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Original Investigation
November 14, 2018

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

Author Affiliations
  • 1Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  • 2Uppsala Clinical Research Center, Uppsala, Sweden
  • 3Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
  • 4AstraZeneca Research and Development, Mölndal, Sweden
  • 5Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
  • 6Baim Clinical Research Institute, Boston, Massachusetts
  • 7Stanford Center for Clinical Research, Stanford School of Medicine, Stanford, California
  • 8Assistance Publique-Hôpitaux de Paris; Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France
  • 9Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France
  • 10NHLI Imperial College, ICMS, Royal Brompton Hospital, London, United Kingdom
  • 11Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
JAMA Cardiol. Published online November 14, 2018. doi:10.1001/jamacardio.2018.3811
Key Points

Question  Do biomarkers provide prognostic information on cause-specific mortality in patients with acute coronary syndromes?

Findings  In this secondary analysis of a randomized clinical trial of 6 biomarkers in 17 095 patients with acute coronary syndromes, N-terminal pro-B-type natriuretic peptide and growth differentiation factor-15 were markers associated with death due to heart failure, as well as from arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and tended to be associated with death due to bleeding.

Meaning  N-terminal pro-B-type natriuretic peptide and growth differentiation factor-15 provide prognostic information in patients with acute coronary syndromes, and their measurement may be warranted to identify high-risk patients with possible benefit from more intense secondary prevention measures.

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.

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