Cerebral Ischemic Events, Cognition Disorders, Dementia
Conditions
Brief summary
Patients will be screened at Intermountain Medical Center and at Intermountain-affiliated anticoagulation clinics in the Salt Lake City region. Patients with non-valvular atrial fibrillation will be considered for study. After written informed consent is obtained, subjects who meet eligibility criteria will be randomized 1:1 to 2 treatment arms: Group 1: Dabigatran etexilate (150 mg BID if CrCL \> 30 mL/min, or 75 mg BID if CrCL \> 15 to 30 mL/min or per USPI; and Group 2: Warfarin (Dose-adjusted (INR 2.0 - 3.0). Assessment of kidney function every 6 months will be done for Group 1. Standard warfarin follow-up and education, based upon system criteria, will be done for Group 2. All subjects will be followed for 24 months, and will be assessed at 1-week, then 3-, 6-, 12-, 18- and 24-months post-anticoagulation visits as well as other visits deem necessary for clinical care. All subjects will undergo protocol-specified laboratory tests and will complete 6 standard, validated questionnaires at each follow-up visit following the week 1 visit, except at the 3-month visit when only one questionnaire will be administered. To determine brain volume and characteristic changes representative of micro-bleeding, the first 10 subjects in each treatment group who are willing and able to undergo the procedure will participate in a MRI sub-study. The cranial MRI will be done at baseline and at 24-months post-anticoagulation on this sub-group.
Interventions
DRUGDabigatran Etexilate
150 mg BID (CrCL \> 30 mL/min) or 75 mg BID (CrCL \> 15 to 30 mL/min); Assessment of kidney function every 6 months.
DRUGWarfarin
Dose-adjusted (INR 2.0 - 3.0); Standard warfarin follow-up and education based upon system criteria.
Sponsors
Intermountain Health Care, Inc.
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female \>65 years of age. 2. Non-valvular atrial fibrillation documented by electrocardiogram, ambulatory event monitor, or telemetry within 12 months of enrollment. 3. Moderate risk of thromboembolism based upon a CHADS score or CHADS2 Vasc score of ≥2. 4. Ability to complete a mini-mental status evaluation. 5. Ability to independently comprehend and complete a quality of life and dementia questionnaires. 6. Ability to provide informed consent for study participation. 7. Willing and able to comply with the prescribed follow-up tests and schedule of evaluations.
Exclusion criteria
1. Inability to take an anticoagulant due to known or perceived bleeding risk. 2. Known coagulopathy that may impact the choice, duration, efficacy and safety of anticoagulation therapy. 3. Atrial Fibrillation in the setting of valvular heart disease. Valvular heart disease defined as any surgical valve, mitral stenosis, or moderate-severe valvular heart disease. 4. Severe renal dysfunction, defined as a creatinine clearance rate \<15 mL/min (documented within the last 3 months). 5. History of any form of dementia. 6. A life expectancy less than 24 months. 7. Inability to comply with the follow-up schedule. 8. Current participation in a clinical investigation that includes an active pharmacologic treatment arm. 9. An upper age limit not to be used if participation inclusion criteria are met. 10. Participation in any other clinical trials involving investigational or marketed products within 30 days prior to entry in the study. 11. Other conditions that in the opinion of the Principal Investigator(s) may increase risk to the subject and/or compromise the quality of the clinical trial. 12. Concurrent pharmacologic treatment that is required to treat a condition long-term in which concurrent use of dabigatran etexilate is contraindicated. 13. Treatment with any anticoagulant drug for stroke prevention for more than 30 days. * Aspirin and P2Y12 inhibitors (e.g. clopidogrel (Plavix), or prasugrel (Effient)) are not considered anticoagulant drugs. * If the subject has received any anticoagulant drug for stroke prevention for less than 30 days, the Principal Investigator(s) or a Co-Investigator will decide whether or not the subject is eligible for this study 14. The Principal Investigator(s) determine(s) that the subject is not eligible for participation in this research study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Incident Dementia Determined by a Formal Diagnosis of Dementia by a Neurologist | 24 months | Incident dementia will be determined by a formal diagnosis of dementia by a neurologist |
| Number of Participants With Moderate Decline in Cognitive Function Based on Results of the Alzheimer's Disease Assessment Scale and the Disability Assessment for Dementia. | 24 months | Determined by measuring the change from baseline to study conclusion on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70, and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100, and higher scores indicating less impairment). An increase in ADAS-cog11 of \>30% is considered significant for moderate cognitive decline. In subjects that score \<50% on the DAD, there is a direct correlation with global deterioration scales and scores. Subjects with a 30% decrease in DAD score or those with a score \<50% will be considered to have moderate cognitive decline. These scores will be aggregated and if a patient meets either one of the cognitive decline definitions they will be deemed positive for cognitive impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Stroke or Transient Ischemic Attack (TIA) or Intracranial Bleed | 24 months | — |
| Percent Change From Baseline in Mini-Mental State Examination Scores. | 24 months | The Mini-Mental State Examination (MMSE) is commonly used to measure cognitive change over time. Scores on the MMSE range from 0 to 30. Any score of 24 or more indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment. We measured the percent change from baseline scores. |
| Changes From Baseline Scores on the Hachinski Ischemic Scale | 24 months | The Hachinski Ischemic Scale (HIS) is commonly used clinical tool to differentiate between different types of dementia. Scores on the HIS range from 0 to 18. A score of less than 4 suggests primary dementia. A score of 4-7 is indeterminate. A score more than 7 suggests vascular dementia. We measured percentage change from baseline scores on the HIS. |
Countries
United States
Participant flow
Recruitment details
Enrolled from March 30, 2017 to March 25, 2019
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 73.7 Years STANDARD_DEVIATION 6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment United States | 51 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 50 | 1 / 51 |
| other Total, other adverse events | 21 / 50 | 21 / 51 |
| serious Total, serious adverse events | 12 / 50 | 23 / 51 |
Outcome results
None listed