Clinical trial NCT06087952: Leiden Thrombosis Recurrence Risk Prevention
Official title: Leiden Thrombosis Recurrence Risk Prevention: Tailored Treatment After a First Venous Thromboembolism
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Venous Thromboembolism
Venous Thromboses
Pulmonary Embolism
Deep Vein Thrombosis
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2023-10-18
Enrollment: 608
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: OTHER

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.

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 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.

Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. 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.
3. Be aged 18 years or above.

Exclusion Criteria:

1. 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
2. Patients who need to continue anticoagulant treatment for another indication (e.g. atrial fibrillation).
3. Patients with a strong indication for long-term antiplatelet therapy despite oral anticoagulation (e.g. those with recent STEMI)
4. Patients with COVID-19 associated VTE (hospital admission because of COVID-19 \<3 months before the VTE) or vaccine-induced immune thrombotic thrombocytopenia (VITT)
5. 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.

Primary outcomes:
measure: Recurrent VTE and major bleeding
timeFrame: 2 years
Secondary outcomes:
measure: Primary outcome weighted for quality of life (EQ-5D-5L)
timeFrame: 2 years
measure: Primary outcome weighted for functional status (PFVS)
timeFrame: 2 years
measure: Cost-effectiveness
timeFrame: Up to 2 years
measure: Recurrent VTE and major bleeding in non-randomised arms
timeFrame: 2 years
measure: Clinically relevant non-major bleeding
timeFrame: 2 years
measure: Reccurent VTE, major bleeding and clinically relevant - non Major bleeding during entire follow-up
timeFrame: Up to 6 years
measure: Predictive performance of the L-TRRiP model
timeFrame: Up to 6 years
measure: Predictive performance of the VTE-BLEED model
timeFrame: Up to 6 years
measure: Natural course of recovery
timeFrame: Up to 6 years
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: South-Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam Medical Center, location AMC
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Drachten
country: Netherlands
facility: Nij Smellinghe Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Goes
country: Netherlands
facility: Admiraal de Ruyter Ziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Leiden University Medical Center
name: Suzanne Cannegieter, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: