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Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis.
Karam, G, Agarwal, A, Sadeghirad, B, Jalink, M, Hitchcock, CL, Ge, L, Kiflen, R, Ahmed, W, Zea, AM, Milenkovic, J, et al
BMJ (Clinical research ed.). 2023;:e072003
Abstract
OBJECTIVE To determine the relative efficacy of structured named diet and health behaviour programmes (dietary programmes) for prevention of mortality and major cardiovascular events in patients at increased risk of cardiovascular disease. DESIGN Systematic review and network meta-analysis of randomised controlled trials. DATA SOURCES AMED (Allied and Complementary Medicine Database), CENTRAL (Cochrane Central Register of Controlled Trials), Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ClinicalTrials.gov were searched up to September 2021. STUDY SELECTION Randomised trials of patients at increased risk of cardiovascular disease that compared dietary programmes with minimal intervention (eg, healthy diet brochure) or alternative programmes with at least nine months of follow-up and reporting on mortality or major cardiovascular events (such as stroke or non-fatal myocardial infarction). In addition to dietary intervention, dietary programmes could also include exercise, behavioural support, and other secondary interventions such as drug treatment. OUTCOMES AND MEASURES All cause mortality, cardiovascular mortality, and individual cardiovascular events (stroke, non-fatal myocardial infarction, and unplanned cardiovascular interventions). REVIEW METHODS Pairs of reviewers independently extracted data and assessed risk of bias. A random effects network meta-analysis was performed using a frequentist approach and grading of recommendations assessment, development and evaluation (GRADE) methods to determine the certainty of evidence for each outcome. RESULTS 40 eligible trials were identified with 35 548 participants across seven named dietary programmes (low fat, 18 studies; Mediterranean, 12; very low fat, 6; modified fat, 4; combined low fat and low sodium, 3; Ornish, 3; Pritikin, 1). At last reported follow-up, based on moderate certainty evidence, Mediterranean dietary programmes proved superior to minimal intervention for the prevention of all cause mortality (odds ratio 0.72, 95% confidence interval 0.56 to 0.92; patients at intermediate risk: risk difference 17 fewer per 1000 followed over five years), cardiovascular mortality (0.55, 0.39 to 0.78; 13 fewer per 1000), stroke (0.65, 0.46 to 0.93; 7 fewer per 1000), and non-fatal myocardial infarction (0.48, 0.36 to 0.65; 17 fewer per 1000). Based on moderate certainty evidence, low fat programmes proved superior to minimal intervention for prevention of all cause mortality (0.84, 0.74 to 0.95; 9 fewer per 1000) and non-fatal myocardial infarction (0.77, 0.61 to 0.96; 7 fewer per 1000). The absolute effects for both dietary programmes were more pronounced for patients at high risk. There were no convincing differences between Mediterranean and low fat programmes for mortality or non-fatal myocardial infarction. The five remaining dietary programmes generally had little or no benefit compared with minimal intervention typically based on low to moderate certainty evidence. CONCLUSIONS Moderate certainty evidence shows that programmes promoting Mediterranean and low fat diets, with or without physical activity or other interventions, reduce all cause mortality and non-fatal myocardial infarction in patients with increased cardiovascular risk. Mediterranean programmes are also likely to reduce stroke risk. Generally, other named dietary programmes were not superior to minimal intervention. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42016047939.
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Saturated fat, the estimated absolute risk and certainty of risk for mortality and major cancer and cardiometabolic outcomes: an overview of systematic reviews.
Talukdar, JR, Steen, JP, Goldenberg, JZ, Zhang, Q, Vernooij, RWM, Ge, L, Zeraatkar, D, Bała, MM, Ball, GDC, Thabane, L, et al
Systematic reviews. 2023;(1):179
Abstract
OBJECTIVE To assess the impact of reducing saturated fat or fatty foods, or replacing saturated fat with unsaturated fat, carbohydrate or protein, on the risk of mortality and major cancer and cardiometabolic outcomes in adults. METHODS We searched MEDLINE, EMBASE, CINAHL, and references of included studies for systematic reviews and meta-analyses (SRMAs) of randomized controlled trials (RCTs) and observational studies in adults published in the past 10 years. Eligible reviews investigated reducing saturated fat or fatty foods or replacing saturated fat with unsaturated fat, carbohydrate or protein, on the risk of cancer and cardiometabolic outcomes and assessed the certainty of evidence for each outcome using, for example, the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach. We assessed the quality of SRMAs using a modified version of AMSTAR-2. Results were summarized as absolute estimates of effect together with the certainty of effects using a narrative synthesis approach. RESULTS We included 17 SRMAs (13 reviews of observational studies with follow-up 1 to 34 years; 4 reviews of RCTs with follow-up 1 to 17 years). The quality of two-thirds of the SRMAs was critically low to moderate; the main limitations included deficient reporting of study selection, absolute effect estimates, sources of funding, and a priori subgroups to explore heterogeneity. Our included reviews reported > 100 estimates of effect across 11 critically important cancer and cardiometabolic outcomes. High quality SRMAs consistently and predominantly reported low to very low certainty evidence that reducing or replacing saturated fat was associated with a very small risk reduction in cancer and cardiometabolic endpoints. The risk reductions where approximately divided, some being statistically significant and some being not statistically significant. However, based on 2 moderate to high quality reviews, we found moderate certainty evidence for a small but important effect that was statistically significant for two outcomes (total mortality events [20 fewer events per 1000 followed] and combined cardiovascular events [16 fewer per 1000 followed]). Conversely, 4 moderate to high quality reviews showed very small effects on total mortality, with 3 of these reviews showing non-statistically significant mortality effects. CONCLUSION Systematic reviews investigating the impact of SFA on mortality and major cancer and cardiometabolic outcomes almost universally suggest very small absolute changes in risk, and the data is based primarily on low and very low certainty evidence. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020172141.
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Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data.
Goldenberg, JZ, Day, A, Brinkworth, GD, Sato, J, Yamada, S, Jönsson, T, Beardsley, J, Johnson, JA, Thabane, L, Johnston, BC
BMJ (Clinical research ed.). 2021;372:m4743
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Plain language summary
Diet modification has long been recognised as a component for the treatment of diabetes. Diets low in carbohydrates have been extensively researched, as a diet for those with Type 2 Diabetes (T2D). This systematic review and meta-analysis aimed to determine the effect of low carbohydrate diets on T2D. The systematic review found 23 studies, including 1357 individuals, investigating the role of low carbohydrate diets on T2D outcomes. Low carbohydrate diet was defined as less than 130g of carbohydrate (less than 26% of calories from carbohydrate) for at least 12 weeks. Results reported at 6 months, found low carbohydrate diets were more effective than a normal diet at achieving diabetes remission. However, this effect diminished at 12 months, although longer term improvements were seen in blood lipids, weight loss and measures of prediabetes. It was concluded that individuals with T2D, eating a low carbohydrate diet for 6 months may reverse the disease. This study could be used by healthcare professionals to recommend a short-term low carbohydrate diet to individuals with T2D, to improve their chance of going into remission.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Type 2 diabetes remains a significant and worsening problem worldwide, despite many pharmaceutical developments and a global emphasis on glycemic control.
- This review highlights structured LCDs as a worthwhile option for the management and treatment of diabetes, providing an opportunity for Nutritional Therapy Practitioners to support clients in adopting evidence-informed, modifiable dietary and lifestyle changes for Type Two Diabetes.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
- Type 2 diabetes is the most common form of diabetes, accounting for 90-95% of cases.
- Previous randomised trials assessed low carbohydrate diets (LCDs) (<26-45% of daily calories from carbohydrate) as encouraging to improve blood glucose control and outcomes of type 2 diabetes but did not systematically assessed remission of diabetes using low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes.
- Systematic reviews (SR) and meta-analyses represent the most valuable, reliable, and objective tool to summarise evidence from primary studies.
