Blood Thinners for Atrial Fibrillation

(COBRRA-AF Trial)

Recruiting at 8 trial locations

Overseen By Lana Castellucci, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ottawa Hospital Research Institute

Must be taking: Anticoagulants

Must not be taking: CYP 3A4/5 inhibitors

Disqualifiers: Active bleeding, Mechanical valve, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

3018 Participants Needed

Trial Summary

What is the purpose of this trial?

Atrial Fibrillation (AF) affects 200,000 Canadians and increases risk of stroke, morbidity and mortality. Having a stroke can affect a patient's ability to speak, eat, walk, work, care for themselves, and interact with others. Not only can it ruin one's life, but it can also be fatal. A stroke occurs when blood flow to the brain is blocked by a clot, depriving brain cells of oxygen. In people with atrial fibrillation, blood flow is sluggish in the top chambers of the heart, and blood clots can form there. When a piece of a clot breaks off, it can travel to the brain and cause a stroke. That's where blood thinners come in. Blood thinners, or anticoagulants, decrease the chances of blood clots forming in the heart, reducing the risk of stroke. Studies show that blood thinners are highly effective at reducing the risk of stroke by up to 95%. The conventional blood thinner is warfarin, taken by mouth. Warfarin requires regular blood tests to make sure a patient getting the correct dose. The patient also may have to avoid certain foods since the medication can interact with them. Newer blood thinners, known as direct-oral anticoagulants (DOACs) are available, which do not require regular blood tests and do not interact with foods. Two of the new blood thinners are called rivaroxaban and apixaban. Like warfarin, they can be taken by mouth, and studies have shown them to be as effective as warfarin. Both rivaroxaban and apixaban have been approved for stroke prevention in AF by Health Canada. However, there have been no direct head-to-head comparisons of these two anticoagulants, meaning comparative safety data is not available. Increasing use of DOACs for stroke prevention in AF and patient values around bleeding highlight the need for a comparison trial to ensure patients receive the anticoagulant with the greatest balance of benefit to potential harm. The trial is to assess bleeding rates and superiority of using apixaban versus rivaroxaban in patients with non-valvular atrial fibrillation.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using medications that strongly interact with the trial drugs, you may need to stop those. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Apixaban for atrial fibrillation?

Research shows that Apixaban is effective in reducing the risk of stroke and systemic embolism (blockage of a blood vessel) in patients with atrial fibrillation, as it was found to be more effective than warfarin and aspirin in clinical trials. ^{1 2 3 4 5}

Is it safe to use blood thinners like Apixaban and Rivaroxaban for atrial fibrillation?

Apixaban (Eliquis) and Rivaroxaban (Xarelto) are blood thinners that have been studied for safety in treating conditions like atrial fibrillation and venous thromboembolism (blood clots). They are generally considered safe, but there is a risk of bleeding, which is why additional safety measures like educational materials are provided to help manage this risk. ^{3 5 6 7 8}

How do the drugs Apixaban and Rivaroxaban differ from other treatments for atrial fibrillation?

Apixaban and Rivaroxaban are newer oral blood thinners that target a specific part of the blood clotting process (factor Xa), offering a more convenient alternative to the older drug warfarin, as they do not require regular blood monitoring and have fewer dietary restrictions. ^{3 9 10 11 12}

Research Team

Lana Castellucci, MD, FRCPC

Principal Investigator

Ottawa Hospital Research Institute

Eligibility Criteria

This trial is for adults over 18 with a new diagnosis of atrial fibrillation confirmed by ECG who need blood thinners according to guidelines. It's not for those with severe kidney issues, active bleeding, mechanical heart valves, other anticoagulation needs, certain liver diseases, or if pregnant/breastfeeding.

Inclusion Criteria

I have a new diagnosis of atrial fibrillation and need blood thinners.

Exclusion Criteria

I can safely take blood thinners like apixaban or rivaroxaban without any health risks.

