Edoxaban for Atrial Fibrillation

(ENRICH-AF Trial)

Not currently recruiting at 163 trial locations

Overseen By Amanda Taylor, BSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Population Health Research Institute

Must not be taking: NSAIDs

Disqualifiers: Recent intracranial hemorrhage, uncontrolled 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether edoxaban, a daily medication, can reduce the risk of stroke or blood clots in individuals with atrial fibrillation who have previously experienced a brain bleed. The trial compares edoxaban to either not taking blood-thinning medications or using simpler blood-thinners, such as aspirin. Suitable candidates for the trial have atrial fibrillation and a history of brain bleed, without the need for ongoing blood-thinner treatments for other conditions. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment benefits a broader range of patients.

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

The trial does not specify if you must stop all current medications. However, you cannot participate if you need ongoing oral anticoagulant therapy for conditions other than atrial fibrillation or if you need antiplatelet therapy where edoxaban isn't a suitable substitute. Chronic use of NSAIDs is also not allowed.

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 need ongoing oral anticoagulant or antiplatelet therapy for conditions other than atrial fibrillation. It's best to discuss your current medications with the trial team.

What is the safety track record for these treatments?

Research has shown that edoxaban is generally well-tolerated by people with atrial fibrillation, a condition causing an irregular and often fast heartbeat. In studies, some patients experienced safety issues like bleeding, occurring in about 5.9% of those taking edoxaban each year. This rate is slightly higher than the 4.5% of people who had similar issues without the drug.

Evidence indicates that edoxaban can increase the risk of major bleeding by 42% compared to other similar medications. However, the risk of dying from any cause remains similar between edoxaban and other treatments. Real-world data suggests that the rates of bleeding requiring hospitalization might be lower than earlier research indicated.

Overall, while some risks exist, many people tolerate edoxaban well. Its FDA approval for other uses adds to its safety profile. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Unlike the standard of care for atrial fibrillation, which typically involves anticoagulants like warfarin or other direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban, Edoxaban offers a unique dosing flexibility. Researchers are excited about Edoxaban because it can be administered in different doses (60 mg or 30 mg daily) based on individual clinical criteria, potentially improving patient safety and minimizing bleeding risks. Additionally, Edoxaban has a predictable pharmacokinetic profile, meaning it has fewer interactions with food and other medications, making management easier for patients and healthcare providers alike.

What is the effectiveness track record for edoxaban in reducing stroke risk in high-risk atrial fibrillation patients?

Research has shown that edoxaban, which participants in this trial may receive, lowers the risk of stroke in people with atrial fibrillation, an irregular heartbeat. One study found that people taking edoxaban experienced fewer strokes compared to those not taking the medication. Specifically, about 3.2% of edoxaban users experienced strokes per year, compared to 4.0% of those not using it. Long-term use of edoxaban also resulted in low and stable rates of both strokes and major bleeding. This indicates that edoxaban can help prevent strokes while keeping the risk of bleeding manageable. ^{2 3 4 6 7}

Who Is on the Research Team?

Ashkan Shoamanesh, MD, FRCPC

Principal Investigator

Population Health Research Institute

Are You a Good Fit for This Trial?

This trial is for adults over 45 who've had a non-traumatic brain bleed, have atrial fibrillation with a CHA2DS2-VASc score of at least 2, and are stable. It's not for those with bleeding risks like ulcers, clotting disorders, liver disease, or sensitivity to edoxaban. Pregnant women and those unlikely to follow the study plan are also excluded.

Inclusion Criteria

I have been diagnosed with atrial fibrillation.

Written informed consent provided

CHA2DS2-VASc score ≥2

Exclusion Criteria

My brain bleed isn't due to cancer, infection, or major blood vessel issues.

I have not had a brain bleed in the last 14 days.

Close affiliation with the investigational site; e.g. a close relative for the investigator, dependent person (e.g., employee or student of the investigational site)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomly assigned to receive either edoxaban 60/30 mg daily or non-anticoagulant medical therapy

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Edoxaban
• Non-anticoagulant medical therapy

Trial Overview The ENRICH-AF trial is testing if edoxaban (a blood thinner) is better than standard care without anticoagulants in preventing strokes in patients with atrial fibrillation who previously had a brain hemorrhage.

How Is the Trial Designed?

