Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women's Health Initiative

Abstract

Importance: Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear.

Objective: We evaluated the predictive accuracy of the PCE in the Women's Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims.

Design, setting, and participants: The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years.

Main outcomes and measures: For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death.

Results: Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738).

Conclusions and relevance: Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events.

Trial registration: ClinicalTrials.gov identifier: NCT00000611.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mora has received research grant support from the National Heart, Lung, and Blood Institute (NHLBI) (HL136852 and HL134811), and Atherotech Diagnostics for research outside the current work, and received personal fees for scientific advisory board participation for Amgen, Lilly, Pfizer, and Quest Diagnostics. Dr Wenger has received research grants/contracts/trial steering from Alnylam Pharmaceuticals, Gilead Sciences, and NHLBI, served on committee/trial data safety and monitoring board for Pfizer and the Society for Women’s Health Research, and as a consultant to Amgen, AstraZeneca, Gilead Sciences, and Merck. Dr Limacher has National Institutes of Health grant support for the Women’s Health Institute Regional Centers N01 WH04354 and R18 HL112720. Dr Ridker received research grant support from AstraZeneca, Kowa, Novartis, Amgen, Pfizer, and NHLBI, and is listed as a coinventor on patents held by the Brigham and Women's Hospital related to the use of inflammatory biomarkers in CVD (licensed to AstraZeneca and Siemens). Dr Robinson has received institutional research grants from Amarin, Amgen, Astra-Zeneca, Eli Lilly, Esai, Esperion, Glaxo-Smith Kline, Merck, Pfizer, Regeneron/Sanofi, and Takeda, and served as consultant to Akcea/Ionis, Amgen, Dr Reddy, Eli Lilly, Esperion, Merck, Pfizer, and Regeneron/Sanofi. The remaining authors have no disclosures.

Figures

Figure 1.. Observed vs Predicted Risk by Baseline 10-Year Risk Categories

Kaplan-Meier observed unadjusted (dark blue bars) and predicted (light blue bars) 10-year risks of atherosclerotic cardiovascular disease events by baseline 10-year risk categories of less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more before (A) and after (B) weighting to the age and racial/ethnic distribution of the overall WHI cohort. Observed events were WHI-adjudicated events.

Figure 2.. Observed vs Predicted Risk by Baseline 10-Year Risk Categories, Weighted to the Age and Racial Distribution of the Overall Women's Health Initiative (WHI) Cohort

Kaplan-Meier observed unadjusted (blue bars), observed adjusted for statin and aspirin use during follow-up (light blue bars), and predicted (white bars) 10-year risks of atherosclerotic cardiovascular disease events by baseline 10-year risk categories of less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more, weighted to the age and racial/ethnic distribution of the overall WHI cohort. Panel A is for all participants and panel B is after excluding active hormone arm. Observed events were WHI-adjudicated events.

Figure 3.. Observed vs Predicted Risk by Baseline 10-Year Risk Categories in Women 65 Years and Older Enrolled in Medicare A or A/B (n = 6071)

In women 65 years and older enrolled in Medicare A or A/B, Kaplan-Meier observed unadjusted (dark blue bars), observed adjusted for statin and aspirin use during follow-up (light blue bars), and predicted (white bars) 10-year risks of atherosclerotic cardiovascular disease events by baseline 10-year risk categories of less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more. Panels A and B are before including Centers for Medicare and Medicaid (CMS) events (A, participants enrolled in Medicare A or A/B fee for service; and B after excluding active hormone therapy arm); panels C and D also excluded active hormone therapy arm but included events ascertained from the CMS, assuming a positive predictive value (ie, proportion of true cases) of 60% for principal discharge diagnosis (C) or 85% for principal or secondary diagnosis (D). aExcludes hormone therapy.