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Advanced Neurology Anticoagulants as neuroprotective therapeutics

study of elderly, new-user AF patients (2011 – 2014). driven neuropathogenesis in AD with caution despite
158
The higher risk of bleeding associated with rivaroxaban decades of cardiology experience showing the benefits of
compared to dabigatran may be explained by rivaroxaban’s anticoagulants and evidence of their anti-dementia effects
greater ability to cross the BBB. Physiochemical properties in elderly patients (Section 5.2). The primary concern
159
and pharmacological data suggest that rivaroxaban has the remains the risk of bleeding, especially the risk of severe
highest risk of BBB penetration, followed by apixaban, intracranial hemorrhage during long-term treatment in
edoxaban, and dabigatran, which has the lowest risk. 159 the elderly. 15,16,22-28

The beneficial safety properties of dabigatran were Therefore, a detailed consideration of the pros and
further confirmed in studies using mouse models of AD cons – concerning dosage form, anti-dementia efficacy,
and CAA, where no increase in intracerebral bleeding or bleeding risk, and other potential side effects – is essential
microbleeds was observed even after long-term use. 15,90 for determining the suitability of such therapies and
When evaluating stroke prevention, bleeding risk, and identifying the best drug candidates. Recent review articles
cost-effectiveness of OACs in AF patients, a systematic have also discussed these benefit-risk considerations. 15,16,24
review and meta-analysis concluded that apixaban ranked Parenteral anticoagulants, administered intravenously
160
best for most outcomes. However, this ranking was dose- or subcutaneously, are typically used for short-term
dependent, especially for dabigatran. 16,160 In a 2-year study antithrombotic prophylaxis and acute therapy. 15,28 This
involving approximately 18,000 AF patients, the lowest class includes indirect thrombin inhibitors (e.g., heparin-
rates of life-threatening bleeding, intracranial bleeding, type enoxaparin and fondaparinux) and direct thrombin
and major or minor bleeding were observed with a 110 mg inhibitors (e.g., hirudin, bivalirudin, and argatroban). 15,28
twice-daily dose of dabigatran. These rates increased Although enoxaparin has shown beneficial effects on Aβ
with the 150 mg twice-daily dose of dabigatran and were pathology, inflammation, and cognitive function in AD
highest with warfarin use. As a result, the administration 102,103
161
of lower doses of dabigatran has been proposed to further mice, the long-term use of heparins is limited by several
The limitations of long-term heparin use
side effects.
15,28
improve its safety behavior. 153
include an increased risk of bleeding, thrombocytopenia,
In addition to dabigatran, apixaban is a preferred unpredictable anticoagulation due to non-specific plasma
DOAC, particularly with respect to safety profile. 16,26,160 In a protein binding, and inadequate inhibition of fibrin-bound
double-blind study of AF patients, apixaban was superior to thrombin, which can lead to thrombus formation. 15,28
warfarin in reducing the risk of stroke, systemic embolism,
major bleeding, and mortality. Furthermore, apixaban Natural hirudin, while effective in inhibiting both
162
was associated with lower rates of major bleeding and thrombin and fibrin-bound thrombin without directly
15,109
ischemic stroke in AF patients with dementia compared affecting platelets, is often associated with severe
to other OACs (dabigatran, rivaroxaban, and warfarin). 163 bleeding complications and the development of anti-
hirudin antibodies, which reduce its efficacy and may
Collectively, to minimize safety concerns, particularly cause side effects. 15,109 Collectively, for potential long-term
the risk of intracranial bleeding, dabigatran and apixaban therapy in AD, heparins and hirudin are less suitable due
– followed by edoxaban and rivaroxaban – are promising to their bleeding risk, difficulties in controlling these risks,
DOAC candidates for studying their suitability as disease- and the invasive nature of daily injections.
modifying therapies in AD. 15,16,22-24,26,27 For betrixaban,
which was introduced only a few years ago, clinical data Small-molecule OACs are the preferred alternative to
remain limited. parenteral anticoagulants. This preference is based on the
extensive evidence of OAC efficacy and safety in long-term
5.3. Portfolio of anticoagulants for potential use use, as well as the convenience of oral administration,
provided that adherence to the prescribed regimen is
Anticoagulants have been used for decades in clinical ensured. 15,28,32,34 OACs include VKAs, such as warfarin
practice as life-sustaining, antithrombotic therapies
for millions of elderly individuals, including those and phenprocoumon, which have been in use for decades,
with AD. 15,16,22,28,32-34 Their production, application, and DOACs, which have been introduced in the past
15,28,32,164
pharmacokinetics, efficacy, and safety profiles in daily 15 years. DOACs were specifically developed to
use are well established. Therefore, repurposing current address the significant challenges associated with the non-
anticoagulants as disease-modifying therapies in AD offers specific VKAs.
the potential for a time- and cost-efficient development The limitations of VKAs in stroke prevention are largely
and approval process. However, clinical neurologists often due to their pharmacological properties and variability in
approach the use of anticoagulants in treating vascular- antithrombotic action. The main disadvantages of VKAs

Volume 3 Issue 4 (2024) 22 doi: 10.36922/an.3799