- Email: [email protected]
Complementary and alternative medicine for lowering blood lipid levels: A systematic review of systematic reviews
Accepted Manuscript Title: Complementary and alternative medicine for lowering blood lipid levels: a systematic review of systematic reviews Authors: Paul Posadzki PhD Abdullah M.N. AlBedah MBBS, FFCM (KSU) Mohamed M.K. Khalil MBBCh, MPH, MSc, MD Meshari S. AlQaed MBBS PII: DOI: Reference:
S0965-2299(16)30188-1 http://dx.doi.org/doi:10.1016/j.ctim.2016.09.019 YCTIM 1621
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
23-10-2015 16-7-2016 19-9-2016
Please cite this article as: Posadzki Paul, AlBedah Abdullah MN, Khalil Mohamed MK, AlQaed Meshari S.Complementary and alternative medicine for lowering blood lipid levels: a systematic review of systematic reviews.Complementary Therapies in Medicine http://dx.doi.org/10.1016/j.ctim.2016.09.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
(A second revision for CTIM)
Title: Complementary and alternative medicine for lowering blood lipid levels: a systematic review of systematic reviews
Running title: CAM and high blood lipid levels
Correspondence to: Paul Posadzki, PhD Research Fellow in eLearning Health Services and Outcomes Research Programme Lee Kong Chian School of Medicine Imperial College & Nanyang Technological University 3 Fusionopolis Link, #06-13, Nexus@One-North, South tower, Singapore 138543 DID: 6340 2476, Email: [email protected] AND Honorary
Research
Plymouth University Peninsula Schools of Medicine and Dentistry Email: [email protected] Cell: +4407950441367
Abdullah M.N. AlBedah, MBBS, FFCM (KSU) National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Mohamed M.K. Khalil, MBBCh, MPH, MSc, MD 1
Fellow
National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Meshari S. AlQaed, MBBS National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Funding sources: None. Disclosures: All authors declare no competing interests. Word count: 2707
2
Highlights
This article summarizes and critically evaluates the evidence from systematic reviews of complementary and alternative medicine for lowering blood lipid levels published over the past 16 years
Twenty-seven SRs of predominantly high methodological quality were included in our analyses
The evidence for the effectiveness of complementary and alternative medicine in lowering various lipid fractions, is, in majority of the evaluated SRs, equivocal
Abstract Background: The aim of this article is to summarize and critically evaluate the evidence from systematic reviews (SRs) of complementary and alternative medicine (CAM) for lowering blood lipid levels (BLL). Methods: Eight electronic databases were searched until March 2016. Additionally, all the retrieved references were inspected manually for further relevant papers. Systematic reviews were considered eligible, if they included patients of any age and/or gender with elevated blood lipid levels using any type of CAM. We used the Oxman and AMSTAR criteria to critically appraise the methodological quality of the included SRs. Results: Twenty-seven SRs were included in the analyses. The majority of the SRs were of high methodological quality (mean Oxman score =4.81, SD=4.88; and the mean AMSTAR score=7.22, SD=3.38). The majority of SRs (56%) arrived at equivocal conclusions (of these 8 were of high quality); 7 SRs (37%) arrived at positive conclusions (of these 6 were of high quality), and 2 (7%) arrived at negative conclusions (both were of high quality). There was conflicting evidence regarding the effectiveness of garlic; and promising evidence for yoga. Conclusions: To conclude, the evidence from SRs evaluating the effectiveness of CAM in lowering BLL is predominantly equivocal and confusing. Several limitations exist, such as variety of doses and preparations, confounding effects of diets and lifestyle factors, or heterogeneity of the primary trials among others.
Keywords: Cardiovascular Diseases; Complementary and Alternative Medicine; Systematic reviews; Effectiveness. 3
Introduction Abnormally elevated blood lipids levels (BLL) are associated with many diseases including, diabetes, or cardiovascular diseases (CVD) which are, according the WHO, leading cause of mortality and morbidity worldwide.
12
The risk of heart attack is 3-fold higher in subjects
with elevated BLL than in subjects with normal lipid status.3 The prevalence of the condition varies from country to country (73% in Bulgaria to 24% in Finland) with the overall/global estimate of 38%.4 Several contributing and modifiable risk factors such as inappropriate diet rich in excessive animal proteins and fat, tobacco/alcohol consumption, or lack of regular physical activity (sedentary lifestyles), as well as psychological stress have been identified.5
Complementary and alternative medicine (CAM) is encompasses a broad variety of disparate modalities which can operationally be defined as ‘diagnosis, treatment and/or prevention which complements mainstream medicine by contributing to a common whole, satisfying a demand not met by orthodoxy, or diversifying the conceptual framework of medicine’.6 There is no data on BLL specifically but recent systematic review reported that the prevalence rate of CAM use in patients with CVD ranged from 4% to 61%, with biologicallybased therapies such as dietary supplements and herbal medicine being the most popular (range 22% to 68%).7 The reasons for this high popularity are multidimensional but assumed effectiveness and safety of CAM play a crucial role.6 Some patients with BLL may also perceive statins as burdened with unnecessary side-effects and, as a result, seek for alternatives.
A significant number of randomized clinical trials (RCTs) of CAM in CVD (in general) and BLL (more specifically) have been published in recent years.8-15 Their results are typically gathered and pooled in systematic reviews/meta-analyses (SRs/MAs). These SRs/MAs often 4
arrive at contradictory conclusions which create confusions. To the best of our knowledge, no attempts have been made to summarize and rigorously evaluate the data from SRs of CAM in patients with high BLL. Therefore, this SR is aimed at reviewing and critically assessing the existing evidence from SRs of CAM in elevated BLL.
Methods The Preferred Reporting Items for Systematic Reviews & Meta Analyses (PRISMA) guidelines
16
as well as the Cochrane Handbook for Systematic Reviews of Interventions
17
were meticulously adhered to while reporting of this SR.
Data sources In addition to hand-searches and screening reference lists of all relevant papers, 8 electronic databases were inspected to March 2016: AMED (Ebsco), CINAHL (Ebsco), the Cochrane Library, EMBASE (Ovid), Web of Science, MEDLINE (Ovid), PsycARTICLES (Ovid), and Scopus. We narrowed our searches to articles published since January 2000, as we believed the evidence prior to that date will be scarce and outdated. A detailed search strategy for MEDLINE is presented in the appendix 1.
Study selection Systematic reviews evaluating the effectiveness of CAM in lowering BLL in patients of any age, gender and ethnicity were eligible for inclusion. In this SR, we only included SRs published in English language. Systematic reviews were defined as research articles that include reproducible eligibility (inclusion and exclusion) criteria for primary studies (all types) and a comprehensive literature searches. Non-SRs, MSc or PhD theses or abstracts
5
were excluded. For clarity and to avoid confusion, update SRs (articles that depended upon previous SRs for their primary data) were also excluded.
The following CAM modalities were considered eligible for the present review: acupuncture, Ayurvedic medicine, aromatherapy, (Bach) flower remedies, biofeedback, chiropractic, herbal medicine, homeopathy, hypnosis, massage, meditation, naturopathy, osteopathy, qi gong, spirituality/spiritual healing, tai chi, Traditional Chinese Medicine (TCM) and yoga. We excluded from our analyses vitamins, physical exercises, physiotherapeutic or psychotherapeutic modalities; complex or package interventions, and/or SRs published as abstracts only.
Data screening and selection processes was performed by the first reviewer (PP), and verified and validated by the second (MK), third (AA), and the fourth (MA).
Outcome measures Studies reporting elevated BLL as primary outcome measures were included.
Data Extraction First reviewer (PP) performed data extraction using an a priori defined data extraction form. Then the second (MK), third (AA), and the fourth (MA) reviewer verified and validated the data entries. The following information was extracted: first authors’ names and publication date, aims, type of CAM modality, total number of primary RCTs, quality of primary studies as judged by the authors of the primary studies (poor, moderate, high), whether meta-analysis had been conducted, quality of SR (Oxman and AMSTAR Scores), overall result (quote), direction of conclusion as judged by the present authors (positive, negative or equivocal)18-20, 6
whether SR had mentioned adverse effects (AEs) (yes or no), authors’ conflicts of interest (COI) (declared or not declared), source of funding (SOF) (mentioned or not mentioned), and any comments relating to primary or secondary research.
Risk of Bias /Quality Assessments We used both the Oxman and Guyatt criteria
21
and the AMSTAR tool
22
for judging the
methodological quality of review papers. These are standardized tools evaluate the quality of SRs in the following domains: reporting of search strategy, comprehensiveness of searches, repeatable eligibility criteria, avoidance of selection bias, presence or absence of a validity assessment tool, appropriate use of the validity assessment tool, robustness of data analysis and synthesis and supportiveness of conclusions, whether likelihood of publication bias was assessed; conflict of interest was stated; characteristics of included studies was provided; status of publication (i.e. grey literature) used as an inclusion criterion and ‘a priori’ research question was defined. For the Oxman tool, each domain is scored as 1 (fulfilled), 0 (partially fulfilled), or -1 (not fulfilled); and a final score may range between -9 and 9. A result of 1 or less means the SR has extensive flaws; 2–3 major flaws; 4–5 minor flaws, and 6–9 minimal or no flaws. The scoring system for the AMSTAR tool is as follows: yes; no; can’t answer; and not applicable; with a maximum score of 11 points indicating high methodological quality. This process was carried out by the first reviewer (PP) and subsequently validated by the remaining authors.
Data synthesis The results are presented in a narrative fashion using tables. Descriptive statistics is used to analyze and synthesize the data.
7
Results Study description The searches generated a total of 1302 records and 27 SRs met the eligibility criteria (Figure 1). Of those, 6 (22%) were Cochrane SRs, and the remaining 21 (78%) were non-Cochrane SRs. The key findings from the included SRs are summarized in Table 1. Tables 2 and 3 present the methodological quality of the included SRs.
Characteristics of included SRs The following CAM modalities were evaluated in the SRs: garlic (n=8), herbals overall (n=4), specific herbs including artichoke (n=1), green tea (n=2), guggul (n=1); qi gong (n=1), tai chi (n=2), yoga (n=6), red yeast rice (RYR) (n=1), Reishi mushroom (n=1). The number of primary studies ranged from 1 to 45 (mean= 18.9; SD=18.1). The largest number of primary studies evaluated garlic (N=183), followed by yoga (N=106). The quality of the primary trials ranged from poor to high (overall= moderate). Fourteen (52%) SRs employed meta-analyses of the primary data; and 13 (48%) did not. Fifteen SRs (56%) arrived at equivocal conclusions, 10 SRs (37%) arrived at positive conclusions, and 2 (7%) arrived at negative conclusions. A wide variety of BLL-related outcome measures/indices were evaluated including TG, TC, LDL, VLDL and HDL. Nineteen (70%) SRs did mention CAM related adverse effects; and 8 (30%) did not. Twelve (44%) SRs did not mention any potential conflicts of interests. Sources of funding were mentioned in 16 (59%) SRs.
Characteristics of included populations SRs evaluated both healthy individuals as well as medically compromised patients of both sexes aged 18 years and above. In addition to elevated total cholesterol (TC), triglycerides (TG), or lipoproteins (HDL, LDL and VLDL), co-morbidities of the patients included 8
advanced atherosclerosis, blood hypercoagulation, cardiac dysrhythmia, coronary heart disease, diabetes mellitus, history of renal transplantation or myocardial infraction, heart failure, hypertension, hyperuricemia, ischemic heart disease, infectious diseases (HIV), metabolic syndrome, mental disorders, obesity, or peripheral vascular disease. The subjects were often taking medications for their respective diseases. Comparison groups included placebo, no treatment, pharmacological or non-pharmacological (behavioural) interventions as well as usual care.
Effectiveness of CAM (outcomes) Positive conclusions were reached for garlic (n=2), green tea (n=1), herbals overall (n=1), tai chi (n=1), RYR extract (n=1), and yoga (n=4), meaning effectiveness in reducing LDL, HDL, TG, or TC. Negative conclusions were reached for garlic (n=1), and Reishi mushrooms (n=1), meaning lack of effectiveness. Equivocal conclusions were reached for garlic (n=5), green tea (n=1), artichoke (n=1), guggul (n=1), herbals overall (n=3), qi gong (n=1), tai chi (n=1), and yoga (n=2), meaning effectiveness in reducing certain lipid profiles and ineffectiveness in lowering others.
