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The Use of Ginkgo Biloba Extract in Acute Ischemic Stroke
THE COCHRANE COLUMN
THE USE OF GINKGO BILOBA EXTRACT IN ACUTE ISCHEMIC STROKE Jianping Liu, MD, PhD
he Cochrane Complementary Medicine Field is the group within the Cochrane Collaboration focused on facilitating the conduct of Cochran systematic reviews of CAM therapies. The CAM Field represents an international collaborative effort among researchers, clinicians, consumers, and CAM practitioners from nearly every continent. The Field’s central office is located at the Center for Integrative Medicine, University of Maryland School of Medicine, 2200 Kernan Drive, Kernan Hospital Mansion, Baltimore, MD 21207-6697. For more information contact Eric Manheimer at: [email protected]. The coordination of the series of Cochrane columns is made possible by grant number 1 R24 AT001293-01 from the National Center for Complementary and Alternative Medicine (NCCAM). The contents of the column are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, the National Institutes of Health, or the Cochrane Collaboration.
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ABSTRACT OF THE COCHRANE REVIEW Background: Ginkgo biloba extract is widely used in the treatment of acute ischemic stroke in China. The Cochrane Review authors aimed to assess the evidence from randomized controlled trials and quasirandomized controlled trials on the use of Ginkgo biloba extract in acute ischemic stroke. Objectives: The primary objective is to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischemic stroke. Secondary objectives are to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life. Search Strategy: The authors searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials
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Register of the Cochrane Complementary Medicine Field (last searched October 2004), and the Chinese Stroke Trials Register (last searched June 2004). In addition, the authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002), and the China Biological Medicine Database (CBM-disk, 1979 to August 2004). The authors searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies. Selection Criteria: Randomized controlled trials or quasirandomized controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischemic stroke. Data Collection and Analysis: Two authors independently selected trials for inclusion, assessed trial quality, and extracted data. Main Results: Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials, follow-up was performed at 14 to 35 days after stroke. In all studies, neurological outcome was assessed, but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analyzing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI): 1.793.94). One placebo-controlled trial, as-
sessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI: ⫺8.9-10.52). No deaths or major adverse events were reported during the follow-up period. Conclusions: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomized controlled trials are needed to test its efficacy. DOES THIS REVIEW ADDRESS AN IMPORTANT CLINICAL QUESTION? The objective of this systematic review1 is to assess the clinical efficacy and safety of Ginkgo biloba for the treatment of patients with acute ischemic stroke. Given the widespread use of this herbal medicine in clinical practice, this question is pertinent and is relevant to the patient’s needs. WERE THE CRITERIA FOR INCLUSION OF STUDIES CLEARLY DESCRIBED AND FAIRLY APPLIED? This review has clear inclusion criteria. It includes randomized controlled trials and quasirandomized controlled trials that compare Ginkgo biloba to placebo or no treatment in people with acute ischemic stroke. The outcomes measured are clinically relevant, including death, disability, neurological impairement, quality of life, and adverse events. The authors have applied these criteria to all the potentially relevant studies and have given specific reasons for excluding some studies. However, it would be useful to have information about the relative benefit of Ginkgo biloba compared with conventional treatment or other herbal remedies.
The Cochrane Column
WAS THE SEARCH FOR STUDIES THOROUGH? One of the big differences between traditional narrative reviews and systematic reviews is that systematic reviews use a comprehensive search to find all relevant studies. The range of databases and trial registers searched, the dates of the searches, the search terms used, as well as the permitted publication languages and publication status, are important components of such a search strategy. The authors searched the Trials Register of the Cochrane Stroke Group and other trial registers (such as CENTRAL) and medical electronic databases (for example MEDLINE, EMBASE, and AMED); these sources were searched from their inception until shortly before the review was published. The search terms used are appropriate. The authors clearly stated that they attempted to locate unpublished studies or ongoing trials by contacting pharmaceutical companies that manufacture Gingko biloba preparations.
WAS THE STUDY QUALITY ASSESSED? Less rigorous trials tend to overestimate the effectiveness of therapeutic interventions.2 The authors included both randomized and quasirandomized controlled trials. They assessed the methodological quality of these trials in terms of method of randomization, allocation concealment, blinding, intention-to-treat analysis, and numbers of lost to follow-up. However, the authors did not specify the criteria for assessment and the inclusion of quasirandomized trials in their assessment of methodological quality. Only one trial of the 10 included trials has adequate allocation concealment, and the remaining trials are assessed as with low quality. The methodological weakness of the included
The Cochrane Column
studies has been incorporated into the interpretation of the findings.
needs to be investigated in large, rigorous trials.