Group I: Edoxaban 60/30mg daily Experimental Treatment 1 Intervention

Edoxaban 60/30 mg daily (lower dose depending on clinical criteria)

Group II: Non-anticoagulant medical therapy Active Control 1 Intervention

Non-anticoagulant medical therapy: no antithrombotic therapy or antiplatelet monotherapy (at discretion of local investigator)

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

Approved in United States as Savaysa for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Prevention of thromboembolism in atrial fibrillation

Approved in European Union as Lixiana for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Approved in Japan as Lixiana for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Published Research Related to This Trial

In the ENGAGE AF-TIMI 48 trial involving patients with nonvalvular atrial fibrillation, edoxaban was found to be noninferior to warfarin in preventing strokes and systemic embolic events over a median treatment duration of 907 days.

Edoxaban demonstrated a significantly lower risk of major bleeding and cardiovascular-related deaths compared to warfarin, making it a safer and effective oral anticoagulant option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Edoxaban: a review in nonvalvular atrial fibrillation. McCormack, PL.[2016]

Edoxaban is an effective direct oral anticoagulant that reduces the risk of bleeding compared to warfarin while providing similar protection against thromboembolism, based on large phase III trials.

It is approved for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, with specific dosing considerations for patients with moderate renal impairment and those weighing ≤60 kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct factor Xa inhibitor edoxaban: from bench to clinical practice. Brekelmans, M., Middeldorp, S., Coppens, M.[2016]

Ribociclib combined with fulvestrant provides significant health benefits for patients with hormone receptor-positive and HER2-negative advanced breast cancer, resulting in an estimated gain of 0.96 quality-adjusted life-years (QALYs) compared to fulvestrant alone.

The cost-effectiveness analysis shows that ribociclib plus fulvestrant has an incremental cost-effectiveness ratio (ICER) of $157,343 per QALY gained, suggesting it is a potentially cost-effective treatment option for this patient population in Canada.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Ribociclib in Combination with Fulvestrant for the Treatment of Postmenopausal Women with HR+/HER2- Advanced Breast Cancer Who Have Received No or Only One Prior Line of Endocrine Therapy: A Canadian Healthcare Perspective. Stellato, D., Thabane, ME., Park, J., et al.[2021]

In a study of 21,038 atrial fibrillation patients in Germany, edoxaban was found to be more effective than other oral anticoagulants, showing significantly lower risks of ischemic stroke or systemic embolism compared to apixaban, dabigatran, rivaroxaban, and vitamin K antagonists.

Edoxaban also exhibited a favorable safety profile, with lower risks of major bleeding compared to rivaroxaban and vitamin K antagonists, while showing similar bleeding risks to apixaban and dabigatran.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of clinical outcomes of edoxaban versus apixaban, dabigatran, rivaroxaban, and vitamin K antagonists in patients with atrial fibrillation in Germany: A real-world cohort study. Marston, XL., Wang, R., Yeh, YC., et al.[2022]

In a pilot study involving 18 postmenopausal women with advanced breast cancer, Formestane demonstrated a 25% objective response rate and 32% disease stabilization, indicating reasonable efficacy as a treatment option.

The treatment was well tolerated, with only 18% of patients experiencing mild and transient side effects, such as hot flushes and lethargy, and no patients needed to stop the medication due to toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of formestane in postmenopausal women with breast cancer. Joseph, JK., Lim, AK.[2015]

In a study involving 309 women with uterine fibroids, vilaprisan demonstrated significant efficacy in reducing heavy menstrual bleeding, with up to 60% of patients experiencing complete absence of bleeding at the highest dose compared to only 1.7% in the placebo group.

Vilaprisan was well tolerated with no safety concerns, and it led to reductions in fibroid volume of up to 41%, indicating its potential as an effective treatment option for managing symptoms associated with uterine fibroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vilaprisan in women with uterine fibroids: the randomized phase 2b ASTEROID 1 study. Bradley, LD., Singh, SS., Simon, J., et al.[2019]

Fulvestrant (Faslodex) is now approved for treating advanced or metastatic breast cancer in postmenopausal women, and it is administered intramuscularly by healthcare professionals, typically resulting in minimal pain and infrequent injection-site reactions.

The manuscript includes case histories that illustrate the practical application of fulvestrant in clinical settings, emphasizing its role in patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with fulvestrant ('Faslodex'): a nurse's perspective. Owers, R.[2018]

In a study of 409 postmenopausal women with advanced metastatic breast cancer, formestane showed comparable efficacy to tamoxifen, with 33% of patients responding to formestane and 37% to tamoxifen, indicating both treatments are effective options.

