Effects of Dabigatran on Dementia Pathogenesis and Neuropsychological Function: A Review

Abstract

Background:

Patients with atrial fibrillation (AF) carry higher risks of cognitive consequences and psychological burden. An optimal anticoagulant therapy would be expected to better preserve neuropsychological function in addition to effective prevention of stroke and systemic thromboembolism.

Objective:

The aim of this review is to explore the effects of the non-vitamin K antagonist oral anticoagulant (NOAC) dabigatran, a direct thrombin inhibitor, on cognitive and psychological function as well as dementia pathogenesis.

Methods:

We performed a comprehensive search of PubMed/Medline for all types of relevant articles using a combination of dabigatran and associated keywords updated to August 31, 2021. All titles and abstracts were screened for eligibility, and potentially relevant papers were collected for inclusion.

Results:

The pooled results demonstrated neutral to positive impacts of dabigatran on cognitive and psychological outcomes, including laboratory results in animal models of Alzheimer’s disease, and reduced incidences of anxiety/depression and dementia for AF patients. Dabigatran also exhibited better therapeutic profiles than warfarin in preclinical and observational research.

Conclusion:

Given limited strength of evidence from heterogeneous studies, our review proposed modest beneficial effects of dabigatran on neuropsychological function. Further clinical trials are warranted to affirm the pleiotropic protective effects of NOACs on dementia treatment.

Keywords

Anticoagulant atrial fibrillation cognitive dabigatran dementia psychological function

INTRODUCTION

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia which has a major disease burden in the aging population worldwide. AF is a well-known significant risk factor for heart failure, myocardial infarction, and mortality, and is associated with a four- to five-fold risk of ischemic stroke [1, 2]. Furthermore, concern has been raised on causative adverse effects of AF on cognitive decline and dementia, independent of stroke [3]. In a small matched-control study, AF was found to be related to subclinical but significant neuropsychological impairment, especially in attention and memory function, in patients without known cerebrovascular disease [4]. Although detailed mechanisms involved in the association between AF and cognitive decline have not been fully investigated, therapies including catheter ablation and anticoagulation have shown to potentially reduce the risk of deterioration of cognitive function [5 –7].

Alzheimer’s disease (AD) is a devastating neurodegenerative disease which still lacks disease-modifying therapies despite intense research efforts. Accumulating evidence has implicated the linkage between thrombin signaling and aggregation of both tau and amyloid-β (Aβ), pathological hallmarks of AD [8]. Thrombin is a key mediator in both intrinsic and extrinsic coagulation pathways and also participates in several cellular events and inflammation by activating protease-activated receptors [9]. Thrombin is considered to be a pathological driver of dementia and AD via triggering cerebrovascular endothelial activation, neuroinflammation, and neurodegeneration [8]. Given that thrombin is a convergence point for risk factors of AD, thrombin-based therapeutics have been believed to possess potential efficacy by targeting multiple sites of AD pathology [10].

Dabigatran is a direct thrombin inhibitor which has been proven to possess comparable efficacy in preventing ischemic stroke and a lower risk for intracranial hemorrhage relative to warfarin in the randomized controlled trial and real-world clinical practice [11, 12]. By inhibiting synthesis or activity of thrombin, dabigatran can block inflammatory thrombin and fibrin for microglia activation and inhibit formation of degradation-resistant Aβ-containing fibrin clots [13]. Dabigatran is thus considered to have the potential to preserve cerebral perfusion, and to prevent inflammatory and neurodegenerative process in early AD. Beneficial effects of non-vitamin K antagonist oral anticoagulants (NOACs) in lowering risk of incident dementia have recently been shown in retrospective observational studies in patients with newly diagnosed AF without a history of cognitive impairment [14, 15]. However, the clinical effects of dabigatran on cognitive function have yet to be fully elucidated. Besides, a high prevalence of psychological distress including depression and anxiety was observed in patients with AF, causing much influence on future quality of life and clinical management in these patients [16, 17]. In this review, current evidence of therapeutic effects of dabigatran on neuropsychological function as well as dementia pathogenesis will be systematically summarized.

