Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761®

Abstract Background The Ginkgo biloba special extract, EGb 761® has been widely used in the treatment of neuropsychiatric disorders, including Alzheimer’s disease (AD). Methods To guide clinical practice in the Asian region, the Asian Clinical Expert Group on Neurocognitive Disorders compiled evidence‐based consensus recommendations regarding the use of EGb 761® in neurocognitive disorders with/without cerebrovascular disease. Results Key randomized trials and robust meta‐analyses have demonstrated significant improvement in cognitive function, neuropsychiatric symptoms, activities of daily living (ADL) and quality of life with EGb 761®versus placebo in patients with mild‐to‐moderate dementia. In those with mild cognitive impairment (MCI), EGb 761® has also demonstrated significant symptomatic improvement versus placebo. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and N‐methyl‐D‐aspartate (NMDA) antagonists e.g. memantine (Grade 3 recommendation; Level B evidence). Only EGb 761® had Level B evidence in improving cognition, behaviour, and ADL in both AD and vascular dementia patients. Safety analyses show EGb 761® to have a positive risk‐benefit profile. While concerns have been raised regarding a possible increased bleeding risk, several randomized trials and two meta‐analyses have not supported this association. Conclusions The Expert Group foresee an important role for EGb 761®, used alone or as an add‐on therapy, in the treatment of MCI and dementias, particularly when patients do not derive benefit from acetylcholinesterase inhibitors or NMDA antagonists. EGb 761® should be used in alignment with local clinical practice guidelines.


| INTRODUC TI ON
The rapid aging of the global population is resulting in an increasing prevalence of mild cognitive impairment (MCI) and dementias. 1,2 Age is a key risk factor for dementia and Alzheimer's disease (AD) 1 ; after the age of 65 years, the prevalence of dementia doubles with every five additional years. 2 Prevalence is higher among women than men, largely because women tend to live longer. 2 In 2018, the number of individuals worldwide with dementia was estimated to be 50 million. This number has been projected to increase exponentially to 82 million by 2030, and to 152 million by 2050. 4 In high-income countries, estimates of dementia prevalence are around 5%-10% in the population aged 65 years or older 2 ; however, evidence suggests the prevalence in such countries may be reaching a plateau. 5,6 In the developing world, however, the increasingly maturing population is expected to be mirrored by a continued rise in the prevalence of dementia, 3,7,8 with an estimated 68% of dementia cases expected to be found in low-to-middle income countries by the year 2050. 3 Asian data indicate a crude estimated dementia prevalence of 4.7% in the over-60 population; although there is country-to-country variation. 3,8 National reports of dementia prevalence in various Asian countries range between approximately 2%-13%, 8,9 and this is expected to rise dramatically in coming years. 8 Cerebrovascular disease (CVD) frequently coexists with AD. In Asia, AD + CVD accounts for up to 20% of all dementia cases, 9 and there is some evidence for a higher prevalence of AD + CVD in the Asian region compared with Western populations. 10 Globally, but also in Asia, AD + CVD is thought to be underdiagnosed, primarily due to lack of awareness resulting from a lack of defined diagnostic criteria, but also due to the high cost of investigations, a lack of adequate diagnostic facilities, and other resource constraints. 9 It has been suggested that some Asian epidemiology studies may be influenced by "survivor bias" due to a high proportion of early deaths. 9 Epidemiology study methodologies and findings are also heterogeneous; among dementia patients across Asia, estimated proportions of dementia patients with AD + CVD range between 7% (Sri Lanka) and 50% (Japan). 9 Dementias place an appreciable burden on patients, their families, and the healthcare system. Quality of life (QoL) is decreased for patients as well as for their families and caregivers, and a severe cost burden also results from long-term medication use, hospitalization, and home-based healthcare. 2,11

| Definitions and symptoms
Mild cognitive impairment is understood to be a neurocognitive state between normal cognitive aging and dementia, and can be an early manifestation of, and a risk factor for, AD or other neurodegenerative disorders. 12,13 MCI is not linked to any specific etiology, 13 but in the context of AD biomarkers, MCI is considered to be a prodromal stage of AD dementia. 12

