Lee Hooper

Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.

Abstract Objective To review systematically the evidence for an effect of long chain and shorter chain omega 3 fatty acids on total mortality, cardiovascular events, and cancer. Data sources Electronic databases searched to February 2002; authors contacted and bibliographies of randomised controlled trials (RCTs) checked to locate studies. Review methods Review of RCTs of omega 3 intake for 3 6 months in adults (with or without risk factors for cardiovascular disease) with data on a relevant outcome. Cohort studies that estimated omega 3 intake and related this to clinical outcome during at least 6 months were also included. Application of inclusion criteria, data extraction, and quality assessments were performed independently in duplicate. Results Of 15 159 titles and abstracts assessed, 48 RCTs (36 913 participants) and 41 cohort studies were analysed. The trial results were inconsistent. The pooled estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87, 95% confidence interval 0.73 to 1.03) or combined cardiovascular events (0.95, 0.82 to 1.12) in participants taking additional omega 3 fats. The few studies at low risk of bias were more consistent, but they showed no effect of omega 3 on total mortality (0.98, 0.70 to 1.36) or cardiovascular events (1.09, 0.87 to 1.37). When data from the subgroup of studies of long chain omega 3 fats were analysed separately, total mortality (0.86, 0.70 to 1.04; 138 events) and cardiovascular events (0.93, 0.79 to 1.11) were not clearly reduced. Neither RCTs nor cohort studies suggested increased risk of cancer with a higher intake of omega 3 (trials: 1.07, 0.88 to 1.30; cohort studies: 1.02, 0.87 to 1.19), but clinically important harm could not be excluded. Conclusion Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer.

Effect of lower sodium intake on health: systematic review and meta-analyses

Objective To assess the effect of decreased sodium intake on blood pressure, related cardiovascular diseases, and potential adverse effects such as changes in blood lipids, catecholamine levels, and renal function. Design Systematic review and meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, the Latin American and Caribbean health science literature database, and the reference lists of previous reviews. Study selection Randomised controlled trials and prospective cohort studies in non-acutely ill adults and children assessing the relations between sodium intake and blood pressure, renal function, blood lipids, and catecholamine levels, and in non-acutely ill adults all cause mortality, cardiovascular disease, stroke, and coronary heart disease. Study appraisal and synthesis Potential studies were screened independently and in duplicate and study characteristics and outcomes extracted. When possible we conducted a meta-analysis to estimate the effect of lower sodium intake using the inverse variance method and a random effects model. We present results as mean differences or risk ratios, with 95% confidence intervals. Results We included 14 cohort studies and five randomised controlled trials reporting all cause mortality, cardiovascular disease, stroke, or coronary heart disease; and 37 randomised controlled trials measuring blood pressure, renal function, blood lipids, and catecholamine levels in adults. Nine controlled trials and one cohort study in children reporting on blood pressure were also included. In adults a reduction in sodium intake significantly reduced resting systolic blood pressure by 3.39 mm Hg (95% confidence interval 2.46 to 4.31) and resting diastolic blood pressure by 1.54 mm Hg (0.98 to 2.11). When sodium intake was <2 g/day versus ≥2 g/day, systolic blood pressure was reduced by 3.47 mm Hg (0.76 to 6.18) and diastolic blood pressure by 1.81 mm Hg (0.54 to 3.08). Decreased sodium intake had no significant adverse effect on blood lipids, catecholamine levels, or renal function in adults (P>0.05). There were insufficient randomised controlled trials to assess the effects of reduced sodium intake on mortality and morbidity. The associations in cohort studies between sodium intake and all cause mortality, incident fatal and non-fatal cardiovascular disease, and coronary heart disease were non-significant (P>0.05). Increased sodium intake was associated with an increased risk of stroke (risk ratio 1.24, 95% confidence interval 1.08 to 1.43), stroke mortality (1.63, 1.27 to 2.10), and coronary heart disease mortality (1.32, 1.13 to 1.53). In children, a reduction in sodium intake significantly reduced systolic blood pressure by 0.84 mm Hg (0.25 to 1.43) and diastolic blood pressure by 0.87 mm Hg (0.14 to 1.60). Conclusions High quality evidence in non-acutely ill adults shows that reduced sodium intake reduces blood pressure and has no adverse effect on blood lipids, catecholamine levels, or renal function, and moderate quality evidence in children shows that a reduction in sodium intake reduces blood pressure. Lower sodium intake is also associated with a reduced risk of stroke and fatal coronary heart disease in adults. The totality of evidence suggests that most people will likely benefit from reducing sodium intake.

Dissemination and publication of research findings: an updated review of related biases.