WERE THE TREATMENT EFFECTS SIMILAR AND THE SUMMARIZED RESULTS VALID? The results from metaanalysis of nine trials showed a significant improvement of neurological deficit in patients treated with Ginkgo biloba compared with placebo or routine treatment (Peto OR, 2.66; 95% CI: 1.79-3.94). It may not be appropriate to combine data from trials comparing placebo and routine treatment in this metaanalysis. When the neurological improvement is presented as an outcome measure in continuous data, the benefit is not statistically significant (weighted mean difference, 0.81; 95% CI: ⫺8.910.52). No trial provided data on clinical outcome such as death, disability, or quality of life. The authors presented adverse effect data from only three trials (as described in the “Characteristics of Included Studies”). An explanation of this discrepancy would be helpful. Ideally, metaanalyses weight studies according to their size and quality. The authors state that only one placebo-controlled trial was assessed to be good quality, and it is not meaningful to conduct a sensitivity analysis. Therefore, we don’t know about the potential impact of the low-quality trials on the beneficial effects of Gingko biloba.
CONCLUSIONS Systematic reviews that summarize scientific evidence are useful for clinicians trying to make decisions.3 In this review, the evidence for the benefit of Ginkgo biloba to improve neurological impairment after acute ischemic stroke appears promising but not sufficient to warrant clinical routine use. There was also variation in the doses used in the studies (from 120 to 240 mg/day) and treatment duration (20 to 28 days). Subgroup analysis showed no evidence of a difference in neurological improvement between Ginkgo biloba extract tablets and intravenous injections. No major adverse effects associated with Ginkgo biloba extract were reported from three trials and also from some of the excluded trials.
ARE THE RECOMMENDATIONS BASED FIRMLY ON THE QUALITY OF THE EVIDENCE PRESENTED? In the authors’ conclusions, several methodological shortcomings were mentioned, such as small size, lack of adequate concealment of allocation, blinding, and long-term follow-up as well as potential publication bias. The potential benefit
REFERENCES 1. Zeng X, Liu M, Yang Y, Li Y, Asplund K. Ginkgo Biloba for Acute Ischaemic Stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2005. Chichester, UK: John Wiley & Sons, Ltd. 2. Schulz KF, Chalmers I, Hayes R, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408-412. 3. Oxman AD, Cook DJ, Guyatt GH. Users’ guide to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA. 1994;272:13671371.
Jianping Liu, MD, is a professor at Beijing University of Chinese Medicine’s Evidencebased Chinese Medicine Centre for Clinical Research and Evaluation. He is also on staff at the National Research Centre in Complementary and Alternative Medicine at Norway’s University of Tromso.
EXPLORE May 2006, Vol. 2, No. 3 263
THE USE OF GINKGO BILOBA EXTRACT IN ACUTE ISCHEMIC STROKE Jianping Liu, MD, PhD
he Cochrane Complementary Medicine Field is the group within the Cochrane Collaboration focused on facilitating the conduct of Cochran systematic reviews of CAM therapies. The CAM Field represents an international collaborative effort among researchers, clinicians, consumers, and CAM practitioners from nearly every continent. The Field’s central office is located at the Center for Integrative Medicine, University of Maryland School of Medicine, 2200 Kernan Drive, Kernan Hospital Mansion, Baltimore, MD 21207-6697. For more information contact Eric Manheimer at: [email protected]. The coordination of the series of Cochrane columns is made possible by grant number 1 R24 AT001293-01 from the National Center for Complementary and Alternative Medicine (NCCAM). The contents of the column are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, the National Institutes of Health, or the Cochrane Collaboration.
T
ABSTRACT OF THE COCHRANE REVIEW Background: Ginkgo biloba extract is widely used in the treatment of acute ischemic stroke in China. The Cochrane Review authors aimed to assess the evidence from randomized controlled trials and quasirandomized controlled trials on the use of Ginkgo biloba extract in acute ischemic stroke. Objectives: The primary objective is to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischemic stroke. Secondary objectives are to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life. Search Strategy: The authors searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials
262 EXPLORE May 2006, Vol. 2, No. 3
Register of the Cochrane Complementary Medicine Field (last searched October 2004), and the Chinese Stroke Trials Register (last searched June 2004). In addition, the authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002), and the China Biological Medicine Database (CBM-disk, 1979 to August 2004). The authors searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies. Selection Criteria: Randomized controlled trials or quasirandomized controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischemic stroke. Data Collection and Analysis: Two authors independently selected trials for inclusion, assessed trial quality, and extracted data. Main Results: Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials, follow-up was performed at 14 to 35 days after stroke. In all studies, neurological outcome was assessed, but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analyzing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI): 1.793.94). One placebo-controlled trial, as-
sessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI: ⫺8.9-10.52). No deaths or major adverse events were reported during the follow-up period. Conclusions: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomized controlled trials are needed to test its efficacy. DOES THIS REVIEW ADDRESS AN IMPORTANT CLINICAL QUESTION? The objective of this systematic review1 is to assess the clinical efficacy and safety of Ginkgo biloba for the treatment of patients with acute ischemic stroke. Given the widespread use of this herbal medicine in clinical practice, this question is pertinent and is relevant to the patient’s needs. WERE THE CRITERIA FOR INCLUSION OF STUDIES CLEARLY DESCRIBED AND FAIRLY APPLIED? This review has clear inclusion criteria. It includes randomized controlled trials and quasirandomized controlled trials that compare Ginkgo biloba to placebo or no treatment in people with acute ischemic stroke. The outcomes measured are clinically relevant, including death, disability, neurological impairement, quality of life, and adverse events. The authors have applied these criteria to all the potentially relevant studies and have given specific reasons for excluding some studies. However, it would be useful to have information about the relative benefit of Ginkgo biloba compared with conventional treatment or other herbal remedies.
