Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of large-scale trials of statin therapy

Abstract

Multiple randomized controlled trials (RCTs) have established the efficacy of statins for the prevention of cardiovascular disease. The benefits observed are often framed in terms of percentage reductions in low-density lipoprotein (LDL) cholesterol from baseline or percentage reductions between control and treatment groups, although epidemiologic data suggest that the absolute intergroup difference in LDL cholesterol (DeltaLDL(Control-Rx)) is the more informative measure. A systematic review of large-scale trials of statins versus placebo, usual care, or active (lower dose statin) control was conducted to calculate updated summary estimates of risk reduction in coronary artery disease and all-cause mortality. Meta-regression analysis was used to ascertain the relations of different LDL cholesterol metrics to outcomes. In 20 eligible RCTs, there were significant overall reductions for coronary artery disease (odds ratio 0.72, 95% confidence interval 0.67 to 0.78) and mortality (odds ratio 0.89, 95% confidence interval 0.84 to 0.94), but with substantial variability in trial results. DeltaLDL(Control-Rx) was the strongest determinant of coronary artery disease risk reduction, particularly after excluding active-comparator studies, and was independent of baseline LDL cholesterol. In contrast, baseline LDL cholesterol edged out DeltaLDL(Control-Rx) as the strongest determinant of mortality, but neither was significant after the exclusion of active-comparator studies. The exclusion of 3 RCTs involving distinct populations, however, rendered DeltaLDL(Control-Rx) the predominant determinant of mortality reduction. In conclusion, these findings underscore the primacy of absolute reductions in LDL cholesterol in the design and interpretation of RCTs of lipid-lowering therapies and in framing treatment recommendations on the basis of the proved coronary benefits of these drugs.

Figure 1

a. Pooled odds ratio of coronary heart disease for statins versus placebo or usual care. b. Pooled odds ratio of all-cause mortality for statins versus placebo, usual care.

Figure 1

a. Pooled odds ratio of coronary heart disease for statins versus placebo or usual care. b. Pooled odds ratio of all-cause mortality for statins versus placebo, usual care.

Figure 2

a. Meta-regression of odds ratio for coronary heart disease relative to absolute difference in post-treatment LDL-C between treatment arms in trials of statins versus placebo or usual care. b. Meta-regression of odds ratio for all-cause mortality relative to absolute difference in post-treatment LDL-C between treatment arms in trials of statins versus placebo or usual care.

Figure 2

a. Meta-regression of odds ratio for coronary heart disease relative to absolute difference in post-treatment LDL-C between treatment arms in trials of statins versus placebo or usual care. b. Meta-regression of odds ratio for all-cause mortality relative to absolute difference in post-treatment LDL-C between treatment arms in trials of statins versus placebo or usual care.