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Ginkgo Biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials
Ginkgo Biloba Extract for the Treatment of Intermittent Claudication: A Meta-Analysis of Randomized Trials Max H. Pittler, MD, Edzard Ernst, MD, PhD PURPOSE: The optimal treatment of intermittent claudication has not yet been identified. Ginkgo biloba extract has been reported to have beneficial effects. We performed a metaanalysis of the efficacy of Ginkgo biloba extract for intermittent claudication based on the results of randomized, placebo-controlled, double-blind trials. METHODS: Literature searches of MEDLINE, EMBASE, BIOSIS, AMED, CISCOM, and the Cochrane Library were performed to identify studies on the topic. Manufacturers of commercial Ginkgo biloba products and authors of original publications and reviews were contacted to provide additional information. No language restrictions were imposed. RESULTS: Eight randomized, placebo-controlled, double-
blind trials were included. Meta-analysis found a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba (weighted mean difference: 34 meters, 95% confidence interval [CI]: 26 to 43 meters). In studies using similar methodological features (ergometer speed: 3 km/h, inclination: 12%) this difference was 33 meters in favor of Ginkgo biloba (95% CI: 22 to 43 meters). Adverse effects were rare, mild, and transient. CONCLUSIONS: These results suggest that Ginkgo biloba extract is superior to placebo in the symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is modest and of uncertain clinical relevance. Am J Med. 2000;108:276 –281. 䉷2000 by Excerpta Medica, Inc.
P
herb in the United States (19), at a time when US sales of herbal medicines reached $4 billion, with an annual growth rate of 25% (20,21). Ginkgo has been more extensively researched than many other medicinal plants (22). We assessed the efficacy of Ginkgo biloba extract for intermittent claudication in a meta-analysis of the results of randomized, placebo-controlled, double-blind trials.
eripheral arterial disease, a common cause of morbidity in the elderly and a potential threat to functional independence, may result in hospitalization, surgery, and even death (1,2). The annual incidence of intermittent claudication, an early symptom of peripheral arterial disease, increases sharply with age (3– 6), from 7 to 19 cases per 10,000 persons between the ages of 45 to 54 years to 54 to 61 cases per 10,000 persons between 65 and 74 years of age (4). Treatment of intermittent claudication is usually conservative (7) and consists largely of regular physical exercise and pharmacological interventions (8 –10). Regular walking to near-maximal pain for 2 to 6 months is effective (8,9), but compliance is often poor. Pentoxifylline is approved in the United States for the pharmacologic treatment of intermittent claudication (11,12), but its clinical effects are modest. Recently cilostazol has also been approved for this condition (13). Extract of Ginkgo biloba leaves has been suggested as a treatment for intermittent claudication by a number of controlled but nonrandomized studies (14 –17). Nonrandomization, however, may have resulted in a substantial overestimation of the effect size (18). In 1998, Ginkgo biloba was the top selling medicinal
From the Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, United Kingdom. Requests for reprints should be addressed to Max H. Pittler, MD, Department of Complementary Medicine, University of Exeter, 25 Victoria Park Road, Exeter, EX2 4NT, United Kingdom. Manuscript submitted February 26, 1999, and accepted in revised form November 11, 1999. 276
䉷2000 by Excerpta Medica, Inc. All rights reserved.
METHODS Systematic literature searches of MEDLINE, EMBASE, BIOSIS, AMED (British Library), CISCOM (Research Council for Complementary Medicine, London, UK), and the Cochrane Library (all from their respective inception to June 1998) were performed to identify all randomized trials of Ginkgo biloba for intermittent claudication. The search terms were ginkgo, gingko, and maidenhair tree. A manual search was performed of the bibliographies of studies and reviews located through the computer search and through scanning our own files. In addition, manufacturers of commercial Ginkgo biloba products were asked to contribute published and unpublished material. Most trials reported data that were not suitable for statistical pooling. Therefore, the authors of these original publications and authors of earlier reviews of the subject [eg (23)] were contacted to provide additional data. Trials were included if they were randomized, double blind, and placebo controlled. Studies that were performed using Ginkgo biloba in combination with other medications or remedies or that did not assess walking distance were excluded. No language restrictions were 0002-9343/00/$–see front matter PII S0002-9343(99)00454-4
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst
Table 1. Instrument Used to Assess Methodologic Quality* Each “yes” scores 1 point A. Study described as randomized (this includes the use of words such as random, randomly, and randomization)? B. Study described as double-blind? C. Description of withdrawals and dropouts? D. Method to generate the sequence of randomization described and appropriate (table of random numbers, computer generated, etc.)? E. Method of double-blinding described and appropriate (identical placebo, active placebo, dummy, etc.)? Deduct 1 point if: F. Method to generate the sequence of randomization described and inappropriate (patients were allocated alternately, or according to their date of birth, hospital number, etc.)? G. Method of double-blinding described and inappropriate (comparison of tablet versus injection with no double dummy, etc.)? * From Jadad et al (24).
imposed. Data extraction and evaluation were performed independently by the two reviewers using standardized, predefined criteria. Articles in languages other than English or German were translated in-house. The common outcome measure was pain-free walking distance, and the mean change compared with baseline was used to assess differences between the ginkgo and placebo groups. Maximal walking distance was assessed when possible. The scoring system developed by Jadad et al (24) (Table 1) was used to evaluate methodologic quality. Disagreements in the assessment of data were resolved by discussion and consensus was reached in all cases. Statistical pooling of results was performed using standard meta-analysis software (RevMan 3.01, Update Software Ltd., Oxford, England). Summary estimates of the treatment effect were calculated using the weighted means of the within-study treatment effects (25). Weighted mean differences and 95% confidence intervals (CI) were calculated using a random effects model. In a funnel plot, estimates of the common outcome measure were plotted against trial sample size (26).