Methodological quality of the included SRs and RCTs The methodological quality of all the included SRs was, on average acceptable (mean Oxman score =4.81, SD=4.88; range: -6 to 9; and the mean AMSTAR score=7.22, SD=3.38; range: 0-11), indicating minor methodological flaws. Sixteen (59%) SRs had minimal or no flaws (Oxman score 6-9). Eleven SRs (41%) had methodological limitations (Oxman score 5 or less). Six (22%) SRs which arrived at positive conclusions had also minimal or no flaws as assessed by the Oxman scale. Eight (30%) SRs which arrived at equivocal conclusions were 9
also judged to be of highest methodological quality. Four (15%) SRs that were of high methodological quality and arrived at positive conclusions were based on moderate to high quality primary trials. These SRs evaluated the effectiveness of garlic (n=2), and yoga (n=2). In contrast, four SRs (15%) which were of lower methodological quality (Oxman score < 6) arrived at positive conclusions but were based on poor to moderate quality primary trials. These SRs evaluated the effectiveness of Ayurvedic herbs, tai chi, RYR extract and yoga (each n=1). Overall, the majority of SRs (67%) evaluated the effectiveness of biologically based therapies, i.e. herbs, whereas 9 (33%) SRs were concerned with mind-body modalities such as qi gong, tai chi, or yoga.
Discussion This SR was aimed at summarizing and critically evaluating the existing evidence from SRs of CAM in lowering BLL. Twenty-seven SRs met the ‘a priori’ defined inclusion criteria. The majority of SRs were of good methodological quality; and most of them arrived at equivocal conclusions indicating that there was insufficient evidence to judge whether a therapy was effective or not.
Within the scope of this SR, CAM modalities in question could operationally be categorized into biologically based therapies (majority) and mind-body therapies (minority). Garlic was the most frequently evaluated type of CAM (n=8) followed by various mono-herbal and polyherbal preparations (n=7). These included Ayurvedic, or TCM herbals, artichoke, green tea, and guggul. Other biologically based therapies included red yeast rice (RYR), and Reishi mushroom. Mind-body CAM modalities included yoga (n=6), followed by tai chi (n=2) and qi gong (n=1).
10
Multiple SRs evaluated garlic, green tea, herbals and yoga. For instance, for garlic, two SRs arrived at positive; one SR arrived at negative; and 5 arrived at equivocal conclusions. This discrepancy may have arisen from the fact three SRs arriving at equivocal conclusions were also of suboptimal quality (Oxman score less than 6), and/or were based on poor to moderate quality RCTs or garlic preparations were effective for certain lipid fractions and ineffective for others. Furthermore, the SR by Khoo et al.23 that arrived at negative conclusions had included the relatively small number of RCTs (n=13) compared with 29 and 39 in SRs by Reinhart (2009) 24 and Ried 25 (2013) respectively. In addition, Khoo et al. 23 did not perform subgroup analyses by trial duration (short vs. long term efficacy); which proved effective (RCTs longer than 8 weeks) in SR by Ried.25 Given the good safety profile of garlic preparations, the risk-benefit ratio seems to favour this treatment. For green tea, two SRs 26 27 concluded that significant reductions in serum TC and LDL-cholesterol concentrations, but no effect on HDL cholesterol. For this CAM modality, however, moderately severe interactions with antilipaemics have been identified;28 hence the risk-benefit ratio remains uncertain. For yoga, three high quality SRs,29-31 one moderate quality SR,32 and one low quality SR
33
all suggested reductions in HDL and TG; indicating potential benefits as the
safety profile and the risk-benefit ratio of this therapy is good. For other CAM modalities and herbal remedies included, there is still insufficient evidence to recommend them due to small number of primary studies and equivocal conclusions reached.
Our confidence in the overall conclusions is undermined by the fact that there was a considerable number of confounding factors both in primary RCTs and SRs. Examples include heterogeneity of populations, e.g. diabetes or hypertension (metabolic syndrome) and healthy individuals; complex interventions such as yoga based on whole systems philosophy; heterogeneous trial designs (duration, intensity, frequency); comparator groups (active such 11
as statins vs inert placebo); and outcome measures/BLL indices ranging from TC, HDL, LDL, VLDL, TG. This consequently resulted in significant heterogeneity of some of the meta-analyses (I2 >75%) and a small overall effect size. More needs to be done with regards to primary data including formal power and sample size calculations, control for placeboeffects (in mind-body modalities), or standardized intervention regimes (duration, intensity and frequency of treatments); objective outcome measures; transparent reporting of potential competing interest that would all warrant independent replications.
In this SR, we used both Oxman
21
and AMSTAR criteria
22
for evaluating the
methodological quality of SRs in order to strengthen confidence and precision of our judgements. Sixteen (59%) of the included SRs were of high methodological quality (Oxman score 6 or more; and the mean AMSTAR score=7.22, SD=3.38); 11 SRs (41%) had some methodological flaws (Oxman score 5 or less). In general, the included SRs were of acceptable methodological rigor which suggests their concllusions were reliable. However, 10 (37%) of high quality SRs drew their conclusions on poor quality evidence, which in a sense may be counterintuitive.
A recent SR concluded that a large proportion of patients do not inform medical practitioners about their CAM use; and up to 90% of treating physicians did not discuss CAM use with their patients.7 This is potentially dangerous situation as serious adverse effects and interactions with conventional cardiovascular medications exist for many herbs and supplements. Clinicians should communicate the use of any herbals and supplements as these are biologically active substances that have the potential to harm. Other safety concerns included significantly higher risk of adverse effects in the Reishi groups compared with controls (RR 1.67; 95% CI 0.86 to 3.24), and this was based on high quality SR.34 12
Several limitations need to be taken into consideration when interpreting the results of this SR. Our searches were limited to SRs published in English, after year 2000, and therefore some articles published in other languages and before that date were missed. It is also conceivable that, while reviewing SRs we might have overlooked some methodological nuances of the primary data. A phenomenon known as publication bias is also the inherent part of SRs; and might have distorted the overall picture. One of the criticism of SRs of SRs (tertiary research) pertains to the overlap (double-counting) of primary studies. For instance, 8 of the included SRs focused on garlic preparations but the majority of those relied on the same RCTs. We did so because the problem of double-counting in overviews of SRs is methodologically unavoidable, i.e. non-Cochrane SRs including large proportions of the same RCTs already included in Cochrane reviews and vice versa. This overview has its strengths too including the use of two standardized sound tools for assessing the methodological quality of SRs; and critical analysis of both primary and secondary research.
Conclusion In conclusion, a considerable number of SRs of CAM in lowering BLL exists. The evidence for the effectiveness of CAM in lowering various indices of BLL, is, in majority of the evaluated SRs, equivocal which creates confusion. Patients, policy makers and clinicians need to consider the existence of wide variety of limitations in the evidence base. For instance, for garlic, the conclusions are predominantly equivocal whereas for the remainder of herbal remedies as well as other CAM modalities, the evidence is still preliminary and more research needs to be done to clearly inform the above groups. However, for yoga, conclusions were predominantly positive.
13
Appendix 1. A detailed search strategy for MEDLINE (via OVID)
Concept 1 exp hyperlipidemia / OR exp hyperlipidaemia / OR exp hyperlipoproteinemia / OR exp hyperlipoproteinaemia / OR exp metabolic syndrome / OR exp Reaven Syndrome OR exp cardiovascular diseases / OR exp heart diseases / OR exp vascular diseases / OR cerebrovascular disorders / OR exp brain ischemia / OR exp carotid artery diseases / OR exp dementia, vascular / OR exp intracranial arterial diseases / OR exp intracranial hemorrhages / OR exp stroke / OR (coronar$ adj5 (bypas$ or graft$ or disease$ or event$)).mp. OR (cerebrovasc$ or cardiovasc$ or mortal$ or angina$ or stroke or strokes).mp. OR (myocardi$ adj5 (infarct$ or revascular$ or ischaemi$ or ischemi$)).mp. OR (morbid$ adj5 (heart$ or coronar$ or ischaem$ or ischem$ or myocard$)).mp. OR (vascular$ adj5 (peripheral$ or disease$ or complication$)).mp. OR (heart$ adj5 (disease$ or attack$ or bypass$)).mp.
Concept 2 (Alternative adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR (Complementary adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR (integrat$ adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR CAM.ti,ab. OR exp Complementary Therapies/
Concept 3 review.ti
SEARCHES= 1 AND 2 AND 3 14
References 1. Genest J, Libby, P. Lipoprotein disorders and cardiovascular disease. In: Bonow RO, Mann, D.L., Zipes, D.P., Libby, P., eds., ed. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed: Philadelphia, PA: Elsevier Saunders, 2011. 2. World Health Organization (WHO). 2008–2013 Action Plan for the Global Strategy for the Prevention and Control of Noncommunicable Diseases: Prevent and Control Cardiovascular Diseases, Cancers, Chronic Respiratory Diseases and Diabetes. Geneva, Switzerland: WHO; 2008., 2008. 3. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364(9438):937-52. 4. Venkitachalam L, Wang K, Porath A, et al. Global variation in the prevalence of elevated cholesterol in outpatients with established vascular disease or 3 cardiovascular risk factors according to national indices of economic development and health system performance. Circulation 2012;125(15):1858-69. 5. Uthman OA, Hartley L, Rees K, et al. Multiple risk factor interventions for primary prevention of cardiovascular disease in low- and middle-income countries. Cochrane Database Syst Rev 2015;8:CD011163. 6. Ernst E, Pittler, M.H., Wider, B., Boddy, K. The Desktop Guide to Complementary and Alternative Medicine, 2nd edn. . Edinburgh.: Elsevier Mosby., 2006. 7. Grant SJ, Bin YS, Kiat H, et al. The use of complementary and alternative medicine by people with cardiovascular disease: a systematic review. BMC public health 2012;12:299. 8. Budoff MJ, Ahmadi N, Gul KM, et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 2009;49(2-3):101-7. 9. Jung ES, Park SH, Choi EK, et al. Reduction of blood lipid parameters by a 12-wk supplementation of aged black garlic: a randomized controlled trial. Nutrition 2014;30(9):1034-9. 10. Mahdavi-Roshan M, Zahedmehr A, Mohammad-Zadeh A, et al. Effect of garlic powder tablet on carotid intima-media thickness in patients with coronary artery disease: a preliminary randomized controlled trial. Nutr Health 2013;22(2):143-55. 11. Bundy R, Walker AF, Middleton RW, et al. Artichoke leaf extract (Cynara scolymus) reduces plasma cholesterol in otherwise healthy hypercholesterolemic adults: a randomized, double blind placebo controlled trial. Phytomedicine 2008;15(9):668-75. 12. Maron DJ, Lu GP, Cai NS, et al. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Arch Intern Med 2003;163(12):144853. 13. Papp ME, Lindfors P, Nygren-Bonnier M, et al. Effects of High-Intensity Hatha Yoga on Cardiovascular Fitness, Adipocytokines, and Apolipoproteins in Healthy Students: A Randomized Controlled Study. J Altern Complement Med 2016;22(1):81-7. 14. Thiyagarajan R, Pal P, Pal GK, et al. Additional benefit of yoga to standard lifestyle modification on blood pressure in prehypertensive subjects: a randomized controlled study. Hypertens Res 2015;38(1):48-55. 15. Thomas GN, Hong AW, Tomlinson B, et al. Effects of Tai Chi and resistance training on cardiovascular risk factors in elderly Chinese subjects: a 12-month longitudinal, randomized, controlled intervention study. Clin Endocrinol (Oxf) 2005;63(6):663-9. 15
16. Gitelson E, Al-Saleem T, Millenson M, et al. Cutaneous B-cell lymphoma responds to rituximab: A report of five cases and a review of the literature. Leukemia and Lymphoma 2006;47(9):1902-07. 17. Connock M, Burls A, Frew E, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: A systematic review. Health Technology Assessment 2006;10(24):iii-iv+77-83. 18. Ernst E, Posadzki P, Lee MS. Complementary and alternative medicine (CAM) for sexual dysfunction and erectile dysfunction in older men and women: an overview of systematic reviews. Maturitas 2011;70(1):37-41. 19. Ernst E, Lee MS, Choi TY. Acupuncture: does it alleviate pain and are there serious risks? A review of reviews. Pain 2011;152(4):755-64. 20. Furlan AD, Clarke J, Esmail R, et al. A critical review of reviews on the treatment of chronic low back pain. Spine (Phila Pa 1976) 2001;26(7):E155-62. 21. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991;44(11):1271-8. 22. Shea BJ, Hamel C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. Journal of clinical epidemiology 2009;62(10):1013-20. 23. Khoo YS, Aziz Z. Garlic supplementation and serum cholesterol: a meta-analysis. J Clin Pharm Ther 2009;34(2):133-45. 24. Reinhart KM, Talati R, White CM, et al. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutrition research reviews 2009;22(1):39-48. 25. Ried K, Toben C, Fakler P. Effect of garlic on serum lipids: an updated meta-analysis. Nutrition reviews 2013;71(5):282-99. 26. Kim A, Chiu A, Barone MK, et al. Green tea catechins decrease total and low-density lipoprotein cholesterol: a systematic review and meta-analysis. Journal of the American Dietetic Association 2011;111(11):1720-9. 27. Zheng XX, Xu YL, Li SH, et al. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. The American journal of clinical nutrition 2011;94(2):601-10. 28. Posadzki P, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol 2013;75(3):603-18. 29. Hartley L, Dyakova M, Holmes J, et al. Yoga for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;5:CD010072. 30. Cramer H, Lauche R, Haller H, et al. A systematic review of yoga for heart disease. Eur J Prev Cardiol 2015;22(3):284-95. 31. Cramer H, Lauche R, Haller H, et al. Effects of yoga on cardiovascular disease risk factors: a systematic review and meta-analysis. Int J Cardiol 2014;173(2):170-83. 32. Innes KE, Bourguignon C, Taylor AG. Risk indices associated with the insulin resistance syndrome, cardiovascular disease, and possible protection with yoga: A systematic review. Journal of the American Board of Family Practice 2005;18(6):491-519. 33. Yang K. A review of yoga programs for four leading risk factors of chronic diseases. Evidence-based complementary and alternative medicine : eCAM 2007;4(4):487-91. 34. Klupp NL, Chang D, Hawke F, et al. Ganoderma lucidum mushroom for the treatment of cardiovascular risk factors. Cochrane Database Syst Rev 2015;2:CD007259. 35. Ackermann RT, Mulrow CD, Ramirez G, et al. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 2001;161(6):813-24.
16
36. Alder R, Lookinland, S., Berry, J.A., Williams, M. A systematic review of the effectiveness of garlic as an anti-hyperlipidemic agent. J Am Acad Nurse Pract 2003;15(3):120-9. 37. Chu P, Gotink RA, Yeh GY, et al. The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and metaanalysis of randomized controlled trials. Eur J Prev Cardiol 2016;23(3):291-307. 38. Dalusung-Angosta A. The impact of Tai Chi exercise on coronary heart disease: A systematic review. Journal of the American Academy of Nurse Practitioners 2011;23(7):376-81. 39. Gerards MC, Terlou RJ, Yu H, et al. Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain - A systematic review and meta-analysis. Atherosclerosis 2015;240(2):415-23. 40. Hartley L, Flowers N, Lee MS, et al. Tai chi for primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;4:CD010366. 41. Hartley L, Lee MS, Kwong JS, et al. Qigong for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2015;6:CD010390. 42. Hasani-Ranjbar S, Nayebi N, Moradi L, et al. The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review. Current Pharmaceutical Design 2010;16(26):2935-47. 43. Liu ZL, Li, G.Q., Bensoussan, A, Kiat, H, Chan, K, Liu, J.P. Chinese herbal medicines for hypertriglyceridaemia. Cochrane Database Syst Rev 2013;7(CD008305.). 44. Singh BB, Vinjamury SP, Der-Martirosian C, et al. Ayurvedic and collateral herbal treatments for hyperlipidemia: A systematic review of randomized controlled trials and quasi-experimental designs. Alternative Therapies in Health and Medicine 2007;13(4):22-28. 45. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. A metaanalysis of randomized clinical trials. Ann Intern Med 2000;133(6):420-9. 46. Thompson Coon JS, Ernst E. Herbs for serum cholesterol reduction: A systematic review. Journal of Family Practice 2003;52(6):468-78. 47. Ulbricht C, Basch E, Szapary P, et al. Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration. Complementary Therapies in Medicine 2005;13(4):279-90. 48. Ulbricht C, Isaac R, Milkin T, et al. An evidence-based systematic review of stevia by the Natural Standard Research Collaboration. Cardiovascular & Hematological Agents in Medicinal Chemistry 2010;8(2):113-27. 49. Wider B, Pittler MH, Thompson-Coon J, et al. Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database Syst Rev 2013;3:CD003335. 50. Zeng T, Zhang CL, Zhao XL, et al. The roles of garlic on the lipid parameters: a systematic review of the literature. Critical Reviews in Food Science & Nutrition 2013;53(3):215-30. 51. Posadzki P, Ernst E. Spinal manipulation: an update of a systematic review of systematic reviews. N Z Med J 2011;124(1340):55-71.
17
Figure 1. Flow diagram for included studies
Total number of hits for electronic search (n=1300)
Additional records identified through manual search (n=2)
Duplicates removed (n=75)
Records screened (n =1227)
Full-text articles assessed for eligibility (n =145)
Total number of articles included (n=27)
18
Excluded: not SR (n=1055); published before 2000 (n=27)
Excluded: not CAM (n=118)
Figure 1 Legend: CAM-complementary and alternative medicine; SR-systematic review.
19
Table 1. Systematic Reviews of Complementary and Alternative Medicines for Elevated BLL First author (year) [ref]
Aims
Ackerman (2001) 35
Alder (2003) 36
Chu (2016) 37
Interventio n(s)/CAM modality
N*
Quality of RCTs
Meta anal ysis
Oxman /AMST AR Score
Overall result (quote)
“To summarize the Garlic effects of garlic on several CVDrelated factors and to note its adverse effects.” “To conduct a Garlic thorough search of the literature for RCTs addressing the efficacy of garlic as an antihyperlipidemic agent (…)”
45
Poor
Yes
4/6
10
Poor
No
“(…) to evaluate Yoga the evidence on the effectiveness of yoga for modifying risk factors for CVD and metabolic syndrome in adults (…)”
37
Moderate
Yes
Menti COI on of advers e effects
SOF
Comment
“Conclusions regarding (+/-) clinical significance are limited by the marginal quality and short duration of many trials (…)”
Yes
n.m.
n.m.
Outcomes also included hypertension, diabetes or blood hypercoagulation
6/7
“Six of ten studies (+/-) found garlic to be effective. The average drop in TC was 24.8 mg/dL (9.9%), LDL 15.3 mg/dL (11.4%), and TG 38 mg/dL (9.9%).”
No
n.m.
n.m.
Diet was confounding factor in most RCTs which were typically of short duration, poor quality and heterogeneous designs
8/10
“There is promising (+) evidence of yoga on improving cardio-metabolic health. Findings are limited by small trial sample sizes, heterogeneity, and moderate quality of RCTs”
No
None declared
None declared
For LDL- I2 was over 75%; no sensitivity analyses were performed; double counting of data (analysis 3.2.1)
20
Dire ction of concl usio n**
Cramer (2014) 31
“(…) to Yoga systematically assess and metaanalyse the effects of yoga on modifiable biological CVD risk factors in the general population and in high-risk disease groups”
44
Poor
Yes
9/9
Cramer (2015) 30
“(…) to evaluate the quality of evidence and the strength of recommendation for yoga as an ancillary intervention for heart disease” “To explore current studies on Tai Chi and its impact on CHD (…)” “To verify the safety and effectiveness of traditional Chinese RYR extract for reduction of LDL cholesterol” “To determine the effect of any type
Yoga
7
Poor
No
7/9
Tai Chi
1
Moderate
No
RYR extract
20
Moderate to high
Yes
Yoga
11
Poor to Yes moderate
DalusungAngosta (2001) 38
Gerards (2015) 39
Hartley (2014) 29
“This meta-analysis (+) revealed evidence for clinically important effects of yoga on most biological CVD risk factors. Despite methodological drawbacks of the included studies, yoga can be considered as an ancillary intervention for the general population and for patients with increased risk of CVD.” “(…) weak (+/-) recommendations can be made for the ancillary use of yoga for patients with CHD, heart failure, and cardiac dysrhythmia at this point.”
Yes
n.m.
Declared
For HDL- I2 was 90%; most studies suffered methodological limitations
Yes
None declared
Declared
Small total number of patients; heterogeneous populations, and poor overall quality of the evidence
-4/3
“Implementing Tai Chi (+) exercise may improve serum lipids, blood pressure, and heart rate.”
No
n.m.
n.m.
Poor quality SR with overinflated conclusions
5/6
“RYR exerts a clinically (+) and statistically significant reduction of 1.02 mmol/L LDL cholesterol.”
Yes
None declared
None declared
35% of RCTs lacked blinding; significant amount of heterogeneity of the analyses
9/10
“There is some evidence (+) that yoga has favourable
Yes
None declared
None declared
Analyses involved 800 participants
21
Hartley (2014) 40
of yoga on the primary prevention of CVD” “To determine the Tai Chi effectiveness of tai chi for the primary prevention of CVD”
13
Poor
Yes
9/10
Hartley (2015) 41
“To determine the Qi Gong effectiveness of Qi Gong for the primary prevention of CVD”
11
Poor
No
9/10
HasaniRanjbar (2010)
“This review Herbals focuses on the efficacy and safety of effective herbal medicines in the management of hyperlipidemia in human.” “To conduct a Yoga systematic review of […] the effects of yoga […] on specific anthropometric and physiologic indices of CVD risk and on related
43
Moderate
No
2/5
5
Poor
No
2/5
42
Innes (2005) 32
effects on diastolic blood pressure, HDL cholesterol and TG, and uncertain effects on LDL cholesterol” “There was some (+/-) suggestion of beneficial effects of tai chi on CVD risk factors but this was not consistent across all studies.” “(…) further trials of high (+/-) methodological quality […] are needed to be incorporated in an update of this review before the effectiveness of qigong for CVD prevention can be established” “Conflicting data exist for (+/-) red yeast rice, garlic and guggul. […]”
“(…) the methodologic and (+/-) other limitations characterizing most of these studies preclude drawing firm conclusions.”
22
only; cautions in interpreting the results were advised Yes
None declared
None declared
Heterogeneity (I2) ranged from 75% for TG to 98% for HDL cholesterol
Yes
None declared
None declared
Favourable effects of Qi Gong were in one RCT for TC, LDL and TG, and two RCTs favoured Qi Gong in reducing HDL cholesterol
Yes
n.m.
None declared
Missing or incomplete data entries in the review
No
None declared
Declared
Confounding effects of multimodal interventions such as diet, education and stress management
clinical endpoints” Khoo (2009) 23
Kim (2011) 26
“(..) to critically Garlic summarize the evidence on the effect of garlic on serum cholesterol.” “(…) to determine Green tea the effect of GTCs on serum lipid parameters was conducted.”
“To evaluate the effectiveness of G lucidum for the treatment of pharmacologically modifiable risk factors of CVD in adults” Liu (2013) “To assess the 43 effects and safety of Chinese herbal medicines for hypertriglyceridae mia” Klupp (2015) 34
13
High
Yes
9/11
“The available evidence (-) from RCT does not demonstrate any beneficial effects of garlic on serum cholesterol.”
No
None declared
Declared
20
Moderate
Yes
4/9
“The consumption of (+/-) GTCs is associated with a statistically significant reduction in total and LDL cholesterol levels; however, there was no significant effect on HDL cholesterol or TG levels.”
Yes
None declared
Declared
Ganoderma lucidum (Reishi) mushroom
5
Poor high
9/10
“Evidence from a small (-) number of RCTs does not support the use of G lucidum for treatment of CVD risk factors in people with type 2 diabetes mellitus”
Yes
None declare
None declared
There was a higher risk of AEs in the Reishi groups (RR 1.67; 95% CI 0.86 to 3.24)
Herbals
3
Unclear
9/10
“The present systematic (+/-) review suggests that Chinese herbal medicines may have positive effects on hypertriglyceridaemia. […] However, based on an unclear risk of bias in included studies and lack of patient-important long-term outcomes, no definite
Yes
None declare
Declared
Very small number of primary trials; significant inconsistency
to Yes
No
23
A variety of garlic doses were used; healthy and hypercholesterolemic patients were analysed Studies with different endpoints or green tea preparations; funnel plots not reported
conclusion reached.”
Reinhart (2009) 24
To determine the Garlic impact of garlic on TC, TG levels, as well as LDL and HDL
29
Moderate to high
Yes
9/11
Ried (2013) 25
To test the effects Garlic of garlic on serum lipids
39
Moderate to high
Yes
7/9
Singh (2007) 44
To evaluate the Herbals clinical data on Ayurvedic and collateral herbal cholesterollowering products To investigate the Garlic effect of garlic on TC level in persons with elevated levels
36
Moderate
No
1/2
13
High
Yes
7/9
Stevinson (2000) 45
could
be
“Garlic reduces TC to a modest extent, an effect driven mostly by the modest reductions in TAG, without appreciable LDL lowering or HDL elevation.” “This updated metaanalysis suggests garlic to be superior to placebo for reducing elevated total serum cholesterol on a clinically significant level.” “Ayurvedic herbs reviewed here should be considered by physicians when trying to manage hyperlipidemia in their patients” “The use of garlic for hypercholesterolemia is therefore of questionable value”
24
(+)
No
None declare
None declared
Poorer quality trials were associated with greater reductions in TC, HDL and TG
(+)
Yes
None declared
Declared
Garlic was effective in individuals with elevated baseline TC (>200 mg/dL); and longer than 8 weeks
(+)
Yes
n.m
n.m
Quality assessment score lacked standardisations; majority of RCTs were of garlic
(+/-)
Yes
n.m
n.m
Majority of RCTs had small sample size; in 77% of RCTs, CIs crossed the line of no effect
TompsonCoon (2003) 46
Ulbricht (2005) 47
Ulbricht (2010) 48
“To systematically Herbals review the clinical evidence for herbal medicinal products in the treatment of hypercholesterole mia.” “To evaluate the Guggul scientific evidence on guggul for hyperlipidemia including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.” “(…) to evaluate Garlic the scientific evidence on garlic, including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.”
25
Poor
No
6/7
“(…) only a limited amount (+/-) of clinical research exists to support their [herbals] efficacy.”
Yes
n.m.
Declared
Conclusions limited to studies published in English
10
Moderate to high
No
2/5
“The effects of guggul in (+/-) patients with high cholesterol are not clear, with some studies finding cholesterol-lowering effects, and other research suggesting no benefits.”
Yes
n.m.
n.m.
Review also includes uncontrolled beforeafter studies and case series
*
*
No
-6/1
“Small reductions in LDL (+/-) (by <10 mg/dL) and TG (by <20 mg/dL) have also been indicated in the short-term, although results were variable. HDL levels were not found to be significantly affected”
Yes
n.m.
n.m.
Lack of formal quality assessments
25
Wider (2013) 49
Yang (2007) 33
Zeng (2014) 50
Zheng (2011) 27
“To assess the efficacy and safety of ALE in the treatment of hypercholesterolae mia.” “(…) to review published studies using yoga programs and to determine the effect of yoga interventions on common risk factors of chronic [CVD] diseases” To investigate the roles of garlic on the lipid parameters
Artichoke (ALE)
3
Poor to Yes moderate
9/10
“There is an indication that (+/-) ALE has potential in lowering cholesterol levels, but the evidence is, as yet, not convincing.”
Yes
None declared
None (external) declared
Yoga
2
Poor
No
-3/0
“The studies found that (+) yoga interventions are generally effective in reducing […] high cholesterol […]”
No
n.m.
n.m.
Garlic
34
Poor high
to No
-6/1
No
n.m.
Declared
Animal studies were also included
14
Poor
“Future studies with larger (+/-) samples are needed to further clarify the effects of garlic used at higher but non-toxic doses on specific groups.” “The analysis of eligible (+) studies showed that the administration of green tea beverages or extracts resulted in significant reductions in serum TC and LDL-cholesterol concentrations, but no effect on HDL cholesterol was observed”
Yes
None declared
Declared
Various doses and preparations were used; heterogeneous populations and endpoints; random effects should have been used
“(…) to identify Green tea and quantify the effect of green tea and its extract on total cholesterol (TC), LDL cholesterol, and HDL cholesterol.”
Yes
7/10
Table 1 Legend:
26
Limited number of primary trials; considerable heterogeneity in two meta-analyses was detected Studies investigating lipid levels were of observational design; subject also suffered from hypertension, diabetes or CAD
ALE- Artichoke leaf extract; CAD- coronary artery disease; CHD- coronary heart disease; CI- confidence intervals; CVD- cardiovascular disease; GTC- green tea catechins; NCCAM- National Center for Complementary and Alternative Medicine; n.m. – not mentioned; POMsprimary outcome measures; RCT- randomized clinical trial; RYR- red yeast rice; TC- total cholesterol; TG- triglycerides; TCM-Traditional Chinese Medicine. N*- total number of RCTs Direction of conclusions**: (-) – negative, (+) – positive, (+/-) equivocal- an approach previously utilized (amongst others) by 18-20 COI- conflict of interest SOF- source of funding
27
Table 2. Quality ratings for included SRs of CAMs for elevated BLL (Oxman Score) Study, Year [Ref]
Search Metho ds? (a)
Ackerman (2001) 1
Search Comprehensive ? (b)
Inclusion Criteria? (c)
Bias Avoided? (d)
Validity Criteria? (e)
Validity Assessed? (f)
Methods for Appropriately Conclusions Combining Combined? Supported? Studies? (h) (i) (g)
Sum
1
0
0
0
0
0
1
1
4
35
Alder (2003) 36
1
1
1
0
1
1
0
0
1
6
Chu (2016) 37
1
1
1
1
1
1
1
1
0
8
Cramer (2014) 31 Cramer (2015) 30 DalusungAngosta (2001)
1 1 1
1 1 1
1 1 0
1 1 -1
1 1 -1
1 1 -1
1 1 -1
1 -1 -1
1 1 -1
9 7 -4
Gerards (2015) 39
1
0
0
1
0
0
1
1
1
5
Hartley (2014) 29 Hartley (2014) 40 Hartley (2015) 41 Hasani- Ranjbar (2010)
1 1 1 1
1 1 1 0
1 1 1 0
1 1 1 0
1 1 1 1
1 1 1 0
1 1 1 0
1 1 1 0
1 1 1 0
9 9 9 2
Innes (2005) 32
1
1
0
0
0
0
0
0
0
2
23
1
1
1
1
1
1
1
1
1
9
Kim (2011) 26
1
1
0
1
1
0
0
0
0
4
Klupp (2015) 34
1
1
1
1
1
1
1
1
1
9
38
42
Khoo (2009)
28
Liu (2013) 43
1
1
1
1
1
1
1
1
1
9
Reinhart (2009) 24
1
1
1
1
1
1
1
1
1
9
1
1
1
1
0
0
1
1
1
7
1
0
0
0
0
0
1
-1
0
1
Stevinson (2000) 1
1
0
0
1
1
1
1
1
7
Ried (2013)
25
Singh (2007)
44
45
Tompson-Coon 46
1
1
1
0
1
1
0
0
1
6
47
0
1
0
-1
1
1
0
-1
1
2
Ulbricht (2010) 48
Ulbricht (2005)
0
0
-1
-1
-1
-1
-1
-1
0
-6
49
Wider (2013) Yang (2007) 33 Zeng (2014) 50
1 1 1
1 1 0
1 0 -1
1 0 -1
1 -1 -1
1 -1 -1
1 -1 -1
1 -1 -1
1 -1 -1
9 -3 -6
Zheng (2011) 27
1
1
0
1
1
1
1
0
1
7
Table 2 Legend: Scoring: Each Question is Scored as 1, 0, or -1. 1 means that: (a) the review states the databases used, date of most recent searches, and some mention of search terms; (b) the review searches at least 2 databases and looks at other sources; (c) the review states the criteria used for deciding which studies to include in the overview; (d) the review reports how many studies were identified by searches, numbers excluded, and appropriate reasons for excluding them; (e) the review states the criteria used for assessing the validity of the included studies; (f) the review reports validity assessment and did some type of analysis with it; (g) the report mentions that quantitative analysis was not possible and reasons that it could not be done; (h) the review performs a test for heterogeneity before pooling or does appropriate subgroup testing, appropriate sensitivity analysis, or other such analysis; (i) the conclusions made by the author(s) are supported by the data and/or analysis reported in the review. 0 means that the above mentioned criteria were partially fulfilled. -1 means that none of the above criteria were fulfilled. * Operationalisation of the Oxman criteria21, adapted from reference 51.
29
Table 3. Quality assessments of the included SRs of CAMs for elevated BLL (AMSTAR Tool) Study, Year [Ref]
