bivalirudin and Venous-Thromboembolism

The efficacy and safety of heparin and low-molecular-weight heparins (LMWHs) are well documented in venous and arterial thromboembolism. Several drawbacks of heparins have inspired the development of newer parenteral anticoagulants for specific indications, including heparin-induced thrombocytopenia (HIT) and percutaneous coronary interventions (PCI). The direct thrombin inhibitors recombinant hirudin and argatroban are now established alternatives for HIT patients, and bivalirudin is one of the most used anticoagulants in PCI. The pentasaccharide fondaparinux is an alternative for LMWH for thromboprophylaxis in various clinical settings and for patients with an acute coronary syndrome (ACS) not scheduled for PCI. In Europe, it was recently approved for treatment of superficial vein thrombosis. Further development of new parenteral anticoagulants is slow and the emphasis has shifted towards development of new oral anticoagulants and antiplatelet drugs. Still, promising new anticoagulants, some targeting less conventional targets in the coagulation system, have been developed and will undergo further clinical evaluation.

Topics: Acute Coronary Syndrome; Antithrombins; Arginine; Fondaparinux; Hirudin Therapy; Hirudins; Humans; Infusions, Parenteral; Peptide Fragments; Percutaneous Coronary Intervention; Pipecolic Acids; Polysaccharides; Randomized Controlled Trials as Topic; Recombinant Proteins; Sulfonamides; Thrombin; Venous Thromboembolism

Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy.

Topics: Anticoagulants; Antithrombins; Arginine; Benzimidazoles; Dabigatran; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Pyridines; Recombinant Proteins; Sulfonamides; Thrombin; Venous Thromboembolism

Venous thrombosis and pulmonary embolism rarely occur in children but are associated with significant morbidity and mortality. Venous thromboembolism (VTE) mostly affects children with severe underlying conditions and multiple risk factors. Newborns and adolescents are at the highest risk. Standard and low molecular weight heparins and vitamin K antagonists are routinely used for the prevention and treatment of VTE. The new anticoagulants, both parenteral such as argatroban, bivalirudin and fondaparinux and oral such as dabigatran and rivaroxaban, have favourable pharmacological properties, all are approved for clinical use in adults and are currently being investigated in children. Argatroban is the only new anticoagulant licensed for use in children so far. The role of these new anticoagulants as alternative anticoagulants for children remains to be defined. This review focuses on the characteristics of VTE in children and reviews current knowledge on the use of the new thrombin and factor Xa inhibitors in this population.

Topics: Adolescent; Anticoagulants; Arginine; Benzimidazoles; beta-Alanine; Child; Child, Preschool; Dabigatran; Drug Approval; Factor Xa Inhibitors; Fondaparinux; Hirudins; Humans; Infant; Infant, Newborn; Morpholines; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Risk Factors; Rivaroxaban; Sulfonamides; Thiophenes; Thrombin; Venous Thromboembolism

Thromboembolic complications are becoming more frequent in children and the use of anticoagulation has increased considerably. The most widely used agents in children, heparin, low molecular weight heparin, and warfarin all have limitations which are exaggerated in children. This has led to the study of newer agents with improved pharmacologic properties such as bivalirudin, argatroban, and fondaparinux. Clinical trials are under way to assess several new oral anticoagulants that are in late phase studies or already licensed in adults. Based on the completed studies in children, several recommendations for the use of currently available agents (bivalirudin, argatroban, and fondaparinux) are suggested for clinical use today. Additional studies need to be conducted for the these agents, so that their use may be expanded in selected indications. New regulatory requirements are leading to a number of studies in the newer anticoagulants that are yet to be licensed in adults for treatment of venous thromboembolism. Pediatric thrombosis is entering a fruitful era of research in anticoagulation management, which is sure to lead to significant changes in how children are treated in the next 10 years.

Topics: Anticoagulants; Arginine; Fondaparinux; Heparin, Low-Molecular-Weight; Hirudins; Humans; Infant; Infant, Newborn; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Venous Thromboembolism; Warfarin

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin. Patients are at markedly increased risk of thromboembolism.. These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about diagnosis and management of HIT.. ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment.. The panel agreed on 33 recommendations. The recommendations address screening of asymptomatic patients for HIT, diagnosis and initial management of patients with suspected HIT, treatment of acute HIT, and special situations in patients with acute HIT or a history of HIT, including cardiovascular surgery, percutaneous cardiovascular intervention, renal replacement therapy, and venous thromboembolism prophylaxis.. Strong recommendations include use of the 4Ts score rather than a gestalt approach for estimating the pretest probability of HIT and avoidance of HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score. Conditional recommendations include the choice among non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) for treatment of acute HIT.

Topics: Administration, Oral; Anticoagulants; Arginine; Cardiovascular Surgical Procedures; Chondroitin Sulfates; Dermatan Sulfate; Evidence-Based Medicine; Fondaparinux; Heparin; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Platelet Count; Recombinant Proteins; Renal Replacement Therapy; Sulfonamides; Thrombocytopenia; Venous Thromboembolism

Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants.

Topics: Anticoagulants; Arginine; Blood Coagulation; Child; Drug Monitoring; Fondaparinux; Heparin; Hirudins; Humans; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Thrombosis; Venous Thromboembolism; Warfarin