Review ArticleDirect Oral Anticoagulant Agents: Pharmacologic Profile, Indications, Coagulation Monitoring, and Reversal Agents
Introduction
Conventional anticoagulants, such as vitamin K antagonists (VKAs), have been in use for more than 60 years for thromboprophylaxis and for the treatment of venous thromboembolism and other thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF).1 In recent years, there has been an emergence of direct oral anticoagulants (DOACs, also known as nonwarfarin anticoagulants, nonvitamin K oral anticoagulants, or novel oral anticoagulants),2 which demonstrate greater advantages and a more stable pharmacologic profile over VKAs,3 such as warfarin (Coumadin [Bristol-Myers-Squibb, New York City, New York]). DOACs include direct thrombin (factor II) inhibitors (i.e., dabigatran) and direct factor Xa (FXa) inhibitors (i.e., rivaroxaban, apixaban, edoxaban, and betrixaban). Unlike VKA, DOACs significantly reduce the risk of intracranial bleeding (ICB) and do not require consistent coagulation monitoring.2, 3, 4 They also have decreased drug and food interactions, a rapid onset and offset of action, and predictable dose-response properties.3, 4, 5
Despite these benefits, DOACs exhibit a few important limitations, including cost, shorter half-life (thus, disallowing a patient protection if a dose is missed), higher risk of gastrointestinal bleeding, and the shortage of available specific reversal agents and coagulation assays to monitor their anticoagulation effects.6 Currently, the cost of DOACs is more expensive than VKA due to their ongoing improvements and recent approval for clinical use. The average cost of each of the 5 Food and Drug Administration (FDA)-approved DOACs (dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban) is approximately U.S. $436/month, or U.S. $5233/year per patient (with dosing ranging from 2.5 to 150 mg/tablet),7, 8, 9, 10, 11 compared with warfarin's average retail price of U.S. $18.66/month.7
Importantly, there is a dearth of reversal agents to DOACs in life-threatening cases of bleeding or emergency surgery. Several specific reversal agents, including idarucizumab, andexanet alfa, and aripazine, have undergone randomized, double-blind, placebo-controlled clinical trials in recent years. Nonetheless, as thrombosis involves multiple mechanisms, polypharmacy is essential to appropriately address this issue and its associated complications. In addition to a need for more reversal agents, there is uncertainty surrounding proper laboratory monitoring of DOACs. Although monitoring of DOACs is not required, there are circumstances in which routine anticoagulation assessments would be useful, such as emergency surgery, reduced renal function, or major bleeding.12 The uncertainty renders routine monitoring of DOAC activity difficult in clinical practice especially in emergency situations in which knowledge of anticoagulant activity is critical for decision making.
We have chosen to discuss only current FDA-approved uses of these agents because a discussion of all potential uses of these agents is beyond the scope of this review article. This article provides a review of the pharmacologic profile and anticoagulation monitoring of DOACs, as well as the characteristics and ongoing or completed clinical trials of specific and nonspecific reversal agents.
Section snippets
Direct Oral Anticoagulants (DOACs)
The limitations of VKA have prompted the recent developments of DOACs as alternatives, which specifically target the catalytic sites of enzymes in the coagulation cascade to inhibit their activity. Currently, there are 5 FDA-approved DOACs, including direct thrombin (factor II) inhibitor dabigatran and the FXa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. Table 1 summarizes the key characteristics of the DOACs.
Management Strategies for Bleeding Complications among Patients Receiving DOAC Treatment
Clinicians should be aware of the lack of specific reversal agents for DOAC treatment, which are critical in cases such as urgent invasive surgery, severe bleeding, and/or renal and hepatic dysfunction. Thus, clinicians must exercise the utmost caution when prescribing DOACs, taking into consideration patients' risk factors and medical history. A couple of risk assessment schemes specific for VKA, including the HAS-BLED and CHA(2)DS(2)-VASc (formerly CHADS2), are useful for practitioners to
Conclusion
As the number of FDA-approved DOACs increases, so does the potential complications of their use. Thus, there is growing concern regarding the paucity of specific, FDA-approved reversal agents for DOAC-associated bleeding, as well as appropriate coagulation assessments of their activity. There is a lack of consensus regarding the optimal method of monitoring the activity of the DOACs. Although there is some agreement for the optimal method of monitoring the activity of the FXa inhibitors
References (69)
- et al.
Specific antidotes against direct oral anticoagulants: a comprehensive review of clinical trials data
Int J Cardiol
(2016) - et al.
In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939-an oral, direct Factor Xa inhibitor
J Thromb Haemost
(2005) Which test to use to measure the anticoagulant effect of rivaroxaban: the anti-factor Xa assay
J Thromb Haemost
(2013)- et al.
Idarucizumab, a specific reversal agent for dabigatran: mode of action, pharmacokinetics and pharmacodynamics, and safety and efficacy in phase 1 subjects
Am J Med
(2016) - et al.
A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors [Abstract]
Blood J
(2014) - et al.
Intracerebral hemorrhagic expansion occurs in patients using non-vitamin K antagonist oral anticoagulants comparable with patients using warfarin
J Stroke Cerebrovasc Dis
(2017) Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency
Thromb Res
(1999)- et al.
Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers
Thromb Haemost
(2014) - et al.
Discovery of anticoagulant drugs: a historical perspective
Curr Drug Discov Technol
(2012) - et al.
Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups
Thrombosis
(2013)
Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development
Clin Pharmacokinet
Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation
Europace
Practical considerations for the use of direct oral anticoagulants in patients with atrial fibrillation
Clin Appl Thromb
Warfarin prices and warfarin coupons
Edoxaban prices and edoxaban coupons
Rivaroxaban prices and rivaroxaban coupons
Apixaban prices and apixaban coupons
Bevyxxa/betrixaban cost, side effects, dosage, uses for venous thromboembolism
Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study
Ann Pharmacother
Pradaxa prescribing information
A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system
Thromb Haemost
Drug interactions with novel oral anticoagulants
Dabigatran: drug information
New oral anticoagulants—a practical guide
Polish J Cardio-Thoracic Surg
Clinical use of coagulation tests
Xarelto prescribing information
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation
N Engl J Med
Rivaroxaban: drug information
Pharmacological profile of non-vitamin K antagonist oral anticoagulants
African J Pharm Pharmacol
What is the effect of rivaroxaban on routine coagulation tests?
Eliquis prescribing information
Apixaban: Drug Information
Apixaban metabolism and pharmacokinetics after oral administration to humans
Drug Metab Dispos
Pharmacology of new oral anticoagulants: mechanism of action, pharmacokinetics, pharmacodynamics
Ital J Med
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