1. Was an ‘a priori’ design provided?
2. Was there duplicate study selection and data extraction?
3. Was a comprehensiv e literature search performed?
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
5. Was a list of studies (included and excluded) provided?
6. Were the characteristi cs of the included studies provided?
7. Was the scientific quality of the included studies assessed and documented ?
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
9. Were the methods used to combine the findings appropri ate?
10. Was the likelihood of publicati on bias assessed?
11. Was Sum the conflict of interest stated?
Acker man (2001)
Yes
Yes
Yes
Yes
No
Yes
Can’t answer
Can’t answer
Yes
Can’t answer
No
6
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Can’t answer
Not applicab le
No
7
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Yes
Yes
10
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
9
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Can’t answer
Yes
9
35
Alder (2003) 36
Chu (2016) 37
Cramer (2014) 31
Crame r (2015)
30
30
Dalusu ngAngost a (2001)
Yes
Can’t answer
Yes
Yes
No
No
No
No
No
Not applicab le
No
3
Yes
Yes
No
Can’t answer
Yes
Yes
Can’t answer
Can’t answer
Yes
No
Yes
6
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
38
Gerard s (2015) 39
Hartle y (2014) 29
Hartle y (2014) 40
Hartle y (2015) 41
31
Hasani Ranjba r (2010)
Yes
Yes
No
Can’t answer
No
Yes
Yes
Can’t answer
Can’t answer
Not applicab le
Yes
5
Yes
Can’t answer
Yes
Yes
No
Yes
Can’t answer
Can’t answer
Can’t answer
Not applicab le
Yes
5
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
11
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Can’t answer
Yes
Yes
9
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
42
Innes (2005) 32
Khoo (2009) 23
Kim (2011) 26
Klupp (2015) 34
32
Liu (2013)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
11
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Can’t answer
Yes
Yes
Yes
9
Yes
No
No
Can’t answer
No
Yes
Can’t answer
Can’t answer
No
Not applicabl e
No
2
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
No
9
43
Reinha rt (2009) 24
Ried (2013) 25
Singh (2007) 44
Stevin son (2000) 45
33
Tomps onCoon
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Can’t answer
Can’t answer
No
7
Yes
Can’t answer
Yes
Can’t answer
No
Yes
Yes
Yes
No
Not applicabl e
No
5
Yes
Can’t answer
No
Can’t answer
No
No
Can’t answer
Can’t answer
No
Not applicabl e
No
1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
No
Can’t answer
No
No
No
No
No
No
No
No
0
46
Ulbric ht (2005) 47
Ulbric ht (2010) 48
Wider (2013) 49
Yang Can’t (2007) answer 33
34
Zeng (2014)
Yes
Can’t answer
No
Can’t answer
No
No
Can’t answer
Can’t answer
No
Not applicabl e
No
1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Yes
Yes
10
50
Zheng (2011) 27
Scoring system for the AMSTAR tool: Yes=1; No=0; Can’t answer=0; Not applicable
35
S0965-2299(16)30188-1 http://dx.doi.org/doi:10.1016/j.ctim.2016.09.019 YCTIM 1621
To appear in:
Complementary Therapies in Medicine
Received date: Revised date: Accepted date:
23-10-2015 16-7-2016 19-9-2016
Please cite this article as: Posadzki Paul, AlBedah Abdullah MN, Khalil Mohamed MK, AlQaed Meshari S.Complementary and alternative medicine for lowering blood lipid levels: a systematic review of systematic reviews.Complementary Therapies in Medicine http://dx.doi.org/10.1016/j.ctim.2016.09.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
(A second revision for CTIM)
Title: Complementary and alternative medicine for lowering blood lipid levels: a systematic review of systematic reviews
Running title: CAM and high blood lipid levels
Correspondence to: Paul Posadzki, PhD Research Fellow in eLearning Health Services and Outcomes Research Programme Lee Kong Chian School of Medicine Imperial College & Nanyang Technological University 3 Fusionopolis Link, #06-13, Nexus@One-North, South tower, Singapore 138543 DID: 6340 2476, Email: [email protected] AND Honorary
Research
Plymouth University Peninsula Schools of Medicine and Dentistry Email: [email protected] Cell: +4407950441367
Abdullah M.N. AlBedah, MBBS, FFCM (KSU) National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Mohamed M.K. Khalil, MBBCh, MPH, MSc, MD 1
Fellow
National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Meshari S. AlQaed, MBBS National Center for Complementary and Alternative Medicine, Riyadh, Saudi Arabia
Funding sources: None. Disclosures: All authors declare no competing interests. Word count: 2707
2
Highlights
This article summarizes and critically evaluates the evidence from systematic reviews of complementary and alternative medicine for lowering blood lipid levels published over the past 16 years
Twenty-seven SRs of predominantly high methodological quality were included in our analyses
The evidence for the effectiveness of complementary and alternative medicine in lowering various lipid fractions, is, in majority of the evaluated SRs, equivocal
Abstract Background: The aim of this article is to summarize and critically evaluate the evidence from systematic reviews (SRs) of complementary and alternative medicine (CAM) for lowering blood lipid levels (BLL). Methods: Eight electronic databases were searched until March 2016. Additionally, all the retrieved references were inspected manually for further relevant papers. Systematic reviews were considered eligible, if they included patients of any age and/or gender with elevated blood lipid levels using any type of CAM. We used the Oxman and AMSTAR criteria to critically appraise the methodological quality of the included SRs. Results: Twenty-seven SRs were included in the analyses. The majority of the SRs were of high methodological quality (mean Oxman score =4.81, SD=4.88; and the mean AMSTAR score=7.22, SD=3.38). The majority of SRs (56%) arrived at equivocal conclusions (of these 8 were of high quality); 7 SRs (37%) arrived at positive conclusions (of these 6 were of high quality), and 2 (7%) arrived at negative conclusions (both were of high quality). There was conflicting evidence regarding the effectiveness of garlic; and promising evidence for yoga. Conclusions: To conclude, the evidence from SRs evaluating the effectiveness of CAM in lowering BLL is predominantly equivocal and confusing. Several limitations exist, such as variety of doses and preparations, confounding effects of diets and lifestyle factors, or heterogeneity of the primary trials among others.
Keywords: Cardiovascular Diseases; Complementary and Alternative Medicine; Systematic reviews; Effectiveness. 3
Introduction Abnormally elevated blood lipids levels (BLL) are associated with many diseases including, diabetes, or cardiovascular diseases (CVD) which are, according the WHO, leading cause of mortality and morbidity worldwide.
12
The risk of heart attack is 3-fold higher in subjects
with elevated BLL than in subjects with normal lipid status.3 The prevalence of the condition varies from country to country (73% in Bulgaria to 24% in Finland) with the overall/global estimate of 38%.4 Several contributing and modifiable risk factors such as inappropriate diet rich in excessive animal proteins and fat, tobacco/alcohol consumption, or lack of regular physical activity (sedentary lifestyles), as well as psychological stress have been identified.5
Complementary and alternative medicine (CAM) is encompasses a broad variety of disparate modalities which can operationally be defined as ‘diagnosis, treatment and/or prevention which complements mainstream medicine by contributing to a common whole, satisfying a demand not met by orthodoxy, or diversifying the conceptual framework of medicine’.6 There is no data on BLL specifically but recent systematic review reported that the prevalence rate of CAM use in patients with CVD ranged from 4% to 61%, with biologicallybased therapies such as dietary supplements and herbal medicine being the most popular (range 22% to 68%).7 The reasons for this high popularity are multidimensional but assumed effectiveness and safety of CAM play a crucial role.6 Some patients with BLL may also perceive statins as burdened with unnecessary side-effects and, as a result, seek for alternatives.
A significant number of randomized clinical trials (RCTs) of CAM in CVD (in general) and BLL (more specifically) have been published in recent years.8-15 Their results are typically gathered and pooled in systematic reviews/meta-analyses (SRs/MAs). These SRs/MAs often 4
arrive at contradictory conclusions which create confusions. To the best of our knowledge, no attempts have been made to summarize and rigorously evaluate the data from SRs of CAM in patients with high BLL. Therefore, this SR is aimed at reviewing and critically assessing the existing evidence from SRs of CAM in elevated BLL.
Methods The Preferred Reporting Items for Systematic Reviews & Meta Analyses (PRISMA) guidelines
16
as well as the Cochrane Handbook for Systematic Reviews of Interventions
17
were meticulously adhered to while reporting of this SR.
Data sources In addition to hand-searches and screening reference lists of all relevant papers, 8 electronic databases were inspected to March 2016: AMED (Ebsco), CINAHL (Ebsco), the Cochrane Library, EMBASE (Ovid), Web of Science, MEDLINE (Ovid), PsycARTICLES (Ovid), and Scopus. We narrowed our searches to articles published since January 2000, as we believed the evidence prior to that date will be scarce and outdated. A detailed search strategy for MEDLINE is presented in the appendix 1.
Study selection Systematic reviews evaluating the effectiveness of CAM in lowering BLL in patients of any age, gender and ethnicity were eligible for inclusion. In this SR, we only included SRs published in English language. Systematic reviews were defined as research articles that include reproducible eligibility (inclusion and exclusion) criteria for primary studies (all types) and a comprehensive literature searches. Non-SRs, MSc or PhD theses or abstracts
5
were excluded. For clarity and to avoid confusion, update SRs (articles that depended upon previous SRs for their primary data) were also excluded.
The following CAM modalities were considered eligible for the present review: acupuncture, Ayurvedic medicine, aromatherapy, (Bach) flower remedies, biofeedback, chiropractic, herbal medicine, homeopathy, hypnosis, massage, meditation, naturopathy, osteopathy, qi gong, spirituality/spiritual healing, tai chi, Traditional Chinese Medicine (TCM) and yoga. We excluded from our analyses vitamins, physical exercises, physiotherapeutic or psychotherapeutic modalities; complex or package interventions, and/or SRs published as abstracts only.
Data screening and selection processes was performed by the first reviewer (PP), and verified and validated by the second (MK), third (AA), and the fourth (MA).
Outcome measures Studies reporting elevated BLL as primary outcome measures were included.
Data Extraction First reviewer (PP) performed data extraction using an a priori defined data extraction form. Then the second (MK), third (AA), and the fourth (MA) reviewer verified and validated the data entries. The following information was extracted: first authors’ names and publication date, aims, type of CAM modality, total number of primary RCTs, quality of primary studies as judged by the authors of the primary studies (poor, moderate, high), whether meta-analysis had been conducted, quality of SR (Oxman and AMSTAR Scores), overall result (quote), direction of conclusion as judged by the present authors (positive, negative or equivocal)18-20, 6
whether SR had mentioned adverse effects (AEs) (yes or no), authors’ conflicts of interest (COI) (declared or not declared), source of funding (SOF) (mentioned or not mentioned), and any comments relating to primary or secondary research.
Risk of Bias /Quality Assessments We used both the Oxman and Guyatt criteria
21
and the AMSTAR tool
22
for judging the
methodological quality of review papers. These are standardized tools evaluate the quality of SRs in the following domains: reporting of search strategy, comprehensiveness of searches, repeatable eligibility criteria, avoidance of selection bias, presence or absence of a validity assessment tool, appropriate use of the validity assessment tool, robustness of data analysis and synthesis and supportiveness of conclusions, whether likelihood of publication bias was assessed; conflict of interest was stated; characteristics of included studies was provided; status of publication (i.e. grey literature) used as an inclusion criterion and ‘a priori’ research question was defined. For the Oxman tool, each domain is scored as 1 (fulfilled), 0 (partially fulfilled), or -1 (not fulfilled); and a final score may range between -9 and 9. A result of 1 or less means the SR has extensive flaws; 2–3 major flaws; 4–5 minor flaws, and 6–9 minimal or no flaws. The scoring system for the AMSTAR tool is as follows: yes; no; can’t answer; and not applicable; with a maximum score of 11 points indicating high methodological quality. This process was carried out by the first reviewer (PP) and subsequently validated by the remaining authors.
Data synthesis The results are presented in a narrative fashion using tables. Descriptive statistics is used to analyze and synthesize the data.
7
Results Study description The searches generated a total of 1302 records and 27 SRs met the eligibility criteria (Figure 1). Of those, 6 (22%) were Cochrane SRs, and the remaining 21 (78%) were non-Cochrane SRs. The key findings from the included SRs are summarized in Table 1. Tables 2 and 3 present the methodological quality of the included SRs.
Characteristics of included SRs The following CAM modalities were evaluated in the SRs: garlic (n=8), herbals overall (n=4), specific herbs including artichoke (n=1), green tea (n=2), guggul (n=1); qi gong (n=1), tai chi (n=2), yoga (n=6), red yeast rice (RYR) (n=1), Reishi mushroom (n=1). The number of primary studies ranged from 1 to 45 (mean= 18.9; SD=18.1). The largest number of primary studies evaluated garlic (N=183), followed by yoga (N=106). The quality of the primary trials ranged from poor to high (overall= moderate). Fourteen (52%) SRs employed meta-analyses of the primary data; and 13 (48%) did not. Fifteen SRs (56%) arrived at equivocal conclusions, 10 SRs (37%) arrived at positive conclusions, and 2 (7%) arrived at negative conclusions. A wide variety of BLL-related outcome measures/indices were evaluated including TG, TC, LDL, VLDL and HDL. Nineteen (70%) SRs did mention CAM related adverse effects; and 8 (30%) did not. Twelve (44%) SRs did not mention any potential conflicts of interests. Sources of funding were mentioned in 16 (59%) SRs.
Characteristics of included populations SRs evaluated both healthy individuals as well as medically compromised patients of both sexes aged 18 years and above. In addition to elevated total cholesterol (TC), triglycerides (TG), or lipoproteins (HDL, LDL and VLDL), co-morbidities of the patients included 8
advanced atherosclerosis, blood hypercoagulation, cardiac dysrhythmia, coronary heart disease, diabetes mellitus, history of renal transplantation or myocardial infraction, heart failure, hypertension, hyperuricemia, ischemic heart disease, infectious diseases (HIV), metabolic syndrome, mental disorders, obesity, or peripheral vascular disease. The subjects were often taking medications for their respective diseases. Comparison groups included placebo, no treatment, pharmacological or non-pharmacological (behavioural) interventions as well as usual care.
Effectiveness of CAM (outcomes) Positive conclusions were reached for garlic (n=2), green tea (n=1), herbals overall (n=1), tai chi (n=1), RYR extract (n=1), and yoga (n=4), meaning effectiveness in reducing LDL, HDL, TG, or TC. Negative conclusions were reached for garlic (n=1), and Reishi mushrooms (n=1), meaning lack of effectiveness. Equivocal conclusions were reached for garlic (n=5), green tea (n=1), artichoke (n=1), guggul (n=1), herbals overall (n=3), qi gong (n=1), tai chi (n=1), and yoga (n=2), meaning effectiveness in reducing certain lipid profiles and ineffectiveness in lowering others.