- This SR assessed 23 randomised controlled trials comparing LCDs with mostly low fat control diets in individuals / subjects / participants with type 2 diabetes. LCDs were defined as diets with less than 130 g/day or less than 26% of calories from carbohydrates, based on 2000 kcal/day. The authors used the Cochrane Risk of Bias tool 2.0 (RoB 2) to assess methodological quality of evidence, GRADE to assess the certainty of evidence
- On the basis of assessment of moderate to low certainty evidence, individuals / subjects / participants adhering to a LCD for six months may experience remission of type 2 diabetes without adverse consequences.
- Primary outcomes of interest were remission of type 2 diabetes (dichotomously defined as HbA1c <6.5% or fasting glucose <7.0 mmol/L), with or without the use of diabetes medication.
- Eight studies reported on remission of diabetes at six months. Pooled analysis showed that when remission was defined by an HbA1c level below 6.5% independent of medication use, LCDs increased remissions by an additional 32 per 100 patients followed (risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264; GRADE=moderate)
- When remission was defined by an HbA1c level below 6.5% and the absence of diabetes medication, LCDs increased remissions at a lower rate (risk difference 0.05, –0.05 to 0.14; 5 studies, n=199; GRADE=low)
- Additional primary outcomes were weight loss, HbA1c:
- 18 studies reported on Weight loss results (mean difference –3.46, 95% confidence interval –5.25 to –1.67; n=882 (note that positive results not sustained at 12 mo)
- Seventeen studies reported on HbA1c levels at six months, LCDs achieved greater reductions in HbA1c than did control diets (mean difference –0.47%, –0.60 to –0.34; n=747
- Limitations of study: 1) the definition of remission of diabetes, 2) Self-reported dietary intake data are prone to measurement error, particularly in dietary trials in which participants are not blinded
- This SR was funded in part by Texas A&M University.
- The authors declared no conflicts of interest.
Clinical practice applications:
The Authors highlight LCD diets incorporating carbohydrate of less than 130 g/day or less than 26% of calories (based on 2000 kcal/day) may be a safe strategy to help individuals with type 2 diabetes achieve weight loss and better blood glucose control over a six-month period. Results may not be sustained at 12 months.
Considerations for future research:
- The definition of diabetes remission needs clarification, especially with regard to threshold concentrations of Hb1Ac or fasting glucose and the use of diabetes medication.
- Safety concerns have been raised with LCDs. Although no significant or clinically important increase in total or serious adverse events was identified in this SR, these outcomes should be reported in future trials to confirm the certainty of evidence for safety.
- The Authors suggest long term, well designed, calorie controlled randomised trials are needed to determine the effects of LCD on sustained weight loss and remission of diabetes.
- Larger treatment effects for LCDs in shorter term trials (3 to <6 months), may be trialed as an effect modifier
Abstract
OBJECTIVE To determine the efficacy and safety of low carbohydrate diets (LCDs) and very low carbohydrate diets (VLCDs) for people with type 2 diabetes. DESIGN Systematic review and meta-analysis. DATA SOURCES Searches of CENTRAL, Medline, Embase, CINAHL, CAB, and grey literature sources from inception to 25 August 2020. STUDY SELECTION Randomized clinical trials evaluating LCDs (<130 g/day or <26% of a 2000 kcal/day diet) and VLCDs (<10% calories from carbohydrates) for at least 12 weeks in adults with type 2 diabetes were eligible. DATA EXTRACTION Primary outcomes were remission of diabetes (HbA1c <6.5% or fasting glucose <7.0 mmol/L, with or without the use of diabetes medication), weight loss, HbA1c, fasting glucose, and adverse events. Secondary outcomes included health related quality of life and biochemical laboratory data. All articles and outcomes were independently screened, extracted, and assessed for risk of bias and GRADE certainty of evidence at six and 12 month follow-up. Risk estimates and 95% confidence intervals were calculated using random effects meta-analysis. Outcomes were assessed according to a priori determined minimal important differences to determine clinical importance, and heterogeneity was investigated on the basis of risk of bias and seven a priori subgroups. Any subgroup effects with a statistically significant test of interaction were subjected to a five point credibility