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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).
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rivaroxaban | Experimental |
| |
| Rivaroxaban and single antiplatelet drug | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rivaroxaban and single antiplatelet drug (aspirin, clopidogrel or prasugrel) | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Composite endpoint of cardiovascular events | stroke, non-CNS embolism, myocardial infarction, unstable angina pectoris requiring revascularizations or all-cause mortality | mean duration: 2 years, maximum duration: 3 years |
| Major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria | mean duration: 2 years, maximum duration: 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Net adverse clinical and cerebral events (NACCE) | composite of all-cause death, myocardial infarction, stroke and major bleeding. | mean duration: 2 years, maximum duration: 3 years |
| Ischemic cardiovascular events and death |
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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.
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Saburo Saito | Contact | +81-6-6872-0010 | afire@jcvrf.jp |
| Name | Affiliation | Role |
|---|---|---|
| Hisao Ogawa | Japan Cardiovascular Research Foundation | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Japan Cardiovascular Research Foundation | Recruiting | Suita | Osaka | 565-8565 | Japan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40802193 | Derived | Yamaguchi J, Arashi H, Hagiwara N, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Matsui K, Ogawa H; AFIRE Investigators. Age-Stratified Effect of Rivaroxaban Monotherapy for Atrial Fibrillation in Stable Coronary Artery Disease: A Post Hoc Analysis of the AFIRE Randomized Clinical Trial. JAMA Cardiol. 2025 Aug 13;10(10):990-9. doi: 10.1001/jamacardio.2025.2611. Online ahead of print. | |
| 37815031 |
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|
| Rivaroxaban | Drug | 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. |
|
| mean duration: 2 years, maximum duration: 3 years |
| All bleeding events | mean duration: 2 years, maximum duration: 3 years |
| Adverse events excluding hemorrhagic events | mean duration: 2 years, maximum duration: 3 years |
| Comparison of the primary endpoints, ischemic cardiovascular events and mortality between patients treated with aspirin and patients treated with thienopyridine derivatives | mean duration: 2 years, maximum duration: 3 years |
| Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to the CHADS2 score and CHA2DS2-VASc score | mean duration: 2 years, maximum duration: 3 years |
| Subgroup analysis of primary endpoints, ischemic cardiovascular events and mortality according to subject characteristics | mean duration: 2 years, maximum duration: 3 years |
| 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 | mean duration: 2 years, maximum duration: 3 years |
| Comparison of the incidence of bleeding events according to whether or not proton pump inhibitors (PPIs) are used | mean duration: 2 years, maximum duration: 3 years |
| Comparison of the incidence of the primary endpoints according to whether rivaroxaban is administered in the morning or evening | 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. | mean duration: 2 years, maximum duration: 3 years |
| Correlation of discontinuation of antithrombotic agents with ischemic cardiovascular events, bleeding events and adverse events | mean duration: 2 years, maximum duration: 3 years |
| 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 | mean duration: 2 years, maximum duration: 3 years |
| 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). | mean duration: 2 years, maximum duration: 3 years |
| Derived |
| Iijima R, Tokue M, Nakamura M, Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H; AFIRE Investigators. Thrombocytopenia as a Bleeding Risk Factor in Atrial Fibrillation and Coronary Artery Disease: Insights From the AFIRE Study. J Am Heart Assoc. 2023 Oct 17;12(20):e031096. doi: 10.1161/JAHA.123.031096. Epub 2023 Oct 10. |
| 37173099 | Derived | Ishii M, Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Nishihara E, Nakamura S, Matsui K, Ogawa H, Tsujita K; AFIRE Investigators. Risk prediction score for clinical outcome in atrial fibrillation and stable coronary artery disease. Open Heart. 2023 May;10(1):e002292. doi: 10.1136/openhrt-2023-002292. |
| 36713761 | Derived | Ishii M, Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, Miyauchi K, Hagiwara N, Kimura K, Hirayama A, Matsui K, Ogawa H, Tsujita K; AFIRE Investigators. Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories. JACC Asia. 2022 Aug 27;2(7):882-893. doi: 10.1016/j.jacasi.2022.08.004. eCollection 2022 Dec. |
| 35704345 | Derived | 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. |
| 35697255 | Derived | 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. |
| 35209924 | Derived | 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. |
| 34736731 | Derived | 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. |
| 34658247 | Derived | 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. |
| 34474583 | Derived | 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. |
| 34261738 | Derived | 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. |
| 33657403 | Derived | 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. |
| 31475793 | Derived | 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. |
| ID | Term |
|---|---|
| D001281 | Atrial Fibrillation |
| ID | Term |
|---|---|
| D001145 | Arrhythmias, Cardiac |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000069552 | Rivaroxaban |
| D010975 | Platelet Aggregation Inhibitors |
| D001241 | Aspirin |
| D000077144 | Clopidogrel |
| D000068799 | Prasugrel Hydrochloride |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D009025 | Morpholines |
| D010078 | Oxazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006401 | Hematologic Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D011725 | Pyridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010879 | Piperazines |
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