Methodological quality of the included SRs and RCTs The methodological quality of all the included SRs was, on average acceptable (mean Oxman score =4.81, SD=4.88; range: -6 to 9; and the mean AMSTAR score=7.22, SD=3.38; range: 0-11), indicating minor methodological flaws. Sixteen (59%) SRs had minimal or no flaws (Oxman score 6-9). Eleven SRs (41%) had methodological limitations (Oxman score 5 or less). Six (22%) SRs which arrived at positive conclusions had also minimal or no flaws as assessed by the Oxman scale. Eight (30%) SRs which arrived at equivocal conclusions were 9
also judged to be of highest methodological quality. Four (15%) SRs that were of high methodological quality and arrived at positive conclusions were based on moderate to high quality primary trials. These SRs evaluated the effectiveness of garlic (n=2), and yoga (n=2). In contrast, four SRs (15%) which were of lower methodological quality (Oxman score < 6) arrived at positive conclusions but were based on poor to moderate quality primary trials. These SRs evaluated the effectiveness of Ayurvedic herbs, tai chi, RYR extract and yoga (each n=1). Overall, the majority of SRs (67%) evaluated the effectiveness of biologically based therapies, i.e. herbs, whereas 9 (33%) SRs were concerned with mind-body modalities such as qi gong, tai chi, or yoga.
Discussion This SR was aimed at summarizing and critically evaluating the existing evidence from SRs of CAM in lowering BLL. Twenty-seven SRs met the ‘a priori’ defined inclusion criteria. The majority of SRs were of good methodological quality; and most of them arrived at equivocal conclusions indicating that there was insufficient evidence to judge whether a therapy was effective or not.
Within the scope of this SR, CAM modalities in question could operationally be categorized into biologically based therapies (majority) and mind-body therapies (minority). Garlic was the most frequently evaluated type of CAM (n=8) followed by various mono-herbal and polyherbal preparations (n=7). These included Ayurvedic, or TCM herbals, artichoke, green tea, and guggul. Other biologically based therapies included red yeast rice (RYR), and Reishi mushroom. Mind-body CAM modalities included yoga (n=6), followed by tai chi (n=2) and qi gong (n=1).
10
Multiple SRs evaluated garlic, green tea, herbals and yoga. For instance, for garlic, two SRs arrived at positive; one SR arrived at negative; and 5 arrived at equivocal conclusions. This discrepancy may have arisen from the fact three SRs arriving at equivocal conclusions were also of suboptimal quality (Oxman score less than 6), and/or were based on poor to moderate quality RCTs or garlic preparations were effective for certain lipid fractions and ineffective for others. Furthermore, the SR by Khoo et al.23 that arrived at negative conclusions had included the relatively small number of RCTs (n=13) compared with 29 and 39 in SRs by Reinhart (2009) 24 and Ried 25 (2013) respectively. In addition, Khoo et al. 23 did not perform subgroup analyses by trial duration (short vs. long term efficacy); which proved effective (RCTs longer than 8 weeks) in SR by Ried.25 Given the good safety profile of garlic preparations, the risk-benefit ratio seems to favour this treatment. For green tea, two SRs 26 27 concluded that significant reductions in serum TC and LDL-cholesterol concentrations, but no effect on HDL cholesterol. For this CAM modality, however, moderately severe interactions with antilipaemics have been identified;28 hence the risk-benefit ratio remains uncertain. For yoga, three high quality SRs,29-31 one moderate quality SR,32 and one low quality SR
33
all suggested reductions in HDL and TG; indicating potential benefits as the
safety profile and the risk-benefit ratio of this therapy is good. For other CAM modalities and herbal remedies included, there is still insufficient evidence to recommend them due to small number of primary studies and equivocal conclusions reached.
Our confidence in the overall conclusions is undermined by the fact that there was a considerable number of confounding factors both in primary RCTs and SRs. Examples include heterogeneity of populations, e.g. diabetes or hypertension (metabolic syndrome) and healthy individuals; complex interventions such as yoga based on whole systems philosophy; heterogeneous trial designs (duration, intensity, frequency); comparator groups (active such 11
as statins vs inert placebo); and outcome measures/BLL indices ranging from TC, HDL, LDL, VLDL, TG. This consequently resulted in significant heterogeneity of some of the meta-analyses (I2 >75%) and a small overall effect size. More needs to be done with regards to primary data including formal power and sample size calculations, control for placeboeffects (in mind-body modalities), or standardized intervention regimes (duration, intensity and frequency of treatments); objective outcome measures; transparent reporting of potential competing interest that would all warrant independent replications.
In this SR, we used both Oxman
21
and AMSTAR criteria
22
for evaluating the
methodological quality of SRs in order to strengthen confidence and precision of our judgements. Sixteen (59%) of the included SRs were of high methodological quality (Oxman score 6 or more; and the mean AMSTAR score=7.22, SD=3.38); 11 SRs (41%) had some methodological flaws (Oxman score 5 or less). In general, the included SRs were of acceptable methodological rigor which suggests their concllusions were reliable. However, 10 (37%) of high quality SRs drew their conclusions on poor quality evidence, which in a sense may be counterintuitive.
A recent SR concluded that a large proportion of patients do not inform medical practitioners about their CAM use; and up to 90% of treating physicians did not discuss CAM use with their patients.7 This is potentially dangerous situation as serious adverse effects and interactions with conventional cardiovascular medications exist for many herbs and supplements. Clinicians should communicate the use of any herbals and supplements as these are biologically active substances that have the potential to harm. Other safety concerns included significantly higher risk of adverse effects in the Reishi groups compared with controls (RR 1.67; 95% CI 0.86 to 3.24), and this was based on high quality SR.34 12
Several limitations need to be taken into consideration when interpreting the results of this SR. Our searches were limited to SRs published in English, after year 2000, and therefore some articles published in other languages and before that date were missed. It is also conceivable that, while reviewing SRs we might have overlooked some methodological nuances of the primary data. A phenomenon known as publication bias is also the inherent part of SRs; and might have distorted the overall picture. One of the criticism of SRs of SRs (tertiary research) pertains to the overlap (double-counting) of primary studies. For instance, 8 of the included SRs focused on garlic preparations but the majority of those relied on the same RCTs. We did so because the problem of double-counting in overviews of SRs is methodologically unavoidable, i.e. non-Cochrane SRs including large proportions of the same RCTs already included in Cochrane reviews and vice versa. This overview has its strengths too including the use of two standardized sound tools for assessing the methodological quality of SRs; and critical analysis of both primary and secondary research.
Conclusion In conclusion, a considerable number of SRs of CAM in lowering BLL exists. The evidence for the effectiveness of CAM in lowering various indices of BLL, is, in majority of the evaluated SRs, equivocal which creates confusion. Patients, policy makers and clinicians need to consider the existence of wide variety of limitations in the evidence base. For instance, for garlic, the conclusions are predominantly equivocal whereas for the remainder of herbal remedies as well as other CAM modalities, the evidence is still preliminary and more research needs to be done to clearly inform the above groups. However, for yoga, conclusions were predominantly positive.
13
Appendix 1. A detailed search strategy for MEDLINE (via OVID)
Concept 1 exp hyperlipidemia / OR exp hyperlipidaemia / OR exp hyperlipoproteinemia / OR exp hyperlipoproteinaemia / OR exp metabolic syndrome / OR exp Reaven Syndrome OR exp cardiovascular diseases / OR exp heart diseases / OR exp vascular diseases / OR cerebrovascular disorders / OR exp brain ischemia / OR exp carotid artery diseases / OR exp dementia, vascular / OR exp intracranial arterial diseases / OR exp intracranial hemorrhages / OR exp stroke / OR (coronar$ adj5 (bypas$ or graft$ or disease$ or event$)).mp. OR (cerebrovasc$ or cardiovasc$ or mortal$ or angina$ or stroke or strokes).mp. OR (myocardi$ adj5 (infarct$ or revascular$ or ischaemi$ or ischemi$)).mp. OR (morbid$ adj5 (heart$ or coronar$ or ischaem$ or ischem$ or myocard$)).mp. OR (vascular$ adj5 (peripheral$ or disease$ or complication$)).mp. OR (heart$ adj5 (disease$ or attack$ or bypass$)).mp.
Concept 2 (Alternative adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR (Complementary adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR (integrat$ adj3 (heal$ or medic$ or remed$ or therap$ or treatment$)).ti,ab. OR CAM.ti,ab. OR exp Complementary Therapies/
Concept 3 review.ti
SEARCHES= 1 AND 2 AND 3 14
References 1. Genest J, Libby, P. Lipoprotein disorders and cardiovascular disease. In: Bonow RO, Mann, D.L., Zipes, D.P., Libby, P., eds., ed. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed: Philadelphia, PA: Elsevier Saunders, 2011. 2. World Health Organization (WHO). 2008–2013 Action Plan for the Global Strategy for the Prevention and Control of Noncommunicable Diseases: Prevent and Control Cardiovascular Diseases, Cancers, Chronic Respiratory Diseases and Diabetes. Geneva, Switzerland: WHO; 2008., 2008. 3. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364(9438):937-52. 4. Venkitachalam L, Wang K, Porath A, et al. Global variation in the prevalence of elevated cholesterol in outpatients with established vascular disease or 3 cardiovascular risk factors according to national indices of economic development and health system performance. Circulation 2012;125(15):1858-69. 5. Uthman OA, Hartley L, Rees K, et al. Multiple risk factor interventions for primary prevention of cardiovascular disease in low- and middle-income countries. Cochrane Database Syst Rev 2015;8:CD011163. 6. Ernst E, Pittler, M.H., Wider, B., Boddy, K. The Desktop Guide to Complementary and Alternative Medicine, 2nd edn. . Edinburgh.: Elsevier Mosby., 2006. 7. Grant SJ, Bin YS, Kiat H, et al. The use of complementary and alternative medicine by people with cardiovascular disease: a systematic review. BMC public health 2012;12:299. 8. Budoff MJ, Ahmadi N, Gul KM, et al. Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial. Prev Med 2009;49(2-3):101-7. 9. Jung ES, Park SH, Choi EK, et al. Reduction of blood lipid parameters by a 12-wk supplementation of aged black garlic: a randomized controlled trial. Nutrition 2014;30(9):1034-9. 10. Mahdavi-Roshan M, Zahedmehr A, Mohammad-Zadeh A, et al. Effect of garlic powder tablet on carotid intima-media thickness in patients with coronary artery disease: a preliminary randomized controlled trial. Nutr Health 2013;22(2):143-55. 11. Bundy R, Walker AF, Middleton RW, et al. Artichoke leaf extract (Cynara scolymus) reduces plasma cholesterol in otherwise healthy hypercholesterolemic adults: a randomized, double blind placebo controlled trial. Phytomedicine 2008;15(9):668-75. 12. Maron DJ, Lu GP, Cai NS, et al. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Arch Intern Med 2003;163(12):144853. 13. Papp ME, Lindfors P, Nygren-Bonnier M, et al. Effects of High-Intensity Hatha Yoga on Cardiovascular Fitness, Adipocytokines, and Apolipoproteins in Healthy Students: A Randomized Controlled Study. J Altern Complement Med 2016;22(1):81-7. 14. Thiyagarajan R, Pal P, Pal GK, et al. Additional benefit of yoga to standard lifestyle modification on blood pressure in prehypertensive subjects: a randomized controlled study. Hypertens Res 2015;38(1):48-55. 15. Thomas GN, Hong AW, Tomlinson B, et al. Effects of Tai Chi and resistance training on cardiovascular risk factors in elderly Chinese subjects: a 12-month longitudinal, randomized, controlled intervention study. Clin Endocrinol (Oxf) 2005;63(6):663-9. 15
16. Gitelson E, Al-Saleem T, Millenson M, et al. Cutaneous B-cell lymphoma responds to rituximab: A report of five cases and a review of the literature. Leukemia and Lymphoma 2006;47(9):1902-07. 17. Connock M, Burls A, Frew E, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: A systematic review. Health Technology Assessment 2006;10(24):iii-iv+77-83. 18. Ernst E, Posadzki P, Lee MS. Complementary and alternative medicine (CAM) for sexual dysfunction and erectile dysfunction in older men and women: an overview of systematic reviews. Maturitas 2011;70(1):37-41. 19. Ernst E, Lee MS, Choi TY. Acupuncture: does it alleviate pain and are there serious risks? A review of reviews. Pain 2011;152(4):755-64. 20. Furlan AD, Clarke J, Esmail R, et al. A critical review of reviews on the treatment of chronic low back pain. Spine (Phila Pa 1976) 2001;26(7):E155-62. 21. Oxman AD, Guyatt GH. Validation of an index of the quality of review articles. J Clin Epidemiol 1991;44(11):1271-8. 22. Shea BJ, Hamel C, Wells GA, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. Journal of clinical epidemiology 2009;62(10):1013-20. 23. Khoo YS, Aziz Z. Garlic supplementation and serum cholesterol: a meta-analysis. J Clin Pharm Ther 2009;34(2):133-45. 24. Reinhart KM, Talati R, White CM, et al. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutrition research reviews 2009;22(1):39-48. 25. Ried K, Toben C, Fakler P. Effect of garlic on serum lipids: an updated meta-analysis. Nutrition reviews 2013;71(5):282-99. 26. Kim A, Chiu A, Barone MK, et al. Green tea catechins decrease total and low-density lipoprotein cholesterol: a systematic review and meta-analysis. Journal of the American Dietetic Association 2011;111(11):1720-9. 27. Zheng XX, Xu YL, Li SH, et al. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. The American journal of clinical nutrition 2011;94(2):601-10. 28. Posadzki P, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol 2013;75(3):603-18. 29. Hartley L, Dyakova M, Holmes J, et al. Yoga for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;5:CD010072. 30. Cramer H, Lauche R, Haller H, et al. A systematic review of yoga for heart disease. Eur J Prev Cardiol 2015;22(3):284-95. 31. Cramer H, Lauche R, Haller H, et al. Effects of yoga on cardiovascular disease risk factors: a systematic review and meta-analysis. Int J Cardiol 2014;173(2):170-83. 32. Innes KE, Bourguignon C, Taylor AG. Risk indices associated with the insulin resistance syndrome, cardiovascular disease, and possible protection with yoga: A systematic review. Journal of the American Board of Family Practice 2005;18(6):491-519. 33. Yang K. A review of yoga programs for four leading risk factors of chronic diseases. Evidence-based complementary and alternative medicine : eCAM 2007;4(4):487-91. 34. Klupp NL, Chang D, Hawke F, et al. Ganoderma lucidum mushroom for the treatment of cardiovascular risk factors. Cochrane Database Syst Rev 2015;2:CD007259. 35. Ackermann RT, Mulrow CD, Ramirez G, et al. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med 2001;161(6):813-24.
