Serum cholesterol reduction and risk of ischaemic heart disease

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The randomised controlled trials of serum cholesterol reduction have been the subject of a number of meta-analyses1419 20 and much controversy. In conjunction with the review of the 10 prospective studies just described, the results of 28 randomised trials available in 1994 were summarised;14 this omits the results of trials of serum cholesterol reduction, notably those using statins, that have become available more recently. The aim was to quantify the effect of serum cholesterol reduction on the risk of ischaemic heart disease in the short term, the trials having an average duration of about five years. There was considerable clinical heterogeneity between the trials in the interventions tested (different drugs, different diets, and in one case surgical intervention using partial ileal bypass grafting), in the duration of the trials (0-3-10 years), in the average extent of serum cholesterol reduction achieved (0-3-1-5 mmol/l), and in the selection criteria for the patients such as pre-existing disease (for example, primary or secondary prevention trials) and level of serum cholesterol concentration at entry. As before it would seem likely that these substantial clinical differences would lead to some heterogeneity in the observed results.

Forest plots such as in Figure 9.1, are not very useful for investigating heterogeneity. A better diagram for this purpose was proposed by Galbraith,21 and is shown for the cholesterol lowering trials in Figure 9.4. For each trial the ratio of the log odds ratio of ischaemic heart disease to its

Log Odds Ratio
Figure 9.4 Galbraith plot of odds ratios of ischaemic heart disease in 28 trials of serum cholesterol reduction (see text for explanation). Two trials were omitted because of no events in one group.

standard error (the z-statistic) is plotted against the reciprocal of the standard error. Hence the least precise results from small trials appear towards the left of the figure and results from the largest trials towards the right. An overall log odds ratio is represented by the slope of the solid line in the figure; this is an unweighted regression line constrained to pass through the origin. The dotted lines are positioned two units above and below the solid line and delimit an area within which, in the absence of statistical heterogeneity, the great majority (that is, about 95%) of the trial results would be expected to lie. It is thus interesting to note the characteristics of those trials which lie near or outside these dotted lines. For example, in Figure 9.4, there are two dietary trials that lie above the upper line and showed apparently adverse effects of serum cholesterol reduction on the risk of ischaemic heart disease. One of these trials achieved only a very small cholesterol reduction while the other had a particularly short duration.22 Conversely the surgical trial, below the bottom dotted line and showing a large reduction in the risk of ischaemic heart disease, was both the longest trial and the one that achieved the greatest cholesterol reduction.22 These observations add weight to the need to investigate heterogeneity of results according to extent and duration of cholesterol reduction.

0-25

Average cholesterol reduction (mmol/l)

Figure 9.5 Odds ratios of ischaemic heart disease (and 95% confidence intervals) according to the average extent of serum cholesterol reduction achieved in each of 28 trials. Overall summary of results indicated by sloping line. Results of the nine smallest trials have been combined.

Figure 9.5 shows the results according to average extent of cholesterol reduction achieved. There is very strong evidence (P = 0-002) that the proportionate reduction in the risk of ischaemic heart disease increases with the extent of average cholesterol reduction; the appropriate methods for this analysis are explained in the next section. A suitable summary of the trial results, represented by the sloping line in Figure 9.5, is that the risk of ischaemic heart disease is reduced by an estimated 18% (95% confidence interval 13 to 22%) for each 0.6 mmol/l reduction in serum cholesterol concentration.22 Obtaining data subdivided by time since randomisation14 to investigate the effect of duration was also informative (Figure 9.6). Whereas the reduction in the risk of ischaemic heart disease in the first two years was rather limited, the reductions thereafter were around 25% per 0-6 mmol/l reduction. After extent and duration of cholesterol reduction were allowed for in this way, the evidence for further heterogeneity of the results from the different trials was limited (P = 0-11). In particular there was no evidence of further differences in the results between the drug and the dietary trials, or between the primary prevention and the secondary prevention trials.14,22

This investigation of heterogeneity was again crucial to the conclusions

Duration of cholesterol lowering (years)

Figure 9.6 Odds ratios of ischaemic heart disease (and 95% confidence intervals) per 0-6 mmol/l serum cholesterol reduction in 28 trials, according to the duration of cholesterol lowering.

reached. The analysis quantified how the percentage reduction in the risk of ischaemic heart disease depends both on the extent and the duration of cholesterol reduction. Meta-analyses ignoring these factors may well be misleading. It also seems that these factors are more important determinants of the proportionate reduction in ischaemic heart disease than the mode of intervention or the underlying risk of the patient.

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