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Ginkgo biloba for intermittent claudication

  1. Saskia PA Nicolaï1,
  2. Lotte M Kruidenier2,
  3. Bianca LW Bendermacher2,
  4. Martin H Prins3,
  5. Rutger A Stokmans2,3,
  6. Pieter PHL Broos2,
  7. Joep AW Teijink2,3,*

Editorial Group: Cochrane Peripheral Vascular Diseases Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 13 MAR 2013

DOI: 10.1002/14651858.CD006888.pub3


How to Cite

Nicolaï SPA, Kruidenier LM, Bendermacher BLW, Prins MH, Stokmans RA, Broos PPHL, Teijink JAW. Ginkgo biloba for intermittent claudication. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD006888. DOI: 10.1002/14651858.CD006888.pub3.

Author Information

  1. 1

    Maastricht University, Department of General Practice, Maastricht, Netherlands

  2. 2

    Catharina Hospital, Department of Vascular Surgery, Eindhoven, Netherlands

  3. 3

    CAPHRI Research School, Maastricht University, Department of Epidemiology, Maastricht, Netherlands

*Joep AW Teijink, joep.teijink@cze.nl.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 6 JUN 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of the condition

Patients with peripheral arterial disease (PAD) suffer from a progressive narrowing and hardening of the arteries in one or both legs (atherosclerosis). The most common symptom of PAD is intermittent claudication (IC) defined as pain in the muscles of the leg occurring during exercise which is relieved by a short period of rest. This clinical phenomenon affects 1.6% to 4.5% of all people in the general population (Fowkes 1991; Hooi 1998; Meijer 1998; Murabito 2002).

 

Description of the intervention

Basic conservative treatment for patients with IC includes risk-factor modification and exercise therapy. Intermittent claudication is a manifestation of systemic atherosclerosis, thus all patients with this symptom should be treated with medical therapy for cardiovascular risk factors. Glucose and cholesterol metabolism and blood pressure should be optimised and, as smoking is considered the most important modifiable vascular risk factor, attention should be paid to smoking cessation. Antiplatelet therapy is indicated for all patients with IC to reduce the risk of a cardiovascular event (ATC 2002). Exercise therapy can improve the absolute claudication distance (ACD) by 150% (Leng 2004) and should be prescribed for symptom relief. A supervised exercise programme has more clinical benefits than an unsupervised exercise programme. A recent Cochrane review showed approximately a 150 metre difference in increased walking distance after three months in favour of supervised exercise therapy programmes compared with non-supervised therapy (Bendermacher 2006). Pharmacological treatments reported to be associated with improvement of leg symptoms include cilostazol, pentoxifylline, naftidrofuryl, statins, angiotensin-converting enzyme inhibitors and Ginkgo biloba extract (Bendermacher 2005; Hankey 2006).

 

How the intervention might work

Ginkgo biloba extract is derived from the leaves of Ginkgo biloba, the only surviving species of the Ginkgoaceae family of trees. It has been used in traditional Chinese medicine for centuries. In the western world Ginkgo biloba extract is prescribed mainly for IC, cerebral insufficiency and tinnitus. The extract is made from dried leaves, and preparations for use are standardised to contain the same ingredients in similar doses of 24% ginkgo flavonoids and 6% terpenoids. Flavonoids are believed to contribute to Ginkgo's antioxidant properties. In vitro studies of Ginkgo biloba demonstrated free-radical scavenging properties (Pincemail 1989) and prolongation of the half-life of endothelial-derived relaxing factor (Robak 1988) resulting in improved microcirculation by inducing relaxation of contracted blood vessels (Kleijnen 1992). In other in vitro experiments, the ginkgolides, components of the terpenoids, inhibit the activity of platelet-activating factor (Korth 1988), resulting in diminished platelet aggregation, neutrophil degranulation and oxygen-free radical production (Kleijnen 1992). Based on the use of Ginkgo biloba in traditional Chinese medicine and the vasoactive properties of Ginkgo biloba, Ginkgo biloba is being used in Western medicine for the relief of symptoms of PAD.

 

Why it is important to do this review

To establish the clinical effect in patients with PAD we performed a systematic review. Possible problems with such a review of Ginkgo biloba extract is the potential for small unpublished studies, especially from relatively inexperienced and small research groups. Moreover, strong beliefs and financial interest could hamper the publication of negative trials. Hence, it is important to explore the possibility of publication bias in detail.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To determine the effect of Ginkgo biloba extract on the walking capacity of people with intermittent claudication.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All randomised controlled trials of Ginkgo biloba extract versus placebo in people with IC (stage II according to Fontaine (Fontaine 1954); stages 1 to 3 according to Rutherford (Rutherford 1997).

 

Types of participants

Adults (18 years and older) with IC, according to Fontaine stage II or Rutherford stages 1 to 3.

 

Types of interventions

Ginkgo biloba extract was compared with placebo for IC. Incuded studies used standardised Ginkgo biloba extracts. All studies were included irrespective of dosage.

 

Types of outcome measures

 

Primary outcomes

The primary outcome measurement was the absolute claudication distance (ACD) at the end of the study.

 

Secondary outcomes

Secondary outcomes were initial claudication distance (ICD), ankle brachial index (ABI), quality of life (QoL) and adverse reactions.

 

Search methods for identification of studies

 

Electronic searches

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (March 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 2, part of The Cochrane Library, (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the (Specialised Register) section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).

For the previous version of the review the authors searched MEDLINE/PUBMED (January 1966 to May 2008) and EMBASE (January 1985 to May 2008) using the search strategy described in Appendix 2 which was adapted for each database.

 

Searching other resources

We checked the reference lists of all retrieved articles. In addition, we attempted to identify unpublished studies and contacted manufacturers of Ginkgo biloba products to ask for information about any published and unpublished studies. We did not apply any language restrictions.

 

Data collection and analysis

 

Selection of trials

For the 2013 update, two authors (RS and PB) independently assessed trials identified by the literature search. In the previous version, two authors (SN and LK) independently selected eligible trials identified by the literature search.

 

Quality of trials

Two authors (SN and LK) independently assessed the selected trials for methodological quality using The Cochrane Collaboration tool for assessing risk of bias (Higgins 2008). Trials were assessed with respect to sequence generation, allocation concealment and blinding in each group. We resolved discrepancies by discussion, or, if this failed, by consulting authors MP and JT. The results were checked for accuracy by BB.

 

Data extraction

Two authors (SN and LK) independently extracted data using standardised data extraction forms.

 

Data analysis

Data were analysed using Review Manager (RevMan 5) software. Treadmill testing is the main assessment used to quantify therapy effect and walking ability in patients with PAD. In studies concerning medical therapy for PAD, the change in walking distance is assessed by different treadmill protocols that vary in speed and incline of the treadmill. Owing to the diverse workloads of different protocols, it is difficult to compare increases in walking distance (metres) or time. To standardise walking distance caloric expenditure is used to express the difference. This was calculated from the speed and incline of the treadmill.

We explored publication bias by relating the observed treatment effect  to the standard error of the mean difference. We used meta-regression to assess statistically the effect of publication bias. For this purpose the square root of the size of the study was introduced as a covariate in the assessment of the size of the treatment effect. Three domains of quality assessment were applied according to The Cochrane Collaboration tool for assessing risk of bias (Figure 1; Figure 2) (Higgins 2008). As many studies were assessed as unclear risk of bias, all studies were included in the primary analysis (see Risk of Bias section). Additionally, we explored dose-effect relationship using meta-regression.

 FigureFigure 1. Methodological quality summary: review authors' judgments about each methodological quality item for each included study.
 FigureFigure 2. Methodological quality graph: review authors' judgments about each methodological quality item presented as percentages across all included studies.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

 

Results of the search

See Appendix 1.

No additional studies were identified for inclusion in this update. One additional study was excluded (Sandreau 1989).

 

Included studies

For details of included studies see Characteristics of included studies.

We included 14 randomised controlled trials; 11 published trials and three unpublished trials. Five of the published articles were published in German (Bauer 1984; Blume 1996; Blume 1998; Bulling 1991; Salz 1980); five in English (Gardner 2008; Mouren 1994; Peters 1998; Thomson 1990; Wang 2007); and one in Danish (Drabaek 1996). One clinical trial was published as an abstract (Schoop 1997). Two internal reports with unpublished data (Diehm 1990; Natali 1985) which were mentioned in other published meta-analyses (Horsch 2004; Letzel 1992; Pittler 2000; Schneider 1992) were requested from the manufacturers. We contacted all authors of trials who did not report means and standard deviation for walking distances. However, we only received additional data for one trial (Gardner 2008). The two most recent trials were published in 2007 and 2008 (Gardner 2008; Wang 2007). The remaining 12 trials were published between 1984 and 1998.

The fourteen included trials involved a total of 739 participants. All these studies compared Ginkgo biloba with placebo in people with IC. The trials were conducted in Germany (8), France (2), Denmark (1), United States of America (1), United Kingdom (1) and Australia (1).The number of participants included in each trial varied between 18 and 209. The majority of trials included less than 50 participants and only two trials included more than 100 patients (Peters 1998; Schoop 1997). The mean age of the participants in the included trials varied between 60.9 and 71.6 years. Eleven trials included male and female participants. In three trials the gender of the participants was not described (Drabaek 1996; Mouren 1994; Thomson 1990).

In one trial maximal trained participants who did not further improve after a walking program of three to four times per week were included (Blume 1996). In another trial all participants received exercise therapy in combination with participation in the study (Bulling 1991), and one trial offered exercise therapy to all patients (Peters 1998). In this trial no information was given regarding how many patients actually participated in the exercise training program.

 

Inclusion criteria

In all 14 trials the patients had PAD according to Fontaine stage II (Fontaine 1954). Six trials mentioned that the situation should have been stable for a given period (three months to one year) (Bauer 1984; Blume 1998; Drabaek 1996; Mouren 1994; Natali 1985; Wang 2007), and in three trials the diagnosis was confirmed by angiography (Blume 1996; Blume 1998; Peters 1998). Four trials applied an age restriction; 40 to 75 years (Diehm 1990); 35 to 75 years (Mouren 1994); 30 to 75 years (Natali 1985); and 50 to 80 years (Wang 2007). In nine studies an upper limit of the ACD or ICD was used as an inclusion criterion. Inclusion criterion for the ACD were an ACD < 300 metres (Bauer 1984), ACD between 50 and 500 metres (Drabaek 1996; Gardner 2008) or an ACD between 100 and 500 metres (Mouren 1994) as assessed by treadmill testing. Inclusion criteria for the ICD were an ICD < 150 metres (Blume 1996; Peters 1998), ICD < 300 metres (Thomson 1990) or an ICD between 50 and 200 metres (Bulling 1991; Diehm 1990).

