Rivaroxaban Plus Aspirin to Manage Recurrent Venous Thromboembolic Events

Rivaroxaban Plus Aspirin Versus Acenocoumarol to Manage Recurrent Venous Thromboembolic Events Despite Systemic Anticoagulation With Rivaroxaban

Venous thromboembolism affects around 10 million people per year worldwide, however, despite its high incidence, there is no systematic review or randomized trial focused on the treatment of patients with recurrent deep vein thrombosis (DVT) and/or or pulmonary embolism (PE) during anticoagulant treatment. The objective was to compare the use of Rivaroxaban plus Aspirin versus Acenocoumarol in patients with recurrent venous thromboembolism treated with rivaroxaban.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism; Pulmonary Embolism; Anticoagulant-induced Bleeding; Venous Thromboses
• Intervention / Treatment: Drug: Rivaroxaban 20 MG [Xarelto]; Drug: Aspirin 300mg; Drug: Acenocoumarol Oral Tablet

Detailed Description

Venous thromboembolism has two manifestations, deep vein thrombosis (DVT) and pulmonary embolism (PE), affects around 10 million people per year worldwide, with an annual incidence of 1-2 cases per 1000 population and increases exponentially with age. [1,2,3] DVT is a multicausal disease thought to be triggered by interactions between multiple triggering factors that may be additive or synergistic, such as active cancer, antiphospholipid syndrome (APS), or other chronic inflammatory disorders. [2,4] The contribution of genetics to the risk of thromboembolism venous traditionally includes protein C, protein S, and antithrombin deficiencies, prothrombin gene mutation, and factor V Leiden. [5] The exact epidemiology in Mexico is unknown, however, the estimated prevalence of deficiencies in a population studied in Mexico City were Protein C (PC) 0.65%, Protein S (PS) 0.65%, Antithrombin (AT) 2.04% and Plasminogen ( Plg) 2.5%. [6] For the treatment of patients with DVT and/or PE, the American Society of Hematology (ASH) guideline panel suggests using direct oral anticuagulants (DOACs) over vitamin K antagonists (VKAs), [7] however the use of a DOAC instead of a VKA for patients with DVT does not impact mortality, the use of DOACs has also been related to a reduction in the risk of DVT and major bleeding, although this was not statistically significant, the greatest advantage is that the use of DOACs do not require frequent dose adjustment, monitoring of the INR, or dietary restrictions, [8 -31] in our work center we started with DOACs as the first line of treatment.

Recurrent DVT despite anticoagulation has been related to the presence of active cancer, subtherapeutic anticoagulation, use of concomitant anticancer drugs, younger age at presentation (<65 years), and PE as the initial DVT. [32-40] Insertion of an inferior vena cava (IVC) filter was previously recommended in patients with recurrent DVT while receiving anticoagulant therapy. [41] However, the risk of recurrent DVT after IVC filter insertion is as high as 32% in cancer patients and has been associated with significant morbidity and poor quality of life; [42-46] It has been suggested that increasing the dose of low molecular weight heparin (LMWH) may be an alternative to IVC filter insertion in patients with recurrent DVT, [47-49] however, to date, there is no systematic review or randomized trial focused on the treatment of patients with recurrent DVT and/or PE during anticoagulant treatment.

The aim of the current study was to compare the use of Rivaroxaban plus Aspirin versus Acenocoumarol in the prevention of thromboembolic and bleeding events in patients with recurrent venous thromboembolism treated with rivaroxaban.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Mexico
  • Estado De Mexico
    • Metepec, Estado De Mexico, Mexico, 55056
      • Instituto Mexicano del Seguro Social

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Objectively proven first episode of venous thromboembolism (upper extremity deep vein thrombosis, proximal lower extremity deep vein thrombosis, or pulmonary embolism).

Objectively documented recurrent venous thromboembolism (either new or extended upper extremity deep vein thrombosis, proximal lower extremity deep vein thrombosis or pulmonary embolism) while taking systemic anticoagulation medication (Rivaroxaban).

Exclusion Criteria:

Previous hemorrhagic stroke Ischemic stroke in the last 3 months Severe renal impairment (CrCl rates < 30 ml/min) Active liver disease (any etiology) Concomitant use of any antiplatelet (aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidine, etc.) Increased risk of bleeding (congenital or acquired) Uncontrolled SAH Gastrointestinal hemorrhage within the past year Anemia (Hb level < 10 g/dl) or thrombocytopenia (platelet count < 100 × 109/l) Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rivaroxaban plus Aspirin; Drug: Rivaroxaban 15 mg Rivaroxaban 15 mg BID Other Names: Xarelto 15 mg Rivaroxabana 15 mg Drug: Aspirin 300 mg	Drug: Rivaroxaban 20 MG [Xarelto]; It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization); Other Names: Xarelto 20 mg; Drug: Aspirin 300mg; It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization); Other Names: Acetilsalicilic acid
Placebo Comparator: Acenocoumarol; Drug: Acenocoumarol Other Name: Vitamin K antagonist	Drug: Acenocoumarol Oral Tablet; It was adopted an equal allocation of patients to each treatment (i.e., 1:1 randomization); Other Names: Vitamin K antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy outcome The presence of thromboembolic events	Recurrent ipsilateral Deep vein thrombosis, Recurrent contralateral Deep vein thrombosis, Pulmonary emboli, Ischemic stroke and Myocardial infarction	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major or clinically relevant nonmajor bleeding	The primary safety outcome was major or clinically relevant nonmajor bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and Bleeding Academic Research Consortium (BARC)	90 days

Collaborators and Investigators

• Sponsor: Instituto Mexicano del Seguro Social

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2021
• Primary Completion (Actual): January 9, 2022
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: August 18, 2022
• First Submitted That Met QC Criteria: August 24, 2022
• First Posted (Actual): August 25, 2022

Study Record Updates

• Last Update Posted (Actual): August 25, 2022
• Last Update Submitted That Met QC Criteria: August 24, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Aspirin; Rivaroxaban; venous thromboembolism; Acenocoumarol
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Thromboembolism; Venous Thromboembolism; Pulmonary Embolism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Aspirin; Vitamin K; Rivaroxaban; Acenocoumarol
• Other Study ID Numbers: 000001 (Kaiser Permanente Southern California IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes