A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart

• ClinicalTrials.gov Identifier: NCT02415400
• Recruitment Status: Completed
• First Posted: April 14, 2015
• Results First Posted: February 7, 2020
• Last Update Posted: June 11, 2020
• Sponsor: Bristol-Myers Squibb
• Collaborators: Pfizer; Duke Clinical Research Institute
• Information provided by (Responsible Party): Bristol-Myers Squibb

Tracking Information

• First Submitted Date: April 9, 2015
• First Posted Date: April 14, 2015
• Results First Submitted Date: November 7, 2019
• Results First Posted Date: February 7, 2020
• Last Update Posted Date: June 11, 2020
• Actual Study Start Date: June 4, 2015
• Actual Primary Completion Date: November 10, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 3, 2020)

• The Rate of International Society on Thrombosis and Haemostasis (ISTH) Major or Clinically Relevant Non-Major (CRNM) Bleeding With Apixaban Versus Vitamin K Antagonist (VKA) During the Treatment Period [ Time Frame: Approximately 6 months ]
  Time to first ISTH major or CRNM bleeding during the 6-month period of treatment with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with major or CRNM bleeding divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
• The Rate of ISTH Major or CRNM Bleeding With Aspirin Versus no Aspirin During the Treatment Period [ Time Frame: Approximately 6 months ]
  Time to first ISTH major or CRNM bleeding during the treatment period of 6 months with aspirin or placebo. N is the number of participants with aspirin or placebo. n is the number of participants treated with aspirin or placebo with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.

Original Primary Outcome Measures (submitted: April 13, 2015)

• Time to first occurrence of International Society on Thrombosis and Haemostasis (ISTH) major or Clinically Relevant Non-Major (CRNM) bleeding during the treatment period between Apixaban and VKA [ Time Frame: Approximately 6 months ]
  time to first occurrence of ISTH major or CRNM bleeding during the time the patient is taking the medicine which is 6 months
• Time to first occurrence of major or CRNM bleeding during the treatment period between No aspirin and aspirin [ Time Frame: Approximately 6 months ]
  time to first occurrence of ISTH major or CRNM bleeding during the time the patient is taking the medicine which is 6 months

Current Secondary Outcome Measures (submitted: February 3, 2020)

• Superiority on ISTH Major or CRNM Bleeding for Apixaban Versus VKA [ Time Frame: Approximately 6 months ]
  Time to first occurrence during the time the participants were treated with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with major or CRNM bleeding in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with event of interest divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
• The Rate of All-cause Death or All-cause Rehospitalization With Apixaban Versus VKA [ Time Frame: Approximately 6 months ]
  Time to first all-cause death or all-cause hospitalization during the during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
• The Rate of All-cause Death or All-cause Rehospitalization With Aspirn Versus no Aspirin [ Time Frame: Approximately 6 months ]
  Time to first all-cause death or all-cause hospitalization during the 6-month period of treatment with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with all-cause death or all-cause hospitalization in each treatment group during the 6-month period of treatment. Event rates are calculated based on the number of participants with all-cause death or all-cause hospitalization divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
• The Rate of the Composite Endpoint of Death or Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Apixaban Versus VKA [ Time Frame: Approximately 6 months ]
  Time to first occurrence during the 6-month treatment period with Apixaban or VKA. N is the number of participants treated with Apixaban or VKA. n is the number of participants treated with Apixaban or VKA with death or ischemic events in each treatment group during the during the 6-month period of treatment. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.
• The Composite Endpoints of Death and Ischemic Events (Stroke, Myocardial Infarction, Stent Thrombosis, Urgent Revascularization) With Aspirin Versus no Aspirin [ Time Frame: Approximately 6 months ]
  Time to first death or ischenic event during the 6-month treatment period with aspirin or placebo. N is the number of participants treated with aspirin or placebo. n is the number of participants treated with aspirin or placebo with death or ischemic events in each treatment group during the 6-month treatment period. Event rates are calculated based on the number of participants with death or ischemic events divided by the sum of the number of days from the first dose of study drug to the event date or censoring date and expressed as percentage per year.

