1. In this systematic review and meta-analysis, more intensive compared with less itensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels.
2. The greatest benefit from LDL-C lowering therapy occurred for patients with baseline LDL-C levels greater or equal to 100 mg/dL.
Evidence Rating: 1 (Excellent)
Study Rundown: It is well studied that statins reduce total cardiovascular events, and further lowering of LDL-C levels by increasing statin therapy, adding ezetimibe, or adding a PCKS9 inhibitor provides additional reduction in cardiovascular risks. However, there is much variability in baseline LDL-C levels and the magnitude of LDL-C lowering with reductions in individual mortality and cardiovascular endpoints among the various trials. In this systematic review and meta-analysis of multiple randomized clinical trials, more intensive LDL-C lowering therapy was associated with a progressive reduction in total mortality with higher baseline LDL-C levels, however this relationship did not hold with baseline LDL-C levels less than 100 mg/dL. Higher baseline LDL-C levels were associated with a progressively increased risk reduction in myocardial infarction, decreased revascularization procedures, and decreased major adverse cardiovascular events.
This robust analysis of multiple large-scale clinical trials suggests that LDL-C lowering therapy provides the largest mortality and cardiovascular risk reduction in those with higher baseline LDL-C levels. This may help explain why there is a lack of cardiovascular or all-cause mortality risk reduction noted in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial. However, this study did have a few limitations. First, the analysis included only trial level data with main trial results. Also, end of trial LDL-C levels were used in the analysis, which may represent an underestimation of the actual effect of the magnitude of LDL-C lowering therapy. Further, the heterogeneity identified in subgroup analysis for major cardiovascular events and mortality may be secondary to pre-specified groupings rather than actual variability across different trials.
In-Depth [meta-analysis and systematic review]: This study examined 34 trials from 1994 to 2017 for a total of 270 288 patients. Main inclusion criteria included randomized controlled trials including at least 1000 patients receiving pharmacologic LDL-C lowering therapy for a minimum of 48 weeks, use of statin, non-statin, or combination of statin with non-statin therapies, and reported cardiovascular and mortality outcomes of interest. More intensive (136 299 patients) versus less intensive (133 989 patients) therapy was defined as the more potent pharmacologic strategy versus the control group of the original trial, respectively. More intensive therapy was associated with a greater reduction in all-cause mortality with higher baseline LDL levels (change in RR per 40 mg/dL increase in baseline LDL-C is 0.91; CI95 0.86-0.96; p = 0.001) and greater reduction in cardiovascular mortality (change in RR per 40 mg/dL increase in baseline LDL-C is 0.86; CI95 0.80-0.94; p < 0.001). Studies with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72; CI95 0.62-0.84; p < 0.001).
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