General ReviewDirect Oral Anticoagulants in the Treatment of Venous Thromboembolic Disease
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
References (71)
- et al.
Pulmonary embolism and deep vein thrombosis
Lancet
(2012) - et al.
Consenso nacional sobre el diagnóstico, estratificación de riesgo y tratamiento de los pacientes con tromboembolia pulmonar
Arch Bronconeumol
(2013) - et al.
Anticoagulant therapy after venous thromboembolism and 10-year mortality
Int J Cardiol
(2016) - et al.
Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials
Blood
(2014) - et al.
Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis
J Thromb Haemost
(2014) - et al.
Editor's choice–efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials
Eur J Vasc Endovasc Surg
(2014) - et al.
Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis
Thromb Res
(2014) - et al.
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report
Chest
(2016) - et al.
Nuevos anticoagulantes orales en el tratamiento del tromboembolismo venoso: análisis crítico de los resultados clínicos
Angiología
(2015) - et al.
Cost-effectiveness analysis of extended duration anticoagulation with rivaroxaban to prevent recurrent venous thromboembolism
Thromb Res
(2014)
The economic burden of incident venous thromboembolism in the United States: A review of estimated attributable healthcare costs
Thromb Res
Timing of recurrent venous thromboembolism early after the index event: a meta-analysis of randomized controlled trials
Thromb Res
A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein-DVT dose-ranging study
Blood
Clot resolution after 3 weeks of anticoagulant treatment for pulmonary embolism: comparison of computed tomography and perfusion scintigraphy
J Thromb Haemost
Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial
Thromb Res
Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials
Lancet Heamatol
Duration of anticoagulation after venous thromboembolism in real world clinical practice
Thromb Res
Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry
Blood
Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study
Lancet Haematol
Rivaroxaban for the treatment of venous thromboembolism. A “real-life” perspective in 103 patients
Thromb Res
Trends in the management and outcomes of acute pulmonary embolism: analysis from the RIETE registry
J Am Coll Cardiol
Actualización del Consenso nacional sobre el diagnóstico, estratificación de riesgo y tratamiento de los pacientes con tromboembolia de pulmón
Arch Bronconeumol
Efficacy and safety of rivaroxaban in patients with venous thromboembolism and active malignancy– A single-center registry
Am J Med
Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis
Chest
Managing pulmonary embolism from presentation to extended treatment
Thromb Res
2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism
Eur Heart J
The epidemiology of venous thromboembolism in the community
Arterioscler Thromb Vasc Biol
30-year mortality after venous thromboembolism: a population-based cohort study
Circulation
Rate and duration of hospitalization for deep vein thrombosis and pulmonary embolism in real-world clinical practice
Ann Med
Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism
J Thromb Thrombolysis
Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism
J Thromb Thrombolysis
Venous thromboembolism in Germany: results of the GermAn VTE registry (GATE-registry)
Int J Clin Pract
Benefit-risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism
Thromb Haemost
New oral anticoagulants for the treatment of venous thromboembolism: understanding differences and similarities
Drugs
Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment
J Thromb Thrombolysis
Cited by (5)
Unmet needs in pulmonary embolism: Simplified anticoagulation and much more
2017, Revista Portuguesa de CardiologiaRivaroxaban for the treatment of venous thromboembolism in real life: A single-center prospective study
2019, Medicine (United States)Study on prevention of venous thromboembolic disease after gynecological cancer surgery method based on power feedback method
2018, Journal of Environmental Protection and Ecology