inDividual, Targeted thrombosIS Prophylaxis Versus the Standard 'One Size Fits All' Approach in Patients Undergoing Total hIp or Total kNee replaCemenT (DISTINCT)

Leiden University Medical Center (LUMC)

Status and phase: Enrolling; Phase 4

Conditions: Pulmonary Embolism; Venous Thromboembolism; Deep Vein Thrombosis; Venous Thromboses

Treatments: Other: Short duration prophylaxis; Other: Higher intensity and longer duration prophylaxis; Other: Control

Study type: Interventional

Funder types: Other

Identifiers

NCT06581965

U1111-1305-2311 (Registry Identifier)

2023-510186-98-00 (EU Trial (CTIS) Number)

P24.031

Details and patient eligibility

About

After hip or knee replacement all patients receive a standardized treatment with blood thinners, this medication is called thrombosis prophylaxis. However, despite this standard treatment some individuals still develop venous thrombosis (VTE), while others experience bleeding. This indicates that not all patients have the same VTE risk following surgery. Individualizing the amount of thrombosis prophylaxis following surgery might lead to less thrombotic and bleeding events. In this study the investigators individualize the treatment with thrombosis prophylaxis based on the medical history of a patient.

The main questions this study aims to answer are:

Can thrombosis prophylaxis be shortened in patients with a low VTE risk to decrease the risk of bleeding without increasing the risk of VTE? Does an increase in the dose and duration of thrombosis prophylaxis in patients with a high VTE risk reduce the risk of VTE without inducing an unacceptable risk of bleeds?

Researchers will compare both the shortened treatment in low VTE risk patients and the intensified and extended treatment in high VTE risk patients with the standard treatment to assess the risk of VTE and bleeding in comparison to the standard treatment.

Participants will receive 4 questionnaires to evaluate whether they have experienced a VTE or bleed. For this study no additional hospital visits are necessary.

Full description

Background

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are associated with an overall symptomatic venous thromboembolism (VTE) risk of about 1.3% despite the use of prophylactic anticoagulants in all patients. While not preventing all VTEs, the uniform application of anticoagulant prophylaxis is at the same time associated with a major bleeding risk of at least 0.5%. Considering that a large proportion of all patients actually have a low VTE risk, this group is unnecessarily exposed to the burden and risks of thrombosis prophylaxis. On the contrary, some patients with a high VTE risk experience a VTE despite the use of the same prophylactic anticoagulants. These VTE cases could have possibly been prevented by intensified prophylaxis.

Objectives

Overall objective: To study whether the application of a targeted anticoagulation strategy leads to less thrombotic and bleeding complications in this large patient group.

Primary objective DISTINCT study arm 1 : To determine whether in-hospital thrombosis prophylaxis only is as effective compared with the standard thrombosis prophylaxis approach to prevent symptomatic VTE after total knee and hip arthroplasty in patients with a low VTE risk.

Primary objective DISTINCT study arm 2: To determine the incidence of symptomatic VTE after total knee and hip arthroplasty in patients with an intermediate VTE risk.

Primary objective DISTINCT study arm 3: To determine whether intensified thrombosis prophylaxis is more effective and equally safe compared with standard thrombosis prophylaxis to prevent symptomatic VTE in patients with a high VTE risk by comparing symptomatic VTE and bleeding complications.

Methods

The investigators hypothesize that:

1. In patients with a low VTE risk the thromboprophylaxis can be safely shortened to in-hospital duration only, without increasing the VTE risk (in comparison with the standard duration). In addition, this will lead to less bleeds.
2. In patients with a high VTE risk (individual predicted risk >1.5%), a therapeutic dose of thrombosis prophylaxis for 6 weeks is more effective to prevent symptomatic VTE, in comparison with the standard thromboprophylaxis. In addition, the investigators expect that the benefits of this approach (less symptomatic VTEs) outweigh the induced bleeds.

