title: Utility of Nontraditional Risk Markers in Individuals Ineligible for Statin Therapy According to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines.
abstract: BACKGROUND
  In the general population, the majority of cardiovascular events occur in people at the low to moderate end of population risk distribution. The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol recommends consideration of statin therapy for adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% based on traditional risk factors. Whether use of nontraditional risk markers can improve risk assessment in those below this threshold for statin therapy is unclear.
  
  
  RESULTS
  Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population sample free of clinical CVD at baseline, we calibrated the Pooled Cohort Equations (cPCE). ASCVD was defined as myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke. Adults with an initial cPCE <7.5% and elevated levels of additional risk markers (abnormal test) whose new calculated risk was ≥7.5% were considered statin eligible: low-density lipoprotein cholesterol ≥160 mg/dL; family history of ASCVD; high-sensitivity C-reactive protein ≥2 mg/dL; coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; and ankle-brachial index <0.9. We compared the absolute and relative ASCVD risks among those with versus without elevated posttest estimated risk. We calculated the number needed to screen to identify 1 person with abnormal test for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by the number with an abnormal test reclassified as statin eligible. Of 5185 participants not taking statins with complete data (age, 45-84 years), 4185 had a cPCE risk <7.5%. During 10 years of follow-up, 57% of the ASCVD events (183 of 320) occurred among adults with a cPCE risk <7.5%. When people with diabetes mellitus were excluded, the coronary artery calcium criterion reclassified 6.8% upward, with an event rate of 13.3%, absolute risk of 10%, relative risk of 4.0 (95% confidence interval [CI], 2.8-5.7), and number needed to screen of 14.7. The corresponding numbers for family history of ASCVD were 4.6%, 15.1%, 12%, 4.3 (95% CI, 3.0-6.4), and 21.8; for high-sensitivity C-reactive protein criteria, 2.6%, 10%, 6%, 2.6 (95% CI, 1.4-4.8), and 39.2; for ankle-brachial index criteria, 0.6%, 9%, 5%, 2.3 (95% CI, 0.6-8.6), and 176.5; and for low-density lipoprotein cholesterol criteria, 0.5%, 5%, 1%, 1.2 (95% CI, 0.2-8.4), and 193.3, respectively. Of the 3882 with <7.5% cPCE risk, 431 (11.1%) were reclassified to ≥7.5% (statin eligible) by at least 1 of the additional risk marker criteria.
  
  
  CONCLUSIONS
  In this generally low-risk population sample, a large proportion of ASCVD events occurred among adults with a 10-year cPCE risk <7.5%. We found that the coronary artery calcium score, high-sensitivity C-reactive protein, family history of ASCVD, and ankle-brachial index recommendations by the American College of Cardiology/American Heart Association cholesterol guidelines (Class IIB) identify small subgroups of asymptomatic population with a 10-year cPCE risk <7.5% but with observed ASCVD event rates >7.5% who may warrant statin therapy considerations.
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.). jyeboah@wakehealth.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Yeboah
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Tamar S
authors.initials: TS
authors.lastname: Polonsky
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Rebekah
authors.initials: R
authors.lastname: Young
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Robyn L
authors.initials: RL
authors.lastname: McClelland
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Delaney
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Farah
authors.initials: F
authors.lastname: Dawood
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blaha
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miedema
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Sibley
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: J Jeffrey
authors.initials: JJ
authors.lastname: Carr
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burke
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: David C
authors.initials: DC
authors.lastname: Goff
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: Philip
authors.initials: P
authors.lastname: Greenland
authors.affiliation: From Heart and Vascular Center of Excellence, Wake Forest Baptist Health, Winston Salem, NC (J.Y., F.D., D.M.H.); Section of Cardiology, Department of Internal Medicine, University of Chicago, IL (T.S.P.); Department of Biostatistics (R.Y., R.L.M., J.C.D.) and Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services (B.M.P.), University of Washington, Seattle; Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD (M.J.B.); Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, MN (M.D.M.); Radiology, Oregon Health and Science University, Portland (C.T.S.); Radiology, Vanderbilt University School of Medicine, Nashville, TN (J.J.C.); Public Health, Wake Forest University School of Medicine, Winston Salem, NC (G.L.B.); Public Health, University of Colorado School of Public Health, Aurora (D.C.G.); Group Health Research Institute, Group Health Cooperative, Seattle, WA (B.M.P.); and Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (P.G.).
authors.forename: David M
authors.initials: DM
authors.lastname: Herrington
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000572:American Heart Association; D050197:Atherosclerosis / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D002309:Cardiology / Q000592:standards*; D002784:Cholesterol / Q000097:blood*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic / Q000592:standards*; D011446:Prospective Studies; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol
keywords: cholesterol; coronary artery calcium; epidemiology; hydroxymethylglutaryl-CoA reductase inhibitors; primary prevention