scholarly journals Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cho Yeow Koh ◽  
Norrapat Shih ◽  
Christina Y. C. Yip ◽  
Aaron Wei Liang Li ◽  
Weiming Chen ◽  
...  
Keyword(s):  
Antiplatelet Therapy ◽  
Anticoagulant Activity ◽  
Standard Of Care ◽  
Therapeutic Index ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Human Antibody ◽  
Next Generation ◽  
Pharmacologic Activity

AbstractDespite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.

Abstract 15510: Trials of Dual Antiplatelet Therapy Do Not Include Evidence-Based Strategies for Gastrointestinal Bleeding Prevention

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jacob E Kurlander ◽  
Geoffrey Barnes ◽  
Devraj Sukul ◽  
Danielle Helminski ◽  
Alex Kokaly ◽  
...  
Keyword(s):  
Gastrointestinal Bleeding ◽  
Antiplatelet Therapy ◽  
Dual Antiplatelet Therapy ◽  
Standard Of Care ◽  
Coronary Intervention ◽  
Flow Diagram ◽  
Clinical Trial Registries ◽  
Study Protocols ◽  
Registration Number ◽  
Hemorrhagic Risk

Background: Proton pump inhibitors (PPIs) substantially reduce the risk of upper gastrointestinal bleeding (GIB) and are recommended for high-risk patients by professional cardiology societies but remain underused in clinical practice. By reducing hemorrhagic risk associated with dual antiplatelet therapy (DAPT), PPIs may affect the risk-benefit equation of varying durations of DAPT and should be considered in such clinical trials. We sought to determine the extent to which randomized controlled trials (RCTs) evaluating DAPT after percutaneous coronary intervention (PCI) provide guidance on the use of PPIs for GIB prevention. Methods: A previously completed systematic review was updated to identify all RCTs comparing varying durations of DAPT between June 1983 and October 2019. Primary publications, online supplements, clinical trial registries and additional publications linked to the trial registration number were reviewed for protocol information. Results: Of 21 included studies (n=58,625; Figure), none of the study protocols provided guidance on the use of PPIs by trial participants. One study stated that the decision to use PPIs was left to the discretion of the treating physician. Two studies specified that treating physicians could prescribe non-mandated medications concordant with standard of care but did not specifically mention PPIs. Only 5 studies reported rates of PPI use, which ranged from 25.6-69.1%. Conclusions: Trials of DAPT regimens did not provide guidance on the use of PPI gastroprotection, a guideline-supported strategy for prevention of bleeding from the GI tract, the most common site of bleeding in patients using DAPT. Guidance on and reporting of PPI use should be mandatory in future antithrombotic trials to enhance their safety and interpretability. Figure 1. PRISMA flow diagram

scholarly journals Bivalirudin Use in an Infant With Persistent Clotting on Unfractionated Heparin

2011 ◽  
Vol 16 (2) ◽  
pp. 108-112
Author(s):  
Katherine M. Malloy ◽  
Tara A. McCabe ◽  
Robert J. Kuhn
Keyword(s):  
Unfractionated Heparin ◽  
Pediatric Population ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
First Year ◽  
Heparin Infusion ◽  
Percutaneous Coronary ◽  
First Year Of Life

ABSTRACT Bivalirudin is a direct thrombin inhibitor approved for use in adult patients with heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention. Recently, its use in the pediatric population has increased due to its anti-thrombin-independent mechanism of action. As heparin products produce great inter- and intraindividual variability in pediatric patients, often due to decreased anti-thrombin concentrations in the first year of life, some practitioners have turned to direct thrombin inhibitors, such as bivalirudin, for more predictable pharmacokinetics and effects on bound and circulating thrombin. We report our experience using bivalirudin in a 2-month-old female with recurrent systemic thrombi despite continuous unfractionated heparin infusion. Due to the patient's inability to maintain therapeutic activated partial thromboplastin time (aPTT) values during heparin infusion, bivalirudin was initiated at 0.1 mg/kg/h and increased due to subtherapeutic aPTTs to a maximum of 0.58 mg/kg/h. Therapeutic aPTTs were achieved at the increased dose; however, the patient's worsening renal impairment with resultant drug accumulation and overwhelming sepsis on day 5 of therapy led to discontinuation of the infusion and the initiation of comfort measures.

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.

A marriage of enhancement: fibrinolysis and conjunctive therapy

2004 ◽  
Vol 92 (12) ◽  
pp. 1194-1200 ◽  
Author(s):  
Robert Welsh ◽  
Paul Armstrong
Keyword(s):  
Coronary Intervention ◽  
The Elderly ◽  
Added Value ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
St Segment Elevation ◽  
St Segment ◽  
Percutaneous Coronary

SummaryPharmacologic reperfusion of patients with acute ST segment elevation myocardial infarction is designed to achieve prompt high-quality reperfusion, prevent recurrent ischemia and reinfarction, maintain long-term patency, and to enhance patient survival and quality of life. Because monotherapy with fibrinolytics is by itself unable to achieve all of these objectives, antithrombotic, anti-platelet, and other novel agents are required. We discuss herein the role of unfractionated and enoxaparin, the potential added value of direct thrombin inhibitors, and the importance of aspirin. Despite the promise of glycoprotein IIb/IIIa inhibitors, risks associated with intracranial hemorrhage in the elderly have led to restraint in their application to broad populations. Facilitation of urgent percutaneous coronary intervention with combination reduced-dose fibrinolytic and glycoprotein IIb/IIIa inhibitors remains a promising potential future path. The future is likely to emphasize greater application of the already effective therapies at our disposal and the development of novel anti-platelet and anti-thrombin agents as well as those directed toward inflammation.

