◽  
Meera Gangam ◽  
Seth Mark Berney ◽  
Sarwat Umer
Keyword(s):  
Clinical Features ◽  
Antiphospholipid Syndrome ◽  
Treatment Options ◽  
Anticoagulation Therapy ◽  
Clinical Manifestations ◽  
Skin Lesions ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Thrombotic Risk

Antiphospholipid syndrome (APS) is an autoantibody disorder characterized by the presence of antiphospholipid (APL) antibodies and heterogeneous clinical manifestations. Patients may present with recurrent thrombosis, obstetric morbidity, cardiac valvular lesions, thrombocytopenia, skin lesions, renal or neurologic abnormalities. We provide a comprehensive review of these diverse clinical features except renal and obstetric complications. Treatment of APS can be challenging as one tries to balance the benefit of anticoagulation therapy in this hypercoagulable state while minimizing the risk of bleeding. We discuss the various therapeutic options including the role of aspirin, warfarin, low molecular weight heparin, new direct thrombin inhibitors, hydroxychloroquine, intravenous gamma globulin, rituximab and others. Lower risk APS patients (i.e. first venous thrombosis) should receive warfarin with a target INR of 2.0-3.0. Higher risk patients (i.e. arterial thrombosis or recurrent venous events) have a target INR of >3.0. Currently, warfarin remains the mainstay in treatment of APS. Because of lack of adequate data, the newer oral direct inhibitors should be considered only when there is a known allergy/ intolerance or poor control with warfarin. Additional vascular and thrombotic risk factors should be aggressively reduced. Further studies involving large number of APS patients, diagnosed according to accepted criteria, are needed to better define the role of newer anticoagulants and other novel therapies.

The uncalibrated prothrombinase-induced clotting time test

2010 ◽  
Vol 30 (04) ◽  
pp. 212-216 ◽  
Author(s):  
R. Jovic ◽  
M. Hollenstein ◽  
P. Degiacomi ◽  
M. Gautschi ◽  
A. Ferrández ◽  
...  
Keyword(s):  
Factor Xa ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Coagulation Cascade ◽  
Diagnostic Tools ◽  
Direct Thrombin Inhibitors ◽  
Functional Assay ◽  
Clotting Time ◽  
Coagulation Time ◽  
Time Test

SummaryThe activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT’s dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®-PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

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