Max H. Pittler

Garlic for Treating Hypercholesterolemia: A Meta-Analysis of Randomized Clinical Trials

In all cultures, increased serum total cholesterol levels are directly associated with an increased risk for coronary heart disease (1); 5.17 mmol/L (200 mg/dL) has been identified as the point at which strategies for reducing levels should be considered (2, 3). Nonpharmacologic interventions consisting largely of diet modification and increased physical activity are the first-line approach for both primary and secondary prevention of coronary heart disease (4). Lipid-lowering drugs used for treating high-risk persons include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, fibrates, and nicotinates (3). None of these pharmacologic options are free of adverse effects (3), and some have been associated with potential carcinogenicity (5). A harmless yet effective therapy for lowering cholesterol levels would therefore be of considerable interest. The lipid-lowering effects of garlic (Allium sativum) have been demonstrated in animal experiments (6), and garlics efficacy in lowering cholesterol levels in humans has been the subject of randomized clinical trials. A meta-analysis of the effect of garlic on total serum cholesterol level (7) found a significant reduction in total cholesterol levels of 0.59 mmol/L (22.8 mg/dL), which was equivalent to a decrease of approximately 9% compared with placebo. This figure was based on four statistically homogeneous trials that included 324 participants. A subsequent meta-analysis (8) assessing 952 persons from 16 trials reached a similar conclusion, reporting a reduction of 0.77 mmol/L (29.7 mg/dL); this represented a 12% average decrease in total cholesterol level. When these authors later reanalyzed the data, including the results of their own trial of 115 persons (9), the overall reduction in total cholesterol level had diminished to 0.65 mmol/L (25.1 mg/dL); however, it remained significantly greater than that seen with placebo. Because several additional trials have since been published, we decided to reevaluate the totality of available data. We used rigorous criteria to select studies for statistical pooling in an attempt to determine the specific effect of garlic on total serum cholesterol level in persons with elevated levels. Methods We performed systematic searches on the MEDLINE, EMBASE, BIOSIS, AMED, Cochrane Library, and CISCOM databases. The search terms used were garlic, Allium sativum, and Knoblauch (the German term for A. sativum). Each database was searched from its inception until November 1998. We asked manufacturers of garlic preparations and experts in the field about any published or unpublished trials, and we searched the bibliographies of all papers for further studies. There were no language restrictions. Selected studies were required to state that they were randomized, double-blind, and placebo-controlled; use garlic monopreparations; include patients with a mean total cholesterol level of at least 5.17 mmol/L (200 mg/dL); and report total cholesterol level as an end point. Reviewers were blinded to the authors, institutions, addresses, and publication details of each paper. Data were extracted in a systematic manner according to predefined criteria. When information was insufficient for statistical pooling, the authors of the study and manufacturers were approached in an attempt to obtain more details. Methodologic quality was assessed by the Jadad scale, which quantifies the likelihood of bias inherent in trials on the basis of their description of randomization, blinding, and withdrawals (10). Two of the authors extracted data and evaluated methodologic quality independently, and discrepancies were resolved through discussion. The mean change in total cholesterol level compared with baseline was defined as the common end point and was used to assess the differences between the garlic and placebo groups. Weighted means and 95% CIs intervals were calculated by using standard meta-analysis software (RevMan 3.01, Update Software Ltd., Oxford, United Kingdom), which uses the inverse of the variance to assign a weight to the mean of the within-study treatment effect. Most studies, however, did not report enough information to allow us to directly calculate the variance of the preintervention to postintervention change. Studies generally reported data on the preintervention mean and standard deviation and the postintervention mean and standard deviation, but not the standard deviation of the change. It has been suggested that the variance of the change can be imputed by assuming a correlation of 0.4 between preintervention and postintervention values (11). This assumption and the reported values were used to impute the variance of the change, which was then used to assign a weight to the mean of the within-study treatment effect. Summary estimates of the treatment effect were calculated by using a random-effects model. The chi-square test for homogeneity was performed to