Blood Thinners for Pulmonary Embolism Prevention After Hip and Knee Replacement

(PEPPER Trial)

No longer recruiting at 31 trial locations

Overseen By Carol A Lambourne, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Dartmouth-Hitchcock Medical Center

Must not be taking: Chronic anticoagulants

Disqualifiers: Bilateral replacement, Hemorrhage, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine which of three blood thinners—enteric coated aspirin, warfarin, or rivaroxaban (Xarelto)—most effectively prevents blood clots in individuals who have undergone hip or knee replacement surgery. Blood clots pose a serious risk after these surgeries, making it crucial to identify the best prevention method. Participants must be undergoing elective hip or knee replacement surgery and able to adhere to the study requirements. As a Phase 4 trial, the treatments are already FDA-approved and proven effective, and this research seeks to understand how they benefit a broader range of patients.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic anticoagulation other than antiplatelet medications, you cannot participate in the trial.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic anticoagulation (blood thinners) other than antiplatelet medications. It's best to discuss your current medications with the trial team.

What is the safety track record for these treatments?

Research has shown that enteric-coated aspirin is generally safe for preventing blood clots after joint surgeries. One study found it effective and safe for patients without major clotting risks, though it may not work as well as other options in some cases.

For rivaroxaban, studies indicate a very low rate of blood clots and related complications. Fewer than 1% of patients experienced serious issues, and bleeding rates remain low, making it a well-tolerated choice for many.

Warfarin, also known as Coumadin, is another option for preventing clots and has been used for many years. However, it requires regular monitoring to ensure the blood maintains the right thickness. Bleeding complications can occur, but regular blood tests manage them effectively.

These treatments have been proven safe in numerous studies, making them trusted options for preventing blood clots after hip or knee surgeries. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for preventing pulmonary embolism after hip and knee replacements because they offer unique benefits compared to standard blood thinners like heparin and low molecular weight heparin. Warfarin, also known as Coumadin, allows for precise dose adjustments based on INR values, which can help in achieving optimal blood thinning with minimized bleeding risks. Enteric coated aspirin is appealing due to its simplicity and reduced gastrointestinal side effects, offering an accessible and potentially safer option for long-term use. Rivaroxaban, marketed as Xarelto, stands out for its convenience, as it requires no routine blood monitoring and can be taken just once daily, making it a user-friendly choice. These alternatives could simplify anticoagulation therapy and improve patient compliance while effectively preventing dangerous blood clots.

What evidence suggests that this trial's treatments could be effective for preventing pulmonary embolism after hip and knee replacement?

In this trial, participants will be assigned to one of three treatment arms to prevent blood clots after hip or knee replacement surgery. Research has shown that enteric-coated aspirin, administered to participants in one arm, can help prevent blood clots, though its effectiveness varies. It tends to be more beneficial for those with knee replacements, while individuals with hip replacements might gain more from other treatments. Participants in another arm will receive Rivaroxaban, which has proven to be very effective, with a low risk of blood clot issues like deep vein thrombosis (DVT) and pulmonary embolism (PE). Studies indicate that Rivaroxaban often outperforms traditional options like enoxaparin in preventing these problems. The third arm involves Warfarin, which effectively reduces the risk of blood clots after hip or knee surgery but carries a higher risk of causing bleeding. Each treatment offers advantages, so the best choice depends on individual health needs and risks. ^{1 3 4 6 7}

Who Is on the Research Team?

Vincent D Pellegrini, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Carol A Lambourne, PhD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

This trial is for adults over 21 who are having hip or knee replacement surgery and can follow the study plan. They must be able to take at least two of the medications being tested, not be pregnant, and weigh more than 41 kg. People with recent serious bleeding, uncontrolled high blood pressure, or on other trials that affect these drugs can't join.

Inclusion Criteria

I am 21 years old or older.

I am scheduled for a hip/knee replacement or hip resurfacing surgery.

Is not pregnant on the day of surgery

Exclusion Criteria

I am having surgery to replace both my hips or knees.

My blood pressure is not higher than 220/120 mmHg.

I have a bleeding disorder that has required blood transfusions and treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of three anticoagulants (aspirin, warfarin, or rivaroxaban) for 30 days post-surgery to prevent DVT and PE

4 weeks

Daily administration with monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of joint function and adverse events

6 months

Routine postoperative follow-up through central telephone surveillance and on-site research coordinator visits

What Are the Treatments Tested in This Trial?

