Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers

Benoit J. Arsenault, Philip Barter, David A. DeMicco, Weihang Bao, Gregory M. Preston, John C. LaRosa, Scott M Grundy, Prakash Deedwania, Heiner Greten, Nanette K. Wenger, James Shepherd, David D. Waters, John J P Kastelein

Research output: Contribution to journalArticle

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Abstract

Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive - 2014 Arsenault et al. This Funding: This study was funded by Pfizer Inc. Benoit J. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en santé du Québec and the Fondation de l9Institut universitaire de cardiologie et de pneumologie de Québec. Two authors are Pfizer employees and may hold stock in the company. As sponsor, Pfizer in cooperation with the steering committee had a role in all aspects of the study. The secondary biomarker analysis was funded by Pfizer. However, the decision to publish and preparation of the manuscript was driven solely by the authors. of recurrent MCVEs (P#0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.

Original languageEnglish (US)
Article numbere114519
JournalPLoS One
Volume9
Issue number12
DOIs
StatePublished - Dec 22 2014

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
neopterin
Biomarkers
lipoproteins
biomarkers
Neopterin
Lipids
Plasmas
Lipoprotein(a)
Coronary Disease
prediction
C-reactive protein
lipids
receptors
insulin
osteopontin
natriuretic peptides
cystatins
cardiac arrest
C-Reactive Protein

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. / Arsenault, Benoit J.; Barter, Philip; DeMicco, David A.; Bao, Weihang; Preston, Gregory M.; LaRosa, John C.; Grundy, Scott M; Deedwania, Prakash; Greten, Heiner; Wenger, Nanette K.; Shepherd, James; Waters, David D.; Kastelein, John J P.

In: PLoS One, Vol. 9, No. 12, e114519, 22.12.2014.

Research output: Contribution to journalArticle

Arsenault, BJ, Barter, P, DeMicco, DA, Bao, W, Preston, GM, LaRosa, JC, Grundy, SM, Deedwania, P, Greten, H, Wenger, NK, Shepherd, J, Waters, DD & Kastelein, JJP 2014, 'Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers', PLoS One, vol. 9, no. 12, e114519. https://doi.org/10.1371/journal.pone.0114519
Arsenault, Benoit J. ; Barter, Philip ; DeMicco, David A. ; Bao, Weihang ; Preston, Gregory M. ; LaRosa, John C. ; Grundy, Scott M ; Deedwania, Prakash ; Greten, Heiner ; Wenger, Nanette K. ; Shepherd, James ; Waters, David D. ; Kastelein, John J P. / Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. In: PLoS One. 2014 ; Vol. 9, No. 12.
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abstract = "Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive - 2014 Arsenault et al. This Funding: This study was funded by Pfizer Inc. Benoit J. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en sant{\'e} du Qu{\'e}bec and the Fondation de l9Institut universitaire de cardiologie et de pneumologie de Qu{\'e}bec. Two authors are Pfizer employees and may hold stock in the company. As sponsor, Pfizer in cooperation with the steering committee had a role in all aspects of the study. The secondary biomarker analysis was funded by Pfizer. However, the decision to publish and preparation of the manuscript was driven solely by the authors. of recurrent MCVEs (P#0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.",
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T1 - Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers

AU - Arsenault, Benoit J.

AU - Barter, Philip

AU - DeMicco, David A.

AU - Bao, Weihang

AU - Preston, Gregory M.

AU - LaRosa, John C.

AU - Grundy, Scott M

AU - Deedwania, Prakash

AU - Greten, Heiner

AU - Wenger, Nanette K.

AU - Shepherd, James

AU - Waters, David D.

AU - Kastelein, John J P

PY - 2014/12/22

Y1 - 2014/12/22

N2 - Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive - 2014 Arsenault et al. This Funding: This study was funded by Pfizer Inc. Benoit J. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en santé du Québec and the Fondation de l9Institut universitaire de cardiologie et de pneumologie de Québec. Two authors are Pfizer employees and may hold stock in the company. As sponsor, Pfizer in cooperation with the steering committee had a role in all aspects of the study. The secondary biomarker analysis was funded by Pfizer. However, the decision to publish and preparation of the manuscript was driven solely by the authors. of recurrent MCVEs (P#0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.

AB - Several plasma non-lipid biomarkers have been shown to predict major cardiovascular events (MCVEs) in population studies. Our objective was to investigate the relationship between lipid and non-lipid biomarkers levels achieved during statin therapy and the incidence of MCVEs in patients with stable coronary heart disease (CHD). We conducted a substudy of the TNT (Treating to New Targets) study, which was a randomized trial that compared the efficacy of high (80 mg) versus low (10 mg) dose atorvastatin for the secondary prevention of CHD. Fasting plasma levels of standard lipids and of 18 non-lipid biomarkers were obtained after an 8-week run-in period on atorvastatin 10 mg in 157 patients who experienced MCVEs during the 4.9 years of study follow-up and in 1349 controls. MCVE was defined as CHD death, nonfatal, non-procedure-related myocardial infarction, resuscitated cardiac arrest, and fatal or nonfatal stroke. After adjusting for age, sex and treatment arm, plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, high-sensitivity C-reactive protein (hsCRP), insulin, neopterin, N-terminal pro-brain natriuretic peptide (BNP), lipoprotein(a) [Lp(a)], and the soluble receptor for advanced glycation end products (sRAGE) were predictive - 2014 Arsenault et al. This Funding: This study was funded by Pfizer Inc. Benoit J. Arsenault is supported by a post-doctoral fellowship from the Fonds de la recherche en santé du Québec and the Fondation de l9Institut universitaire de cardiologie et de pneumologie de Québec. Two authors are Pfizer employees and may hold stock in the company. As sponsor, Pfizer in cooperation with the steering committee had a role in all aspects of the study. The secondary biomarker analysis was funded by Pfizer. However, the decision to publish and preparation of the manuscript was driven solely by the authors. of recurrent MCVEs (P#0.02 for each doubling of plasma concentration). However, no significant association was observed between the risk of recurrent MCVEs and plasma levels of low-density lipoprotein cholesterol, adiponectin, cystatin C, lipoprotein-associated phospholipase A2, monocyte chemotactic protein-1, matrix metalloproteinase-9, myeloperoxidase, osteopontin, soluble CD40 ligand, soluble intercellular adhesion molecule-1, or soluble vascular cell adhesion molecule-1. After further adjustment for diabetes, hypertension, smoking, and BMI, the relationship between hsCRP, insulin and MCVE were no longer significant, while the relationship between Lp(a), neopterin, NT-proBNP and sRAGE and MCVE remained statistically significant. In conclusion, in patients with CHD treated with atorvastatin, plasma levels of Lp(a), neopterin, NT-proBNP, and sRAGE are associated with the risk of recurrent MCVEs.

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