RESULTS Twelve double-blind, placebo-controlled, randomized trials of Ginkgo biloba extract for intermittent claudication were retrieved (27–38). Four trials were excluded because they either were a duplicate publication (27) or did not assess walking distance (28 –30). Pain-free walking distance was measured in all eight remaining studies and was the primary efficacy criterion in four trials (31,34,37,38). It was defined using devices that forced the patients to walk at a set speed. Intermittent claudication was categorized according to the Fontaine criteria in all 415 studied patients. Six trials scored at least 4 points on the 5-point scoring system for quality (Table 2). Seven of the eight trials showed weighted mean differences that favored Ginkgo biloba extract compared with placebo (Table 2, Figure 1). Four of these trials had 95% confidence intervals that did not overlap an effect size of
zero, indicating significant differences. Statistical pooling of the results from all trials showed a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba compared with placebo (weighted mean difference: 34 meters, 95% CI: 26 to 43 meters). Three trials (involving 51% of the total patients who were studied) were performed using similar methodological features: an ergometer speed of 3 km/h at an inclination of 12% (31,37,38). The patients in these three studies received 120 to 160 mg of standardized Ginkgo biloba extract for 24 weeks. Meta-analysis of these results also showed a significant difference in the increase in painfree walking distance in favor of Ginkgo biloba compared with placebo (weighted mean difference: 33 meters, 95% CI: 22 to 43 meters). Analysis of the six trials scoring 4 or 5 points for methodological quality (31–36) yielded similar results (weighted mean difference: 37 meters, 95% CI: 26 to 47 meters). The mean difference in pain-free walking distance from baseline reported in the placebo group ranged from 4 to 33 meters. Three of the four negative studies (33,34,36) reported the largest improvements in the placebo group (from 22 to 33 meters). Seven studies reported results for maximal walking distance (Table 2). Six of these found significant differences in favor of Ginkgo biloba extract (31–33,35,37,38); the range of improvement varied from 36 to 189 meters. One study reported a deterioration in maximal walking distance in patients receiving ginkgo (36). A funnel plot of all the trials is presented in Figure 2. Studies with smaller sample sizes seem evenly distributed around the weighted mean difference in pain-free walking distance, while larger studies more closely resemble the combined overall estimate. However, there were too few studies for a firm conclusion on whether publication bias influenced the overall result. Five trials reported adverse effects from Ginkgo biloba extract. Abdominal complaints, nausea, and dyspepsia were reported most often. Three studies (34,37,38), representing 48% of the studied patients, did not report any March 2000
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Table 2. Double-blind, Placebo-controlled, Randomized Trials of Ginkgo biloba Extract for Intermittent Claudication
First Author (Ref)
Mean Baseline Pain-free Walking Distance (m)
Mean Increase in Mean Increase in Maximal Pain-free Walking Walking Distance (m) Distance (m)
Patients Daily Dose of Quality Entered Ginkgo biloba Ginkgo Placebo Ginkgo Placebo Ginkgo Placebo Extract Score (Analyzed)
Blume (31)
5
60 (58)
Natali (32)
4
25 (18)
Bauer (33)
4
80 (79)
Thomson (34)
4
49 (37)
Salz (35)§
4
29 (26)
Drabœk (36)§
4
20 (18)
Blume (37)
3
41 (40)
Peters (38)
3
111 (109)
120 mg for 24 weeks* 160 mg for 24 weeks 120 mg for 24 weeks‡ 120 mg for 24 weeks 160 mg for 6 weeks 120 mg for 12 weeks 160 mg for 24 weeks* 120 mg for 24 weeks*‡
51†
16†
Ergometer Test Speed, km/h (Grade, %)
100
110
47
11
78
100
61
16
188
⫺1
3 (5)
59
79
64
28
112
29
3 (10)
81
101
38
33
258
194
113
4
126
96
96
21
22
⫺1†
3†
81
74
38
4
46
5
3 (12)
108
104
45
21
61
25
3 (12)
3 (12)
4 (10) ⫺35
120 steps/min on flat ground 2.5–4 (8–16)
* Ginkgo biloba extract 761. † Median values. ‡ Advised to exercise. § Crossover study.
adverse effects in patients treated with Ginkgo biloba extract. The approximate daily treatment costs based on retail prices (July 1999) for a 1-month supply of medication were obtained for the American and German market. Costs for a dose of Ginkgo biloba extract (120 mg) range from $0.41 to $0.84 in the United States, and from $0.83 to $0.97 in Germany ($1 ⫽ DM1.84). In comparison, in the United States, costs for a daily dose of pentoxifylline
Figure 1. Effects of Ginkgo biloba extract in patients with intermittent claudication. The weighted mean differences in the change in pain-free walking distance from baseline are given with 95% confidence intervals. The vertical line represents no difference between Ginkgo biloba extract and placebo. 278
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(1,200 mg) range from $1.83 to $1.93, and for cilostazol (200 mg) from $2.90 to $4.23.
DISCUSSION This meta-analysis of double-blind, randomized trials suggests that, compared with placebo, Ginkgo biloba ex-
Figure 2. Funnel plot of the mean difference in pain-free walking distance in trials of Ginkgo biloba extract, plotted against sample size. The vertical line indicates the weighted mean difference of all trials.
