Rivaroxaban + Aspirin for Blood Clot Prevention After Joint Surgery

(EPCATIII Trial)

Overseen By Susan L Pleasance, BScN

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sudeep Shivakumar

Must not be taking: Strong P-gp/CYP3A4 inhibitors/inducers

Disqualifiers: VTE, Metastatic cancer, Major bleeding, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 14-35 days

5400 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of aspirin alone or in combination with rivaroxaban (a blood thinner) in preventing blood clots after hip or knee replacement surgery. Blood clots, known as venous thromboembolism (VTE), pose a serious risk after such surgeries. Participants will take either aspirin for several days or a combination of rivaroxaban and aspirin. This trial suits individuals planning hip or knee replacement surgery who have no history of blood clots and no certain medical conditions or allergies. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using certain drugs that strongly affect liver enzymes (like ketoconazole or rifampicin). It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both aspirin and rivaroxaban are generally safe for preventing blood clots after surgeries such as hip and knee replacements. Aspirin, commonly used for this purpose, is effective and affordable. Studies indicate that its safety is comparable to other blood thinners, though it may carry a slightly higher risk of clots compared to some other medications.

Rivaroxaban has also proven to be effective and safe. Research shows that serious issues like deep vein thrombosis (DVT), pulmonary embolism (PE), and death occur in about 1% of cases or less. It maintains a strong safety record when used after surgeries to prevent blood clots.

Both treatments are usually well-tolerated by patients, with minor side effects like mild bleeding being the most common. Consulting a healthcare provider about any concerns before joining a clinical trial is always advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about these treatments because they explore a more streamlined approach to preventing blood clots after joint surgery, potentially enhancing patient convenience and safety. Unlike the standard of care, which often includes extended use of anticoagulants like rivaroxaban or low-molecular-weight heparin, this protocol tests shorter, varied durations of aspirin and rivaroxaban. The unique combination of rivaroxaban followed by aspirin could offer effective clot prevention with reduced risk of bleeding and easier administration. These trials aim to find out if these regimens can provide a simpler and safer alternative for managing clot risks after knee or hip replacement surgeries.

What evidence suggests that this trial's treatments could be effective for blood clot prevention after joint surgery?

Research has shown that aspirin can help prevent blood clots after joint replacement surgery. Studies have found that aspirin reduces the risk of serious conditions such as pulmonary embolism and deep vein thrombosis. Guidelines recommend aspirin for patients undergoing total hip or knee replacements, as it is considered a safer option compared to other blood thinners. In this trial, some participants will receive aspirin alone, while others will receive a combination of rivaroxaban and aspirin. Rivaroxaban is another medication that prevents blood clots by thinning the blood more strongly. The study aims to determine whether using both aspirin and rivaroxaban together offers better protection against blood clots after surgeries like hip and knee replacements. ^{2 3 5 6 7}

Who Is on the Research Team?

Sudeep P Shivakumar, MD

Principal Investigator

Dalhousie University/Nova Scotia Health Authority

Are You a Good Fit for This Trial?

This trial is for adults undergoing elective hip or knee replacement surgery without a history of significant liver disease, kidney failure, low platelets, recent major surgery, chronic high-dose aspirin use, potential pregnancy or breastfeeding. They must not have had a blood clot before and can't be on certain other medications.

Inclusion Criteria

Written informed consent in accordance with federal, local and institutional guidelines

I am scheduled for elective hip or knee replacement surgery at a participating hospital.

Exclusion Criteria

I have liver disease or another condition that prevents me from taking rivaroxaban.

I am not taking strong medication that affects drug processing in my body.

You have previously taken part in the EPCAT III study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either aspirin alone or aspirin and rivaroxaban following total hip or knee arthroplasty

14-35 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, focusing on venous thromboembolism and bleeding events

90 days

What Are the Treatments Tested in This Trial?

Interventions

• Acetylsalicylic acid 81 mg
• Rivaroxaban

Trial Overview The study is testing whether taking Rivaroxaban along with aspirin is better at preventing blood clots after hip or knee replacement surgery compared to just taking aspirin alone. Participants will be randomly assigned to one of the two treatment groups.

How Is the Trial Designed?

