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

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Deep Vein Thrombosis; Venous Thromboembolism; Pulmonary Embolism; Venous Thromboses
• Intervention / Treatment: Other: Short duration prophylaxis; Other: Control; Other: Higher intensity and longer duration prophylaxis

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.

• Study Type: Interventional
• Enrollment (Estimated): 10078
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Banne Nemeth, dr; Phone Number: +31715264037; Email: B.Nemeth@lumc.nl
• Study Contact Backup: Name: Ruben Y Kok, drs; Phone Number: +31715265633; Email: R.Y.Kok@lumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands, 7334 DZ
      • Recruiting
      • Gelre Ziekenhuizen
  • Limburg
    • Geleen, Limburg, Netherlands, 6162 BG
      • Recruiting
      • Zuyderland
  • North Brabant
    • Geldrop, North Brabant, Netherlands, 5564EH
      • Recruiting
      • Anna Ziekenhuis
    • Roosendaal, North Brabant, Netherlands, 4708 AE
      • Not yet recruiting
      • Bravis Ziekenhuis
    • Tilburg, North Brabant, Netherlands, 5022GC
      • Recruiting
      • Elisabeth-Tweesteden Ziekenhuis
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1091AC
      • Recruiting
      • OLVG
    • Naarden, North Holland, Netherlands, 1411DE
      • Recruiting
      • Bergman Clinics
  • Overijssel
    • Zwolle, Overijssel, Netherlands, 8025AB
      • Recruiting
      • Isala Ziekenhuis
  • South Holland
    • Leiderdorp, South Holland, Netherlands, 2353 GA
      • Recruiting
      • Alrijne
    • Zoetermeer, South Holland, Netherlands, 2725NA
      • Recruiting
      • Reinier Haga Orthopedisch Centrum

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)	Other: 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).
Active Comparator: DISTINCT 1 control; Patients with a low VTE risk (predicted 3-months postoperative VTE risk <1%) based on the TRiP(plasty) score. (Nemeth, 2024)	Other: 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 Names: Standard treatment
Other: 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)	Other: 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 Names: Standard treatment
Experimental: 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)	Other: 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).
Active Comparator: 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)	Other: 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 Names: Standard treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous thromboembolic events	Number of VTEs in the first 3 months postoperative.	90 days postoperative
Major bleeding	Number of major bleeds in the first 3 months postoperative.	90 days postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically relevant non major bleeding	Incidence of clinically relevant non-major bleeding	90 days postoperative
Impact of events on QALY's	Estimated using the EQ-5D-5L	90 days and 1 year postoperative
Healthcare costs	Healthcare costs will be estimated from patient questionnaires at 0, 2, 6, 13 and 52 weeks.	90 days and 1 year postoperative
Prosthetic joint infections	Defined according to the European Bone and Joint Infection Society (EBJIS) definition of periprosthetic joint infection described in Bone Joint J 2021;103-B(1):18-25.	90 days postoperative
Patient reported quality of life	Measured using the EQ-5D-5L (scored as described in: Value in Health 2016, 19(4), 343-352.)	90 days and 1 year postoperative
Patient reported quality of life	Measured using the 36-Item Short Form Health Survey (score 0-100 with a higher score indicating a higher quality of life)	1 year postoperative
Patient reported outcome measures	Measured using Oxford Hip score or Ofxord Knee Score depending on the performed surgery. (score 0-100 with a higher score indicating a better outcome)	1 year postoperative
Myocardial infarction	Incidence of myocardial infarction	90 days postoperative
Ischemic stroke	Incidence of ischemic stroke	90 days postoperative
Death	Incidence of death	90 days postoperative

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Investigators: Principal Investigator: Banne Nemeth, dr, Leiden University Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2024
• Primary Completion (Estimated): May 1, 2030
• Study Completion (Estimated): February 1, 2031

Study Registration Dates

• First Submitted: August 25, 2024
• First Submitted That Met QC Criteria: August 29, 2024
• First Posted (Actual): September 3, 2024

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: August 26, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Randomized controlled trial; Total knee arthroplasty; Total hip arthroplasty; Prophylaxis; Venous thromboembolism; Individualized Medicine
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thromboembolism; Thrombosis; Pulmonary Embolism; Venous Thrombosis; Venous Thromboembolism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Sympathomimetics; Vasoconstrictor Agents; Nasal Decongestants; Oxymetazoline
• Other Study ID Numbers: P24.031; 2023-510186-98-00 (Ctis); U1111-1305-2311 (Registry Identifier: Universal trial number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After data collection and data cleaning are finished deidentified data will be registered in a repository and be made available for further research upon reasonable request to the corresponding author.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No