Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering
Authors: Eliano P. Navarese, Jennifer G. Robinson, Mariusz Kowalewski, Michalina Kolodziejczak, Felicita Andreotti, Kevin Bliden, Udaya Tantry, Jacek Kubica, Paolo Raggi, Paul A. Gurbel
Journal: JAMA (2018)

<h3>Importance</h3> Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)–lowering drug trials. <h3>Objective</h3> To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions. <h3>Data Sourcesand Study Selection</h3> Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. <h3>Data Extraction and Synthesis</h3> Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as “more intensive” (more potent pharmacologic intervention) or “less intensive” (less potent, placebo, or control group). <h3>Main Outcomes and Measures</h3> The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). <h3>Results</h3> In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96];<i>P</i> = .001; absolute risk difference [ARD], −1.05 incident cases per 1000 person-years [95% CI, −1.59 to −0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (<i>P</i> &lt; .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.85 [95% CI, 0.80 to 0.91];<i>P</i> &lt; .001; ARD, −1.0 incident cases per 1000 person-years [95% CI, −1.51 to −0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (<i>P</i> &lt; .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84];<i>P</i> &lt; .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE. <h3>Conclusions and Relevance</h3> In these meta-analyses and meta-regressions, more intensive compared with less intensive 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. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C–lowering therapy may occur for patients with higher baseline LDL-C levels.