Clinical trial NCT06581965: InDividual, Targeted ThrombosIS Prophylaxis Versus the Standard 'one Size Fits All' Approach in Patients Undergoing Total HIp or Total KNee ReplaCemenT
Official title: The DISTINCT Trial: InDividual, Targeted ThrombosIS Prophylaxis Versus the Standard 'one Size Fits All' Approach in Patients Undergoing Total HIp or Total KNee ReplaCemenT: a National, Multicenter, Randomized, Multi-arm, Open-label Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Venous Thromboembolism
Venous Thromboses
Pulmonary Embolism
Deep Vein Thrombosis
Keywords: Venous thromboembolism
Prophylaxis
Individualized Medicine
Total hip arthroplasty
Total knee arthroplasty
Randomized controlled trial
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2024-09-03
Enrollment: 10078
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This trial consists of 3 study arms. DISTINCT 1 (low VTE risk \<1.0%): randomized (2 arms) DISTINCT 2 (intermediate VTE risk 1.0%-1.5%): observational DISTINCT 3 (high VTE risk \>1.5%): randomized (2 arms) Participants will be allocated to a study arm based on their predicted VTE risk which is determined by the TRiP(plasty) score.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Venous thromboembolic events
timeFrame: 90 days postoperative
measure: Major bleeding
timeFrame: 90 days postoperative
Secondary outcomes:
measure: Clinically relevant non major bleeding
timeFrame: 90 days postoperative
measure: Impact of events on QALY's
timeFrame: 90 days and 1 year postoperative
measure: Healthcare costs
timeFrame: 90 days and 1 year postoperative
measure: Prosthetic joint infections
timeFrame: 90 days postoperative
measure: Patient reported quality of life
timeFrame: 90 days and 1 year postoperative
measure: Patient reported quality of life
timeFrame: 1 year postoperative
measure: Patient reported outcome measures
timeFrame: 1 year postoperative
measure: Myocardial infarction
timeFrame: 90 days postoperative
measure: Ischemic stroke
timeFrame: 90 days postoperative
measure: Death
timeFrame: 90 days postoperative
Other outcomes:
Locations:
city: Geldrop
country: Netherlands
facility: Anna Ziekenhuis
state: Noord-Brabant
city: Tilburg
country: Netherlands
facility: Elisabeth-TweeSteden Ziekenhuis
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: OLVG
state: Noord-Holland
city: Naarden
country: Netherlands
facility: Bergman Clinics
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala ziekenhuis
state: Overijssel
city: Zoetermeer
country: Netherlands
facility: Reinier Haga Orthopedisch Centrum
state: Zuid-Holland
Study officials:
affiliation: Leiden University Medical Center
name: Banne Nemeth, dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nemeth B, Smeets M, Pedersen AB, Kristiansen EB, Nelissen R, Whyte M, Roberts L, de Lusignan S, le Cessie S, Cannegieter S, Arya R. Development and validation of a clinical prediction model for 90-day venous thromboembolism risk following total hip and total knee arthroplasty: a multinational study. J Thromb Haemost. 2024 Jan;22(1):238-248. doi: 10.1016/j.jtha.2023.09.033. Epub 2023 Nov 22.