OBJECTIVES To identify and appraise empirical studies on publication and related biases published since 1998; to assess methods to deal with publication and related biases; and to examine, in a random sample of published systematic reviews, measures taken to prevent, reduce and detect dissemination bias. DATA SOURCES The main literature search, in August 2008, covered the Cochrane Methodology Register Database, MEDLINE, EMBASE, AMED and CINAHL. In May 2009, PubMed, PsycINFO and OpenSIGLE were also searched. Reference lists of retrieved studies were also examined. REVIEW METHODS In Part I, studies were classified as evidence or method studies and data were extracted according to types of dissemination bias or methods for dealing with it. Evidence from empirical studies was summarised narratively. In Part II, 300 systematic reviews were randomly selected from MEDLINE and the methods used to deal with publication and related biases were assessed. RESULTS Studies with significant or positive results were more likely to be published than those with non-significant or negative results, thereby confirming findings from a previous HTA report. There was convincing evidence that outcome reporting bias exists and has an impact on the pooled summary in systematic reviews. Studies with significant results tended to be published earlier than studies with non-significant results, and empirical evidence suggests that published studies tended to report a greater treatment effect than those from the grey literature. Exclusion of non-English-language studies appeared to result in a high risk of bias in some areas of research such as complementary and alternative medicine. In a few cases, publication and related biases had a potentially detrimental impact on patients or resource use. Publication bias can be prevented before a literature review (e.g. by prospective registration of trials), or detected during a literature review (e.g. by locating unpublished studies, funnel plot and related tests, sensitivity analysis modelling), or its impact can be minimised after a literature review (e.g. by confirmatory large-scale trials, updating the systematic review). The interpretation of funnel plot and related statistical tests, often used to assess publication bias, was often too simplistic and likely misleading. More sophisticated modelling methods have not been widely used. Compared with systematic reviews published in 1996, recent reviews of health-care interventions were more likely to locate and include non-English-language studies and grey literature or unpublished studies, and to test for publication bias. CONCLUSIONS Dissemination of research findings is likely to be a biased process, although the actual impact of such bias depends on specific circumstances. The prospective registration of clinical trials and the endorsement of reporting guidelines may reduce research dissemination bias in clinical research. In systematic reviews, measures can be taken to minimise the impact of dissemination bias by systematically searching for and including relevant studies that are difficult to access. Statistical methods can be useful for sensitivity analyses. Further research is needed to develop methods for qualitatively assessing the risk of publication bias in systematic reviews, and to evaluate the effect of prospective registration of studies, open access policy and improved publication guidelines.

Methods of assessment of iodine status in humans: a systematic review

BACKGROUND Zinc is an essential micronutrient for human health and has numerous structural and biochemical roles. The search for a reliable, sensitive, and specific index of zinc status has been the subject of considerable research, which has resulted in the identification of a number of potentially useful biomarkers. OBJECTIVE The objective was to assess the usefulness of biomarkers of zinc status in humans. DESIGN The methods included a structured search strategy using Ovid MEDLINE, EMBASE (Ovid), and the Cochrane Library CENTRAL databases; formal inclusion and exclusion criteria; data extraction into an Access database; quality and validity assessment; and meta-analysis. RESULTS Data on 32 potential biomarkers from 46 publications were analyzed. Plasma zinc concentration responded in a dose-dependent manner to dietary manipulation in adults, women, men, pregnant and lactating women, the elderly, and those at low and moderate baseline zinc status. Urinary zinc excretion responded to zinc status overall and in all subgroups for which there were sufficient data. Hair zinc concentration also responded, but there were insufficient studies for subgroup analysis. Platelet, polymorphonuclear cell, mononuclear cell, and erythrocyte zinc concentration and alkaline phosphatase activity did not appear to be effective biomarkers of zinc status. CONCLUSIONS This systematic review confirms that in healthy individuals, plasma, urinary, and hair zinc are reliable biomarkers of zinc status. Further high-quality studies using these biomarkers are required, particularly in infants, adolescents, and immigrant population groups for whom there are limited data. Studies are also required to fully assess a range of additional potential zinc biomarkers.

Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials

BACKGROUND There is substantial interest in chocolate and flavan-3-ols for the prevention of cardiovascular disease (CVD). OBJECTIVE The objective was to systematically review the effects of chocolate, cocoa, and flavan-3-ols on major CVD risk factors. DESIGN We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) of chocolate, cocoa, or flavan-3-ols. We contacted authors for additional data and conducted duplicate assessment of study inclusion, data extraction, validity, and random-effects meta-analyses. RESULTS We included 42 acute or short-term chronic (≤18 wk) RCTs that comprised 1297 participants. Insulin resistance (HOMA-IR: -0.67; 95% CI: -0.98, -0.36) was improved by chocolate or cocoa due to significant reductions in serum insulin. Flow-mediated dilatation (FMD) improved after chronic (1.34%; 95% CI: 1.00%, 1.68%) and acute (3.19%; 95% CI: 2.04%, 4.33%) intakes. Effects on HOMA-IR and FMD remained stable to sensitivity analyses. We observed reductions in diastolic blood pressure (BP; -1.60 mm Hg; 95% CI: -2.77, -0.43 mm Hg) and mean arterial pressure (-1.64 mm Hg; 95% CI: -3.27, -0.01 mm Hg) and marginally significant effects on LDL (-0.07 mmol/L; 95% CI: -0.13, 0.00 mmol/L) and HDL (0.03 mmol/L; 95% CI: 0.00, 0.06 mmol/L) cholesterol. Chocolate or cocoa improved FMD regardless of the dose consumed, whereas doses >50 mg epicatechin/d resulted in greater effects on systolic and diastolic BP. GRADE (Grading of Recommendations, Assessment, Development and Evaluation, a tool to assess quality of evidence and strength of recommendations) suggested low- to moderate-quality evidence of beneficial effects, with no suggestion of negative effects. The strength of evidence was lowered due to unclear reporting for allocation concealment, dropouts, missing data on outcomes, and heterogeneity in biomarker results in some studies. CONCLUSIONS We found consistent acute and chronic benefits of chocolate or cocoa on FMD and previously unreported promising effects on insulin and HOMA-IR. Larger, longer-duration, and independently funded trials are required to confirm the potential cardiovascular benefits of cocoa flavan-3-ols.

Central obesity and breast cancer risk: a systematic review

The specific effect of central rather than general obesity on breast cancer risk is not clear. This review examines the relationship between waist and waist–hip ratio (WHR) and risk of breast cancer in pre‐ and post‐menopausal women using all available cohort and case‐control data. The databases of the Cochrane Library, Medline, Cancer Lit and Embase were searched until October 2002. Relevant cohort and case‐control studies with separate analyses in pre‐ and/or post‐menopausal women were included. Random effects meta‐analyses were carried out, subgrouped by pre‐ or post‐menopausal status and cohort or case‐control design. Sensitivity analyses were also performed. Five cohort studies with 72 1705 person years of observation (453 pre‐menopausal and 2684 post‐menopausal cases), and three case‐control studies comprising 276 pre‐menopausal cases with 758 pre‐menopausal controls and 390 post‐menopausal cases with 1071 post‐menopausal controls were included. Pooled results from cohort studies using the most adjusted data [but without adjustment for weight or body mass index (BMI)] suggest a 39% lower risk of breast cancer in post‐menopausal women with the smallest waist (compared with the largest) and a 24% lower risk in women with the smallest WHR. In pre‐menopausal women, however, pooled results suggest that measurement of waist or WHR have little effect on risk of breast cancer. Adjustment for BMI abolished the relationship between waist or WHR and risk of post‐menopausal breast cancer, but introduced such a relationship amongst pre‐menopausal women. The relationship between a smaller measurement of waist or WHR and lower risk of post‐menopausal breast cancer appears to result from the associated correlation with BMI. Amongst pre‐menopausal women, central (not general) obesity may be specifically associated with an increased risk of breast cancer.

Effect of increased potassium intake on cardiovascular risk factors and disease : systematic review and meta-analyses

Objective To conduct a systematic review of the literature and meta-analyses to fill the gaps in knowledge on potassium intake and health. Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, WHO International Clinical Trials Registry Platform, Latin American and Caribbean Health Science Literature Database, and the reference lists of previous reviews. Study selection Randomised controlled trials and cohort studies reporting the effects of potassium intake on blood pressure, renal function, blood lipids, catecholamine concentrations, all cause mortality, cardiovascular disease, stroke, and coronary heart disease were included. Data extraction and synthesis Potential studies were independently screened in duplicate, and their characteristics and outcomes were extracted. When possible, meta-analysis was done to estimate the effects (mean difference or risk ratio with 95% confidence interval) of higher potassium intake by using the inverse variance method and a random effect model. Results 22 randomised controlled trials (including 1606 participants) reporting blood pressure, blood lipids, catecholamine concentrations, and renal function and 11 cohort studies (127 038 participants) reporting all cause mortality, cardiovascular disease, stroke, or coronary heart disease in adults were included in the meta-analyses. Increased potassium intake reduced systolic blood pressure by 3.49 (95% confidence interval 1.82 to 5.15) mm Hg and diastolic blood pressure by 1.96 (0.86 to 3.06) mm Hg in adults, an effect seen in people with hypertension but not in those without hypertension. Systolic blood pressure was reduced by 7.16 (1.91 to 12.41) mm Hg when the higher potassium intake was 90-120 mmol/day, without any dose response. Increased potassium intake had no significant adverse effect on renal function, blood lipids, or catecholamine concentrations in adults. An inverse statistically significant association was seen between potassium intake and risk of incident stroke (risk ratio 0.76, 0.66 to 0.89). Associations between potassium intake and incident cardiovascular disease (risk ratio 0.88, 0.70 to 1.11) or coronary heart disease (0.96, 0.78 to 1.19) were not statistically significant. In children, three controlled trials and one cohort study suggested that increased potassium intake reduced systolic blood pressure by a non-significant 0.28 (−0.49 to 1.05) mm Hg. Conclusions High quality evidence shows that increased potassium intake reduces blood pressure in people with hypertension and has no adverse effect on blood lipid concentrations, catecholamine concentrations, or renal function in adults. Higher potassium intake was associated with a 24% lower risk of stroke (moderate quality evidence). These results suggest that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the prevention and control of elevated blood pressure and stroke.