 

Exclusion criteria

The exclusion criteria were slightly variable between trials (see Characteristics of included studies). In all studies patients with PAD according to Fontaine stage III or IV were excluded. Patients with other reasons for a limited walking distance, e.g. cardiopulmonary or orthopaedic co-morbidities were also excluded.

 

Dosage and duration of treatment

There were no dose-related restrictions to the included trials in this review. Six trials included a comparison of 120 mg Ginkgo biloba daily versus placebo (Bauer 1984; Blume 1996; Diehm 1990; Drabaek 1996; Peters 1998; Schoop 1997) and three trials included the comparison of 160 mg Ginkgo biloba daily versus placebo (Blume 1998; Natali 1985; Salz 1980). Three trials, including the two most recent ones, compared daily dosages of 240 mg (Wang 2007), 300 mg (Gardner 2008) and 320 mg (Mouren 1994) Ginkgo biloba extract with placebo. The maximal follow-up period of eight trials was 24 weeks, of one trial 16 weeks, of three trials 12 weeks, of one trial six weeks, and of one trial four weeks.

 

Outcome measurements

The primary outcome measurement of the study was ACD. In 13 trials walking distances were mentioned. Data on the walking distances could not be retrieved from one trial (Mouren 1994). In two other studies, only data from ICD were presented (Schoop 1997; Thomson 1990). In 12 trials treadmill testing with different protocols was used to assess the ACD and/or ICD. In one trial (Salz 1980) walking distance was measured by walking on a flat floor with two steps per second.

In six trials data from ankle brachial index (ABI) or ankle pressures were presented (Bauer 1984; Bulling 1991; Drabaek 1996; Gardner 2008; Thomson 1990; Wang 2007).Only one study reported quality of life as administered by the MOS SF-36 questionnaire (Gardner 2008). Four trials presented data of a Visual Analogue Scale (VAS-scale) for the subjective estimate of pain (Bauer 1984; Blume 1996; Drabaek 1996; Thomson 1990) and one trial presents a VAS-scale for functional impairment (Mouren 1994). Nine trials reported on tolerance and adverse reactions of the medication and the placebo (Bauer 1984; Blume 1996; Blume 1998; Bulling 1991; Diehm 1990; Natali 1985; Peters 1998; Schoop 1997; Thomson 1990).

 

Excluded studies

For this update one additional study (Sandreau 1989) was excluded because it only included patients diagnosed with PAD stage III according to Fontaine. Twelve randomised controlled trials were excluded from analysis in 2009. Five of these trials compared Ginkgo biloba with another pharmacological treatment; dextran (Baitsch 1986), buflomedil (Berndt 1987), pentoxifylline (Bohmer 1988), naftidrofuryl (Horsch 1998), and the combination of Ginkgo biloba extract with magnesium and Levo-arginine compared with acetylsalicylic acid (Michelini 1998). In four trials, conducted in 1975, 1977 and 1981, the inclusion criterion to include patients only with PAD stage II according to Fontaine was not met and separate data for patients diagnosed with PAD stage II according to Fontaine were not available (Ambrosi 1975; Courbier 1977; Frileux 1975; Garzya 1981). In one trial the primary aim was to compare diabetic and non-diabetic PAD patients (Li 1998) and one double blind randomised cross-over study evaluated the short term effect (within 60 minutes) of Ginkgo biloba extract versus placebo in patients with PAD stage II according to Fontaine (Rudofsky 1987). One study compared two dosages of Ginkgo biloba extract without a placebo group (Schweizer 1999).

 

Risk of bias in included studies

 

Allocation

All 14 trials were randomised trials, however explicit generation of the allocation sequence was only described in six trials (Blume 1996; Diehm 1990; Gardner 2008; Mouren 1994; Salz 1980; Wang 2007) where a random number generator was used.

 

Blinding

Only one trial explicitly described an adequate allocation concealment. In this trial the allocation sequence was administered by a third party who was not involved in the study (Wang 2007). All trials were reported to be double blinded. However, only three trials describe explicitly how this blinding was performed and stated that participants and trial personnel were blinded to treatment assignment until the end of the study (Blume 1996; Gardner 2008; Wang 2007). Because most of the studies were assessed as unclear risk of bias, all studies were included in the primary analysis (Figure 1; Figure 2).

 

Effects of interventions

 

Absolute claudication distance

Data for the ACD at the end of the study were available in 11 trials with a total sample size of 477 participants. The effect was calculated after standardisation of the presented walking distances. The total caloric expenditure was calculated from the speed and incline of the treadmill and if possible the weight of the participants. At the end of the study the ACD increased with an overall effect size of 3.57 kcal (confidence interval (CI) -0.10 to 7.23, P = 0.06) (Figure 3), in favour of the Ginkgo biloba group, using a random-effects model. For a 70 kg weighted person this can be translated to an increase of 64.5 metres (CI -1.8 to 130.7) on a flat treadmill with an average speed of 3.2 km/h, which is most comparable with walking in daily life. 

 FigureFigure 3. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.1 Absolute claudication distance (expressed as kilocalories) at the end of the study.