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst
tract is effective for intermittent claudication. This finding corroborates the results of previous analyses of less extensive data (23,39). Overall, the increase in pain-free walking distance was 34 meters in favor of Ginkgo biloba, a modest effect that is of uncertain clinical relevance. Pharmacological interventions for intermittent claudication approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol (11–13). A meta-analysis of all trials of pentoxifylline suggested a mean increase in pain-free walking distance of 57% compared with placebo (40). In another meta-analysis, a difference of about 21 meters for pain-free walking distance and 44 meters for maximal walking distance was estimated (41). A comparative study of pentoxifylline and Ginkgo biloba extract found a similar increase in pain-free and maximal walking distance for both treatments (42). Cilostazol is also efficacious for patients with intermittent claudication (43,44). However, the increase in pain-free walking distance with regular physical exercise is substantially greater than for medications, ranging from 88% to 190% improvement from baseline (8,9). A recent metaanalysis found a significant average increase in pain-free walking distance of 139 meters in favor of exercise training compared with placebo tablets or no intervention (41). One disadvantage of exercise therapy for intermittent claudication is the poor compliance with such programs. Pooling data in meta-analyses can be criticized (45,46). Findings from large trials do not always agree with results from meta-analyses of relatively small studies. The results of this meta-analysis, however, are consistent with the largest trial (38), and were consistent across studies and within subgroups. Not all studies may have been identified by our search; European journals, in particular, may be underrepresented in MEDLINE (47). This finding is of particular interest in relation to herbal medicine, as all reviewed trials originated from Europe, and only three were published by authors from non–German-speaking countries (32,34,36). In addition, negative trials may have gone unpublished (48), particularly for journals of complementary or alternative medicine in which studies with positive findings may be overrepresented (49,50). We located only one unpublished trial (32), but we are aware of at least one more unpublished, double-blind, placebocontrolled trial that could not be retrieved. That trial assessed patients treated with Ginkgo biloba extract (120 mg) during a 12-week time period. However, it is unlikely that the omission of one trial would have altered the direction of our main results. Although all trials scored at least 3 of 5 points on a scale that assessed the likelihood of bias (24), only one trial (31) reported the randomization procedure that was used. Thus, it is not certain whether adequate randomization procedures were used, and whether the allocation to treatment or control group was properly concealed.
These shortcomings could have contributed to an overestimation of the treatment effects (22). In addition, neither of the studies that used a crossover design (35,36) reported a wash-out period between treatments to reduce possible carry-over effects. The possibility that Ginkgo biloba may be effective for intermittent claudication is supported by its pharmacological actions. The main active principals are flavonoides and terpene trilactones, comprising bilobalide and ginkgolides (51). The latter, in particular ginkgolide B, inhibits platelet activating factor (52). Other actions include a decrease in eythrocyte aggregation and blood viscosity, as well as anti-ischemic effects through the increase of trancutaneous partial pressure of oxygen (28,29,53,54). Furthermore, recent in-vitro experiments have suggested that the vasorelaxing effects of Ginkgo biloba extract are related to the release of nitric oxide which, in turn, may be influenced by the free radical-scavenging activity of the extract (51). The relative importance of these actions for the clinical effects of Ginkgo biloba in intermittent claudication is, however, not known. Ginkgo biloba extracts seem to be relatively safe. Three studies, representing almost half of the entire patient sample, did not report any adverse effects in patients treated with Ginkgo biloba. Adverse effects most often reported in the ginkgo group in the other studies were stomach complaints, nausea, and dyspepsia. Pentoxifylline, on the other hand, is associated with cardiac arrhythmias, bleeding, and increased serum aminotransferase levels (55), while the most frequent adverse effects of cilostazol include headache and gastrointestinal symptoms (43). Finally, treatment costs are important. Calculated on the basis of the cost required to increase pain-free walking distance by 10%, the cost effectiveness of vasoactive compounds may be favorable compared with exercise programs (56). Similar studies comparing such data with data for Ginkgo biloba extract would be of interest. In conclusion, this meta-analysis suggests that oral medication with Ginkgo biloba extract prolongs the painfree (and maximal) walking distance in patients with intermittent claudication. The overall effect seems modest, and several caveats about the available trials prevent a final judgment on the efficacy of this treatment.
ACKNOWLEDGMENT The authors gratefully acknowledge Barbara Wider, MA, Department of Complementary Medicine, University of Exeter, for the translation of Danish and French articles. We would like to thank Katherine Gundling, MD, Department of Medicine, University of California, Davis, for the retrieval of cost data. March 2000
