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Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory (GEM) Study. The trial previously reported that Ginkgo biloba (G. biloba) had no effect on the primary outcome, incident dementia.
The double-blind trial randomized 3069 participants over 75 years of age to 120 mg of G. biloba EGb 761 twice daily or placebo. Mean follow up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G. biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and gender. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G. biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207) or stroke (151) between G. biloba and placebo. There were 24 hemorrhagic strokes, 16 on G. biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease (PVD) events, 12 (0.8%) on G. biloba and 23 (1.5%) on placebo (p=0.04 exact test). Most of the PVD cases had either vascular surgery or amputation.
There was no evidence that G. biloba reduced total or CVD mortality or CVD events. There were more PVD events in the placebo arm. G. biloba cannot be recommended for preventing CVD. Further clinical trials of PVD outcomes might be indicated.
We report the vascular disease secondary endpoints from the Ginkgo Evaluation of Memory (GEM) Study of Ginkgo biloba (G. biloba), a randomized double-blind placebo-controlled clinical trial conducted between 2000 and 2008. (1,2) Vascular endpoints included cardiovascular disease (CVD), defined as angina pectoris, myocardial infarction (MI), congestive heart failure (CHF), stroke/cerebrovascular accident (CVA), transient ischemic attack (TIA), peripheral vascular disease (PVD) and CV-related deaths. There have been no previous clinical trials to evaluate whether G. biloba in the form of EGb 761, a highly purified extract of G. biloba, prevents CVD. (3–5) We reported previously that G. biloba had no effect on the primary outcome, incidence of dementia and Alzheimer’s disease (AD). (2)
G. biloba has been widely used in Europe for the treatment of (PVD). Randomized clinical trials have suggested that G. biloba is associated with increasing walking distance prior to the development of symptoms of lower extremity pain, intermittent claudication. (6)
The physiological effects of G. biloba on the cardiovascular system are uncertain. Several studies have suggested antioxidant and free-radical scavenger effects. There is also suggestion of inhibition of platelet aggregation. There have been reports of association G. biloba with bleeding, which has been attributed to antiplatelet aggregation effects. It was also suggested that G. biloba improved blood flow by increased release of nitric oxide and the inhibition of nitric oxide degradation in the endothelium. (7–10)
Flavonoids are a component of G. biloba. There is considerable interest in the potential antioxidant, anti-inflammatory, vasodilation and platelet inhibition activity by various flavonoids. Several but not necessarily all large longitudinal studies have suggested some benefit of overall consumption of flavonoids on risk of coronary heart disease (CHD). (11–18)
A detailed description of the study methods and recruitment has been published. (1) The study was conducted under an investigational new drug application with the Food and Drug Administration under the auspices of the National Center of Complementary and Alternative Medicine (NCCAM). The study was built upon the infrastructure of the Cardiovascular Health Study (CHS) clinical study at the University of Pittsburgh, University of California Davis, Johns Hopkins University and Wake Forest University. (19) A Clinical Coordinating Center located at the Wake Forest University) was charged with the oversight of clinical operations. The Cognitive Diagnostic Center was located at the University of Pittsburgh. The Data Coordinating Center (DCC) was at the University of Washington in Seattle and the Laboratory Center at the University of Vermont.
The secondary endpoints were defined at the beginning of the trial and the analysis planned prior to the availability of the results of the trial, i.e. prespecified.
