Cited by 549Lipoproteins and Cardiovascular HealthCancer, Lipids, and MetabolismAcute Myocardial Infarction Research

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

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Navarese, Eliano P., Robinson, Jennifer G., Kowalewski, Mariusz, Kolodziejczak, Michalina, Andreotti, Felicita, Bliden, Kevin, Tantry, Udaya, Kubica, Jacek, Raggi, Paolo, Gurbel, Paul A.·2018·JAMA

DOI 10.1001/jama.2018.2525PMC PMC5933331

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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.

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Authors: Navarese, E. P., Robinson, J. G., Kowalewski, M., Kolodziejczak, M., Andreotti, F., Bliden, K., Tantry, U., Kubica, J., Raggi, P., & Gurbel, P. A.
Affiliations: Inova Health System (US)
University of Iowa (US)
Antoni Jurasz University Hospital (PL)
Systematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Cardiovascular Research Network
Università Cattolica del Sacro Cuore (IT)
Nicolaus Copernicus University (PL)
University of Alberta (CA)
Corresponding author: Robinson, Jennifer G.
ORCID: Navarese, Eliano P.
Robinson, Jennifer G.
Kowalewski, Mariusz
Andreotti, Felicita
Tantry, Udaya
Kubica, Jacek
Raggi, Paolo
Gurbel, Paul A.
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2018-04-17
Volume: 319
Issue: 15
Pages: 1566
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2018.2525
PMC: PMC5933331
OpenAlex: W2800876320
Semantic Scholar: e998030b0bef031f54619a07cde9f01df4ce9807
Cited by: 549
References: 58
Citations by year: 2026: 36 · 2025: 74 · 2024: 81 · 2023: 70 · 2022: 56 · 2021: 76 · 2020: 62 · 2019: 68 · 2018: 26
FWCI: 12.88
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords: LDL cholesterol, LDL cholesterol lowering, statins, ezetimibe, PCSK9 inhibitors, all-cause mortality, cardiovascular mortality, major adverse cardiac events, lipid-lowering therapy, dose-response relationship, treatment intensity, risk stratification, randomized controlled trials, meta-regression, risk of bias assessment, risk difference, relative risk, number needed to harm
MeSH terms: Ezetimibe, Proprotein Convertase 9, PCSK9 Inhibitors, Antibodies, Monoclonal, Anticholesteremic Agents, Cardiovascular Diseases, Humans, Cholesterol, LDL, Mortality, Regression Analysis, Risk, Confounding Factors, Epidemiologic, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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

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