Original Secondary Outcome Measures (submitted: April 13, 2015)

• Superiority on major + CRNM bleeding between Apixaban versus VKA [ Time Frame: Approximately 6 months ]
  time to first occurrence during the time the patient is taking the medicine which is 6 months
• The composite endpoints of death and ischemic events (stroke, myocardial infarction, stent thrombosis, urgent revascularization) between Apixaban versus VKA [ Time Frame: Approximately 6 months ]
  time to first occurrence during the time the patient is taking the medicine which is 6 months
• First re-hospitalization for any cause between Apixaban versus VKA [ Time Frame: Approximately 6 months ]
  time to first occurrence during the time the patient is taking the medicine which is 6 months
• The composite endpoints of death and ischemic events (stroke, myocardial infarction, stent thrombosis, urgent revascularization) between aspirin versus placebo [ Time Frame: Approximately 6 months ]
  time to first occurrence during the time the patient is taking the medicine which is 6 months
• First re-hospitalization for any cause between aspirin versus placebo [ Time Frame: Approximately 6 months ]
  time to first occurrence during the time the patient is taking the medicine which is 6 months

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart
• Official Title: An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention
• Brief Summary: The purpose of this study is to determine if Apixaban is safer than a Vitamin K Antagonist given for 6 months in terms of bleeding in patients with an irregular heart beat (atrial fibrillation) and a recent heart attack or a recent procedure to open up a blood vessel in the heart. All patients would also be taking a class of medicines called P2Y12 inhibitors (such as clopidogrel/Plavix) and be treated for up to 6 months. The primary focus will be a comparison of the bleeding risk of Apixaban, with or without aspirin, versus a Vitamin K antagonist, such as warfarin, with or without aspirin.

Detailed Description

Patients will be recruited from either inpatient coronary care or general medical units, or recruited from outpatient cardiology offices.

Masking:

Apixaban: Open label.

VKA: Open label.

Acetylsalicylic acid film coated tablet: Double Blinded.

Placebo matching Acetylsalicylic acid film coated tablet: Double Blinded.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Acute Coronary Syndromes

Intervention

• Drug: Apixaban
  Other Name: BMS-562247
• Drug: vitamin K antagonist
• Drug: Acetylsalicylic acid
  Other Name: Aspirin 81 mg
• Other: Acetylsalicylic acid placebo
  Other Name: aspirin placebo

Study Arms

• Active Comparator: Apixaban
  5 mg or 2.5 mg Apixaban tablets orally twice per day
  Intervention: Drug: Apixaban
• Active Comparator: Vitamin K Antagonist
  VKA tablets orally once daily
  Intervention: Drug: vitamin K antagonist
• Placebo Comparator: Acetylsalicylic acid film coated tablet
  81 mg Acetylsalicylic acid film coated tablet orally once daily
  Intervention: Drug: Acetylsalicylic acid
• Placebo Comparator: Placebo matching Acetylsalicylic acid film coated tablet
  Placebo matching Acetylsalicylic acid film coated tablet once daily
  Intervention: Other: Acetylsalicylic acid placebo