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REFERENCES 1. Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: a review. J Clin Epidemiol. 1992;45:529 –542. 2. Gillium RF. Peripheral arterial occlusive disease of the extremeties in the United States. Hospitalization and mortality. Am Heart J. 1990;120:1414 –1418. 3. Criqui MH, Fronek A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510 –515. 4. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2:221–226. 5. Kannel WB, McGee DL. Update on some epidemiologic features on intermittent claudication: the Framingham Study. J Am Geriatr Soc. 1985;33:13–18. 6. Balkau B, Vray M, Eschwege E. Epidemiology of peripheral arterial disease. J Cardiovasc Pharmacol. 1994;23(suppl 3):8 –16. 7. Coffman JD. Intermittent claudication— be conservative. NEJM. 1991;325:577–578. 8. Ernst E, Fialka V. A review of the clinical effectiveness of exercise therapy for intermittent claudication. Arch Intern Med. 1993;153: 2357–2360. 9. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA. 1995; 274:975–980. 10. McNamara DB, Champion HC, Kadowitz PJ. Pharmacologic management of peripheral vascular disease. Surg Clin North Am. 1998; 78:447– 464. 11. Lindga¨rde F, Jelnes R, Bjo¨rkman H, et al. Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease. Circulation. 1989;80:1549 –1556. 12. Gillings DB. Pentoxifylline and intermittent claudication: review of clinical trials and cost-effectiveness analyses. J Cardiovasc Pharmacol. 1995;25(suppl 2):44 –50. 13. Miller JL. Cilostazol approved for use in intermittent claudication. Am J Health Syst Pharm. 1999;56:404. 14. Courbier R, Jausseran JM, Reggi M. E´tude a` double insu croise´e du tanakan dans les arte´riopathies des membres infe´rieurs. Me´diterrane´e Me´dicale. 1977;126:61– 64. 15. Ambrosi C, Bourde C. Nouveaute´ the´rapeutique me´dicale dans les arte´riopathies des membres infe´rieurs: Tanakan. Gazette Me´dicale de France. 1975;82:628 – 633. 16. Frileux C, Cope´ R. L’extrait concentre´ de ginkgo biloba dans les troubles vasculaires pe´riphe´riques. Cahiers d’Arte´riologie de Royat. 1975;3:117–122. 17. Bulling B, Bary von S. Behandlung der chronischen peripheren arteriellen Verschlußkrankheit mit physikalischem Training und Ginkgo-biloba-extrakt 761. Med Welt. 1991;42:702–708. 18. Schulz KF, Chalmers J, Hyes RJ, Altman DG. Empirical evidence of bias. JAMA. 1995;273:408 – 412. 19. Brevoort P. The booming US botanical market—a new overview. Herbalgram. 1998;44:33– 46. 20. Brevoort P. The US botanical market—an overview. Herbalgram. 1996;36:49 –57. 21. Muller JL, Clauson KA. Pharmaceutical considerations of common herbal medicine. Am J Man Care. 1997;3:1753–1770. 22. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:1136 –1139. 23. Schneider B. Ginkgo-biloba-Extrakt bei peripheren arteriellen Verschlußkrankheiten. Arzneim-Forsch/Drug Res. 1992;42:428 – 436. 24. Jadad AR, Moore A, Carroll D, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Cont Clin Trials. 1996;17:1–12. 25. Follmann D, Elliot P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45:769 –773. 280
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26. Egger M, Davey Smith G. Misleading meta-analysis. BMJ. 1995;310: 752–754. 27. Bauer U. Ginkgo biloba extract in the treatment of lower limb arteritis. La Presse Me´dicale. 1986;15:1546 –1549. 28. Rudofsky G. The effect of ginkgo biloba extract in cases of arterial occlusive disease. Fortschr Med. 1987;105:397– 400. 29. Mouren X, Caillard PH, Schwartz F. Study of the antiischemic action of EGb 761 in the treatment of peripheral arterial occlusive disease by TcPo2 determination. Angiology. 1994;45:413– 417. 30. Saudreau F, Serise JM, Pillet J, et al. Efficiency of ginkgo-biloba extract in treatment of stage III (Fontaine classification) chronic occlusive arterial diseases of the lower limbs. J Maladies Vasculaires (Paris). 1989;14:177–182. 31. Blume J, Kieser M, Ho¨lscher U. Placebokontrollierte Doppelblindstudie zur Wirksamkeit von Ginkgo-biloba-Spezialextrakt EGb 761 bein austrainierten Patienten mit Claudicatio intermittens. VASA. 1996;25:265–274. 32. Natali J, Boissier P. Internal report. Schwabe. 1985. 33. Bauer U. Six-month double-blind randomised clinical trial of ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneim-Forsch/Drug Res. 1984;34:716 –720. 34. Thomson GJL, Vohra RK, Carr MH, Walker MG. A clinical trial of Ginkgo biloba extract in patients with intermittent claudication. Int Angiol. 1990;9:75–78. 35. Salz H. Zur Wirksamkeit eines Ginkgo-biloba-Pra¨parats bei arteriellen Durchblutungsto¨rungen der unteren Extremita¨ten. Therapie Gegenwart. 1980;119:1345–1356. 36. Drabœk H, Petersen JR, Wiinberg N, et al. Effekten af Ginkgo biloba-ekstrakt hos patienter med claudicatio intermittens. Ugeskr Lœger. 1996;158:3928 –3931. 37. Blume J, Kieser M, Ho¨lscher U. Ginkgo-Spezialextrakt EGb 761 bei peripherer arterieller Verschlußkrankheit. Fortschr Med (Originalien). 1998;116:137–143. 38. Peters H, Kieser M, Ho¨lscher U. Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication. A placebo-controlled, double-blind multicenter trial. VASA. 1998; 27:106 –110. 39. Ernst E. Ginkgo biloba in der Behandlung der Claudicatio intermittens. Fortschr Med. 1996;114:85– 87. 40. Letzel H, Schoop W. Ginkgo-biloba extract Egb 761 und Pentoxifyllin bei Claudicatio intermittens. Sekunda¨ranalyse zur klinischen Wirksamkeit. VASA. 1992;21:403– 410. 41. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxilylline or nafronyl. Arch Intern Med. 1999;159:337–345. 42. Bo¨hmer D, Kalinski S, Michaelis P, Szo¨gy A. Behandlung der PAVK mit Ginkgo-biloba-extrakt (GBE) oder Pentoxifyllin. Herz Kreislauf. 1988;20:5– 8. 43. Dawson DL, Cutler BS, Meissner MH, Strandness E. Cilostazol has beneficial effects in the treatment of intermittent claudication. Circulation. 1998;98:678 – 686. 44. Sorkin EM, Markham A. Cilostazol. Drugs Aging. 1999;14:63–71. 45. Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998;351:47–52. 46. Lau J, Ioannidis JPA, Schmid CH. Summing up evidence: one answer is not always enough. Lancet. 1998;351:123–127. 47. Nieminen P, Isohanni M. Bias against European journals in medical publication databases. Lancet. 1999;353:1592. 48. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337:867– 872. 49. Ernst E, Pittler MH. Alternative therapy bias. Nature. 1997;385:480. 50. Pittler MH, Abbot NC, Harkness EF, Ernst E. Location bias in controlled clinical trials of complementary/alternative therapies. J Clin Epidemiol. In press.
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst 51. van Beek TA, Bombardelli E, Morazzoni P, Peterlongo F. Ginkgo biloba L. Fitoterapia. 1998;69:195–244. 52. Reuter HD. Ginkgo biloba— botany, constituents, pharmacology and clinical trials. Br J Phytother. 1995/96;4:3–20. 53. Jung F, Mrowietz C, Kiesewetter H, Wenzel E. Effect of ginkgo biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneim-Forsch/Drug Res. 1990;40:589 –593.
54. Ernst E, Matrai A. Ha¨morheologische in-vitro Effekte von Ginkgo biloba. Herz Kreislauf. 1986;18:350 –360. 55. Bundesverband der Pharmazeutischen Industrie. Frankfurt, Germany: Editio Cantor; 1999. 56. Rudofsky G, van Laak HH. Treatment costs of peripheral arterial occlusive disease in Germany: a comparison of costs and efficacy. J Cardiovasc Pharmacol. 1994;23(suppl.3):S22–S25.
