Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis

Abstract

Importance: Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials.

Objective: To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions.

Data sourcesand study selection: 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.

Data extraction and synthesis: 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).

Main outcomes and measures: 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).

Results: 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]; P = .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 (P < .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, 0.86 [95% CI, 0.80 to 0.94]; P < .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 (P < .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]; P < .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.

Conclusions and relevance: 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.

Figure 1.. Search and Selection Process of Randomized Clinical Trials Evaluating the Effect of Low-Density Lipoprotein Cholesterol–Lowering Therapies on Cardiovascular Outcomes

LDL-C indicates low-density lipoprotein cholesterol. ^aComparison of different groups of drugs in monotherapy.

Figure 2.. Meta-regression Analysis of All-cause Mortality by Baseline LDL-C Level (34 RCTs)

Change in rate ratios (RRs) and 95% confidence intervals of more intensive vs less intensive low-density lipoprotein cholesterol (LDL-C)–lowering therapies plotted against baseline LDL-C level in the more intensive treatment group. Numbers indicate reference numbers of randomized clinical trials (RCTs). Size of the data markers is proportional to the weight in the meta-regression. Data marker colors represent the classes of lipid-lowering agents used in the active treatment group as per trial randomization design. Baseline levels are from the more intensive treatment group. The solid line represents the meta-regression slope of the change in rate ratio for treatment across increasing levels of baseline LDL-C. Results do not change when using baseline LDL-C values from the less intensive treatment group. To convert LDL-C values to mmol/L, multiply by 0.0259.

Figure 3.. Meta-analysis of All-cause Mortality Stratified by Baseline LDL-C Level

Rate ratios (RRs) and 95% confidence intervals of more intensive vs less intensive low-density lipoprotein cholesterol (LDL-C)–lowering therapies. Size of study data markers is proportional to the weight in the meta-analysis. To convert LDL-C values to mmol/L, multiply by 0.0259.

Figure 4.. Meta-regression Analysis of Cardiovascular Mortality by Baseline LDL-C Level (34 RCTs)

Change in rate ratios (RRs) and 95% confidence intervals of more intensive vs less intensive low-density lipoprotein cholesterol (LDL-C)–lowering therapies plotted against baseline LDL-C level in the more intensive treatment group. Numbers indicate reference numbers of randomized clinical trials (RCTs). Size of the data markers is proportional to the weight in the meta-regression. Data marker colors represent the classes of lipid-lowering agents used in the active treatment group as per trial randomization design. Baseline levels are from the more intensive treatment group. The solid line represents the meta-regression slope of the change in rate ratio for treatment across increasing levels of baseline LDL-C. Results do not change when using baseline LDL-C values from the less intensive treament group. To convert LDL-C values to mmol/L, multiply by 0.0259.

Figure 5.. Meta-analysis of Cardiovascular Mortality Stratified by Baseline LDL-C Level

Rate ratios (RRs) and 95% confidence intervals of more intensive vs less intensive low-density lipoprotein cholesterol (LDL-C)–lowering therapies. Size of study data markers is proportional to the weight in the meta-analysis. To convert the values for LDL cholesterol to mmol/L, multiply by 0.0259.

Figure 6.. Meta-regression Analysis of (A) Myocardial Infarction; and (B) Cerebrovascular Events by Baseline LDL-C Level (34 RCTs)

Change in rate ratios (RRs) and 95% confidence intervals of more intensive vs less intensive low-density lipoprotein cholesterol (LDL-C)–lowering therapies plotted against baseline LDL-C level in the more intensive treatment group. Numbers indicate reference numbers of randomized clinical trials (RCTs). Size of the data markers is proportional to the weight in the meta-regression. Data marker colors represent the classes of lipid-lowering agents used in the active treatment group as per trial randomization design. Baseline levels are from the more intensive treatment group. The solid line represents the meta-regression slope of the change in rate ratio for treatment across increasing levels of baseline LDL-C. Results do not change when using baseline LDL-C values from the less intensive treatment group. To convert LDL-C values to mmol/L, multiply by 0.0259.