16
36. Alder R, Lookinland, S., Berry, J.A., Williams, M. A systematic review of the effectiveness of garlic as an anti-hyperlipidemic agent. J Am Acad Nurse Pract 2003;15(3):120-9. 37. Chu P, Gotink RA, Yeh GY, et al. The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and metaanalysis of randomized controlled trials. Eur J Prev Cardiol 2016;23(3):291-307. 38. Dalusung-Angosta A. The impact of Tai Chi exercise on coronary heart disease: A systematic review. Journal of the American Academy of Nurse Practitioners 2011;23(7):376-81. 39. Gerards MC, Terlou RJ, Yu H, et al. Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain - A systematic review and meta-analysis. Atherosclerosis 2015;240(2):415-23. 40. Hartley L, Flowers N, Lee MS, et al. Tai chi for primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;4:CD010366. 41. Hartley L, Lee MS, Kwong JS, et al. Qigong for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2015;6:CD010390. 42. Hasani-Ranjbar S, Nayebi N, Moradi L, et al. The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review. Current Pharmaceutical Design 2010;16(26):2935-47. 43. Liu ZL, Li, G.Q., Bensoussan, A, Kiat, H, Chan, K, Liu, J.P. Chinese herbal medicines for hypertriglyceridaemia. Cochrane Database Syst Rev 2013;7(CD008305.). 44. Singh BB, Vinjamury SP, Der-Martirosian C, et al. Ayurvedic and collateral herbal treatments for hyperlipidemia: A systematic review of randomized controlled trials and quasi-experimental designs. Alternative Therapies in Health and Medicine 2007;13(4):22-28. 45. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia. A metaanalysis of randomized clinical trials. Ann Intern Med 2000;133(6):420-9. 46. Thompson Coon JS, Ernst E. Herbs for serum cholesterol reduction: A systematic review. Journal of Family Practice 2003;52(6):468-78. 47. Ulbricht C, Basch E, Szapary P, et al. Guggul for hyperlipidemia: a review by the Natural Standard Research Collaboration. Complementary Therapies in Medicine 2005;13(4):279-90. 48. Ulbricht C, Isaac R, Milkin T, et al. An evidence-based systematic review of stevia by the Natural Standard Research Collaboration. Cardiovascular & Hematological Agents in Medicinal Chemistry 2010;8(2):113-27. 49. Wider B, Pittler MH, Thompson-Coon J, et al. Artichoke leaf extract for treating hypercholesterolaemia. Cochrane Database Syst Rev 2013;3:CD003335. 50. Zeng T, Zhang CL, Zhao XL, et al. The roles of garlic on the lipid parameters: a systematic review of the literature. Critical Reviews in Food Science & Nutrition 2013;53(3):215-30. 51. Posadzki P, Ernst E. Spinal manipulation: an update of a systematic review of systematic reviews. N Z Med J 2011;124(1340):55-71.
17
Figure 1. Flow diagram for included studies
Total number of hits for electronic search (n=1300)
Additional records identified through manual search (n=2)
Duplicates removed (n=75)
Records screened (n =1227)
Full-text articles assessed for eligibility (n =145)
Total number of articles included (n=27)
18
Excluded: not SR (n=1055); published before 2000 (n=27)
Excluded: not CAM (n=118)
Figure 1 Legend: CAM-complementary and alternative medicine; SR-systematic review.
19
Table 1. Systematic Reviews of Complementary and Alternative Medicines for Elevated BLL First author (year) [ref]
Aims
Ackerman (2001) 35
Alder (2003) 36
Chu (2016) 37
Interventio n(s)/CAM modality
N*
Quality of RCTs
Meta anal ysis
Oxman /AMST AR Score
Overall result (quote)
“To summarize the Garlic effects of garlic on several CVDrelated factors and to note its adverse effects.” “To conduct a Garlic thorough search of the literature for RCTs addressing the efficacy of garlic as an antihyperlipidemic agent (…)”
45
Poor
Yes
4/6
10
Poor
No
“(…) to evaluate Yoga the evidence on the effectiveness of yoga for modifying risk factors for CVD and metabolic syndrome in adults (…)”
37
Moderate
Yes
Menti COI on of advers e effects
SOF
Comment
“Conclusions regarding (+/-) clinical significance are limited by the marginal quality and short duration of many trials (…)”
Yes
n.m.
n.m.
Outcomes also included hypertension, diabetes or blood hypercoagulation
6/7
“Six of ten studies (+/-) found garlic to be effective. The average drop in TC was 24.8 mg/dL (9.9%), LDL 15.3 mg/dL (11.4%), and TG 38 mg/dL (9.9%).”
No
n.m.
n.m.
Diet was confounding factor in most RCTs which were typically of short duration, poor quality and heterogeneous designs
8/10
“There is promising (+) evidence of yoga on improving cardio-metabolic health. Findings are limited by small trial sample sizes, heterogeneity, and moderate quality of RCTs”
No
None declared
None declared
For LDL- I2 was over 75%; no sensitivity analyses were performed; double counting of data (analysis 3.2.1)
20
Dire ction of concl usio n**
Cramer (2014) 31
“(…) to Yoga systematically assess and metaanalyse the effects of yoga on modifiable biological CVD risk factors in the general population and in high-risk disease groups”
44
Poor
Yes
9/9
Cramer (2015) 30
“(…) to evaluate the quality of evidence and the strength of recommendation for yoga as an ancillary intervention for heart disease” “To explore current studies on Tai Chi and its impact on CHD (…)” “To verify the safety and effectiveness of traditional Chinese RYR extract for reduction of LDL cholesterol” “To determine the effect of any type
Yoga
7
Poor
No
7/9
Tai Chi
1
Moderate
No
RYR extract
20
Moderate to high
Yes
Yoga
11
Poor to Yes moderate
DalusungAngosta (2001) 38
Gerards (2015) 39
Hartley (2014) 29
“This meta-analysis (+) revealed evidence for clinically important effects of yoga on most biological CVD risk factors. Despite methodological drawbacks of the included studies, yoga can be considered as an ancillary intervention for the general population and for patients with increased risk of CVD.” “(…) weak (+/-) recommendations can be made for the ancillary use of yoga for patients with CHD, heart failure, and cardiac dysrhythmia at this point.”
Yes
n.m.
Declared
For HDL- I2 was 90%; most studies suffered methodological limitations
Yes
None declared
Declared
Small total number of patients; heterogeneous populations, and poor overall quality of the evidence
-4/3
“Implementing Tai Chi (+) exercise may improve serum lipids, blood pressure, and heart rate.”
No
n.m.
n.m.
Poor quality SR with overinflated conclusions
5/6
“RYR exerts a clinically (+) and statistically significant reduction of 1.02 mmol/L LDL cholesterol.”
Yes
None declared
None declared
35% of RCTs lacked blinding; significant amount of heterogeneity of the analyses
9/10
“There is some evidence (+) that yoga has favourable
Yes
None declared
None declared
Analyses involved 800 participants
21
Hartley (2014) 40
of yoga on the primary prevention of CVD” “To determine the Tai Chi effectiveness of tai chi for the primary prevention of CVD”
13
Poor
Yes
9/10
Hartley (2015) 41
“To determine the Qi Gong effectiveness of Qi Gong for the primary prevention of CVD”
11
Poor
No
9/10
HasaniRanjbar (2010)
“This review Herbals focuses on the efficacy and safety of effective herbal medicines in the management of hyperlipidemia in human.” “To conduct a Yoga systematic review of […] the effects of yoga […] on specific anthropometric and physiologic indices of CVD risk and on related
43
Moderate
No
2/5
5
Poor
No
2/5
42
Innes (2005) 32
effects on diastolic blood pressure, HDL cholesterol and TG, and uncertain effects on LDL cholesterol” “There was some (+/-) suggestion of beneficial effects of tai chi on CVD risk factors but this was not consistent across all studies.” “(…) further trials of high (+/-) methodological quality […] are needed to be incorporated in an update of this review before the effectiveness of qigong for CVD prevention can be established” “Conflicting data exist for (+/-) red yeast rice, garlic and guggul. […]”
“(…) the methodologic and (+/-) other limitations characterizing most of these studies preclude drawing firm conclusions.”
22
only; cautions in interpreting the results were advised Yes
None declared
None declared
Heterogeneity (I2) ranged from 75% for TG to 98% for HDL cholesterol
Yes
None declared
None declared
Favourable effects of Qi Gong were in one RCT for TC, LDL and TG, and two RCTs favoured Qi Gong in reducing HDL cholesterol
Yes
n.m.
None declared
Missing or incomplete data entries in the review
No
None declared
Declared
Confounding effects of multimodal interventions such as diet, education and stress management
clinical endpoints” Khoo (2009) 23
Kim (2011) 26
“(..) to critically Garlic summarize the evidence on the effect of garlic on serum cholesterol.” “(…) to determine Green tea the effect of GTCs on serum lipid parameters was conducted.”
“To evaluate the effectiveness of G lucidum for the treatment of pharmacologically modifiable risk factors of CVD in adults” Liu (2013) “To assess the 43 effects and safety of Chinese herbal medicines for hypertriglyceridae mia” Klupp (2015) 34
13
High
Yes
9/11
“The available evidence (-) from RCT does not demonstrate any beneficial effects of garlic on serum cholesterol.”
No
None declared
Declared
20
Moderate
Yes
4/9
“The consumption of (+/-) GTCs is associated with a statistically significant reduction in total and LDL cholesterol levels; however, there was no significant effect on HDL cholesterol or TG levels.”