determine whether the distribution of the results was compatible with the assumption that intertrial differences were attributable to chance variation alone. Calculations were made in traditional units (mg/dL), and a factor of 0.0259 was used to convert the resulting figures to SI units (mmol/L). Publication bias was assessed by using a funnel plot, whereby effect estimates of the common outcome measure were plotted against trial sample size. The funnel plot was examined visually and tested for symmetry by using a regression method developed by Egger and colleagues (12). Results Our search revealed 39 trials in the literature; no unpublished studies were identified. Thirteen of these trials met the inclusion criteria (9, 13-24) and provided data suitable for statistical pooling. Twenty-one trials were excluded because they were not placebo-controlled (25-33), were not randomized (34, 35), were not double-blind (36-38), did not test a monopreparation (39, 40), did not report total cholesterol level (41-43), or reported a mean baseline total cholesterol level less than 5.17 mmol/L (200 mg/dL) (44, 45). Five other trials reported in four papers (46-49) met the inclusion criteria, but data necessary for statistical pooling could not be obtained. Although these studies could not be included in the meta-analysis, they are presented in Table 1. Table 1. Randomized, Double-Blind, Placebo-Controlled Trials That Lacked Data for Statistical Pooling Key data from the 13 included trials are presented in Table 2. A total of 796 persons were involved. Baseline values (mean SD) in the garlic groups ranged from 5.78 1.06 mmol/L (223 41 mg/dL) to 7.72 3.37 mmol/L (298 130 mg/dL). In the placebo groups, the baseline values ranged from 5.62 0.70 mmol/L (217 27 mg/dL) to 7.64 1.55 mmol/L (295 60 mg/dL). Table 2. Randomized, Double-Blind, Placebo-Controlled Trials of the Effect of Garlic on Total Cholesterol The results of the meta-analysis are displayed in Figure 1. Ten trials report mean differences that favor garlic over placebo. Three trials show 95% CIs that do not overlap the line of zero effect indicating significant differences. Meta-analysis of all trials indicated a significant difference (P <0.01) in the reduction of total cholesterol level from baseline in favor of garlic compared with placebo; the weighted mean difference was 0.41 mmol/L (95% CI, 0.66 to 0.15 mmol/L) (15.7 mg/dL [CI, 25.6 to 5.7 mg/dL]). This is equivalent to a 5.8% reduction in total cholesterol levels from baseline due to garlic. Figure 1. Mean differences and 95% CIs of randomized, double-blind, placebo-controlled trials of the effect of garlic on total cholesterol. The chi-square test for homogeneity indicated a degree of heterogeneity (chi-square=36.76). A graphical display identified one outlier (15); if this outlier was removed, homogeneity could be demonstrated across the remaining trials (chi-square=16.33). Pooling the data for only the 12 homogeneous trials resulted in a slightly smaller reduction in cholesterol level; the weighted mean difference was 0.30 mmol/L (CI, 0.48 to 0.11 mmol/L) (11.4 mg/dL [CI, 18.6 to 4.2 mg/dL]), representing an improvement of 4.3%. We produced a funnel plot of all trials included in the meta-analysis, plotting the mean difference against trial sample size (Figure 2). Visual inspection indicated a reasonably symmetrical funnel plot. Studies with smaller sample sizes were distributed around the overall weighted mean difference of the total cholesterol reduction, whereas larger studies more closely resembled this overall weighted estimate. Symmetry of the funnel plot was confirmed by a regression test (12) of all trials (P >0.2). Figure 2. Funnel plot of mean difference in total cholesterol level against sample size in randomized, double-blind, placebo-controlled trials of garlic. Two sensitivity analyses were conducted to test the robustness of the results of the overall analysis. The first sensitivity analysis involved five trials with similar methodologic features. All five used the same garlic preparation standardized to 1.3% alliin, the main ingredient of garlic (Kwai, Lichtwer Pharma GmbH, Berlin, Germany), at the same dose of 900 mg over a treatment period of 3 to 6 months, and all controlled for dietary factors (9, 18, 19, 21, 23). Meta-analysis of these data revealed a weighted mean difference of 0.19 mmol/L (CI, 0.39 to 0.01 mmol/L) (7.3 mg/dL [CI, 15.0 to 0.3 mg/dL]), indicating no significant difference in the reduction of total cholesterol level in persons receiving garlic compared with placebo (Figure 1). The second sensitivity analysis involved only the six diet-controlled trials with the highest scores (4 or 5 points on the Jadad scale) for methodologic quality (9, 20-24). Meta-analysis of these data showed no significant difference between garlic and placebo; the weighted mean difference was 0.11 mmol/L (CI, 0.30 to 0.08 mmol/L) (4.3 mg/dL [CI, 11.7 to 3.1 mg/dL]) (Figure 1). Our meta-analysis focused on the effect of garlic

