The flow diagram for the 3069 participants randomized to either placebo (n=1524) or G biloba (n=1545) during the enrollment period from September 2000 to June 2002 is shown in . The G biloba and placebo groups were similar in their baseline characteristics. Mean age at entry for all participants was 79.1 years and 46% were women (). Because of a lower-than-expected dementia rate early in the trial, study follow-up was extended in 2006. After reaching the required number of dementia outcomes (n=439), participant closeout was initiated in October 2007 and completed in April 2008. Median follow-up at closeout was 6.1 years (maximum, 7.3 years). Although the dementia rate was extremely low during the first year (<1% in both treatment groups), the rate steadily increased over the remainder of the study follow-up.
Flow of Participants Through the Ginkgo Evaluation of Memory (GEM) Study
Baseline Characteristics of Study Participants by Study Drug Assignment (Ginkgo biloba vs Placebo)
During the intervention period, 523 participants were diagnosed with dementia, 246 (16.1%) in the placebo group and 277 (17.9%) in the G biloba group. There were 379 deaths from any cause. Cognitive status was known for 93.6% of all participants at trial end. There were 195 individuals (6.3%) who were either lost to follow-up or withdrew consent (97 in the G biloba group and 98 in the placebo group). The 195 participants who declined to continue the study after randomization did not differ from the 2874 who remained in the study by age, sex, minority race/ethnicity, baseline disease categories (eg, myocardial infarction, stroke, heart failure, cancer), or smoking status. However, a difference in MCI status at baseline was found with 22.6% of dropouts classified with this condition compared with 15.2% of those who completed the study (P=.01).
As shown in , at the end of the trial, 60.3% of active participants were taking their assigned study medication, and adherence did not differ between the 2 groups. Because of a concern about possible drug interaction increasing the risk of bleeding, initiation of warfarin therapy was specifically stated in the protocol as a reason for discontinuing the study medication. Institution of warfarin therapy resulted in participant discontinuation of assigned study medication in 214 participants (15.4% of total discontinuations), 112 in the G biloba group and 102 in the placebo group. Neither missing cognitive function assessment nor study medication discontinuation differed significantly by assigned treatment group. A total of 161 participants (86 taking G biloba and 75 taking placebo) initiated cholinesterase inhibitors or memantine during the study.
Cumulative Adherence to Assigned Study Tablets by Scheduled 6-Month Follow-up Visit (Excluding Death and Incident Dementia)
shows the cumulative rate of all-cause dementia by treatment with G biloba vs placebo during the course of the GEM Study. The 2 primary outcomes were all-cause dementia and AD. Of the total dementia cases, 92% were classified as AD. The rates of overall dementia and dementia by subtype for participants assigned to G biloba vs placebo in the GEM Study are compared in . The rate of total dementia did not differ between participants assigned to G biloba vs placebo (3.3/100 person-years vs 2.9/100 person-years; HR, 1.12; 95% CI, 0.94–1.33; P=.21), and as also shown in , the rate of Alzheimer-type dementia also did not differ between the 2 treatment groups (3.0/100 person-years vs 2.6/100 person-years; HR, 1.16; 95% CI, 0.97–1.39; P=.11). The results were no different when the end point was AD only vs AD with evidence of vascular disease of the brain (). There was no evidence for effect modification by age, sex, or MCI (tests for interaction, P = .16, P = .54, and P = .94, respectively).
Cumulative Dementia Rates by Treatment
Table 2 Incidence Rates (per 100 Person-Years) and Hazard Ratios From Cox Regression Analyses: All Dementia and Subtypes of Dementia Comparing G biloba With Placebo for All Participants and Those Classified at Baseline With Normal Cognition and Mild Cognitive (more ...)
In an exploratory analysis, there was a statistically significant interaction with treatment in those participants reporting a history of CVD at baseline (P=.02). The adjusted HR for dementia for those participants free of CVD at baseline was 0.98 (95% CI, 0.79–1.20; P = .81). For the smaller subgroup of those with CVD at baseline (394 placebo, 392 G biloba), the HR was 1.56 (95% CI, 1.14–2.15; P = .006). also shows the HR for G biloba compared with placebo for the secondary end point of vascular dementia. Only 24 individuals were classified as having new-onset vascular dementia alone (ie, without concomitant AD), and the rate of dementia in this classification for G biloba vs placebo was 0.08 per 100 person-years and 0.20 per 100 person-years, respectively (HR, 0.41; 95% CI, 0.17–0.98; P=.05). The test for deviations from proportional hazards for the primary end point of dementia was not significant. Lastly, while APOE genotype for those with at least 1 APOE ε4 allele was associated strongly with incident dementia (HR, 2.12; 95% CI, 1.63–2.96; P<.001), there was no evidence of any interaction between APOE status and treatment (P=.75).
The adverse event profiles for G biloba and placebo were similar and there were no statistically significant differences in the rate of serious adverse events, as shown in . The mortality rate was similar in the 2 treatment groups () (HR, 1.04; 95% CI, 0.85–1.26; P = .72). There were no differences in the incidence of coronary heart disease (myocardial infarction, angina, angioplasty, or coronary artery bypass graft) or stroke of any type by treatment group. Of particular note, as shown in , rates of major bleeding did not differ between the treatment groups (HR, 0.97; 95% CI, 0.77–1.23; P=.81), and bleeding incidence did not differ for individuals taking aspirin and assigned to either G biloba or placebo (rates of 1.98 and 1.76 per 100 person-years, respectively, P = .44). Although there were twice as many hemorrhagic strokes in the G biloba group compared with the placebo group (16 vs 8), the number of cases was small and nonsignificant in the analysis. A complete listing of the rates of adverse events by organ system can be found online (eTable 2).
Specific Serious Adverse Events