checklist. RESULTS Searches identified 14 759 citations yielding 23 trials (1357 participants), and 40.6% of outcomes were judged to be at low risk of bias. At six months, compared with control diets, LCDs achieved higher rates of diabetes remission (defined as HbA1c <6.5%) (76/133 (57%) v 41/131 (31%); risk difference 0.32, 95% confidence interval 0.17 to 0.47; 8 studies, n=264, I2=58%). Conversely, smaller, non-significant effect sizes occurred when a remission definition of HbA1c <6.5% without medication was used. Subgroup assessments determined as meeting credibility criteria indicated that remission with LCDs markedly decreased in studies that included patients using insulin. At 12 months, data on remission were sparse, ranging from a small effect to a trivial increased risk of diabetes. Large clinically important improvements were seen in weight loss, triglycerides, and insulin sensitivity at six months, which diminished at 12 months. On the basis of subgroup assessments deemed credible, VLCDs were less effective than less restrictive LCDs for weight loss at six months. However, this effect was explained by diet adherence. That is, among highly adherent patients on VLCDs, a clinically important reduction in weight was seen compared with studies with less adherent patients on VLCDs. Participants experienced no significant difference in quality of life at six months but did experience clinically important, but not statistically significant, worsening of quality of life and low density lipoprotein cholesterol at 12 months. Otherwise, no significant or clinically important between group differences were found in terms of adverse events or blood lipids at six and 12 months. CONCLUSIONS On the basis of moderate to low certainty evidence, patients adhering to an LCD for six months may experience remission of diabetes without adverse consequences. Limitations include continued debate around what constitutes remission of diabetes, as well as the efficacy, safety, and dietary satisfaction of longer term LCDs. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42020161795.
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Western herbal medicines in the treatment of irritable bowel syndrome: A systematic review and meta-analysis.
Hawrelak, JA, Wohlmuth, H, Pattinson, M, Myers, SP, Goldenberg, JZ, Harnett, J, Cooley, K, Van De Venter, C, Reid, R, Whitten, DL
Complementary therapies in medicine. 2020;:102233
Abstract
OBJECTIVE To evaluate the efficacy of Western herbal medicines in the treatment of irritable bowel syndrome (IBS). DESIGN A computer-based search of MEDLINE, EMBASE, CINAHL, AMED, GreenFILE, Health Source: Nursing/Academic Edition, and the Cochrane Library was conducted. A hand-search of the bibliographies of relevant papers and previous meta-analyses and reviews was also undertaken. Trials were included in the review if they were double-blind and placebo-controlled investigating the effects of Western herbal medicines on IBS-related symptoms or quality of life. There were no language restrictions. Eligibility assessment and data extraction were performed by two independent researchers. For herbal medicines where there was more than 1 trial of similar design, data were synthesised using relative risk of symptoms improving using the random effects model. RESULTS Thirty-three trials were identified that met all eligibility criteria. Seventeen of these evaluated peppermint essential oil, fifteen other Western herbal medicines, and one trial evaluated peppermint oil in one arm and aniseed essential oil in the other arm. Eighteen different herbal preparations were evaluated in these trials. Data suggests that a number of Western herbal medicines may provide relief of IBS symptoms. Meta-analyses suggest that peppermint essential oil is both efficacious and well-tolerated in the short-term management of IBS. Aloe vera and asafoetida also demonstrated efficacy in reducing global IBS symptoms in meta-analyses. The herbal formulas STW 5, STW 5-II and Carmint, along with Ferula assa-foetida, Pimpenella anisum oil, the combination of Curcumin and Foeniculum vulgare oil, and the blend of Schinopsis lorentzii, Aesculus hippocastanum, and peppermint essential oil also demonstrated efficacy in rigorously-designed clinical trials. CONCLUSION A number of Western herbal medicines show promise in the treatment of IBS. With the exception of peppermint essential oil, Aloe vera, and asafoetida, however, none of the positive trials have been replicated. This lack of replication limits the capacity to make definitive statements of efficacy for these herbal medicines.