EFFICACY OF KAVA EXTRACT FOR TREATING ANXIETY: SYSTEMATIC REVIEW AND META-ANALYSIS

Synthetic anxiolytic drugs are effective for treating anxiety, but they are burdened with adverse effects. Constraints on resources and time often render therapies such as psychologic interventions impracticable. Thus, an effective oral medication with few adverse effects would be a welcome addition to the therapeutic repertoire. This systematic review and meta-analysis was aimed at assessing the evidence for or against the efficacy of kava extract as a symptomatic treatment for anxiety. Systematic literature searches were performed in the computerized databases MEDLINE, EMBASE, BIOSIS, AMED, CISCOM, and the Cochrane Library (all from their respective inception to June 1998). The search terms used were kava, kawa, kavain, Piper methysticum, and Rauschpfeffer (German term for Piper methysticum). Experts on the subject were contacted to provide further information. There were no restrictions regarding the language of publication. Double-blind, randomized, placebo-controlled trials of oral kava extract for the treatment of anxiety were included. All publications were blinded before assessment by a person not involved in the study. Data were extracted in a standardized, predefined fashion independently by the two reviewers. The methodologic quality of all trials was assessed. Superiority of kava extract over placebo was suggested by all seven reviewed trials. The meta-analysis of three trials suggests a significant difference in the reduction of the total score on the Hamilton Rating Scale for Anxiety in favor of kava extract (weighted mean difference, 9.69; 95% confidence interval, 3.54-15.83). These data imply that kava extract is superior to placebo as a symptomatic treatment for anxiety. Therefore, kava extract is an herbal treatment option for anxiety that is worthy of consideration.

Ginkgo Biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials

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 meta-analysis 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.

Hawthorn extract for treating chronic heart failure: Meta-analysis of randomized trials

Abstract The aim of this meta-analysis was to assess the evidence from rigorous clinical trials of the use of hawthorn extract to treat patients with chronic heart failure. We searched the literature using MEDLINE, EMBASE, the Cochrane Library, CINAHL, CISCOM, and AMED. Experts on and manufacturers of commercial preparations containing hawthorn extract were asked to contribute published and unpublished studies. There were no restrictions about the language of publication. Two reviewers independently performed the screening of studies, selection, validation, data extraction, and the assessment of methodological quality. To be included, studies were required to state that they were randomized, double-blind, and placebo controlled, and used hawthorn extract monopreparations. Thirteen trials met all inclusion criteria. In most of the studies, hawthorn was used as an adjunct to conventional treatment. Eight trials including 632 patients with chronic heart failure (New York Heart Association classes I to III) provided data that were suitable for meta-analysis. For the physiologic outcome of maximal workload, treatment with hawthorn extract was more beneficial than placebo (weighted mean difference, 7 Watt; 95% confidence interval [CI]: 3 to 11 Watt; P

