2.3.2 Meta-analysis to explore group differences Although the purpose of the analysis was to assess whether there is a threshold that defines a sodium intake below which there is no effect on blood pressure, a meta-analysis was undertaken to confirm whether the inclusion and exclusion criteria used in our analysis would yield a dataset that reflected previous findings. Sub-group meta-analysis was done for factors which might be important in affecting the change in BP and which would therefore need to be taken into account before attributing effects to sodium intake. These factors were: hypertensive status of the subjects, posture of resting BP measurement (sitting versus supine because both postures were commonly classed as resting), parallel versus cross-over design and use of dietary advice to achieve the difference in intake versus placing all subjects on a low sodium diet and randomising to sodium or placebo pills (a surrogate for blinding). A random effects meta-analysis was done. The results were graphed using a forest plot and a funnel plot was done to examine whether publication bias might be evident. 95% CI were calculated der Simonian-Laird method [].The heterogeneity among the studies was described using I2. “I2 describes the “percentage of total variation across studies that is due to heterogeneity rather than chance” and 0%, 25%, 50% and 75% could be interpreted as indicating no, low, medium and high heterogeneity respectively [] . In the case that there is a dose-response relationship, variation in aspects such as dose or study duration among studies may cause heterogeneity. The inverse variance weights were saved and used in subsequent analyses. The inverse variance weights from the meta-analysis were used to weight the averages for SBP per 500mg decrease in Na and 24 hr Na excretion in the various analyses using categories of Na excretion to explore confounding by differences in the range of Na doses tested among the studies. Random-effects meta-analyses were also conducted for total cholesterol, HDL cholesterol and LDL cholesterol data using the previously described methods. Further statistical analysis of data on diastolic blood pressure was not done due to time constraints. The EWG prioritised the analysis if systolic blood pressure data as this has been demonstrated to be of greater clinical importance [].
Examination of data for upper level purposes A number of approaches were taken to examine the data for the purposes of considering whether it would be possible to set a UL for sodium. The difference in dose of sodium between the high and low arms of the studies varied greatly, and so the impact on blood pressure would also be expected to vary among the studies assuming that there is a dose-response relationship between sodium intake and blood pressure. The meta-analysis done above does not take this into account but compares all low sodium arms to all high sodium arms. To remove confounding between studies to testing of different dose ranges, the change in SBP was re-expressed per 500mg increment in the difference in Na excretion between the high and low Na group in each study. The range in effect size was examined. The simple and weighted average differences in SBP, SBP per 500mg decrease in Na and difference in Na for the groups defined by the moving dichotomous cutpoints of the low sodium group were graphed. This allowed inspection for patterns (converging or diverging lines) which might indicate that the effect was increasing with increasing excretion (i.e. a UL) or that effect was decreasing (e.g. had reached a threshold of effect, this is not a UL). The graphs were created for all studies and for the largest subgroup, hypertensives, who also show a larger response than do normotensives. 2.3.4 Examination of data for SDT purposes For SDT purposes, data was considered on the range of 24-hour Na excretion in which a relationship between decrease in sodium intake and decrease in SBP could be observed. The issue of a dose response relationship was considered. The proximity of the lower end of observed data to the upper end of the AI range was another consideration, bearing in mind that at least 50% of population intakes should be above the AI. The overall meta-analysis result is dependent of the relative proportions of normotensive and hypertensives in the studies is not the same as in the Australian and New Zealand populations. Hence the overall meta-analysis result cannot be interpreted as the difference in
Hypertension status N N N N HT or 27 19 2 48 NT 1 11 1 13 Total 28 30 3 61 Influence of intervention type (diet or pills) on blood pressure results Influence of design (cross-over or parallel) on blood pressure results Figure A1.1 Meta-analysis of the difference in SBP in the with lower 24 hour urinary Na excretion compared to the group with higher Na excretion, by hypertension status of participants at baseline and posture when blood pressure was measured, ordered by decreasing width of 95% confidence interval
Appendix 3 Results of selected analyses repeated including Alli et al and van Berge-Landry et al Meta-analysis Figure A3.1 Meta-analysis of the difference in SBP in the group with lower 24 hour urinary Na excretion compared to the group with higher Na excretion, by hypertension status of participants at baseline, ordered by decreasing width of 95% confidence interval (compare to Figure 9) Examination of evidence for non-linear The data illustrated in Figure A3.1 are given in Tables A3.1 and A3.2 Figure A3.2 Mean difference in SBP (top), 24-hour urinary Na excretion (middle) and Na excretion (bottom) above and below a moving cutpoint in the low sodium group calculated using a simple average (left) or weighted using weights from the meta-analysis (right hand series), in 63 observations (compare to Figure 10)