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Multinutrients for the Treatment of Psychiatric Symptoms in Clinical Samples: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Johnstone, JM, Hughes, A, Goldenberg, JZ, Romijn, AR, Rucklidge, JJ
Nutrients. 2020;(11)
Abstract
This systematic review and meta-analysis focused on randomized controlled trials (RCT) of multinutrients consisting of at least four vitamins and/or minerals as interventions for participants with psychiatric symptoms. A systematic search identified 16 RCTs that fit the inclusion criteria (n = 1719 participants) in six psychiatric categories: depression, post-disaster stress, antisocial behavior, behavioral deficits in dementia, attention-deficit/hyperactivity disorder, and autism. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to rate the evidence base. Significant clinical benefit was assessed using minimal clinically important differences (MIDs). Due to heterogeneity in participants, multinutrient formulas, outcome measures, and absence of complete data, only the Attention-Deficit/Hyperactivity Disorder (ADHD) category was eligible for meta-analyses. In ADHD populations, statistically and clinically significant improvements were found in global functioning, Mean Difference (MD) -3.3, p = 0.001, MID -3.26; Standardized Mean Difference (SMD) -0.49 p = 0.001 MD -0.5), clinician ratings of global improvement (MD -0.58, p = 0.001, MID -0.5) and ADHD improvement (MD -0.54, p = 0.002, MID -0.5), and clinician (but not observer) measures of ADHD inattentive symptoms (MD -1.53, p = 0.05, MID -0.5). Narrative synthesis also revealed a pattern of benefit for global measures of improvement, for example: in autism, and in participants with behavioral deficits in dementia. Post-natural disaster anxiety and the number of violent incidents in prison populations also improved. Broad-spectrum formulas (vitamins + minerals) demonstrated more robust effects than formulas with fewer ingredients. This review highlights the need for robust methodology-RCTs that report full data, including means and standard deviations for all outcomes-in order to further elucidate the effects of multinutrients for psychiatric symptoms.
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Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
Guo, Q, Goldenberg, JZ, Humphrey, C, El Dib, R, Johnston, BC
The Cochrane database of systematic reviews. 2019;(4):CD004827
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Abstract
BACKGROUND Antibiotics alter the microbial balance commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via providing gut barrier, restoration of the gut microflora, and other potential mechanisms of action. OBJECTIVES The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. SEARCH METHODS MEDLINE, Embase, CENTRAL, CINAHL, and the Web of Science (inception to 28 May 2018) were searched along with registers including the ISRCTN and Clinicaltrials.gov. We also searched the NICE Evidence Services database as well as reference lists from relevant articles. SELECTION CRITERIA Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. DATA COLLECTION AND ANALYSIS Study selection, data extraction, and risk of bias assessment were conducted independently by two authors. Dichotomous data (incidence of AAD, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea) as mean difference (MD), along with corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. For studies reporting on microbiome characteristics using heterogeneous outcomes, we describe the results narratively. The certainty of the evidence was evaluated using GRADE. MAIN RESULTS Thirty-three studies (6352 participants) were included. Probiotics assessed included Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. The risk of bias was determined to be high in 20 studies and low in 13 studies. Complete case (patients who did not complete the studies were not included in the analysis) results from 33 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control.After 5 days to 12 weeks of follow-up, the incidence of AAD in the probiotic group was 8% (259/3232) compared to 19% (598/3120) in the control group (RR 0.45, 95% CI 0.36 to 0.56; I² = 57%, 6352 participants; NNTB 9, 95% CI 7 to 13; moderate certainty evidence). Nineteen studies had loss to follow-up ranging from 1% to 46%. After making assumptions for those lost, the observed benefit was still statistically significant using an extreme plausible intention-to-treat (ITT) analysis, wherein the incidence of AAD in the probiotic group was 12% (436/3551) compared to 19% (664/3468) in the control group (7019 participants; RR 0.61; 95% CI 0.49 to 0.77; P <0.00001; I² = 70%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥ 5 billion CFUs per day) is more effective than low probiotic dose (< 5 billion CFUs per day), interaction P value = 0.01. For the high dose studies the incidence of AAD in the probiotic group was 8% (162/2029) compared to 23% (462/2009) in the control group (4038 participants; RR 0.37; 95% CI 0.30 to 0.46; P = 0.06; moderate certainty evidence). For the low dose studies the incidence of AAD in the probiotic group was 8% (97/1155) compared to 13% (133/1059) in the control group (2214 participants; RR 0.68; 95% CI 0.46 to 1.01; P = 0.02). Again, assumptions for loss