Study Objectives and Design

This was a randomized, prospective, open-label clinical study with blinded endpoint assessment. The methodology and design have been published elsewhere.11 Patients (>65 years) with moderate- to high-risk (defined as a CHADS2 score or CHA2DS2-Vasc score of ≥2)12 non-valvular AF were randomly assigned to standard dosing dabigatran etexilate or warfarin, adjusted to a target INR of 2.0-3.0 were enrolled from March 30, 2017 to March 25, 2019.
The primary functional endpoint of this study was to demonstrate whether long-term anticoagulation therapy with dabigatran etexilate (150 mg BID or 75 mg BID, dose based upon renal clearance) would reduce incident dementia and worsening cognitive decline compared to dose-adjusted warfarin. Incident dementia was defined as a formal diagnosis of dementia by a neurologist. Subjects that scored <24 upon completing the mini-mental status evaluation (MMSE) and reported memory loss affecting quality of life were referred to neurology for further evaluation of dementia. Cognitive decline was determined by measuring the change from baseline to study conclusion on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS, 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% was considered significant for moderate cognitive decline. In subjects that scored <50% on the DAD, there was a direct correlation with global deterioration scales and scores. Subjects with a 30% decrease in DAD score or those with a score <50% were considered to have moderate cognitive decline. Secondary endpoints included new stroke (clinical or subclinical) or transient ischemic attack (TIA) and intracranial bleed.
We previously published the power analysis based upon background community work to detect a difference in the primary endpoint of 1,100 study participants.13In regard to the enrollment need and uncertainty regarding the true impact of different anticoagulants on cognitive performance in patients with AF, we first chose to enroll 120 subjects using a vanguard study design. This number of subjects was chosen to provide a more precise understanding of the incidence of both dementia and moderate cognitive decline in each anticoagulation group. The data derived from the vanguard analysis informed the primary endpoint analysis and optimization of study sample size as well as decision making regarding enrollment, retention, and study feasibility.
The was a single center trial that was conducted at Intermountain Medical Center in Murray, Utah approved by the Intermountain Heart Scientific Review Board and the Internal Review Board. A data safety monitoring board was created and reviewed patient events and study progress at predetermined intervals.

Subject Selection Criteria

All patients had to be able to take oral anticoagulation, complete serial testing of cognition and functional status, and have a moderate risk of stroke at enrollment (CHADS2 score or CHA2DS2-Vasc score of ≥2). Patients were excluded if they did not meet inclusion criteria, had severe renal dysfunction (CrCl <15 mL/min) that impaired use of dabigatran anticoagulation, or had a diagnosis of dementia.
Time and Events Schedule
Subject medical records were collected as part of usual medical care prior to enrollment to obtain baseline demographics for the 6 months preceding randomization. The six cognitive and clinical assessment questionnaires were administered at the baseline visit, and repeated at the 6-, 12-, 18- and 24-month visits were the Mini-Mental Status Evaluation (MMSE), Hachinski Ischemic scale (HIS), cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS), Disability Assessment for Dementia (DAD), Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti-Clot Treatment Scale Quality of Life Survey. All testing was performed by experienced research coordinators that received institutional assessment and certification regarding education, efficacy and consistency before they begin to administer the tools.
In each group, 10 subjects were selected to undergo a cranial MRI at baseline to determine brain volume and characteristic changes representative of microbleeding, with a repeat MRI at 24 months. These subjects were selected at time of enrollment until all slots have been filled (i.e., first 10 subjects in each treatment arm who are willing and able to undergo the procedure). Brain volume was defined as per routine description.19-21