METHODS

We systematically searched relevant articles on PubMed/Medline using a combination of dabigatran and the following keywords: cognition, cognitive, dementia, Alzheimer’s disease, psychosis, psychiatric, behavior, behavioral, mood, depression, anxiety, aggression, irritability, and quality of life. We enrolled only original studies published in English before August 31, 2021, including case reports, case series, randomized clinical trials, and prospective and retrospective observational studies. We also reviewed bibliographies from retrieved articles and pertinent publications for additional references.

Of 129 titles/abstracts identified by PubMed/Medline search, 37 articles were retrieved for full-text review. 16 review articles were further excluded due to not relevant to cognitive or behavioral function. Finally, 21 articles were included based on our selection criteria, including eight in vitro and animal studies, four case reports, four case series, one randomized controlled trial, three cohort studies, and one meta-analysis (Fig. 1). Among the enrolled studies, eight of which researched on the disease model of dementia/Alzheimer’s disease, seven studies focused on outcomes of cognitive function and dementia, and six studies investigated or mentioned about psychological aspects. All retrieved studies in our review are listed in the Table 1.

Fig. 1

Flow chart of article selection process.

Table 1

Summary of the enrolled studies

References	Study type	Study objects	Intervention	Measurement	Key findings	Outcomes of effect
Vittal Rao et al. 2021 [23]	Test-tube lab research	Cultured Human brain microvascular endothelial cells (HBMVECs)	Glucose-induced brain microvascular endothelial injury. 30 mM glucose±100 nM thrombin and±250 nM dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9	Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates	Treatment of HBMVECs with 30 mM glucose increased thrombin activity and expression of inflammatory proteins TNFα, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran	Improving (AD model)
Iannucci et al. 2020 [18]	Animal research study	Aged Tg4510 mice (late-stage tau-based AD mouse model)	Dabigatran (100 mg/kg) or vehicle for 7 days	Western blot and data-independent proteomics using mass spectrometry performed to evaluate proteins related to oxidative stress, intracellular signaling, inflammation, and AD pathology	Dabigatran reduced iNOS, NOX4, and phosphorylation of tau. Additionally, dabigatran treatment increased expression of several signaling proteins related to cell survival and synaptic function	Improving (AD model)
Johnson et al. 2020 [24]	Animal research study	Transgenic Parkinson’s disease (PD) model, LRRK2 mutant Drosophila melanogaster	Dabigatran (25μM) diluted in 5% sucrose for 7 days	Locomotor activity and indices of oxidative stress	Dabigatran treatment could improve motor function in PD by reducing oxidative stress	Improving (PD/AD model)
Cortes-Canteli et al. 2019 [19]	Animal research study	TgCRND8 AD mice	Dabigatran (5 mg/g) or placebo for 1 year	Spatial memory (using the Barnes maze) and cerebral perfusion (arterial spin labeling). Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood–brain barrier (BBB) integrity	Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice	Improving (AD model)
Pétraultt et al. 2019 [25]	Animal research study	Wild-type mice	Anticoagulated with NOAC (apixaban, rivaroxaban, or dabigatran), or warfarin for 10 days	Working memory and visual recognition memory are examined through spontaneous alternation test and novel object recognition (NOR) test respectively	No difference was found in the performance on spontaneous alternation test between all groups. A significant difference was found in the performance on NOR test compared to non-lesioned mice at 9 months and 12 months	Neutral to improving (AD model)