Your kidneys are not working well, and a certain calculation shows that your kidneys may not be able to filter waste properly.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either apixaban or rivaroxaban for 12 months to assess bleeding rates and safety

12 months

Monthly visits for monitoring and medication adherence checks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Apixaban
• Rivaroxaban

Trial Overview The study compares the bleeding risks when using two oral blood thinners—Apixaban and Rivaroxaban—in patients with non-valvular atrial fibrillation. It aims to determine which drug has a better balance between benefits and potential harm.

Participant Groups

Group I: Rivaroxaban Group Active Control 1 Intervention

20 mg PO, once daily for 12 months of treatment. A dose reduction\* to 15 mg daily will apply to patients with creatinine clearance \<50 ml/min. \*Patients with AF who are receiving DOAC should have their renal function assessed at baseline and at least annually

Group II: Apixaban group Active Control 1 Intervention

5 mg PO, twice daily for 12 months of treatment. A dose reduction\* to 2.5 mg twice daily will apply if patients meet 2 of 3 following criteria: age \> 80 years; weight \< 60 kg; creatinine \>133 micromol/L. \*Patients with AF who are receiving DOAC should have their renal function assessed at baseline and at least annually

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

Approved in European Union as Eliquis for:

• Deep vein thrombosis
• Pulmonary embolism
• Nonvalvular atrial fibrillation

Approved in United States as Eliquis for:

• Deep vein thrombosis
• Pulmonary embolism
• Nonvalvular atrial fibrillation
• Stroke prevention

Who Is Running the Clinical Trial?

Ottawa Hospital Research Institute

Lead Sponsor

Trials

585

Recruited

3,283,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

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

Collaborator

Trials

12

Recruited

17,500+

Findings from Research

Apixaban is an effective oral anticoagulant for treating and preventing venous thromboembolism (VTE), showing noninferiority to the traditional enoxaparin/warfarin treatment in large phase III trials over 6 months.

It has a lower risk of major bleeding compared to enoxaparin/warfarin and is well tolerated, making it a safer alternative for patients with VTE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: A Review in Venous Thromboembolism. Greig, SL., Garnock-Jones, KP.[2020]

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]

Apixaban, an oral direct factor Xa inhibitor, has been approved in the EU for preventing venous thromboembolism (VTE) after hip or knee replacement surgeries, demonstrating its efficacy in reducing the risk of blood clots in these patients.

The drug is also undergoing phase III trials for preventing strokes in patients with atrial fibrillation, indicating its potential for broader applications in thrombotic disorders, although development for acute coronary syndromes has been halted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: first global approval. Watson, J., Whiteside, G., Perry, C.[2021]

In the ARISTOTLE trial, apixaban significantly reduced the risk of stroke, systemic embolism, major bleeding, and death compared to warfarin in patients with nonvalvular atrial fibrillation, showing consistent benefits across various patient subgroups.

The AVERROES trial demonstrated that apixaban was more effective than aspirin in preventing stroke or systemic embolism in patients unsuitable for vitamin K antagonist therapy, without increasing the risk of major bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Keating, GM.[2021]

In a study of 600 patients treated for acute venous thromboembolism (VTE), both apixaban and rivaroxaban showed comparable efficacy, with low rates of VTE recurrence (2.3% for apixaban and 2% for rivaroxaban).

Apixaban was associated with a significantly lower rate of clinically relevant nonmajor bleeding (2.3%) compared to rivaroxaban (6.7%), suggesting it may be a safer option in terms of bleeding complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism. Bott-Kitslaar, DM., McBane, RD., Casanegra, AI., et al.[2020]

The review compares the effectiveness and safety of four oral anticoagulants—warfarin, dabigatran, rivaroxaban, and apixaban—in preventing thromboembolism in patients with atrial fibrillation.

New data suggests that these anticoagulants may vary in their effectiveness and safety profiles, which is crucial for guiding treatment decisions in patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Anticoagulants in the prevention of complications in patients with atrial fibrillation]. Skibitskiĭ, VV., Kanorskiĭ, SG.[2017]

Healthcare professionals (HCPs) and patients demonstrated satisfactory knowledge of bleeding risks associated with apixaban, with 96.1% of HCPs recognizing symptoms that require immediate attention and 71.2% of patients identifying abnormal bleeding as a significant side effect.