Yes
None declared
Declared
Ganoderma lucidum (Reishi) mushroom
5
Poor high
9/10
“Evidence from a small (-) number of RCTs does not support the use of G lucidum for treatment of CVD risk factors in people with type 2 diabetes mellitus”
Yes
None declare
None declared
There was a higher risk of AEs in the Reishi groups (RR 1.67; 95% CI 0.86 to 3.24)
Herbals
3
Unclear
9/10
“The present systematic (+/-) review suggests that Chinese herbal medicines may have positive effects on hypertriglyceridaemia. […] However, based on an unclear risk of bias in included studies and lack of patient-important long-term outcomes, no definite
Yes
None declare
Declared
Very small number of primary trials; significant inconsistency
to Yes
No
23
A variety of garlic doses were used; healthy and hypercholesterolemic patients were analysed Studies with different endpoints or green tea preparations; funnel plots not reported
conclusion reached.”
Reinhart (2009) 24
To determine the Garlic impact of garlic on TC, TG levels, as well as LDL and HDL
29
Moderate to high
Yes
9/11
Ried (2013) 25
To test the effects Garlic of garlic on serum lipids
39
Moderate to high
Yes
7/9
Singh (2007) 44
To evaluate the Herbals clinical data on Ayurvedic and collateral herbal cholesterollowering products To investigate the Garlic effect of garlic on TC level in persons with elevated levels
36
Moderate
No
1/2
13
High
Yes
7/9
Stevinson (2000) 45
could
be
“Garlic reduces TC to a modest extent, an effect driven mostly by the modest reductions in TAG, without appreciable LDL lowering or HDL elevation.” “This updated metaanalysis suggests garlic to be superior to placebo for reducing elevated total serum cholesterol on a clinically significant level.” “Ayurvedic herbs reviewed here should be considered by physicians when trying to manage hyperlipidemia in their patients” “The use of garlic for hypercholesterolemia is therefore of questionable value”
24
(+)
No
None declare
None declared
Poorer quality trials were associated with greater reductions in TC, HDL and TG
(+)
Yes
None declared
Declared
Garlic was effective in individuals with elevated baseline TC (>200 mg/dL); and longer than 8 weeks
(+)
Yes
n.m
n.m
Quality assessment score lacked standardisations; majority of RCTs were of garlic
(+/-)
Yes
n.m
n.m
Majority of RCTs had small sample size; in 77% of RCTs, CIs crossed the line of no effect
TompsonCoon (2003) 46
Ulbricht (2005) 47
Ulbricht (2010) 48
“To systematically Herbals review the clinical evidence for herbal medicinal products in the treatment of hypercholesterole mia.” “To evaluate the Guggul scientific evidence on guggul for hyperlipidemia including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.” “(…) to evaluate Garlic the scientific evidence on garlic, including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.”
25
Poor
No
6/7
“(…) only a limited amount (+/-) of clinical research exists to support their [herbals] efficacy.”
Yes
n.m.
Declared
Conclusions limited to studies published in English
10
Moderate to high
No
2/5
“The effects of guggul in (+/-) patients with high cholesterol are not clear, with some studies finding cholesterol-lowering effects, and other research suggesting no benefits.”
Yes
n.m.
n.m.
Review also includes uncontrolled beforeafter studies and case series
*
*
No
-6/1
“Small reductions in LDL (+/-) (by <10 mg/dL) and TG (by <20 mg/dL) have also been indicated in the short-term, although results were variable. HDL levels were not found to be significantly affected”
Yes
n.m.
n.m.
Lack of formal quality assessments
25
Wider (2013) 49
Yang (2007) 33
Zeng (2014) 50
Zheng (2011) 27
“To assess the efficacy and safety of ALE in the treatment of hypercholesterolae mia.” “(…) to review published studies using yoga programs and to determine the effect of yoga interventions on common risk factors of chronic [CVD] diseases” To investigate the roles of garlic on the lipid parameters
Artichoke (ALE)
3
Poor to Yes moderate
9/10
“There is an indication that (+/-) ALE has potential in lowering cholesterol levels, but the evidence is, as yet, not convincing.”
Yes
None declared
None (external) declared
Yoga
2
Poor
No
-3/0
“The studies found that (+) yoga interventions are generally effective in reducing […] high cholesterol […]”
No
n.m.
n.m.
Garlic
34
Poor high
to No
-6/1
No
n.m.
Declared
Animal studies were also included
14
Poor
“Future studies with larger (+/-) samples are needed to further clarify the effects of garlic used at higher but non-toxic doses on specific groups.” “The analysis of eligible (+) studies showed that the administration of green tea beverages or extracts resulted in significant reductions in serum TC and LDL-cholesterol concentrations, but no effect on HDL cholesterol was observed”
Yes
None declared
Declared
Various doses and preparations were used; heterogeneous populations and endpoints; random effects should have been used
“(…) to identify Green tea and quantify the effect of green tea and its extract on total cholesterol (TC), LDL cholesterol, and HDL cholesterol.”
Yes
7/10
Table 1 Legend:
26
Limited number of primary trials; considerable heterogeneity in two meta-analyses was detected Studies investigating lipid levels were of observational design; subject also suffered from hypertension, diabetes or CAD
ALE- Artichoke leaf extract; CAD- coronary artery disease; CHD- coronary heart disease; CI- confidence intervals; CVD- cardiovascular disease; GTC- green tea catechins; NCCAM- National Center for Complementary and Alternative Medicine; n.m. – not mentioned; POMsprimary outcome measures; RCT- randomized clinical trial; RYR- red yeast rice; TC- total cholesterol; TG- triglycerides; TCM-Traditional Chinese Medicine. N*- total number of RCTs Direction of conclusions**: (-) – negative, (+) – positive, (+/-) equivocal- an approach previously utilized (amongst others) by 18-20 COI- conflict of interest SOF- source of funding
27
Table 2. Quality ratings for included SRs of CAMs for elevated BLL (Oxman Score) Study, Year [Ref]
Search Metho ds? (a)
Ackerman (2001) 1
Search Comprehensive ? (b)
Inclusion Criteria? (c)
Bias Avoided? (d)
Validity Criteria? (e)
Validity Assessed? (f)
Methods for Appropriately Conclusions Combining Combined? Supported? Studies? (h) (i) (g)
Sum
1
0
0
0
0
0
1
1
4
35
Alder (2003) 36
1
1
1
0
1
1
0
0
1
6
Chu (2016) 37
1
1
1
1
1
1
1
1
0
8
Cramer (2014) 31 Cramer (2015) 30 DalusungAngosta (2001)
1 1 1
1 1 1
1 1 0
1 1 -1
1 1 -1
1 1 -1
1 1 -1
1 -1 -1
1 1 -1
9 7 -4
Gerards (2015) 39
1
0
0
1
0
0
1
1
1
5
Hartley (2014) 29 Hartley (2014) 40 Hartley (2015) 41 Hasani- Ranjbar (2010)
1 1 1 1
1 1 1 0
1 1 1 0
1 1 1 0
1 1 1 1
1 1 1 0
1 1 1 0
1 1 1 0
1 1 1 0
9 9 9 2
Innes (2005) 32
1
1
0
0
0
0
0
0
0
2
23
1
1
1
1
1
1
1
1
1
9
Kim (2011) 26
1
1
0
1
1
0
0
0
0
4
Klupp (2015) 34
1
1
1
1
1
1
1
1
1
9
38
42
Khoo (2009)
28
Liu (2013) 43
1
1
1
1
1
1
1
1
1
9
Reinhart (2009) 24
1
1
1
1
1
1
1
1
1
9
1
1
1
1
0
0
1
1
1
7
1
0
0
0
0
0
1
-1
0
1
Stevinson (2000) 1
1
0
0
1
1
1
1
1
7
Ried (2013)
25
Singh (2007)
44
45
Tompson-Coon 46
1
1
1
0
1
1
0
0
1
6
47
0
1
0
-1
1
1
0
-1
1
2
Ulbricht (2010) 48
Ulbricht (2005)
0
0
-1
-1
-1
-1
-1
-1
0
-6
49
Wider (2013) Yang (2007) 33 Zeng (2014) 50
1 1 1
1 1 0
1 0 -1
1 0 -1
1 -1 -1
1 -1 -1
1 -1 -1
1 -1 -1
1 -1 -1
9 -3 -6
Zheng (2011) 27
1
1
0
1
1
1
1
0
1
7
Table 2 Legend: Scoring: Each Question is Scored as 1, 0, or -1. 1 means that: (a) the review states the databases used, date of most recent searches, and some mention of search terms; (b) the review searches at least 2 databases and looks at other sources; (c) the review states the criteria used for deciding which studies to include in the overview; (d) the review reports how many studies were identified by searches, numbers excluded, and appropriate reasons for excluding them; (e) the review states the criteria used for assessing the validity of the included studies; (f) the review reports validity assessment and did some type of analysis with it; (g) the report mentions that quantitative analysis was not possible and reasons that it could not be done; (h) the review performs a test for heterogeneity before pooling or does appropriate subgroup testing, appropriate sensitivity analysis, or other such analysis; (i) the conclusions made by the author(s) are supported by the data and/or analysis reported in the review. 0 means that the above mentioned criteria were partially fulfilled. -1 means that none of the above criteria were fulfilled. * Operationalisation of the Oxman criteria21, adapted from reference 51.
29
Table 3. Quality assessments of the included SRs of CAMs for elevated BLL (AMSTAR Tool) Study, Year [Ref]
1. Was an ‘a priori’ design provided?
2. Was there duplicate study selection and data extraction?
3. Was a comprehensiv e literature search performed?
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?
5. Was a list of studies (included and excluded) provided?
6. Were the characteristi cs of the included studies provided?
7. Was the scientific quality of the included studies assessed and documented ?
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
9. Were the methods used to combine the findings appropri ate?
10. Was the likelihood of publicati on bias assessed?
11. Was Sum the conflict of interest stated?
Acker man (2001)
Yes
Yes
Yes
Yes
No
Yes
Can’t answer
Can’t answer
Yes
Can’t answer
No
6
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Can’t answer
Not applicab le
No
7
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Yes
Yes
10
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
9
Yes
Yes
Yes
Can’t answer
Yes
Yes
Yes
Yes
Yes
Can’t answer
Yes
9
35
Alder (2003) 36
Chu (2016) 37
Cramer (2014) 31
Crame r (2015)
30
30
Dalusu ngAngost a (2001)
Yes
Can’t answer
Yes
Yes
No
No
No
No
No
Not applicab le
No
3
Yes
Yes
No
Can’t answer
Yes
Yes
Can’t answer
Can’t answer
Yes
No
Yes
6
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
38
Gerard s (2015) 39
Hartle y (2014) 29
Hartle y (2014) 40
Hartle y (2015) 41
31
Hasani Ranjba r (2010)
Yes
Yes
No
Can’t answer
No
Yes
Yes
Can’t answer
Can’t answer
Not applicab le
Yes
5
Yes
Can’t answer
Yes
Yes
No
Yes
Can’t answer
Can’t answer
Can’t answer
Not applicab le
Yes
5
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
11
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Can’t answer
Yes
Yes
9
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
42
Innes (2005) 32
Khoo (2009) 23
Kim (2011) 26
Klupp (2015) 34
32
Liu (2013)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
11
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Can’t answer
Yes
Yes
Yes
9
Yes
No
No
Can’t answer
No
Yes
Can’t answer
Can’t answer
No
Not applicabl e
No
2
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
No
9
43
Reinha rt (2009) 24
Ried (2013) 25
Singh (2007) 44
Stevin son (2000) 45
33
Tomps onCoon
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Can’t answer
Can’t answer
No
7
Yes
Can’t answer
Yes
Can’t answer
No
Yes
Yes
Yes
No
Not applicabl e
No
5
Yes
Can’t answer
No
Can’t answer
No
No
Can’t answer
Can’t answer
No
Not applicabl e
No
1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
10
No
Can’t answer
No
No
No
No
No
No
No
No
0
46
Ulbric ht (2005) 47
Ulbric ht (2010) 48
Wider (2013) 49
Yang Can’t (2007) answer 33
34
Zeng (2014)
Yes
Can’t answer
No
Can’t answer
No
No
Can’t answer
Can’t answer
No
Not applicabl e
No
1
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Can’t answer
Yes
Yes
10
50
Zheng (2011) 27
Scoring system for the AMSTAR tool: Yes=1; No=0; Can’t answer=0; Not applicable
35