title: Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism.
abstract: The treatment of acute venous thromboembolism (VTE) is being completely modified with the development of direct oral anticoagulants (DOACs). Rivaroxaban, apixaban and edoxaban directly inhibit factor Xa, whereas dabigatran inhibits factor IIa. All these drugs are proposed orally, and share pharmacological similarities: fixed doses without any therapeutic drug monitoring, key role of the transporter proteins P-glycoprotein for all of them and metabolism mediated by CYP3A4 for the anti-Xa, short half-life with variable rate of renal elimination. More than 25 000 patients with acute VTE were included in phase-III studies. Rivaroxaban and apixaban challenged all the conventional therapy (parenteral heparins followed by anti-vitamin K antagonists) whereas edoxaban and dabigatran challenged only anti-vitamin K antagonists. All the DOACs met the non-inferiority efficacy endpoint (recurrent VTE during treatment), whereas the large non-inferiority margin was debated for dabigatran. However, they were associated with better safety and a decreased risk of major bleeding. According to indirect comparisons, there were no statistically significant differences between DOACs in terms of efficacy but some differences are not excluded in term of safety. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, their risk/benefit ratio is questioned in elderly patients, patients with mild-to-severe renal impairment, and in some clinical subgroups such as cancer or chronic thromboembolic pulmonary hypertension. Validated reversal strategies (potentially based on laboratory monitoring) are expected for patients with major bleeding, overdose or with a need for surgery.
authors.affiliation: CHU Saint-Etienne, Médecine Vasculaire et Thérapeutique, Saint-Etienne, France; INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; INSERM, CIC1408, Saint-Etienne, France. Electronic address: laurent.bertoletti@gmail.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bertoletti
authors.affiliation: INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; CHU Saint-Etienne, Laboratoire de Pharmacologie, Toxicologie et Gaz du sang, Saint-Etienne, France. Electronic address: ed.ollier@gmail.com.
authors.forename: Edouard
authors.initials: E
authors.lastname: Ollier
authors.affiliation: CHU Saint-Etienne, Médecine Vasculaire et Thérapeutique, Saint-Etienne, France. Electronic address: cecile.duvillard@chu-st-etienne.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Duvillard
authors.affiliation: INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; CHU Saint-Etienne, Laboratoire de Pharmacologie, Toxicologie et Gaz du sang, Saint-Etienne, France. Electronic address: xavier.delavenne@chu-st-etienne.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Delavenne
authors.affiliation: INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; CHU Saint-Etienne, Centre Régional de Pharmacovigilance, Saint-Etienne, France. Electronic address: m.noelle.beyens@chu-st-etienne.fr.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Beyens
authors.affiliation: CHU Saint-Etienne, Médecine Vasculaire et Thérapeutique, Saint-Etienne, France; INSERM, CIC1408, Saint-Etienne, France. Electronic address: elodie.demagalhaes@chu-st-etienne.fr.
authors.forename: Elodie
authors.initials: E
authors.lastname: De Magalhaes
authors.affiliation: CHU Saint-Etienne, Centre Régional de Pharmacovigilance, Saint-Etienne, France. Electronic address: florelle.bellet@chu-st-etienne.fr.
authors.forename: Florelle
authors.initials: F
authors.lastname: Bellet
authors.affiliation: INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; CHU Saint-Etienne, Laboratoire de Pharmacologie, Toxicologie et Gaz du sang, Saint-Etienne, France. Electronic address: thierry.basset@chu-st-etienne.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Basset
authors.affiliation: CHU Saint-Etienne, Médecine Vasculaire et Thérapeutique, Saint-Etienne, France; INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; INSERM, CIC1408, Saint-Etienne, France. Electronic address: patrick.mismetti@chu-st-etienne.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mismetti
authors.affiliation: INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne, France; CHU Saint-Etienne, Unité de Recherche Clinique et d'Innovation Pharmacologique, Saint-Etienne, France. Electronic address: silvy.laporte@chu-st-etienne.fr.
authors.forename: Silvy
authors.initials: S
authors.lastname: Laporte
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D054556:Venous Thromboembolism / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants
keywords: Apixaban; Dabigatran; Direct oral anticoagulant; Edoxaban; Randomized clinical trials; Rivaroxaban