Interventions

• Enteric Coated Aspirin
• Rivaroxaban
• Warfarin

Trial Overview

The PEPPER study is randomly assigning patients undergoing joint replacement surgery to one of three blood thinners: enteric coated aspirin, low intensity warfarin, or rivaroxaban. It aims to find out which is best at preventing clots without causing problems.

How Is the Trial Designed?

Group I: Arm 3: Rivaroxaban Other Names: Xarelto Experimental Treatment 1 Intervention

Rivaroxaban 10 mg will be first administered approximately 24 hours after completion of the index operation. Medication will then be administered in the evening on postoperative day #2 and thereafter each evening until completion.

Group II: Arm 2: Warfarin Other Names: Coumadin Experimental Treatment 1 Intervention

Warfarin will be administered starting on the day of operation, prior to surgery, with a sip of water. The initial dose will be empirically determined by body weight: less than 125 lbs (56.7 kg) - 2.5 mg; 125-250 lbs (56.7-113.4 kg) - 5 mg; greater than 250 lbs (113.4 kg) - 7.5mg. The initial dose will be repeated on the evening of surgery if the preoperative dose was administered prior to noon on the day of operation; no warfarin will be given on the evening of surgery if the preoperative dose was received after noon on the day of operation. Thereafter, starting on postoperative day #1, warfarin will be given each evening based on INR values to achieve a target of 2.0 (range 1.7-2.2).

Group III: Arm 1: Enteric Coated Aspirin Experimental Treatment 1 Intervention

Enteric coated aspirin (162 mg po) will be administered on the day of operation, prior to surgery, with a sip of water. Thereafter, starting on postoperative day #1, all patients in the aspirin group will receive 81 mg po bid to complete the treatment period of 30 days. Patients on preoperative cardiac dose aspirin may continue their usual dosing regimen prior to the morning of surgery, and then commence the PEPPER trial aspirin dose of 81 mg po bid on the day after operation.

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

University of Maryland, Baltimore

Collaborator

Trials

729

Recruited

540,000+

Brigham and Women's Hospital

Collaborator

Trials

1,694

Recruited

14,790,000+

Northwestern University

Collaborator

Trials

1,674

Recruited

989,000+

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

Published Research Related to This Trial

In a study of 12,429 patients who underwent total hip or knee replacement and were prescribed rivaroxaban, the incidence of major bleeding (MB) was very low at 0.07%.

This incidence is lower than what was reported in clinical trials, raising questions about whether real-world rates of MB are indeed lower or if the methods used to identify bleeding events may have limitations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing assessment of major bleeding in total hip and total knee replacement surgery patients receiving rivaroxaban. Kwong, LM., Turpie, AGG., Tamayo, S., et al.[2018]

In a study involving 12,729 participants from four large clinical trials, rivaroxaban was found to have a similar incidence of post-operative complications, such as bleeding and adverse surgical events, compared to enoxaparin after total hip or knee replacement.

Both rivaroxaban and enoxaparin showed comparable rates of blood loss, wound drainage, and transfusion requirements, indicating that rivaroxaban is a safe alternative for preventing venous thromboembolism in these surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. Lassen, MR., Gent, M., Kakkar, AK., et al.[2015]

In a study of 103 patients undergoing 151 total hip or knee replacement surgeries, short-term subcutaneous heparin effectively prevented symptomatic venous thromboembolism (VTE), with only one case of deep venous thrombosis reported during a one-year follow-up.

Despite some minor bleeding complications occurring in 13% of procedures, the overall safety profile of using low molecular weight heparin, combined with daily NSAIDs, suggests it is a simple and effective method for VTE prevention in patients with rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of symptomatic thrombosis with short term (low molecular weight) heparin in patients with rheumatoid arthritis after hip or knee replacement. van Heereveld, HA., Laan, RF., van den Hoogen, FH., et al.[2019]

In a study of 873 patients who underwent hip or knee joint replacement, extending the use of enoxaparin for four weeks significantly reduced the risk of venous thromboembolism in hip replacement patients, with an incidence of 8.0% compared to 23.2% in the placebo group (p < 0.001).