Yang et al. 2017 [20]	Animal research study	Wild-type mice and J20 mice (a transgenic AD model)	Dabigatran, enoxaparin, rivaroxaban, and warfarin	The impact of anticoagulants on the degradation of Aβ₄₀ and Aβ₄₂ by the coagulation factor XII-VII pathway	Each anticoagulant significantly elevates plasma level of synthetic Aβ₄₂ in wild-type mice. The differential efficacies of the anticoagulants in elevating plasma Aβ₄₂ level match closely with their inhibitory mechanisms towards the coagulation factor XII-VII pathway	Neutral to worsening (AD model)
Marangoni et al. 2016 [22]	Animal research study	Adult healthy mice	Warfarin versus dabigatran	Astrocyte GFAP and microglia Iba-1 staining, sulfatide level, glial expression	Dabigatran reduced expression of astrocyte GFAP and microglia Iba-1 staining throughout the CNS. Dabigatran also reduced glial activation in a mouse model of AD, although no changes in amyloid plaque burden were observed	Improving (AD model)
Tripathy et al. 2013 [21]	Animal research study	Transgenic AD mice	Dabigatran (100 mg/kg)	Immunofluorescent analysis of the cerebrovasculature in AD mice	Administration of dabigatran to AD mice for 34 weeks significantly decreases expression of inflammatory proteins and reactive oxygen species (ROS). Treatment of endothelial cells with the dabigatran (1 nM) reduces ROS generation and inflammatory protein expression	Improving (AD model)
La Brooy et al. 2015 [32]	Case report	89-year-old male with AF, and no history of neurological or cognitive impairment.	Dabigatran	Folstein Mini-Mental State Examination (MMSE) score	Shortly after commencing dabigatran, the patient developed mild cognitive impairment with short-term memory loss and subtle word finding difficulties. Marked cognitive and physical improvement occurred within 2 weeks of dabigatran cessation	Worsening (cognitive function)
Eryilmaz et al. 2015 [36]	Case report	68-year-old man with AF, and history of depression/anxiety	Dabigatran 110 mg/day	Clinical symptoms	After taking dabigatran for 2 months, the patient became depressed and he gave up the drug. After a year of well-being, he took dabigatran again in addition to the escitalopram that he had been already prescribed. After 2 weeks, the patient experienced some depressive symptoms, such as sleep disturbances and social isolation	Worsening (depression)
Woo et al. 2013 [38]	Case report	57-year-old woman with depression and AF	Dabigatran 150 mg	Clinical symptoms	Intentional acute overdose of dabigatran 11.25 g in a suicide attempt. No significant clinical consequences were reported	Neutral (depression)
Poliwczak et al. 2011 [37]	Case report	72-year-old woman with paroxysmal AF, persistent ductus arteriosus Botalli and depression syndrome	Dabigatran 110 mg twice a day	Clinical symptoms	The exacerbation of the depressive syndrome was partly handled by higher doses of antidepressants, although this increased the risk of drug interactions	Worsening (depression)
Cappellari et al. 2021 [26]	Prospective case series	33 patients with AF and previous ischemic stroke (mean age 72.6±8.0 years; 17 female)	One-year treatment with standard-dose NOACs: Apixaban (n = 19), Dabigatran (n = 7), Edoxaban (n = 5), Rivaroxaban (n = 2); low-dose NOACs (n = 5)	Cognitive test battery (including MoCA and additional tests); cognitive performance using ordinal logistic regression fitted to a 1 point-shift from 4 to 0 on Equivalent Scores (ESs)	Effect of dabigatran use was significant for 1-point ES shift in the inverse direction of poor performance in test for assessment of executive functions	Improving (cognitive function)
Bellmann et al. 2017 [27]	Prospective case series	50 consecutive patients with persistent AF (mean age 69.6±3.5 years; 26 male)	39 patients treated with NOACs after electrical cardioversion: dabigatran (20%), apixaban (42%) and rivaroxaban (16%), and Phenprocoumon (22%)	MoCA test, and cerebral MRI-detected acute brain lesions	Neurological as well as cognitive function were similar before and 2 weeks after electrical cardioversion	Neutral (cognitive function)