K E Y W O R D S
Alzheimer disease, cerebrovascular disease, dementia, EGb 761 ® , Ginkgo biloba in one or more cognitive domains, but, in contrast to overt AD dementia, no significant social or occupational impairments are present; individuals are generally able to maintain independence in daily functioning with minimal assistance. 12,14,15 Clinically overt dementia has a spectrum ranging from mild to severe. 15 Diagnosis involves clinical assessment, neuropsychological evaluation, and often neuroimaging. 9 Core clinical criteria for all-cause dementia, based on DSM-5 criteria for neurocognitive disorders, include cognitive impairments and behavioral symptoms that interfere with functioning and activities of daily living (ADL). Typical cognitive symptoms may include impairments in complex attention, executive function, learning and memory, language function, perceptual motor function, and social cognition. 15 Noncognitive behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms (NPS), are observed across the severity spectrum of dementia, 16 and can include changes in personality or usual conduct, anxiety, agitation, elation, irritability, apathy/indifference, depression/dysphoria, disinhibition, aberrant motor behavior, sleep or appetite changes, and hallucinations or delusions. 15,16 The term "AD dementia" specifically refers to a clinical syndrome arising secondary to the pathophysiological process that leads to AD. 15 AD and vascular dementia (VaD) are considered to be the most common forms of dementia, 9 but more recently, attention has focused on the co-existence of AD and CVD. 18,19 AD and VaD may be considered to be a disease continuum, with pure AD at one end of the spectrum, VaD at the other, and AD with concomitant CVD comprising the majority of cases. 18,21,22 AD and CVD contribute independently, but additively, to the risk of dementia. 23 It is important to distinguish between AD, VaD, and AD + CVD, because of differences in clinical course and cognitive profiles, and differential treatment responses. 9 Diagnosis of AD + CVD can be made when (a) clinical signs of AD dementia are accompanied by evidence of CVD (vascular lesions) on brain imaging; or (b) dementia clinically presenting as sudden-onset, is accompanied by biomarker evidence of AD such as amyloid plaques on positron emission tomography. 9 The neuroimaging hallmarks of CVD include chronic lacunes, white matter hyperintensities (WMH), perivascular spaces, and microbleeds. 9 CVD has been demonstrated to be a risk factor for progression from MCI to AD. 24 WMH have also been shown to be independently associated with BPSD. 25

| Management options
Goals of dementia treatment are stabilization or slowing of disease progression, reduction in psychological and behavioral symptoms, improvement of QoL, and reduction of caregiver burden. 9 Acetylcholinesterase inhibitors (AChEIs; eg, donepezil, rivastigmine, and galantamine) are first-line agents for the treatment of AD and AD + CVD in Asia. Second-line options include N-methyl-D-aspartate (NMDA) receptor antagonists (eg, memantine). 9 The Ginkgo biloba special extract, EGb 761 ® has also been used widely in the treatment of cognitive disorders, including AD and AD + CVD. 26,27 Different parts of the Ginkgo biloba tree have been used for centuries in Chinese herbal medicine to treat a variety of health conditions, and evidence for the use of EGb 761 ® in the symptomatic treatment of dementia, particularly in the presence of NPSs, dates back more than two decades. 27,28 The EGb 761 ® extract is derived through a specific, proprietary process under strict procedural control. EGb 761 ® is a dry extract from Ginkgo biloba leaves, adjusted to 22.0%-27.0% ginkgo flavonoids and 5.0%-7.0% terpene lactones consisting of 2.8%-3.4% ginkgolides A, B, and C, and 2.6%-3.2% bilobalide, and containing less than 5 ppm ginkgolic acids. Depending on local regulatory frameworks, EGb 761 ® is classified as a drug in some countries, including China, the Philippines, Thailand and Vietnam. In Singapore and Malaysia, EGb 761 ® is currently classified as a supplement; in Indonesia, it is classified as a "phytopharmaceutical." EGb 761 ® exhibits various beneficial properties in patients with AD and AD + CVD. The molecular basis for these effects is not fully understood; however, the extract appears to have neuroprotective properties. It is a polyvalent free radical scavenger that improves mitochondrial function, decreases blood viscosity and enhances microperfusion, modulates serotonin levels in various brain areas, increases dopamine levels in prefrontal cortical areas, decreases amyloid-β fibrillogenesis, and attenuates a hyperactivated hypothalamus-pituitary-adrenal axis. 32

| ME THODS
The Asian Clinical Expert Group on Neurocognitive Disorders consists of twenty members including neurologists, geriatricians, psychiatrists and a pharmacist, from around the Asia region. There was also involvement of an expert advisory member from Germany. English language publications on the use of EGb 761 ® in dementia and MCI with or without CVD, and were given sufficient time to review the literature. Experts then completed a pre-meeting survey before gathering to discuss amendments to a series of proposed consensus statements. On the day of the consensus meeting, two presentations on key published findings were delivered by experts in the field. All proposed statements were then discussed in depth, and when necessary, polling of Expert Group members was carried out to choose or formulate statements that were accepted unanimously or by majority vote. This document is intended as a collection of consensus recommendations only, and is not designed to be used as a treatment algorithm. Experts' clinical opinions were based on the available data, and were unrelated to different regulatory classifications in respective countries.

| RE SULTS
The Expert Group identified English language articles relevant to the use of EGb 761 ® in MCI, AD, VaD, and BPSD in the literature. The Group also identified a number of salient aspects relating to the use of EGb 761 ® in clinical practice, and formed specific consensus recommendations based on the available evidence (Table 1). Key trials evaluating EGb 761 ® are summarized in Table 2, and key meta-analyses are discussed below.