No significant benefit of enoxaparin was observed in knee replacement patients, where the rates of venous thromboembolism were similar between the enoxaparin (17.5%) and placebo (20.8%) groups (p = 0.380), indicating that the efficacy of enoxaparin may vary by type of surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. Comp, PC., Spiro, TE., Friedman, RJ., et al.[2019]

In a study involving 17,701 patients across 252 centers, rivaroxaban was found to significantly reduce the incidence of symptomatic thromboembolic events compared to standard thromboprophylaxis, demonstrating its superior efficacy in preventing blood clots after hip or knee surgery.

The safety profile of rivaroxaban was similar to that of standard care, with comparable rates of major bleeding events, confirming its favorable benefit-risk profile in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Turpie, AG., Haas, S., Kreutz, R., et al.[2015]

Patients undergoing total hip or knee surgeries are at high risk for thromboembolic events, and while traditional low molecular weight heparins like enoxaparin have been effective, new oral anticoagulants like dabigatran, rivaroxaban, and apixaban offer a more convenient alternative with similar or better efficacy and safety.

Phase III clinical trials have demonstrated that these new oral anticoagulants can significantly enhance long-term prevention of thromboembolic complications, making them particularly beneficial for patients after discharge in community settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prophylaxis of venous thromboembolism in orthopedic surgery. Role of the new anticoagulants]. Guijarro Merino, R., Villalobos Sánchez, A.[2015]

In a meta-analysis of 7 studies involving 5133 patients, rivaroxaban and aspirin showed no significant difference in preventing venous thromboembolism (VTE) after total hip or knee arthroplasty and hip fracture surgery.

While rivaroxaban did not reduce major bleeding or all-cause mortality compared to aspirin, it was associated with a higher risk of nonmajor bleeding, suggesting that aspirin could be a safer and more cost-effective option for VTE prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban versus aspirin in prevention of venous thromboembolism following total joint arthroplasty or hip fracture surgery: a meta-analysis. Hu, B., Jiang, L., Tang, H., et al.[2021]

In a study of over 342,000 patients who underwent hip or knee arthroplasty, aspirin was found to be as effective as anticoagulants in preventing post-operative venous thromboembolism (VTE), with no increased risk associated with aspirin use.

Aspirin was used as the sole prophylactic agent in only 7.5% of knee and 8.0% of hip arthroplasty patients, indicating it is not a common choice for VTE prevention in these surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The risk of venous thromboembolism with aspirin compared to anticoagulants after hip and knee arthroplasty. Chu, JN., Maselli, J., Auerbach, AD., et al.[2020]

The increasing number of joint replacement surgeries in the aging population raises concerns about the risk of venous thromboembolism, prompting the need for effective preventive measures.

New oral anticoagulants that inhibit Factor II or Factor X have been found to be effective and safe for preventing postoperative venous thromboembolism, offering advantages over traditional agents as they do not require monitoring or have food and drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New oral antithrombotic agents for the prevention of deep venous thrombosis and pulmonary embolism in orthopedic surgery. Merli, GJ.[2010]

A systematic review of five studies involving 4,594 patients found that aspirin is as effective as rivaroxaban in preventing venous thromboembolism (VTE) after total knee and hip arthroplasties, with no significant differences in VTE rates or major bleeding events.

Both aspirin and rivaroxaban showed similar safety profiles, with no notable differences in complications such as readmissions or wound issues, suggesting that aspirin could be a cost-effective alternative for VTE prevention in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of aspirin against rivaroxaban for venous thromboembolism prophylaxis after hip or knee arthroplasty: A meta-analysis. Xu, J., Kanagaratnam, A., Cao, JY., et al.[2020]

In a study involving 3424 patients undergoing total hip or knee arthroplasty, extended prophylaxis with aspirin was found to be noninferior to rivaroxaban in preventing symptomatic venous thromboembolism, with very similar rates of occurrence (0.64% for aspirin vs. 0.70% for rivaroxaban).

The safety profiles were also comparable, with major bleeding complications occurring in 0.47% of the aspirin group and 0.29% in the rivaroxaban group, indicating that aspirin is a safe alternative for extended prophylaxis after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. Anderson, DR., Dunbar, M., Murnaghan, J., et al.[2018]

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