Participants were recruited both from the CHS and volunteers in the communities. Recruitment was done in three phases; cognitive and medical or other exclusions were identified at each phase. The Telephone Interview for Cognitive Status (TICS) was used to screen potential participants prior to inviting them into the clinic for further screening. (1,2) During the initial screening visit, participants completed several cognitive screening tests and additional neuropsychological testing, phlebotomy, and functional assessment. Eligibility for the trial included no current dementia, willingness to participate for five years in the trial, age at least 75 years, English speaking, identification of a person to serve as a proxy and normal levels of specific blood tests (Table 1). Participants with neurological or neurodegenerative diseases were excluded from the study. Anyone on cognitive enhancers or other treatment of AD were excluded as were individuals taking high doses of vitamin E or taking over-the-counter G. biloba. Subjects on anticoagulants were excluded. Eligible participants were invited back for a baseline visit for further eligibility review and randomization. (1)
The baseline examination included a physical examination and a neurological examination, electrocardiogram (EKG), and ankle-brachial index (ABI) measurement. Individuals with prior CVD were allowed into the study. However, individuals having prevalent CHF with disability were excluded. Persons found to have abnormal levels of thyroid stimulating hormones, serum B12, hematocrit, white blood cell count, or platelets at the screening visit were also excluded. (1)
Enrolled participants were randomized to 120 mg G. biloba as EGb 761 or placebo to be taken twice per day. Randomization was done separately for each clinic site. (1,2) Assignment to G. biloba or placebo was determined by permuted block design by site to ensure that allocation between treatment groups was well balanced. Participants assigned to active treatment and placebo were kept in their randomly assigned group regardless of their drug compliance, in accordance with an intention to treat analysis. All clinic center personnel and participants were blinded to treatment assignment for the duration of the study. Semi-annual visits included pulse, blood pressure (BP), current medications, interval medical history and adverse events, functional assessment, drug adherence and cognitive evaluations. (2)
At each six month visit and interim 3 month drug adherence monitoring phone call, subjects or their proxies were asked to report Serious Adverse Events (SAEs) in compliance with Food and Drug Administration regulations. All subjects provided authorization to release medical records. All SAEs reported as overnight hospitalizations or deaths were investigated through the collection of medical records, and reviewed by a blinded field center physician investigator. Records used for review included hospital face sheets with International Classification of Diseases (ICD) Ninth Revision diagnostic codes, discharge summaries, history and physical exams, and other documents depending on the diagnosis. Non-certified death certificates with cause of death were obtained for fatal events.
Identification and classification of vascular outcomes were based on methods from the CHS. (20) Each field center abstracted the ICD codes for diagnoses from the hospitalization face sheet, and codes were searched to flag any possible vascular outcomes. Local physicians were also required to determine if the hospitalization was due to a cardiovascular or cerebrovascular cause, or if the SAE resulted in death. Case records with vascular ICD codes or marked by the local physician as being in any of the vascular disease categories were forwarded to the University of Pittsburgh for abstraction and adjudication. In addition to the face sheet, discharge summary, and history and physical exam, review of coronary events included cardiac consults, and diagnostic laboratory tests and procedures. Cerebrovascular event reviews also included neurological consults. Vascular outcomes were defined as MI, angina pectoris, CHF, cerebrovascular accident (CVA/stroke), TIA, PVD, and coronary revascularization. Cases from all four clinical centers were classified by two reviewers of the University of Pittsburgh blinded to treatment assignment. All deaths were classified by underlying cause of death using death certificates and, if applicable, hospital records and autopsy reports. The classification included atherosclerotic CHD (subclassified as definite fatal MI, definite fatal CHD or possible fatal CHD), cerebrovascular disease (including stroke/CVA or late effect of stroke), atherosclerotic cardiovascular disease non-coronary (including ruptured aortic aneurysm), other cardiovascular disease not CHD or CVA (including valvular heart disease and pulmonary embolism) and all other causes. Morbid CVD events were classified as definite, probable or not present.