Furthermore, the effect size was calculated for 24 weeks of treatment (Figure 4), 12 to 16 weeks of treatment (Figure 5) and 6 to 8 weeks of treatment (Figure 6) with Ginkgo biloba extract versus placebo. After a follow-up period of 24 weeks, data for six trials for ACD were available with a sample size of 321 participants. The ACD was increased with an overall effect size of 4.72 kcal (CI 2.27 to 7.16, P = 0.0002), in favour of the Ginkgo biloba group, using a random-effects model. This can be translated to 85.3 metres (CI 41.0 to 129.4) on a flat treadmill with an average speed of 3.2 km/h. After 12 to 16 weeks of follow-up data of eight trials (n = 339) present an increase in ACD with an overall effect size of 1.36 kcal (CI -2.63 to 5.36, P = 0.50). This was comparable with the overall effect size of 2.19 kcal ( CI -0.62 to 4.99, P = 0.13) after 6 to 8 weeks of follow up (n = 236).

 FigureFigure 4. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.2 Absolute claudication distance (expressed as kilocalories) after 24 weeks.
 FigureFigure 5. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.3 Absolute claudication distance (expressed as kilocalories) after 12 to 16 weeks.
 FigureFigure 6. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.4 Absolute claudication distance (expressed as kilocalories) after 6 to 8 weeks.

 

Initial claudication distance

Data for the ICD were present in 13 trials at the end of the study within a total of 723 participants (Figure 7). The ICD increased with a overall effect size of 1.84 kcal (CI -0.92 to 4.61, P = 0.19) with a random-effects model in favour of the Ginkgo biloba group. This corresponds with an increase in 33.3 metres (CI -16.7 to 83.3) for a 70 kg weighted adult with 3.2 km/h on a flat treadmill. After 24 weeks of treatment the overall effect size was 2.15 kcal (CI -2.06 to 6.36, P = 0.32) in favour of the Ginkgo biloba group (Figure 8). After 12 to 16 weeks (Figure 9) and 6 to 8 weeks (Figure 10) the overall effect sizes were 1.54 kcal (CI -0.04 to 3.12, P = 0.06) and 2.72 kcal (CI 0.75 to 4.69, P = 0.007), respectively.

 FigureFigure 7. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.5 Initial claudication distance (expressed as kilocalories) at the end of the study.
 FigureFigure 8. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.6 Initial claudication distance (expressed as kilocalories) after 24 weeks.
 FigureFigure 9. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.7 Initial claudication distance (expressed as kilocalories) after 12 to 16 weeks.
 FigureFigure 10. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.8 Initial claudication distance (expresses as kilocalories) after 6 to 8 weeks.

 

Ankle brachial index

In three trials the ABI (Drabaek 1996; Gardner 2008; Wang 2007) and in three trials ankle pressures (Bauer 1984; Bulling 1991; Thomson 1990) were presented. Therefore, the standardised mean differences were used to show an overall effect size of -0.22 (CI –0.58 to 0.15, P = 0.25) on the ABI or ankle pressures in favour of the placebo group (Figure 11).

 FigureFigure 11. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.9 Ankle brachial index and ankle pressure at the end of study.

 

Quality of life

One study collected QoL data using the standardised MOS SF-36 questionnaire (Gardner 2008). This study showed a significant improvement for the “role physical” domain in favour of the Ginkgo biloba study group (P = 0.03). The subjective assessment of pain and functional impairment administered by a VAS scale increased with an overall effect of 0.38 (CI –0.94 to 1.70, P = 0.57) in the Ginkgo biloba group (Bauer 1984; Blume 1996; Drabaek 1996; Mouren 1994; Thomson 1990) (Figure 12).

 FigureFigure 12. Forest plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.10 Quality of life (expressed as a Visual Analogue Scale for complaints).

 

Adverse reactions

Most common side effects of Ginkgo biloba included gastro-intestinal complaints, headache, allergic skin reactions. Furthermore, Ginkgo biloba may increase the risk of bleeding. Nine out of 14 studies reported tolerance on Ginkgo biloba, as assessed by adverse reactions. In five trials no side effects were observed (Blume 1998; Bulling 1991; Diehm 1990; Peters 1998; Schoop 1997). In the other four trials the following side effects were reported; nausea (2), gastro-intestinal complaints (2), blood in the urine (1), headache (1) (Bauer 1984; Blume 1996; Natali 1985; Thomson 1990). Overall, a low percentage of adverse reactions, which were all minor side effects, were found.

 

Assessment of publication bias

To explore publication bias two funnel plots in which the standard error of the mean difference was plotted against the mean difference were performed. The funnel plots for the ACD at the end of the study and the ACD after 24 weeks of follow up suggested publication bias as many smaller studies had more positive results. (Figure 13; Figure 14).

 FigureFigure 13. Funnel plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.1 Absolute claudication distance (expressed as kilocalories) at the end of the study. On the horizontal axis the effect estimate of Ginkgo biloba versus placebo on the absolute claudication distance at the end of the study is presented as the mean difference. The vertical axis presents the standard error of the intervention effect on a reversed scale.
 FigureFigure 14. Funnel plot of comparison: 1 Ginkgo biloba versus placebo, outcome: 1.2 Absolute claudication distance (expressed as kilocalories) after 24 weeks. On the horizontal axis the effect estimate of Ginkgo biloba versus placebo on the absolute claudication distance after 24 weeks is presented as the mean difference. The vertical axis presents the standard error of the intervention effect on a reversed scale.

