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)

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.

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 diabetes and 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 Coll Cardiol 2013; Stone, J Am Coll Cardiol 2013

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

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?

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

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.

Pooled Cohort risk equations 𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑒𝑑 𝐴𝑆𝐶𝑉𝐷 𝑟𝑖𝑠𝑘 =1− 𝑆 0 𝑡 𝑒 (𝐼𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒−𝑀𝑒𝑎𝑛 𝑠𝑐𝑜𝑟𝑒) Individual score calculation is based on: Age Total cholesterol HDL cholesterol Systolic blood pressure Use of antihypertensive medication Current smoker Diabetes   S0(t) at 5 years* S0(t) at 10 years Mean score Black women 0.98194 0.9533 86.61 White women 0.98898 0.9665 -29.18 Black men 0.95726 0.8954 19.54 White men 0.96254 0.9144 61.18 * Personal communication (Coady, S). HDL: high-density lipoprotein Goff, et al. Circulation 2013

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

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

Baseline characteristics of participants   Clinically relevant population (n=10,997) Medicare-linked population (n=3,333) Age (years), mean (SD) 62 (8) 71 (4) Blacks, n (%) 4,132 (38) 1,095 (33) Men, n (%) 4,480 (41) 1,476 (44) Current smoking, n (%) 1,626 (15) 348 (10) SBP (mmHg), mean (SD) 124.8 (16) 128.3 (16) Antihypertensive med, n (%) 4,134 (38) 1,491 (45) Total-C (mg/dL), mean (SD) 203 (31) 202 (31) HDL-C (mg/dL), mean (SD) 54 (17) 55 (17) The clinically relevant population included those not taking statins, without ASCVD or diabetes, and with LDL-C 70 to 189 mg/dL. SD: standard deviation; SBP: systolic blood pressure; HDL: high density lipoprotein.

Calibration – Clinically relevant population

Clinically relevant population Results – Calibration and discrimination in the clinically relevant population   Events / person-years Events in 5-years 5-year incidence rate* Discrimination Observed† Predicted (95% CI) C-index 10-year predicted risk Clinically relevant population 0.72 (0.70-0.75) <5% 28 / 14,816 32 33 1.9 (1.3-2.7) 1.9 5% to <7.5% 32 / 6,866 38 4.8 (3.4-6.7) 4.8 7.5% to <10% 34 / 5,853 41 46 6.1 (4.4-8.6) 6.9 ≥10% 244 / 19,946 278 350 12.0 (10.6-13.6) 15.1 REGARDS participants without diabetes, with LDL-C 70 to 189 mg/dL‡ who were not taking statins are included in this table. 95% CI: 95% confidence interval. HDL-C: high density lipoprotein cholesterol; KM: Kaplan-Meier; LDL-C: low density lipoprotein cholesterol; REGARDS: REasons for Geographic And Racial Differences in Stroke. * Per 1,000 person-years. † Kaplan-Meier adjusted. ‡ Or non-HDL-C of 100 - 219 mg/dL for those without a valid LDL-C measurement.

Calibration – REGARDS Medicare-linked population

Medicare linked participants Results - Calibration and discrimination for REGARDS Medicare-linked population   Events / person-years Events in 5-years 5-year incidence rate* Discrimination Observed† Predicted (95% CI) C-index 10-year predicted risk Medicare linked participants 0.67 (0.64-0.71) 5% to <7.5% (Suppressed) 9 7 5.3 (2.8-10.1) 4.0 7.5% to <10% 15 12 7.9 (4.6-13.5) 6.4 ≥10% 212 / 11,754 226 215 17.4 (15.3-19.8) 16.4 REGARDS participants without diabetes, with LDL-C 70 to 189 mg/dL‡ who were not taking statins are included in this table. Suppressed – Medicare data are not presented in these cells due to a small sample size. 95% CI: 95% confidence interval. HDL-C: high density lipoprotein cholesterol; KM: Kaplan-Meier; LDL-C: low density lipoprotein cholesterol; REGARDS: REasons for Geographic And Racial Differences in Stroke. * Per 1,000 person-years. † Kaplan-Meier adjusted. ‡ Or non-HDL-C of 100 - 219 mg/dL for those without a valid LDL-C measurement.

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.

Available at www.jama.com and also at mobile.jamanetwork.com 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