Elsevier

Annals of Vascular Surgery

Volume 42, July 2017, Pages 337-350
Annals of Vascular Surgery

General Review
Direct Oral Anticoagulants in the Treatment of Venous Thromboembolic Disease

https://doi.org/10.1016/j.avsg.2017.01.010Get rights and content

Background

Anticoagulation is the treatment of choice in the management of venous thromboembolic disease. This approach is applied to reduce mortality and the risk of recurrences and associated complications. Standard therapy for non-oncologic patients has traditionally been based on parenteral anticoagulation followed by vitamin K antagonists. However, this approach has many limitations.

Methods

The aim of this manuscript was to critically review current evidence on the use of direct oral anticoagulants in the treatment of venous thromboembolic disease by analyzing the specific characteristics of each drug.

Results

Direct oral anticoagulants have many advantages over standard therapy. While they are equally effective as standard therapy for reducing the possibility of recurrence of venous thromboembolic disease, they carry a lower risk of major bleeding.

Conclusions

Direct oral anticoagulants are an attractive alternative to standard therapy for the treatment of venous thromboembolism.

Introduction

Venous thromboembolic disease (VTED) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). It is a major health problem, both in terms of its incidence and because of its mortality and sequelae.1, 2 Although it is difficult to determine the exact incidence of VTED, since patients may be asymptomatic, global annual incidence is estimated to be approximately 100–200 cases per 100,000 inhabitants.3 In Spain, the incidence of VTED is calculated to be 116–124 cases per 100,000 person-years, with a mortality rate of 11.6% in PE and 2.3% in DVT.4 A recent study showed that patients with VTED had an increased risk of death, especially during the year following the event, although the risk continued to be high in the following decades.5 Both mortality and morbidity are high.6, 7 Thus, at present, 1 of every 2 patients with DVT and 5 of every 6 with PE are hospitalized.6 Furthermore, the risk of recurrence among survivors is high (10% per patient per year), up to 30% of patients present postthrombotic syndrome, and 5% present chronic pulmonary venous hypertension. Consequently, the costs associated with VTED are substantial.1, 4

The traditional approach to VTED has been based on parenteral anticoagulation therapy (unfractionated heparin, low-molecular-weight heparin [LMWH], and fondaparinux) for the first 5–10 days followed by vitamin K antagonists (VKA) for a period that varies depending on the patient's clinical characteristics.1, 2, 4

However, the standard approach has major limitations. On the one hand, it requires intravenous or subcutaneous administration of parenteral anticoagulant drugs, and on the other, VKAs have a narrow therapeutic window, present multiple interactions with food and other drugs, and have a slow onset and offset of action. Therefore, anticoagulation therapy must be monitored periodically, and the dose must be adjusted frequently. Furthermore, the transition from parenteral anticoagulant therapy to treatment with VKAs can be difficult for many patients.8, 9 These limitations mean that treatment of VTED is not managed appropriately in a large number of patients.10

Direct oral anticoagulants (DOACs), on the other hand, have a wide therapeutic window, a constant and predictable anticoagulant effect, few interactions with other drugs, no need for periodic monitoring of anticoagulation, and fixed-dose administration. These advantages could lead to a more marked benefit with respect to standard treatment.11, 12, 13, 14, 15, 16 In recent years, several clinical trials have compared the safety and efficacy profile of DOACs with that of standard therapy in patients with VTED, both in the acute phase and in the long term.17, 18, 19, 20, 21, 22, 23

In this article, the current evidence on the management of DOACs in the treatment of patients with VTED was reviewed, and a critical analysis of this evidence was performed. For this purpose, a search on MEDLINE and EMBASE databases was made. The MEDLINE and EMBASE search included both medical subject headings (MeSH) and keywords including venous thromboembolism OR venous thrombosis OR pulmonary embolism AND Factor Xa Inhibitors OR Antithrombin OR dabigatran OR rivaroxaban OR apixaban OR edoxaban OR warfarin OR acenocoumarol OR heparin. References of the retrieved articles were also screened for additional studies. There were no language restrictions.

Section snippets

DOACs in VTED: Evidence from Clinical Trials

RECOVER and RECOVER II were both randomized clinical trials involving patients with DVT and/or PE treated with LMWH or unfractionated heparin for the first 5 to 11 days after the event and who were randomized to dabigatran 150 mg twice daily (bid) or warfarin for 6 months. In both studies, the primary efficacy variable was recurrence of symptoms of VTED or death associated with VTED, and dabigatran was shown to be noninferior to standard treatment. Although the rate of major bleeding was

DOACs and Registries

Despite the considerable interest of information gained from clinical trials, the study populations are not always exactly the same as patients attended in daily clinical practice. In this sense, registries and “real-world” studies are essential for establishing the safety and efficacy profile of a drug in daily clinical practice. Fortunately, various registries and studies are providing very valuable information.

The Dresden NOAC registry is a prospective registry in Dresden, Germany that

Updated National Consensus on Diagnosis, Risk Stratification, and Treatment of Patients with PE

The publisher is preparing an update of the consensus published in 2013 based on an analysis of the various clinical trials comparing DOACs with standard therapy in patients with VTED.64 The main conclusion is that DOACs should be preferred to standard therapy in patients with PE and no cancer.

Antithrombotic Treatment of VTED: CHEST Guidelines and Expert Panel Report

The present article updates the recommendations made in the ninth edition of the CHEST Guideline.33 The recommendations on DOACs are summarized in the following paragraph.

The recommended long-term

Future Challenges

LMWH has traditionally been recommended for treatment of VTED in patients with active cancer.65 DOACs constitute an attractive alternative in the management of these patients. However, given that inclusion of this population in phase III trials has been limited and that some chemotherapy agents are subject to interactions with CYP3A4 or the efflux transporter P-gp, DOACs should be used with caution.56, 65 On the other hand, combined data from the EINSTEIN studies, which included the largest

Conclusions

Anticoagulation agents are considered the first-line therapy for the treatment of VTED. However, VKAs have many limitations that hamper their application in daily clinical practice. Moreover, standard anticoagulation therapy (parenteral therapy/VKAs) carries a risk of both recurrence and bleeding.

In addition to their ability to overcome the majority of limitations of standard therapy, DOACs have proven to be as efficacious as standard treatment for the prevention of recurrences of VTED, but

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