Leiden Thrombosis Recurrence Risk Prevention

Study Overview
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Brief Summary
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The goal of this clinical trial is to evaluate tailored duration of long-term anticoagulant treatment after a first venous thromboembolism based on individualized risk assessments of recurrent VTE and major bleeding risks. Participants will be asked to fill in a questionnaire and take a buccal swab, which are used for an individual estimation of the risks of recurrent VTE and bleeding. Based on these risks a treatment advise will be made, or randomised in a subgroup of patients.

Detailed Description
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Background: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. A recurrent VTE can be prevented by prolonged anticoagulant therapy, but this may come at the cost of major bleeding. The L-TRRiP and VTE-BLEED prediction scores have been developed to classify the risk of recurrent VTE (low, intermediate, high) and major bleeding (low vs high), respectively. However, their combined use in finding the optimal balance to minimize both long-term risks is unclear. Aims: To evaluate tailored duration of long-term anticoagulant treatment based on individualized risk assessments of recurrent VTE and major bleeding risks. Methods: The L-TRRiP study is a multicenter, open-label, cohort based randomized controlled trial in which patients with a first VTE will be included. For each patient the risk of recurrent VTE (low, medium, high) and major bleeding (low, high) will be determined using the L-TRRiP and VTE-BLEED prediction scores, respectively. After three months of initial anticoagulant therapy, patients with a low recurrent VTE risk (<6% in 2 years) will discontinue anticoagulants, whereas patients with a high recurrent VTE risk(>14% in 2 years) and low major bleeding risk will continue. The other groups, with unclear benefit of prolonged treatment, will be randomized to continue or discontinue anticoagulants. Patients will be followed for at least two years, during which they will be asked to fill in a questionnaire every 3 months during the first two years, followed by a questionnaire once a year for the remaining duration of the study (i.e., 2 years after inclusion of the last participant; which is expected to be in 2027). The total follow-up duration is therefore expected to vary between 2 to 6 years. The follow-up questionnaires are used to screen for potential outcomes (including recurrent VTE and bleeding), and includes the EQ-5D-5L to assess quality of life, the Post VTE functional status scale to assess functional outcomes and the Medical Consumption and Productivity Costs Questionnaire to asses cost-effectiveness. In case of a potential outcome additional information is retrieved from the medical record for adjudication. The clinical outcomes will be evaluated and classified by an independent committee blinded for treatment allocation. Sample size: The sample size of this study is based on the randomized part of the study. To demonstrate a 7% difference in the combined endpoint (i.e., 10.6% vs 3.6%) with an alpha of 0.05 and a power of 90%, a sample size of 552 subjects for the randomized part of the study is required. Taking into account a drop-out rate of 10%, the aim is to include 608 patients in the randomized part of the study. After inclusion of 608 randomized patients, inclusion will stop. Based on the derivation studies it is expected the randomized group will form about 40% of the total included population, in which case the estimated total number of included patients will be 1600. Of note, this total number may change depending on the final proportion of the randomized group. Ethics: The study has been approved by the Medical Ethics Committee Leiden Den Haag Delft. All participants will provide informed consent.

Official Title
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Leiden Thrombosis Recurrence Risk Prevention: Tailored Treatment After a First Venous Thromboembolism

Conditions
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Venous Thromboembolism, Venous Thromboses, Pulmonary Embolism, Deep Vein Thrombosis

Intervention / Treatment
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* Other: Randomised treatment advice (discontinue vs continue after 3 months)
* Diagnostic Test: VTE-BLEED score
* Diagnostic Test: L-TRRiP score
* Other: Advise to continue anticoagulant treatment after 3 months
* Other: Advise to discontinue anticoagulant treatment after 3 months


