The objective of this study was to determine if an extract of Ginkgo biloba (EGb 761) would lengthen the amount of time adults with peripheral artery disease were capable of walking on a treadmill. A moderately large but non-significant increase in maximal walking time and a negligible increase in pain-free walking time were observed for the Ginkgo group relative to the placebo group after 4 months of treatment. Similar to the results for maximal walking time, a modest but non-significant increase in flow mediated vasodilation was observed for the Ginkgo group compared to placebo. There was no impact of treatment on antibodies to epitopes of oxidized LDL.
In a meta-analysis of 8 studies using Ginkgo biloba for patients with peripheral artery disease, 6 of the 7 studies reporting data on maximal walking time observed significant differences that favored the active Ginkgo treatment.3
The range of net improvement, relative to the placebo group, varied from 36-189 meters. In the current study, the net difference in pre-post walking time improvement for the Ginkgo group was equivalent to 87 meters, which in absolute numbers was of greater magnitude than that of 3 of the 6 studies from the meta-analysis that reported statistically significant improvements. The sample sizes of the studies included in the meta-analysis ranged from 20-111 with a mean of 52, placing the current study with 62 patients as one of the larger studies in this set. Six of the studies in the meta-analysis had a duration of 24 weeks. The only study that did not report a significant improvement in walking times for the Ginkgo group had a 12-week duration. The current study had a 16-week duration. It is possible that a longer duration in the current study would have yielded a larger effect. Overall, despite the lack of significant difference achieved for the Ginkgo group in the current study, our findings suggest a trend that is relatively consistent with the small benefits for ginkgo reported in the meta- analysis for maximal treadmill walking time.
One potential moderator of effect in the current study was the baseline walking time. A primary inclusion/exclusion criterion was a baseline maximal walking time of at least 1 minute but not more than 10 minutes (average of 2 assessments). A small number of participants, 6 in the Ginkgo group and 5 in the placebo group, had baseline maximal walking times at the upper end of the allowable range, between 5 and 10 minutes. Among these individuals, 3 of the 6 in the Ginkgo group experienced more than a doubling of their maximal walking time. In contrast, none of the 5 participants in the placebo group with a 5-10 minute baseline walking time experienced dramatic improvements. In a statistical model that included baseline walking time as a potential effect moderator, this factor did not achieve statistical significance. The opportunity to detect a significant moderating or threshold effect was likely limited by the small numbers of study participants in the upper half of the range of baseline walking time. However, it is plausible that individuals with more advanced peripheral artery disease and shorter maximal walking times would be less responsive to therapy. In future studies it may be important to determine if there is a threshold of walking time or of the progression of PAD below which the opportunity for benefit from Ginkgo therapy is substantially diminished.
There are very few available treatments for the intermittent claudication of patients with PAD. Two pharmacological therapies that have received FDA approval are pentoxifylline (Trental) and cilostazol (Pletal). One trial contrasting Pentoxifylline with Ginkgo reported similar, but modest effects on claudication for both therapies, relative to placebo.32
Of the 2 FDA approved medicines, cilostazol is reported to be the more effective of the two.33, 34
We are not aware of any head-to-head comparisons of Cilostazol and Ginkgo. However, neither of the FDA approved medications is currently as effective as exercise therapy. A review of available data on exercise for intermittent claudication identified 10 published trials that met specific inclusion/exclusion criteria related to study quality and data presentation.35
Overall improvement in treadmill walking time was 150% (range 74-230%). At this time, exercise is considered the most effective therapy for PAD.
A secondary goal of the study was to seek mechanisms for any beneficial effects. Although the lack of significance for the main endpoint of increased walking duration in this study provides little reason to explore possible mechanisms, the data collected to examine this question may be of relevance to other studies with other endpoints and health outcomes. Recent as well as earlier studies have reported in vitro and in vivo effects of Ginkgo biloba on nitric oxide production consistent with vasodilatory effects36,37
and antioxidant effects.38,39
We did not observe significant effects for either FMVD or in levels of antibodies to epitopes of oxidized LDL in the current human trial.
There were several strengths and limitations for the current study. The randomized, double-blind, placebo controlled design of the trial was a strength. Other strengths included a high retention rate, good adherence to study tablets, and the use of a well-characterized and standardized Ginkgo product. A limitation may have been the 4-month duration; a greater effect may have been detectable with a longer treatment period. Finally, although not necessarily a limitation, it was notable that the participants in this study suffered from a number of comorbidities as evidenced by their extensive use of prescribed medications. Given the range and frequency of their comorbid conditions, this may have limited the opportunity to demonstrate the effect of Ginkgo supplementation on the outcome of treadmill walking duration.
Currently there are limited pharmacological therapies for the millions of individuals who suffer from the intermittent claudication of PAD. Identifying and testing potential new therapies is of great clinical importance.40
Although previous studies and a meta-analysis have suggested Ginkgo biloba may be a useful herbal therapy for this condition, the results observed in the current trial provide little evidence for effectiveness. Exercise remains the most effective therapy, which typically implies walking activities. However, given that it is walking that brings on the intermittent claudication, this can be a difficult therapy to adhere to for individuals with PAD. Therapies that produce even small benefits in increasing pain-free and maximal walking time could provide helpful adjuvant therapy by making it easier to participate in walking activities. At this time, the emphasis of therapeutic strategies should continue to focus on increasing the frequency of, and time spent, walking, and on any adjuvant therapies that can help to promote this increased exercise.