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 𝐴𝑆𝐶𝑉𝐷𝑟𝑖𝑠𝑘=1−𝑆0 (𝑡 )𝑒( 𝐼𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑠𝑐𝑜𝑟𝑒 −𝑀𝑒𝑎𝑛𝑠𝑐𝑜𝑟𝑒)

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).

Goff, et al. Circulation 2013

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

Methods – Two sets of outcomes were evaluated

• ASCVD outcomes – Non-fatal myocardial infarction, CHD death or non-fatal or fatal stroke.1. Adjudicated outcomes - Participant were contacted every 6

months and self-reported events were adjudicated.

2. 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

Results – Calibration and discrimination in the clinically relevant population

Events / person-years

Events in 5-years 5-year incidence rate* Discrimination Observed† Predicted Observed†

(95% CI)Predicted C-index

(95% CI)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) 1.95% to <7.5% 32 / 6,866 38 38 4.8 (3.4-6.7) 4.87.5% 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

Results - Calibration and discrimination for REGARDS Medicare-linked population

Events / person-years

Events in 5-years 5-year incidence rate* Discrimination Observed† Predicted Observed†

(95% CI)Predicted C-index

(95% CI)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) 4.07.5% to <10% (Suppressed) 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.

P Muntner and coauthors

Validation of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations

Published online March 29, 2014

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