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Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE)

Primary Purpose

Atrial Fibrillation

Status

Unknown status

Phase

Phase 4

Locations

Japan

Study Type

Interventional

Intervention

Rivaroxaban and single antiplatelet drug (aspirin, clopidogrel or prasugrel)

Rivaroxaban

About this trial

This is an interventional treatment trial for Atrial Fibrillation

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with non-valvular atrial fibrillation complicated with stable coronary artery disease who are 20 years or older, with CHADS2 score are ≧1 , and that fulfill one of the following criteria and can provide written consent for participation in the present study will be eligible.

Patients who underwent percutaneous coronary intervention(PCI), including plain old balloon angioplasty(POBA), at least one year ago
Patients who have coronary stenosis requiring no percutaneous coronary intervention (50% or more stenosis) as indicated by coronary CT or coronary angiography(CAG)
Patients who underwent coronary artery bypass graft (CABG) at least one year ago

Exclusion Criteria:

Patients for whom rivaroxaban is contraindicated
Patients for whom aspirin, thienopyridine derivatives (clopidogrel or prasugrel) are contraindicated
Patients who underwent PCI, including POBA, in the past one year
Patients who are going to undergo revascularization
Patients who have a past history of stent thrombosis
Those who are going to undergo invasive surgery (excluding digestive endoscopy and biopsy)
Patients who have active tumors
Patients who have poorly-controlled hypertension (systolic blood pressure at hospital admission: 160 mmHg or more)
Patients who cannot discontinue treatment with antiplatelet drugs (the physician in charge will make a decision on the basis of the lesion shape, lesion site and type of stents.)
Patients judged as inappropriate for this study by investigators

Sites / Locations

Japan Cardiovascular Research FoundationRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Rivaroxaban

Rivaroxaban and single antiplatelet drug

Arm Description

Outcomes

Primary Outcome Measures

Composite endpoint of cardiovascular events

stroke, non-CNS embolism, myocardial infarction, unstable angina pectoris requiring revascularizations or all-cause mortality

Major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria

Secondary Outcome Measures

Net adverse clinical and cerebral events (NACCE)

composite of all-cause death, myocardial infarction, stroke and major bleeding.

Ischemic cardiovascular events and death

All-cause mortality Cardiovascular death non-cardiovascular death Myocardial infarction Unstable angina pectoris requiring revascularization Ischemic stroke Transient ischemic attack non-CNS embolism (systemic embolism pulmonary embolism, deep vein thrombosis) PCI/CABG Stent thrombosis Ischemic stroke and systemic embolism

All bleeding events

Adverse events excluding hemorrhagic events

Comparison of the primary endpoints, ischemic cardiovascular events and mortality between patients treated with aspirin and patients treated with thienopyridine derivatives

Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to the CHADS2 score and CHA2DS2-VASc score

Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to subject characteristics

Subgroup analysis of major bleeding and all bleeding events according to the HAS-BLED score in patients with and without co-administration of antiplatelet drug and analysis of specificity and sensitivity

Comparison of the incidence of bleeding events according to whether or not proton pump inhibitors (PPIs) are used

Comparison of the incidence of the primary endpoints according to whether rivaroxaban is administered in the morning or evening

Correlation of discontinuation of antithrombotic agents with ischemic cardiovascular events, bleeding events and adverse events

Correlation of prothrombin time at trough with bleeding events and evaluation of the cutoff values in patients with and without co-administration of antiplatelet drug

The incidence of the primary endpoints according to different rates of adherence

Primary endpoints include the composite endpoint of cardiovascular events (stroke, non-CNS embolism, myocardial infarction, unstable angina pectoris requiring revascularization or cardiovascular death) and major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. The rate of adherence will be calculated by dividing the number of prescribed tablets by the period of treatment: e.g., if 240 tablets are prescribed for 300 days, the rate of adherence will be 80.0% (240/300).

Full Information

NCT ID

NCT02642419

First Posted

October 21, 2015

Last Updated

December 26, 2015

Sponsor

Japan Cardiovascular Research Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02642419

Brief Title

Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study

Acronym

AFIRE

Official Title

Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE Study)

Study Type

Interventional

2. Study Status

Record Verification Date

December 2015

Overall Recruitment Status

Unknown status

Study Start Date

January 2015 (undefined)

Primary Completion Date

December 2017 (Anticipated)

Study Completion Date

December 2017 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Japan Cardiovascular Research Foundation

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In patients with atrial fibrillation (AF) complicated with coronary artery disease (CAD), antiplatelet drugs are commonly used for the prevention of recurrence of stent thrombosis and cardiovascular events in combination with anticoagulant drugs. Based on the observations that the incidence of hemorrhagic complications increased when an antiplatelet drug was administered in combination with vitamin K antagonist (VKA), the guidelines for antithrombotic therapy after PCI in the US and EU recommend that DAPT (dual anti-platelets therapy) should be used in AF-complicated CAD patients for as short a time as possible following single anti-platelet and VKA, and that monotherapy with VKA should be started from one year after PCI. In 2013 the European Heart Rhythm Association (EHRA) published the guidelines for the use of NOACs in NVAF patients, which state that NOACs may have advantage to VKAs in terms of anti-thrombotic effects in NVAF patients undergoing PCI. However, no clinical evidence has ever been generated to reveal the efficacy and safety of mono-drug therapy with a NOACs in stable CAD patients one year or more after PCI. AFIRE study is planned to evaluate the efficacy and safety of mono-drug therapy with a rivaroxaban in stable CAD patients. Among NOACs, rivaroxaban was chosen because of the evidence in Japanese patients and the results of a sub-analysis of ROCKET AF suggesting that rivaroxaban is more effective than VKA in reducing the incidence of myocardial infarction (MI).

Detailed Description

Study Design:prospective, randomized, open-label trial Allocation:ratio to rivaroxaban monotherapy and rivaroxaban in co-administration with a single anti-platelet therapy is 1: 1 using WEB system

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atrial Fibrillation

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

2200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Rivaroxaban

Arm Type

Experimental

Arm Title

Rivaroxaban and single antiplatelet drug

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Rivaroxaban and single antiplatelet drug (aspirin, clopidogrel or prasugrel)

Intervention Description

Rivaroxaban will be orally administered after a meal at a dose of 15 mg if the creatinine clearance (CLcr) is 50 mL/min or more and at a dose of 10 mg if the CLcr is 15-49 mL/min (regardless of time) Antiplatelet will be selected from aspirin or thienopyridine derivatives (clopidogrel or prasugrel) Aspirin will be orally administered once a day at a dose of 81 mg or 100 mg Clopidogrel will be orally administered once a day after a meal at a dose of 75 mg. The dose will be reduced to 50mg once a day depending on age, body weight or clinical findings. Prasugrel will be orally administered once a day at a dose of 3.75 mg. If the body weight is 50kg or less a reduced dose(2.5 mg once a day) will be considered depending on the age, renal function or other bleeding and thrombotic risk.

Intervention Type

Drug

Intervention Name(s)

Rivaroxaban

Intervention Description

Rivaroxaban will be orally administered at a dose of 15 mg if the creatinine clearance (CLcr) is 50 mL/min or more and at a dose of 10 mg if the CLcr is 15-49 mL/min.

Primary Outcome Measure Information:

Title

Composite endpoint of cardiovascular events

Description

stroke, non-CNS embolism, myocardial infarction, unstable angina pectoris requiring revascularizations or all-cause mortality

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria

Time Frame

mean duration: 2 years, maximum duration: 3 years

Secondary Outcome Measure Information:

Title

Net adverse clinical and cerebral events (NACCE)

Description

composite of all-cause death, myocardial infarction, stroke and major bleeding.

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Ischemic cardiovascular events and death

Description

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

All bleeding events

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Adverse events excluding hemorrhagic events

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Comparison of the primary endpoints, ischemic cardiovascular events and mortality between patients treated with aspirin and patients treated with thienopyridine derivatives

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to the CHADS2 score and CHA2DS2-VASc score

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to subject characteristics

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Comparison of the incidence of bleeding events according to whether or not proton pump inhibitors (PPIs) are used

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Comparison of the incidence of the primary endpoints according to whether rivaroxaban is administered in the morning or evening

Description

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Correlation of discontinuation of antithrombotic agents with ischemic cardiovascular events, bleeding events and adverse events

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

Correlation of prothrombin time at trough with bleeding events and evaluation of the cutoff values in patients with and without co-administration of antiplatelet drug

Time Frame

mean duration: 2 years, maximum duration: 3 years

Title

The incidence of the primary endpoints according to different rates of adherence

Description

Time Frame

mean duration: 2 years, maximum duration: 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with non-valvular atrial fibrillation complicated with stable coronary artery disease who are 20 years or older, with CHADS2 score are ≧1 , and that fulfill one of the following criteria and can provide written consent for participation in the present study will be eligible. Patients who underwent percutaneous coronary intervention(PCI), including plain old balloon angioplasty(POBA), at least one year ago Patients who have coronary stenosis requiring no percutaneous coronary intervention (50% or more stenosis) as indicated by coronary CT or coronary angiography(CAG) Patients who underwent coronary artery bypass graft (CABG) at least one year ago Exclusion Criteria: Patients for whom rivaroxaban is contraindicated Patients for whom aspirin, thienopyridine derivatives (clopidogrel or prasugrel) are contraindicated Patients who underwent PCI, including POBA, in the past one year Patients who are going to undergo revascularization Patients who have a past history of stent thrombosis Those who are going to undergo invasive surgery (excluding digestive endoscopy and biopsy) Patients who have active tumors Patients who have poorly-controlled hypertension (systolic blood pressure at hospital admission: 160 mmHg or more) Patients who cannot discontinue treatment with antiplatelet drugs (the physician in charge will make a decision on the basis of the lesion shape, lesion site and type of stents.) Patients judged as inappropriate for this study by investigators

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Saburo Saito

Phone

+81-6-6872-0010

afire@jcvrf.jp

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hisao Ogawa

Organizational Affiliation

Japan Cardiovascular Research Foundation

Official's Role

Principal Investigator

Facility Information:

Facility Name

Japan Cardiovascular Research Foundation

City

Suita

State/Province

Osaka

ZIP/Postal Code

565-8565

Country

Japan

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hisao Ogawa

Phone

+81-6-6833-8706

ogawah@ncvc.go.jp

First Name & Middle Initial & Last Name & Degree

Hisao Ogawa, M.D.

12. IPD Sharing Statement

Citations:

PubMed Identifier

35704345

Citation

Naito R, Miyauchi K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators. Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease: A Post Hoc Secondary Analysis of the AFIRE Trial. JAMA Cardiol. 2022 Aug 1;7(8):787-794. doi: 10.1001/jamacardio.2022.1561.

Results Reference

derived

PubMed Identifier

35697255

Citation

Arashi H, Yamaguchi J, Hagiwara N, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE investigators. Rivaroxaban Underdose for Atrial Fibrillation with Stable Coronary Disease: The AFIRE Trial Findings. Thromb Haemost. 2022 Sep;122(9):1584-1593. doi: 10.1055/s-0042-1744543. Epub 2022 Jun 13.

Results Reference

derived

PubMed Identifier

35209924

Citation

Matsui K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Ogawa H. The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial. BMC Med. 2022 Feb 25;20(1):69. doi: 10.1186/s12916-022-02268-6.

Results Reference

derived

PubMed Identifier

34736731

Citation

Matoba T, Yasuda S, Kaikita K, Akao M, Ako J, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators. Rivaroxaban Monotherapy in Patients With Atrial Fibrillation After Coronary Stenting: Insights From the AFIRE Trial. JACC Cardiovasc Interv. 2021 Nov 8;14(21):2330-2340. doi: 10.1016/j.jcin.2021.07.045.

Results Reference

derived

PubMed Identifier

34658247

Citation

Matsuzawa Y, Kimura K, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators. Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial. J Am Heart Assoc. 2021 Nov 2;10(21):e020907. doi: 10.1161/JAHA.121.020907. Epub 2021 Oct 18.

Results Reference

derived

PubMed Identifier

34474583

Citation

Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H. Bleeding and Subsequent Cardiovascular Events and Death in Atrial Fibrillation With Stable Coronary Artery Disease: Insights From the AFIRE Trial. Circ Cardiovasc Interv. 2021 Nov;14(11):e010476. doi: 10.1161/CIRCINTERVENTIONS.120.010476. Epub 2021 Sep 3.

Results Reference

derived

PubMed Identifier

34261738

Citation

Fukaya H, Ako J, Yasuda S, Kaikita K, Akao M, Matoba T, Nakamra M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H. Aspirin versus P2Y12 inhibitors with anticoagulation therapy for atrial fibrillation. Heart. 2021 Nov;107(21):1731-1738. doi: 10.1136/heartjnl-2021-319321. Epub 2021 Jul 14.

Results Reference

derived

PubMed Identifier

33657403

Citation

Akao M, Yasuda S, Kaikita K, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H. Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis. Am Heart J. 2021 Jun;236:59-68. doi: 10.1016/j.ahj.2021.02.021. Epub 2021 Feb 28.

Results Reference

derived

PubMed Identifier

31475793

Citation

Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators. Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease. N Engl J Med. 2019 Sep 19;381(12):1103-1113. doi: 10.1056/NEJMoa1904143. Epub 2019 Sep 2. Erratum In: N Engl J Med. 2021 Oct 21;385(17):1632.

Results Reference

derived

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Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study

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