Turker et al. 2017 [34]	Prospective case series	50 patients having non-valvular AF (mean age 74.6±8.7 years; 28 women)	Warfarin therapy switched to dabigatran (150 mg)	Beck Depression Scale (BDS) and Hamilton Anxiety Scale (HAS)	Patients with non-valvular AF under treatment of dabigatran had lower BDS and HAS scores compared to warfarin. Dabigatran may increase quality of life and decrease morbidity and mortality due to reduction in anxiety and depression	Improving (anxiety/depression)
Fumagalli et al. 2015 [35]	Prospective case series	30 patients with AF (mean age 81±9 years)	Dabigatran (n = 15) versuss warfarin (n = 15)	Anti-Clot Treatment Scale (ACTS) and Perceived Stress Scale (PSS)	NOAC group showed greater psychological satisfaction, with lower therapy-related burden and higher awareness of benefits. NOACs have an improved psychological impact compared with warfarin in elderly patients	Improving (anxiety/depression)
Monz et al. 2013 [33]	RCT	1,435 patients with AF (subgroup from the RE-LY trial)	Dabigatran 110 mg (n = 497), dabigatran 150 mg (n = 485), warfarin (n = 453)	Changes in health-related quality of life over time and between treatments using the EuroQol- 5 Dimension instrument (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months	Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment.	Neutral (anxiety/depression)
Chen et al. 2018 [28]	Retrospective cohort study	307,099 patients with AF from the MarketScan database, and 161,346 from the Optum database	Warfarin, dabigatran, rivaroxaban, and apixaban	Hazard ratios (HRs) and 95% confidence intervals (CIs) of incident dementia	Patients with AF initiating direct NOACs experienced lower rates of incident dementia than warfarin users (dabigatran: HR 0.85, 95% CI 0.71–1.01). No obvious benefit was observed for any particular NOAC in relation to dementia rates	Improving (incident dementia)
Jacobs et al. 2016 [29]	Retrospective cohort study	5,254 patients were studied (2,627 per group). Average age was 72.4–10.9 years, and 59.0% were men.	Warfarin versus NOAC (rivaroxaban 55.3%, apixaban 22.5%, and dabigatran 22.2%)	Risk of death, stroke/TIA, major bleed, and dementia	In the AF multivariable model patients taking NOAC were 43% less likely to develop stroke/TIA/dementia (HR 0.57, CI 0.17–1.97) than those taking warfarin	Improving (incident dementia)
Kim et al. 2021 [30]	Retrospective cohort study	53,236 dementia-free individuals with non-valvular AF who were aged≥50 years and newly prescribed OACs (mean age 70.7 years; 41.3% women)	Warfarin versus NOAC (rivaroxaban 45.3%, dabigatran 30.0%, and apixaban 24.7%)	Propensity score matching was used to compare the rates of dementia	Relative to propensity-matched warfarin users, NOAC users tended to be at lower risk of dementia (HR 0.78, 95% CI 0.69–0.90). When comparing individual NOACs with warfarin, all the three NOACs were associated with lower dementia risk.	Improving (incident dementia)
Lee et al. 2021 [31]	Systematic review and meta-analysis	611,069 patients (from nine studies: 4 RCTs, 5 retrospective observational studies)	Warfarin (n = 387,934) versus NOAC (n = 223,135)	Risk of composite dementia outcomes	NOACs use was associated with a lower risk of composite dementia outcomes compared with warfarin use [odds ratio (OR) 0.56, 95% CI 0.34–0.94]. No significant difference was found in subtypes of dementia (vascular dementia, AD, and cognitive disorder) between both groups. No significant difference in the risk of composite dementia outcomes between the dabigatran and warfarin groups (OR 0.97, 95% CI 0.88–1.08)	Neutral to improving (incident dementia)