 

Dosage of Ginkgo biloba

Meta-regression analysis did not show a significant effect on the effect of Ginkgo biloba on walking distance; neither did the dosage of the Ginkgo biloba extract.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Summary of main results

Eleven included trials with a total sample size of 477 patients did reveal non significant increases in ACD at the end of the study with a total effect size of 3.57 kcal. This corresponds with an increase of 64.5 metres on a flat treadmill (average speed 3.2 km/h). However, in clinical studies, most frequently a treadmill protocol of 3.2 km/h and 10% incline is used to assess therapy effect. Applying this protocol, 3.57 kcal represents an increase of 31 metres.

After 24 weeks of treatment we found a significant improvement in ACD with an overall effect size of 4.72 kcal, corresponding with 85.3 metres. However, in this analysis the number of patients who contributed was smaller, n = 321, and this analysis is likely to be more prone to publication bias (Figure 14).

For comparison, exercise therapy which is the main conservative treatment for symptomatic relief, is associated with 150% overall improvement of the ACD (Leng 2004). This translates into a benefit of 19.1 to 39.9 kcal, depending on the applied treadmill protocol to assess the improvement in walking distance. (19.1 kcal for 3.2 km/h and 0% increase, 39.9 kcal for 3.2 km/h and 10%, energy expenditures of graded protocols lie in between both). Hence, the effect of exercise therapy can be estimated to be approximately 5 to10 times greater than that of Ginkgo biloba extract. Moreover, supervised exercise therapy programs have an additional and significantly greater benefit than non-supervised regimens (Bendermacher 2006).

Other meta-analyses comparing pharmacological therapy (cilostazol, buflomedil, pentoxifylline and naftidrofuryl) with placebo for IC show similar results (Robless 2008; de Backer 2008; de Backer 2008a; Girolami 1999; Moher 2000). Possibly, the results on walking distance for buflomedil are most conclusive. Although all these comparisons are indirect, they support the generally accepted view that (supervised) exercise therapy is the main conservative therapy for patients with IC.

 

Clinical relevance

The clinical relevance of a non significant improvement of 64.5 metres in ACD is questionable. Quality of life, which is probably more important than the regained walking distance (for the patients' well being), was evaluated in only one trial. In this single study there was a borderline significant improvement of QoL (Gardner 2008). However, five trials assessed subjective assessment of pain and functional impairment by a VAS scale, which failed to show a statistically significant effect (Bauer 1984; Blume 1996; Drabaek 1996; Mouren 1994; Thomson 1990). 

 

Limitations of this review

Eleven out of fourteen studies reported data on ACD. Authors of the three other studies were contacted for the walking distances. However, they did not respond (Mouren 1994; Schoop 1997; Thomson 1990). In two articles only the median was presented with the corresponding 95% confidence intervals (CI) (Blume 1996; Drabaek 1996). The authors were contacted but did not reply and the median was used instead of the mean and the standard deviation was calculated from the 95% CI. In one study the standard deviations were not directly available and had to be derived from the reported P values (Blume 1998). Unfortunately, in two studies only the differences to the ACD at the start of the study were available with the corresponding P values. The ACD at baseline was calculated with the known proportions of the ICD and ACD in the other included studies (Peters 1998; Salz 1980).

Figure 13 and Figure 14 suggested publication bias as many smaller studies had more positive results. This publication bias leading to missing data or "negative" trials is likely to have inflated the effect size. Furthermore, most included studies were performed with a small sample size; the majority included less than 50 participants. Special attention should be paid for a more recent study by Wang et al. (Wang 2007) that presented data of 17 participants and is the only study that reported results contrary to the other studies (Figure 3).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Ginkgo biloba has no significant effect on walking distance in people with IC. Even if the small positive point estimate of the effect could be documented to be statistically significant in a larger trial, this effect would be marginal to the effect of (supervised) exercise therapy. Hence, currently no evidence supports the use of Ginkgo biloba in the treatment of PAD.

 
Implications for research

Before Ginkgo biloba can be advised for the use in clinical practice further research would be required. However, given the small absolute summary effect in the reported trials, it is unlikely that the effect of Ginkgo biloba will ever be clinically relevant.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

None

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
Download statistical data

 
Comparison 1. Ginkgo biloba versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Absolute claudication distance (expressed as kilocalories) at the end of the study11477Mean Difference (IV, Random, 95% CI)3.57 [-0.10, 7.23]

 2 Absolute claudication distance (expressed as kilocalories) after 24 weeks6321Mean Difference (IV, Random, 95% CI)4.72 [2.27, 7.16]

 3 Absolute claudication distance (expressed as kilocalories) after 12 to 16 weeks8339Mean Difference (IV, Random, 95% CI)1.36 [-2.63, 5.36]

 4 Absolute claudication distance (expressed as kilocalories) after 6 to 8 weeks5236Mean Difference (IV, Random, 95% CI)2.19 [-0.62, 4.99]

 5 Initial claudication distance (expressed as kilocalories) at the end of the study13723Mean Difference (IV, Random, 95% CI)1.84 [-0.92, 4.61]

 6 Initial claudication distance (expressed as kilocalories) after 24 weeks8564Mean Difference (IV, Random, 95% CI)2.15 [-2.06, 6.36]

