Surveillance vs. Rivaroxaban for Pulmonary Embolism

(SAFE-SSPE Trial)

Recruiting at 37 trial locations

Overseen By Tobias Tritschler, Dr. MD MSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Drahomir Aujesky

Must not be taking: Strong CYP3A4 inhibitors, inducers

Disqualifiers: DVT, Cancer, Pregnancy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

276 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether individuals with isolated subsegmental pulmonary embolism (SSPE) require blood thinners like rivaroxaban. Some experts believe these clots may pose less danger, so the study compares regular monitoring with rivaroxaban use to determine which approach is safer and more effective. It targets those diagnosed with SSPE who lack complicating factors such as cancer or deep vein clots. Participants will take either rivaroxaban or a placebo for 90 days. The study seeks to determine if avoiding blood thinners could be a safe option for some individuals. As a Phase 4 trial, this research aims to enhance understanding of how the already FDA-approved and effective treatment benefits more patients, contributing to broader medical knowledge.

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 strong CYP3A4 inhibitors or inducers, or if you need therapeutic anticoagulation for another reason.

What is the safety track record for these treatments?

Research shows that rivaroxaban is generally well-tolerated, but it carries some risks. One study found that about 2.89% of patients experienced major bleeding while taking rivaroxaban, and the chance of having another blood clot was 1.09%.

Compared to other blood thinners like warfarin, rivaroxaban presented a lower risk of recurring blood clots but a higher chance of bleeding. Another study found that standard doses of rivaroxaban reduced the risk of blood clots returning without increasing the risk of serious bleeding.

Overall, rivaroxaban effectively treats blood clots, but there is a chance of bleeding. Prospective trial participants should discuss these risks with their doctor. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about rivaroxaban for pulmonary embolism because it offers a convenient, straightforward approach to anticoagulation. Unlike traditional treatments that might require frequent monitoring and dose adjustments, rivaroxaban is taken orally with a consistent dosing schedule, reducing the burden on patients. Moreover, it has a rapid onset of action, which is crucial for quickly managing the risk of blood clots. This makes rivaroxaban a potentially safer and more user-friendly option compared to older anticoagulants, enhancing patient adherence and overall quality of care.

What evidence suggests that this trial's treatments could be effective for isolated SSPE?

Research shows that rivaroxaban, a treatment in this trial, effectively treats pulmonary embolism (PE), where blood clots block lung vessels. Studies indicate that over 99% of patients with low-risk PE treated with rivaroxaban did not experience serious issues. Rivaroxaban blocks a protein called factor Xa, crucial in blood clotting, thus preventing clots in veins. This treatment has a lower risk of bleeding compared to others. Overall, evidence supports its effectiveness and safety for managing PE. Participants in this trial will be randomized to receive either rivaroxaban or a placebo to compare outcomes. ^{2 3 4 6 7}

Who Is on the Research Team?

Drahomir Aujesky, Prof. MD MSc

Principal Investigator

Inselspital, Bern University Hospital, University of Bern

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a confirmed diagnosis of isolated subsegmental pulmonary embolism (SSPE), which are small blood clots in the lungs. It's not for those with active cancer, pregnant or breastfeeding women, people at high risk of bleeding, severe kidney or liver issues, or anyone on certain drugs that affect rivaroxaban.

Inclusion Criteria

I have been diagnosed with SSPE, with or without symptoms.

Informed Consent as documented by signature

Exclusion Criteria

I am currently experiencing bleeding or at a high risk of bleeding.

My kidneys are not working well (very low filtration rate).

My liver is not working well (severe issues).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either anticoagulation treatment with rivaroxaban or placebo for 90 days

12 weeks

Regular visits as per protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Rivaroxaban

Trial Overview The study compares clinical surveillance without anticoagulation to treatment with Rivaroxaban in low-risk patients with SSPE. The goal is to see if monitoring alone is as safe and effective as using the medication to prevent further clotting.

How Is the Trial Designed?

Group I: Anticoagulation Active Control 1 Intervention

Patients in the anticoagulation group will receive rivaroxaban 15 mg twice daily for the first 21 days, followed by 20 mg once daily for an overall treatment duration of 90 days.

Group II: No anticoagulation Placebo Group 1 Intervention

Patients in the group without anticoagulation will receive placebo twice daily for the first 21 days, followed by one tablet daily for an overall treatment duration of 90 days.

Rivaroxaban is already approved in United States, European Union for the following indications:

Approved in United States as Xarelto for:

• Deep vein thrombosis (DVT)
• Venous thromboembolism (VTE)
• Stroke prevention in non-valvular atrial fibrillation
• Prevention of VTE in patients undergoing knee or hip replacement surgery

Approved in European Union as Xarelto for:

• Deep vein thrombosis (DVT)
• Venous thromboembolism (VTE)
• Stroke prevention in non-valvular atrial fibrillation
• Prevention of VTE in patients undergoing knee or hip replacement surgery
• Prevention of atherothrombotic events in patients with acute coronary syndrome

Who Is Running the Clinical Trial?

