title: Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial.
abstract: OBJECTIVE
  Treatment decisions in atrial fibrillation (AF) are based on clinical assessment of risk. The CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes mellitus, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) risk score is pragmatic and widely used but has only moderate discrimination.
  
  
  OBJECTIVE
  To develop and test a cardiovascular biomarker score for indication of risk in patients with AF.
  
  
  METHODS
  The ENGAGE AF-TIMI 48 trial was a randomized, double-blind, double-dummy clinical trial comparing 2 once-daily edoxaban dose regimens with warfarin in 21 105 patients with AF at moderate to high risk of stroke. This prespecified subanalysis was performed in 4880 patients enrolled at randomization in the biomarker substudy. Cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and d-dimer levels were measured at baseline. A multimarker risk score was developed to determine the probability of stroke, systemic embolic events, or death by assigning tiered points for higher concentrations of the biomarkers.
  
  
  METHODS
  Risk score and clinical outcomes based on cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and d-dimer levels at baseline.
  
  
  RESULTS
  Of the 5002 patients enrolled in the biomarker substudy of the ENGAGE AF-TIMI 48 trial, 4880 patients (97.6%) had all 3 biomarkers available at randomization (1820 [37.3%] were women; median [interquartile range] age, 71 [64-77] years). After adjustment for the CHA2DS2-VASc score, each biomarker was associated with a 2.8-fold to 4.2-fold gradient of risk comparing the highest vs lowest concentrations across groups of increasing concentrations (P < .001 for trend for each). The multimarker risk score identified a more than 15-fold gradient of risk after adjustment for CHA2DS2-VASc score. When added to the CHA2DS2-VASc score, the biomarker score significantly enhanced prognostic accuracy by improving the C statistic from 0.586 (95% CI, 0.565-0.607) to 0.708 (95% CI, 0.688-0.728) (P < .001) and reclassification with a net reclassification improvement of 59.4% (P < .001).
  
  
  CONCLUSIONS
  A prototype multimarker risk score significantly enhanced risk assessment for stroke, systemic embolic events, or death compared with traditional clinical risk stratification. Incorporation of biomarkers into clinical decision making to define therapeutic management in AF warrants consideration.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00781391.
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Giugliano
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey.
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.affiliation: Department of Pathology and Laboratory Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey.
authors.forename: Michele
authors.initials: M
authors.lastname: Mercuri
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elliott M
authors.initials: EM
authors.lastname: Antman
authors.affiliation: TIMI Study Group 2Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow