Clinical trial NCT02642419: Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study
Official title: Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study (AFIRE Study)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Atrial Fibrillation
Lead sponsor: Japan Cardiovascular Research Foundation
Sponsor class: OTHER
First posted: 2015-12-30
Enrollment: 2200
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

1. Patients who underwent percutaneous coronary intervention(PCI), including plain old balloon angioplasty(POBA), at least one year ago
2. Patients who have coronary stenosis requiring no percutaneous coronary intervention (50% or more stenosis) as indicated by coronary CT or coronary angiography(CAG)
3. 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

Primary outcomes:
measure: Composite endpoint of cardiovascular events
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria
timeFrame: mean duration: 2 years, maximum duration: 3 years
Secondary outcomes:
measure: Net adverse clinical and cerebral events (NACCE)
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Ischemic cardiovascular events and death
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: All bleeding events
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Adverse events excluding hemorrhagic events
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Comparison of the primary endpoints, ischemic cardiovascular events and mortality between patients treated with aspirin and patients treated with thienopyridine derivatives
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to the CHADS2 score and CHA2DS2-VASc score
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to subject characteristics
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: 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
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Comparison of the incidence of bleeding events according to whether or not proton pump inhibitors (PPIs) are used
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Comparison of the incidence of the primary endpoints according to whether rivaroxaban is administered in the morning or evening
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: Correlation of discontinuation of antithrombotic agents with ischemic cardiovascular events, bleeding events and adverse events
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: 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
timeFrame: mean duration: 2 years, maximum duration: 3 years
measure: The incidence of the primary endpoints according to different rates of adherence
timeFrame: mean duration: 2 years, maximum duration: 3 years
Other outcomes:
Locations:
city: Suita
country: Japan
facility: Japan Cardiovascular Research Foundation
state: Osaka
Study officials:
affiliation: Japan Cardiovascular Research Foundation
name: Hisao Ogawa
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.