Long-Term Management of Venous Thromboembolism: Lessons from EINSTEIN CHOICE and Other Extension Trials

Many patients with venous thromboembolism (VTE) are at risk of recurrence if anticoagulant therapy is stopped. Whereas 3 months of anticoagulation treatment is sufficient for patients with VTE provoked by major surgery or trauma, in many cases a longer course is needed. Extended therapy with vitamin K antagonists (VKAs) requires frequent coagulation monitoring and dose adjustments to ensure that the international normalized ratio (INR) remains within the therapeutic range; furthermore, there is a risk of major bleeding even if a therapeutic INR is maintained. Therefore, more convenient and safer anticoagulants are needed.The non-VKA oral anticoagulants (NOACs)—apixaban, dabigatran, edoxaban and rivaroxaban—simplify extended therapy because they can be given in fixed doses without routine coagulation monitoring. Randomized clinical trials have demonstrated the efficacy and safety of NOACs for extended VTE treatment, but bleeding remains a concern. Patients and physicians may, therefore, be reluctant to continue anticoagulation beyond 3 to 6 months except in patients at high risk of recurrence. Acetylsalicylic acid (ASA) is often prescribed instead of an anticoagulant because of its perceived lower risk of bleeding; however, the recent EINSTEIN CHOICE trial demonstrated that once-daily rivaroxaban at a dose of either 20 or 10 mg reduced the risk of recurrent VTE by 70% compared with ASA without significantly increasing the risk of bleeding. In this review, we discuss the EINSTEIN CHOICE trial in the context of previous trials for extended VTE treatment and examine some of the lessons that can be applied to clinical practice.

Download Full-text

Optimal duration of anticoagulant therapy in patients with venous thromboembolism

Italian Journal of Medicine ◽

10.4081/itjm.2018.1077 ◽

2018 ◽

Vol 12 (4) ◽

pp. 235-244

Author(s):

Gualtiero Palareti

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Severe Disease ◽

Direct Oral Anticoagulants ◽

Late Complications ◽

Risk Of Recurrence ◽

Risk Of Bleeding

Venous thromboembolism, a frequent and severe disease, has clinically important early and late complications and a strong tendency to recur. Anticoagulant therapy is the mainstay of treatment, performed by immediate administration of: i) parenteral anticoagulants followed by vitamin K antagonists, either dabigatran or edoxaban, two direct oral anticoagulants (DOACs); or ii) direct rivaroxaban or apixaban, two DOACs that can be used as single-drug approach. Treatment should last no less than 3 months in all patients though how long it should last thereafter is a more complex issue. The risk of recurrence results from several event- or patient-associated factors. Some patients have low risk and may be treated for 3 to 6 months only. Others (the majority) have a high risk of recurrence (approximately 50% in 10 years). Unfortunately, the protective effect of anticoagulation against recurrence is present only during treatment and is lost when therapy is stopped. For this reason, international guidelines recommend that there is no pre-definite period of anticoagulation (e.g. 1 or 2 years, and so on) in patients at high risk and suggest instead indefinite (extended) anticoagulation, provided there is no high risk of bleeding. When the decision is difficult, adjunctive criteria may be adopted, such as male sex and abnormal D-dimer assessed after anticoagulation is stopped, to identify patients at high risk who need indefinite therapy. The use of DOACs, especially at lower doses with a lower risk of bleeding, may make indefinite anticoagulation for patients easier.

Download Full-text

Optimal duration of anticoagulant therapy in patients with venous thromboembolism

Italian Journal of Medicine ◽

10.4081/item.2018.1077 ◽

2018 ◽

Author(s):