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blind trials were included. Meta-analysis found a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba (weighted mean difference: 34 meters, 95% confidence interval [CI]: 26 to 43 meters). In studies using similar methodological features (ergometer speed: 3 km/h, inclination: 12%) this difference was 33 meters in favor of Ginkgo biloba (95% CI: 22 to 43 meters). Adverse effects were rare, mild, and transient. CONCLUSIONS: These results suggest that Ginkgo biloba extract is superior to placebo in the symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is modest and of uncertain clinical relevance. Am J Med. 2000;108:276 –281. 䉷2000 by Excerpta Medica, Inc.
P
herb in the United States (19), at a time when US sales of herbal medicines reached $4 billion, with an annual growth rate of 25% (20,21). Ginkgo has been more extensively researched than many other medicinal plants (22). We assessed the efficacy of Ginkgo biloba extract for intermittent claudication in a meta-analysis of the results of randomized, placebo-controlled, double-blind trials.
eripheral arterial disease, a common cause of morbidity in the elderly and a potential threat to functional independence, may result in hospitalization, surgery, and even death (1,2). The annual incidence of intermittent claudication, an early symptom of peripheral arterial disease, increases sharply with age (3– 6), from 7 to 19 cases per 10,000 persons between the ages of 45 to 54 years to 54 to 61 cases per 10,000 persons between 65 and 74 years of age (4). Treatment of intermittent claudication is usually conservative (7) and consists largely of regular physical exercise and pharmacological interventions (8 –10). Regular walking to near-maximal pain for 2 to 6 months is effective (8,9), but compliance is often poor. Pentoxifylline is approved in the United States for the pharmacologic treatment of intermittent claudication (11,12), but its clinical effects are modest. Recently cilostazol has also been approved for this condition (13). Extract of Ginkgo biloba leaves has been suggested as a treatment for intermittent claudication by a number of controlled but nonrandomized studies (14 –17). Nonrandomization, however, may have resulted in a substantial overestimation of the effect size (18). In 1998, Ginkgo biloba was the top selling medicinal
From the Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, United Kingdom. Requests for reprints should be addressed to Max H. Pittler, MD, Department of Complementary Medicine, University of Exeter, 25 Victoria Park Road, Exeter, EX2 4NT, United Kingdom. Manuscript submitted February 26, 1999, and accepted in revised form November 11, 1999. 276
䉷2000 by Excerpta Medica, Inc. All rights reserved.
METHODS Systematic literature searches of MEDLINE, EMBASE, BIOSIS, AMED (British Library), CISCOM (Research Council for Complementary Medicine, London, UK), and the Cochrane Library (all from their respective inception to June 1998) were performed to identify all randomized trials of Ginkgo biloba for intermittent claudication. The search terms were ginkgo, gingko, and maidenhair tree. A manual search was performed of the bibliographies of studies and reviews located through the computer search and through scanning our own files. In addition, manufacturers of commercial Ginkgo biloba products were asked to contribute published and unpublished material. Most trials reported data that were not suitable for statistical pooling. Therefore, the authors of these original publications and authors of earlier reviews of the subject [eg (23)] were contacted to provide additional data. Trials were included if they were randomized, double blind, and placebo controlled. Studies that were performed using Ginkgo biloba in combination with other medications or remedies or that did not assess walking distance were excluded. No language restrictions were 0002-9343/00/$–see front matter PII S0002-9343(99)00454-4
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst
Table 1. Instrument Used to Assess Methodologic Quality* Each “yes” scores 1 point A. Study described as randomized (this includes the use of words such as random, randomly, and randomization)? B. Study described as double-blind? C. Description of withdrawals and dropouts? D. Method to generate the sequence of randomization described and appropriate (table of random numbers, computer generated, etc.)? E. Method of double-blinding described and appropriate (identical placebo, active placebo, dummy, etc.)? Deduct 1 point if: F. Method to generate the sequence of randomization described and inappropriate (patients were allocated alternately, or according to their date of birth, hospital number, etc.)? G. Method of double-blinding described and inappropriate (comparison of tablet versus injection with no double dummy, etc.)? * From Jadad et al (24).
imposed. Data extraction and evaluation were performed independently by the two reviewers using standardized, predefined criteria. Articles in languages other than English or German were translated in-house. The common outcome measure was pain-free walking distance, and the mean change compared with baseline was used to assess differences between the ginkgo and placebo groups. Maximal walking distance was assessed when possible. The scoring system developed by Jadad et al (24) (Table 1) was used to evaluate methodologic quality. Disagreements in the assessment of data were resolved by discussion and consensus was reached in all cases. Statistical pooling of results was performed using standard meta-analysis software (RevMan 3.01, Update Software Ltd., Oxford, England). Summary estimates of the treatment effect were calculated using the weighted means of the within-study treatment effects (25). Weighted mean differences and 95% confidence intervals (CI) were calculated using a random effects model. In a funnel plot, estimates of the common outcome measure were plotted against trial sample size (26).
