Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study

doi:10.1016/S2352-3026(15)00257-4

The Lancet Haematology

Volume 3, Issue 1, January 2016, Pages e12-e21

https://doi.org/10.1016/S2352-3026(15)00257-4 Get rights and content

Summary

Background

The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed.

Methods

XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007.

Findings

Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0·8% (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0·77 (95% CI 0·40–1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·91 [95% CI 0·54–1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24–1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group).

Interpretation

In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings.

Funding

Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.

Introduction

Venous thromboembolism (comprising of deep-vein thrombosis, or pulmonary embolism, or both) is the third most common cardiovascular disorder,¹ with an incidence of one to two cases per 1000 people in the general population, and increasing risk with age.2, 3 Until recently, standard treatment for most cases of venous thromboembolism included parenteral agents (eg, low-molecular-weight heparin) and vitamin K antagonists, with a target international normalised ratio of 2·0–3·0.⁴ The direct oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban have been shown to be effective in phase 3 randomised trials for acute and long-term treatment of venous thromboembolism.5, 6, 7, 8, 9, 10, 11, 12 The phase 3 EINSTEIN DVT study⁵ showed that rivaroxaban was as effective as low-molecular-weight heparin and vitamin K antagonists, with similar frequency of bleeding, for treatment of deep-vein thrombosis and secondary prevention of recurrent venous thromboembolism. In 2011, rivaroxaban was the first direct oral anticoagulant to be approved by the European Medicines Agency (EMA) for the treatment of acute symptomatic deep-vein thrombosis and secondary prevention of recurrent venous thromboembolism.

Research in context

Evidence before this study

We did not do a formal literature search before we started the XALIA study because at study initiation, EINSTEIN DVT was the only study of a direct oral anticoagulant without parenteral pre-treatment to be published and so there were no published contemporary references. The phase 3 EINSTEIN DVT trial showed similar rates of recurrent venous thromboembolism and major bleeding with rivaroxaban treatment compared with standard anticoagulation (low-molecular-weight heparin, overlapping with and followed by a dose-adjusted vitamin K antagonist) for the treatment of acute deep-vein thrombosis. Additionally, in EINSTEIN EXT, extended treatment with rivaroxaban was superior to placebo for the prevention of venous thromboembolism, with an acceptable risk of bleeding. Subsequent to these studies, rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) became the first direct oral anticoagulant to be approved by the European Medicines Agency for the treatment of acute deep-vein thrombosis and secondary prevention of venous thromboembolism in December, 2011. In June, 2012, the EINSTEIN PE trial showed that rivaroxaban was non-inferior to standard of care, with a significant reduction in major bleeding events; this finding formed the basis of the regulatory approval for the treatment of acute pulmonary embolism in December, 2012. The XALIA study was initiated on June 26, 2012, and on Aug 15, 2013, following the approval by the European Medicines Agency of rivaroxaban for the treatment of pulmonary embolism, the study protocol was amended to allow patients with deep-vein thrombosis and concomitant pulmonary embolism into the study, although patients with isolated pulmonary embolism were still ineligible.

Added value of this study

XALIA is the first prospective, non-interventional study of the safety and effectiveness of a direct oral anticoagulant for the treatment of deep-vein thrombosis, which also included patients with concomitant pulmonary embolism. Propensity score-adjusted analyses showed the rates of major bleeding and recurrent venous thromboembolism to be similar to those recorded with standard anticoagulation therapy (a parenteral agent overlapping with, and followed by, a vitamin K antagonist). Additionally, rivaroxaban was associated with shorter hospital stays than occurred in patients receiving standard anticoagulation therapy.

Implications of all the available evidence

This study is the first international, prospective, non-interventional study of a direct oral anticoagulant, and it shows that the findings from the phase 3 studies of rivaroxaban can be translated to patients with deep-vein thrombosis treated in routine practice. With fixed-dosing regimens and no routine coagulation monitoring, rivaroxaban as a single-drug therapy has the potential to simplify the management of patients with venous thromboembolism, which could offer advantages over the conventional dual-drug anticoagulant therapy.

Phase 3 studies have selective inclusion criteria, and the reproducibility of their findings needs to be assessed in broader patient populations that are seen in routine clinical practice. Additionally, regulators might require studies in routine clinical practice to be done to meet post-authorisation requirements. The XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) study was done to assess the safety and effectiveness of rivaroxaban for the treatment of symptomatic deep-vein thrombosis in patients typically seen and managed in routine practice, and to meet a regulatory request during the assessment procedure for marketing authorisation from the EMA.

Section snippets

Study design and participants

XALIA was a multicentre, international, prospective, non-interventional study of patients with objectively confirmed deep-vein thrombosis treated with rivaroxaban or with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist). The protocol was developed in collaboration with, and approved by, the EMA¹³ and by each centre's institutional review board. An

Results

Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled from hosptials and community care centres in 21 countries (Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Moldova, the Netherlands, Norway, Portugal, Slovenia, Spain, Sweden, Switzerland, Ukraine, and the UK). Six patients did not take any study medication and were excluded from the analysis. A total of 368 patients were defined as “early switchers”. This subgroup was

Discussion

To the best of our knowledge, XALIA is the first large-scale, prospective study of a direct oral anticoagulant, rivaroxaban, showing low rates of major bleeding and recurrent venous thromboembolic events in the treatment of deep-vein thrombosis in routine clinical practice. The findings are consistent with those from the phase 3 EINSTEIN DVT trial,⁵ which confirms that the results of that study can be translated to patients typically treated in routine clinical practice.

The crude rate of major

References (25)

SZ Goldhaber
Venous thromboembolism: epidemiology and magnitude of the problem
Best Pract Res Clin Haematol
(2012)
M Cushman et al.
Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology
Am J Med
(2004)
J Beyer-Westendorf et al.
Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC Registry
Blood
(2014)
MD Silverstein et al.
Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study
Arch Intern Med
(1998)
C Kearon et al.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines
Chest
(2012)
Oral rivaroxaban for symptomatic venous thromboembolism
N Engl J Med
(2010)
Oral rivaroxaban for the treatment of symptomatic pulmonary embolism
N Engl J Med
(2012)
G Agnelli et al.
Apixaban for extended treatment of venous thromboembolism
N Engl J Med
(2013)
G Agnelli et al.
Oral apixaban for the treatment of acute venous thromboembolism
N Engl J Med
(2013)
S Schulman et al.
Dabigatran versus warfarin in the treatment of acute venous thromboembolism
N Engl J Med
(2009)

S Schulman et al.

Extended use of dabigatran, warfarin, or placebo in venous thromboembolism

N Engl J Med

(2013)

S Schulman et al.

Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis

Circulation

(2014)

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ArticlesSafety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Best Pract Res Clin Haematol

Am J Med

Blood

Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study

Arch Intern Med

Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines

Chest

Oral rivaroxaban for symptomatic venous thromboembolism

N Engl J Med

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism

N Engl J Med

Apixaban for extended treatment of venous thromboembolism

N Engl J Med

Oral apixaban for the treatment of acute venous thromboembolism

N Engl J Med

Dabigatran versus warfarin in the treatment of acute venous thromboembolism

N Engl J Med

Extended use of dabigatran, warfarin, or placebo in venous thromboembolism

N Engl J Med

Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis

Circulation

Articles
Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study