Direct thrombin inhibitors in atrial fibrillation reloaded

Embolism of cardiac origin accounts for about 20% of ischemic strokes. Nonvalvular atrial fibrillation is the most frequent cause of cardioembolic stroke. Approximately 1% of population is affected by atrial fibrillation, and its prevalence is growing with ageing in the modern world. Strokes due to cardioembolism are in general severe and prone to early recurrence and have a higher long-term risk of recurrence and mortality. Despite its enormous preventive potential, continuous oral anticoagulation is prescribed for less than half of patients with atrial fibrillation who have risk factors for cardioembolism and no contraindications for anticoagulation. Available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke. Anticoagulation therapy's associated risk of hemorrhage and monitoring requirements have encouraged the investigation of alternative therapies for individuals with atrial fibrillation. New anticoagulants being tested for prevention of stroke are low-molecular-weight heparins (LMWH), unfractionated heparin, factor Xa inhibitors, or direct thrombin inhibitors like dabigatran etexilate and rivaroxaban. The later exhibit stable pharmacokinetics obviating the need for coagulation monitoring or dose titration, and they lack clinically significant food or drug interaction. Moreover, they offer another potential that includes fixed dosing, oral administration, and rapid onset of action. There are several concerns regarding potential harm, including an increased risk for hepatotoxicity, clinically significant bleeding, and acute coronary events. Therefore, additional trials and postmarketing surveillance will be needed.

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Direct Thrombin Inhibitors for Treatment of Heparin Induced Thrombocytopenia, Deep Vein Thrombosis and Atrial Fibrillation

Current Pharmaceutical Design ◽

10.2174/138161205774580570 ◽

2005 ◽

Vol 11 (30) ◽

pp. 3931-3941 ◽

Cited By ~ 3

Author(s):

C. Francis

Keyword(s):

Atrial Fibrillation ◽

Deep Vein Thrombosis ◽

Thrombin Inhibitors ◽

Direct Thrombin Inhibitors ◽

Heparin Induced Thrombocytopenia ◽

Vein Thrombosis ◽

Deep Vein

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Ximelagatran: A new type of oral anticoagulant

International Journal of Technology Assessment in Health Care ◽

10.1017/s026646230505066x ◽

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.

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The Direct Thrombin Inhibitors Dabigatran and Lepirudin Inhibit GPIbα-Mediated Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0039-1685139 ◽

2019 ◽

Vol 119 (06) ◽

pp. 916-929 ◽

Cited By ~ 8

Author(s):

Katharina Trabold ◽

Stephanie Makhoul ◽

Stepan Gambaryan ◽

Joanne van Ryn ◽

Ulrich Walter ◽

...

Keyword(s):

Atrial Fibrillation ◽

Platelet Aggregation ◽

Soluble Guanylate Cyclase ◽

Adenosine Monophosphate ◽

Guanosine Monophosphate ◽

Thrombin Inhibitors ◽

Thrombin Inhibitor ◽

Direct Thrombin Inhibitors ◽

Platelet Receptor ◽

Induced Aggregation

AbstractThe direct thrombin inhibitor (DTI) dabigatran is a non-vitamin K antagonist oral anticoagulant for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. In addition to its anti-thrombotic efficacy, dabigatran has been suggested to exert some pro-thrombotic effect due to fostering the ligation of thrombin to its high affinity platelet receptor glycoprotein (GP) Ibα in patients with atrial fibrillation. On the other hand, we provided evidence that a member of another class of DTIs, lepirudin, stimulates the inhibitory cyclic guanosine monophosphate (cGMP)/soluble guanylate cyclase pathway in human platelets. Here, we investigated the effect of lepirudin and dabigatran spiked to platelets from healthy volunteers on GPIbα-mediated platelet aggregation and agglutination. Ristocetin/von Willebrand factor (vWF)-induced aggregation of platelets in the presence or absence of plasma was significantly inhibited by lepirudin, dabigatran and D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK). However, ristocetin/vWF-mediated platelet agglutination and binding of vWF to platelets were not affected by the DTIs. The anti-aggregatory effect was confirmed by using the GPIbα-specific agonist echicetin beads for human and murine platelets. DTIs diminished echicetin beads-induced Syk Y352 phosphorylation (used here as readout for an early signal occurring during echicetin-induced platelet aggregation), but did not inhibit adenosine diphosphate- or thromboxane A2-induced platelet aggregation. Thrombin was not generated in response to ristocetin/vWF or echicetin beads and therefore did not explain the inhibitory effect of the DTIs. Therapeutic concentration of lepirudin and dabigatran did not affect significantly platelet vasodilator-stimulated phosphoprotein S239 phosphorylation or cGMP and cyclic adenosine monophosphate levels. These data suggest that the DTIs, lepirudin and dabigatran, impair platelet activation measured during platelet aggregation induced by ristocetin/vWF or echicetin beads.

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Neurosurgical complications of direct thrombin inhibitors—catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran

Journal of Neurosurgery ◽

10.3171/2012.2.jns112132 ◽

2012 ◽

Vol 116 (5) ◽

pp. 1093-1096 ◽

Cited By ~ 70

Author(s):

Sarah T. Garber ◽

Walavan Sivakumar ◽

Richard H. Schmidt

Keyword(s):

Atrial Fibrillation ◽

Randomized Clinical Trials ◽

Dabigatran Etexilate ◽

Ground Level ◽

Thrombin Inhibitors ◽

Thrombin Inhibitor ◽

Direct Thrombin Inhibitors ◽

Systemic Embolism ◽

Nonvalvular Atrial Fibrillation ◽

Reversal Agent

Dabigatran etexilate is an oral anticoagulant that acts as a direct, competitive thrombin inhibitor. Large randomized clinical trials have shown higher doses of dabigatran (150 mg taken twice daily) to be superior to warfarin in terms of stroke and systemic embolism rates in patients with nonvalvular atrial fibrillation. As a result, in 2010 the US FDA approved the use of dabigatran for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Dabigatran is especially attractive in the outpatient setting because patients do not require routine monitoring with prothrombin times or international normalized ratios. To date, no effective reversal agent for dabigatran in the event of catastrophic hemorrhage has been identified. The authors report a case of an elderly patient, being treated with dabigatran for atrial fibrillation, who presented with a rapidly expanding intracranial hemorrhage after a ground-level fall. This case highlights an impending neurosurgical quandary of complications secondary to this new anticoagulation agent and suggests potential options for management.

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