RESULTS Twelve double-blind, placebo-controlled, randomized trials of Ginkgo biloba extract for intermittent claudication were retrieved (27–38). Four trials were excluded because they either were a duplicate publication (27) or did not assess walking distance (28 –30). Pain-free walking distance was measured in all eight remaining studies and was the primary efficacy criterion in four trials (31,34,37,38). It was defined using devices that forced the patients to walk at a set speed. Intermittent claudication was categorized according to the Fontaine criteria in all 415 studied patients. Six trials scored at least 4 points on the 5-point scoring system for quality (Table 2). Seven of the eight trials showed weighted mean differences that favored Ginkgo biloba extract compared with placebo (Table 2, Figure 1). Four of these trials had 95% confidence intervals that did not overlap an effect size of
zero, indicating significant differences. Statistical pooling of the results from all trials showed a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba compared with placebo (weighted mean difference: 34 meters, 95% CI: 26 to 43 meters). Three trials (involving 51% of the total patients who were studied) were performed using similar methodological features: an ergometer speed of 3 km/h at an inclination of 12% (31,37,38). The patients in these three studies received 120 to 160 mg of standardized Ginkgo biloba extract for 24 weeks. Meta-analysis of these results also showed a significant difference in the increase in painfree walking distance in favor of Ginkgo biloba compared with placebo (weighted mean difference: 33 meters, 95% CI: 22 to 43 meters). Analysis of the six trials scoring 4 or 5 points for methodological quality (31–36) yielded similar results (weighted mean difference: 37 meters, 95% CI: 26 to 47 meters). The mean difference in pain-free walking distance from baseline reported in the placebo group ranged from 4 to 33 meters. Three of the four negative studies (33,34,36) reported the largest improvements in the placebo group (from 22 to 33 meters). Seven studies reported results for maximal walking distance (Table 2). Six of these found significant differences in favor of Ginkgo biloba extract (31–33,35,37,38); the range of improvement varied from 36 to 189 meters. One study reported a deterioration in maximal walking distance in patients receiving ginkgo (36). A funnel plot of all the trials is presented in Figure 2. Studies with smaller sample sizes seem evenly distributed around the weighted mean difference in pain-free walking distance, while larger studies more closely resemble the combined overall estimate. However, there were too few studies for a firm conclusion on whether publication bias influenced the overall result. Five trials reported adverse effects from Ginkgo biloba extract. Abdominal complaints, nausea, and dyspepsia were reported most often. Three studies (34,37,38), representing 48% of the studied patients, did not report any March 2000
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Table 2. Double-blind, Placebo-controlled, Randomized Trials of Ginkgo biloba Extract for Intermittent Claudication
First Author (Ref)
Mean Baseline Pain-free Walking Distance (m)
Mean Increase in Mean Increase in Maximal Pain-free Walking Walking Distance (m) Distance (m)
Patients Daily Dose of Quality Entered Ginkgo biloba Ginkgo Placebo Ginkgo Placebo Ginkgo Placebo Extract Score (Analyzed)
Blume (31)
5
60 (58)
Natali (32)
4
25 (18)
Bauer (33)
4
80 (79)
Thomson (34)
4
49 (37)
Salz (35)§
4
29 (26)
Drabœk (36)§
4
20 (18)
Blume (37)
3
41 (40)
Peters (38)
3
111 (109)
120 mg for 24 weeks* 160 mg for 24 weeks 120 mg for 24 weeks‡ 120 mg for 24 weeks 160 mg for 6 weeks 120 mg for 12 weeks 160 mg for 24 weeks* 120 mg for 24 weeks*‡
51†
16†
Ergometer Test Speed, km/h (Grade, %)
100
110
47
11
78
100
61
16
188
⫺1
3 (5)
59
79
64
28
112
29
3 (10)
81
101
38
33
258
194
113
4
126
96
96
21
22
⫺1†
3†
81
74
38
4
46
5
3 (12)
108
104
45
21
61
25
3 (12)
3 (12)
4 (10) ⫺35
120 steps/min on flat ground 2.5–4 (8–16)
* Ginkgo biloba extract 761. † Median values. ‡ Advised to exercise. § Crossover study.
adverse effects in patients treated with Ginkgo biloba extract. The approximate daily treatment costs based on retail prices (July 1999) for a 1-month supply of medication were obtained for the American and German market. Costs for a dose of Ginkgo biloba extract (120 mg) range from $0.41 to $0.84 in the United States, and from $0.83 to $0.97 in Germany ($1 ⫽ DM1.84). In comparison, in the United States, costs for a daily dose of pentoxifylline
Figure 1. Effects of Ginkgo biloba extract in patients with intermittent claudication. The weighted mean differences in the change in pain-free walking distance from baseline are given with 95% confidence intervals. The vertical line represents no difference between Ginkgo biloba extract and placebo. 278
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(1,200 mg) range from $1.83 to $1.93, and for cilostazol (200 mg) from $2.90 to $4.23.
DISCUSSION This meta-analysis of double-blind, randomized trials suggests that, compared with placebo, Ginkgo biloba ex-
Figure 2. Funnel plot of the mean difference in pain-free walking distance in trials of Ginkgo biloba extract, plotted against sample size. The vertical line indicates the weighted mean difference of all trials.
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst
tract is effective for intermittent claudication. This finding corroborates the results of previous analyses of less extensive data (23,39). Overall, the increase in pain-free walking distance was 34 meters in favor of Ginkgo biloba, a modest effect that is of uncertain clinical relevance. Pharmacological interventions for intermittent claudication approved by the Food and Drug Administration (FDA) include pentoxifylline and cilostazol (11–13). A meta-analysis of all trials of pentoxifylline suggested a mean increase in pain-free walking distance of 57% compared with placebo (40). In another meta-analysis, a difference of about 21 meters for pain-free walking distance and 44 meters for maximal walking distance was estimated (41). A comparative study of pentoxifylline and Ginkgo biloba extract found a similar increase in pain-free and maximal walking distance for both treatments (42). Cilostazol is also efficacious for patients with intermittent claudication (43,44). However, the increase in pain-free walking distance with regular physical exercise is substantially greater than for medications, ranging from 88% to 190% improvement from baseline (8,9). A recent metaanalysis found a significant average increase in pain-free walking distance of 139 meters in favor of exercise training compared with placebo tablets or no intervention (41). One disadvantage of exercise therapy for intermittent claudication is the poor compliance with such programs. Pooling data in meta-analyses can be criticized (45,46). Findings from large trials do not always agree with results from meta-analyses of relatively small studies. The results of this meta-analysis, however, are consistent with the largest trial (38), and were consistent across studies and within subgroups. Not all studies may have been identified by our search; European journals, in particular, may be underrepresented in MEDLINE (47). This finding is of particular interest in relation to herbal medicine, as all reviewed trials originated from Europe, and only three were published by authors from non–German-speaking countries (32,34,36). In addition, negative trials may have gone unpublished (48), particularly for journals of complementary or alternative medicine in which studies with positive findings may be overrepresented (49,50). We located only one unpublished trial (32), but we are aware of at least one more unpublished, double-blind, placebocontrolled trial that could not be retrieved. That trial assessed patients treated with Ginkgo biloba extract (120 mg) during a 12-week time period. However, it is unlikely that the omission of one trial would have altered the direction of our main results. Although all trials scored at least 3 of 5 points on a scale that assessed the likelihood of bias (24), only one trial (31) reported the randomization procedure that was used. Thus, it is not certain whether adequate randomization procedures were used, and whether the allocation to treatment or control group was properly concealed.