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Be diagnosed with a first confirmed symptomatic deep vein thrombosis (including distal vein thrombosis, in Dutch: 'kuitvenetrombose') or pulmonary embolism with an indication for treatment with anticoagulant therapy for at least 3 months as prescribed by their treating physician. Be aged 18 years or above. Exclusion Criteria: Patients with active cancer (i.e. cancer diagnosis within six months before VTE (excluding basal-cell or squamous-cell carcinoma of the skin), recently recurrent or progressive cancer or any cancer that required anti-cancer treatment within six months before the venous thromboembolism was diagnosed) or antiphospholipid syndrome Patients who need to continue anticoagulant treatment for another indication (e.g. atrial fibrillation). Patients with a strong indication for long-term antiplatelet therapy despite oral anticoagulation (e.g. those with recent STEMI) Patients with COVID-19 associated VTE (hospital admission because of COVID-19 <3 months before the VTE) or vaccine-induced immune thrombotic thrombocytopenia (VITT) Patients in whom the risk of bleeding is deemed extremely high by the treating physician, necessitating discontinuation of anticoagulant treatment for the first VTE after the initial 3 months or even during the initial 3 months.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients with low recurrent VTE risk are advised to stop anticoagulant therapy. Patients with high recurrent VTE risk and low bleeding risk are advised to continue anticoagulant therapy. Patients with intermediate recurrent VTE risk, or high recurrent VTE risk and high bleeding risk are randomised to stop or continue anticoagulant therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Continue anticoagulation<br>Patients with high recurrent VTE risk and low major bleeding risks are advised to continue anticoagulant therapy. | Diagnostic Test: VTE-BLEED score<br>* Predict bleeding risk during extended anticoagulant treatment (high or low) using the VTE-BLEED score<br>Diagnostic Test: L-TRRiP score<br>* Predict VTE recurrence risk after anticoagulant discontinuation (high, intermediate or low) using the L-TRRiP score<br>Other: Advise to continue anticoagulant treatment after 3 months<br>* Advise to continue anticoagulant treatment after 3 months for patients with high VTE recurrence and low bleeding risk<br>|
| Other: Discontinue anticoagulation<br>Patients with low recurrent VTE risk are advised to discontinue anticoagulant therapy. | Diagnostic Test: VTE-BLEED score<br>* Predict bleeding risk during extended anticoagulant treatment (high or low) using the VTE-BLEED score<br>Diagnostic Test: L-TRRiP score<br>* Predict VTE recurrence risk after anticoagulant discontinuation (high, intermediate or low) using the L-TRRiP score<br>Other: Advise to discontinue anticoagulant treatment after 3 months<br>* Advise to discontinue anticoagulant treatment after 3 months for patients with low VTE recurrence risk<br>|
| Other: Randomised to continue anticoagulation<br>Patients with intermediate recurrent VTE risk or high recurrent VTE risk and high major bleeding risk are randomised to continue or discontinue anticoagulant therapy. | Other: Randomised treatment advice (discontinue vs continue after 3 months)<br>* Randomisation to continue or discontinue anticoagulant therapy in 1:1 ratio stratified on risk category of L-TRRiP and VTE-BLEED score<br>Diagnostic Test: VTE-BLEED score<br>* Predict bleeding risk during extended anticoagulant treatment (high or low) using the VTE-BLEED score<br>Diagnostic Test: L-TRRiP score<br>* Predict VTE recurrence risk after anticoagulant discontinuation (high, intermediate or low) using the L-TRRiP score<br>|
| Other: Randomised to discontinue anticoagulation<br>Patients with intermediate recurrent VTE risk or high recurrent VTE risk and high major bleeding risk are randomised to continue or discontinue anticoagulant therapy. | Other: Randomised treatment advice (discontinue vs continue after 3 months)<br>* Randomisation to continue or discontinue anticoagulant therapy in 1:1 ratio stratified on risk category of L-TRRiP and VTE-BLEED score<br>Diagnostic Test: VTE-BLEED score<br>* Predict bleeding risk during extended anticoagulant treatment (high or low) using the VTE-BLEED score<br>Diagnostic Test: L-TRRiP score<br>* Predict VTE recurrence risk after anticoagulant discontinuation (high, intermediate or low) using the L-TRRiP score<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrent VTE and major bleeding | Incidence of the combined endpoint recurrent VTE and major bleeding in the randomised arms | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary outcome weighted for quality of life (EQ-5D-5L) | Recurrent VTE and major bleeding weighted for the impact on quality of life as measured by the EQ-5D-5L | 2 years | 
| Primary outcome weighted for functional status (PFVS) | Recurrent VTE and major bleeding weighted for the impact on functional limitations as measured by the Post-VTE functional status scale (PFVS) a grade for functional outcomes after a VTE, ranging from grade 0 (no functional limitations, symptoms, pain or anxiety) to grade 4 (severe functional limitations, requiring assistance in activities of daily living) or death.. | 2 years | 
| Cost-effectiveness | For the analysis of cost-effectiveness health care costs and productivity losses will be measured every 3 months during follow-up by the Medical Consumption Questionnaire and Productivity Costs Questionnaire from the institute for Medical Technology Assessment. Health care costs will be calculated using Dutch standard prices for economic evaluations. Absence from work will be valued with friction cost method. Quality Adjusted Life Years (QALYs) will be assessed using the EQ-5D-5L score, which is taken every 3 months during follow-up, using the area-under-the-curve approach. Economic evaluation will consists of both a study-based cost-effectiveness analysis (cost per event) as well as cost-utility analysis with a lifetime horizon (costs per QALY). | Up to 2 years | 
| Recurrent VTE and major bleeding in non-randomised arms | Incidence of the combined endpoint in the non-randomised arms | 2 years | 
| Clinically relevant non-major bleeding | Incidence of clinically relevant non-major bleeding in different study arms | 2 years | 
| Reccurent VTE, major bleeding and clinically relevant - non Major bleeding during entire follow-up | Incidence of recurrent VTE, major bleeding and clinically relevant bleeding in different study arms for the entire duration of follow-up (expected to vary between 2 to 6 years) | Up to 6 years | 
| Predictive performance of the L-TRRiP model | Discrimination and calibration of L-TRRiP model in the arms that discontinue anticoagulant treatment | Up to 6 years | 
| Predictive performance of the VTE-BLEED model | Discrimination and calibration of the L-TRRiP model in the arms that continue anticoagulant treatment | Up to 6 years | 
| Natural course of recovery | Natural course of recovery with regard to long-term functional limitations, measured by post VTE functional status scale every 3 months through the follow-up period of 2 years. Using the post VTE functional status scale (PFVS) a grade for functional outcomes after a VTE, ranging from grade 0 (no functional limitations, symptoms, pain or anxiety) to grade 4 (severe functional limitations, requiring assistance in activities of daily living) or death. | Up to 6 years |