The Cochrane Column
WAS THE SEARCH FOR STUDIES THOROUGH? One of the big differences between traditional narrative reviews and systematic reviews is that systematic reviews use a comprehensive search to find all relevant studies. The range of databases and trial registers searched, the dates of the searches, the search terms used, as well as the permitted publication languages and publication status, are important components of such a search strategy. The authors searched the Trials Register of the Cochrane Stroke Group and other trial registers (such as CENTRAL) and medical electronic databases (for example MEDLINE, EMBASE, and AMED); these sources were searched from their inception until shortly before the review was published. The search terms used are appropriate. The authors clearly stated that they attempted to locate unpublished studies or ongoing trials by contacting pharmaceutical companies that manufacture Gingko biloba preparations.
WAS THE STUDY QUALITY ASSESSED? Less rigorous trials tend to overestimate the effectiveness of therapeutic interventions.2 The authors included both randomized and quasirandomized controlled trials. They assessed the methodological quality of these trials in terms of method of randomization, allocation concealment, blinding, intention-to-treat analysis, and numbers of lost to follow-up. However, the authors did not specify the criteria for assessment and the inclusion of quasirandomized trials in their assessment of methodological quality. Only one trial of the 10 included trials has adequate allocation concealment, and the remaining trials are assessed as with low quality. The methodological weakness of the included
The Cochrane Column
studies has been incorporated into the interpretation of the findings.
needs to be investigated in large, rigorous trials.
WERE THE TREATMENT EFFECTS SIMILAR AND THE SUMMARIZED RESULTS VALID? The results from metaanalysis of nine trials showed a significant improvement of neurological deficit in patients treated with Ginkgo biloba compared with placebo or routine treatment (Peto OR, 2.66; 95% CI: 1.79-3.94). It may not be appropriate to combine data from trials comparing placebo and routine treatment in this metaanalysis. When the neurological improvement is presented as an outcome measure in continuous data, the benefit is not statistically significant (weighted mean difference, 0.81; 95% CI: ⫺8.910.52). No trial provided data on clinical outcome such as death, disability, or quality of life. The authors presented adverse effect data from only three trials (as described in the “Characteristics of Included Studies”). An explanation of this discrepancy would be helpful. Ideally, metaanalyses weight studies according to their size and quality. The authors state that only one placebo-controlled trial was assessed to be good quality, and it is not meaningful to conduct a sensitivity analysis. Therefore, we don’t know about the potential impact of the low-quality trials on the beneficial effects of Gingko biloba.
CONCLUSIONS Systematic reviews that summarize scientific evidence are useful for clinicians trying to make decisions.3 In this review, the evidence for the benefit of Ginkgo biloba to improve neurological impairment after acute ischemic stroke appears promising but not sufficient to warrant clinical routine use. There was also variation in the doses used in the studies (from 120 to 240 mg/day) and treatment duration (20 to 28 days). Subgroup analysis showed no evidence of a difference in neurological improvement between Ginkgo biloba extract tablets and intravenous injections. No major adverse effects associated with Ginkgo biloba extract were reported from three trials and also from some of the excluded trials.
ARE THE RECOMMENDATIONS BASED FIRMLY ON THE QUALITY OF THE EVIDENCE PRESENTED? In the authors’ conclusions, several methodological shortcomings were mentioned, such as small size, lack of adequate concealment of allocation, blinding, and long-term follow-up as well as potential publication bias. The potential benefit
REFERENCES 1. Zeng X, Liu M, Yang Y, Li Y, Asplund K. Ginkgo Biloba for Acute Ischaemic Stroke (Cochrane Review). In: The Cochrane Library, Issue 4, 2005. Chichester, UK: John Wiley & Sons, Ltd. 2. Schulz KF, Chalmers I, Hayes R, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408-412. 3. Oxman AD, Cook DJ, Guyatt GH. Users’ guide to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA. 1994;272:13671371.
Jianping Liu, MD, is a professor at Beijing University of Chinese Medicine’s Evidencebased Chinese Medicine Centre for Clinical Research and Evaluation. He is also on staff at the National Research Centre in Complementary and Alternative Medicine at Norway’s University of Tromso.
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