AD, Alzheimer’s disease; AF, atrial fibrillation; MoCA, Montreal Cognitive Assessment Test; NOACs, novel oral anticoagulants; RCT, randomized controlled trial.

RESULTS

Cognitive impacts of dabigatran: evidence from laboratory or animal research studies

A multifactorial mechanism has been proposed for the pathogenesis of AD, including Aβ plaques, tau tangles, neuroinflammation, and brain atrophy. In our review, several animal research studies using transgenic mice model have demonstrated promising effect of dabigatran in reducing oxidative stress and ameliorating neuroinflammation in both amyloid- and tau-based AD models [18 –21]. Furthermore, long-term anticoagulation with dabigatran was found to significantly reduce the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells, and also preserve blood-brain barrier integrity and cognitive function [19]. When comparing the clinical effects of a direct versus indirect thrombin inhibitor, dabigatran but not warfarin reduced basal levels of glial cell and astrocytes activation in adult healthy mice and an AD mouse model but had little impact on amyloid burden [22].

Regarding Aβ metabolism, clinical anticoagulants (enoxaparin, warfarin, dabigatran, and rivaroxaban) with distinct inhibitory activities on the coagulation factor XII-VII proteolysis pathway were noted to markedly and dose-dependently elevate plasma level of Aβ₄₂ in a transgenic mouse model of AD [20]. It seems ambiguous that anticoagulants inhibit procoagulant activities, which are potentially ameliorating AD, but also inhibit plasma Aβ degradation which conceivably contributing to brain Aβ deposition. The exact net effect of anticoagulants on AD pathogenesis remains unclear, and plasma Aβ needs to be further verified in the future studies as an AD biomarker.

An in vitro study designed to explore the role of thrombin in glucose-mediated brain endothelial cell injury has shown that inhibition of thrombin activity by dabigatran, could decrease expression of inflammatory and oxidative stress proteins [23]. In addition, dabigatran was tested in a transgenic Parkinson’s disease model of mutant Drosophila melanogaster, and the results of dabigatran treatment showed significant improvement of locomotor ability and reduced expression of pro-oxidant proteins in male flies [24].

Another wild-type mouse model indicated that the clinical-based doses of NOACs (including dabigatran, n = 9 mice) could preserve the onset of cerebral microhemorrhages from transformation into a symptomatic bleeding, and do not precipitate cognitive impairment (evaluated by spontaneous motor activity, visual recognition and working memory) despite enhancement of cerebral microhemorrhage burden [25].

Cognitive impacts of dabigatran: evidence from observational studies

Anticoagulant therapy for stroke prevention may reduce the risk of cognitive impairment and dementia in patients with AF. One prospective case series study of 33 adult patients with previous ischemic stroke and AF was conducted to assess which factors might influence the subsequent cognitive performance after 1-year treatment with NOAC [26]. The results showed that sustained AF, ischemic heart disease, congestive heart failure, hyperlipidemia, and female gender were the significant factors influencing cognitive performance at one-year follow-up. Effect of dabigatran (n = 7) was significant for better performance in the test for assessment of executive function [26].

For patients with persistent AF, electrical cardioversion is a well-established intervention to convert AF to sinus rhythm. A prospective clinical study enrolling 50 elderly patients with persistent AF evaluated the incidence of acute cerebral lesions and the following neurocognitive function after electrical cardioversion and treatment with oral anticoagulants (dabigatran, n = 10) [27]. No interval improvement or decline in neurocognitive function was observed during two weeks follow-up in this pilot study, and the incidence of acute novel brain lesions after electrical cardioversion in patients using NOACs appears to be low [27]. The findings require to be confirmed in randomized trials with a large number of patients and a longer duration of follow-up.

NOACs are increasingly used as a practical alternative to warfarin in clinical settings; however, long-term outcomes of NOACs therapy remain uncertain. In our review, three retrospective large cohort studies with propensity score-matched design were conducted to compare the risk of dementia incidence among patients with AF taking different oral anticoagulants [28 –30]. The results consistently showed that use of NOACs was associated with lower rates of incident dementia than use of warfarin. A recent systematic review and meta-analysis comprising nine comparative studies also demonstrated the superiority of NOACs over warfarin in preventing dementia in AF patients (composite dementia outcomes: odds ratio 0.56, 95% confidence interval 0.34–0.94, p = 0.03) [31]. When comparing individual NOACs with warfarin, dabigatran use was associated with a comparable or lower dementia risk [30, 31].

In contrast to the pre-existing proposed hypotheses, a single case report has described an octogenarian patient with AF developing mild cognitive impairment with short-term memory loss and subtle word-finding difficulties shortly after commencing dabigatran for stroke prevention [32]. The cessation of dabigatran led to complete neurological and cognitive recovery within two months. Without definite alternative explanation of the underlying pathogenesis, the authors suggested that a concern should be raised when prescribing dabigatran if there is unexplained cognitive decline.

Psychological impacts of dabigatran: evidence from randomized control trials

Traditional vitamin K antagonist therapy requires frequent anticoagulation monitoring, dietary and lifestyle restrictions that complicate clinical management and may interfere health-related quality of life. A subgroup analysis enrolling 1,435 patients without outcome events from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trail investigated the changes in health-related quality of life during one year of stable treatment [33]. The main results showed stable utilities over time and no significant differences in scores of EuroQol–5 Dimension questionnaire and Visual Analogue Scale, including health dimension of anxiety/depression, between the dabigatran and warfarin groups. Given the known complexities of warfarin treatment, the authors inferred that these unexpected findings may be resulted from the controlled trial setting and the type of questionnaire.

