Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study

Abstract

Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.

Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.

Design, setting, and participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.

Main outcomes and measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.

Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.

Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).

Conclusions and relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.

Trial registration: ClinicalTrials.gov Identifier: NCT00391872.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lindholm reports institutional grants from AstraZeneca during the conduct of the study, institutional grants from GlaxoSmithKline outside the submitted work, and consultancy fee to the institution from AstraZeneca outside the submitted work. Dr James reports institutional research grants, honoraria, and consultancy/advisory board fees from AstraZeneca during the conduct of the study; grants and personal fees from Bayer; personal fees from Sanofi; grants and personal fees from The Medicines Company; and consultancy/advisory board fees from Janssen Pharmaceuticals outside the submitted work. Dr Gabrysch reports institutional grants from AstraZeneca during the conduct of the study. Dr Storey reports grants and personal fees from AstraZeneca during the conduct of the study; personal fees from Actelion; grants and personal fees from PlaqueTec; personal fees from Bayer; personal fees from Bristol-Myers Squibb/Pfizer; grants, personal fees, and other support from AstraZeneca; personal fees from Avacta; personal fees from Novartis; personal fees from Idorsia; personal fees from Thromboserin; and consultancy fees from The Medicines Company outside the submitted work. Dr Himmelmann reports grants and personal fees from AstraZeneca and was an employee AstraZeneca during the conduct of the study. Dr Cannon reports grants and personal fees from Amgen; personal fees from Amarin; grants and personal fees from Boehringer Ingelheim; grants and personal fees from Bristol-Myers Squibb; grants from Daiichi Sankyo; grants from Janssen Pharmaceuticals; grants and personal fees from Merck; personal fees from Alnylam; personal fees from Amarin; personal fees from Kowa; personal fees from Pfizer; personal fees from Eisai Co Ltd; personal fees from Sanofi; personal fees from Regeneron outside the submitted work; grants and consultancy/advisory board fees from Arisaph; grants and consultancy/advisory board fees from Takeda; consultancy/advisory board fees from AstraZeneca, consultancy/advisory board fees from GlaxoSmithKline; and consultancy/advisory board fees from LipoMedix outside the submitted work. Dr Mahaffey reports grants from Afferent Pharmaceuticals, Amgen, Apple, AstraZeneca, Cardiva Medical Inc, Daiichi Sankyo, Ferring Pharmaceuticals, Google (Verily), Johnson & Johnson, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Sanofi, St Jude, and Tenax during the conduct of the study; personal fees from Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Merck, Mitsubishi, MyoKardia, Novartis, Oculeve, Portola, Radiometer, Springer Publishing, Theravance, University of California, San Francisco, and WebMD; and other support from BioPrint Fitness outside the submitted work. Dr Steg reports personal fees and nonfinancial support from AstraZeneca during the conduct of the study; grants and personal fees from Bayer/Janssen Pharmaceuticals, Merck, Sanofi, and Amarin; personal fees from Amgen, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Novartis, Regeneron, Eli Lilly and Company, and AstraZeneca; grants and personal fees from Servier outside the submitted work; and speaker/consultancy fees from GlaxoSmithKline outside the submitted work. Dr Held reports grants from GlaxoSmithKline during the conduct of the study and served on the advisory board for AstraZeneca, Bayer, and Boehringer Ingelheim outside the submitted work. Dr Siegbahn reports institutional grants from AstraZeneca and Roche Diagnostics during the conduct of the study; institutional grants from Boehringer Ingelheim, Bristol-Meyers Squibb/Pfizer, and GlaxoSmithKline; and personal fees from Olink Proteomics outside the submitted work. Dr Wallentin reports grants from AstraZeneca and Roche Diagnostics during the conduct of the study; grants from Merck & Co, GlaxoSmithKline, Boehringer Ingelheim, and Bristol-Myers Squibb/Pfizer; personal fees from Abbott outside the submitted work; and has patents EP2047275B1 and US8951742B2 licensed to Roche Diagnostics.

Figures

Figure 1.. Continuous Associations Between Biomarkers and All-Cause Mortality

A and B, Spline plots of associations between biomarkers and death from all causes (unadjusted). C, Strength of association between biomarkers and all-cause death in an adjusted model including all baseline characteristics and all biomarkers. GDF-15 indicates growth differentiation factor-15; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Figure 2.. Associations Between Biomarkers and Cause-Specific Mortality

Biomarkers (log-transformed and standardized) in relation to specific causes of death. Hazard ratios (HRs) reflect upper vs lower quartile adjusted for baseline characteristics. CRP indicates C-reactive protein; GDF-15, growth differentiation factor-15; NT-proBNP, N-terminal pro-B-type natriuretic peptide.