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

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

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 Overview

• Status: Unknown
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Rivaroxaban and single antiplatelet drug (aspirin, clopidogrel or prasugrel)

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

• Study Type: Interventional
• Enrollment (Anticipated): 2200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Osaka
    • Suita, Osaka, Japan, 565-8565
      • Recruiting
      • Japan Cardiovascular Research Foundation
      • Principal Investigator: Hisao Ogawa, M.D.
      • Contact: Hisao Ogawa; Phone Number: +81-6-6833-8706; Email: ogawah@ncvc.go.jp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban	Drug: Rivaroxaban; 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.
Experimental: Rivaroxaban and single antiplatelet drug	Drug: Rivaroxaban and single antiplatelet drug (aspirin, clopidogrel or prasugrel); 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 mgClopidogrel 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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	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

Collaborators and Investigators

• Sponsor: Japan Cardiovascular Research Foundation
• Investigators: Principal Investigator: Hisao Ogawa, Japan Cardiovascular Research Foundation

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: October 21, 2015
• First Submitted That Met QC Criteria: December 26, 2015
• First Posted (Estimate): December 30, 2015

Study Record Updates

• Last Update Posted (Estimate): December 30, 2015
• Last Update Submitted That Met QC Criteria: December 26, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Arrhythmias, Cardiac; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Atrial Fibrillation; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Rivaroxaban; Prasugrel Hydrochloride; Platelet Aggregation Inhibitors
• Other Study ID Numbers: AFIRE Study