Psychological impacts of dabigatran: evidence from observational studies

For AF patients taking oral anticoagulants, psychological tolerability has been further examined between NOACs and warfarin. A small prospective study (n = 50) demonstrated that patients with AF had significantly higher scores of Beck Depression Inventory and Hamilton Anxiety Scale when they used warfarin than when they subsequently switched to dabigatran [34]. Another matched comparative study (warfarin = 15, dabigatran = 15) also reported higher levels of anxiety and depression in elderly patients with AF receiving warfarin [35]. These findings showed that dabigatran has a better psychological impact, lower therapy-related burden and higher awareness of benefits than warfarin, thus may increase quality of life due to reduction in anxiety and depression.

In contrast to the results of positive psychological impact of dabigatran, worsening depressive symptoms had been documented in elderly patients with known history of depression or on antidepressant in few single case reports [36, 37]. Notably, intentional acute overdose of dabigatran (up to 11.25 g) was reported in a patient with a medical history of depression and a suicide attempt [38]. No bleeding complications or significant consequences were found during the clinical course of this patient. Simultaneously administering dabigatran and antidepressants may affect drug effectiveness, which was considered to be the potential cause of increases in depressive symptoms.

DISCUSSION

Concerning the close link between AF and an increased risk of dementia, optimal treatment strategies for stroke prevention and cognitive preservation are crucial in patients requiring anticoagulation therapy. Being the first approved NOAC, dabigatran has been increasingly and widely used in clinical practice. In our updated review, the majority of the enrolled studies suggested the protective effects of dabigatran on cognitive and neuropsychological function, including laboratory evidence from preclinical studies.

Thrombin has been lately recognized as a key inflammatory mediator in the brain beyond its role in coagulation cascade. An elevated level of thrombin was observed in the cerebral microvasculature in AD, causing pro-inflammatory consequences on endothelial cells, microglia, and astrocytes [39]. Dabigatran binds specifically to thrombin and competitively inhibits the enzymatic activity of thrombin for fibrin formation and blocks soluble thrombin which can induce platelet aggregation and neurotoxic effects in the brain [13]. Based on these mechanisms, animal research studies enrolled in our review demonstrated that dabigatran possesses protective effect against parenchymal Aβ-, fibrin-, and thrombin-triggered inflammatory and neurodegenerative processes, and therefore preserves cognitive function [18 , 24]. Furthermore, dabigatran at clinically relevant concentrations was found to effectively inhibit thrombin-induced protease-activated receptor-1 cleavage, activation, and internalization in vitro study, which would theoretically prevent cerebral Aβ accumulation and then contribute to ameliorating cognitive performance in AD [40, 41]. Targeting thrombin inhibition or its downstream signaling effectors, as the pharmacological effects of dabigatran, could be a potential therapeutic strategy for preventing or mitigating dementia and AD pathogenesis [23].

Silent brain infarcts and cerebral microinfarcts caused by covert embolism appear to be a central mechanism behind the association of AF and cognitive impairment [3]. However, it remains a matter of debate that whether anticoagulation efficiently reduces cognitive decline, and which type of anticoagulant is more favorable for preventing dementia. A large Swedish registry demonstrated that anticoagulation treatment at baseline was associated with a lower risk of dementia in AF patients, but no significant difference in dementia risk was observed comparing NOAC therapy with warfarin upon propensity score matching analysis [14]. In contrast, our review found that NOAC users had lower rates of dementia than warfarin users in several cohort studies [28 –30]. A recent meta-analysis of nine comparative studies also illustrated the superiority of NOACs over warfarin in prevention of dementia in AF [31]. Furthermore, dabigatran therapy was found to be associated with a favorable cognitive performance [26], and a better quality of life due to reduction in anxiety and depression [33, 34]. Two prospective ongoing clinical trials, including the Cognitive Impairment Related to AF Prevention Trial (GIRAF) (ClinicalTrials.gov NCT 01994265), and the Impact of Anticoagulation Therapy on the Cognitive Decline and Dementia in Patients with Non-Valvular Atrial Fibrillation (CAF) (ClinicalTrials.gov NCT 03061006) will specifically investigate the clinical efficacy of dabigatran, compared to dose-adjusted warfarin therapy, on cognitive outcomes in patients with AF [42].

