Atrial Fibrillation, Stroke, Transient Ischemic Attack
Conditions
Brief summary
The purpose of this study is to evaluate if Apixaban will decrease the complication of having another stroke for people who have atrial fibrillation if initiated earlier than standard of care.
Detailed description
This is an Open label, randomized, active control, parallel-group pilot trial to examine the effect of initiation of APIXABAN at days 0-3 (TIA), days 3-5 (small stroke) and days 7-9 (medium stroke) to decrease fatal and/or recurrent stroke/TIA in 120 subjects who have suffered a recent( 0 to 48 hours from symptoms) TIA, or small to medium ischemic stroke compared to standard of care warfarin treatment regimen. Subjects will be randomly assigned in a 1:1 ratio to one of two treatment arms (apixaban or warfarin). Subjects will be followed for a total of 180 days during from screening through monthly follow-up visits.
Interventions
DRUGApixaban
DRUGWarfarin
Sponsors
Bristol-Myers Squibb
University of South Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed Written Informed Consent 2. Males and Females over 18 years of age. 3. History of Nonvalvular Atrial Fibrillation (NVAF) by documentation in the medical history or newly diagnosed nonvalvular Atrial Fibrillation at time of study randomization by ECG, device or telemetry . 4. Diagnosis of TIA or small or medium ischemic stroke 0 to 48 hours from signs or symptoms. 5. Women of child-bearing potential must use a reliable method of contraception and must provide a negative pregnancy test at entry into the study and within 24 hours of study treatment initiation. 6. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Apixaban plus 5 half-lives (approximately 3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion. 7. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with Apixaban plus 5 half-lives (approximately 3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion. 8. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly. At a minimum, subjects must agree to the use of one method of highly effective contraception as listed below: HIGHLY EFFECTIVE METHODS OF CONTRACEPTION * Male condoms with spermicide * Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug * IUDs, such as ParaGard™ * Tubal ligation * Vasectomy. * Complete Abstinence
Exclusion criteria
1. Hemorrhagic stroke 2. Large ischemic stroke 3. History of major bleeding within the last 6 months from time of subject enrollment (e.g. GI bleed). 4. History of intracranial bleed a. Traumatic intracranial bleed within one year of randomization. (Traumatic ICH greater than one year of randomization is not an exclusion). 5. Current or history of bleeding disorders (e.g. blood dycrasias) 6. Blood Pressure of 180/100 mmHg on hypertensive therapy day of randomization per PI discretion 20. 7. Current illicit drug use and/or chronic alcohol use per PI discretion. 8. Severe liver disease (AST/ALT 2x upper limit). 9. Patients with kidney disease meeting criteria to take 2.5 mg twice daily who are taking strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin) . 10. Any other suspected etiology for stroke (e.g. ipsilateral carotid disease). 11. Greater than 3 Cerebral Micro-bleeds (CMB) on gradient recovery echo (GRE) or evidence of intracranial hemorrhage on CT at time of randomization. (SWI sequencing may be used if GRE sequencing is not obtainable) 12. Therapeutically anti-coagulated at time of admission (INR at admission greater than 2.0 on warfarin or took two consecutive doses of NOAC). 13. Absolute indication for use of warfarin only.( e.g. Mechanical Valve) 14. Absolute indication for anticoagulation prior to randomization window. (e.g. DVT) 15. Hemoglobin less than 9 gm/dl and/or platelet count less than 100 K/uL. 16. Requires dual antiplatelet therapy. 17. Daily use of NSAIDS 18. Pregnancy or lactation. 19. Any use of an investigational product within the past 30 days. 20. Prisoners or subjects who are involuntarily incarcerated. 21. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness. 22. Concurrent participation in another clinical study where use of an investigational product is used
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With a Composite Endpoint of Fatal Stroke, Recurrent Ischemic Stroke, or TIA | 180 days |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With an Intracranial Hemorrhage Assessed by MRI/CT | 180 days |
Countries
United States
Participant flow
Pre-assignment details
Ninety one patients were enrolled/consented into the study. Three patients of the 91 consented did not meet one or more of the inclusion/exclusion criteria and were excluded prior to randomization assignment.
Participants by arm
| Arm | Count |
|---|---|
| Apixaban Apixaban twice a day for 180 days with drug initiation day 0-3 (TIA), day 3-5(small stroke) or day 7- 9 (medium stroke) respectively
Apixaban | 41 |
| Warfarin standard of care warfarin starting at day 7±5 (TIA) or day 14 ±5 (small to medium ischemic stroke).
