Study Of The Blood Thinner, Apixaban, For Patients Who Have An Abnormal Heart Rhythm (Atrial Fibrillation) And Expected To Have Treatment To Put Them Back Into A Normal Heart Rhythm (Cardioversion) (EMANATE)

• ClinicalTrials.gov Identifier: NCT02100228
• Recruitment Status: Completed
• First Posted: March 31, 2014
• Results First Posted: April 10, 2018
• Last Update Posted: May 23, 2018
• Sponsor: Pfizer
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: February 5, 2014
• First Posted Date: March 31, 2014
• Results First Submitted Date: January 17, 2018
• Results First Posted Date: April 10, 2018
• Last Update Posted Date: May 23, 2018
• Actual Study Start Date: July 14, 2014
• Actual Primary Completion Date: February 8, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 12, 2018)

• Number of Participants With Acute Stroke Event [ Time Frame: Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame) ]
  An acute stroke was defined as a new, important neurological insufficiency of rapid onset that lasted for at least 24 hours and that was not due to a readily identifiable non-vascular cause (like brain tumor or trauma).
• Number of Participants With Systemic Embolism Event [ Time Frame: Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame) ]
  Systemic embolism occurred in participant when there was a clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), which was supported by evidence of embolism from surgical specimens, autopsy, angiography, or other objective testing.
• Number of Participants With Major Bleeding Event [ Time Frame: Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame) ]
  Major bleeding was defined as clinically evident bleeding that was accompanied by one or more of the following: a decrease in hemoglobin of 2 gram per deciliter or more, a transfusion of 2 or more units of packed red blood cells, bleeding that was fatal or bleeding that occurred in at least one of the following critical sites: intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed was not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal.
• Number of Participants With Clinically Relevant Non-Major Bleeding Events [ Time Frame: Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame) ]
  Clinically relevant non-major bleeding was defined as the clinically evident bleeding that consisted of any bleeding that compromised hemodynamics, that led to hospitalization, subcutaneous hematoma larger than 25/100 centimeter square if there was a traumatic cause, intramuscular hematoma documented by ultrasonography, epistaxis, gingival bleeding occurred spontaneously, hematuria that was macroscopic and was spontaneous, macroscopic gastrointestinal hemorrhage included at least one episode of melena or hematemesis, rectal blood loss, hemoptysis or any other bleeding type considered to have clinical consequences for a participant, such as medical intervention, the need for unscheduled contact with a physician, or temporary cessation of a study drug, or associated with pain or impairment of activities of daily life.
• Number of Participants With All Cause Death [ Time Frame: Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame) ]

Original Primary Outcome Measures (submitted: March 26, 2014)

• Acute stroke [ Time Frame: Events will be collected up to 30 days post cardioversion ]
  An acute stroke is defined as a new focal neurological deficit of sudden onset, lasting at least 24 hours, that is not due to a readily identifiable non-vascular cause. This will be assessed by the Investigator.
• Systemic embolism [ Time Frame: Events will be collected up to 30 days post cardioversion ]
  A clinical history consistent with an acute loss of blood flow to a peripheral artery (or arteries), which is supported by evidence of embolism from surgical specimens, autopsy, angiography, or other objective testing. This will be assessed by the Investigator.
• Major Bleeding [ Time Frame: Events will be collected up to 30 days post cardioversion ]
  Defined as new onset, visible bleeding or signs or symptoms suggestive of bleeding with confirmatory imaging techniques which can detect the presence of blood. The definition of major bleeding is adapted from the International Society on Thrombosis and Hemostasis (ISTH) definition. This will be assessed by the Investigator.
• Clinically Relevant Non-Major Bleeding [ Time Frame: Events will be collected up to 30 days post cardioversion ]
  The definition is adapted from International Society on Thrombosis and Hemostasis (ISTH) definition. This will be assessed by the Investigator.
• All cause death [ Time Frame: Events will be collected up to 30 days post cardioversion ]
  Death

Current Secondary Outcome Measures (submitted: March 12, 2018)

• Time to First Attempt of Cardioversion [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  Cardioversion was an effective method of converting an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia to normal rhythm using electricity or drugs. First attempt of cardioversion was defined as the first time the participant was admitted for the cardioversion procedure.
• Number of Participants With Different Type of Cardioversion Events [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  Cardioversion was an effective method of converting an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia to normal rhythm using different type of cardioversion events i.e. electrical and pharmacologic. Electrical cardioversion was a procedure in which an electric current was used to reset the heart's rhythm back to its regular pattern (normal sinus rhythm). Pharmacologic cardioversion, also called chemical cardioversion, used antiarrhythmia medication instead of an electrical shock.
• Number of Cardioversion Attempt of Participants [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  Cardioversion attempts were defined as the number of times the participant was admitted to hospital for the cardioversion procedure and not the number of attempts during a single hospital admission.
• Number of Participants With Their Rhythm Status [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  Rhythm status was further distinguished into sinus rhythm, atrial fibrillation and atrial flutter. Sinus rhythm was defined as a normal heartbeat. Atrial fibrillation was an irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications and atrial flutter was a common abnormal heart rhythm that was usually associated with a fast heart rate (100 or more heart beats per minute).
• Duration of Hospital Stay of Participants [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  Duration of hospital stay was defined as the number of hours from hospital admission to hospital discharge followed by early cardioversion.
• Number of Participants Who Used Image Guidance Approach [ Time Frame: Baseline up to Day of first attempt of cardioversion procedure (Visit 2, up to 130 days) ]
  An image-guided approach helped cardioversion earlier than the conventional minimum of 3 weeks of anticoagulation that would normally be required prior to cardioversion. Transesophageal echocardiography (TEE or TOE) and computed tomography (CT) were 2 image-guided approaches that were used in this study.

