inDividual, Targeted thrombosIS Prophylaxis Versus the Standard 'One Size Fits All' Approach in Patients Undergoing Total hIp or Total kNee replaCemenT
NCT ID: NCT06581965
Last Updated: 2025-09-03
Study Results
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Basic Information
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RECRUITING
PHASE4
10078 participants
INTERVENTIONAL
2024-11-11
2031-02-01
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
PREVENTION
NONE
Study Groups
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DISTINCT 1 short duration prophylaxis
Patients with a low VTE risk (predicted 3-months postoperative VTE risk \<1%) based on the TRiP(plasty) score. (Nemeth, 2024)
Short duration prophylaxis
Only during hospitalization: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guideline "Antitrombotisch beleid". First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use (same type as used for control group).
DISTINCT 1 control
Patients with a low VTE risk (predicted 3-months postoperative VTE risk \<1%) based on the TRiP(plasty) score. (Nemeth, 2024)
Control
4 weeks: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
DISTINCT 2 observational arm
Patients with an intermediate VTE risk (predicted 3-months postoperative VTE risk ≥1%-≤1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)
Control
4 weeks: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
DISTINCT 3 extended prophylaxis
Patients with a high VTE risk (predicted 3-months postoperative VTE risk \>1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)
Higher intensity and longer duration prophylaxis
The use of any thrombocyte aggregation inhibitors should be discontinued 5 days prior to surgery. Day 0-2: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
Day 3: Apixaban 5mg b.i.d., continued until 6 weeks after surgery, conditional on the fact that no active bleeding of the surgical wound can be observed. In case of active bleeding, the prophylactic dose of thrombosis prophylaxis is continued. Thereafter, in case no active bleeding has been observed for 24 hours, the 5mg b.i.d. apixaban treatment will be started.
The 5mg b.i.d. apixaban dose will be adjusted to 2.5mg b.i.d. in case of an impaired kidney function (defined as eGFR 10-30ml/min).
DISTINCT 3 control
Patients with a high VTE risk (predicted 3-months postoperative VTE risk \>1.5%) based on the TRiP(plasty) score. (Nemeth, 2024)
Control
4 weeks: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
Interventions
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Short duration prophylaxis
Only during hospitalization: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guideline "Antitrombotisch beleid". First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use (same type as used for control group).
Higher intensity and longer duration prophylaxis
The use of any thrombocyte aggregation inhibitors should be discontinued 5 days prior to surgery. Day 0-2: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
Day 3: Apixaban 5mg b.i.d., continued until 6 weeks after surgery, conditional on the fact that no active bleeding of the surgical wound can be observed. In case of active bleeding, the prophylactic dose of thrombosis prophylaxis is continued. Thereafter, in case no active bleeding has been observed for 24 hours, the 5mg b.i.d. apixaban treatment will be started.
The 5mg b.i.d. apixaban dose will be adjusted to 2.5mg b.i.d. in case of an impaired kidney function (defined as eGFR 10-30ml/min).
Control
4 weeks: any type of LMWH or DOAC in a prophylactic dose as approved by the Dutch guidelines. First dose of LMWH within 6-24h following surgery. First dose of apixaban within 12-24h following surgery. First dose of rivaroxaban 6-10h following surgery. First dose of dabigatran within 1-4h following surgery. The applied type of anticoagulant is according to the local standard use.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Aged 18 years or older
Exclusion Criteria
* 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
18 Years
ALL
No
Sponsors
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Leiden University Medical Center
OTHER
Responsible Party
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B.Nemeth
Postdoctoral researcher Clinical epidemiology
Principal Investigators
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Banne Nemeth, dr
Role: PRINCIPAL_INVESTIGATOR
Leiden University Medical Center
Locations
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Gelre Ziekenhuizen
Apeldoorn, Gelderland, Netherlands
Zuyderland
Geleen, Limburg, Netherlands
Anna Ziekenhuis
Geldrop, North Brabant, Netherlands
Bravis ziekenhuis
Roosendaal, North Brabant, Netherlands
Elisabeth-TweeSteden Ziekenhuis
Tilburg, North Brabant, Netherlands
OLVG
Amsterdam, North Holland, Netherlands
Bergman Clinics
Naarden, North Holland, Netherlands
Isala ziekenhuis
Zwolle, Overijssel, Netherlands
Alrijne
Leiderdorp, South Holland, Netherlands
Reinier Haga Orthopedisch Centrum
Zoetermeer, South Holland, Netherlands
Countries
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Central Contacts
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References
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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.
Kok RY, van Bodegom-Vos L, Ettema HB, Groenwold RHH, van den Hout WB, Huisman MV, Klok FA, Nelissen RGHH, van Rein N, van Veen M, Vehmeijer SBW, Wiegerinck JJI, Cannegieter SC, Nemeth B. Study protocol for 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, multicentre, randomised, multiarm, open-label trial. BMJ Open. 2025 Oct 6;15(10):e101180. doi: 10.1136/bmjopen-2025-101180.
Other Identifiers
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2023-510186-98-00
Identifier Type: CTIS
Identifier Source: secondary_id
U1111-1305-2311
Identifier Type: REGISTRY
Identifier Source: secondary_id
P24.031
Identifier Type: -
Identifier Source: org_study_id
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