Drahomir Aujesky

Lead Sponsor

Trials

1

Recruited

280+

Bayer

Industry Sponsor

Trials

2,291

Recruited

25,560,000+

Founded

1863

Headquarters

Leverkusen, Germany

Known For

Pharmaceutical Innovations

Top Products

Aspirin, Aleve, Yaz, Nexavar

Bill Anderson

Bayer

Chief Executive Officer since 2023

BSc in Chemical Engineering from the University of Texas, MSc in Chemical Engineering and Management from MIT

Michael Devoy

Bayer

Chief Medical Officer since 2014

MD, PhD

The Ottawa Hospital

Collaborator

Trials

97

Recruited

64,000+

University of Bern

Collaborator

Trials

377

Recruited

1,393,000+

Schweizerischer Nationalfonds

Collaborator

Trials

7

Recruited

2,900+

Leiden University Medical Center

Collaborator

Trials

580

Recruited

623,000+

Published Research Related to This Trial

Rivaroxaban is an effective oral medication that inhibits Factor Xa, showing significant efficacy in preventing and treating thromboembolic disorders, including venous thromboembolism after major orthopedic surgery.

In phase III studies, rivaroxaban was found to be more effective than enoxaparin for preventing blood clots after knee surgery, with a similar low risk of bleeding, making it a promising alternative to existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban. A novel, oral, direct factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Perzborn, E., Kubitza, D., Misselwitz, F.[2015]

Rivaroxaban, a direct Factor Xa inhibitor, significantly reduced the risk of recurrent venous thromboembolism (VTE) in patients after standard treatment, compared to placebo, over a treatment period of 6-12 months.

While effective, rivaroxaban was associated with a moderate increase in bleeding complications, indicating a need for careful consideration of its use, especially in special populations like the elderly and those with renal impairment, who were underrepresented in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Romualdi, E., Donadini, MP., Ageno, W.[2015]

The study evaluated the effectiveness and safety of oral rivaroxaban for treating symptomatic pulmonary embolism, comparing it to standard therapy.

Results indicated that rivaroxaban is a viable alternative to traditional treatments, demonstrating both efficacy in managing pulmonary embolism and a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism: are we ready? Kuuskne, M., Dankoff, J.[2019]

In a study involving 4832 patients with acute pulmonary embolism, rivaroxaban was found to be noninferior to standard therapy (enoxaparin followed by a vitamin K antagonist) for preventing recurrent venous thromboembolism, demonstrating its effectiveness as an alternative treatment.

Rivaroxaban also showed a lower rate of major bleeding (1.1%) compared to standard therapy (2.2%), suggesting a potentially better safety profile while maintaining similar rates of other adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. Büller, HR., Prins, MH., Lensin, AW., et al.[2022]

In a study of over 36,000 patients with unprovoked venous thromboembolism (VTE), rivaroxaban was found to reduce the risk of major bleeding by 27% compared to warfarin, indicating it may be a safer option for these patients.

Rivaroxaban also significantly lowered the risk of gastrointestinal bleeding by 38% and intracranial hemorrhage by 81%, with no specific type of major bleeding occurring more frequently in patients treated with rivaroxaban compared to those on warfarin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative risk of major bleeding with rivaroxaban and warfarin: Population-based cohort study of unprovoked venous thromboembolism. Kohn, CG., Bunz, TJ., Beyer-Westendorf, J., et al.[2019]

In a study of 8187 patients with venous thromboembolism (VTE), there were no significant differences in the risks of all-cause mortality, recurrent VTE, or hospitalized bleeding between those treated with rivaroxaban and those treated with apixaban.

The 180-day risks for all-cause mortality were 5.08% for apixaban and 4.60% for rivaroxaban, while the risks for recurrent VTE were 2.16% and 2.22%, respectively, indicating similar safety and efficacy profiles for both medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of rivaroxaban and apixaban in patients with venous thromboembolism: a nationwide study. Sindet-Pedersen, C., Staerk, L., Pallisgaard, JL., et al.[2019]

In a study involving 5142 patients, rivaroxaban demonstrated a lower incidence of major bleeding (0.8%) compared to standard anticoagulation therapy (2.1%), suggesting it may be a safer option for treating deep-vein thrombosis.

Rivaroxaban also showed comparable effectiveness in preventing recurrent venous thromboembolism (1.4% vs. 2.3% for standard therapy), indicating it is an effective alternative in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Ageno, W., Mantovani, LG., Haas, S., et al.[2022]

In a study involving 2,397 patients with pulmonary embolism, rivaroxaban was associated with greater treatment satisfaction compared to traditional enoxaparin/vitamin K antagonist therapy, indicating a preference for rivaroxaban among patients.

