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Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00412984
Recruitment Status : Completed
First Posted : December 19, 2006
Results First Posted : April 29, 2013
Last Update Posted : July 3, 2018
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Tracking Information
First Submitted Date  ICMJE December 18, 2006
First Posted Date  ICMJE December 19, 2006
Results First Submitted Date  ICMJE January 25, 2013
Results First Posted Date  ICMJE April 29, 2013
Last Update Posted Date July 3, 2018
Actual Study Start Date  ICMJE December 31, 2006
Actual Primary Completion Date May 25, 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
  • Number of Participants With First Event of Ischemic/Unspecified Stroke, Hemorrhagic Stroke, or Systemic Embolism (SE) During the Intended Treatment Period [ Time Frame: Time to first event in "Intended Treatment Period": started on day of randomization, ended at efficacy cut-off date (date target number of primary efficacy events [448] was expected to have occurred; set to 30-Jan-2011, prior to unblinding). ]
    All suspected efficacy events were adjudicated by the Central Events Committee (CEC). Diagnosis of stroke=the nontraumatic focal neurological deficit lasting at least 24 hours, and includes ischemic stroke, hemorrhagic stroke, ischemic stroke with hemorrhagic conversion, stroke of uncertain type, and retinal ischemic event (embolism, infarction). Diagnosis of SE=clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), supported by evidence of embolism from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing.
  • Rate of Adjudicated Stroke or Systemic Embolism (SE) During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    Rate=Number of adjudicated stroke or SE events per 100 patient years. Diagnosis of stroke=the nontraumatic focal neurological deficit lasting at least 24 hours, and includes ischemic stroke, hemorrhagic stroke, ischemic stroke with hemorrhagic conversion, stroke of uncertain type, and retinal ischemic event (embolism, infarction). Diagnosis of SE=clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), supported by evidence of embolism from surgical specimens, autopsy, angiography, vascular imaging, or other objective testing.
Original Primary Outcome Measures  ICMJE
 (submitted: December 18, 2006)		 Time to first occurrence of confirmed stroke or systemic embolism
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2018)
  • Number of Participants With Event of Major (International Society on Thrombosis and Hemostasis [ISTH]) Bleeding During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more, and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.
  • Rate of Adjudicated Major (ISTH) Bleed Events During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of adjudicated major (ISTH) bleed events per 100 patient years. ISTH Bleeding Criteria: Major bleeding=a bleeding event that was: clinically overt bleeding accompanied by a decrease in hemoglobin (Hgb) of 2 g/dL or more and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal.
  • Number of Participants With Events of All-Cause Death During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    Death was defined as all-cause mortality. All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, myocardial infarction (MI), sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).
  • Rate of Adjudicated All-Cause Death During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    All unobserved deaths were assumed to be cardiovascular in nature unless a non-cardiovascular cause could be clearly provided. Cardiovascular=deaths due to ischemic and hemorrhagic stroke, SE, MI, sudden death, heart failure, other cardiovascular, and unobserved deaths. Non-cardiovascular=all deaths due to a clearly documented non-cardiovascular cause (further classified into the categories: bleeding, study drug toxicity other than bleeding, malignancy, infection, trauma, and pulmonary causes of death).
  • Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), and Myocardial Infarction (MI) (as Individual Endpoints) During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    Diagnosis for an acute or evolving MI=elevation of creatine kinase-MB isoenzyme (CK-MB) or Troponin T or I ≥ 2 × the upper limit of normal (ULN), or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1.
  • Rate of Ischemic or Unspecified Stroke, Hemorrhagic Stroke, Systemic Embolism (SE), Myocardial Infarction (MI) and All-Cause Death (ACD) (as Composite Endpoints) During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    Diagnosis for an acute or evolving MI=elevation of CK-MB or Troponin T or I ≥ 2 × the ULN, or if no CK-MB or troponin values are available, a total CK ≥ 2×ULN, or new, significant (≥0.04 s) Q waves in ≥2 contiguous leads. For descriptions of Stroke and SE, see Outcome Measure 1. For description of ACD, see Outcome Measure 5.
  • Number of Warfarin/Vitamin K Antagonist (VKA) Naive Participants With Composite Stroke / Systemic Embolism (SE) / Major Bleeding During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
    For descriptions of Stroke and SE, see Outcome Measure 1. For description of Major bleeding, see Outcome Measure 3.
  • Rate of Composite Stroke / Systemic Embolism / Major Bleeding in Warfarin/Vitamin K Antagonist (VKA) Naive Participants During the Intended Treatment Period [ Time Frame: "Intended Treatment Period" started on the day of randomization and ended at the efficacy cut-off date (date on which it was expected that the target number of primary efficacy events [448] would have occurred; set to 30-Jan-2011, prior to unblinding). ]
  • Number of Participants With Events of Major or Clinically Relevant Nonmajor (CRNM) Bleed During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Major bleeding=bleeding that is clinically overt and that either resulted in a decrease in hemoglobin of 2 g/dL or more over a 24-hour period, led to a transfusion of 2 or more units of packed red blood cells, occurred in a critical site, or led to death. CRNM bleeding=bleeding that is clinically overt, that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event, that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy.
  • Rate of Events of Major or Clinically Relevant Non-Major (CRNM) Bleed During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of major or CRNM bleed events per 100 patient years. Major=clinically overt and either 1) resulted in a decrease in hemoglobin of 2 g/dL or more, or 2) led to a transfusion of 2 or more units of packed red blood cells, or 3) occurred in a critical site, or 4) led to death. CRNM bleeding=clinically overt, but satisfied no additional criteria required to be adjudicated as a major bleeding event, and led to either 1) hospital admission for bleeding or 2) physician guided medical or surgical treatment for bleeding or 3) a change in antithrombotic therapy.
