Dabigatran etexilate: a new thrombin inhibitor

Abstract

Dabigatran etexilate was recently approved by the Therapeutic Goods Administration for thromboprophylactic use in adults undergoing elective total hip or knee replacement. Dabigatran etexilate is the prodrug of the active moiety dabigatran, an orally active agent that could replace enoxaparin in some clinical indications. Dabigatran is a direct thrombin inhibitor; it has stable, predictable pharmacokinetics and does not require routine monitoring. Pooled efficacy data from large‐scale phase III clinical trials of dabigatran use in orthopaedic thromboprophylaxis have shown non‐inferiority to enoxaparin, with total venous thromboembolism results of 3.8% for dabigatran etexilate 150 mg and 3.0% for dabigatran etexilate 220 mg, compared with 3.3% for enoxaparin. Pooled safety results for dabigatran are similar to those for enoxaparin, with major bleeding rates of 1.1% for dabigatran etexilate 150 mg and 1.4% for dabigatran etexilate 220 mg, compared with 1.4% for enoxaparin. Dabigatran failed to demonstrate non‐inferiority compared with enoxaparin 30 mg twice daily for orthopaedic thromboprophylaxis. Issues relating to the use of dabigatran include its lack of antidote, limited application in renal disease, and interaction with drugs such as amiodarone and verapamil. Several trials investigating the use of dabigatran for other indications, such as stroke prevention in atrial fibrillation and acute coronary syndromes, are underway. Given its safety profile, efficacy, oral bioavailability and stable pharmacokinetic properties, dabigatran may be a viable alternative to enoxaparin for thromboprophylaxis in orthopaedic surgery.

Antiplatelet and Anticoagulant Therapies for Prevention of Ischemic Stroke

“…67 Dabigatran has a half-life ranging from 14 to 17 hours. 70 Complications. The most common AE in dabigatran use is dyspepsia and GI bleeding (see Table 4).…”

What neurosurgeons need to know about dabigatran etexilate (pradax®/pradaxa®/prazaxa®)

“…A comprehensive knowledge of novel anticoagulants is an important part of current neurosurgical practice. While warfarin, heparin and its low molecular weight derivative, enoxaparin, have formed the mainstay of treatment for atrial fibrillation, valvular heart disease and the prevention of venous thromboembolism for over 30 years,[ 1 ] new agents have recently been approved that promise to revolutionize the treatment of these conditions. There are compelling medical reasons driving the adoption of these agents and they will have an important impact on neurosurgical practice.…”

“…[ 2 3 ] These include parenteral administration for heparin, slow onset and offset of action for warfarin and variable pharmacokinetics for both agents, necessitating frequent monitoring with serum coagulation studies. [ 1 2 ] These tests are inconvenient for patients and expensive for health care systems.…”

“…While drug interactions do affect dabigatran's absorption and metabolization, co-administration with other agents is greatly simplified when compared to warfarin as it is not metabolized by cytochrome p450 isoenzymes. Dabigatran is a direct thrombin inhibitor[ 1 ] with a terminal half life of eight hours for a single dose and 12 to 14 hours for multiple doses. [ 4 ] Dabigatran is renally excreted and its half life can exceed 24 hours in patients with renal impairment.…”

Síntese e ensaio de análogos estruturais de prolina no estudo da interação com trombina.

“…Entre os grupos de drogas antitrombóticas existentes, de acordo com a ação terapêutica, pode-se destacar: anticoagulantes que inibem a geração e a atividade de trombina; (AKIMOTO et al, 2011;MADABUSHI et al, 2011;RÖSSIG et al, 2011) Outro inibidor direto aprovado e atualmente administrado em casos de acidente vascular cerebral e embolia sistêmica é o dabigatran, disponível como a pró-droga etexilato de dabigatrana. Em mais de 50 países o dabigatran também foi aprovado para a profilaxia do tromboembolismo após cirurgias ortopédicas de substituição da articulação do joelho ou quadril (HÄRTTER et al, 2012;HE et al, 2013;VERMA, 2010). O dabigatran é um inibidor oral, de baixa massa molecular (472 Da ciclohexilalanina KLINE et al, 1991;MARAGANORE, 1993;QIU et al, 1992;WITTING et al, 1992).…”