The study found that a significant majority of HCPs (97.8%) who received the Prescriber Guide utilized it in patient discussions, and 90.9% of patients who received the Patient Alert Card read it at least once, indicating effective distribution and utilization of these educational materials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the Effectiveness of Apixaban Additional Risk Minimisation Measures Using Surveys in Europe. Mayall, S., Kahlon, R., Al-Dakkak, I., et al.[2021]

In a study of 32,675 patients with atrial fibrillation, apixaban and dabigatran were found to significantly lower the risk of major or clinically relevant non-major bleeding compared to warfarin, indicating their safety as anticoagulants.

Rivaroxaban did not show a reduced bleeding risk compared to warfarin and was associated with a higher risk of gastrointestinal bleeding, while apixaban and dabigatran were linked to a lower risk of intracranial bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants. Halvorsen, S., Ghanima, W., Fride Tvete, I., et al.[2020]

Dabigatran, rivaroxaban, and apixaban have rapidly gained popularity in clinical practice for treating atrial fibrillation, making up 62% of new prescriptions by the end of the study period, which included 6893 patients from 2010 to 2013.

However, patients initiating these novel anticoagulants faced significantly higher costs, with an average increase of over $900 in combined spending for the first 6 months compared to those starting warfarin, highlighting the financial impact of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. Desai, NR., Krumme, AA., Schneeweiss, S., et al.[2022]

Novel oral anticoagulants like dabigatran, apixaban, and rivaroxaban have been developed to improve stroke prevention in patients with atrial fibrillation, showing promising results in large-scale clinical trials compared to traditional vitamin K antagonists like warfarin.

These new agents target specific coagulation factors (thrombin and factor Xa) and have received FDA approval, expanding treatment options for patients with nonvalvular atrial fibrillation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A guidance pathway for the selection of novel anticoagulants in the treatment of atrial fibrillation. Wisler, JW., Becker, RC.[2014]

Newer anticoagulants like dabigatran, rivaroxaban, and apixaban are at least as effective as warfarin for preventing strokes in patients with atrial fibrillation, without the need for regular blood monitoring.

When treating older adults with atrial fibrillation, clinicians should consider factors such as patient tolerance, cost, adherence, and the absence of a reversal agent for these newer medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving beyond warfarin-are we ready? A Review of the efficacy and safety of novel anticoagulant agents compared to warfarin for the management of atrial fibrillation in older adults. Ogbonna, KC., Clifford, KM.[2013]

Apixaban is an effective direct oral anticoagulant for treating venous thromboembolism (VTE), showing safety and efficacy in large phase III trials, making it a convenient alternative to warfarin.

However, there is limited research on its use in certain populations, such as patients over 75, those with cancer, and pediatric patients, indicating a need for further studies in these groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive evaluation of apixaban in the treatment of venous thromboembolism. Koehl, JL., Hayes, BD., Al-Samkari, H., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Apixaban: A Review in Venous Thromboembolism. [2020]

2. England pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

Apixaban: first global approval. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. [2021]

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

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism. [2020]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Anticoagulants in the prevention of complications in patients with atrial fibrillation]. [2017]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Evaluating the Effectiveness of Apixaban Additional Risk Minimisation Measures Using Surveys in Europe. [2021]

8. England pubmed.ncbi.nlm.nih.gov

A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants. [2020]

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

Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. [2022]

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

A guidance pathway for the selection of novel anticoagulants in the treatment of atrial fibrillation. [2014]

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

Moving beyond warfarin-are we ready? A Review of the efficacy and safety of novel anticoagulant agents compared to warfarin for the management of atrial fibrillation in older adults. [2013]

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

A comprehensive evaluation of apixaban in the treatment of venous thromboembolism. [2021]