Overview of the New Oral Anticoagulants

Abstract

Please see http://atvb.ahajournals.org/site/misc/ ATVB_in_Focus.xhtml for all articles published in this series. Comparison of the Pharmacological Properties of the NOACs With Those of WarfarinAs outlined in Abstract-The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3) provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential opportunities for the NOACs and identifies the remaining challenges.

Anticoagulation in chronic liver disease

“…Long term use of heparins can be associated with osteopenia, thrombocytopenia, or idiopathic hepatitis (Ansell & Askin, 2011), and care has to be taken if there is significant renal dysfunction; in addition, hypersensitivity reactions are recognised, which may necessitate a switch of heparin preparation and/ or change to an alternative anticoagulant (Schindewolf et al, 2012). The need to develop novel anticoagulants with better ease of use and safer side effect profiles has recently culminated in several new drugs arriving in clinical practice, which inhibit single coagulation proteins such as activated Factor X or thrombin (Yeh et al, 2015) (Table 1, Figure 1). These direct acting drugs have commonly been labeled as direct oral anticoagulants (DOACs).…”

“…Although these are more expensive than conventional anticoagulants, this is offset by a quick onset of action and the lack of need for montoring (Yeh et al, 2015).…”

“…Heparins have a more rapid onset of action, but have to be given parenterally, which is often performed by a healthcare professional if the patient is unwilling. Long term use of heparins can be associated with osteopenia, thrombocytopenia, or idiopathic hepatitis (Ansell & Askin, 2011), and care has to be taken if there is significant renal dysfunction; in addition, hypersensitivity reactions are recognised, which may necessitate a switch of heparin preparation and/ or change to an alternative anticoagulant (Schindewolf et al, Although these are more expensive than conventional anticoagulants, this is offset by a quick onset of action and the lack of need for montoring (Yeh et al, 2015).Clinical experience of DOACs in cirrhotics is limited since many of the initial clinical trials involving these novel anticoagulants excluded patients with advanced liver disease. Data is therefore limited to in vitro and pharmalogical studies, isolated case reports and a small retrospective cohort study (Intagliata et al, 2016b).…”

Reversal agents for use with direct and indirect anticoagulants

“…7 Observational studies have been undertaken to confirm the safety of DOACs in routine practice, where their use occurs outside the domain of strict clinical trial inclusion criteria (i.e., in patients with a high risk of bleeding) and with a less structured monitoring plan. [8][9][10] Several ongoing registries, such as the Global Anticoagulant Registry in the FIELD (GARFIELD) and the Global Registry on LongTerm Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), 11,12 are assessing DOAC safety, and the majority of data from large observational studies so far support the safety of DOAC agents used in routine care. 10,13,14 The lack of a specific reversal agent is often cited as a disadvantage to DOAC use and may prompt some prescribers to preferentially use vitamin K antagonists such as warfarin.…”

“…[8][9][10] Several ongoing registries, such as the Global Anticoagulant Registry in the FIELD (GARFIELD) and the Global Registry on LongTerm Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), 11,12 are assessing DOAC safety, and the majority of data from large observational studies so far support the safety of DOAC agents used in routine care. 10,13,14 The lack of a specific reversal agent is often cited as a disadvantage to DOAC use and may prompt some prescribers to preferentially use vitamin K antagonists such as warfarin. 10,[15][16][17][18] In 2014, FDA, in conjunction with the Cardiac Safety Research Consortium (CSRC), held a think tank to discuss the need for DOAC reversal agents.…”