Participants were randomized to twice-daily doses of either 120-mg G. biloba extract or an identically appearing placebo. G. biloba EGb 761 was supplied for the study by the Schwabe Pharmaceuticals (Karlsruhe, Germany). (1,2) A 120 mg dose in pill form containing 28.8 mg of G. biloba flavone glycosides and 7.2 mg of terpene lactones was prepared for use in this study. These values were confirmed by an independent laboratory for each batch of product used in the GEMS. (2)
Descriptives of demographic characteristics within each treatment group were calculated as count and percent for discrete variables, and mean with standard deviations for continuous variables. The following endpoints were combined for additional analysis: MI and angina pectoris for CHD; stroke and TIA for cerebrovascular accident (CVA); and the combination of CHD and CVA. Time-to-event analyses comparing G. biloba to placebo were completed on (a) total and CVD deaths, b) incident CVD events (time to first event) for persons reported to be free of the specific outcome at baseline, and c) total CVD events (time to first event) allowing both incident and recurrent outcomes to be included. Calculation of rates for incident cardiovascular events excluded those participants who reported the specific condition at baseline. For the combination of incident and prevalent events, all participants were included in the analysis. Person-time in years was calculated as days between date of the baseline clinic visit to the day of the first occurrence of either the cardiovascular event of interest, death, dementia or last follow-up visit. (2)
Differences in time to events between G. biloba and placebo were evaluated using Cox proportional hazards regression adjusted for gender and age using a categorical variable for adjustment in the models (< 80 years, 80–84, and 85 years or older). Differences in incidence rates of myocardial infarction and stroke were also calculated and presented per year in the study using the binomial exact test. All analysis was performed using STATA version 10 (StataCorp, College Station, Texas).
Power estimates were originally based on rates from the CHS, age 75+, stroke 2%, CHD endpoint 5%. Based on those estimates, we had 89% power for a 35% reduction for stroke, 75% power for a 30% decrease and for CHD 99% power for a 35% reduction and 92% power for a 25% reduction. (1) The overall incidence of composite CVD events in the GEMS was approximately 4% per year, and for stroke and TIA about 1.5% per year.
There were 3,069 community volunteers age 75+ (mean age 79 years) randomized to placebo (n=1,524) or G. biloba (n=1545) 120 mg twice daily. (Table 1) Approximately 95% of the participants were white; 23% had some postgraduate education. One quarter of the participants had a history of CVD, approximately 55% reported history of hypertension and 9% had diabetes. Only 4.5% currently smoked cigarettes.
Recruitment began in September, 2000 to June, 2002. Participant close out began in October 2007 and completed in April, 2008. Median follow up was 6.1 years, with a maximum of 7.3 years. Adherence varied from 90% at 6 months, 79% at 2 years, 73% at 4 years and at the end of the trial, 60.3% of those on active therapy were taking their assigned study medication. Adherence did not differ between those on G. biloba and those on placebo. (2)
There were 385 deaths during the trial, 188 (22.2/1000 person-years) in the placebo group and 197 (23.0/1000 person-years) in the G. biloba active arm. (Table 2) Eighty-seven of the deaths were due to CHD, 42 in placebo and 45 in G. biloba arm. There were no differences in the distribution of other CV or noncardiovascular deaths by treatment arm. There were also no differences in distribution of deaths by G. biloba versus placebo for men, 210 (12.8%) or women, 175 (12.3%).
There were 164 hospitalized clinical MIs, 207 cases of reported angina pectoris, 151 strokes, 73 TIAs and 35 peripheral vascular disease events. The measurement of incident CVD was limited, as noted, to those individuals who had no self-reported baseline history of CVD and had their first event during the trial. There were no significant differences in incidence of any of the CV outcomes by G. biloba versus placebo arm. (Table 3) Event rates were slightly higher in men than women, except stroke. There was, however, no difference in event rates by sex by arm in trial.