to follow-up using an extreme plausible ITT analysis was statistically significant. For high dose studies the incidence of AAD in the probiotic group was 13% (278/2218) compared to 23% (503/2207) in control group (4425 participants; RR 0.54; 95% CI 0.42 to 0.70; P <0.00001; I² = 68%; moderate certainty evidence).None of the 24 trials (4415 participants) that reported on adverse events reported any serious adverse events attributable to probiotics. Adverse event rates were low. After 5 days to 4 weeks follow-up, 4% (86/2229) of probiotics participants had an adverse event compared to 6% (121/2186) of control participants (RD 0.00; 95% CI -0.01 to 0.01; P < 0.00001; I² = 75%; low certainty evidence). Common adverse events included rash, nausea, gas, flatulence, abdominal bloating, and constipation.After 10 days to 12 weeks of follow-up, eight studies recorded data on our secondary outcome, the mean duration of diarrhea; with probiotics reducing diarrhea duration by almost one day (MD -0.91; 95% CI -1.38 to -0.44; P <0.00001; low certainty evidence). One study reported on microbiome characteristics, reporting no difference in changes with concurrent antibiotic and probiotic use. AUTHORS' CONCLUSIONS The overall evidence suggests a moderate protective effect of probiotics for preventing AAD (NNTB 9, 95% CI 7 to 13). Using five criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate the subgroup effect based on high dose probiotics (≥ 5 billion CFUs per day) was credible. Based on high-dose probiotics, the NNTB to prevent one case of diarrhea is 6 (95% CI 5 to 9). The overall certainty of the evidence for the primary endpoint, incidence of AAD based on high dose probiotics was moderate due to the minor issues with risk of bias and inconsistency related to a diversity of probiotic agents used. Evidence also suggests that probiotics may moderately reduce the duration of diarrhea, a reduction by almost one day. The benefit of high dose probiotics (e.g. Lactobacillus rhamnosus orSaccharomyces boulardii) needs to be confirmed by a large well-designed multi-centered randomized trial. It is premature to draw firm conclusions about the efficacy and safety of 'other' probiotic agents as an adjunct to antibiotics in children. Adverse event rates were low and no serious adverse events were attributable to probiotics. Although no serious adverse events were observed among inpatient and outpatient children, including small studies conducted in the intensive care unit and in the neonatal unit, observational studies not included in this review have reported serious adverse events in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation.
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Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children.
Goldenberg, JZ, Yap, C, Lytvyn, L, Lo, CK, Beardsley, J, Mertz, D, Johnston, BC
The Cochrane database of systematic reviews. 2017;(12):CD006095
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Abstract
BACKGROUND Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies. OBJECTIVES To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children. SEARCH METHODS We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search. SELECTION CRITERIA Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria. MAIN RESULTS Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. AUTHORS' CONCLUSIONS Based on this systematic review and meta-analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk ≤5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics.
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Probiotics for the prevention of pediatric antibiotic-associated diarrhea.
Goldenberg, JZ, Lytvyn, L, Steurich, J, Parkin, P, Mahant, S, Johnston, BC
The Cochrane database of systematic reviews. 2015;(12):CD004827
Abstract
BACKGROUND Antibiotics are frequently prescribed in children. They alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via restoration of the gut microflora. OBJECTIVES The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. SEARCH METHODS MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to November 2014) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched. SELECTION CRITERIA Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. DATA COLLECTION AND ANALYSIS Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea, mean daily stool frequency) as mean difference (MD), along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, as well as risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS Twenty-three studies (3938 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. Eleven studies used a single strain probiotic, four combined two probiotic strains, three combined three probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one included ten probiotic strains, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 22/23 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 8% (163/1992) compared to 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to 19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.01). The majority of adverse events were in placebo, standard care or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite. AUTHORS' CONCLUSIONS Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events. Future trials would benefit from a standard and valid outcomes to measure AAD.