While both treatments had excellent tolerability, tamoxifen demonstrated a longer median duration of response (20 months) and better outcomes in terms of time to disease progression compared to formestane (15 months).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Pérez Carrión, R., Alberola Candel, V., Calabresi, F., et al.[2016]

In a study involving 21,105 patients with atrial fibrillation followed for a median of 2.8 years, higher-dose edoxaban significantly reduced the risk of stroke or systemic embolic events in patients who had never used vitamin K antagonists (VKA), while showing similar efficacy to warfarin in those with prior VKA experience.

Both higher-dose and lower-dose edoxaban regimens were associated with a significant reduction in major bleeding risk compared to warfarin, regardless of whether patients had prior VKA exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation†. O'Donoghue, ML., Ruff, CT., Giugliano, RP., et al.[2016]

The ELIMINATE-AF trial, involving 632 patients undergoing atrial fibrillation ablation, found that uninterrupted edoxaban therapy resulted in significantly fewer major bleeding events (0.3%) compared to vitamin K antagonists (2.0%), suggesting it may be a safer option during this procedure.

While edoxaban showed a slightly higher rate of the primary endpoint (2.7% vs. 1.7% for VKAs), it still represents a viable alternative to VKAs for stroke prevention in patients undergoing AF ablation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Hohnloser, SH., Camm, J., Cappato, R., et al.[2020]

Edoxaban tosylate is being tested as an oral medication to prevent strokes and treat blood clots, with over 21,000 patients participating in the ENGAGE AF TIMI 48 trial comparing it to warfarin over 24 months.

In addition, the HOKUSAI VTE trial involves around 7,500 patients to evaluate edoxaban's effectiveness against warfarin for preventing recurrent blood clots, highlighting its potential as a safer alternative in thromboembolism management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Edoxaban tosylate. [2016]

Edoxaban (Lixiana®) has been shown to be non-inferior to warfarin in treating deep venous thrombosis and pulmonary embolism, as well as in preventing systemic and cerebral embolisms in patients with non-valvular atrial fibrillation, based on results from the Hokusai-VTE and ENGAGE AF-TIMI 48 trials.

It demonstrated superior safety compared to warfarin, with a significantly lower incidence of major and clinically relevant bleeding episodes, including a notable reduction in cerebral and fatal hemorrhages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Edoxaban (LIXIANA®) : new oral anticoagulant forthetreatment and secondary prevention of thromboembolic disease]. Scheen, AJ., Lancellotti, P.[2019]

The ETAF-TR study is a national, multicenter, prospective observational study in Turkey involving 858 patients, designed to evaluate the safety and effectiveness of edoxaban in real-life clinical practice for patients with atrial fibrillation over a 1-year follow-up period.

The primary focus of the study is to assess the occurrence of any overt bleeding events, which will help determine the safety profile of edoxaban and compare its effectiveness to previous trials like ENGAGE-AF and ETNA-AF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey Study: Design and Rationale. Önsel Türk, U., Alioğlu, E., Mavioğlu, Z., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38697397/

Long-term effectiveness and safety of edoxaban in patients ... In European patients with AF, long-term therapy with edoxaban is associated with low and relatively constant annualised rates of stroke and major bleeding.

2. ahajournals.org ahajournals.org/doi/10.1161/STROKEAHA.123.045098

Effectiveness and Safety of Edoxaban Compared With ... However, edoxaban was associated with a 42% greater major bleeding risk. The risk of all-cause mortality was similar between the 2 DOACs.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303062

Anticoagulation with Edoxaban in Patients with Atrial High- ... A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the ...

4. jamanetwork.com jamanetwork.com/journals/jamacardiology/fullarticle/2820443

Dose Reduction of Edoxaban in Patients 80 Years and ... Prescribing patterns and outcomes of edoxaban in atrial fibrillation: 1-year data from the Global ETNA-AF Program.  J Clin Med. 2023;12(5): ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11922593/

Is Lower-Dose Edoxaban Sufficiently Effective and Safe for ... The results showed that, compared with the placebo, edoxaban 15 mg was effective in preventing stroke and systemic embolism without significantly increasing the ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35997978/

Outcomes and Safety of Very-Low-Dose Edoxaban in Frail ... Once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

7. innovationsincrm.com innovationsincrm.com/latest-news/1564-effectiveness-of-lixiana-edoxaban-in-routine-clinical-practice

Large Real-World Data Confirm Safety and Effectiveness of ... In addition, primary (composite) bleeding outcomes requiring hospitalisation were approximately 50% lower than observed in ENGAGE AF-TIMI 48. The real-world ...