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)

A Phase Iv Trial To Assess The Effectiveness Of Apixaban Compared With Usual Care Anticoagulation In Subjects With Non-valvular Atrial Fibrillation Undergoing Cardioversion

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02100228

Acronym

EMANATE

Enrollment

1500

Registered

2014-03-31

Start date

2014-07-14

Completion date

2017-02-08

Last updated

2018-05-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Atrial Fibrillation

Keywords

apixaban, oral anticoagulant, non-valvular atrial fibrillation, 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.

Interventions

DRUGApixaban

Oral, 2.5 or 5 mg BID

DRUGParenteral 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 design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

SUPPORTIVE_CARE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Acute Stroke Event	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	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	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	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	Baseline up to 30 days post cardioversion (or up to 90 days after randomization, if cardioversion was not performed within that time frame)	—

Secondary

Measure	Time frame	Description
Time to First Attempt of Cardioversion	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 Who Used Image Guidance Approach	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.
Number of Participants With Different Type of Cardioversion Events	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	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	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	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.

Countries

Belgium, Canada, Denmark, Germany, Israel, Italy, Japan, Romania, South Korea, Spain, Sweden, United States

Participant flow

Participants by arm

Arm	Count
Apixaban Participants with non-valvular atrial fibrillation undergoing cardioversion, received Apixaban orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of Apixaban was based on investigator's judgement as per local label for the prevention of stroke and systemic embolism in participants.	753
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care) Participants with non-valvular atrial fibrillation undergoing cardioversion, received parenteral heparin and/or oral Vitamin K antagonist as usual care, orally for 30 days after cardioversion or 90 days after randomization if cardioversion was not performed. The dosing of the parenteral heparin and Vitamin K antagonist was based on individual participant's sensitivity to the drug according to the investigators usual practice.	747
Total	1,500

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Administrative reason	0	1
Overall Study	Adverse Event	16	12
Overall Study	Death	1	1
Overall Study	Inclusion/Exclusion criteria not met	12	16
Overall Study	Lost to Follow-up	0	1
Overall Study	Non-compliance	0	3
Overall Study	Other	19	19
Overall Study	Withdrawal by Subject	27	37

Baseline characteristics

Characteristic	Apixaban	Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Total
Age, Continuous	64.7 years STANDARD_DEVIATION 12.19	64.5 years STANDARD_DEVIATION 12.76	64.6 years STANDARD_DEVIATION 12.47
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	9 Participants	17 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	100 Participants	99 Participants	199 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	645 Participants	639 Participants	1284 Participants
Race/Ethnicity, Customized Asian	78 Participants	76 Participants	154 Participants
Race/Ethnicity, Customized Black or African American	21 Participants	20 Participants	41 Participants
Race/Ethnicity, Customized Other	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized White	654 Participants	648 Participants	1302 Participants
Sex: Female, Male Female	248 Participants	250 Participants	498 Participants
Sex: Female, Male Male	505 Participants	497 Participants	1002 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 735	3 / 721
other Total, other adverse events	70 / 735	101 / 721
serious Total, serious adverse events	100 / 735	112 / 721

Outcome results

Primary

Number of Participants With Acute Stroke Event

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).

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)

Population: Full analysis set included all randomized participants.

Arm	Measure	Value (NUMBER)
Apixaban	Number of Participants With Acute Stroke Event	0 participants
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Number of Participants With Acute Stroke Event	6 participants

Comparison: Display exact confidence limits for relative risk and Fisher's exact test for comparisons of two proportions.p-value: 0.015195% CI: [0, 0.6425]Fisher Exact

Primary

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)

Population: Full analysis set included all randomized participants.

Arm	Measure	Value (NUMBER)
Apixaban	Number of Participants With All Cause Death	2 participants
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Number of Participants With All Cause Death	1 participants

Comparison: Display exact confidence limits for relative risk and Fisher's exact test for comparisons of two proportions.p-value: >0.999995% CI: [0.1866, 53.9968]Fisher Exact

Primary

Number of Participants With Clinically Relevant Non-Major Bleeding Events

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.

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)

Population: Safety data set included all treated participants (randomized participants who received at least one dose of study drug).

Arm	Measure	Value (NUMBER)
Apixaban	Number of Participants With Clinically Relevant Non-Major Bleeding Events	11 participants
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Number of Participants With Clinically Relevant Non-Major Bleeding Events	13 participants

Comparison: Display exact confidence limits for relative risk and Fisher's exact test for comparisons of two proportions.p-value: 0.685195% CI: [0.3433, 1.8916]Fisher Exact

Primary

Number of Participants With Major Bleeding Event

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.

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)

Population: Safety data set included all treated participants (randomized participants who received at least one dose of study drug).

Arm	Measure	Value (NUMBER)
Apixaban	Number of Participants With Major Bleeding Event	3 participants
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Number of Participants With Major Bleeding Event	6 participants

Comparison: Display exact confidence limits for relative risk and Fisher's exact test for comparisons of two proportions.p-value: 0.337895% CI: [0.1046, 2.0678]Fisher Exact

Primary

Number of Participants With Systemic Embolism Event

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.

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)

Population: Full analysis set included all randomized participants.

Arm	Measure	Value (NUMBER)
Apixaban	Number of Participants With Systemic Embolism Event	0 participants
Parenteral Heparin/Oral Vitamin K Antagonist (Usual Care)	Number of Participants With Systemic Embolism Event	0 participants

Secondary

Duration of Hospital Stay of Participants

Duration of hospital stay was defined as the number of hours from hospital admission to hospital discharge followed by early cardioversion.