Chromium picolinate for reducing body weight: Meta-analysis of randomized trials

The aim of this meta-analysis was to assess the evidence of chromium picolinate for reducing body weight. Literature searches were conducted on Medline, Embase, The Cochrane Library, Amed and Ciscom. Nine experts and four manufacturers of commercial preparations containing chromium picolinate were asked to contribute published and unpublished studies. There were no restrictions regarding the language of publication. The screening of studies, selection, data extraction, validation and the assessment of methodological quality were performed independently by two reviewers. To be included, studies were required to state that they were randomized, double-blind and placebo-controlled, and report on body weight. Ten trials met all inclusion criteria and provided data, which were suitable for statistical pooling. For body weight a significant differential effect was found in favour of chromium picolinate (weighted mean difference: −1.1 kg; 95% confidence interval (CI): −1.8 to −0.4 kg, n=489). Sensitivity analysis suggests that this effect is largely dependent on the results of a single trial (weighted mean difference: −0.9 kg; 95% CI: −2.0 to 0.2 kg, n=335). Three of the reviewed trials reported on adverse events, indicating their absence in the treatment groups. In conclusion, our meta-analysis suggests a relatively small effect of chromium picolinate compared with placebo for reducing body weight. The clinical relevance of the effect is debatable and the lack of robustness means that the result has to be interpreted with caution.

Ginkgo biloba for Dementia

AbstractObjective: To systematically review the clinical evidence of Ginkgo biloba preparations as a symptomatic treatment for dementia. Methods: Computerised literature searches were performed to identify all double-blind, randomised, placebo-controlled trials assessing clinical end-points of Ginkgo biloba extract as a treatment for dementia. Databases included Medline, Embase, Biosis and the Cochrane Library. There were no restrictions regarding the language of publication. Data were extracted in a standardised, predefined fashion, independently by both authors. Results: Nine double-blind, randomised, placebo-controlled trials met the inclusion criteria and were reviewed. These studies are of varying methodological quality. They collectively suggest that Ginkgo biloba extract is more effective for dementia than placebo. However, a number of caveats pertain. Few, generally mild, adverse effects were reported. Conclusion: These findings are encouraging and warrant independent, large scale confirmatory and comparative trials.

Guar gum for body weight reduction: meta-analysis of randomized trials.

PURPOSE To determine the efficacy of the dietary fiber guar gum as a therapeutic option for reducing body weight by conducting a meta-analysis of randomized controlled trials. METHODS Literature searches were performed on the electronic databases Medline, Embase, Biosis, Amed, and the Cochrane Library. Manufacturers of commercial guar gum preparations and experts on the subject were contacted to provide any published or unpublished trials. For inclusion, trials had to state that they were randomized, double blinded, and placebo controlled, used guar gum monopreparations, and reported body weight as an endpoint. No language restrictions were imposed. Two reviewers independently extracted data in a standardized manner according to predefined criteria and evaluated methodological quality using the scoring system developed by Jadad. Discrepancies were settled through discussion. RESULTS Thirty-four trials were identified and 20 could be included. Eleven trials provided data that were suitable for statistical pooling. The meta-analysis indicated a nonsignificant difference in patients receiving guar gum compared with patients receiving placebo (weighted mean difference -0.04 kg; 95% confidence interval (CI): -2.2 to 2.1). Analysis of six trials with similar methodologic features corroborates these findings (weighted mean difference -0.3 kg; 95% CI: -4.0 to 3.5). Adverse events most frequently reported were abdominal pain, flatulence, diarrhea, and cramps. Overall, 11 patients (3%) dropped out owing to adverse events. CONCLUSIONS This meta-analysis suggests that guar gum is not efficacious for reducing body weight. Considering the adverse events associated with its use, the risks of taking guar gum outweigh its benefits for this indication. Therefore, guar gum cannot be recommended as a treatment for lowering body weight.

Qigong for hypertension: a systematic review of randomized clinical trials.

Objectives To assess systematically the clinical evidence of qigong for hypertension. Methods Databases were searched up to August 2006. All randomized clinical trials (RCTs) testing qigong in patients with hypertension of any origin and assessing clinically relevant outcomes were considered. Trials using any type of control intervention were included. The selection of studies, data extraction and quality assessment were performed independently by at least two reviewers. Methodological quality was evaluated using the Jadad score. Results A total of 121 potentially relevant articles were identified and 12 RCTs were included. Seven RCTs tested qigong in combination with antihypertensive drugs compared with antihypertensive drugs alone. The meta-analysis of two trials reporting adequate data suggested beneficial effects in favour of qigong [weighted mean difference, systolic blood pressure (SBP) −12.1 mmHg, 95% confidence interval (CI) −17.1 to −7.0; diastolic blood pressure −8.5 mmHg, 95% CI −12.6 to −4.4]. Qigong was compared with waiting list control in two RCTs and was found to reduce SBP significantly (weighted mean difference −18.5 mmHg, 95% CI −23.1 to −13.9). In three further RCTs the comparisons made were: qigong combined with conventional therapy versus muscle relaxation combined with conventional therapy; qigong as a sole treatment versus exercise. All reported positive results in at least some of the relevant outcome measures. The methodological quality of the studies was low. Conclusion There is some encouraging evidence of qigong for lowering SBP, but the conclusiveness of these findings is limited. Rigorously designed trials are warranted to confirm these results.