Rivaroxaban was reported to be significantly less burdensome than enoxaparin/VKA therapy, suggesting that it may enhance patient compliance and overall treatment experience.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial. Prins, MH., Bamber, L., Cano, SJ., et al.[2022]

Rivaroxaban is a direct factor Xa inhibitor that is effective in preventing venous thromboembolism in patients undergoing elective knee or hip replacement surgery, with a recommended dose of 10 mg per day.

In patients with non-valvular atrial fibrillation, rivaroxaban (20 mg per day) is approved for stroke prevention, and its low dose (2.5 mg twice daily) has shown promise in reducing cardiovascular events in those with recent acute coronary syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rivaroxaban in the prevention and treatment of thromboembolic disorders]. Helbing, T., Bode, C., Moser, M.[2015]

Patients with pulmonary embolism treated with rivaroxaban mono-therapy had a significantly shorter hospital stay (9.29 days) compared to those receiving standard therapy with enoxaparin and vitamin K antagonists (11.38 days).

The rivaroxaban group experienced significantly fewer mild hemorrhages (16.7%) compared to the standard therapy group (50%) after one month, indicating a better safety profile for rivaroxaban in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of rivaroxaban mono-therapy and standard-therapy adjusted by CYP2C9 and VKORC1 genotypes in symptomatic pulmonary embolism. Duan, L., Zhang, N., Yan, H., et al.[2017]

In a study of 499 patients with acute symptomatic venous thromboembolism (VTE) treated with rivaroxaban, the major and clinically relevant bleeding rate was lower (5.4%) compared to those treated with vitamin K antagonists (VKAs) and heparin/fondaparinux, indicating rivaroxaban's safety profile is favorable.

Rivaroxaban also demonstrated a significantly lower rate of recurrent VTE (1.4%) compared to VKAs (3.1%) and heparin/fondaparinux (11.6%), suggesting it is an effective treatment option for preventing VTE recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): Analysis of 6-month outcomes. Gaertner, S., Cordeanu, EM., Nouri, S., et al.[2017]

This systematic review aims to evaluate the efficacy and safety of rivaroxaban in treating pulmonary embolism (PE) by analyzing randomized controlled trials, ensuring a comprehensive assessment of its effects on all-cause mortality and major bleeding.

The study will also investigate secondary outcomes such as recurrent venous thromboembolism, hospital stay duration, quality of life, patient satisfaction, and adverse events, providing a thorough understanding of rivaroxaban's overall impact on patients with PE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of rivaroxaban for pulmonary embolism. Jia, J., Xue, SM., Xu, N.[2022]

Rivaroxaban is a direct factor Xa inhibitor that offers a simplified alternative to traditional vitamin K antagonists like warfarin, allowing for once-daily dosing without the need for frequent monitoring or dose adjustments.

In phase-II and phase-III trials involving over 24,000 patients, rivaroxaban has demonstrated safety and efficacy for preventing and treating venous thromboembolism, and is also being studied for other conditions like pulmonary embolism and stroke prevention in atrial fibrillation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral direct factor Xa inhibitors, with special emphasis on rivaroxaban. Mousa, SA.[2015]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9409848/

Rivaroxaban Monotherapy in Patients with Pulmonary Embolism The use of DOACs has been associated with a similar degree of antithrombotic effect and a significant reduction in risk for major bleeding.

2. jacc.org jacc.org/doi/10.1016/j.jacadv.2025.101714

A Comparison of Outcomes With Apixaban, Rivaroxaban ... We observed that bleeding was highest with rivaroxaban, followed by warfarin, and then apixaban. Rates of thrombosis were higher with apixaban than with ...

3. xareltohcp.com xareltohcp.com/dvt-pe/

DVT & PE | XARELTO® (rivaroxaban) HCP XARELTO® is the only DOAC to show safe and effective outpatient treatment in patients with low-risk PE · >99% of patients with low-risk PE did not experience ...

4. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/697/531539/Effectiveness-and-Safety-of-Rivaroxaban-Versus

Effectiveness and Safety of Rivaroxaban Versus Warfarin in ... Conclusion: These findings suggest that among patients with PE and RVD, rivaroxaban was associated with a reduced risk of recurrent VTE compared ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1113572

Oral Rivaroxaban for the Treatment of Symptomatic ... Current data suggest that rivaroxaban, an oral direct inhibitor of factor Xa, is effective and safe for the prevention of venous thromboembolism ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37245989/

Safety Profile and Effectiveness of Rivaroxaban for Patients ... Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/ ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2213333X23002548

The clinical outcomes of different doses of rivaroxaban in ... Standard-dose rivaroxaban reduced the risk of VTE recurrence without increasing the risk of major bleeding in patients with IDDVT.