Rivaroxaban + Aspirin for Peripheral Artery Disease

Overseen By Caroline Crush, MSHA

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

Must be taking: Aspirin

Must not be taking: Non-aspirin antiplatelets, Anticoagulants, CYP 3A4 inhibitors, CYP 3A4 inducers

Disqualifiers: High bleeding risk, Recent stroke, Severe heart failure, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the drug rivaroxaban (Xarelto), combined with aspirin, can improve symptoms for people with peripheral artery disease (PAD), a condition where narrowed blood vessels in the legs reduce blood flow. Participants will receive either rivaroxaban plus aspirin or a placebo plus aspirin to assess the treatment's impact on their symptoms. Individuals who have undergone procedures like bypass surgery or amputation due to PAD, or who have specific blood flow issues in their legs, may be suitable candidates. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment can benefit more patients.

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

The trial requires participants to be on aspirin therapy before enrolling. You cannot take dual-antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy. If you are on medications that are strong inhibitors or inducers of CYP 3A4, you may need to stop those. The protocol does not specify a washout period.

What is the safety track record for rivaroxaban and aspirin?

Research has shown that using rivaroxaban with aspirin can benefit people with peripheral artery disease. One study found that this combination reduced the risk of serious issues, such as sudden blood flow loss to a limb and major amputations. Although it slightly increased bleeding, the bleeding was usually not severe or life-threatening.

The combination of rivaroxaban and aspirin is already approved for other uses, indicating a known safety record. Doctors are familiar with it, and it is generally well-tolerated. Participating in clinical trials like this one provides important information about the safety and effectiveness of treatments, benefiting others with similar conditions. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about combining rivaroxaban with aspirin for peripheral artery disease because this approach targets blood clot prevention more aggressively than standard treatments. Unlike typical therapies that may only use aspirin, adding rivaroxaban—a potent anticoagulant—enhances the blood-thinning effect, potentially reducing the risk of complications like heart attacks or strokes. This combination aims to address the limitations of existing treatments, offering a new way to manage the disease more effectively.

What evidence suggests that rivaroxaban and aspirin could be effective for peripheral artery disease?

Research has shown that taking rivaroxaban with aspirin can benefit people with peripheral artery disease. In this trial, participants in the intervention arm will receive rivaroxaban alongside aspirin. One study found that fewer people taking rivaroxaban experienced major heart problems compared to those taking a placebo, which contains no active medicine. Another study discovered that rivaroxaban reduced the risk of serious leg issues, such as a sudden drop in blood flow to the leg or the need for a major amputation, by 30%. Overall, these findings suggest that using rivaroxaban with aspirin can significantly help manage symptoms and complications of peripheral artery disease. ^{1 2 3 5 6}

Who Is on the Research Team?

Aaron W Aday, MD

Principal Investigator

VUMC Cardiovascular Medicine

Are You a Good Fit for This Trial?

This trial is for adults with peripheral artery disease (PAD), evidenced by specific symptoms or past surgeries related to PAD. They must be taking aspirin and able to consent. Excluded are those in other drug studies, with recent or upcoming surgeries, severe heart failure, high bleeding risk, certain drug treatments (like strong CYP3A4 inhibitors/inducers), active infections, poor kidney function, serious non-cardiovascular diseases, known allergies to study drugs, liver issues affecting blood clotting, or women who could become pregnant without effective birth control.

Inclusion Criteria

I am currently taking aspirin.

I have had a limb or foot amputated due to poor blood flow.

I have a significant narrowing in my arteries.

Exclusion Criteria

I have not had a stroke or a bleeding in the brain in the last month.

I am not pregnant, breastfeeding, and if capable of becoming pregnant, I am using effective birth control.

My heart is very weak (EF<30%) or I have severe symptoms limiting my daily activities.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 81mg of aspirin + rivaroxaban 2.5mg twice daily or placebo for 30 days

4 weeks

1 visit (in-person) at baseline, 1 visit (in-person) at end of treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Aspirin 81Mg Ec Tab
• Placebo
• Rivaroxaban 2.5 Mg Oral Tablet

Trial Overview The study tests if rivaroxaban can improve PAD symptoms compared to a placebo. Participants will also take low-dose aspirin. The goal is to see how rivaroxaban affects blood clots formation and the health of blood vessels and platelets.

How Is the Trial Designed?

Group I: Intervention Experimental Treatment 2 Interventions

Participants will receive 81mg of aspirin + rivaroxaban 2.5mg twice daily for 30 days.

Group II: Control Placebo Group 2 Interventions

Participants will receive 81mg daily of aspirin + placebo for 30 days.

