Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial

Abstract

Background: Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown.

Objectives: This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD.

Methods: In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE.

Results: Patients with events (n = 156) had higher randomization levels of OxPL-apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24).

Conclusions: Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691).

Keywords: atherosclerosis; biomarker; coronary heart disease; inflammatory; oxidation-specific epitope.

Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Association Between OxPL-apoB Levels at Randomization and Subsequent Major CV Events

Hazard ratios versus tertile 1 were adjusted for age, sex, body mass index, diabetes mellitus, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apoB, and difference between treatment groups. Within each panel, the p values refer to comparisons of tertile 2 or 3 to tertile 1. ATV = atorvastatin; OxPL-apoB = oxidized phospholipids on apolipoprotein B-100.

FIGURE 2. Changes in OxPL-apoB Levels from Randomization to Year 1

Both percent and absolute changes in OxPL-apoB levels are shown according to (A) treatment group and (B) whether the patient experienced a major cardiovascular (CV) event. The p values are from comparisons using the 2-sided Wilcoxon rank sum test. Other abbreviations as in Figure 1.

FIGURE 2. Changes in OxPL-apoB Levels from Randomization to Year 1

Both percent and absolute changes in OxPL-apoB levels are shown according to (A) treatment group and (B) whether the patient experienced a major cardiovascular (CV) event. The p values are from comparisons using the 2-sided Wilcoxon rank sum test. Other abbreviations as in Figure 1.

FIGURE 3. Spearman Correlation Analysis of OxPL-apoB and Lp(a)

Correlation between OxPL-apoB and lipoprotein(a) (Lp[a]) is shows (A) at randomization according to treatment; (B) at randomization according to whether the patient experienced a major CV event; (C) at 1 year according to treatment; and (D) at 1 year according to whether the patient experienced a major CV event. Other abbreviations as in Figures 1 and 2.

FIGURE 3. Spearman Correlation Analysis of OxPL-apoB and Lp(a)

Correlation between OxPL-apoB and lipoprotein(a) (Lp[a]) is shows (A) at randomization according to treatment; (B) at randomization according to whether the patient experienced a major CV event; (C) at 1 year according to treatment; and (D) at 1 year according to whether the patient experienced a major CV event. Other abbreviations as in Figures 1 and 2.

FIGURE 3. Spearman Correlation Analysis of OxPL-apoB and Lp(a)

Correlation between OxPL-apoB and lipoprotein(a) (Lp[a]) is shows (A) at randomization according to treatment; (B) at randomization according to whether the patient experienced a major CV event; (C) at 1 year according to treatment; and (D) at 1 year according to whether the patient experienced a major CV event. Other abbreviations as in Figures 1 and 2.

FIGURE 3. Spearman Correlation Analysis of OxPL-apoB and Lp(a)

Correlation between OxPL-apoB and lipoprotein(a) (Lp[a]) is shows (A) at randomization according to treatment; (B) at randomization according to whether the patient experienced a major CV event; (C) at 1 year according to treatment; and (D) at 1 year according to whether the patient experienced a major CV event. Other abbreviations as in Figures 1 and 2.

CENTRAL ILLUSTRATION. Oxidized Phospholipids, Statin Therapy, and CV Outcomes

Upper panel: The bar graph depicts the hazard or odds ratio of oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) for the primary endpoint in each study indicated, comparing the highest to the lowest tertile or quartile. These studies included subjects without or with prior cardiovascular disease (CVD), defined as myocardial infarction, stroke, or peripheral arterial disease The data are derived from prior publications including the Bruneck Study (17), EPIC (European Prospective Investigation of Cancer)-Norfolk Trial (9), Nurses’ Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) (38), Mayo Study (11) and Treating to New Targets (TNT) Trial. The Mayo Study (11) reflect odds ratio for angiographically-determined coronary artery disease. Lower panel: The illustration depicts the risk of CVD mediated by increased circulating levels of OxPL-apoB in the context of intensity of statin therapy in patients with subclinical atherosclerosis, angiographically-determined CAD, and in established CAD by clinical criteria. As the intensity of statin therapy increases, the risk of new events (denoted a ruptured plaque on the cartoon) mediated by OxPL-apoB decreases but is not completely abrogated.