In the trial participants are allocated to one of three study arms based on the postoperative venous thromboembolism (VTE) risk predicted with the TRiP(plasty) score. (Nemeth, 2024)

• DISTINCT 1 (low VTE risk, <1.0%) will be a randomized study arm.
• DISTINCT 2 (intermediate VTE risk, 1.0%-1.5%) will be an observational study arm.
• DISTINCT 3 (high VTE risk, >1.5%) will be a randomized study arm.

Participants will receive a questionnaire before surgery and 2 weeks, 6 weeks and 3 months after surgery. To assess the outcome measures. Furthermore an additional questionnaire is send 1 year after surgery if the participant experienced a VTE, major bleed or prosthesis infection. This questionnaire is focused on quality of life and joint function. Participants without such an event can be invited to complete this questionnaire as well. No extra hospital visits are needed and the surgery does not change.

Sample size calculations

In DISTINCT study arm 1, the expected 3-month cumulative incidence of symptomatic VTE in the control arm is 0.75%. No risk reduction or increase is anticipated, so the expected risk in the short-duration prophylaxis group is also 0.75%. With a non-inferiority limit set at 1%, a sample size of 3,130 patients is needed to achieve a power of 90%, leading to an aim to include 1,739 patients in each group, totaling 3,478 patients after accounting for a maximum dropout rate of 10%.

For DISTINCT study arm 2, in the intermediate-risk group, the expected cumulative incidence of VTE within 3 months is 1.3%. With a sample size of 2,500, a 95% confidence interval width of 0.9% - 1.7% is expected, ensuring a probability of less than 15% that the upper bound of a two-sided 95% confidence interval will exceed the 2% margin.

In DISTINCT study arm 3, a 3-month cumulative incidence of symptomatic VTE of 2.5% is expected in the control group. With an anticipated relative risk reduction of 50% in the intervention group, a sample size of 3,694 patients is necessary to achieve 80% power. Considering an interim analysis and a slightly stricter statistical significance level at the final analysis, a total of 3,748 patients is required, with 2,050 patients in each arm after accounting for a maximum dropout rate of approximately 9%, totalling 4,100 patients.

Ethics: The study has been approved by the Medical Ethics Committee Leiden Den Haag Delft. All participants will provide informed consent.

Enrollment: 10,078 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Scheduled to undergo an elective total hip arthroplasty or total knee arthroplasty
• Aged 18 years or older

Exclusion criteria

• Primary arthroplasty for fractures
• Revision surgery
• Hemiarthroplasty
• Pregnancy
• Current use of therapeutic anticoagulant therapy of any type (e.g., LMWH, DOAC, vitamin K antagonist)
• A contraindication for either study drug
• Insufficient knowledge of the Dutch language
• Insufficient mental or physical ability to fulfil trial requirements
• Active malignancy (i.e. cancer diagnosis within six months before surgery (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 surgery)
• Patients using thrombocyte aggregation inhibitors that cannot be temporarily discontinued at the discretion of their treating physician

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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10,078 participants in 5 patient groups

DISTINCT 1 short duration prophylaxis

Experimental group

Description:

Patients with a low VTE risk (predicted 3-months postoperative VTE risk \<1%) based on the TRiP(plasty) score. (Nemeth, 2024)

Treatment:

Other: Short duration prophylaxis

DISTINCT 1 control

Active Comparator group

Description:

Patients with a low VTE risk (predicted 3-months postoperative VTE risk \<1%) based on the TRiP(plasty) score. (Nemeth, 2024)

Treatment:

Other: Control

DISTINCT 2 observational arm

Other group

Description:

Patients with an intermediate VTE risk (predicted 3-months postoperative VTE risk ≥1%-≤1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)

Treatment:

Other: Control

DISTINCT 3 extended prophylaxis

Experimental group

Description:

Patients with a high VTE risk (predicted 3-months postoperative VTE risk \>1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)

Treatment:

Other: Higher intensity and longer duration prophylaxis

DISTINCT 3 control

Active Comparator group

Description:

Patients with a high VTE risk (predicted 3-months postoperative VTE risk \>1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)

Treatment:

Other: Control