HIP Fracture Oral thromboPROphylaxis (Hip PRO Pilot)

Hip Fractures Clinical Trial

— HIP PRO Pilot  

Official title:

HIP Fracture Oral thromboPROphylaxis: A Pilot Randomized Controlled Trial (Hip PRO Pilot)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05775965
• Other study ID #: REB22-1085
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 2023
• Est. completion date: March 1, 2026

Study information

• Verified date: February 2023
• Source: University of Calgary
• Contact: Prism S Schneider, MD, PhD
• Phone: (403) 944-4518
• Email: prism.schneider[@]albertahealthservices.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

As our Canadian population ages, hip fractures in these older adults are becoming very common. The best treatment for the majority of these injuries is urgent treatment with surgery. However, the hip fracture itself, the surgery required, and the immobility following these injuries are all risk factors for developing blood clots in the legs (deep vein thrombosis or DVT) and blood clots in the lungs (pulmonary embolism or PE). These complications are a common cause of death in patients with hip fractures and often result in prolonged medical treatment and hospital stays.

Patients with hip fractures who require surgery are traditionally given injectable blood thinners to help prevent blood clots; however, these medications are costly, may not be tolerated well, and can be difficult to take, as prescribed. Oral blood thinning medications are being used more commonly, but it is unknown which of these medications is the most effective in preventing blood clots in patients after a hip fracture.

Thrombelastography (TEG) technology uses a small sample of blood to evaluate a person's clotting ability. Our research has used TEG technology to evaluate blood clotting risk after hip fracture surgery and the investigators have found that platelets may play an important role in abnormal blood clotting after a hip fracture. The investigators have also shown that acetylsalicylic acid (ASA or Aspirin) may help reduce the abnormal platelet hyperactivity associated with blood clotting. This medication warrants investigation for blood clot prevention after hip fracture.

The investigators propose to directly compare different oral medication regimens after hip fracture surgery, in order to determine which is safest and most effective in preventing blood clots. Our multi-disciplinary research team includes physicians, surgeons, and scientists with experience evaluating different medications for blood clot prevention. Our results will help determine the best medical treatment for preventing DVT and PE, which will benefit patients with hip fractures worldwide.

Description:

1. Background:

With over 30,000 hip fractures in Canada annually, these injuries are an epidemic. Venous thromboembolism (VTE) events are common following hip fracture surgery (HFS) and include life-threatening pulmonary embolism (PE; a leading cause of preventable mortality) and debilitating deep vein thromboses (DVTs; second most common complication). Thromboprophylaxis reduces VTE, but the optimal medication remains unknown.

Low molecular weight heparin (LMWH) has been the mainstay, but adherence is poor: only 1 in 5 patients adhere after HFS, limiting its effectiveness. Meta-analyses support that direct oral anticoagulants (DOACs) are as effective as LMWH in prevention of VTE, but the data are limited by borderline effect sizes, small sample sizes, and inconsistent outcomes. Our survey found that surgeons report safety concerns and are reluctant to use DOACs due to post-operative bleeding risk.

Our research demonstrates platelet-dominant hypercoagulability using serial thrombelastography (TEG), reduced platelet activity with aspirin (ASA) use, and maybe increasing comfort with prescribing ASA post-HFS. Randomized controlled trials (RCTs) comparing LMWH and ASA post-injury are limited by non-standardized therapy duration, asymptomatic DVT inclusion, and patient heterogeneity. ASA has been favourably compared to DOACs and LMWH in arthroplasty RCTs examining oral thromboprophylaxis following total hip and total knee arthroplasty. Continued morbidity and mortality, patient and surgeon preference, and our network meta-analysis support the need for comparison between DOAC and ASA for VTE prevention after HFS. Based on our research, our resent network meta-analysis supporting oral thromboprophylaxis, along with patient preference for oral medications, there is a need for comparison between DOAC and ASA for prevention of VTE to reduce the continued morbidity and mortality that ensues following HFS.

2. Objectives:

Specific Aims:

1. Feasibility: This pilot trial will evaluate the feasibility of a full-scale RCT comparing the safety and efficacy of rivaroxaban versus ASA for thromboprophylaxis after HFS, based on achieving recruitment targets, study drug adherence, and participant retention.

2. Safety and Efficacy: Key clinical data will be collected to estimate VTE and bleeding complications to inform the full-scale RCT.

(3) Methods:

This is a multi-centre double-blind pilot trial consisting of consecutive eligible patients 50 years or older requiring HFS who will be randomized (1:1) via web-based randomization to rivaroxaban 10 mg daily for 35 days or ASA 81 mg daily for 35 days, with 90-day follow-up. The primary feasibility outcome measure is an estimate of the mean monthly recruitment rate over 12 months across participating sites, including 95% confidence intervals, with a priori feasibility criteria determining progression to the full trial. Secondary feasibility outcomes are consent and retention rates, and drug adherence.