Original Secondary Outcome Measures (submitted: March 26, 2014)

• Cardioversion Details [ Time Frame: up to 90 days ]
  The timing, type, and the attempts of cardioversion will be collected.
• Length of in-hospital stay [ Time Frame: Number of hours will be collected from admission for cardioversion to 30 days post cardioversion. ]
  Length of in-hospital stay is defined as the number of hours from hospital admission to hospital discharge for cardioversion. Mean and median duration will be summarized.
• Rhythm status [ Time Frame: Pre & post cardioversion and 30 days post cardioversion ]
  Rhythm status pre- and post cardioversion as recorded by ECG will be collected.

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

Descriptive Information

• Brief Title: Study Of The Blood Thinner, Apixaban, For Patients Who Have An Abnormal Heart Rhythm (Atrial Fibrillation) And Expected To Have Treatment To Put Them Back Into A Normal Heart Rhythm (Cardioversion)
• Official Title: A Phase Iv Trial To Assess The Effectiveness Of Apixaban Compared With Usual Care Anticoagulation In Subjects With Non-valvular Atrial Fibrillation Undergoing Cardioversion
• Brief Summary: Some people can develop an abnormal heart beat known as "Atrial fibrillation" or "AF" that puts them at risk of developing clots in the heart. Those clots can travel in the blood circulation to the brain and cause a brain attack ("a stroke"). To prevent those clots forming, blood thinners (anti-coagulants) are used. Apixaban is a blood thinner that works by stopping one of the blood substances required for clotting ("Factor Xa"). It is approved and used to prevent clots forming in people with "AF". Other established blood thinners work by stopping clotting substances being made, known as "Vitamin K antagonists" or "VKAs". An example of this type is Warfarin (Coumadin). The good effects of all blood thinners are preventing clots, and they may also have bad effects of increasing the chance of bleeding. People with "AF", abnormal heart beat, may benefit from changing it back to a normal regular rhythm, known medically as "cardioversion". When this is done, people are currently most commonly treated with a "VKA" blood thinner (e.g. warfarin). The purpose of this study is to assess the good and bad effects ("efficacy" and "safety") of apixaban compared with warfarin in people with "AF" in whom an early cardioversion is planned.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Supportive Care
• Condition: Atrial Fibrillation

Intervention

• Drug: Apixaban
  Oral, 2.5 or 5 mg BID
• Drug: Parenteral heparin and/or oral Vitamin K antagonist
  Parenteral heparin and/or locally used oral Vitamin K antagonist e.g. warfarin (excludes other novel oral anticoagulants)

Study Arms

• Experimental: Apixaban
  Intervention: Drug: Apixaban
• Active Comparator: Parenteral heparin and/or oral Vitamin K antagonist
  Parenteral heparin and/or locally used oral Vitamin K antagonist e.g. warfarin (excludes other novel oral anticoagulants)
  Intervention: Drug: Parenteral heparin and/or oral Vitamin K antagonist

• Publications *: Ezekowitz MD, Pollack CV Jr, Halperin JL, England RD, VanPelt Nguyen S, Spahr J, Sudworth M, Cater NB, Breazna A, Oldgren J, Kirchhof P. Apixaban compared to heparin/vitamin K antagonist in patients with atrial fibrillation scheduled for cardioversion: the EMANATE trial. Eur Heart J. 2018 Aug 21;39(32):2959-2971. doi: 10.1093/eurheartj/ehy148.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 26, 2014): 1500
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 8, 2017
• Actual Primary Completion Date: February 8, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subjects with non-valvular atrial fibrillation (as documented by electrocardiogram (ECG) at Visit 1) indicated for cardioversion and initiation of anticoagulation in accordance with the approved local label. Subjects presenting with atrial flutter with no evidence of atrial fibrillation are not eligible for enrolment.
• Age ≥18 years (Age ≥ 19 years for Korea only and Age ≥ 20 years for Japan only).
• Evidence of a personally signed and dated informed consent document indicating that the subject (or their legally-recognized representative) has been informed of all pertinent aspects of the study.
• The subject is willing to provide contact details for at least one alternate person for study staff to contact regarding their whereabouts, should the subject be lost-to-follow-up over the course of the study. (Subject to IRB/IEC approval)
• Female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active.
• Subjects who are willing and able to comply with scheduled visits, treatment plan, and other study procedures.

Exclusion Criteria:

• Subjects having taken more than 48 hours of an anticoagulant (oral and/or parenteral) immediately prior to randomization.
• Contraindications to apixaban or usual care (eg, VKA) in accordance with the approved local label.
• Severe haemodynamically compromised subjects requiring emergent cardioversion.
• Patients with hemodynamically significant mitral stenosis, mechanical or biological prosthetic valve or valve repair.
• Conditions other than atrial fibrillation that require chronic anticoagulation (eg, a prosthetic heart valve).
• Simultaneous treatment with both aspirin and a thienopyridine (eg, clopidogrel, ticlopidine, prasugrel) or simultaneous treatment with both aspirin and ticagrelor.
• Pregnant females; breastfeeding females; females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after last dose of investigational product.
• Participation in other studies involving investigational drug(s) (Phases 1-4) within 30 days before the current study begins and/or during study participation. Note: Subjects cannot be randomized into this study more than once.
• Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
• Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are BMS/Pfizer employees directly involved in the conduct of the trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Denmark, Germany, Israel, Italy, Japan, Korea, Republic of, Romania, Spain, Sweden, United States

Administrative Information

• NCT Number: NCT02100228
• Other Study ID Numbers: B0661025; CV185-267 ( Other Identifier: Alias Study Number ); 2014-001231-36 ( EudraCT Number ); EMANATE ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: May 2018