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JAMA. 2018 Apr 17;319(15):1566-1579. doi: 10.1001/jama.2018.2525.

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

Author information

1
Interventional Cardiology and Cardiovascular Medicine Research, Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia.
2
Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Cardiovascular Research Network.
3
Cardiovascular Institute, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
4
Prevention Intervention Center, Departments of Epidemiology and Medicine, University of Iowa, Iowa City.
5
Department of Cardiac Surgery, Cardiovascular Institute, Dr Antoni Jurasz Memorial University Hospital, Bydgoszcz, Poland.
6
Institute of Cardiology, Catholic University Medical School, Rome, Italy.
7
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

Erratum in

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.

PMID:
29677301
PMCID:
PMC5933331
DOI:
10.1001/jama.2018.2525
[Indexed for MEDLINE]
Free PMC Article

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