Family Medicine Physician, Special Interest: Integrative Medicine, LGHP Family Medicine Quentin, Lebanon, PA

Dr. Orner reports no financial relationships relevant to this field of study.

SYNOPSIS: Supplementation with Ginkgo biloba extract may improve cognitive functioning after an acute ischemic stroke.

SOURCE: Li S, Zhang X, Fang Q, et al. Ginkgo biloba extract improved cognitive and neurological functions of acute ischaemic stroke: A randomised controlled trial. Stroke Vasc Neurol 2017;2:189-197.

Each year, more than 795,000 people in the United States have a stroke.¹ A cerebrovascular accident (CVA) doubles the risk of dementia, with studies showing that approximately 30% of stroke survivors develop dementia.² Given this prevalence and the downstream burden to families, there is increasing research on treatment options and prevention for cognitive decline after a CVA.

Ginkgo biloba is a tree native to China whose leaf traditionally has been used to treat memory and cognitive conditions. The Gingko biloba extract (EGb761), is reported to scavenge free radicals and protect against insecticide brain injury in rodent models.³ It also is reported to increase cerebral blood flow by suppressing angiotensin-converting enzyme activity.⁴ Given this information, Li et al evaluated the potential use of G. biloba extract (GBE) in ischemic stroke treatment and its effect on cognitive decline.

These researchers conducted a multicenter, prospective, randomized, open-label, controlled clinical trial in China comparing 450 mg of GBE with 100 mg aspirin to an aspirin-only control group.⁵ The primary endpoint was the decline in the Montreal Cognitive Assessment (MoCA) score at six months. The MoCA is a screening tool for cognitive impairment that tests orientation and attention, memory, language, visuospatial skills, executive function, verbal fluency, and abstract thought.⁶ The maximum MoCA score is 30 and a score < 26 indicates cognitive impairment. A low score indicates more serious cognitive impairment. Li et al reported outcomes as a decline in MoCA scores (deMoCA). The deMoCA was negative, as enrollees’ MoCA scores improved after the initial assessment. The MoCA test was performed at admission and at 12, 30, 90, and 180 days.

Study participants were enrolled from August 2012 to June 2014 from tertiary hospitals in the Jiangsu Stroke Research Collaborative Group in China. There were 348 patients enrolled: 179 in the GBE group and 169 in the control group. The dropout rate was 5.17%, and 18 patients were lost to follow-up.

Inclusion criteria were age 18 to 80 years; acute ischemic stroke onset within seven days, confirmed by computed tomography scan or magnetic resonance imaging; admission National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20; first onset stroke or patients with reemergence of previous stroke-related deficits with a previous modified Rankin Scale score of ≤ 1; and willingness to participate in the follow-up examinations.⁵

Exclusion criteria were history of intracranial hemorrhage or subarachnoid hemorrhage; cardiogenic cerebral embolism; low platelet count, antiplatelet contraindication, or receiving other antiplatelet drugs during the study; severe cardiac, hepatic, or renal insufficiency, pulmonary infection, terminal stage of disease or physical disability; severe mental or cognitive disorder and inability to cooperate with the study; allergy to G. biloba; participation in another trial within three months; and other conditions not appropriate for this study.⁵ However, the latter criterion was not defined further.

The modified Rankin Scale measures the degree of disability after a stoke; a higher score means a greater degree of disability. The NIHSS quantifies stroke severity. Patients with a score < 5 are likely to have a good clinical outcome and can be discharged home.⁷ The mean NIHSS score at enrollment was 5.

The ginkgo ketone ester tablets procured for the study were dispersible tablets, which disintegrate into water or other liquids. The extract included 44% flavone glycosides, 10% terpene lactones, 2.5% ginkgolide B, and < 2 ppm harmful ginkgolic acid. These compounds are thought to be some of the active constituents of ginkgo, and are commonly the phytochemicals to which extracts are standardized.

Both the GBE and control groups noted an improvement in MoCA scores between day 0 and day 180. However, the group taking G. biloba with aspirin had higher MoCA scores after 12, 30, 90, and 180 days, with a statistical difference in the change of the MoCA score at days 30, 90, and 180. The deMoCA scores are shown in Table 1. A negative deMoCA indicates an improvement in the MoCA score. The GBE group had a greater improvement in MoCA scores at 30, 90, and 180 days.

Over the six-month study period, 10 adverse events were reported. Only one, vomiting, was considered possibly related to the treatment group. Other adverse events included recurrent stroke, pneumonia, myocardial infarction, nephritis, sinus syndrome, and respiratory failure. Episodes of recurrent stroke and pneumonia were considered possibly not related to the study. The others were considered definitely not related to the study. Professional neurological investigators monitored for and reported serious adverse events, but the authors did not discuss how adverse events were determined to be related to the study. There was no statistically significant difference in vascular events during the two-year follow-up.

COMMENTARY

There are some methodological concerns that compromise the validity and applicability of the results. For example, demographically, effects in a Chinese population may not be generalizable to a multiethnic population such as that in the United States. Also, it may be difficult to obtain a product with a similar formulation to the one used in the study. A commonly available and researched product (EGb761) has a different phytochemical profile (i.e., 24% flavone glycosides and 6% terpenes), so it may not have the same physiological effect. Furthermore, this was an open-label, unblinded, non-placebo-controlled study, and, as such, it is fraught with potential confounding variables and other methodological flaws. Such studies need to be corroborated with a prospective, randomized, controlled trial to determine the efficacy and safety of G. biloba more definitively in this population.

More data are needed before providers should consider changing their post-stroke clinical practice. One aspect of the clinical use of G. biloba is related to potential effects on bleeding risk. Interestingly, in this study people with low platelets or taking antiplatelet drugs were excluded, compromising commentary on this topic: Caution is advised until research specifically explores this further.

REFERENCES

1. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics—2017 Update: A Report from the American Heart Association. Circulation 2017;135:e146-e603.
2. Leys D, Hénon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lancet Neurol 2005;4:752-759.
3. Abdel-Wahab BA, Abd El-Aziz SM. Ginkgo biloba protects against intermittent hypoxia-induced memory deficits and hippocampal DNA damage in rats. Phytomedicine 2012;19:444-450.
4. Mansour SM, Bahgat AK, El-Khatib AS, Khayyal MT. Ginkgo biloba extract (EGb 761) normalizes hypertension in 2K, 1C hypertensive rats: Role of antioxidant mechanisms, ACE inhibiting activity and improvement of endothelial dysfunction. Phytomedicine 2011;18:641-647.
5. Li S, Zhang X, Fang Q, et al. Ginkgo biloba extract improved cognitive and neurological functions of acute ischaemic stroke: A randomised controlled trial. Stroke Vasc Neurol 2017;2:189-197.
6. Burton L, Tyson SF. Screening for cognitive impairment after stroke: A systematic review of psychometric properties and clinical utility. J Rehabil Med 2015;47:193-203.
7. Schlegel D, Kolb SJ, Luciano JM, et al. Utility of the NIH Stroke Scale as a predictor of hospital disposition. Stroke 2003;34:134-137.