Discussion
As few therapies to halt progression of cognitive decline and dementia
have been ineffective, attention has been turned towards identification
of moderate-high risk patients and early use of potential preventative
treatments.10 In the setting of patients with AF,
rhythm control and early use of anticoagulation are potential means to
reduce the risk of cognitive decline and dementia.19
Before considering the findings of this study of anticoagulation for
patients with AF, it is important to recognize this was a vanguard study
and the event rates were lower than expected. As described above, we
used event rates of prior observational studies to calculate a power to
determine a difference in the primary endpoint. However observational
trials have limitations and as such we prespecified in the protocol that
this would be a vanguard study that would enroll 120 patients to
“determine trends of cognition in the prospective study design that
include incidence of dementia and the percent of patients that develop
moderate decline in each study group to compare amongst the rates
observed in the general population, the feasibility of recruitment,
study design and subject retention, budget adherence and likelihood of
obtaining the desired outcomes for potential future trial design and
planning”. The neutrality of the outcomes and the biomarkers that
showed very similar efficacy of both strategies were considered in the
decision to not move forward with a larger, fully powered study based
upon these randomized prospective data and their event rates.
Nonetheless, the current trial resulted in several key and interesting
observations:
- Anticoagulation use in this prospective randomized trial, whether with
warfarin or dabigatran was associated with very low dementia and
stroke rates. These findings with contemporary management for other
associated cardiovascular disease states suggest that a trial to
detect any differences would need to be much larger and likely require
an extended follow-up period beyond 2 years.
- Serial cognitive testing results after anticoagulation initiation in
did not demonstrate cognitive decline and trended towards modest
improvement. We hypothesized that the generalized cognitive scoring
improvement may reflect recall bias from serial
testing20, improved follow-up and management, and
perhaps influence of the anticoagulant as it related to brain
perfusion with a reduction in risk of ischemic brain injury over time.
- Anticoagulation use in patients results in a durable reduction of
thrombotic and ischemic biomarkers that have been shown, when
elevated, to be associated with the risk of stroke and vascular
injury. However, similar to many trials of anticoagulation and
population-based studies of anticoagulation use, long-term use and
compliance remains a challenge.5-7 In this study
approximately 1/3 discontinued their anticoagulation for a variety of
reasons. Underuse has clearly been shown to increase risk of stroke.
In this analysis, those at discontinued therapy also impacted our
ability to study both therapies as to how they relate to
anticoagulation.21
- Stroke, dementia, and cognitive outcomes were similar with both
routine start prescription of dabigatran or CPAS-directed warfarin
anticoagulation in patients with AF at 2 years.
We observed a lower rate of moderate-severe cognitive decline and
dementia than expected based on findings from a routine population of
patients with AF treated with warfarin.22 These lower
rates may be from early and effective use of anticoagulation after AF
diagnosis that has been shown to lower dementia risk as this trial
involved all patients referred for AF management that included a goal of
anticoagulation initiation.23 It is also possible that
the relatively small patient population, with approximately 1/3
discontinuing anticoagulation, rendered the trial unable to detect a
true incidence within the defined study follow-up period. Finally, in a
prospective, randomized trial with frequent follow-up visits the
outcomes may be different due to more frequent assessment of drug
efficacy, identification and management of risk factors for AF-related
comorbidities, more close management of anticoagulation, and selection
bias that occurs in patients that are willing to enroll in these types
of studies.
These data are complementary to those recently presented from the GIRAF
(CoGnitive Impairment Related to Atrial Fibrillation) trial which was a
two-year randomized, multi-center, prospective trial in Brazil that
evaluated the effects of dabigatran and warfarin on cognitive and
functional impairment, bleeding, and cerebrovascular complications in
patients (>70 years of age) with atrial
fibrillation.24 In this trial, patients underwent
90-minute cognitive and functional evaluations at the one-year and
two-year follow-up visits as well as MRI brain imaging. At the
conclusion of the trial, there were no patients that developed dementia
and cognitive scoring assessments were identical in both treatment
groups (<1 point difference). The study investigators
concluded, similar to our study, that either strategy was acceptable as
means to treat patients with AF to lower stroke risk and that neither
can be used to preferentially impact risk of cognitive decline. These
data combined with ours now comprise over 250 patients with serial
testing of cognition after anticoagulation initiation with either
dabigatran or warfarin.
Our data provide some additional mechanistic understanding into the
equivalent outcomes when the biomarkers are considered. In our analysis,
multiple markers of vascular injury, thrombosis, and inflammation were
similar throughout the study in both treatment groups. This would
suggest that both anticoagulation strategies were highly effective at
the primary goal of reducing risk of micro and macro thromboembolism
with reasonable safety of use. These data also support very well managed
patients on warfarin anticoagulation. Highly effective warfarin can be
accomplished in centers such as ours that use a dedicated
\community pharmacy anticoagulation service (CPAS)
guidance and administration; however in the general community both
general warfarin use and compliance to DOAC therapies can be less
optimal and the result in higher rates of brain
injury.25, 26 In this community setting of less
efficacy, a drug with a larger therapeutic window compared to warfarin
may improve outcomes that were explored in this analysis.
The study has several limitations. First, this was a vanguard analysis
and as such was underpowered to detect a significant difference in the
endpoints considered in this analysis. This study design was pursued to
inform on a subsequent study design, however the lack of any signal of
difference and nearly equivalent outcomes between anticoagulation
strategies in this analysis did not affirm a decision to perform a
larger study; as such there was value in this study design and the
results. Next, common to all anticoagulation studies, long-term
adherence was suboptimal and reflects many decisions including a desire
to not use anticoagulation therapy in general. In a recent
community-based trial of predictors of contemporary oral anticoagulants
use and adherence, persistence use at 2 years was approximately 80% and
continued to steadily decline to approximately 70% at 4 years. In this
analysis, lack of adherence significantly correlated with higher rates
of stroke and stroke-related mortality.21 Finally,
patients were enrolled that were willing and able to complete the
battery of cognitive tests. This may have selected a patient population
that would perform better on these tests compared to a general
population and long-term results as well can be influenced by sequential
testing and learned responses.