Effect of Low-Density Lipoprotein Cholesterol Lowering by Ezetimibe/Simvastatin on Outcome Incidence: Overview, Meta-Analyses, and Meta-Regression Analyses of Randomized Trials

Abstract

This analysis investigated the extent of different outcome reductions from low-density lipoprotein cholesterol (LDL-C) lowering following ezetimibe/simvastatin treatment and the proportionality of outcome to LDL-C reductions. The authors searched PubMed between 1997 and mid-June 2015 (any language) and the Cochrane Library to identify all randomized controlled trials comparing ezetimibe/simvastatin with placebo or less intensive LDL-C lowering. Risk ratios (RR) and 95% confidence intervals (CIs), standardized to 20 mg/dL LDL-C reduction, were calculated for 5 primary outcomes (fatal and nonfatal) and 4 secondary outcomes (non-cardiovascular [CV] death, cancer, myopathy, and hepatopathy). Five ezetimibe/simvastatin RCTs (30 051 individuals) were eligible, 2 comparing ezetimibe/simvastatin vs placebo and 3 vs less intensive treatment. Outcomes reduced almost to the same extent were stroke (RR: -13%, 95% CI: -21% to -3%), coronary heart disease (CHD; RR: -12%, 95% CI: -19% to -5%), and composite of stroke and CHD (RR: -14%, 95% CI: -20% to -8%). Absolute risk reductions: 5 strokes, 10 CHD events, and 16 stroke and CHD events prevented for every 1000 patients treated for 5 years. Residual risk was almost 7× higher than absolute risk reduction for all the above outcomes. All death outcomes were not reduced, and secondary outcomes did not differ between groups. Logarithmic risk ratios were not associated with LDL-C lowering. Our meta-analysis provides evidence that, in patients with different CV disease burden, major CV events are safely reduced by LDL-C lowering with ezetimibe/simvastatin, while raising the hypothesis that the extent of LDL-C lowering might not be accompanied by incremental clinical-event reduction.

Figure 1

Identification process for inclusion of randomized controlled trials.

Figure 2

Relative and absolute risk reduction of various outcomes in EZE/SIMVA trials of LDL‐C lowering. Standardized RR is to an LDL‐C reduction of 20 mg/dL. Absolute risk reduction refers to the number (and 95% CI) of events prevented every 1000 patients treated for 5 years with a standardized RR. NNT is the numbers (and 95% CI) of patients needed to treat for 5 years to prevent 1 event. Abbreviations: CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; ENHANCE, Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; EZE/SIMVA, ezetimibe/simvastatin; FU, follow‐up; LDL‐C, low‐density lipoprotein cholesterol; n, number; NNT, number needed to treat; P heter., P for heterogeneity; RR, Mantel‐Haenszel risk ratios. * Weighted for the inverse variance. † ENHANCE trial reported 0 non‐CV deaths.

Figure 3

Relationships of (A) primary outcome reductions to the extent of LDL‐C reductions. Meta‐regressions of risk ratios on absolute LDL‐C differences (active treatment group minus placebo or less active treatment group). Relationships of (B) outcome reductions to percentage LDL reductions. The meta‐regressions of (A) are calculated on percentage LDL‐C differences (LDL‐C difference as percentage of on‐treatment LDL‐C in the control group). Regressions relative to stroke are in continuous lines; CHD, in dotted lines; composite of stroke and CHD, in dashed lines. Abbreviations: CHD, coronary heart disease; Δ‐LDL, LDL‐C difference; LDL‐C, low‐density lipoprotein cholesterol; RR, risk ratio.