 7 Initial claudication distance (expressed as kilocalories) after 12 to 16 weeks9441Mean Difference (IV, Random, 95% CI)1.54 [-0.04, 3.12]

 8 Initial claudication distance (expresses as kilocalories) after 6 to 8 weeks6335Mean Difference (IV, Random, 95% CI)2.72 [0.75, 4.69]

 9 Ankle brachial index and ankle pressure at the end of study6274Std. Mean Difference (IV, Random, 95% CI)-0.22 [-0.58, 0.15]

 10 Quality of life (expressed as a Visual Analoque Scale for complaints)5208Std. Mean Difference (IV, Random, 95% CI)0.38 [-0.94, 1.70]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. 2013 CENTRAL search strategy


#1MeSH descriptor: [Arteriosclerosis] this term only893

#2MeSH descriptor: [Arteriolosclerosis] this term only0

#3MeSH descriptor: [Arteriosclerosis Obliterans] this term only71

#4MeSH descriptor: [Atherosclerosis] this term only382

#5MeSH descriptor: [Arterial Occlusive Diseases] this term only755

#6MeSH descriptor: [Intermittent Claudication] this term only711

#7MeSH descriptor: [Ischemia] this term only753

#8MeSH descriptor: [Peripheral Vascular Diseases] explode all trees2150

#9MeSH descriptor: [Vascular Diseases] this term only381

#10(atherosclero* or arteriosclero* or PVD or PAOD or PAD) 17195

#11(arter*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 4872

#12(vascular) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 1378

#13(vein*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 713

#14(veno*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 976

#15(peripher*) near (*occlus* or steno* or obstuct* or lesio* or block* or obliter*) 1358

#16peripheral near/3 dis* 3243

#17arteriopathic 10

#18(claudic* or hinken*) 1436

#19(isch* or CLI) 16827

#20dysvascular* 14

#21leg near/4 (obstruct* or occlus* or steno* or block* or obliter*) 176

#22limb near/4 (obstruct* or occlus* or steno* or block* or obliter*) 228

#23(lower near/3 extrem*) near/4 (obstruct* or occlus* or steno* or block* or obliter*) 137

#24(aort* or iliac or femoral or popliteal or femoropop* or fempop* or crural) near/3 (obstruct* or occlus*) 322

#25#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 39158

#26MeSH descriptor: [Ginkgo biloba] this term only231

#27(ginkgo* or gingko* or gingkco* or ginko* or gingho or gincosan):ti,ab,kw 654

#28(bilobalid* or tebonin* or kaveri* or tanakan or tanakene or tebokan or rokan or supergin* or (li next 1370)):ti,ab,kw 57

#29(EGB761 or "EGB 761" or EGB-761):ti,ab,kw 134

#30#26 or #27 or #28 or #29 670

#31#25 and #30 in Trials90



 

Appendix 2. Search strategy used by authors to search MEDLINE and EMBASE

#1 Peripheral arterial disease
#2 Peripheral arterial occlusive disease
#3 PAD
#4 Intermittent claudication
#5 (#1 OR #2 OR #3 OR #4)
#6 Ginkgo biloba
#7 Egb 761
#8 Tavonin
#9 Tebonin
#10 Rokan
#11 (#6 OR #7 OR #8 OR #9 OR #10)
#12 (#5 AND #11)

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 13 March 2013.


DateEventDescription

13 March 2013New citation required but conclusions have not changedSearches were rerun. No new studies were included. One new study was excluded. Minor copy edits made. Two authors added to review team. Conclusions not changed.

13 March 2013New search has been performedSearches were rerun. No new studies were included. One new study was excluded.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 2008
Review first published: Issue 2, 2009


DateEventDescription

15 April 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Saskia Nicolaï and Lotte Kruidenier independently selected trials for inclusion, assessed study quality and extracted data. Bianca Bendermacher checked all results for accuracy. Martin Prins and Joep Teijink resolved disagreements. For the 2013 update, Rutger Stokmans and Pieter Broos independently selected trials for inclusion.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

MP reports his institution has received funds for his Board membership of clinical studies and invited speaker activities from Bayer, Pfizer, Leo, Daichi Sankyo and Sanofi-Aventis. These were not related to this review.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, Scottish Government, UK.
    The PVD Group editorial base is supported by the Chief Scientist Office.

