Clare Stevinson

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

Validating a new non-penetrating sham acupuncture device: two randomised controlled trials

For clinical trials of acupuncture, it would be desirable to have a sham procedure that is indistinguishable from the real treatment, yet inactive. A sham needle has been designed which telescopes instead of penetrating the skin. The Park Sham Device involves an improved method of supporting the sham needle and requires validation. The objective of these studies was to test whether the sham procedure using the new device was 1) indistinguishable from the same procedure using real needles in acupuncture naïve subjects, and 2) inactive, where the specific needle sensation (de qi) is taken as a surrogate measure of activity. The studies were designed as subject and assessor blind, randomised controlled trials. Study 1) included 58 patients enrolled in a clinical trial of acupuncture for acute stroke. Study 2) included 63 healthy, acupuncture naïve, adult volunteers. The interventions used were real or sham acupuncture using the Park Sham Device. Study 1) was set in a district general hospital, and study 2) in a university laboratory. The outcome measure in study 1) was the form of treatment that patients believed they had received. In study 2) the outcome measure was experience of de qi, as judged by three acupuncture experts. No patient in either group(study 1) believed he or she had been treated with the sham needle. In 40 volunteers (study 2) for whom experts achieved consensus, the relative risk of experiencing de qi with real acupuncture to that with sham acupuncture was 15.38 (95% CI 2.26 to 104.86). The inter-rater reliability of all 13 experts (study 2), calculated from their judgements on 10 subjects selected by randomisation, was 0.52 (95% CI 0.19 to 0.61). In conclusion, the results suggest that the procedure using the new device is indistinguishable from the same procedure using real needles in acupuncture naïve subjects, and is inactive, where the specific needle sensation (de qi) is taken as a surrogate measure of activity. It is therefore a valid control for acupuncture trials. The findings also lend support to the existence of de qi, a major concept underlying traditional Chinese acupuncture.

Randomized Controlled Trial of the Effects of Aerobic Exercise on Physical Functioning and Quality of Life in Lymphoma Patients

PURPOSE Lymphoma patients commonly experience declines in physical functioning and quality of life (QoL) that may be reversed with exercise training. PATIENTS AND METHODS We conducted a randomized controlled trial in Edmonton, Alberta, Canada, between 2005 and 2008 that stratified 122 lymphoma patients by major disease type and current treatment status and randomly assigned them to usual care (UC; n = 62) or 12 weeks of supervised aerobic exercise training (AET; n = 60). Our primary end point was patient-rated physical functioning assessed by the Trial Outcome Index-Anemia. Secondary end points were overall QoL, psychosocial functioning, cardiovascular fitness, and body composition. RESULTS Follow-up assessment for our primary end point was 96% (117 of 122) at postintervention and 90% (110 of 122) at 6-month follow-up. Median adherence to the supervised exercise program was 92%. At postintervention, AET was superior to UC for patient-rated physical functioning (mean group difference, +9.0; 95% CI, 2.0 to 16.0; P = .012), overall QoL (P = .021), fatigue (P = .013), happiness (P = .004), depression (P = .005), general health (P < .001), cardiovascular fitness (P < .001), and lean body mass (P = .008). Change in peak cardiovascular fitness mediated the change in patient-rated physical functioning. AET did not interfere with chemotherapy completion rate or treatment response. At 6-month follow-up, AET was still borderline or significantly superior to UC for overall QoL (P = .054), happiness (P = .034), and depression (P = .009) without an increased risk of disease recurrence/progression. CONCLUSION AET significantly improved important patient-rated outcomes and objective physical functioning in lymphoma patients without interfering with medical treatments or response. Exercise training to improve cardiovascular fitness should be considered in the management of lymphoma patients.

Valerian for insomnia: a systematic review of randomized clinical trials

Objective: To systematically review the evidence for the effects of the herb valerian (Valeriana officinalis) on insomnia, based on randomized, placebo-controlled, double-blind trials.Background: Valerian has long been advocated and used for promoting sleep but until quite recently evidence was solely anecdotal. However, during the last two decades a number of clinical trials have been conducted.Materials and methods: Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the effect of valerian monopreparations on sleep in human participants. Data were extracted in a standardized manner and methodological quality was assessed by the Jadad score.Results: Nine trials were located meeting the selection criteria. The findings of the studies were contradictory and there was great inconsistency between trials in terms of patients, experimental design and procedures and methodological quality.Conclusion: The evidence for valerian as a treatment for insomnia is inconclusive. There is a need for rigorous trials to determine its efficacy.