Group I: TKA-study arm Experimental Treatment 1 Intervention

Total Knee Arthroplasty: 14 days of aspirin

Group II: THA-study arm Experimental Treatment 1 Intervention

Total Hip Arthroplasty: 35 days of aspirin

Group III: TKA-control arm Active Control 1 Intervention

Total Knee Arthroplasty: 5 days of rivaroxaban, followed by 9 days of aspirin

Group IV: THA-control arm Active Control 1 Intervention

Total Hip Arthroplasty: 5 days of rivaroxaban, followed by 30 days of aspirin

Acetylsalicylic acid 81 mg is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Migraine
• Arthritis
• Cardiovascular disease prevention
• Venous thromboembolism prevention

Approved in European Union as Acetylsalicylic acid for:

• Pain relief
• Fever reduction
• Inflammation
• Migraine
• Arthritis
• Cardiovascular disease prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Migraine
• Arthritis
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

Sudeep Shivakumar

Lead Sponsor

Trials

1

Recruited

5,400+

Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network

Collaborator

Trials

12

Recruited

17,500+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Nova Scotia Health Authority

Collaborator

Trials

302

Recruited

95,300+

Published Research Related to This Trial

In a study involving 1,448 patients who had recent coronary artery bypass graft (CABG) surgery, the combination of rivaroxaban (2.5 mg twice daily) and aspirin did not significantly reduce graft failure rates compared to aspirin alone.

However, the combination treatment was associated with a trend towards fewer major adverse cardiovascular events (MACE) compared to aspirin alone, although this did not reach statistical significance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study. Lamy, A., Eikelboom, J., Sheth, T., et al.[2019]

In a study involving 5,435 participants across 8 trials, rofecoxib, a COX-2 inhibitor, showed similar rates of thrombotic cardiovascular adverse events compared to nonselective NSAIDs and placebo, indicating no increased cardiovascular risk associated with rofecoxib.

The incidence of thrombotic cardiovascular events was 1.93/100 patient-years for rofecoxib and 2.27/100 patient-years for nonselective NSAIDs, demonstrating that rofecoxib does not pose a higher risk than traditional NSAIDs or placebo in terms of cardiovascular safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). Reicin, AS., Shapiro, D., Sperling, RS., et al.[2019]

In a study of 6548 patients undergoing total hip or knee replacement, the extended aspirin regimen was found to be as effective as modified rivaroxaban in preventing venous thromboembolism, with rates of 1.04% for both groups.

The only significant risk factor for post-operative venous thromboembolism was a history of venous thromboembolism, highlighting the importance of patient history in assessing risk and the safety of using aspirin as a thromboprophylaxis option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin compared to enoxaparin or rivaroxaban for thromboprophylaxis following hip and knee replacement. Ní Cheallaigh, S., Fleming, A., Dahly, D., et al.[2021]

In a study of 40 patients undergoing total knee arthroplasty, both aspirin (300 mg/day) and rivaroxaban (10 mg/day) were found to be equally effective in preventing venous thromboembolism (VTE), with no cases of deep vein thrombosis or pulmonary embolism reported.

Both medications were safe, showing no significant increase in wound complications or bleeding, indicating that either could be a suitable option for VTE prophylaxis after knee surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin versus Rivaroxaban to Prevent Venous Thromboembolism after Total Knee Arthroplasty: A Double-blinded, Randomized Controlled Trial. Hongnaparak, T., Janejaturanon, J., Iamthanaporn, K., et al.[2022]

Aspirin and newer nonsteroidal anti-inflammatory drugs (NSAIDs) are essential treatments for rheumatoid arthritis, but their mechanisms and long-term safety profiles are not fully understood, with newer NSAIDs potentially offering better safety.

While NSAIDs can effectively reduce inflammation, they may cause gastrointestinal issues and renal complications, particularly in vulnerable populations like the elderly or those with existing kidney problems, necessitating careful monitoring and cautious prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of nonsteroidal anti-inflammatory drugs. Practical review for clinicians. O'Brien, WM.[2019]

In a study of 85,938 patients undergoing hip or knee arthroplasty, aspirin was associated with significantly lower odds of bleeding complications compared to enoxaparin, making it a safer option for thromboprophylaxis.

While rivaroxaban also showed a trend toward increased bleeding compared to aspirin, the differences were not statistically significant, suggesting that aspirin may be the preferred choice for minimizing bleeding risks post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of bleeding risk with rivaroxaban, enoxaparin, and aspirin following total joint arthroplasty or revision. Watts, PJ., Kopstein, M., Harkness, W., et al.[2022]

In a study of 15,526 patients, adding rivaroxaban to aspirin or aspirin plus clopidogrel showed a reduction in mortality during the first year, but the results are questionable due to significant missing data.

The addition of rivaroxaban increased the risk of bleeding complications, including major bleeding and intracranial hemorrhage, suggesting that its use after an acute coronary syndrome may not be safe or beneficial, especially in patients at higher risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban 2.5 mg. No justification for using this anticoagulant after an acute coronary syndrome. [2015]

Ascolong, a new buccal form of aspirin with a very low dose of 12.5 mg, demonstrated a reliable antiaggregant effect in both single and regular doses, although it was less pronounced than that of standard 100 mg aspirin tablets.

