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