Gualtiero Palareti

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Severe Disease ◽

Direct Oral Anticoagulants ◽

Late Complications ◽

Risk Of Recurrence ◽

Risk Of Bleeding

Venous thromboembolism (VTE), a frequent and severe disease, has clinically important early and late complications and a strong tendency to recur. Anticoagulant therapy is the mainstay of treatment, performed by immediate administration of: a) parenteral anticoagulants followed by vitamin K antagonists (VKAs), either dabigatran or edoxaban, two direct oral anticoagulants (DOACs); or b) direct rivaroxaban or apixaban, two DOACs that can be used as single-drug approach. Treatment should last no less than 3 months in all patients though how long it should last thereafter is a more complex issue. The risk of recurrence results from several event- or patient-associated factors. Some patients have low risk and may be treated for 3 to 6 months only. Others (the majority), have a high risk of recurrence (approximately 50% in 10 years). Unfortunately, the protective effect of anticoagulation against recurrence is present only during treatment and is lost when therapy is stopped. For this reason, international guidelines recommend there be no pre-definite period of anticoagulation (e.g. 1 or 2 years, and so on) in patients at high risk and suggest instead indefinite (extended) anticoagulation, provided there is no high risk of bleeding. When the decision is difficult, adjunctive criteria may be adopted, such as male sex and abnormal Ddimer assessed after anticoagulation is stopped, to identify patients at high risk who need indefinite therapy. The use of DOACs, especially at lower doses with a lower risk of bleeding, may make indefinite anticoagulation for patients easier.

Download Full-text

Direct Oral Anticoagulants: From Randomized Clinical Trials to Real-World Clinical Practice

Frontiers in Pharmacology ◽

10.3389/fphar.2021.684638 ◽

2021 ◽

Vol 12 ◽

Author(s):

Roberta Roberti ◽

Luigi Francesco Iannone ◽

Caterina Palleria ◽

Antonio Curcio ◽

Marco Rossi ◽

...

Keyword(s):

Clinical Practice ◽

Venous Thromboembolism ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Pharmacokinetic Profile ◽

Nonvalvular Atrial Fibrillation ◽

Clinical Indications ◽

Oncologic Patients

Direct oral anticoagulants (DOACs) are a more manageable alternative than vitamin K antagonists (VKAs) to prevent stroke in patients with nonvalvular atrial fibrillation and to prevent and treat venous thromboembolism. Despite their widespread use in clinical practice, there are still some unresolved issues on optimizing their use in particular clinical settings. Herein, we reviewed the current clinical evidence on uses of DOACs from pharmacology and clinical indications to safety and practical issues such as drugs and food interactions. Dabigatran is the DOAC most affected by interactions with drugs and food, although all DOACs demonstrate a favorable pharmacokinetic profile. Management issues associated with perioperative procedures, bleeding treatment, and special populations (pregnancy, renal and hepatic impairment, elderly, and oncologic patients) have been discussed. Literature evidence shows that DOACs are at least as effective as VKAs, with a favorable safety profile; data are particularly encouraging in using low doses of edoxaban in elderly patients, and edoxaban and rivaroxaban in the treatment of venous thromboembolism in oncologic patients. In the next year, DOAC clinical indications are likely to be further extended.

Download Full-text

The optimal duration of anticoagulant therapy after unprovoked venous thromboembolism – still a challenging issue

VASA ◽

10.1024/0301-1526/a000597 ◽

2017 ◽

Vol 46 (2) ◽

pp. 87-95 ◽

Cited By ~ 2

Author(s):

Giovanna Elmi ◽

Giuseppe Di Pasquale ◽

Raffaele Pesavento

Keyword(s):

Venous Thromboembolism ◽

Safety Profile ◽

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Bleeding Risk ◽

Risk Of Recurrence ◽

Extended Treatment

Abstract. As about 50 % of patients with unprovoked venous thromboembolism (VTE) will develop new episodes after discontinuing therapy, indefinite treatment is suggested in patients with low or moderate bleeding risk. Baseline and post-baseline factors can help clinicians to identify patients at high risk of recurrence, who require extended treatment. Residual vein obstruction and D-dimer assay have been shown to be suitable methods for assessing the risk of VTE recurrences after a first unprovoked VTE. In treatment for VTE the use of direct oral anticoagulants (DOAC) is growing instead of the standard adjusted dose of vitamin K antagonists. The DOAC safety profile has recently been strengthened with systematic reviews and meta-analyses. Idarucizumab is only approved for the reversal of dabigatran etexilate; intravenous antidotes for factor Xa inhibitors are under development. Their advent is of great interest. In the extended treatment of VTE sulodexide has been demonstrated to significantly decrease the risk of recurrences with an excellent safety profile. Aspirin is substantially less effective than oral anticoagulants in preventing recurrences but could play a role among patients who decided to stop anticoagulants. In conclusion, for the secondary prevention of VTE several options are available, without a recognised best choice regarding the treatment duration and the choice of drugs. An individual strategy taking into account risk of recurrence, bleeding risk, therapeutic options, and patient preferences is appropriate.

