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Advanced Neurology Anticoagulants as neuroprotective therapeutics

The varying results in relation to the anti-dementia clinical investigation in the form of randomized, placebo-
efficacy of VKAs versus DOACs may be partly attributed controlled, double-blind trials has been recommended
to methodological differences between studies, such as to evaluate the potential of OACs as a novel disease-
variations in the age range of participants, small sample modifying therapy in AD. 15,16,22-24,26,27
sizes, short follow-up durations, and differing criteria for
diagnosing dementia. 16,137,138,143 5.2.2. Reduced risk of intracranial bleeding in DOAC
use
At first glance, the beneficial effects of OACs on
cognitive health in AF patients might be simplistically In patients with AF, the use of DOACs has been shown
attributed to the reduction in stroke incidence. However, to significantly reduce the risk of severe intracranial
substantial meta-analyses of observational studies hemorrhage compared to VKAs. For instance, a meta-
have revealed a link between AF and dementia that is analysis of phase III clinical studies (2009 – 2013) revealed
independent of a history of clinical stroke. 150,151 Mechanisms that DOACs (apixaban, dabigatran, edoxaban, and
such as brain hypoperfusion, recurrent silent ischemia, rivaroxaban) were associated with a 52% lower risk of
microhemorrhage, inflammation, and genetic factors have intracranial hemorrhage compared to warfarin (HR = 0.48;
153
been proposed as underlying contributors. 151 95% CI = 0.39 – 0.59; P < 0.0001). In addition, a significant
decrease in thromboembolic events and all-cause
Moreover, as previously discussed, recent observational mortality was observed with DOAC use. However, the risk
studies have evidenced that OAC treatment can significantly of gastrointestinal bleeding increased by 25% (HR = 1.25;
lower the risk of dementia, including AD. 104,124-149 This 95% CI = 1.01 – 1.55; P = 0.04), depending on the dose
result is not surprising, as OACs directly or indirectly of DOACs used. These results are consistent with those
153
inhibit thrombin, thereby normalizing thrombin- of a large US retrospective observational study (2013 –
mediated procoagulant and proinflammatory states in AD 2015), as well as a cohort study of new AF patients with
154
(Figure 2). Consequently, inflammatory and thrombotic dementia (2011 – 2017). In addition, a recent systematic
155
events in the cerebral vasculature can be prevented. This review and meta-analysis assessed the overall impact of
preservation of vascular and BBB integrity, CBF, brain DOACs versus VKAs in AF patients over the age of 80.
156
perfusion, nutrient supply, and neuronal and cognitive In the DOAC group, lower all-cause mortality and a 43%
function is likely the primary reason for the anti-dementia reduction in intracranial bleeding were reported compared
effects of OACs (Figure 2). When evaluating the efficacy of to warfarin (relative risk = 0.47; 95% CI = 0.36 – 0.60;
different OAC types in reducing dementia incidence in AF P < 0.001), suggesting that DOACs represent a safe and
patients, DOACs were typically associated with the greatest effective therapy for elderly patients. 156
cognitive benefit, followed by VKAs, and then antiplatelet
therapy. 15,16,127,129,134-146 A recent comprehensive literature When examining the effect of individual DOACs,
review, which included experimental studies and meta- dabigatran appears to lower the risk of intracranial
analyses, confirmed these findings, although antiplatelet bleeding the most compared to warfarin, followed by the
24
therapy offered less benefit. Few studies have made FXa inhibitors apixaban, edoxaban, and rivaroxaban. In a
152
precise distinctions between different dementia subtypes, retrospective FDA study involving approximately 134,000
such as AD, vascular dementia, and other/unspecified AF patients over 65 years old (2010 – 2012), dabigatran
dementia. 127,128,129,137,139,143,148 Most studies reported OAC reduced the incidence of severe intracranial hemorrhage
effects on composite dementia. 104,124,126,131-136,138,140-142,144-147,149 by 66%, from 9.6 cases per 1000 person-year with warfarin
to 3.3 cases with dabigatran (HR = 0.34; 95% CI = 0.26
In summary, small-molecule OACs, particularly 157
DOACs, are effective drugs against dementia, including – 0.46; 186 vs. 60 events). Furthermore, dabigatran was
AD, in AF patients. 104,124,125-149,152 Cognitive benefits associated with a 14% reduction in mortality risk (HR =
have been particularly observed in elderly patients over 0.86; 95% CI = 0.77 – 0.96) and a 20% reduction in ischemic
stroke risk (HR = 0.80; 95% CI = 0.67 – 0.96). However, the
65 years of age, irrespective of their dementia or stroke risk of major gastrointestinal bleeding increased by 28%
history. 104,126,128,137 This applies to both low-risk AF and (HR = 1.28; 95% CI = 1.14 – 1.44). 157
newly diagnosed AF individuals. 126,143 As a result, it has
been hypothesized that anti-dementia benefits could In addition, dabigatran demonstrated long-term safety
be achieved if OACs are administered not only for AF and efficacy in elderly AF patients over a 30-month study.
129
or other cardiovascular diseases but also as disease- Compared to rivaroxaban, dabigatran appeared to have a
modifying therapy in AD. 15,16,22-24,26,27 Despite positive data more favorable safety profile regarding both intracranial
from recent global clinical observations, the approval of and extracranial hemorrhage, including gastrointestinal
OACs for use in AD remains pending. Therefore, detailed bleeding. This conclusion was drawn from a retrospective

Volume 3 Issue 4 (2024) 21 doi: 10.36922/an.3799