  • Number of Participants With All Bleeding Events During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    All bleeding events include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.
  • Rate of All Bleeding Events During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of all bleeding events per 100 patient years. "All bleeding events" include major bleeding, CRNM bleeding (see Outcome Measure 12 Description for definitions), plus events of minor bleeding and fatal bleeding. Minor bleeding: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding. Fatal bleeding is defined as a bleeding event that the Clinical Events Committee determines is the primary cause of death or contributes directly to death.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2006)		 Time to first occurrence of confirmed ischemic stroke, hemorrhagic stroke, systemic embolism, all cause death
Current Other Pre-specified Outcome Measures
 (submitted: March 15, 2013)
  • Number of Participants With Adverse Events (AEs), Bleeding AEs, Serious Adverse Events (SAEs), Discontinuations Due to AEs, or Deaths During the Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    AE: all SAEs or AEs with onset from first dose through 2 days (AEs) or 30 days (SAEs) after the last dose of blinded study drug (BSD). SAE: all SAEs with onset from first dose through 30 days after the last dose of BSD. Bleeding AE: all serious or non-serious bleeding-related AEs with onset from first dose through 2 days after the last dose of BSD. Discontinuations due to AE: all SAEs or AEs with onset from first dose of BSD and with action taken=drug discontinued. Deaths: all deaths occurring from first dose through 30 days after the last dose of BSD.
  • Rate of Adjudicated Bleeding Endpoints Per Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) During the Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of adjudicated GUSTO bleeding events per 100 patient years. GUSTO Bleeding Criteria: GUSTO severe (or life-threatening) bleeding: either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention. GUSTO moderate bleeding: bleeding that requires blood transfusion but does not result in hemodynamic compromise.
  • Rate of Adjudicated Bleeding Endpoints Per Thrombolysis in Myocardial Infarction (TIMI) During the Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of adjudicated TIMI bleeding events per 100 patient years. TIMI Bleeding Criteria: Major bleeding=Intracranial bleeding and/or clinically overt bleeding associated with ≥5 gm/dL fall in Hgb or 15% fall in hematocrit (Hct) from baseline, accounting for transfusions. Minor bleeding=Clinically overt bleeding associated with ≥3 gm/dL fall in Hgb or a ≥10% fall in Hct from baseline, accounting for transfusions.
  • Number of Participants With Net-Clinical Benefit During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding.
  • Rate of Net-Clinical Benefit During Treatment Period [ Time Frame: "Treatment Period" started with first dose of blinded study drug and ended 2 days after the last dose of blinded study drug. Mean duration of exposure to double-blind study drug was 1.7 years in each treatment group. ]
    Rate=number of events of net-clinical benefit per 100 patient years. Net-Clinical Benefit = Composite of stroke, systemic embolism and ISTH major bleeding
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation
Official Title  ICMJE A Phase 3, Active (Warfarin) Controlled, Randomized, Double-Blind, Parallel Arm Study to Evaluate Efficacy and Safety of Apixaban in Preventing Stroke and Systemic Embolism in Subjects With Nonvalvular Atrial Fibrillation
Brief Summary The trial seeks to determine if apixaban, an investigational anticoagulant (blood-thinner) is as effective as standard therapy (warfarin) in preventing stroke and systemic embolism in subjects with atrial fibrillation and risk factors for stroke.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Atrial Fibrillation
  • Atrial Flutter
Intervention  ICMJE
  • Drug: warfarin
    Oral tablets, 2.0 mg, adjusted to an INR of 2.5 (range 2.0 to 3.0)
    Other Names:
    • Coumadin
    • BMS-565793
  • Drug: apixaban
    Oral tablets, 5.0 mg or 2.5 mg, twice daily
    Other Name: BMS-562247
Study Arms  ICMJE
  • Active Comparator: 1
    Intervention: Drug: warfarin
  • Experimental: 2
    Intervention: Drug: apixaban
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 5, 2018)		 20976
Original Enrollment  ICMJE
 (submitted: December 18, 2006)		 15000
Actual Study Completion Date  ICMJE May 25, 2011
Actual Primary Completion Date May 25, 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Males and females ≥ 18 yrs with atrial fibrillation (AF) and one or more of the following risk factors for stroke:
  • Age ≥ 75, previous stroke
  • transient ischemic attack (TIA) or Systemic Embolism (SE)
  • Symptomatic congestive heart failure or left ventricular dysfunction with left ventricular ejection fraction (LVEF) ≤ 40%
  • Diabetes mellitus or hypertension requiring pharmacological treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Chile,   China,   Colombia,   Czechia,   Denmark,   Finland,   France,   Germany,   Hong Kong,   Hungary,   India,   Israel,   Italy,   Japan,   Korea, Republic of,   Malaysia,   Mexico,   Netherlands,   Norway,   Peru,   Philippines,   Poland,   Puerto Rico,   Romania,   Russian Federation,   Singapore,   South Africa,   Spain,   Sweden,   Switzerland,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Portugal,   Thailand
 
Administrative Information
NCT Number  ICMJE NCT00412984
Other Study ID Numbers  ICMJE CV185-030
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Bristol-Myers Squibb
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE Bristol-Myers Squibb
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
PRS Account Bristol-Myers Squibb
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP