Validation of the Pooled Cohort 10-year Atherosclerotic Cardiovascular Disease Risk Equations

1. Validation of the Pooled Cohort 10-year Atherosclerotic Cardiovascular Disease Risk Equations Paul Muntner, Lisandro D Colantonio, Mary Cushman, David C Goff Jr., George Howard, Virginia J Howard, Brett Kissela, Emily B Levitan, Donald M. Lloyd-Jones, Monika M Safford University of Alabama at Birmingham, University of Vermont, University of Colorado, University of Cincinnati, Northwestern University. On behalf of REGARDS and REGARDS-MI This study was supported by U01 NS041588 (NINDS) and R01 HL080477, K24 HL111154 (NHLBI)

2. Disclosures • Drs. Muntner, Howard, Levitan, and Safford have received grant funding from Amgen Inc. for work unrelated to this presentation. • Dr. Muntner has served on an advisory board for Amgen Inc. • Drs. Cushman and Safford have served as consultants for DiaDexus.

3. Background • In 2013, the American College of Cardiology / American Heart Association (ACC/AHA) published a guideline for the estimation of atherosclerotic cardiovascular disease (ASCVD) risk. • This guideline included the development of the Pooled Cohort risk equations for estimating 10-year risk for incident ASCVD. • These equations can be used to guide the decision to initiate statins for people 40-79 years without ASCVD or diabetesand with LDL-C of 70 to 189 mg/dL – “clinically relevant population”. • Consideration of statin treatment is recommended for adults with a 10-year ASCVD risk ≥ 7.5% Goff, J Am CollCardiol2013; Stone, J Am CollCardiol 2013

4. Background • The Pooled Cohort risk equations were developed using data from several studies conducted before 2000. Marked declines in ASCVD incidence have occurred over the past 2 decades. • These equations were reported to over-estimate risk in analyses of the Women’s Health Study, Women’s Health Initiative and the Physicians Health Study. • Prior analyses: • Did not focus on the population for whom the equations may inform a discussion to initiate statins. • Did not have surveillance components Rosamond, Circulation 2012; Kleindorfer, Stroke 2010; Ridker, Lancet 2013

5. Objective • To evaluate the validity of the Pooled Cohort risk equations in a contemporary US population for whom the equations are intended to inform discussions about initiating statins. • We assessed • Calibration: • Do the Pooled Cohort risk equations accurately estimate the observed absolute risk level? • Discrimination: • Are individuals with higher predicted risk more likely to have events?

6. Methods • We used data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study: • Population-based cohort of 30,239 blacks and whites • ≥45 years of age residing in 48 contiguous US states and Washington, DC • Enrolled between January 2003 and October 2007. • All participants provided written informed consent. • Primary analyses focused on the “clinically relevant population” • Those for whom 10-year ASCVD risk can be used to guide decision-making • We excluded participants taking statins, with ASCVD or diabetes, an LDL-C ≥ 190 mg/dL or < 70 mg/dL, and 80 years of age or older. Howard, Neuroepidemiology 2005; Safford, JAMA 2012

7. Methods – Statistical Methods • We calculated 10-year ASCVD predicted risk at baseline using the race-sex specific Pooled Cohort risk equations. • Participants were stratified by decile of 10-year predicted risk. • Calibration was analyzed by comparing observed and predicted number of ASCVD events at 5 years: • We used a modified Hosmer-Lemeshow test. • A chi-square >20 or p-value <0.05 indicates poor calibration. • Discrimination was analyzed: • We used the C-index. • A C-index between 0.70 and 0.80 is good and ≥0.80 is excellent.

8. Pooled Cohort risk equations • Individual score calculation is based on: • Age • Total cholesterol • HDL cholesterol • Systolic blood pressure • Use of antihypertensive medication • Current smoker • Diabetes HDL: high-density lipoprotein * Personal communication (Coady, S). Goff, et al. Circulation 2013

9. Methods – Two sets of outcomes were evaluated • ASCVD outcomes – Non-fatal myocardial infarction, CHD death or non-fatal or fatal stroke. • Adjudicated outcomes - Participant were contacted every 6 months and self-reported events were adjudicated. • Surveillance outcomes - Medicare claims were searched for myocardial infarction and stroke events: • Limited to participants 65 years of age and older. • Medicare Part A coverage required • Outcomes identified using validated algorithms. • Outcomes were available through December 31, 2010. Kiyota, Am Heart J 2004, Tirschwell, Stroke 2002

10. Flowchart of participants included in the analysis † Defined by use of digoxin. ‡ Or non-HDL-C of 100 - 219 mg/dLfor those without a valid LDL-C measurement.

11. Baseline characteristics of participants

12. Calibration – Clinically relevant population

13. Results – Calibration and discrimination in the clinically relevant population

14. Calibration – REGARDS Medicare-linked population

15. Results - Calibration and discrimination for REGARDS Medicare-linked population

16. Conclusion • In this cohort of US adults for whom statin initiation may be considered based on 10-year predicted ASCVD risk: • Observed and predicted 5-year ASCVD risks were similar indicating that these risk equations were well calibrated. • Discrimination was moderate/good. • Previous results of over-estimation of ASCVD risk are likely due to incomplete capture of ASCVD events and inclusion of participants taking statins. • The current study supports the validity of the Pooled Cohort risk equations to inform clinical management decisions.

17. P Muntner and coauthors Validation of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations Published online March 29, 2014 Available at www.jama.com and also at mobile.jamanetwork.com jamanetwork.com