Systematic review of long term effects of advice to reduce dietary salt in adults

Abstract Objective: To assess the long term effects of advice to restrict dietary sodium in adults with and without hypertension. Design: Systematic review and meta-analysis of randomised controlled trials. Data sources: Cochrane library, Medline, Embase, and bibliographies. Study selection: Unconfounded randomised trials that aimed to reduce sodium intake in healthy adults over at least 6 months. Inclusion decisions, validity and data extraction were duplicated. Random effects meta-analysis, subgrouping, sensitivity analysis, and meta-regression were performed. Outcomes: Mortality, cardiovascular events, blood pressure, urinary sodium excretion, quality of life, and use of antihypertensive drugs. Results: Three trials in normotensive people (n=2326), five trials in those with untreated hypertension (n=387), and three trials in people being treated for hypertension (n=801) were included, with follow up from six months to seven years. The large high quality (and therefore most informative) studies used intensive behavioural interventions. Deaths and cardiovascular events were inconsistently defined and reported. There were 17 deaths, equally distributed between intervention and control groups. Systolic and diastolic blood pressures were reduced (systolic by 1.1 mm Hg, 95% confidence interval 1.8 to 0.4 mm Hg; diastolic by 0.6 mm Hg, 1.5 to 0.3 mm Hg) at 13 to 60 months, as was urinary 24 hour sodium excretion (by 35.5 mmol/24 hours, 47.2 to 23.9). Degree of reduction in sodium intake and change in blood pressure were not related. Conclusions: Intensive interventions, unsuited to primary care or population prevention programmes, provide only small reductions in blood pressure and sodium excretion, and effects on deaths and cardiovascular events are unclear. Advice to reduce sodium intake may help people on antihypertensive drugs to stop their medication while maintaining good blood pressure control.

Reduced Dietary Salt for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials (Cochrane Review)

BACKGROUND Although meta-analyses of randomized controlled trials (RCTs) of salt reduction report a reduction in the level of blood pressure (BP), the effect of reduced dietary salt on cardiovascular disease (CVD) events remains unclear. METHODS We searched for RCTs with follow-up of at least 6 months that compared dietary salt reduction (restricted salt dietary intervention or advice to reduce salt intake) to control/no intervention in adults, and reported mortality or CVD morbidity data. Outcomes were pooled at end of trial or longest follow-up point. RESULTS Seven studies were identified: three in normotensives, two in hypertensives, one in a mixed population of normo- and hypertensives and one in heart failure. Salt reduction was associated with reductions in urinary salt excretion of between 27 and 39 mmol/24 h and reductions in systolic BP between 1 and 4 mm Hg. Relative risks (RRs) for all-cause mortality in normotensives (longest follow-up-RR: 0.90, 95% confidence interval (CI): 0.58-1.40, 79 deaths) and hypertensives (longest follow-up RR 0.96, 0.83-1.11, 565 deaths) showed no strong evidence of any effect of salt reduction CVD morbidity in people with normal BP (longest follow-up: RR 0.71, 0.42-1.20, 200 events) and raised BP at baseline (end of trial: RR 0.84, 0.57-1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause mortality in those with heart failure (end of trial RR 2.59, 1.04-6.44, 21 deaths).We found no information on participants health-related quality of life. CONCLUSIONS Despite collating more event data than previous systematic reviews of RCTs (665 deaths in some 6,250 participants) there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or CVD morbidity. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved.

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review

Abstract Objectives To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)—H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs—in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life. Data sources The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included. Review methods Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity. Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed. Results Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter). Conclusions Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.