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Bauer 1984 {published data only}
  • Bauer U. 6-Month double-blind randomised clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittelforschung 1984;34(6):716-20.
Blume 1996 {published data only}
  • Blume J, Kieser M, Holscher U. [Placebo-controlled double-blind study of the effectiveness of Ginkgo biloba special extract EGb 761 in trained patients with intermittent claudication]. Vasa 1996;25(3):265-74.
Blume 1998 {published data only}
  • Blume J, Kieser M, Hölscher U. Ginkgo-special-extract EGb 761 in peripheral arterial occlusive diseases stage IIb according to Fontaine. Fortschritte der Medizin 1998;116(35-6):36-7.
Bulling 1991 {published data only}
  • Bulling B, von Bary S. Treatment of chronic peripheral occlusive disease with physical training and ginkgo biloba extract 761 [Behandlung der chronischen peripheren arteriellen Verschlusskrankheit met physikalischem Training und Ginkgo-biloba-Extrakt 761, Ergebnisse einer placebokontrollierten Doppelblindstudie]. Medizinische Welt 1991;42(8):702-8.
Diehm 1990 {unpublished data only}
  • Diehm C, Heinrich F, Mörl H. Placebo-controlled, multicentre, randomised, double-blind pilot study examining the effectiveness of Ginkgo biloba extract EGb 761® in patients with Fontaine stage IIb peripheral aterial disease [Placebokontrollierte, multizentrische, randomisierte, doppelblinde Pilotstudie zur Prüfung der Wirksamkeit des Ginkgo-biloba-Extraktes EGb 761® bei Patienten mit peripherer arterieller Verschlusskrankheit im Stadium IIb nach Fontaine]. Internal report. Dr. Willmar Schwabe GmbH & Co. 1990.
Drabaek 1996 {published data only}
  • Drabaek H, Petersen JR, Winberg N, Hansen KF, Mehlsen J. The effect of Ginkgo biloba extract in patients with intermittent claudication. Ugeskrift for Laeger 1996;158(27):3928-31.
Gardner 2008 {published and unpublished data}
  • Gardner CD, Taylor-Piliae RE, Kiazand A, Nicholus J, Rigby AJ, Farquhar JW. Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral arterial disease: a randomized clinical trial. Journal of Cardiopulmonary Rehabilitation and Prevention 2008;28(4):258-65.
Mouren 1994 {published data only}
Natali 1985 {unpublished data only}
  • Natali J. Protocol for a study comparing Ginkgo biloba extract and placebo in patients with arteriopathy of the lower extremities [Protocole d'étude de l'extrait de Ginkgo biloba face au placebo dans l'artéropathie des membres inférieurs]. Internal Study Report, Ipsen, Paris 1985.
Peters 1998 {published data only}
  • Peters H, Kieser M, Holscher 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(2):106-10.
Salz 1980 {published data only}
  • Salz H. The effectiveness of a Ginkgo biloba preparation in arterial ischemic diseases of the leg. Controlled double-blind cross-over study. Therapie der Gegenwart 1980;119(11):1345-56.
Schoop 1997 {published data only}
  • Schoop W, Breddin K, Diehm C, Grub J, Held K, Horsch S, et al. Clinical test with ginkgo biloba EGb 761 extract for patients with peripheral arterial occlusive disease stage IIb fontaine in comparison with placebo [Klinische prufung mit ginkgo biloba-spezialextrakt EGb 761 bei patienten mit peripherer arterieller verschlusskrankheit im stadium IIb nach fontaine im vergleich zu placebo]. Vasa 1997;26(160):P15.
Thomson 1990 {published data only}
  • Thomson GJL, Vohra RK, Carr MH, Walker MG. A clinical trial of gingko biloba extract in patients with intermittent claudication. International Angiology 1990;9(2):75-8.
Wang 2007 {published data only}
  • Wang J, Zhou S, Bronks R, Graham J, Myers S. Supervised exercise training combined with ginkgo biloba treatment for patients with peripheral arterial disease. Clinical Rehabilitation 2007;21(7):579-86.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Ambrosi 1975 {published data only}
  • Ambrosi C, Bourde C. A new therapeutic intervention arteriopathies of the lower extremities: Tanakan. Clinical trial and study of liquid crystals [Nouveauté thèrapeutique médicinale dans les artériopathies des membres d'inferieur: Tanakan. Essai clinique et étude par les cristaux liquides]. Gazette médicale de France 1975;82(6):628-33.
Baitsch 1986 {published data only}
  • Baitsch G. Treatment of obliterative arterial disease in diabetics Fontaine's stage IV with moist gangrene, an open randomized trial of Ginkgo-biloba extract Roekan vs. Dextran 40. Clinical Trials Journal 1986;23(1):11-9.
Berndt 1987 {published data only}
  • Berndt ED, Kramer M. Medicational therapy of peripheral arterial occlusive disease in stage IIb [Medikamentöse Therapie der peripheren arteriellen Verschlusskrankheit im Staium IIb]. die Therapiewoche 1986;37:2815-9.
Bohmer 1988 {published data only}
  • Bohmer D, Kalinski S, Michaelis P, Szogy A. Efficacy and tolerance of Ginkgo biloba extract compared to that of pentoxifylline in the treatment of patients suffering from peripheral chronic arterial occlusive disease. Hers Kreislauf 1988;20(1):5-8.
Courbier 1977 {published data only}
  • Courbier R, Jausseran JM, Reggi M. Double blind, cross over trial of Tanakan in arteriopathies of the lower extremities [Étude à double insu croisée du Tanakan dans les arteriopathies des membres inférieurs]. Méditerranée Médicale 1977;126:61-4.
Frileux 1975 {published data only}
  • Frileux C, Cop R. Concentrated extract of Ginkgo biloba in peripheral vascular disorders [L'extrait concentré de Ginkgo biloba* dans les troubles vasculaires périphériques]. Cahiers d'Artériologie de Royat 1975;3:117-22.