These shortcomings could have contributed to an overestimation of the treatment effects (22). In addition, neither of the studies that used a crossover design (35,36) reported a wash-out period between treatments to reduce possible carry-over effects. The possibility that Ginkgo biloba may be effective for intermittent claudication is supported by its pharmacological actions. The main active principals are flavonoides and terpene trilactones, comprising bilobalide and ginkgolides (51). The latter, in particular ginkgolide B, inhibits platelet activating factor (52). Other actions include a decrease in eythrocyte aggregation and blood viscosity, as well as anti-ischemic effects through the increase of trancutaneous partial pressure of oxygen (28,29,53,54). Furthermore, recent in-vitro experiments have suggested that the vasorelaxing effects of Ginkgo biloba extract are related to the release of nitric oxide which, in turn, may be influenced by the free radical-scavenging activity of the extract (51). The relative importance of these actions for the clinical effects of Ginkgo biloba in intermittent claudication is, however, not known. Ginkgo biloba extracts seem to be relatively safe. Three studies, representing almost half of the entire patient sample, did not report any adverse effects in patients treated with Ginkgo biloba. Adverse effects most often reported in the ginkgo group in the other studies were stomach complaints, nausea, and dyspepsia. Pentoxifylline, on the other hand, is associated with cardiac arrhythmias, bleeding, and increased serum aminotransferase levels (55), while the most frequent adverse effects of cilostazol include headache and gastrointestinal symptoms (43). Finally, treatment costs are important. Calculated on the basis of the cost required to increase pain-free walking distance by 10%, the cost effectiveness of vasoactive compounds may be favorable compared with exercise programs (56). Similar studies comparing such data with data for Ginkgo biloba extract would be of interest. In conclusion, this meta-analysis suggests that oral medication with Ginkgo biloba extract prolongs the painfree (and maximal) walking distance in patients with intermittent claudication. The overall effect seems modest, and several caveats about the available trials prevent a final judgment on the efficacy of this treatment.
ACKNOWLEDGMENT The authors gratefully acknowledge Barbara Wider, MA, Department of Complementary Medicine, University of Exeter, for the translation of Danish and French articles. We would like to thank Katherine Gundling, MD, Department of Medicine, University of California, Davis, for the retrieval of cost data. March 2000
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REFERENCES 1. Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: a review. J Clin Epidemiol. 1992;45:529 –542. 2. Gillium RF. Peripheral arterial occlusive disease of the extremeties in the United States. Hospitalization and mortality. Am Heart J. 1990;120:1414 –1418. 3. Criqui MH, Fronek A, Barrett-Connor E, et al. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510 –515. 4. Criqui MH, Denenberg JO, Langer RD, Fronek A. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2:221–226. 5. Kannel WB, McGee DL. Update on some epidemiologic features on intermittent claudication: the Framingham Study. J Am Geriatr Soc. 1985;33:13–18. 6. Balkau B, Vray M, Eschwege E. Epidemiology of peripheral arterial disease. J Cardiovasc Pharmacol. 1994;23(suppl 3):8 –16. 7. Coffman JD. Intermittent claudication— be conservative. NEJM. 1991;325:577–578. 8. Ernst E, Fialka V. A review of the clinical effectiveness of exercise therapy for intermittent claudication. Arch Intern Med. 1993;153: 2357–2360. 9. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA. 1995; 274:975–980. 10. McNamara DB, Champion HC, Kadowitz PJ. Pharmacologic management of peripheral vascular disease. Surg Clin North Am. 1998; 78:447– 464. 11. Lindga¨rde F, Jelnes R, Bjo¨rkman H, et al. Conservative drug treatment in patients with moderately severe chronic occlusive peripheral arterial disease. Circulation. 1989;80:1549 –1556. 12. Gillings DB. Pentoxifylline and intermittent claudication: review of clinical trials and cost-effectiveness analyses. J Cardiovasc Pharmacol. 1995;25(suppl 2):44 –50. 13. Miller JL. Cilostazol approved for use in intermittent claudication. Am J Health Syst Pharm. 1999;56:404. 14. Courbier R, Jausseran JM, Reggi M. E´tude a` double insu croise´e du tanakan dans les arte´riopathies des membres infe´rieurs. Me´diterrane´e Me´dicale. 1977;126:61– 64. 15. Ambrosi C, Bourde C. Nouveaute´ the´rapeutique me´dicale dans les arte´riopathies des membres infe´rieurs: Tanakan. Gazette Me´dicale de France. 1975;82:628 – 633. 16. Frileux C, Cope´ R. L’extrait concentre´ de ginkgo biloba dans les troubles vasculaires pe´riphe´riques. Cahiers d’Arte´riologie de Royat. 1975;3:117–122. 17. Bulling B, Bary von S. Behandlung der chronischen peripheren arteriellen Verschlußkrankheit mit physikalischem Training und Ginkgo-biloba-extrakt 761. Med Welt. 1991;42:702–708. 