There was no evidence of any reduction in risk of total CVD or CHD events, including recurrent events, for G. biloba versus placebo for men or women. No differences were found between the G.biloba and placebo arms of the study for incident plus recurrent cardiovascular events. (Table 4)
Incidence of stroke was slightly higher in the G. biloba than the placebo arm of the trial but the difference was not statistically significant. (Table 3) Mortality from stroke was higher in the placebo, although this difference was not significant statistically. (Table 2) The incidence of pure vascular dementia was previously reported to be higher in the placebo arm. We also previously reported that there were 24 hemorrhagic stroke cases, 16 on G. biloba and 8 on placebo, HR 1.97 (0.84–4.16) (p=.12). (2) Of the 24 hemorrhagic strokes, 2 were subarachnoid hemorrhage and 22 intracranial hemorrhage. Five of 16 participants in the G. biloba arm and 2 of 8 in the placebo were off therapy at the time of the intracranial hemorrhage. Only 2 participants were on anticoagulants at the visit prior to hemorrhagic stroke (medical need required cessation of drug although subjects were still followed). Thus, 11 hemorrhagic strokes occurred on treatment with G. biloba and 6 such strokes occurred in the placebo arm, not statistically significant.
Rates of major bleeding did not differ between treatment groups, HR 0.97 (0.77–1.23) (p=.81). The incidence of bleeding did not differ by use of aspirin therapy assigned to either G. biloba or placebo, 1.98 versus 1.76/100 person-years (p=.44). (1)
There were only 35 peripheral vascular disease (PVD) events in the trial, 12 (0.8%) in G. biloba arm and 23 (1.5%) on placebo (p=.04 exact test). Most (27 of 35 [77%]) of PVD cases had a surgical, revascularization or amputation procedure for symptomatic PVD, 18 of 23 (78.3%) on placebo and 9 of 12 (75.0%) on G. biloba. There was one case of popliteal aneurysm secondary to a diagnostic procedure in the placebo arm. The risk of PVD, incident CHD or total mortality was related directly to ABI at baseline with most cases occurring in participants with ABI ≤1.1. (Table 5) The incidence of PVD was 10.2/1000 person-years for ABI <0.9 in the G. biloba arm (n=7) versus 17.5/1000 person-years for placebo, n=12 (p=.26). For participants who entered with ABI in the 3rd or 4th quartile ≥1.1, there were only 2 events in the G. biloba arm and 4 in the placebo group. Two participants did not have measurement of ABI at baseline. We further reviewed records that had some PVD codes on hospital discharge records but did not reach criteria for clinical PVD in the study. There were 54 records, 16 had a history of lower extremity PVD in the hospital record, usually a history of claudication but no concurrent therapy, 7 in G. biloba and 9 in placebo arm.
We further evaluated the incidence of CV events by age at entry to the trial, <80, 80–84 and 85+. (not shown) There were no differences in the incidence of any of the CV outcomes in any age group as defined by age at entry to the trial. The incidence of CHD, MI and angina pectoris increased little by age, from 14.3/1000 person-years <80 to 16.3/1000 person-years age 85+. The incidence of CHF, however, increased dramatically from 14.35 in those <80 to 30.1/1000 person years age 85+. There was also no difference in the incidence of MI or stroke by time in the trial for G. biloba versus placebo. (not shown)
The GEM Study did not demonstrate that G. biloba 120 mg twice daily in older individuals age 75+ reduced the risk of either CHD or CVD mortality, total hospitalizations or incident CVD/CHD events. G. biloba 120 mg twice daily cannot be recommended for prevention of CV mortality, or incident or recurrent CVD/CHD events in this age group. Results were similar for men or women or by age groups for incidence or mortality by G. biloba versus placebo. There is no evidence of any benefit by longer duration in the trial. It remains possible, however, that benefits of G. biloba, should there be any, require many years of therapy, perhaps beginning at an earlier age. GEMS participants likely had extensive atherosclerotic disease even without a history of clinical disease. The potential physiological effects of G. biloba on thrombosis, i.e. platelet function and endothelial function (1,2,4), would have been expected to decrease incidence of CVD/CHD if there was a true benefit. It is also possible that G. biloba reduces the risk of CHD if taken at younger ages.
