The search yielded 31 candidate RCTs meeting sample size and duration criteria, of which 11 did not meet additional inclusion criteria (4 for acute coronary syndromes or enrollment following cardiac catheterization; 2 for assessing drug-combinations; 2 owing to a focus on end-stage renal disease or renal transplantation; 1 with an intermediate primary endpoint; 1 for failed randomization; and 1 because of incompleteness of endpoint ascertainment). The characteristics of the 20 large-scale trials2–5,7–9,23–35
selected for inclusion are presented in . There were a total of 155,255 participants, of whom 11,508 experienced major CHD events, and 13,687 had all-cause fatal events. With exclusion of the 3 active-comparator trials 2–4
, there were 124,302 individuals, with 8,332 and 10,448 developing major CHD and fatal events, respectively.
Characteristics of Large-scale Randomized Controlled Trials
Analysis of all 20 RCTs showed significant overall reductions in risk of CHD (OR=0.72, 95% CI=0.67–0.78) and mortality (OR=0.89, 95% CI=0.84–0.94), but this was associated with significant underlying heterogeneity for both outcomes (P≤0.005). The lack of consistency in study findings was not attributable to chance, with moderate-to-high (I2=69.7%) or moderate (I2=51.1%) variability in effect estimates across RCTs. shows the corresponding findings for the analysis focused on the 17 RCTs of statins versus placebo or usual care. Significant risk reductions were again achieved for CHD and mortality, with less, though still significant, heterogeneity for both outcomes.
a. Pooled odds ratio of coronary heart disease for statins versus placebo or usual care.
The results of meta-regression modeling of risk reduction as a function of various measures of LDL-C or trial duration are shown in . Taking all trials into account, ΔLDLControl-Rx exhibited the strongest inverse association (highest negative standardized regression coefficient, β) with relative reduction in CHD events, while that for the percent difference (%ΔLDLControl-Rx) was minimally weaker. According to the random-effects model, every 39 mg/dL (1mmol/L) inter-group difference in achieved LDL-C was associated with a 25% relative reduction in CHD risk (OR=0.75, 95% CI=0.68–0.82). There were significant, but weaker associations for baseline LDLRx, and absolute – though not percent – reduction in LDL-C in the treatment arm (ΔLDLBaseline-Final), whereas trial duration bore no significant relation to CHD risk reduction.
Meta-Regression* for Coronary Heart Disease or Death as a Function of Lipid Measures or Trial Duration
When active-comparator trials were excluded, the absolute inter-group difference in LDL-C (ΔLDLControl-Rx) again showed the strongest association to CHD risk reduction, followed by %ΔLDLControl-Rx (). The associations between these inter-group differences, whether in absolute or percent terms, and CHD risk decreased with exclusion of active-comparator trials. shows that, based on the model, there was a 23% relative reduction in CHD risk for every 39 mg/dL absolute inter-group decrease in LDL-C (OR=0.77, 95% CI=0.66–0.89). As compared with ΔLDLControl-Rx, ΔLDLBaseline-Final was more modest and fell just short of significance. No other variables were significantly related to CHD risk reduction.
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.
Regarding all-cause mortality, analysis of all 20 RCTs showed significant relations only for ΔLDLControl-Rx and baseline LDLRx, but it was baseline LDLRx that had the higher negative regression coefficient. Accordingly, for every 39 mg/dL higher value for baseline LDL-C there was an associated 10% reduction in the relative risk of death (OR=0.90, 95% CI=0.83–0.99). The corresponding reduction for every 39 mg/dL of ΔLDLControl-Rx was 12% (OR=0.88, 95% CI=0.78–0.99). Notably, analyses of the 17-RCT subset revealed no significant associations for any of the independent measures ( and ).
The association between ΔLDLControl-Rx and relative risk of CHD was not meaningfully altered by adjustment for baseline LDLRx, whether or not active-comparator trials were taken into account (data not shown). With respect to mortality, inclusion of both ΔLDLControl-Rx and baseline LDLRx in the full meta-regression model rendered both variables non-significant (P≥0.116).
Since exclusion of active-comparator RCTs was found to reduce heterogeneity, sensitivity analyses focused on the 17 trials of statin versus placebo or usual care. Exclusion of each of these RCTs individually did not materially influence estimates of risk reduction for CHD or mortality (data not shown). Selected individual and multiple exclusions based in part on outliers in meta-regression analysis () are shown in .
Sensitivity Analysis of Trials of Statins versus Placebo or Usual Care – Effect Estimate and Correlations to Lowering or Baseline Value of Low-Density Lipoprotein Cholesterol
For both outcomes, exclusion of ALLHAT-LLT 5
and the Scandinavian Simvastatin Survival Study (4S)23
individually led to a decrease in variability across studies. Omission of each also led to appreciable weakening in the relationship between ΔLDLControl-Rx
and either outcome. So too did exclusion of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE),31
particularly for CHD, but this was accompanied by an even more marked decrease in effect estimate for ΔLDLBaseline-Final
. The same effect was evident with exclusion of high-risk CHD trials, of which ALLHAT-LLT, 4S, and GREACE are part. By contrast, exclusion of the Management of Elevated cholesterol in the primary prevention Group of Adult Japanese (MEGA) study,34
the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)29
, and the Controlled Rosuvastatin in Multinational Trial in Heart Failure (CORONA),8
both individually and collectively, resulted in strengthening of the associations between ΔLDLControl-Rx
and both outcomes, as well as ΔLDLBaseline-Final
with regard to CHD events. In fact, exclusion of all three RCTs uncovered a significant association between ΔLDLControl-Rx
and mortality. Last, exclusion of low-risk CHD trials, led to a stronger relation for ΔLDLBaseline-Final
with respect to CHD events, but this depended entirely on exclusion of the MEGA study (data not shown). It also resulted in a stronger and significant association of baseline LDLRx
with mortality, driven by exclusion of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study.7