In terms of psychological aspects, accumulative findings from clinical longitudinal and large-scale population-based studies demonstrated an association between negative affectivity (e.g., depression) and the incidence and clinical prognosis of AF [43]. Among biological pathways linking psychosocial factors to AF, research on autonomic regulation has shown that the onset of AF is associated with simultaneous sympatho-vagal activation [43]. AF patients were reported to have elevated levels of anxiety and depression, and warfarin-treated patients were noted to have compromised health-related quality of life and higher levels of self-reported psychological symptoms compared with NOAC-treated patients [16, 44]. In our review, evidence from prospective observational studies has suggested that dabigatran therapy seems to be psychologically better accepted than warfarin therapy in AF patients [34, 35]. The results may be explained by a more predictable pharmacokinetic and safety profile of dabigatran, whose anticoagulant effects can be rapidly and effectively reversed by a highly specific and selective reversal agent idarucizumab. However, caution should be taken when concurrently prescribing dabigatran with antidepressants, because dabigatran etexilate is an in vitro and in vivo substrate of P-glycoprotein which may competitively affect antidepressant effectiveness and therefore worsened depressive symptoms [36].

Another important issue which has increasingly attracted much attention is that whether all NOACs possess a comparable protective effect on cognitive function. Based on diverse and plausible results from the observational studies [28 –30], we have not yet concluded an overall agreement. In a recently published Korean nationwide cohort study, NOACs appeared more beneficial than warfarin in lowering the risk of incident dementia, particularly in people aged 65 to 74 years or those with prior stroke [45]. Moreover, the authors also suggested that potential residual confounding factors (e.g., patient selection, proportion of the labelled dose) should be carefully considered to interpret findings between the specific NOACs. Further larger cohorts and longer follow-up, or clinical trials are still required to contribute to a better understanding of dementia incidence across NOAC groups.

Despite the significance of the present review, some limitations should be addressed. First, the heterogeneous definition of main outcome measures may limit the extent of interpretation of our results. A diagnosis of incident dementia has been a common indicator used in large cohort studies, while performance in cognitive test batteries was often evaluated in individual case report and case series [26 , 32]. The lack of standard, universal evaluation tools for neuropsychological assessment makes it difficult to perform a specified comparison of the pre-existing results. Second, the dosage effect of dabigatran on cognitive or neuropsychological outcomes cannot be well elucidated based on current evidence. Only one subgroup study from RE-LY trial compared the impact of the choice of the anticoagulant on health-related quality of life between the standard-/lower-dose of dabigatran and warfarin therapy [33]. A large nationwide Danish cohort study reported no clinically meaningful difference in dementia rates between users of warfarin or NOACs apart from a higher dementia risk in NOAC users beyond 80 years of age [46]. However, a dose reduction of dabigatran is recommended for elderly patients > 75 years although standard dose may be associated with better clinical effects for older patients carrying increased risk of cognitive decline. Third, individual patient factors such as medical compliance, baseline cognitive status and cerebrovascular burden were insufficiently obtained from the included studies, all of which were considered to have essential impacts on cognitive outcomes. Finally, our review included individual case reports and some case series with a small sample size which may involve selection and sampling bias. Caution must be taken when extrapolating conclusions from case report analysis to larger populations, although the case reports provided more detailed information regarding the patient characteristics and clinical neuropsychological symptoms related to dabigatran therapy.

Conclusions

To the best of our knowledge, this is the first comprehensive review article to elaborate the clinical effects of dabigatran on neuropsychological function. The overall certainty of evidence is limited by the heterogeneity between the enrolled studies and methodological limitations. Despite these limitations, the findings from our review will provide a blueprint for treatment considerations in patients requiring optimal anticoagulant therapy. Further large-scale studies with a prospective, controlled design are warranted to verify the pleiotropic effect of dabigatran and to more extent other NOACs for repositioning for dementia treatment.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-5513r1).

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