Download Full-text

Venous Thromboembolism in Children: From Diagnosis to Management

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17144993 ◽

2020 ◽

Vol 17 (14) ◽

pp. 4993

Author(s):

Giuseppe Lassandro ◽

Viviana Valeria Palmieri ◽

Valentina Palladino ◽

Anna Amoruso ◽

Maria Felicia Faienza ◽

...

Keyword(s):

Venous Thromboembolism ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Treatment Options ◽

Diagnostic Tools ◽

Inherited Thrombophilia ◽

Increased Sensitivity ◽

Common Risk Factors

Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

Download Full-text

Edoxaban (LIXIANA®) in the treatment of venous thromboembolism

Future Cardiology ◽

10.2217/fca-2020-0139 ◽

2020 ◽

Author(s):

Roberta Bottino ◽

Andreina Carbone ◽

Biagio Liccardo ◽

Antonello D’Andrea ◽

Anna Rago ◽

...

Keyword(s):

Clinical Trials ◽

Venous Thromboembolism ◽

Vitamin K ◽

Standard Therapy ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Term Therapy ◽

Long Term Therapy

Standard therapy for venous thromboembolism (VTE) includes the use of heparins and vitamin K antagonists. Randomized clinical trials have shown that non-vitamin K oral anticoagulants are as effective and safe as standard therapy in VTE treatment, with an improved pharmacological profile. Edoxaban, a direct inhibitor of factor Xa, has demonstrated noninferiority to standard therapy for the treatment of VTE, preserving a high safety profile even in long-term therapy, in frail patients and in severe clinical presentations. The present paper focuses on the role of edoxaban in VTE treatment, from general population to cancer patients, presenting the available data from randomized clinical trials and real world, to discuss edoxaban use in clinical practice.

Download Full-text

Incidence of Recurrent Thromboembolic and Bleeding Complications Among Patients With Venous Thromboembolism in Relation to Both Malignancy and Achieved International Normalized Ratio: A Retrospective Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.17.3078 ◽

2000 ◽

Vol 18 (17) ◽

pp. 3078-3083 ◽

Cited By ~ 495

Author(s):

Barbara A. Hutten ◽

Martin H. Prins ◽

Michael Gent ◽

Jeff Ginsberg ◽

Jan G. P. Tijssen ◽

...

Keyword(s):

Venous Thromboembolism ◽

Retrospective Analysis ◽

Vitamin K ◽

Major Bleeding ◽

Randomized Clinical Trials ◽

Oral Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

International Normalized Ratio ◽

Bleeding Complications ◽

Venous Thromboembolic

PURPOSE: Initial heparinization followed by vitamin K antagonists is the treatment of choice for patients with venous thromboembolism. There is controversy whether known malignancy is a risk factor for recurrences and bleeding complications during this treatment. Furthermore, the incidence of such events in these patients is dependent on the achieved International Normalized Ratio (INR). The aim of this study was to assess the incidence of venous thromboembolic recurrence and major bleeding among patients with venous thromboembolism in relation to both malignancy and the achieved INR.PATIENTS AND METHODS: In a retrospective analysis, the INR-specific incidence of venous thromboembolic and major bleeding events during oral anticoagulant therapy was calculated separately for patients with and without malignancy. Eligible patients participated in two multicenter, randomized clinical trials on the initial treatment of venous thromboembolism. Patients were initially treated with heparin (standard or low-molecular weight). Treatment with vitamin K antagonists was started within 1 day and continued for 3 months, with a target INR of 2.0 to 3.0.RESULTS: In 1,303 eligible patients (264 with malignancy), 35 recurrences and 12 bleeds occurred. Patients with malignancy, compared with nonmalignant patients, had a clinically and statistically significantly increased overall incidence of recurrence (27.1 v 9.0, respectively, per 100 patient-years) as well as bleeding (13.3 v 2.1, respectively, per 100 patient-years). In both groups of patients, the incidence of recurrence was lower when the INR was above 2.0 compared with below 2.0.CONCLUSION: Although adequately dosed vitamin K antagonists are effective in patients with malignant disease, the incidence of thrombotic and bleeding complications remains higher than in patients without malignancy.

