Direct oral anticoagulants (DOACs) target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of Alzheimer’s disease (AD). Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood–brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD.
The preferential areas in human AD brain, where vascular Aß deposits and parenchymal Aß dense core plaques are diagnosed, are the neocortex and hippocampus, which are key for higher-order cognition, behavior, and motor skills . The neocortex is involved in brain functions, which include sensory perception, motor commands, cognition and spatial reasoning, social and emotional behavior, memory, as well as learning and language processes. The hippocampus acts as a switchboard between perception and memory . Early in AD, these cerebral areas show the dysfunction and hyperactivity of neurons, which are accompanied by progressing synapse and neuron cell death, closely correlated with the severity of cognitive impairment .
The first clinical studies on anticoagulant medication against dementia in small groups of senile-presenile patients extend far back into the 1960s and resulted in decelerated cognitive decline and reduced morbidity and mortality . In addition, over the last 20 years, multiple observer studies on patients with anticoagulant use due to atrial fibrillation (AF) suggest that oral anticoagulants, particularly DOACs, safeguard against incidence of dementia like AD, as shown in persons without a dementia history before treatment .
The parenteral administration of a drug by injection or infusion directly into the blood stream are less suitable for a permanent therapy from their handling alone. This would be the case when treating parenteral, indirect thrombin-inhibiting heparins (e.g., enoxaparin), heparinoid danaparoid sodium, and fondaparinux or direct thrombin-inhibiting hirudin, bivalirudin, and the synthetic L-arginine derivative argatroban. Heparins, hirudin, and derivatives are usually administered for short-term prophylaxis of thromboembolic events and for therapy of acute venous thrombosis . Undesirable side effects of treatment with heparins are given by abnormally low levels of platelets in the blood (thrombocytopenia) and increased risk of bleeding. In addition, anticoagulation by heparins is unpredictably affected by unspecific plasma protein binding. Furthermore, heparins do not inhibit fibrin-bound thrombin and related thrombus formation . In contrast to heparins, hirudin inactivates thrombin bound to clots and does not directly interact with platelets. However, in therapeutic application, bleeding complications have been frequently observed .
With respect of administration and handling, oral treatment with anticoagulants for therapy would certainly be preferable to a parenteral application, if the efficacy and safety profile of the oral drug is also favorable and the patient can take the medication on a consistent basis. For oral administration, anticoagulants are available on the market from VKA-type, such as warfarin, phenprocoumon, as well as from DOAC-type with the direct thrombin inhibitor dabigatran and the direct FXa inhibitors apixaban, betrixaban, edoxaban, rivaroxaban . Dabigatran, rivaroxaban, and apixaban were approved for antithrombotic use already at the beginning of the 2010s years . Approval of edoxaban and, subsequently, betrixaban was in the second half of the decade . The development of the new class of antithrombotic DOACs that directly target to specific factors in intrinsic coagulation was particularly desired due to serious disadvantages of the conventional VKAs .
Compared to VKAs, DOACs provide constant therapeutic efficacy and a more favorable safety profile, as well as avoidance of adverse effects from vitamin K deficiency due to their different mechanism of action. In detail, the advantages of DOACs include (i) rapid onset of action, (ii) short half-life, (iii) less drug–drug interactions and no dietary interactions, and (iv) safe antidote strategies in situations of bleeding risk. Therefore, the lower intra- and interindividual variability in the DOAC-effect allows fixed dosing and a predictable anticoagulative response without the need for continuous monitoring of the drug level in patients . Since DOACs, especially dabigatran, are eliminated to a large extent via the kidney, the renal function in patients should be routinely monitored, particularly in elderly persons due to increasing renal impairment and associated co-morbidities . In patients with renal impairment, dependent on severity, DOAC use requires dose adjustments or is contraindicated . In addition, DOAC-type anticoagulants also hold the risk of bleeding, particularly of serious intracranial hemorrhage .
In a systematic review and meta-analysis of phase III trials for stroke and systemic embolism prevention in patients with AF (2009–2013), DOACs (apixaban, dabigatran, edoxaban, rivaroxaban) showed a more favorable risk–benefit profile compared with warfarin . In addition, reductions in all-cause mortality and systemic embolic events, these agents reduced the risk of hemorrhagic stroke by 51% and the risk of intracranial hemorrhage by 52% . This favorable efficacy and safety profile was consistent with many subgroups and ethnicities including the Asian population . Conversely, dose-dependently, the risk of gastrointestinal bleeding was 25% higher with DOACs than with warfarin . Similar results were obtained in a large retrospective observational study of ca. 400,000 AF patients, based on US claims data (2013–2015) . Treatment with DOACs (dabigatran, apixaban, rivaroxaban) was associated with lower rates of stroke and systemic embolism, compared with warfarin. In addition, apixaban and dabigatran showed lower rates of major bleeding, including gastrointestinal bleeding, intracranial hemorrhage, and major bleeding at other key sites, whereas rivaroxaban had a higher rate of major bleeding, compared with warfarin . This is in accordance with results from a new-user retrospective cohort study of patients with AF and dementia (2011–2017), comparing DOAC treatment versus warfarin . DOAC-treated patients, who were older and had more comorbidities than the warfarin-treated individuals, showed similar prevention of thromboembolic events, compared to warfarin, but a reduced risk of intracranial bleeding . However, the risk of gastrointestinal bleeding was increased in the DOAC treatment .
Altogether, the wide range of clinical observer studies, conducted in the last 15 years particularly in elderly individuals with AF, demonstrate that DOAC-type anticoagulants exhibit a predictable therapeutic effect in preventing stroke and systemic embolic events. In addition, DOACs show a safety profile that more than halves the risk of dangerous intracranial hemorrhage in elderly people compared to VKAs . These properties, along with their pharmacological advantages, give DOACs a clear preference over VKAs, particularly when anticoagulants are administered to elderly people, who are more vulnerable individuals. In addition, gastrointestinal bleedings, which are more likely to be promoted by DOACs compared to VKAs , can be treated better and stopped immediately after occurrence by effective antidote strategies. These strategies have been successfully developed for various DOACs in the recent years . In the case of dabigatran, the specific antidote idarucizumab (Praxbind®) was introduced in 2016 . This antibody binds to dabigatran with high affinity and leads within minutes to a rapid cancellation of the anticoagulative effect, e.g., in emergency operations or in situations of uncontrollable bleeding . In the case of the FXa inhibitors apixaban and rivaroxaban, andexanet alfa (AndexXa®) was recently approved as a fast-acting antidote . Andexanet alfa is a recombinantly modified, human FXa molecule, which itself has no effect on blood clotting. It acts as a kind of decoy protein that binds the FXa-inhibitors and thus restores blood clotting . Generally, availability of an efficient and fast acting reversal agent should be a prerequisite for a long-term anticoagulative treatment. This is especially the case in elderly and comorbid AD patients, showing inherent bleeding risk due to fragile blood vessels .