The study, involving 43 healthy men and 19 patients with coronary or cerebrovascular disorders, found that Ascolong was well tolerated and effectively delivered acetylsalicylic acid (ASA) into the bloodstream, reducing its metabolism into a less active form, making it a promising option for patients who cannot take traditional oral aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ascolong: a new buccal dosage form of acetylsalicylic acid to be used and antiaggregant]. Kokurina, EV., Suslina, ZA., Khromov, GL., et al.[2013]

Extended-release aspirin (NHP-554C) shows a similar ability to inhibit thromboxane production as immediate-release aspirin (ASA), but with less impact on prostacyclin production, suggesting it may be a safer option for patients needing antiplatelet therapy.

In a study involving 36 healthy subjects, both forms of aspirin effectively reduced thromboxane levels, but NHP-554C maintained higher prostacyclin levels during treatment, indicating a potential advantage in preserving vascular function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effects of immediate-release and extended-release aspirin on basal and bradykinin-stimulated excretion of thromboxane and prostacyclin metabolites. Gamboa, JL., Devin, JK., Ramirez, CE., et al.[2021]

Long-term aspirin use (L-AU) in patients undergoing primary total knee arthroplasty (TKA) is associated with a significant reduction in perioperative complications and in-hospital mortality, suggesting it may enhance patient safety during surgery.

Despite its benefits, L-AU is linked to an increased risk of acute postoperative pain and slightly higher overall costs, indicating a need for careful management of aspirin use around the time of surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients receiving knee arthroplasty with pre-existing long-term aspirin use suffer lower risk of perioperative complications but feel more postoperative pain. Liang, F., Pan, X., Shi, Z., et al.[2023]

In the COMPASS trial, adding rivaroxaban 2.5 mg twice daily to aspirin (ASA) significantly reduced the risk of adverse cardiovascular events, such as stroke and cardiovascular death, compared to ASA alone, with a hazard ratio of 0.80, indicating a favorable net clinical benefit.

The combination therapy was particularly beneficial for high-risk patients, such as those with multiple vascular diseases or diabetes, showing a greater absolute risk reduction in adverse outcomes, while the increase in major bleeding events was minimal and less impactful.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. Steffel, J., Eikelboom, JW., Anand, SS., et al.[2021]

In a 52-week double-blind study involving 823 patients with chronic pain, ketorolac tromethamine (10 mg, 4 times a day) was found to be safer and more effective than aspirin (650 mg, 4 times a day) for long-term analgesic therapy.

Patients taking aspirin were more likely to withdraw from the study due to lack of efficacy, while safety-related withdrawals were similar for both medications, indicating that ketorolac may provide better pain relief without compromising safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of long-term safety of ketorolac tromethamine and aspirin in the treatment of chronic pain. Rubin, P., Yee, JP., Ruoff, G.[2013]

Aspirin, originally thought to be a prodrug for salicylic acid, has been shown to have its own therapeutic effects, particularly through its ability to inhibit cyclooxygenase (COX) enzymes, which reduces the production of prostaglandins and thromboxane, leading to its analgesic, antipyretic, and anti-inflammatory properties.

Despite the development of newer aspirin-like drugs that selectively block COX-2, these have not demonstrated superior efficacy for traditional uses compared to older non-selective NSAIDs, and they may carry significant side effects, suggesting that traditional aspirin remains a key treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Aspirin. Acetylsalicylic acid and aspirinlike drugs. A review.]. Jóhannesson, T.[2006]

Citations

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Aspirin thromboprophylaxis in joint replacement surgery The available prospective data include the PEP trial, which showed a reduction in fatal pulmonary embolism (PE) and proximal deep vein ...

2. arthroplastyjournal.org arthroplastyjournal.org/article/S0883-5403(23)00197-3/fulltext

Aspirin for Venous Thromboembolic Prophylaxis Following ... Total Hip Arthroplasty Outcomes. THA patients treated with aspirin experienced lower rates of PE (0.17% versus 0.21%, P = .249) and DVT (0.31% ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S088354032400682X

Aspirin is an Effective Prophylaxis for Venous ... This study demonstrated that aspirin is a viable and potentially safer option than other anticoagulants, exhibiting comparable efficacy in preventing VTE ...

4. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK565479/

Acetylsalicylic Acid for Venous Thromboembolism Prophylaxis ... All three included guidelines recommend the use of aspirin for venous thromboembolism prophylaxis in patients undergoing total hip or knee arthroplasty based ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1712746

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip ... Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6441713/

Aspirin for venous thromboembolism prophylaxis after hip or ... Aspirin prophylaxis was found to be associated with similar efficacy and safety outcomes when compared with anticoagulants.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0002934325001974

Aspirin for Venous Thromboembolism Prophylaxis in Hip ... Aspirin is an inexpensive, effective, and frequently used option for venous thromboembolism prevention after hip fracture surgery, total hip arthroplasty, and ...