Surveillance vs. Rivaroxaban for Pulmonary Embolism

(SAFE-SSPE Trial)

Recruiting at 33 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

Trial Summary

What is the purpose of this trial?

The clinical significance of pulmonary embolism (PE) limited to the subsegmental pulmonary arteries, so called isolated subsegmental pulmonary embolism (SSPE), remains controversial. Whether isolated SSPE represents "true" PE, a clinically more benign form of PE, a physiologic lung clearing process, or a false positive result (artifact) is currently unclear and hence, whether patients with isolated SSPE benefit from anticoagulant treatment is uncertain. Despite growing evidence from observational studies that withholding anticoagulation may be a safe option in selected patients with isolated SSPE (i.e., those without concomitant deep vein thrombosis, cancer, etc.), most patients with isolated SSPE receive anticoagulant treatment, which is associated with an increased risk of bleeding. The overall objective of the randomized controlled SAFE-SSPE trial is to evaluate the efficacy and safety of clinical surveillance without anticoagulation compared to anticoagulation treatment in low-risk patients with isolated SSPE.

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 data supports the effectiveness of the drug Rivaroxaban for treating pulmonary embolism?

Research shows that Rivaroxaban, an oral drug that prevents blood clots, is as effective as standard treatments for pulmonary embolism and deep vein thrombosis, without needing regular blood tests or dose changes. It has been approved for these uses based on studies like the EINSTEIN PE trial, which found it to be a convenient and effective option. ^{1 2 3 4 5}

Is rivaroxaban safe for humans?

Rivaroxaban has been evaluated in large clinical trials involving over 24,000 patients and is considered generally safe for treating conditions like deep-vein thrombosis and pulmonary embolism. It offers benefits such as simplified dosing and fewer drug interactions compared to older treatments, but as with any medication, it may have risks, so it's important to discuss with a healthcare provider. ^{2 6 7 8 9}

How does the drug Rivaroxaban differ from other treatments for pulmonary embolism?

Rivaroxaban is unique because it is an oral medication that directly inhibits Factor Xa, a key protein in the blood clotting process, and does not require routine blood monitoring, unlike traditional treatments like warfarin. It offers a convenient fixed dosing schedule and has a rapid onset of action, making it a promising alternative for treating pulmonary embolism. ^{2 10 11 12 13}

Research Team

Drahomir Aujesky, Prof. MD MSc

Principal Investigator

Inselspital, Bern University Hospital, University of Bern

Eligibility Criteria

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

I am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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]

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]

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]

References

1. United States 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. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of rivaroxaban mono-therapy and standard-therapy adjusted by CYP2C9 and VKORC1 genotypes in symptomatic pulmonary embolism. [2017]

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

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Comparative risk of major bleeding with rivaroxaban and warfarin: Population-based cohort study of unprovoked venous thromboembolism. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of rivaroxaban and apixaban in patients with venous thromboembolism: a nationwide study. [2019]

6. England 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. [2022]

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

Efficacy of rivaroxaban for pulmonary embolism. [2022]

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

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

9. Netherlands pubmed.ncbi.nlm.nih.gov

Rivaroxaban versus standard anticoagulation for symptomatic venous thromboembolism (REMOTEV observational study): Analysis of 6-month outcomes. [2017]

10. Germany pubmed.ncbi.nlm.nih.gov

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

11. Germany pubmed.ncbi.nlm.nih.gov

[Rivaroxaban in the prevention and treatment of thromboembolic disorders]. [2015]

12. England pubmed.ncbi.nlm.nih.gov

Oral rivaroxaban for the treatment of symptomatic pulmonary embolism: are we ready? [2019]

13. England pubmed.ncbi.nlm.nih.gov

Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). [2015]