scholarly journals Vorapaxar

2013 ◽  
pp. 88-95
Author(s):  
Gianluca Airoldi ◽  
Mauro Campanini
Keyword(s):  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Dual Antiplatelet Therapy ◽  
Absolute Risk ◽  
Standard Of Care ◽  
Adenosine Diphosphate ◽  
Coronary Intervention ◽  
Human Platelets ◽  
P2y12 Receptor ◽  
Thrombin Inhibition

Antiplatelet drugs are the cornerstone of treatment for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Clopidogrel and aspirin improve long-term vascular clinical outcomes in these patients and have become a standard of care. However, many patients still experience ischemic/thrombotic events, and it appears that insufficient response to both aspirin and clopidogrel contribute to this failure. Newer P2Y12 receptor blocker therapy resulted in only an approximately 2% reduction in absolute risk compared with clopidogrel. This indicates that residual ischemic events are mediated by other pathways that are unblocked by current dual antiplatelet therapy. Thrombin is the most potent platelet agonist (over 1000 times more than adenosine diphosphate on a molar basis). Thrombin-mediated platelet activation depends on proteaseactivated receptor (PAR) binding. PAR-1 is the main receptor for thrombin on human platelets; PAR-4 may contribute to platelet activation at much higher concentrations of thrombin. Inhibition of the PAR-1 may provide additional benefits over the standard dual antiplatelet therapy in attenuating ischemic event in patients with ACS. Vorapaxar is a new highly selective oral PAR-1 antagonist that inhibits thrombin-induced platelet activation. We review the pharmacokinetic, pharmacodynamic and clinical profile of vorapaxar. Although preliminary data indicated that vorapaxar may have the potential to improve ischemic outcomes without significantly increasing bleeding, more recent larger clinical trials seem to be less optimistic about both its effectiveness and safety. At this time, the role of vorapaxar in the settings of atherothrombotic disorders is not clear. Although it may be associated with less bleeding than P2Y12 receptor blockers, its antithrombotic effectiveness and side effects are major concerns.

Antiplatelet agents

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 267-272 ◽  
Author(s):  
David Varon ◽  
Galia Spectre
Keyword(s):  
Drug Therapy ◽  
Clinical Outcome ◽  
Antiplatelet Therapy ◽  
Dose Adjustment ◽  
New Drugs ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Multiple Drug ◽  
Increased Risk ◽  
Multiple Drug Therapy

Abstract The introduction of aspirin as an anti-thrombotic agent some 50 years ago has changed the therapeutic approach in cardiovascular medicine. Since platelets play a key role in the development of arterial thrombosis, antiplatelet drugs serve as a cornerstone in the prevention and the treatment of these conditions. After many years of a “monopoly” of aspirin, ADP receptor P2Y12 inhibitors were introduced with a significant improvement in clinical outcome. Nowadays dual antiplatelet therapy is the common practice for both acute events and secondary prevention in selected groups of patients. Another revolution was the development of potent inhibitors of the platelet integrin GPIIbIIIa, which significantly improved the outcome of percutaneous interventions (PCI), in cardiology. The improved efficacy of multiple-drug therapy is associated with an increased risk of bleeding, which raises the issue of the dosing of these drugs. Recently, numerous studies have reported a variable laboratory response to aspirin and clopidogrel, which correlates with clinical outcome. Several mechanisms have been proposed to cause this variable response, including genetic variability, disease burden and others. A major obstacle in this field is the lack of a standardized method for testing these responses, and thus some studies cannot be compared to others. Ongoing studies are currently investigating the potential translation of these observations into clinical practice. Such studies may lead to a change in the paradigm of antiplatelet therapy, where individual dose adjustment may improve efficacy and safety. Finally, a variety of new drugs are currently in different stages of development, including new P2Y12 receptor inhibitors, thromboxane receptor blockers, direct thrombin inhibitors and other signaling pathway inhibitors including oral GPIIbIIIa inhibitors. Thus, antiplatelet therapy is currently under intensive development toward multiple-drug therapy and personal-dose adjustment, which may improve clinical outcome.

New Treatment Options for Heparin-Induced Thrombocytopenia

2002 ◽  
Vol 15 (4) ◽  
pp. 305-317
Author(s):  
Sallie K. Young
Keyword(s):  
Cardiopulmonary Bypass ◽  
Treatment Options ◽  
Common Adverse Effect ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Type I ◽  
Type Ii ◽  
Heparin Induced Thrombocytopenia ◽  
Increased Risk

Heparin, in various forms, is used in a variety of conditions including prophylaxis and treatment of thromboembolic disorders. Although the most common adverse effect related to the use of heparin is bleeding, heparin-induced thrombocytopenia (HIT) can also occur. Two types of HIT exist, HIT type I and type II. HIT type I is a mild and self-limiting disease in which the patient’s platelet count may decrease slightly but will recover with continued treatment. This is in contrast to HIT type II, which may lead to potentially devastating complications. Patients with HIT type II are at increased risk for thromboembolic complications that are mediated through autoimmune reactions and therefore require anticoagulation with danaparoid or one of the direct thrombin inhibitors, including lepirudin, argatroban, or bivalirudin. Limited data are available on the use of these agents in special populations including patients who are pregnant or those undergoing procedures such as percutaneous coronary intervention, cardiopulmonary bypass and dialysis, and pregnancy. Future therapies may include the use of unfractionated heparin in combination with glycoprotein IIb/IIIa inhibitors during cardiopulmonary bypass.

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