18. Schulz KF, Chalmers J, Hyes RJ, Altman DG. Empirical evidence of bias. JAMA. 1995;273:408 – 412. 19. Brevoort P. The booming US botanical market—a new overview. Herbalgram. 1998;44:33– 46. 20. Brevoort P. The US botanical market—an overview. Herbalgram. 1996;36:49 –57. 21. Muller JL, Clauson KA. Pharmaceutical considerations of common herbal medicine. Am J Man Care. 1997;3:1753–1770. 22. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet. 1992;340:1136 –1139. 23. Schneider B. Ginkgo-biloba-Extrakt bei peripheren arteriellen Verschlußkrankheiten. Arzneim-Forsch/Drug Res. 1992;42:428 – 436. 24. Jadad AR, Moore A, Carroll D, et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Cont Clin Trials. 1996;17:1–12. 25. Follmann D, Elliot P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45:769 –773. 280
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26. Egger M, Davey Smith G. Misleading meta-analysis. BMJ. 1995;310: 752–754. 27. Bauer U. Ginkgo biloba extract in the treatment of lower limb arteritis. La Presse Me´dicale. 1986;15:1546 –1549. 28. Rudofsky G. The effect of ginkgo biloba extract in cases of arterial occlusive disease. Fortschr Med. 1987;105:397– 400. 29. Mouren X, Caillard PH, Schwartz F. Study of the antiischemic action of EGb 761 in the treatment of peripheral arterial occlusive disease by TcPo2 determination. Angiology. 1994;45:413– 417. 30. Saudreau F, Serise JM, Pillet J, et al. Efficiency of ginkgo-biloba extract in treatment of stage III (Fontaine classification) chronic occlusive arterial diseases of the lower limbs. J Maladies Vasculaires (Paris). 1989;14:177–182. 31. Blume J, Kieser M, Ho¨lscher U. Placebokontrollierte Doppelblindstudie zur Wirksamkeit von Ginkgo-biloba-Spezialextrakt EGb 761 bein austrainierten Patienten mit Claudicatio intermittens. VASA. 1996;25:265–274. 32. Natali J, Boissier P. Internal report. Schwabe. 1985. 33. Bauer U. Six-month double-blind randomised clinical trial of ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneim-Forsch/Drug Res. 1984;34:716 –720. 34. Thomson GJL, Vohra RK, Carr MH, Walker MG. A clinical trial of Ginkgo biloba extract in patients with intermittent claudication. Int Angiol. 1990;9:75–78. 35. Salz H. Zur Wirksamkeit eines Ginkgo-biloba-Pra¨parats bei arteriellen Durchblutungsto¨rungen der unteren Extremita¨ten. Therapie Gegenwart. 1980;119:1345–1356. 36. Drabœk H, Petersen JR, Wiinberg N, et al. Effekten af Ginkgo biloba-ekstrakt hos patienter med claudicatio intermittens. Ugeskr Lœger. 1996;158:3928 –3931. 37. Blume J, Kieser M, Ho¨lscher U. Ginkgo-Spezialextrakt EGb 761 bei peripherer arterieller Verschlußkrankheit. Fortschr Med (Originalien). 1998;116:137–143. 38. Peters H, Kieser M, Ho¨lscher U. Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication. A placebo-controlled, double-blind multicenter trial. VASA. 1998; 27:106 –110. 39. Ernst E. Ginkgo biloba in der Behandlung der Claudicatio intermittens. Fortschr Med. 1996;114:85– 87. 40. Letzel H, Schoop W. Ginkgo-biloba extract Egb 761 und Pentoxifyllin bei Claudicatio intermittens. Sekunda¨ranalyse zur klinischen Wirksamkeit. VASA. 1992;21:403– 410. 41. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxilylline or nafronyl. Arch Intern Med. 1999;159:337–345. 42. Bo¨hmer D, Kalinski S, Michaelis P, Szo¨gy A. Behandlung der PAVK mit Ginkgo-biloba-extrakt (GBE) oder Pentoxifyllin. Herz Kreislauf. 1988;20:5– 8. 43. Dawson DL, Cutler BS, Meissner MH, Strandness E. Cilostazol has beneficial effects in the treatment of intermittent claudication. Circulation. 1998;98:678 – 686. 44. Sorkin EM, Markham A. Cilostazol. Drugs Aging. 1999;14:63–71. 45. Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet. 1998;351:47–52. 46. Lau J, Ioannidis JPA, Schmid CH. Summing up evidence: one answer is not always enough. Lancet. 1998;351:123–127. 47. Nieminen P, Isohanni M. Bias against European journals in medical publication databases. Lancet. 1999;353:1592. 48. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet. 1991;337:867– 872. 49. Ernst E, Pittler MH. Alternative therapy bias. Nature. 1997;385:480. 50. Pittler MH, Abbot NC, Harkness EF, Ernst E. Location bias in controlled clinical trials of complementary/alternative therapies. J Clin Epidemiol. In press.
Ginkgo Biloba Extract for Intermittent Claudication/Pittler and Ernst 51. van Beek TA, Bombardelli E, Morazzoni P, Peterlongo F. Ginkgo biloba L. Fitoterapia. 1998;69:195–244. 52. Reuter HD. Ginkgo biloba— botany, constituents, pharmacology and clinical trials. Br J Phytother. 1995/96;4:3–20. 53. Jung F, Mrowietz C, Kiesewetter H, Wenzel E. Effect of ginkgo biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneim-Forsch/Drug Res. 1990;40:589 –593.
54. Ernst E, Matrai A. Ha¨morheologische in-vitro Effekte von Ginkgo biloba. Herz Kreislauf. 1986;18:350 –360. 55. Bundesverband der Pharmazeutischen Industrie. Frankfurt, Germany: Editio Cantor; 1999. 56. Rudofsky G, van Laak HH. Treatment costs of peripheral arterial occlusive disease in Germany: a comparison of costs and efficacy. J Cardiovasc Pharmacol. 1994;23(suppl.3):S22–S25.
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