Exercise interventions for cancer patients: systematic review of controlled trials

AbstractObjective: To systematically review controlled trials investigating the effects of exercise interventions in cancer patients. Methods: Studies were located through searching seven electronic databases (Medline, Embase, Cochrane Library, CancerLit, PsycInfo, Cinahl, SportDiscus), scanning reference lists of relevant articles, contacting experts (n = 20), and checking the contents lists of journals available through ZETOC (Electronic Table of Contents). To be included, trials had to be prospective, controlled, involve participants diagnosed with cancer and test an exercise intervention. Types of outcome were not restricted. Two reviewers independently applied the selection criteria. ResultsThirty-three controlled trials (including 25 randomized trials) were included in the review. There was some evidence that physical function was increased among those who exercised. Furthermore, symptoms of fatigue did not appear to be increased and there were few adverse effects reported. There was insufficient evidence to determine effects on other outcomes, such as quality of life, with results hampered by the heterogeneity between studies as well as poor methodological quality. Data were also lacking on the long term effects of exercise relating to cancer recurrence or survival. Conclusions There is preliminary evidence that exercise interventions for cancer patients can lead to moderate increases in physical function and are not associated with increased symptoms of fatigue. However, it is impossible from current evidence to determine whether exercise has long term beneficial effects on survival or quality of life.

Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.)

AbstractObjective: This paper provides a systematic review of adverse drug reactions (ADRs) associated with the use of extracts of the herb St. Johns wort (Hypericum perforatum L.) for the treatment of mild to moderate depression. Methods: Searches of four computerized literature databases were performed for records of (ADRs). Manufacturers of hypericum products, the international drug monitoring centre of the World Health Organization (WHO) and the national drug safety monitoring bodies of Germany and the United Kingdom were also contacted for information. Results: Information on (ADRs) originates from case reports, clinical trials, post-marketing surveillance and drug monitoring studies. Collectively, the data suggest that hypericum is well tolerated, with an incidence of adverse reactions similar to that of placebo. The most common adverse effects are gastrointestinal symptoms, dizziness/confusion and tiredness/sedation. A potential serious adverse effect is photosensitivity, but this appears to occur extremely rarely. Conclusions: Hypericum has an encouraging safety profile. However, as most of the current data originate from short-term investigations, more long-term studies are desirable.

A systematic review of physical activity in prostate cancer survivors: outcomes, prevalence, and determinants

IntroductionWe reviewed physical activity (PA) studies in prostate cancer (PC) survivors investigating (a) the effects of PA on health outcomes, (b) the prevalence of PA, and (c) the determinants of PA.Materials and methodsA systematic search of the literature identified nine studies on the outcomes of PA, six studies on the prevalence of PA, and four studies on the determinants of PA in PC survivors.ResultsResults showed promising effects of PA on muscular fitness, physical functioning, fatigue, and health-related quality of life. The prevalence of PA varied widely from <30% to >70%, depending on the type of measure used. PA in PC survivors was predicted by motivational variables such as intentions, perceived behavioral control, and subjective norms.ConclusionAlthough preliminary research is promising, there remains a significant amount of research to be done on the role of PA in PC survivors. Moreover, future research would benefit from larger samples using randomized controlled trial methodology.

Risks associated with spinal manipulation

The aim of this systematic review was to summarize the evidence about the risks of spinal manipulation. Articles were located through searching three electronic databases (MEDLINE, EMBASE, Cochrane Library), contacting experts (n =9), scanning reference lists of relevant articles, and searching departmental files. Reports in any language containing data relating to risks associated with spinal manipulation were included, irrespective of the profession of the therapist. Where available, systematic reviews were used as the basis of this article. All papers were evaluated independently by the authors. Data from prospective studies suggest that minor, transient adverse events occur in approximately half of all patients receiving spinal manipulation. The most common serious adverse events are vertebrobasilar accidents, disk herniation, and cauda equina syndrome. Estimates of the incidence of serious complications range from 1 per 2 million manipulations to 1 per 400,000. Given the popularity of spinal manipulation, its safety requires rigorous investigation.

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.

Neurological complications of cervical spine manipulation.

To obtain preliminary data on neurological complications of spinal manipulation in the UK all members of the Association of British Neurologists were asked to report cases referred to them of neurological complications occurring within 24 hours of cervical spine manipulation over a 12-month period. The response rate was 74%. 24 respondents reported at least one case each, contributing to a total of about 35 cases. These included 7 cases of stroke in brainstem territory (4 with confirmation of vertebral artery dissection), 2 cases of stroke in carotid territory and 1 case of acute subdural haematoma. There were 3 cases of myelopathy and 3 of cervical radiculopathy. Concern about neurological complications following cervical spine manipulation appears to be justified. A large long-term prospective study is required to determine the scale of the hazard.