There were only 35 peripheral vascular events in the trial. The difference between G. biloba (12) and placebo (22) was significant but based on very small numbers. These results are consistent with studies in Europe that reported increased walking time or distance without pain in trials of G. biloba versus placebo among clinical PVD patients. (6, 21) A recent report from the Stanford Prevention Research Center evaluated pain-free walking distance among 62 adults with claudication symptoms. Maximal treadmill walking time increased 20 ±80 seconds (10%) in the placebo and 91 ±242 seconds (40%) in the participants given 300 mg of EGb 761 G. biloba over a four month period (p=.12). Lack of statistical significance may have been due to the small sample size. There was also substantial heterogeneity of the results. (22) A randomized trial from Australia, using 22 subjects, noted that exercise but not G. biloba improved walking times in patients with PVD. (23) The PVD cases in GEMS had severe PVD, usually requiring surgery or amputation. We do not have data on symptomatic PVD that did not require hospitalization or surgical procedure, such as outpatient diagnoses. The number of events is too small to determine definitively whether G. biloba might have a unique effect on PVD. (4) We measured ankle-brachial BP at entry to the trial but did not have repeat measures of ankle-brachial BP or other measures of peripheral vascular disease during the trial. We also did not measure out-of-hospital PVD diagnoses or hospitalizations that included PVD but in which there was not a specific diagnostic or surgical procedure for PVD. It is possible that G. biloba has a unique effect on peripheral vascular disease by increasing blood flow secondary to effects on endothelial function, i.e. nitric oxide. (4,6) A larger study would be needed to evaluate the PVD endpoint.
The higher number of cerebral hemorrhages, 16 in G. biloba arm versus 8 in placebo (and 11 versus 6 in the groups on treatment), would also be consistent with the reported increased risk of bleeding among patients on G. biloba. (21)
A limitation of this trial is the absence of measures of blood levels or urinary excretion of the flavonoids or terpenoids in participants on EGb 761 G. biloba. We were limited to data on drug adherence in two arms and analysis of the chemical composition of the pills. (1) It is very difficult to measure the amount of G. biloba that was absorbed and their metabolic products. (24) One study has successfully reported isolation of both quercetin and kaempferol in blood. One small sample of older individuals reported similar absorption in elderly versus younger individuals. (25) The other major limitation of the study is the absence of measures of PVD at the end of the trial. There is no evidence at the present time from clinical trials that G. biloba reduces the risk of CVD, either primary or secondary prevention.
An important issue is whether the reduced risk of clinical PVD is strong enough for either a new larger trial of G. biloba or for clinical use for older individuals with low ABI. A new clinical trial would likely have to be restricted to individuals with low ABI, i.e. first quartile, <1. The trial would be limited by high risk of CHD, stroke, and other medication use, especially statins, aspirin, antihypertensive therapy, diabetes mellitus. A large sample size and need for careful measurement of PVD outcomes would be required.
We do not believe that the results of the GEMS trial are a definitive indication for use of G. biloba for individuals with low ABI but do add to the data on potential benefit of G. biloba in PVD.
Funding sources: Supported by U01 AT000162 from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements, and support from the National Institute on Aging, National Heart, Lung, and Blood Institute, the University of Pittsburgh Alzheimer’s Disease Research Center (P50AG05133), the Roena Kulynych Center for Memory and Cognition Research, and National Institute of Neurological Disorders and Stroke. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, or the NIH. We are indebted to Stephen Straus, MD, the late former director of NCCAM, who championed efforts to evaluate complementary and alternative therapies in rigorous scientific fashion. We gratefully acknowledge the contribution of Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany, for their donation of the G. biloba tablets and identical placebos, in blister packs, for the study. We are also grateful to our volunteers, whose faithful participation in this longitudinal study made it possible.
Subject Codes: 17, 121, 64, 91, 100
Clinical Trial Registration: clinicaltrials.gov identifier: NCT00010803
Disclosures: Authors have no conflicts of interest to disclose.