Publications *

• Bahit MC, Vora AN, Li Z, Wojdyla DM, Thomas L, Goodman SG, Aronson R, Jordan JD, Kolls BJ, Dombrowski KE, Vinereanu D, Halvorsen S, Berwanger O, Windecker S, Mehran R, Granger CB, Alexander JH, Lopes RD. Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial. JAMA Cardiol. 2022 Jul 1;7(7):682-689. doi: 10.1001/jamacardio.2022.1166.
• Welsh RC, Dehghani P, Lopes R, Wojdyla DM, Aronson R, Granger CB, Windecker S, Vora AN, Vinereanu D, Halvorsen S, Parkhomenko A, Mehran R, Alexander JH, Goodman S. Impact of prior oral anticoagulant use and outcomes on patients from secondary analysis in the AUGUSTUS trial. Open Heart. 2022 Feb;9(1):e001892. doi: 10.1136/openhrt-2021-001892.
• Harskamp RE, Fanaroff AC, Lopes RD, Wojdyla DM, Goodman SG, Thomas LE, Aronson R, Windecker S, Mehran R, Granger CB, Alexander JH. Antithrombotic Therapy in Patients With Atrial Fibrillation After Acute Coronary Syndromes or Percutaneous Intervention. J Am Coll Cardiol. 2022 Feb 8;79(5):417-427. doi: 10.1016/j.jacc.2021.11.035.
• Hijazi Z, Alexander JH, Li Z, Wojdyla DM, Mehran R, Granger CB, Parkhomenko A, Bahit MC, Windecker S, Aronson R, Berwanger O, Halvorsen S, de Waha-Thiele S, Sinnaeve P, Darius H, Storey RF, Lopes RD. Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial. Circulation. 2021 Mar 23;143(12):1215-1223. doi: 10.1161/CIRCULATIONAHA.120.051020. Epub 2021 Jan 19.
• Alexander JH, Wojdyla D, Vora AN, Thomas L, Granger CB, Goodman SG, Aronson R, Windecker S, Mehran R, Lopes RD. Risk/Benefit Tradeoff of Antithrombotic Therapy in Patients With Atrial Fibrillation Early and Late After an Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From AUGUSTUS. Circulation. 2020 May 19;141(20):1618-1627. doi: 10.1161/CIRCULATIONAHA.120.046534. Epub 2020 Mar 29.
• Lopes RD, Leonardi S, Wojdyla DM, Vora AN, Thomas L, Storey RF, Vinereanu D, Granger CB, Goodman SG, Aronson R, Windecker S, Thiele H, Valgimigli M, Mehran R, Alexander JH. Stent Thrombosis in Patients With Atrial Fibrillation Undergoing Coronary Stenting in the AUGUSTUS Trial. Circulation. 2020 Mar 3;141(9):781-783. doi: 10.1161/CIRCULATIONAHA.119.044584. Epub 2019 Nov 11. No abstract available.
• Windecker S, Lopes RD, Massaro T, Jones-Burton C, Granger CB, Aronson R, Heizer G, Goodman SG, Darius H, Jones WS, Aschermann M, Brieger D, Cura F, Engstrom T, Fridrich V, Halvorsen S, Huber K, Kang HJ, Leiva-Pons JL, Lewis BS, Malaga G, Meneveau N, Merkely B, Milicic D, Morais J, Potpara TS, Raev D, Sabate M, de Waha-Thiele S, Welsh RC, Xavier D, Mehran R, Alexander JH; AUGUSTUS Investigators. Antithrombotic Therapy in Patients With Atrial Fibrillation and Acute Coronary Syndrome Treated Medically or With Percutaneous Coronary Intervention or Undergoing Elective Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial. Circulation. 2019 Dec 3;140(23):1921-1932. doi: 10.1161/CIRCULATIONAHA.119.043308. Epub 2019 Sep 26.
• Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R, Goodman SG, Windecker S, Darius H, Li J, Averkov O, Bahit MC, Berwanger O, Budaj A, Hijazi Z, Parkhomenko A, Sinnaeve P, Storey RF, Thiele H, Vinereanu D, Granger CB, Alexander JH; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17.
• Lopes RD, Vora AN, Liaw D, Granger CB, Darius H, Goodman SG, Mehran R, Windecker S, Alexander JH. An open-Label, 2 x 2 factorial, randomized controlled trial to evaluate the safety of apixaban vs. vitamin K antagonist and aspirin vs. placebo in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention: Rationale and design of the AUGUSTUS trial. Am Heart J. 2018 Jun;200:17-23. doi: 10.1016/j.ahj.2018.03.001. Epub 2018 Mar 9.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 10, 2019): 4614
• Original Estimated Enrollment (submitted: April 13, 2015): 4600
• Actual Study Completion Date: November 10, 2018
• Actual Primary Completion Date: November 10, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Adults with either active or a history of non-valvular atrial fibrillation or flutter with the planned or existing use of an oral anticoagulant for prophylaxis of thromboembolism. In addition, subjects must have had an acute coronary syndrome or percutaneous coronary intervention with a stent within the prior 14 days
• Planned use of antiplatelet agents for at least 1 to 6 months
• Males and Females ≥ 18 years of age
• Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug

Exclusion Criteria:

• Conditions other than atrial fibrillation that require chronic anticoagulation. (e.g. prosthetic mechanical heart valve)
• Severe renal insufficiency (serum creatinine > 2.5 mg/dL or a calculated creatinine clearance < 30 mL/min
• Patients with a history of intracranial hemorrhage
• Patients have had or will undergo Coronary arterial bypass graft (CABG) for their index acute coronary syndrome (ACS) event
• Patients with known ongoing bleeding and patients with known coagulopathies
• Any contraindications or allergies to VKA, apixaban, or to intended P2Y12 antagonists or to aspirin

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 95 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Denmark, France, Germany, Hungary, India, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Puerto Rico, Romania, Russian Federation, Serbia, Slovakia, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States, Virgin Islands (U.S.)
• Removed Location Countries: Czech Republic, Venezuela

Administrative Information

• NCT Number: NCT02415400
• Other Study ID Numbers: CV185-316; 2014-002004-24 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bristol-Myers Squibb
• Original Responsible Party: Same as current
• Current Study Sponsor: Bristol-Myers Squibb
• Original Study Sponsor: Same as current

Collaborators

• Pfizer
• Duke Clinical Research Institute

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Bristol-Myers Squibb
• Verification Date: June 2020