L-TRRiP: Leiden Thrombosis Recurrence Risk Prevention

Sponsor

Leiden University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT06087952

Collaborator

(none)

608

Enrollment

Locations

Arms

71.4

Anticipated Duration (Months)

35.8

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Venous Thromboembolism Venous Thromboses Pulmonary Embolism Deep Vein Thrombosis	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 anticoaguant treatment after 3 months	N/A

Detailed Description

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 two years, during which they will be asked to fill in a questionnaire every 3 months. These questionnaire is 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

608 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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)

Masking Description:

Blinded endpoint adjudication

Primary Purpose:

Other

Official Title:

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

Actual Study Start Date :

Jun 18, 2021

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Recurrent VTE and major bleeding [2 years]
Incidence of the combined endpoint recurrent VTE and major bleeding in the randomised arms

Secondary Outcome Measures

Primary outcome weighted for quality of life (EQ-5D-5L) [2 years]
Recurrent VTE and major bleeding weighted for the impact on quality of life as measured by the EQ-5D-5L
Primary outcome weighted for functional status (PFVS) [2 years]
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..
Recurrent VTE and major bleeding in non-randomised arms [2 years]
Incidence of the combined endpoint in the non-randomised arms
Cost-effectiveness [Up to 2 years]
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).
Natural course of recovery [Up to 2 years]
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.
Clinically relevant non-major bleeding [2 years]
Incidence of clinically relevant non-major bleeding in different study arms

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Leiden University Medical Center	Leiden	South-Holland	Netherlands	2333 ZA
2	Amsterdam Medical Center, location AMC	Amsterdam		Netherlands
3	Wilhelmina Ziekenhuis	Assen		Netherlands
4	Rode Kruis Ziekenhuis	Beverwijk		Netherlands
5	Amphia Ziekenhuis	Breda		Netherlands
6	Haaglanden Medisch Centrum	Den Haag		Netherlands
7	HagaZiekenhuis	Den Haag		Netherlands
8	Nij Smellinghe Ziekenhuis	Drachten		Netherlands
9	Ziekenhuis Gelderse Vallei	Ede		Netherlands
10	Admiraal de Ruyter Ziekenhuis	Goes		Netherlands
11	Groene Hart Ziekenhuis	Gouda		Netherlands
12	Martini Ziekenhuis	Groningen		Netherlands
13	University Medical Center Groningen	Groningen		Netherlands
14	Radboud University Medical Center	Nijmegen		Netherlands
15	Ikazia Ziekenhuis	Rotterdam		Netherlands
16	Diakonessenhuis	Utrecht		Netherlands
17	Isala Klinieken	Zwolle		Netherlands