Download Full-text

Meta-analysis comparing impact of age, sex and renal function on the efficacy and safety of new oral anticoagulants vs. vitamin K antagonists for the treatment of acute venous thromboembolisms

European Heart Journal ◽

10.1093/ehjci/ehaa946.2374 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J She ◽

B.Z Zhuo

Keyword(s):

Renal Function ◽

Venous Thromboembolism ◽

Creatinine Clearance ◽

Vitamin K ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Funding Source ◽

Efficacy And Safety ◽

Acute Venous Thromboembolism

Abstract Background New direct oral anticoagulants (NOACs), as a preferable treatment option for acute venous thromboembolism (VTE) have been recommended with practical advantages as compared to Vitamin K antagonists (VKAs) in clinical practice. Purpose In our study, we performed a meta-analysis to determine the efficacy and safety of NOACs vs. VKAs in patients with different age, sex and renal function for the treatment of VTE. Methods Electronic databases (accessed October 2019) were systematically searched to identify RCTs evaluating apixaban, dabigatran, edoxaban, and rivaroxaban versus VKAs for the treatment of acute venous thromboembolism. Results NOACs was associated with a borderline higher efficacy in female (OR 0.79, 95% CI 0.62–1.02), and a significantly higher efficacy in patients with age more than 75 (OR 0.51, 95% CI 0.32–0.80) and creatinine clearance less than 50 mL/min (OR 0.57, 95% CI 0.32–0.99). NOACs also show advantage in terms of major or clinically relevant non-major bleeding in male (OR 0.72, 95% CI 0.60–0.86), and patients with creatinine clearance more than 50 mL/min (OR 0.75, 95% CI 0.67–0.84). Conclusions NOACs have exhibited clinical preference among patients with acute VTE as compared to VKA with significantly decreased thrombosis events and lower bleeding complications, especially in patients with age more than 75 and creatinine clearance less than 50 mL/min. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by the National Natural Science Foundation of China (81800390) and the Natural Science Foundation of Shaanxi province (2018KW067).

Download Full-text

The NOACs: clinical pharmacology

ESC CardioMed ◽

10.1093/med/9780198784906.003.0056 ◽

2018 ◽

pp. 268-272

Author(s):

Jeffrey Weitz

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Active Site ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Phase Iii ◽

High Affinity

The limitations of vitamin K antagonists prompted the development of new oral anticoagulants that could be administered in fixed doses without routine coagulation monitoring. Focusing on thrombin and factor Xa because of their prominent roles in coagulation, structure-based design led to the development of small molecules that bind to the active site pockets of these enzymes with high affinity and specificity. Four non-vitamin K antagonist oral anticoagulants are now licensed: dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. In phase III randomized clinical trials that included over 100,000 patients these agents have proven to be at least as effective as vitamin K antagonists for prevention of stroke in patients with non-valvular atrial fibrillation and for treatment of venous thromboembolism, and to produce less bleeding, particularly less intracranial bleeding.

Download Full-text

First-Line Therapies for VTE Treatment and Secondary Prophylaxis in Patients With Cancer: A New Direction

Journal of Pharmacy Practice ◽

10.1177/0897190018775580 ◽

2018 ◽

Vol 33 (3) ◽

pp. 356-363

Author(s):

Samantha M. Vogel ◽

Leticia V. Smith ◽

Evan J. Peterson

Keyword(s):

Venous Thromboembolism ◽

English Language ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Secondary Prophylaxis ◽

Careful Consideration ◽

Patients With Cancer ◽

Study Selection ◽

Meta Analyses

Objective: To review evidence behind anticoagulants in cancer-associated venous thromboembolism (VTE) with a focus on low-molecular-weight heparins (LMWH) and the role of direct oral anticoagulants (DOACs). Data Sources: PubMed was searched using terms “venous thromboembolism,” “cancer,” and “anticoagulation.” This search was restricted to clinical trials, meta-analyses, and subgroup analyses. Additional references were identified from reviewing literature citations. Study Selection: English-language prospective and retrospective studies assessing the efficacy and safety of LMWH and DOACs in patients with cancer. Data Analysis: Several trials were analyzed that compared anticoagulation therapies for prevention of recurrent VTE in patients with cancer. Many studies comparing LMWH and vitamin K antagonists (VKAs) found nonsignificant differences between therapies. A single study demonstrated that LMWHs are superior to VKAs. This evidence supporting LMWH for long-term VTE treatment in patients with cancer is based on comparison to VKA, but results are limited by methodological issues, and the benefit of LMWH may be driven by poor control. Subanalyses of DOAC trials suggest these are equally or more effective as VKA in cancer, but this conclusion is underpowered. Conclusion: DOACs have the potential to bypass many challenges with traditional therapy. After analyzing the evidence available, we conclude that after careful consideration of risks and benefits, use of DOACs for VTE treatment are a reasonable option in patients with cancer.

Download Full-text