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9.
Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children.
Goldenberg, JZ, Ma, SS, Saxton, JD, Martzen, MR, Vandvik, PO, Thorlund, K, Guyatt, GH, Johnston, BC
The Cochrane database of systematic reviews. 2013;(5):CD006095
Abstract
BACKGROUND Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora. OBJECTIVES The primary objectives were to assess the efficacy and safety of probiotics for preventing Clostridium difficile-associated diarrhea (CDAD) or C. difficile infection in adults and children. SEARCH METHODS On February 21, 2013 we searched PubMed (1966-2013), EMBASE (1966-2013), Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), CINAHL (1982-2013), AMED (1985-2013), and ISI Web of Science. Additionally, we conducted an extensive grey literature search including contact with industry representatives. SELECTION CRITERIA Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently and in duplicate extracted data and assessed risk of bias using pre-constructed, and piloted, data extraction forms. Any disagreements were resolved by a third adjudicator. For articles published in abstract form only, further information was sought by contacting principal authors. The primary outcome was the incidence of CDAD. Secondary outcomes included the incidence of C. difficile infection, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval (95% CI). Continuous outcomes (e.g. length of hospital) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias.The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. MAIN RESULTS A total of 1871 studies were identified with 31 (4492 participants) meeting eligibility requirements for our review. Overall 11 studies were rated as a high risk of bias due mostly to missing outcome data. A complete case analysis (i.e. participants who completed the study) of those trials investigating CDAD (23 trials, 4213 participants) suggests that probiotics significantly reduce this risk by 64%. The incidence of CDAD was 2.0% in the probiotic group compared to 5.5% in the placebo or no treatment control group (RR 0.36; 95% CI 0.26 to 0.51). Sixteen of 23 trials had missing CDAD data ranging from 5% to 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our judgment is that the overall evidence warrants moderate confidence in this large relative risk reduction. We downgraded the overall quality of evidence for CDAD to 'moderate' due to imprecision. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared to 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). Adverse events were assessed in 26 studies (3964 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, we consider the strength of this evidence to be moderate. AUTHORS' CONCLUSIONS Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea.
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10.
Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis.
Johnston, BC, Ma, SS, Goldenberg, JZ, Thorlund, K, Vandvik, PO, Loeb, M, Guyatt, GH
Annals of internal medicine. 2012;(12):878-88
Abstract
BACKGROUND Antibiotic treatment may disturb the resistance of gastrointestinal flora to colonization. This may result in complications, the most serious of which is Clostridium difficile–associated diarrhea (CDAD). PURPOSE To assess the efficacy and safety of probiotics for the prevention of CDAD in adults and children receiving antibiotics. DATA SOURCES Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Allied and Complementary Medicine Database, Web of Science, and 12 gray-literature sources. STUDY SELECTION Randomized, controlled trials including adult or pediatric patients receiving antibiotics that compared any strain or dose of a specified probiotic with placebo or with no treatment control and reported the incidence of CDAD. DATA EXTRACTION Two reviewers independently screened potentially eligible articles; extracted data on populations, interventions, and outcomes; and assessed risk of bias. The Grading of Recommendations Assessment, Development and Evaluation guidelines were used to independently rate overall confidence in effect estimates for each outcome. DATA SYNTHESIS Twenty trials including 3818 participants met the eligibility criteria. Probiotics reduced the incidence of CDAD by 66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I(2) = 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1000 persons. Of probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I(2) = 17%). LIMITATIONS In 13 trials, data on CDAD were missing for 5% to 45% of patients. The results were robust to worst-plausible assumptions regarding event rates in studies with missing outcome data. CONCLUSION Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events. PRIMARY FUNDING SOURCE None.