Rivaroxaban 2.5 Mg Oral Tablet is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xarelto for:

• Prevention of venous thromboembolic events (VTE) in patients who have undergone total hip replacements and total knee replacement surgery
• Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Reduction of risk of recurrent DVT and/or PE

Approved in United States as Xarelto for:

• Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Reduction of risk of recurrent DVT and/or PE
• Reduction of risk of major cardiovascular events in patients with chronic coronary artery disease or peripheral artery disease

Approved in Canada as Xarelto for:

• Prevention of venous thromboembolic events (VTE) in patients who have undergone total hip replacements and total knee replacement surgery
• Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Reduction of risk of recurrent DVT and/or PE

Approved in Japan as Xarelto for:

• Prevention of venous thromboembolic events (VTE) in patients who have undergone total hip replacements and total knee replacement surgery
• Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Reduction of risk of recurrent DVT and/or PE

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

The COMPASS trial demonstrated that combining rivaroxaban with aspirin significantly reduces the risk of major cardiovascular and limb events in patients with peripheral artery disease (PAD), achieving a 28% reduction in net clinical benefit outcomes.

This combination therapy addresses both platelet activation and the coagulation cascade, providing a more comprehensive approach to managing the high vascular risk associated with PAD compared to traditional antiplatelet therapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reducing residual thrombotic risk in patients with peripheral artery disease: impact of the COMPASS trial. Hernández, JL., Lozano, FS., Riambau, V., et al.[2020]

In a study of 27,395 patients with coronary or peripheral artery disease, the combination of rivaroxaban and aspirin significantly increased the risk of major and minor bleeding compared to aspirin alone, particularly within the first year of treatment.

The gastrointestinal tract was the most common site for major bleeding, with about 75% of these events being of mild or moderate intensity, and most bleeding was manageable with standard supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin. Eikelboom, JW., Bosch, JJ., Connolly, SJ., et al.[2020]

In the COMPASS trial, patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) who received rivaroxaban plus aspirin experienced a significant reduction in major adverse cardiovascular events (MACE) and major adverse limb events (MALE) compared to those taking aspirin alone.

The economic analysis showed that the combination treatment resulted in a minimal incremental cost of $0.16 per member per month, indicating a net health benefit, especially for patients with two or more risk factors for MACE or MALE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic Implications of Preventing Major Cardiovascular and Limb Events with Rivaroxaban plus Aspirin in Patients with Coronary or Peripheral Artery Disease in the United States. Hernandez, L., Shah, A., Zhao, Q., et al.[2022]

In a trial involving 27,395 patients with stable coronary artery disease or peripheral artery disease, the combination of rivaroxaban and aspirin reduced the risk of cardiovascular death, stroke, or heart attack by 24% and decreased overall mortality by 18%.

Rivaroxaban alone did not provide additional benefits compared to aspirin, but the combination therapy also significantly lowered the risk of major limb events, such as amputations, in patients with peripheral artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose rivaroxaban plus aspirin for the prevention of cardiovascular events: an evaluation of COMPASS. Bhagirath, VC., Eikelboom, JW., Anand, SS.[2019]

In a meta-analysis of 11,560 patients with peripheral artery disease (PAD), low-dose rivaroxaban combined with aspirin significantly reduced the risk of major cardiovascular events and limb complications compared to aspirin alone, with a hazard ratio of 0.79.

While the combination treatment increased the risk of major bleeding (hazard ratio of 1.51), it did not lead to a significant rise in severe bleeding events, indicating a favorable safety profile for this treatment strategy in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose rivaroxaban and aspirin among patients with peripheral artery disease: a meta-analysis of the COMPASS and VOYAGER trials. Anand, SS., Hiatt, W., Dyal, L., et al.[2022]

A secondary analysis of the COMPASS trial indicates that the combination of rivaroxaban (2.5 mg twice daily) and aspirin (100 mg daily) may provide significant benefits for patients with peripheral arterial disease.

This treatment regimen has the potential to change standard management practices for peripheral arterial disease, which currently has limited therapeutic options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does rivaroxaban have a role in treating patients with PAD? Thomas, R.[2020]

In the COMPASS trial involving 27,395 patients, the combination of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily significantly reduced overall mortality compared to aspirin alone, with a hazard ratio of 0.82 over a median follow-up of 23 months.

The combination therapy also led to a significant reduction in cardiovascular (CV) deaths (1.7% vs 2.2% for aspirin alone), particularly benefiting patients with higher baseline risk factors, indicating a tailored approach to treatment could enhance outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease. Eikelboom, JW., Bhatt, DL., Fox, KAA., et al.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2000052

Rivaroxaban in Peripheral Artery Disease after ... The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan–Meier estimates of the incidence at 3 ...

2. ahajournals.org ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.063806

Insights From VOYAGER PAD | Circulation For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34380322/

Insights From the VOYAGER PAD Trial After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S107858842400621X

Effect of Peripheral Interventions in Patients with ... This subanalysis of XATOA found that prior LER was associated with increased rates of limb events, consistent with results of COMPASS and VOYAGER PAD.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03746275

NCT03746275 | Study to Gain Insights in Treatment ... The study aims to collect real-world data on treatment patterns and decision points for treatment in patients with coronary artery disease (CAD) and/ or ...

6. ejves.com ejves.com/article/S1078-5884(24)00621-X/fulltext

Analyses from the XATOA Registry dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin significantly reduced the incidence of major adverse ...