| Efficacy of EGb 761 ® in placebocontrolled trials
Older placebo-controlled clinical trials have been heterogeneous in study design, EGb 761 ® dosage, and effect sizes, but overall have shown modest improvement in cognitive function and ADL. 27,42,43 However, more recently, three multicenter, randomized, doubleblind, placebo-controlled trials of comparable design were con-  (Table 1). 29,30 Randomized, double-blind, placebo-controlled trials in patients with MCI have also shown significant improvements in NPS, cognitive performance, memory function, concentration, and anxiety with EGb 761 ® vs placebo. 44,45

| Efficacy findings in key meta-analyses
Results of a 2014 meta-analysis by Gauthier and Schlaefke con- EGb 761 ® . Caregiver distress was also reduced. 50

| Does EGb 761 ® prevent progression to dementia?
Two multicenter, randomized, double-blind, placebo-controlled trials (the GuidAge 51 and Gingko Evaluation of Memory [GEM] 52 studies) evaluated the use of EGb 761 ® in the prevention of dementia.
The GuidAge trial included 2,850 French primary care patients with memory complaints, who were prospectively followed up over five years. 51 The GEM study (USA) randomized a total of 3069 individuals aged ≥75 years with normal cognition or MCI at baseline, and assessed them every six months, with a median follow-up of 6.1 years. 52 Neither study demonstrated a clear preventative effect in initial analyses. 51

| EGb 761 ® safety
EGb 761 ® has been shown to have a positive risk-benefit profile. 42,47 Studies have consistently shown no significantly increased overall risk of adverse events (AEs) compared with placebo. 27,[29][30][31]44,46 This finding was confirmed in a recent safety meta-analysis of 44 trials in a total of over 6000 patients; odds ratios for dizziness and nausea in fact favoured EGb 761 ® over placebo. 54

Consensus statement 3: Management of comorbidities
Concomitant management of co-morbidities, such as hypertension, in patients with AD, VaD, and BPSD is highly important Expert recommendation

Consensus statement 4: EGb 761 ® does not appear to prevent dementia
EGb 761 ® cannot currently be recommended for the prevention of dementia Class of recommendation III; level of evidence A

Consensus statement 5: EGb 761 ® is well tolerated
Current safety evidence suggests a good tolerability profile with EGb 761 ® in the treatment of MCI, AD, VaD, and BPSD

Consensus statement 6: No overall increased bleeding risk
Based on existing data in AD, VaD, and mixed dementia (including the GINDEM, GOTADAY, and GOT-IT! studies), and two meta-analyses, there appears to be no overall added risk of bleeding with EGb 761 ®

Level of evidence A
Further studies are required in certain patient subgroups, including those with a high cerebral microbleed load (>4 microbleeds) in the cortical areas. In such cases, patients should be warned of a possible increased risk of bleeding Expert recommendation showed significantly higher dropout rates due to side effects, compared with placebo. 48 In a comparative trial, combination therapy with EGb 761 ® plus donepezil resulted in fewer AEs compared with donepezil monotherapy. 55 Some concern has been raised regarding a possible increased risk

| Current guidelines regarding the use of EGb 761 ®
The Expert Panel is in agreement that there is a pressing need to take into account the evidence supporting EGb 761 ® from the above key clinical trials 1,27,[29][30][31]42,44,46 and recent meta-analyses. 47,49,50 Notably, there are no specific diagnostic and treatment guidelines for AD + CVD in Asia, 9 representing an unmet need in the region. Respective countries have their own guidelines. Countries approach the issue of "level of evidence" slightly differently, based on the system used to evaluate the data, and based on the local classification of EGb 761 ® (drug vs supplement).
In Importantly, EGb 761 ® does not appear to increase overall bleeding risk, 40,58,59 nor to interact with common antiplatelet agents or anticoagulants. 62,63 However, these studies were performed in young, healthy volunteers, and it is unclear how accurately the data can be extrapolated to the elderly patient population with multiple co-morbidities. Further data are also required to address this concern in certain patient subgroups, such as those harboring a high microbleed load; or those with a history of gastrointestinal bleeding or mild renal insufficiency who are usually excluded from clinical trials. In addition, data are needed to assess bleeding risks at higher EGb 761 ® doses. It is suggested that future studies should include imaging criteria as outcome measures, allowing for better insights into the mechanism of action of EGB 761 ® . The inclusion of gradient recalled echo imaging will also allow for risk estimates of cerebral bleeding among patients with cognitive impairment having microbleeds.

ACK N OWLED G EM ENT
Medical writing and editorial assistance was provided by Geraldine K Hosking of Pharma-Med Ltd.