Tai chi for osteoarthritis: a systematic review

The aim of this study was to evaluate data from controlled clinical trials testing the effectiveness of tai chi for treating osteoarthritis. Systematic searches were conducted on MEDLINE, AMED, British Nursing Index, CINAHL, EMBASE, PsycInfo, The Cochrane Library 2007, Issue 2, the UK National Research Register and ClinicalTrials.gov, Korean medical databases, the Qigong and Energy database and Chinese medical databases (until June 2007). Hand searches included conference proceedings and our own files. There were no restrictions regarding the language of publication. All controlled trials of tai chi for patients with osteoarthritis were considered for inclusion. Methodological quality was assessed using the Jadad score. Five randomised clinical trials (RCTs) and seven non-randomised controlled clinical trials (CCTs) met all inclusion criteria. Five RCTs assessed the effectiveness of tai chi on pain of osteoarthritis (OA). Two RCTs suggested significant pain reduction on visual analog scale or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared to routine treatment and an attention control program in knee OA. Three RCTs did not report significant pain reduction on multiple sites pain. Four RCTs tested tai chi for physical functions. Two of these RCTs suggested improvement of physical function on activity of daily living or WOMAC compared to routine treatment or wait-list control, whilst two other RCTs failed to do so. In conclusion, there is some encouraging evidence suggesting that tai chi may be effective for pain control in patients with knee OA. However, the evidence is not convincing for pain reduction or improvement of physical function. Future RCTs should assess larger patient samples for longer treatment periods and use appropriate controls.

Vitex agnus castus: a systematic review of adverse events.

Vitex agnus castus L. (VAC) [Verbenaceae] is a deciduous shrub that is native to Mediterranean Europe and Central Asia. Traditionally, VAC fruit extract has been used in the treatment of many female conditions, including menstrual disorders (amenorrhoea, dysmenorrhoea), premenstrual syndrome (PMS), corpus luteum insufficiency, hyperprolactinaemia, infertility, acne, menopause and disrupted lactation. The German Commission E has approved the use of VAC for irregularities of the menstrual cycle, premenstrual disturbances and mastodynia. Clinical reviews are available for the efficacy of VAC in PMS, cycle disorders, hyperprolactinaemia and mastalgia, but so far no systematic review has been published on adverse events or drug interactions associated with VAC. Therefore, this review was conducted to evaluate all the available human safety data of VAC monopreparations.Literature searches were conducted in six electronic databases, in references lists of all identified papers and in departmental files. Data from spontaneous reporting schemes of the WHO and national drug safety bodies were also included. Twelve manufacturers of VAC-containing preparations and five herbalist organisations were contacted for additional information. No language restrictions were imposed. Combination preparations including VAC or homeopathic preparations of VAC were excluded. Data extraction of key data from all articles reporting adverse events or interactions was performed independently by at least two reviewers, regardless of study design.Data from clinical trials, postmarketing surveillance studies, surveys, spontaneous reporting schemes, manufacturers and herbalist organisations indicate that the adverse events following VAC treatment are mild and reversible. The most frequent adverse events are nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritus and erythematous rash. No drug interactions were reported. Use of VAC should be avoided during pregnancy or lactation. Theoretically, VAC might also interfere with dopaminergic antagonists.Although further rigorous studies are needed to assess the safety of VAC, the data available seem to indicate that VAC is a safe herbal medicine.