Warfarin | 47 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Thrombus on transesophageal echocardiogram | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Total | Warfarin | Apixaban |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 63 Participants | 35 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 12 Participants | 13 Participants |
| Age, Continuous | 73.5 years STANDARD_DEVIATION 12.7 | 74.3 years STANDARD_DEVIATION 10.5 | 72.6 years STANDARD_DEVIATION 14.9 |
| Body Mass Index | 29.63 kg/m^2 STANDARD_DEVIATION 7.16 | 30.05 kg/m^2 STANDARD_DEVIATION 7.6 | 29.15 kg/m^2 STANDARD_DEVIATION 6.68 |
| Body Surface Area | 1.95 m^2 STANDARD_DEVIATION 0.3 | 1.99 m^2 STANDARD_DEVIATION 0.31 | 1.90 m^2 STANDARD_DEVIATION 0.28 |
| Chronic Kidney Disease Stage 3 | 22 Participants | 15 Participants | 7 Participants |
| Chronic Kidney Disease Stage 4 | 3 Participants | 2 Participants | 1 Participants |
| Chronic Kidney Disease Stage 5 | 0 Participants | 0 Participants | 0 Participants |
| Congestive Heart Failure Symptoms | 12 Participants | 9 Participants | 3 Participants |
| Coronary artery disease (CAD) | 31 Participants | 18 Participants | 13 Participants |
| Current Alcohol Use | 12 Participants | 6 Participants | 6 Participants |
| Current Tobacco Use | 4 Participants | 4 Participants | 0 Participants |
| Diabetes Mellitus | 32 Participants | 22 Participants | 10 Participants |
| Diastolic Blood Pressure | 72.03 mmHg STANDARD_DEVIATION 18.7 | 70.26 mmHg STANDARD_DEVIATION 19.5 | 74.07 mmHg STANDARD_DEVIATION 17.76 |
| Former Alcohol Use History | 3 Participants | 2 Participants | 1 Participants |
| Former Illegal Drug Use History | 2 Participants | 1 Participants | 1 Participants |
| Former Tobacco Use History | 23 Participants | 13 Participants | 10 Participants |
| Heart Rate | 76.60 bpm STANDARD_DEVIATION 15.56 | 76.62 bpm STANDARD_DEVIATION 16.61 | 76.56 bpm STANDARD_DEVIATION 14.46 |
| Height | 1.69 m STANDARD_DEVIATION 0.13 | 1.712 m STANDARD_DEVIATION 0.14 | 1.67 m STANDARD_DEVIATION 0.11 |
| Hyperlipidemia | 58 Participants | 34 Participants | 24 Participants |
| Hypertension | 84 Participants | 46 Participants | 38 Participants |
| New Onset Atrial Fibrillation | 28 Participants | 14 Participants | 14 Participants |
| Obstructive Sleep Apnea | 12 Participants | 7 Participants | 5 Participants |
| Occasional Alcohol Use | 17 Participants | 8 Participants | 9 Participants |
| Occasional Tobacco Use | 0 Participants | 0 Participants | 0 Participants |
| Past Medical History Left Ventricular Ejection Fraction < 40% | 19 Participants | 13 Participants | 6 Participants |
| Peripheral Artery Disease | 13 Participants | 9 Participants | 4 Participants |
| Prior Stroke | 19 Participants | 10 Participants | 9 Participants |
| Prior Use of Anticoagulation within last 3 months | 14 Participants | 11 Participants | 3 Participants |
| Prosthetic Heart Valve / Valve Replacement | 5 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 12 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic | 9 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 66 Participants | 35 Participants | 31 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment United States | 88 participants | 47 participants | 41 participants |
| Sex: Female, Male Female | 49 Participants | 23 Participants | 26 Participants |
| Sex: Female, Male Male | 39 Participants | 24 Participants | 15 Participants |
| Systolic Blood Pressure | 132.82 mmHg STANDARD_DEVIATION 19.43 | 134.53 mmHg STANDARD_DEVIATION 20.13 | 130.85 mmHg STANDARD_DEVIATION 18.64 |
| Thromboembolism History | 3 Participants | 3 Participants | 0 Participants |
| Thyroid Disease | 22 Participants | 13 Participants | 9 Participants |
| Transient Ischemic Attack | 7 Participants | 3 Participants | 4 Participants |
| Weight | 85.29 kg STANDARD_DEVIATION 24.48 | 88.08 kg STANDARD_DEVIATION 24.73 | 82.10 kg STANDARD_DEVIATION 24.09 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 41 | 4 / 47 |
| other Total, other adverse events | 36 / 41 | 41 / 47 |
| serious Total, serious adverse events | 11 / 41 | 14 / 47 |
Outcome results
Primary
Number of Participants With a Composite Endpoint of Fatal Stroke, Recurrent Ischemic Stroke, or TIA
Time frame: 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants With a Composite Endpoint of Fatal Stroke, Recurrent Ischemic Stroke, or TIA | 7 Participants |
| Warfarin | Number of Participants With a Composite Endpoint of Fatal Stroke, Recurrent Ischemic Stroke, or TIA | 12 Participants |
Secondary
Number of Participants With an Intracranial Hemorrhage Assessed by MRI/CT
Time frame: 180 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Apixaban | Number of Participants With an Intracranial Hemorrhage Assessed by MRI/CT | 5 Participants |
| Warfarin | Number of Participants With an Intracranial Hemorrhage Assessed by MRI/CT | 6 Participants |