Garzya 1981 {published data only}
  • Garzya G, Picari M. Treatment of peripheral vasculopathies with Ginkgo biloba extract [Trattamento della vasculopatie periferiche con una nuova sostanza estrattiva: il Tanakan]. Clinica Europea 1981;20(5):936-44.
Horsch 1998 {published data only}
  • Horsch S, Holscher U. Infusion therapy with ginkgo biloba special extract EGb 761 in patients with PAOD fontaine stages III and IV - A reference- controlled double-blind clinical trial. Munchener Medizinische Wochenschrift 1998;140(16):232-6.
Li 1998 {published data only}
  • Li AL, Shi YD, Landsmann B, Schanowski-Bouvier P, Dikta G, Bauer U, et al. Hemorheology and walking of peripheral arterial occlusive diseases patients during treatment with Ginkgo biloba extract. Acta pharmacologica Sinica 1998;19(5):417-21.
Michelini 1998 {published data only}
  • Michelini S, Micci A, Failla A, Moneta G, Ottaviani A. Study on the efficacy of ginkgo biloba extract, magnesium and levo-arginine in the treatment of patients with 2d stage arteriopathies. A preliminary study [Studio sull'efficiaca dell'estratto di ginkgo biloba, magnesio e levo-arginina nel trattamento dei pazienti arteriopatici al II stadio]. Minerva Cardioangiologica 1998;46(9):319-20.
Rudofsky 1987 {published data only}
  • Rudofsky G. Effect of Ginkgo biloba extract in cases of arterial occlusive disease. Randomized placebo controlled crossover study. Fortschritte der Medizin 1987;105(20):397-400.
Sandreau 1989 {published data only}
  • Saudreau F, Serise JM, Pillet J, Maiza D, Mercier V, Kretz JG, et al. Efficiency of Ginkgo-biloba extract in treatment of stages III (fontaine classification) chronic occlusive arterial diseases of the lower limbs. Journal des Maladies Vasculaires 1989;14(3):177-82.
Schweizer 1999 {published data only}
  • Schweizer J, Hautmann C. Comparison of two dosages of ginkgo biloba extract EGb 761 in patients with peripheral arterial occlusive disease Fontaine's stage IIb: A randomised, double-blind, multicentric clinical trial. Arzneimittel-Forschung 1999;49(11):900-4.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
ATC 2002
  • Antithrombotic Trialist's Collaboration (ATC). Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. British Medical Journal 2002;324(7329):71-86.
Bauer 1986a
Bauer 1986b
  • Bauer U. A two-year study of ginkgo biloba extract in the treatment of peripheral arterial disease (Fontaine stage IIb). What is New in Angiology? Trends and Controversies. Zuckschwerdt,W, 1986:531-2.
Bauer 1986c
  • Bauer U. Long-term treatment of the peripheral arterial clasp illness with Ginkgo biloba extract (GBE); a 3-year-investigation [Langzeitbehandlung der peripheren arteriellen Verschlusskrankheit met Ginkgo biloba Extrakt (GBE); eine 3-Jahres-Untersuchung]. Vasa 1986;15:S26.
Bendermacher 2005
Bendermacher 2006
de Backer 2008
de Backer 2008a
  • De Backer TLM, Vander Stichele R, Lehert P, Van Bortel L. Naftidrofuryl for intermittent claudication. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: 10.1002/14651858.CD001368.pub3]
Fontaine 1954
  • Fontaine R, Kim M, Kieny R. Surgical treatment for peripheral vascular disease [Die chirurgische Behandlung der peripheren Durchblutungsstörungen]. Helvetica Chirurgica Acta 1954;5/6:499-533.
Fowkes 1991
  • Fowkes FG, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. International Journal of Epidemiology 1991;20(2):384-92.
Girolami 1999
  • Girolami B, Bernardi E, Prins MH, ten Cate JW, Hettiarachchi R, Prandoni P, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl. A meta-analysis. Archives of Internal Medicine 1999;159(4):337-45.
Hankey 2006
Higgins 2008
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Hooi 1998
  • Hooi JD, Stoffers HEJH, Kester ADM, Rinkens PELM, Kaiser V, van Ree JW, et al. Risk factors and cardiovascular diseases associated with asymptomatic peripheral arterial occlusion disease. The Limburg PAOD study. Peripheral Arterial Occlusive Disease. Scandinavian Journal of Primary Health Care 1998;16(3):177-82.
Horsch 2004
  • Horsch S, Walther C. Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD) - a review based on randomized, controlled studies. International Journal of Clinical Pharmacology and Therapeutics 2004;42(2):63-72.
Kleijnen 1992
Korth 1988
Leng 2004
  • Leng GC, Fowler B, Ernst E. Exercise for intermittent claudication. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD000990]
Letzel 1992
  • Letzel H, Schoop W. Gingko biloba extract EGb 761 and pentoxifylline in intermittent claudication. Secondary analysis of the clinical effectiveness [Ginkgo-biloba-Extrakt EGb 761 und Pentoxifyllin bei Claudicatio intermittens. Sekundäranalyse zur klinischen Wirksamkeit]. VASA 1992;21(4):403-10.
Meijer 1998
Moher 2000
Murabito 2002
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Pincemail 1989
  • Pincemail J, Dupuis M, Nasr C, Hans P, Haag-Berrurier M, Anton R, et al. Superoxide anion scavenging effect and superoxide dismutase activity of Ginkgo biloba extract. Experientia 1989;45(8):708-12.
Pittler 2000
Robak 1988
Robless 2008
Rutherford 1997
  • Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. Journal of Vascular Surgery 1997;26(3):517-38.
Schneider 1992
  • Schneider B. Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies [Ginkgo-biloba-Extraxt bei peripheren arteriellen Verschlusskrankheiten; Meta-analyse von kontrolierten klinischen Studien]. Arzneimittel-Forschung 1992;42(4):428-36.