Blood Thinners for Pulmonary Embolism Prevention After Hip and Knee Replacement

(PEPPER Trial)

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

20000 Participants Needed

Trial Summary

What is the purpose of this trial?

PEPPER is a randomized study comparing the three most commonly used anticoagulants in North America in patients who have elected to undergo primary or revision hip or knee joint replacement surgery. The anticoagulants being compared are enteric coated aspirin, low intensity warfarin, and rivaroxaban.

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 data supports the idea that Blood Thinners for Pulmonary Embolism Prevention After Hip and Knee Replacement is an effective treatment?

The available research shows that blood thinners like rivaroxaban and aspirin are effective in preventing blood clots after hip and knee replacement surgeries. Studies comparing rivaroxaban to aspirin found that both can help prevent clots, but rivaroxaban might be more effective, although it could increase the risk of bleeding. Aspirin is noted to be a more cost-effective option and still provides good protection against clots. Newer drugs like rivaroxaban and apixaban have been shown to be as effective or better than older treatments, with fewer side effects, making them a good choice for long-term prevention. ^{1 2 3 4 5}

What data supports the effectiveness of blood thinners like aspirin and rivaroxaban for preventing blood clots after hip and knee replacement surgeries?

Research shows that both aspirin and rivaroxaban are effective in preventing blood clots after hip and knee surgeries. Rivaroxaban is a newer drug that works well but may increase bleeding risk, while aspirin is more cost-effective and also helps prevent clots. ^{1 2 3 4 5}

What safety data exists for blood thinners used to prevent pulmonary embolism after hip and knee replacement?

Safety data for blood thinners like rivaroxaban, aspirin, and warfarin in preventing pulmonary embolism after hip and knee replacement includes several studies. Rivaroxaban has been shown to have a similar safety profile to enoxaparin, with a low incidence of major bleeding events. A meta-analysis found rivaroxaban to be effective and safe compared to aspirin. The XAMOS study confirmed rivaroxaban's favorable benefit-risk profile, with low rates of thromboembolic and bleeding events. Aspirin is included in guidelines as an option, but its efficacy compared to anticoagulants is less defined. Overall, these treatments have been evaluated for safety in preventing venous thromboembolism in orthopedic surgery. ^{1 2 6 7 8}

Is it safe to use blood thinners like rivaroxaban or aspirin after hip or knee replacement surgery?

Rivaroxaban and aspirin have been studied for safety in preventing blood clots after hip or knee replacement surgery. Rivaroxaban showed a similar safety profile to other treatments, with a low rate of major bleeding events. Aspirin is also considered safe for selected patients, but its effectiveness compared to other anticoagulants is less clear. ^{1 2 6 7 8}

Is the drug Enteric Coated Aspirin, Rivaroxaban, Warfarin promising for preventing blood clots after hip and knee replacement?

Rivaroxaban is a promising drug for preventing blood clots after hip and knee replacement. It has been shown to be as effective and safe as traditional treatments like enoxaparin, with the added convenience of being an oral medication. This makes it easier for patients to take consistently, which can improve long-term prevention of blood clots. ^{2 5 9 10 11}

How does the drug combination of Enteric Coated Aspirin, Rivaroxaban, and Warfarin differ from other drugs for preventing pulmonary embolism after hip and knee replacement?

This drug combination is unique because it includes both traditional anticoagulants like Warfarin and newer options like Rivaroxaban, which are oral and have fewer interactions, alongside Aspirin, which is being explored as a simpler alternative for some patients. This approach may offer a balance between established and newer therapies, potentially improving adherence and outcomes. ^{2 5 9 10 11}

Research Team

Vincent D Pellegrini, MD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Carol A Lambourne, PhD

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rivaroxaban versus aspirin in prevention of venous thromboembolism following total joint arthroplasty or hip fracture surgery: a meta-analysis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

The risk of venous thromboembolism with aspirin compared to anticoagulants after hip and knee arthroplasty. [2020]

3. England pubmed.ncbi.nlm.nih.gov

A comparison of aspirin against rivaroxaban for venous thromboembolism prophylaxis after hip or knee arthroplasty: A meta-analysis. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. [2018]

5. Spain pubmed.ncbi.nlm.nih.gov

[Prophylaxis of venous thromboembolism in orthopedic surgery. Role of the new anticoagulants]. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. England pubmed.ncbi.nlm.nih.gov

A post-marketing assessment of major bleeding in total hip and total knee replacement surgery patients receiving rivaroxaban. [2018]

8. Germany 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. [2015]

9. United States pubmed.ncbi.nlm.nih.gov

Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. [2019]

10. England 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. [2015]

11. England 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. [2019]