Secondary clinical outcomes will include symptomatic VTE, major bleeding, clinically relevant non-major bleeding, and 90-day mortality (independently and blindly adjudicated). Intention-to-treat analysis will be used, and subgroup analysis will compare age, sex, gender, and surgical type. Additional patient-reported (the Cumulated Ambulation Score and Clinical Frailty Scale), value-based (direct and indirect costs) and translational (coagulation) outcomes will be included.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 250
• Est. completion date: March 1, 2026
• Est. primary completion date: March 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

Patients aged 50 years or older with an acute hip fracture (presentation to hospital within 24 hours of injury) that requires surgical treatment will be approached for inclusion in the study:

1. Age = 50 years with a hip fracture (AO-OTA classification 31-A1-A3 and 31-B1-B3) amenable to surgical treatment (presentation to hospital within 24 hours of injury). Patients with additional injuries will be included and any additional injuries will be documented.

2. Both open and closed fractures will be included, and open fractures will be documented.

3. Patients on single agent anti-platelet therapy (i.e., acetylsalicylic acid or clopidogrel) will be included.

4. Signed informed consent or surrogate consent to participate in study.

Exclusion Criteria:

1. Delayed presentation (over 24 hours between hip fracture and presentation to hospital).

2. Pathological fractures secondary to primary cancer or metastatic bone disease.

3. Peri-prosthetic femur fractures.

4. Received more than two doses of any thromboprophylaxis agent post-operatively, prior to randomization.

5. Pre-hospital therapeutic intensity antithrombotic therapy, including LMWH, Warfarin, DOACs, clopidogrel/ticagrelor, or chronic ASA use of any dose in the three months prior to hip fracture.

6. Known inherited bleeding or clotting disorder (factor V Leiden gene mutation, prothrombin gene mutation, protein C or protein S deficiency, antithrombin deficiency).

7. Intracranial hemorrhage requiring serial CT scans of the brain and/or surgical intervention.

8. Contraindication to ASA use (allergy, documented gastrointestinal ulcer within the past year, severe thrombocytopenia [platelet count <50 x109/L at the time of hospital admission]).

9. Contraindication to rivaroxaban use (allergy, acute renal failure [CrCl <30 mL/min]).

10. Participant or surrogate unable to or unwilling to provide consent or complete follow-up. Or surrogate consent not available.

11. Under age 50 years (more likely high energy, multiple injuries).

12. Multiply injured patients who require prolonged thromboprophylaxis or delayed thromboprophylaxis initiation.

13. Patient unable to attend follow-up visits.

14. Currently incarcerated, at a correctional facility.

Related Conditions & MeSH terms

• Fractures, Bone
• Hip Fractures

Intervention

Drug:
• Rivaroxaban 10mg
Rivaroxaban 10mg daily for 35 days post hip fracture surgery
• acetylsalicylic acid (ASA) 81mg Oral Tablet
acetylsalicylic acid (ASA) 81mg daily for 35 days post hip fracture surgery

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta

Sponsors (2)

Lead Sponsor	Collaborator
University of Calgary	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recruitment Rate	Mean number of participants recruited per centre per month, calculated based on the total recruitment	12 months
Secondary	Treatment fidelity	Adherence to study medication and pilot trial protocol	12 months
Secondary	Retention rate	Participant completion of the pilot trial protocol	12 months
Secondary	Consent rates	Consent rates for eligible participants who are approached, including reasons for non-consent	12 months
Secondary	Trial implementation barriers Questionnaire	Trial implementation barriers will be assessed using an implementation barrier questionnaire developed for this study. The questionnaire will include questions about barriers and challenges related to the following: data capture, study management, study team infrastructure, participant-specific, site-specific, intervention, and study design. The implementation barriers will be summarized at the end of the study.	12 months
Secondary	Healthcare cost	Direct and indirect healthcare costs including number of hospital admissions, and number of visits to healthcare providers.	12 months
Secondary	Venous thromboembolism events	Number of venous thromboembolism events	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge, 2-week, 4-week, 6-week, 12-week
Secondary	Arterial thromboembolism events	Number of arterial thromboembolism events	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge, 2-week, 4-week, 6-week, 12-week
Secondary	Bleeding complications	Major bleeding, clinically relevant non-major bleeding	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge, 2-week, 4-week, 6-week, 12-week
Secondary	Mortality	Mortality within 90 days after hip fracture surgery	90 days
Secondary	Frailty	Frailty is measured by Clinical Frailty Scale. A valid tool for evaluating these patients' frailty levels. The score ranges from 1 to 9. The higher scores mean better frailty (worse outcome).	Baseline
Secondary	Complete Blood Counts	Complete Blood Counts	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge
Secondary	Partial thromboplastin time	Partial thromboplastin time	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge
Secondary	activated partial thromboplastin time	activated partial thromboplastin time	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge
Secondary	Cumulated Ambulation Score	A valid tool for evaluating these patients' basic mobility. The score ranges from 0 to 6. The higher scores mean better mobility.	Baseline and 2 weeks follow up
Secondary	Study Medication Adherence	Adherence to study medications	Baseline, Post-operative day 1, Post-operative day 2, Post-operative day 3, Post-operative day 4, Post-operative day 5, Post-operative day 6, or until hospital discharge, 2-week, 4-week, 6-week, 12-week